CA2978537C - Therapeutic uses of ibogaine and related compounds - Google Patents
Therapeutic uses of ibogaine and related compounds Download PDFInfo
- Publication number
- CA2978537C CA2978537C CA2978537A CA2978537A CA2978537C CA 2978537 C CA2978537 C CA 2978537C CA 2978537 A CA2978537 A CA 2978537A CA 2978537 A CA2978537 A CA 2978537A CA 2978537 C CA2978537 C CA 2978537C
- Authority
- CA
- Canada
- Prior art keywords
- ibogaine
- dosage
- patient
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- HSIBGVUMFOSJPD-CFDPKNGZSA-N ibogaine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(OC)C=C12 HSIBGVUMFOSJPD-CFDPKNGZSA-N 0.000 title claims abstract description 939
- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 title claims abstract description 673
- VOXIUXZAOFEFBL-UHFFFAOYSA-N Voacangin Natural products CCC1CC2CN3CC1C(C2)(OC(=O)C)c4[nH]c5ccc(OC)cc5c4C3 VOXIUXZAOFEFBL-UHFFFAOYSA-N 0.000 title claims abstract description 667
- OLOCMRXSJQJJPL-UHFFFAOYSA-N ibogaine Natural products CCC1CC2CC3C1N(C2)C=Cc4c3[nH]c5ccc(OC)cc45 OLOCMRXSJQJJPL-UHFFFAOYSA-N 0.000 title claims abstract description 667
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 101
- 150000001875 compounds Chemical class 0.000 title description 201
- 150000003839 salts Chemical class 0.000 claims abstract description 294
- 239000012453 solvate Substances 0.000 claims abstract description 271
- 230000037396 body weight Effects 0.000 claims description 203
- 238000011282 treatment Methods 0.000 claims description 176
- 210000002966 serum Anatomy 0.000 claims description 158
- 208000024891 symptom Diseases 0.000 claims description 118
- 238000012423 maintenance Methods 0.000 claims description 91
- 239000003814 drug Substances 0.000 claims description 88
- 229940079593 drug Drugs 0.000 claims description 69
- 208000011117 substance-related disease Diseases 0.000 claims description 61
- 201000009032 substance abuse Diseases 0.000 claims description 54
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 206010013663 drug dependence Diseases 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 206010013654 Drug abuse Diseases 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 230000002035 prolonged effect Effects 0.000 claims description 16
- 230000000737 periodic effect Effects 0.000 claims description 15
- NVVDQMVGALBDGE-PZXGUROGSA-N (-)-coronaridine Chemical compound C([C@@H]1C[C@@H]([C@H]2[C@]3(C1)C(=O)OC)CC)N2CCC1=C3NC2=CC=CC=C12 NVVDQMVGALBDGE-PZXGUROGSA-N 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 claims description 8
- MMAYTCMMKJYIAM-RUGRQLENSA-N (-)-voacangine Chemical compound C([C@H]1C[C@@H]([C@H]2[C@]3(C1)C(=O)OC)CC)N2CCC1=C3NC2=CC=C(OC)C=C12 MMAYTCMMKJYIAM-RUGRQLENSA-N 0.000 claims description 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- DTJQBBHYRQYDEG-SVBQBFEESA-N 18-methoxycoronaridine Chemical compound C([C@@H]1C[C@@H]([C@H]2[C@]3(C1)C(=O)OC)CCOC)N2CCC1=C3NC2=CC=CC=C12 DTJQBBHYRQYDEG-SVBQBFEESA-N 0.000 claims description 6
- NVVDQMVGALBDGE-UHFFFAOYSA-N Dihydrocatharanthin Natural products C1C2(C(=O)OC)C3C(CC)CC1CN3CCC1=C2NC2=CC=CC=C12 NVVDQMVGALBDGE-UHFFFAOYSA-N 0.000 claims description 6
- GKWYINOZGDHWRA-UHFFFAOYSA-N catharanthine Natural products C1C(CC)(O)CC(CC2C(=O)OC)CN1CCC1=C2NC2=CC=CC=C12 GKWYINOZGDHWRA-UHFFFAOYSA-N 0.000 claims description 6
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 6
- LRLCVRYKAFDXKU-YGOSVGOTSA-N ibogamine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=CC=C12 LRLCVRYKAFDXKU-YGOSVGOTSA-N 0.000 claims description 6
- 229940070765 laurate Drugs 0.000 claims description 6
- CKWXDLJHOHJWOX-UHFFFAOYSA-N voacangine hydroxyindolenine Natural products CCC1CC2N3CCC4(O)C(=Nc5ccc(OC)cc45)C2(CC1C3)C(=O)OC CKWXDLJHOHJWOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- YKMOJVPLIUXEIP-JNBMDGLNSA-N 18-methylaminocoronaridine Chemical compound C([C@@H]([C@H]1[C@]2(C3)C(=O)OC)CCNC)C3CN1CCC1=C2NC2=CC=CC=C12 YKMOJVPLIUXEIP-JNBMDGLNSA-N 0.000 claims description 4
- 101100516572 Caenorhabditis elegans nhr-8 gene Proteins 0.000 claims description 4
- 101100516554 Caenorhabditis elegans nhr-5 gene Proteins 0.000 claims description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- 102100038546 Fibronectin type III and SPRY domain-containing protein 1 Human genes 0.000 claims 1
- 101001030521 Homo sapiens Fibronectin type III and SPRY domain-containing protein 1 Proteins 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 105
- 239000000203 mixture Substances 0.000 abstract description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 116
- 208000002193 Pain Diseases 0.000 description 101
- 208000035475 disorder Diseases 0.000 description 81
- 230000036407 pain Effects 0.000 description 73
- 238000011287 therapeutic dose Methods 0.000 description 70
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 51
- 229960002715 nicotine Drugs 0.000 description 50
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 50
- 208000019901 Anxiety disease Diseases 0.000 description 44
- 239000000014 opioid analgesic Substances 0.000 description 38
- 201000010099 disease Diseases 0.000 description 35
- 239000000126 substance Substances 0.000 description 35
- 208000007848 Alcoholism Diseases 0.000 description 34
- 208000030990 Impulse-control disease Diseases 0.000 description 34
- 238000012360 testing method Methods 0.000 description 34
- 230000001154 acute effect Effects 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 206010057852 Nicotine dependence Diseases 0.000 description 31
- 208000028173 post-traumatic stress disease Diseases 0.000 description 30
- 235000019441 ethanol Nutrition 0.000 description 28
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 28
- 230000000694 effects Effects 0.000 description 26
- 235000019788 craving Nutrition 0.000 description 25
- 230000006378 damage Effects 0.000 description 25
- -1 debilitating Diseases 0.000 description 24
- 208000025569 Tobacco Use disease Diseases 0.000 description 22
- 230000000202 analgesic effect Effects 0.000 description 22
- 201000007930 alcohol dependence Diseases 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- 208000019906 panic disease Diseases 0.000 description 21
- 125000001072 heteroaryl group Chemical group 0.000 description 20
- 206010012335 Dependence Diseases 0.000 description 19
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 description 19
- 230000036506 anxiety Effects 0.000 description 19
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 235000012631 food intake Nutrition 0.000 description 19
- 229940005483 opioid analgesics Drugs 0.000 description 19
- 208000027418 Wounds and injury Diseases 0.000 description 18
- 125000000623 heterocyclic group Chemical group 0.000 description 18
- 208000014674 injury Diseases 0.000 description 18
- 238000012544 monitoring process Methods 0.000 description 18
- 230000037406 food intake Effects 0.000 description 17
- 238000002560 therapeutic procedure Methods 0.000 description 17
- 239000003981 vehicle Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 210000004556 brain Anatomy 0.000 description 16
- 230000002354 daily effect Effects 0.000 description 16
- 208000001294 Nociceptive Pain Diseases 0.000 description 15
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 15
- 208000000094 Chronic Pain Diseases 0.000 description 14
- 208000005298 acute pain Diseases 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 230000001419 dependent effect Effects 0.000 description 14
- 229960005181 morphine Drugs 0.000 description 14
- 230000009467 reduction Effects 0.000 description 14
- 241000282412 Homo Species 0.000 description 13
- 230000006399 behavior Effects 0.000 description 13
- 229940127240 opiate Drugs 0.000 description 13
- 239000000546 pharmaceutical excipient Substances 0.000 description 13
- 239000006187 pill Substances 0.000 description 13
- 231100000736 substance abuse Toxicity 0.000 description 13
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 12
- 206010056465 Food craving Diseases 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 206010041250 Social phobia Diseases 0.000 description 12
- 230000006872 improvement Effects 0.000 description 12
- 230000000747 cardiac effect Effects 0.000 description 11
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 11
- 208000004296 neuralgia Diseases 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- 206010010219 Compulsions Diseases 0.000 description 10
- 206010001584 alcohol abuse Diseases 0.000 description 10
- 208000025746 alcohol use disease Diseases 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 230000009429 distress Effects 0.000 description 10
- 208000021722 neuropathic pain Diseases 0.000 description 10
- 230000001575 pathological effect Effects 0.000 description 10
- 230000002085 persistent effect Effects 0.000 description 10
- 230000001105 regulatory effect Effects 0.000 description 10
- 230000000391 smoking effect Effects 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 9
- 230000002411 adverse Effects 0.000 description 9
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 208000024714 major depressive disease Diseases 0.000 description 9
- 210000000929 nociceptor Anatomy 0.000 description 9
- 108091008700 nociceptors Proteins 0.000 description 9
- 239000000902 placebo Substances 0.000 description 9
- 229940068196 placebo Drugs 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 8
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 8
- 208000011688 Generalised anxiety disease Diseases 0.000 description 8
- 206010033664 Panic attack Diseases 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 208000029364 generalized anxiety disease Diseases 0.000 description 8
- 229960001797 methadone Drugs 0.000 description 8
- 230000002685 pulmonary effect Effects 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 206010029897 Obsessive thoughts Diseases 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 230000003542 behavioural effect Effects 0.000 description 7
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 7
- 238000012048 forced swim test Methods 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000036651 mood Effects 0.000 description 7
- 229940023488 pill Drugs 0.000 description 7
- 201000000980 schizophrenia Diseases 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 208000027691 Conduct disease Diseases 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000000730 antalgic agent Substances 0.000 description 6
- 208000024823 antisocial personality disease Diseases 0.000 description 6
- 208000030963 borderline personality disease Diseases 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 229960004126 codeine Drugs 0.000 description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Natural products C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 6
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 208000015046 intermittent explosive disease Diseases 0.000 description 6
- 238000007912 intraperitoneal administration Methods 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 238000002483 medication Methods 0.000 description 6
- 229960002085 oxycodone Drugs 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 230000000306 recurrent effect Effects 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 208000019116 sleep disease Diseases 0.000 description 6
- 208000022925 sleep disturbance Diseases 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 208000009935 visceral pain Diseases 0.000 description 6
- 206010052804 Drug tolerance Diseases 0.000 description 5
- 208000001613 Gambling Diseases 0.000 description 5
- 206010022998 Irritability Diseases 0.000 description 5
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 5
- 206010033307 Overweight Diseases 0.000 description 5
- 206010034158 Pathological gambling Diseases 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 229940049706 benzodiazepine Drugs 0.000 description 5
- 150000001557 benzodiazepines Chemical class 0.000 description 5
- 229960001736 buprenorphine Drugs 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000007894 caplet Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 5
- 229960000240 hydrocodone Drugs 0.000 description 5
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 5
- 238000001361 intraarterial administration Methods 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 230000033001 locomotion Effects 0.000 description 5
- 208000035824 paresthesia Diseases 0.000 description 5
- 230000035807 sensation Effects 0.000 description 5
- 235000019615 sensations Nutrition 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 5
- 230000000472 traumatic effect Effects 0.000 description 5
- 208000002271 trichotillomania Diseases 0.000 description 5
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 4
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 4
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 4
- 208000008811 Agoraphobia Diseases 0.000 description 4
- 206010012374 Depressed mood Diseases 0.000 description 4
- 208000001836 Firesetting Behavior Diseases 0.000 description 4
- 208000004547 Hallucinations Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000019022 Mood disease Diseases 0.000 description 4
- 206010049816 Muscle tightness Diseases 0.000 description 4
- 206010028813 Nausea Diseases 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- 206010033888 Paraphilia Diseases 0.000 description 4
- 208000001431 Psychomotor Agitation Diseases 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- 206010044565 Tremor Diseases 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 229930003827 cannabinoid Natural products 0.000 description 4
- 239000003557 cannabinoid Substances 0.000 description 4
- 229940065144 cannabinoids Drugs 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- MKXZASYAUGDDCJ-NJAFHUGGSA-N dextromethorphan Chemical compound C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-NJAFHUGGSA-N 0.000 description 4
- 229960001985 dextromethorphan Drugs 0.000 description 4
- 208000002173 dizziness Diseases 0.000 description 4
- 230000008482 dysregulation Effects 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 4
- 229960001410 hydromorphone Drugs 0.000 description 4
- RAUCDOKTMDOIPF-UHFFFAOYSA-N hydroxyibogamine Natural products CCC1CC(C2)CC3C1N2CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-UHFFFAOYSA-N 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 206010023461 kleptomania Diseases 0.000 description 4
- 229960003406 levorphanol Drugs 0.000 description 4
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 4
- RHCSKNNOAZULRK-UHFFFAOYSA-N mescaline Chemical compound COC1=CC(CCN)=CC(OC)=C1OC RHCSKNNOAZULRK-UHFFFAOYSA-N 0.000 description 4
- 239000003612 morphinomimetic agent Substances 0.000 description 4
- 230000008693 nausea Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 208000020016 psychiatric disease Diseases 0.000 description 4
- 201000004645 pyromania Diseases 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 230000001568 sexual effect Effects 0.000 description 4
- 239000000779 smoke Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000006190 sub-lingual tablet Substances 0.000 description 4
- 229960005126 tapentadol Drugs 0.000 description 4
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 description 4
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 4
- 229930003945 thebaine Natural products 0.000 description 4
- 229960004380 tramadol Drugs 0.000 description 4
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000027448 Attention Deficit and Disruptive Behavior disease Diseases 0.000 description 3
- 206010067948 Compulsive shopping Diseases 0.000 description 3
- 206010012225 Delirium tremens Diseases 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 3
- 206010013975 Dyspnoeas Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 3
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- VAYOSLLFUXYJDT-RDTXWAMCSA-N Lysergic acid diethylamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N(CC)CC)C2)=C3C2=CNC3=C1 VAYOSLLFUXYJDT-RDTXWAMCSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 244000061176 Nicotiana tabacum Species 0.000 description 3
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 3
- 206010033557 Palpitations Diseases 0.000 description 3
- 240000001090 Papaver somniferum Species 0.000 description 3
- 208000028017 Psychotic disease Diseases 0.000 description 3
- 206010038743 Restlessness Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000000033 alkoxyamino group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000001055 chewing effect Effects 0.000 description 3
- 235000019504 cigarettes Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 229960002069 diamorphine Drugs 0.000 description 3
- 230000003292 diminished effect Effects 0.000 description 3
- 208000024732 dysthymic disease Diseases 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002428 fentanyl Drugs 0.000 description 3
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 description 3
- 125000005368 heteroarylthio group Chemical group 0.000 description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 3
- IKJFDJLQPHDRTD-ISYVNWANSA-N ibogaine hydrochloride Chemical compound Cl.N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(OC)C=C12 IKJFDJLQPHDRTD-ISYVNWANSA-N 0.000 description 3
- 239000002117 illicit drug Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229960003299 ketamine Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 229950002454 lysergide Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 231100000862 numbness Toxicity 0.000 description 3
- 208000024196 oppositional defiant disease Diseases 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229960005118 oxymorphone Drugs 0.000 description 3
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 3
- 229960005301 pentazocine Drugs 0.000 description 3
- 208000022821 personality disease Diseases 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 230000003252 repetitive effect Effects 0.000 description 3
- 230000001953 sensory effect Effects 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 229960004739 sufentanil Drugs 0.000 description 3
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 230000035900 sweating Effects 0.000 description 3
- 230000009182 swimming Effects 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 230000000451 tissue damage Effects 0.000 description 3
- 231100000827 tissue damage Toxicity 0.000 description 3
- 230000009278 visceral effect Effects 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- VLOWUTVRYMTRJO-HHNICDRHSA-N 12,13-dimethoxyibogamine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC(OC)=C(OC)C=C12 VLOWUTVRYMTRJO-HHNICDRHSA-N 0.000 description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
- MLQRZXNZHAOCHQ-UHFFFAOYSA-N 3-methylfentanyl Chemical group C=1C=CC=CC=1N(C(=O)CC)C(C(C1)C)CCN1CCC1=CC=CC=C1 MLQRZXNZHAOCHQ-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- 206010001298 Adjustment disorder with disturbance of conduct Diseases 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010008479 Chest Pain Diseases 0.000 description 2
- 206010008469 Chest discomfort Diseases 0.000 description 2
- 206010067947 Compulsive sexual behaviour Diseases 0.000 description 2
- 208000032538 Depersonalisation Diseases 0.000 description 2
- 206010012422 Derealisation Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 206010060800 Hot flush Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- DEXMFYZAHXMZNM-UHFFFAOYSA-N Narceine Chemical compound OC(=O)C1=C(OC)C(OC)=CC=C1C(=O)CC1=C(CCN(C)C)C=C(OCO2)C2=C1OC DEXMFYZAHXMZNM-UHFFFAOYSA-N 0.000 description 2
- 208000027120 Narcissistic personality disease Diseases 0.000 description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 2
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 2
- FRPRNNRJTCONEC-UHFFFAOYSA-N Ohmefentanyl Chemical group C=1C=CC=CC=1N(C(=O)CC)C(C(C1)C)CCN1CC(O)C1=CC=CC=C1 FRPRNNRJTCONEC-UHFFFAOYSA-N 0.000 description 2
- 239000008896 Opium Substances 0.000 description 2
- 208000004983 Phantom Limb Diseases 0.000 description 2
- 206010056238 Phantom pain Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 229910006069 SO3H Inorganic materials 0.000 description 2
- 206010041243 Social avoidant behaviour Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000003639 Student–Newman–Keuls (SNK) method Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241001246918 Tabernanthe iboga Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 206010065341 Ventricular tachyarrhythmia Diseases 0.000 description 2
- ODEGQXRCQDVXSJ-RHSMWYFYSA-N [(3r,4r)-3-ethyl-1-methyl-4-phenylpiperidin-4-yl] propanoate Chemical compound CC[C@@H]1CN(C)CC[C@]1(OC(=O)CC)C1=CC=CC=C1 ODEGQXRCQDVXSJ-RHSMWYFYSA-N 0.000 description 2
- 206010000059 abdominal discomfort Diseases 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- FRCVRUHRFLXLAI-PZXGUROGSA-N ac1l4hbb Chemical compound N1([C@H]2[C@@H](CCO)C[C@@H](C1)C[C@]21C(=O)OC)CCC2=C1NC1=CC=CC=C21 FRCVRUHRFLXLAI-PZXGUROGSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 239000003263 anabolic agent Substances 0.000 description 2
- 229940070021 anabolic steroids Drugs 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- XBMIVRRWGCYBTQ-GCJKJVERSA-N betacetylmethadol Chemical compound C=1C=CC=CC=1C(C[C@@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-GCJKJVERSA-N 0.000 description 2
- 229950003254 betacetylmethadol Drugs 0.000 description 2
- JEFVHLMGRUJLET-UHFFFAOYSA-N betahydroxythiofentanyl Chemical group C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CC(O)C1=CC=CC=C1 JEFVHLMGRUJLET-UHFFFAOYSA-N 0.000 description 2
- 229950004879 betameprodine Drugs 0.000 description 2
- 235000019658 bitter taste Nutrition 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229960004782 chlordiazepoxide Drugs 0.000 description 2
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 201000001883 cholelithiasis Diseases 0.000 description 2
- 235000019506 cigar Nutrition 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000000586 desensitisation Methods 0.000 description 2
- BCQMRZRAWHNSBF-UHFFFAOYSA-N desmethylprodine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCN(C)CC1 BCQMRZRAWHNSBF-UHFFFAOYSA-N 0.000 description 2
- 238000001784 detoxification Methods 0.000 description 2
- 229960004193 dextropropoxyphene Drugs 0.000 description 2
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000003571 electronic cigarette Substances 0.000 description 2
- 230000002996 emotional effect Effects 0.000 description 2
- 230000001667 episodic effect Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000007667 floating Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 208000001130 gallstones Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 125000004468 heterocyclylthio group Chemical group 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 2
- 229960004801 imipramine Drugs 0.000 description 2
- 230000037120 immobility Effects 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000005032 impulse control Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000011819 intense anxiety Diseases 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- MKXZASYAUGDDCJ-CGTJXYLNSA-N levomethorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(C)[C@@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-CGTJXYLNSA-N 0.000 description 2
- 238000011866 long-term treatment Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 229960001027 opium Drugs 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 235000006502 papoula Nutrition 0.000 description 2
- 208000024817 paranoid personality disease Diseases 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 208000019899 phobic disease Diseases 0.000 description 2
- 239000010695 polyglycol Substances 0.000 description 2
- 229920000151 polyglycol Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000010149 post-hoc-test Methods 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 230000001003 psychopharmacologic effect Effects 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 208000000029 referred pain Diseases 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 208000013220 shortness of breath Diseases 0.000 description 2
- 201000002859 sleep apnea Diseases 0.000 description 2
- 230000005586 smoking cessation Effects 0.000 description 2
- 230000003997 social interaction Effects 0.000 description 2
- 230000000392 somatic effect Effects 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 229940098466 sublingual tablet Drugs 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 206010047302 ventricular tachycardia Diseases 0.000 description 2
- 108020001612 μ-opioid receptors Proteins 0.000 description 2
- UVITTYOJFDLOGI-UHFFFAOYSA-N (1,2,5-trimethyl-4-phenylpiperidin-4-yl) propanoate Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CC(C)N(C)CC1C UVITTYOJFDLOGI-UHFFFAOYSA-N 0.000 description 1
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 description 1
- FJIKWRGCXUCUIG-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound O=C([C@H](O)N=1)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1Cl FJIKWRGCXUCUIG-HNNXBMFYSA-N 0.000 description 1
- FOJYFDFNGPRXDR-SQILNHJXSA-N (4r,4ar,7s,7ar,12bs)-10-[(4r,4ar,7s,7ar,12bs)-7,9-dihydroxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-10-yl]-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol Chemical compound C([C@H]12)=C[C@H](O)[C@@H]3OC4=C(O)C(C=5C=C6C7=C(C=5O)O[C@@H]5[C@]77CCN([C@H](C6)[C@@H]7C=C[C@@H]5O)C)=CC5=C4[C@]13CCN(C)[C@@H]2C5 FOJYFDFNGPRXDR-SQILNHJXSA-N 0.000 description 1
- LGFMXOTUSSVQJV-NEYUFSEYSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;1-[(3,4-dimethoxyphenyl)methyl]-6 Chemical compound Cl.Cl.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 LGFMXOTUSSVQJV-NEYUFSEYSA-N 0.000 description 1
- 239000001124 (E)-prop-1-ene-1,2,3-tricarboxylic acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- ZLFQTZYFXYOGLS-UHFFFAOYSA-N 1-methyl-4-phenylpiperidine-4-carbonitrile Chemical compound C1CN(C)CCC1(C#N)C1=CC=CC=C1 ZLFQTZYFXYOGLS-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JDFGPEMCSCTFBG-VYGKMDHKSA-N 18-benzyloxycoronaridine Chemical compound C([C@H]1CC2C[C@@]3([C@H]1N(C2)CCC=1C2=CC=CC=C2NC3=1)C(=O)OC)COCC1=CC=CC=C1 JDFGPEMCSCTFBG-VYGKMDHKSA-N 0.000 description 1
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- OLFXZBDPKBSIPG-SAJNPJMVSA-N 2-methoxyethyl 18-methoxycoronaridinate Chemical compound N1([C@H]2[C@@H](CCOC)CC(C1)C[C@]21C(=O)OCCOC)CCC2=C1NC1=CC=CC=C21 OLFXZBDPKBSIPG-SAJNPJMVSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- SHXWCVYOXRDMCX-UHFFFAOYSA-N 3,4-methylenedioxymethamphetamine Chemical compound CNC(C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- IYNWSQDZXMGGGI-NUEKZKHPSA-N 3-hydroxymorphinan Chemical compound C1CCC[C@H]2[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 IYNWSQDZXMGGGI-NUEKZKHPSA-N 0.000 description 1
- SRARDYUHGVMEQI-UHFFFAOYSA-N 3-methylthiofentanyl Chemical group C=1C=CC=CC=1N(C(=O)CC)C(C(C1)C)CCN1CCC1=CC=CS1 SRARDYUHGVMEQI-UHFFFAOYSA-N 0.000 description 1
- IGPROYLOGZTOAM-UHFFFAOYSA-N 3-phenylsulfanylpropanoic acid Chemical compound OC(=O)CCSC1=CC=CC=C1 IGPROYLOGZTOAM-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- KXUBAVLIJFTASZ-UHFFFAOYSA-N 4-fluorofentanyl Chemical group C=1C=C(F)C=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 KXUBAVLIJFTASZ-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- FDQGNLOWMMVRQL-UHFFFAOYSA-N Allobarbital Chemical compound C=CCC1(CC=C)C(=O)NC(=O)NC1=O FDQGNLOWMMVRQL-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 206010050012 Bradyphrenia Diseases 0.000 description 1
- 206010006797 Burns first degree Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 240000007681 Catha edulis Species 0.000 description 1
- 235000006696 Catha edulis Nutrition 0.000 description 1
- 208000001387 Causalgia Diseases 0.000 description 1
- 206010064012 Central pain syndrome Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 description 1
- 240000008772 Cistus ladanifer Species 0.000 description 1
- 235000005241 Cistus ladanifer Nutrition 0.000 description 1
- 244000089742 Citrus aurantifolia Species 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- LBBNRFISSBZUDC-UHFFFAOYSA-N Conopharyngine Natural products CC(N)C1CCC2C3CC=C4CC(CCC4(C)C3CCC12C)OC5OC(CO)C(O)C(O)C5O LBBNRFISSBZUDC-UHFFFAOYSA-N 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000288030 Coturnix coturnix Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- 206010011971 Decreased interest Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- IJVCSMSMFSCRME-KBQPJGBKSA-N Dihydromorphine Chemical compound O([C@H]1[C@H](CC[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O IJVCSMSMFSCRME-KBQPJGBKSA-N 0.000 description 1
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 description 1
- OGDVEMNWJVYAJL-UHFFFAOYSA-N Ethylmorphine Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OCC OGDVEMNWJVYAJL-UHFFFAOYSA-N 0.000 description 1
- KJTKYGFGPQSRRA-UHFFFAOYSA-N Etoxeridine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(CCOCCO)CC1 KJTKYGFGPQSRRA-UHFFFAOYSA-N 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 206010066482 Exaggerated startle response Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010016754 Flashback Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- WYCLKVQLVUQKNZ-UHFFFAOYSA-N Halazepam Chemical compound N=1CC(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 WYCLKVQLVUQKNZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010048533 Hypervigilance Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 206010022524 Intentional self-injury Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ZAGRKAFMISFKIO-UHFFFAOYSA-N Isolysergic acid Natural products C1=CC(C2=CC(CN(C2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-UHFFFAOYSA-N 0.000 description 1
- ALFGKMXHOUSVAD-UHFFFAOYSA-N Ketobemidone Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCN(C)CC1 ALFGKMXHOUSVAD-UHFFFAOYSA-N 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 208000006670 Multiple fractures Diseases 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- 108020001305 NR1 subfamily Proteins 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 1
- 208000000224 Night Terrors Diseases 0.000 description 1
- 206010029412 Nightmare Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- VWCUGCYZZGRKEE-UHFFFAOYSA-N Noracymethadol Chemical compound C=1C=CC=CC=1C(CC(C)NC)(C(OC(C)=O)CC)C1=CC=CC=C1 VWCUGCYZZGRKEE-UHFFFAOYSA-N 0.000 description 1
- ONBWJWYUHXVEJS-ZTYRTETDSA-N Normorphine Chemical compound C([C@@H](NCC1)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ONBWJWYUHXVEJS-ZTYRTETDSA-N 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- 206010033864 Paranoia Diseases 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 229920005439 Perspex® Polymers 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- MWQCHHACWWAQLJ-UHFFFAOYSA-N Prazepam Chemical compound O=C1CN=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N1CC1CC1 MWQCHHACWWAQLJ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FOJYFDFNGPRXDR-UHFFFAOYSA-N Pseudomorphine Natural products C12C=CC(O)C3OC4=C(O)C(C=5C=C6C7=C(C=5O)OC5C77CCN(C(C6)C7C=CC5O)C)=CC5=C4C23CCN(C)C1C5 FOJYFDFNGPRXDR-UHFFFAOYSA-N 0.000 description 1
- 206010071368 Psychological trauma Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 206010037213 Psychomotor retardation Diseases 0.000 description 1
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 208000005560 Self Mutilation Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010041347 Somnambulism Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- 206010042464 Suicide attempt Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 1
- 241001061127 Thione Species 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- GRHZLQBPAJAHDM-SPRQWYLLSA-N [(3as,4r,6ar)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] n-[(2s,4s,5s)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]carbamate Chemical compound CC1=CC=CC(C)=C1OCC(=O)N[C@H]([C@@H](O)C[C@H](CC=1C=CC=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)CC1=CC=CC=C1 GRHZLQBPAJAHDM-SPRQWYLLSA-N 0.000 description 1
- UVAZQQHAVMNMHE-BBRMVZONSA-N [(3s,4s)-1,3-dimethyl-4-phenylpiperidin-4-yl] propanoate Chemical compound C=1C=CC=CC=1[C@]1(OC(=O)CC)CCN(C)C[C@@H]1C UVAZQQHAVMNMHE-BBRMVZONSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 102000015296 acetylcholine-gated cation-selective channel activity proteins Human genes 0.000 description 1
- 108040006409 acetylcholine-gated cation-selective channel activity proteins Proteins 0.000 description 1
- XBMIVRRWGCYBTQ-UHFFFAOYSA-N acetylmethadol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-UHFFFAOYSA-N 0.000 description 1
- 229950005506 acetylmethadol Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940091181 aconitic acid Drugs 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- GJSLOMWRLALDCT-UHFFFAOYSA-N adinazolam Chemical compound C12=CC(Cl)=CC=C2N2C(CN(C)C)=NN=C2CN=C1C1=CC=CC=C1 GJSLOMWRLALDCT-UHFFFAOYSA-N 0.000 description 1
- 229960003148 adinazolam Drugs 0.000 description 1
- CGNMLOKEMNBUAI-UHFFFAOYSA-N adrafinil Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)NO)C1=CC=CC=C1 CGNMLOKEMNBUAI-UHFFFAOYSA-N 0.000 description 1
- 229960002820 adrafinil Drugs 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229960000880 allobarbital Drugs 0.000 description 1
- KGYFOSCXVAXULR-UHFFFAOYSA-N allylprodine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCN(C)CC1CC=C KGYFOSCXVAXULR-UHFFFAOYSA-N 0.000 description 1
- 229950004361 allylprodine Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229950007385 alphacetylmethadol Drugs 0.000 description 1
- XBMIVRRWGCYBTQ-XMSQKQJNSA-N alphacetylmethadol Chemical compound C=1C=CC=CC=1C(C[C@@H](C)N(C)C)([C@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-XMSQKQJNSA-N 0.000 description 1
- QIRAYNIFEOXSPW-YLJYHZDGSA-N alphamethadol Chemical compound C=1C=CC=CC=1C(C[C@@H](C)N(C)C)([C@H](O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-YLJYHZDGSA-N 0.000 description 1
- 229950006873 alphamethadol Drugs 0.000 description 1
- YPOXDUYRRSUFFG-UHFFFAOYSA-N alphamethylthiofentanyl Chemical group C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1C(C)CC1=CC=CS1 YPOXDUYRRSUFFG-UHFFFAOYSA-N 0.000 description 1
- 229960001349 alphaprodine Drugs 0.000 description 1
- UVAZQQHAVMNMHE-XJKSGUPXSA-N alphaprodine Chemical compound C=1C=CC=CC=1[C@@]1(OC(=O)CC)CCN(C)C[C@@H]1C UVAZQQHAVMNMHE-XJKSGUPXSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 229960002512 anileridine Drugs 0.000 description 1
- LKYQLAWMNBFNJT-UHFFFAOYSA-N anileridine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC1=CC=C(N)C=C1 LKYQLAWMNBFNJT-UHFFFAOYSA-N 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960003153 aprobarbital Drugs 0.000 description 1
- UORJNBVJVRLXMQ-UHFFFAOYSA-N aprobarbital Chemical compound C=CCC1(C(C)C)C(=O)NC(=O)NC1=O UORJNBVJVRLXMQ-UHFFFAOYSA-N 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229960004823 armodafinil Drugs 0.000 description 1
- YFGHCGITMMYXAQ-LJQANCHMSA-N armodafinil Chemical compound C=1C=CC=CC=1C([S@](=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-LJQANCHMSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000002567 autonomic effect Effects 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- UVTBZAWTRVBTMK-UHFFFAOYSA-N benzethidine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCOCC1=CC=CC=C1 UVTBZAWTRVBTMK-UHFFFAOYSA-N 0.000 description 1
- 229950002302 benzethidine Drugs 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- RDJGWRFTDZZXSM-RNWLQCGYSA-N benzylmorphine Chemical compound O([C@@H]1[C@]23CCN([C@H](C4)[C@@H]3C=C[C@@H]1O)C)C1=C2C4=CC=C1OCC1=CC=CC=C1 RDJGWRFTDZZXSM-RNWLQCGYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- QIRAYNIFEOXSPW-XLIONFOSSA-N betamethadol Chemical compound C=1C=CC=CC=1C(C[C@@H](C)N(C)C)([C@@H](O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-XLIONFOSSA-N 0.000 description 1
- 229950003767 betamethadol Drugs 0.000 description 1
- 229950000011 betaprodine Drugs 0.000 description 1
- FLKWNFFCSSJANB-UHFFFAOYSA-N bezitramide Chemical compound O=C1N(C(=O)CC)C2=CC=CC=C2N1C(CC1)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 FLKWNFFCSSJANB-UHFFFAOYSA-N 0.000 description 1
- 229960004611 bezitramide Drugs 0.000 description 1
- 230000000669 biting effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 229950002261 brallobarbital Drugs 0.000 description 1
- DYODAJAEQDVYFX-UHFFFAOYSA-N brallobarbital Chemical compound BrC(=C)CC1(CC=C)C(=O)NC(=O)NC1=O DYODAJAEQDVYFX-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 1
- 229960001113 butorphanol Drugs 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- CHCISLOJADQUNQ-UHFFFAOYSA-N climazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1Cl CHCISLOJADQUNQ-UHFFFAOYSA-N 0.000 description 1
- 229950001490 climazolam Drugs 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- GPZLDQAEBHTMPG-UHFFFAOYSA-N clonitazene Chemical compound N=1C2=CC([N+]([O-])=O)=CC=C2N(CCN(CC)CC)C=1CC1=CC=C(Cl)C=C1 GPZLDQAEBHTMPG-UHFFFAOYSA-N 0.000 description 1
- 229950001604 clonitazene Drugs 0.000 description 1
- 229960004362 clorazepate Drugs 0.000 description 1
- XDDJGVMJFWAHJX-UHFFFAOYSA-N clorazepic acid Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)O)N=C1C1=CC=CC=C1 XDDJGVMJFWAHJX-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- DUFLXLVGASPEMV-BPYGGHBPSA-N conopharyngine Chemical compound C([C@H]1C[C@@H]([C@H]2[C@]3(C1)C(=O)OC)CC)N2CCC1=C3NC2=CC(OC)=C(OC)C=C12 DUFLXLVGASPEMV-BPYGGHBPSA-N 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 229940125368 controlled substance Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000009223 counseling Methods 0.000 description 1
- 230000009193 crawling Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000013500 data storage Methods 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229950003851 desomorphine Drugs 0.000 description 1
- LNNWVNGFPYWNQE-GMIGKAJZSA-N desomorphine Chemical compound C1C2=CC=C(O)C3=C2[C@]24CCN(C)[C@H]1[C@@H]2CCC[C@@H]4O3 LNNWVNGFPYWNQE-GMIGKAJZSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 229960001042 dexmethylphenidate Drugs 0.000 description 1
- DUGOZIWVEXMGBE-CHWSQXEVSA-N dexmethylphenidate Chemical compound C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-CHWSQXEVSA-N 0.000 description 1
- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 description 1
- 229960003701 dextromoramide Drugs 0.000 description 1
- INUNXTSAACVKJS-OAQYLSRUSA-N dextromoramide Chemical compound C([C@@H](C)C(C(=O)N1CCCC1)(C=1C=CC=CC=1)C=1C=CC=CC=1)N1CCOCC1 INUNXTSAACVKJS-OAQYLSRUSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229960003461 dezocine Drugs 0.000 description 1
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- RXTHKWVSXOIHJS-UHFFFAOYSA-N diampromide Chemical compound C=1C=CC=CC=1N(C(=O)CC)CC(C)N(C)CCC1=CC=CC=C1 RXTHKWVSXOIHJS-UHFFFAOYSA-N 0.000 description 1
- 229950001059 diampromide Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- CBYWMRHUUVRIAF-UHFFFAOYSA-N diethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(CC)CC)C1=CC=CS1 CBYWMRHUUVRIAF-UHFFFAOYSA-N 0.000 description 1
- 229950009987 diethylthiambutene Drugs 0.000 description 1
- 229960005493 difenoxin Drugs 0.000 description 1
- UFIVBRCCIRTJTN-UHFFFAOYSA-N difenoxin Chemical compound C1CC(C(=O)O)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 UFIVBRCCIRTJTN-UHFFFAOYSA-N 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 1
- BRTSNYPDACNMIP-FAWZKKEFSA-N dihydroetorphine Chemical compound O([C@H]1[C@@]2(OC)CC[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O BRTSNYPDACNMIP-FAWZKKEFSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- RHUWRJWFHUKVED-UHFFFAOYSA-N dimenoxadol Chemical compound C=1C=CC=CC=1C(C(=O)OCCN(C)C)(OCC)C1=CC=CC=C1 RHUWRJWFHUKVED-UHFFFAOYSA-N 0.000 description 1
- 229950011187 dimenoxadol Drugs 0.000 description 1
- QIRAYNIFEOXSPW-UHFFFAOYSA-N dimepheptanol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-UHFFFAOYSA-N 0.000 description 1
- 229950004655 dimepheptanol Drugs 0.000 description 1
- CANBGVXYBPOLRR-UHFFFAOYSA-N dimethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)C)C1=CC=CS1 CANBGVXYBPOLRR-UHFFFAOYSA-N 0.000 description 1
- 229950005563 dimethylthiambutene Drugs 0.000 description 1
- 229950008972 dioxaphetyl butyrate Drugs 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229960004192 diphenoxylate Drugs 0.000 description 1
- SVDHSZFEQYXRDC-UHFFFAOYSA-N dipipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCCCC1 SVDHSZFEQYXRDC-UHFFFAOYSA-N 0.000 description 1
- 229960002500 dipipanone Drugs 0.000 description 1
- 230000009189 diving Effects 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000001544 dysphoric effect Effects 0.000 description 1
- 238000004049 embossing Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- ZOWQTJXNFTWSCS-IAQYHMDHSA-N eptazocine Chemical compound C1N(C)CC[C@@]2(C)C3=CC(O)=CC=C3C[C@@H]1C2 ZOWQTJXNFTWSCS-IAQYHMDHSA-N 0.000 description 1
- 229950010920 eptazocine Drugs 0.000 description 1
- CDCHDCWJMGXXRH-UHFFFAOYSA-N estazolam Chemical compound C=1C(Cl)=CC=C(N2C=NN=C2CN=2)C=1C=2C1=CC=CC=C1 CDCHDCWJMGXXRH-UHFFFAOYSA-N 0.000 description 1
- 229960002336 estazolam Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MORSAEFGQPDBKM-UHFFFAOYSA-N ethylmethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)CC)C1=CC=CS1 MORSAEFGQPDBKM-UHFFFAOYSA-N 0.000 description 1
- 229950006111 ethylmethylthiambutene Drugs 0.000 description 1
- 229960004578 ethylmorphine Drugs 0.000 description 1
- PXDBZSCGSQSKST-UHFFFAOYSA-N etonitazene Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC([N+]([O-])=O)=CC=C2N1CCN(CC)CC PXDBZSCGSQSKST-UHFFFAOYSA-N 0.000 description 1
- 229950004538 etonitazene Drugs 0.000 description 1
- CAHCBJPUTCKATP-FAWZKKEFSA-N etorphine Chemical compound O([C@H]1[C@@]2(OC)C=C[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O CAHCBJPUTCKATP-FAWZKKEFSA-N 0.000 description 1
- 229950004155 etorphine Drugs 0.000 description 1
- 229950004151 etoxeridine Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 210000000256 facial nerve Anatomy 0.000 description 1
- 208000015700 familial long QT syndrome Diseases 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000010006 flight Effects 0.000 description 1
- 229960002200 flunitrazepam Drugs 0.000 description 1
- 229960003528 flurazepam Drugs 0.000 description 1
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- NNCOZXNZFLUYGG-UHFFFAOYSA-N furethidine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCOCC1CCCO1 NNCOZXNZFLUYGG-UHFFFAOYSA-N 0.000 description 1
- 229950011066 furethidine Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 229960002158 halazepam Drugs 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- WTJBNMUWRKPFRS-UHFFFAOYSA-N hydroxypethidine Chemical compound C=1C=CC(O)=CC=1C1(C(=O)OCC)CCN(C)CC1 WTJBNMUWRKPFRS-UHFFFAOYSA-N 0.000 description 1
- 229950008496 hydroxypethidine Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 206010020765 hypersomnia Diseases 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- IFKPLJWIEQBPGG-UHFFFAOYSA-N isomethadone Chemical compound C=1C=CC=CC=1C(C(C)CN(C)C)(C(=O)CC)C1=CC=CC=C1 IFKPLJWIEQBPGG-UHFFFAOYSA-N 0.000 description 1
- 229950009272 isomethadone Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960003029 ketobemidone Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- XBMIVRRWGCYBTQ-AVRDEDQJSA-N levacetylmethadol Chemical compound C=1C=CC=CC=1C(C[C@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-AVRDEDQJSA-N 0.000 description 1
- 229950004990 levomethorphan Drugs 0.000 description 1
- INUNXTSAACVKJS-NRFANRHFSA-N levomoramide Chemical compound C([C@H](C)C(C(=O)N1CCCC1)(C=1C=CC=CC=1)C=1C=CC=CC=1)N1CCOCC1 INUNXTSAACVKJS-NRFANRHFSA-N 0.000 description 1
- RCYBMSQOSGJZLO-BGWNEDDSSA-N levophenacylmorphan Chemical compound C([C@]12CCCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CC(=O)C1=CC=CC=C1 RCYBMSQOSGJZLO-BGWNEDDSSA-N 0.000 description 1
- 229950007939 levophenacylmorphan Drugs 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- VOBHXZCDAVEXEY-JSGCOSHPSA-N lisdexamfetamine Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 VOBHXZCDAVEXEY-JSGCOSHPSA-N 0.000 description 1
- 229960001451 lisdexamfetamine Drugs 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 229960004033 lormetazepam Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical compound C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- YELGFTGWJGBAQU-UHFFFAOYSA-N mephedrone Chemical compound CNC(C)C(=O)C1=CC=C(C)C=C1 YELGFTGWJGBAQU-UHFFFAOYSA-N 0.000 description 1
- 229960000365 meptazinol Drugs 0.000 description 1
- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229950009131 metazocine Drugs 0.000 description 1
- YGSVZRIZCHZUHB-COLVAYQJSA-N metazocine Chemical compound C1C2=CC=C(O)C=C2[C@]2(C)CCN(C)[C@@]1([H])[C@@H]2C YGSVZRIZCHZUHB-COLVAYQJSA-N 0.000 description 1
- GJJQIGFCGLPOQK-UHFFFAOYSA-N methadone intermediate Chemical compound C=1C=CC=CC=1C(C#N)(CC(C)N(C)C)C1=CC=CC=C1 GJJQIGFCGLPOQK-UHFFFAOYSA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- SYHGEUNFJIGTRX-UHFFFAOYSA-N methylenedioxypyrovalerone Chemical compound C=1C=C2OCOC2=CC=1C(=O)C(CCC)N1CCCC1 SYHGEUNFJIGTRX-UHFFFAOYSA-N 0.000 description 1
- 229960001344 methylphenidate Drugs 0.000 description 1
- NPZXCTIHHUUEEJ-CMKMFDCUSA-N metopon Chemical compound O([C@@]1(C)C(=O)CC[C@@H]23)C4=C5[C@@]13CCN(C)[C@@H]2CC5=CC=C4O NPZXCTIHHUUEEJ-CMKMFDCUSA-N 0.000 description 1
- 229950006080 metopon Drugs 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 229960001165 modafinil Drugs 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- JDEDMCKQPKGSAX-UHFFFAOYSA-N morpheridine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCN1CCOCC1 JDEDMCKQPKGSAX-UHFFFAOYSA-N 0.000 description 1
- 229950007193 morpheridine Drugs 0.000 description 1
- 239000002756 mu opiate receptor agonist Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- GODGZZGKTZQSAL-VXFFQEMOSA-N myrophine Chemical compound C([C@@H]1[C@@H]2C=C[C@@H]([C@@H]3OC4=C5[C@]23CCN1C)OC(=O)CCCCCCCCCCCCC)C5=CC=C4OCC1=CC=CC=C1 GODGZZGKTZQSAL-VXFFQEMOSA-N 0.000 description 1
- 229950007471 myrophine Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000938 nalorphine Drugs 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 101150009274 nhr-1 gene Proteins 0.000 description 1
- 229960004300 nicomorphine Drugs 0.000 description 1
- HNDXBGYRMHRUFN-CIVUWBIHSA-N nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 description 1
- 238000002670 nicotine replacement therapy Methods 0.000 description 1
- GWUSZQUVEVMBPI-UHFFFAOYSA-N nimetazepam Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1 GWUSZQUVEVMBPI-UHFFFAOYSA-N 0.000 description 1
- 229950001981 nimetazepam Drugs 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 229940121367 non-opioid analgesics Drugs 0.000 description 1
- 229950008848 noracymethadol Drugs 0.000 description 1
- RAUCDOKTMDOIPF-RYRUWHOVSA-N noribogaine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-RYRUWHOVSA-N 0.000 description 1
- 229950011519 norlevorphanol Drugs 0.000 description 1
- 229960004013 normethadone Drugs 0.000 description 1
- WCJFBSYALHQBSK-UHFFFAOYSA-N normethadone Chemical compound C=1C=CC=CC=1C(CCN(C)C)(C(=O)CC)C1=CC=CC=C1 WCJFBSYALHQBSK-UHFFFAOYSA-N 0.000 description 1
- 229950006134 normorphine Drugs 0.000 description 1
- QKHMFBKXTNQCTM-UHFFFAOYSA-N norpethidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCNCC1 QKHMFBKXTNQCTM-UHFFFAOYSA-N 0.000 description 1
- WCDSHELZWCOTMI-UHFFFAOYSA-N norpipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CCN1CCCCC1 WCDSHELZWCOTMI-UHFFFAOYSA-N 0.000 description 1
- 229950007418 norpipanone Drugs 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940051877 other opioids in atc Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960003294 papaveretum Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008414 paregoric Substances 0.000 description 1
- 229940069533 paregoric Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- BVURVTVDNWSNFN-UHFFFAOYSA-N pepap Chemical compound C1CC(OC(=O)C)(C=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 BVURVTVDNWSNFN-UHFFFAOYSA-N 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LOXCOAXRHYDLOW-UHFFFAOYSA-N phenadoxone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCOCC1 LOXCOAXRHYDLOW-UHFFFAOYSA-N 0.000 description 1
- 229950004540 phenadoxone Drugs 0.000 description 1
- 229950010992 phenallymal Drugs 0.000 description 1
- WOIGZSBYKGQJGL-UHFFFAOYSA-N phenallymal Chemical compound C=1C=CC=CC=1C1(CC=C)C(=O)NC(=O)NC1=O WOIGZSBYKGQJGL-UHFFFAOYSA-N 0.000 description 1
- 229950007248 phenampromide Drugs 0.000 description 1
- DHTRHEVNFFZCNU-OAHLLOKOSA-N phenampromide Chemical compound C([C@@H](C)N(C(=O)CC)C=1C=CC=CC=1)N1CCCCC1 DHTRHEVNFFZCNU-OAHLLOKOSA-N 0.000 description 1
- ZQHYKVKNPWDQSL-KNXBSLHKSA-N phenazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CCC1=CC=CC=C1 ZQHYKVKNPWDQSL-KNXBSLHKSA-N 0.000 description 1
- 229960000897 phenazocine Drugs 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- CFBQYWXPZVQQTN-QPTUXGOLSA-N phenomorphan Chemical compound C([C@]12CCCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CCC1=CC=CC=C1 CFBQYWXPZVQQTN-QPTUXGOLSA-N 0.000 description 1
- 229950011496 phenomorphan Drugs 0.000 description 1
- IPOPQVVNCFQFRK-UHFFFAOYSA-N phenoperidine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(O)C1=CC=CC=C1 IPOPQVVNCFQFRK-UHFFFAOYSA-N 0.000 description 1
- 229960004315 phenoperidine Drugs 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- PXXKIYPSXYFATG-UHFFFAOYSA-N piminodine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCCNC1=CC=CC=C1 PXXKIYPSXYFATG-UHFFFAOYSA-N 0.000 description 1
- 229950006445 piminodine Drugs 0.000 description 1
- IHEHEFLXQFOQJO-UHFFFAOYSA-N piritramide Chemical compound C1CC(C(=O)N)(N2CCCCC2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 IHEHEFLXQFOQJO-UHFFFAOYSA-N 0.000 description 1
- 229960001286 piritramide Drugs 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 230000007824 polyneuropathy Effects 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960004856 prazepam Drugs 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- ZXWAUWBYASJEOE-UHFFFAOYSA-N proheptazine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCCN(C)CC1C ZXWAUWBYASJEOE-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- XJKQCILVUHXVIQ-UHFFFAOYSA-N properidine Chemical compound C=1C=CC=CC=1C1(C(=O)OC(C)C)CCN(C)CC1 XJKQCILVUHXVIQ-UHFFFAOYSA-N 0.000 description 1
- 229950004345 properidine Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- ZBAFFZBKCMWUHM-UHFFFAOYSA-N propiram Chemical compound C=1C=CC=NC=1N(C(=O)CC)C(C)CN1CCCCC1 ZBAFFZBKCMWUHM-UHFFFAOYSA-N 0.000 description 1
- 229950003779 propiram Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 230000009430 psychological distress Effects 0.000 description 1
- 230000004800 psychological effect Effects 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000003016 quadriplegic effect Effects 0.000 description 1
- INUNXTSAACVKJS-UHFFFAOYSA-N racemoramide Chemical compound C1CCCN1C(=O)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C)CN1CCOCC1 INUNXTSAACVKJS-UHFFFAOYSA-N 0.000 description 1
- 229950011009 racemorphan Drugs 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 229960003394 remifentanil Drugs 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 208000012788 shakes Diseases 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 210000001779 taste bud Anatomy 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YMRFZDHYDKZXPA-UHFFFAOYSA-N thienylfentanyl Chemical group C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CS1 YMRFZDHYDKZXPA-UHFFFAOYSA-N 0.000 description 1
- 229960001402 tilidine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 229950009395 trimeperidine Drugs 0.000 description 1
- UVITTYOJFDLOGI-KEYYUXOJSA-N trimeperidine Chemical compound C=1C=CC=CC=1[C@]1(OC(=O)CC)C[C@H](C)N(C)C[C@H]1C UVITTYOJFDLOGI-KEYYUXOJSA-N 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 229960004751 varenicline Drugs 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Landscapes
- Health & Medical Sciences (AREA)
- Addiction (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
This invention relates generally to methods and compositions related to therapeutic uses of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
Description
THERAPEUTIC USES OF IBOGAINE AND RELATED COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No.
61/952,724, filed March 13, 2014, U.S. Provisional Application No. 61/952,725, filed March 13, 2014, U.S.
Provisional Application No. 61/947,397, filed March 3, 2014, U.S. Provisional Application No.
61/952,718, filed March 13, 2014, U.S. Provisional Application No. 61/952,740, filed March 13, 2014, U.S. Provisional Application No. 61/952,736, filed March 13, 2014, U.S. Provisional Application No. 61/952,743, filed March 13, 2014, and U.S. Provisional Application No.
62/049,968, filed September 12, 2014.
FIELD OF THE INVENTION
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No.
61/952,724, filed March 13, 2014, U.S. Provisional Application No. 61/952,725, filed March 13, 2014, U.S.
Provisional Application No. 61/947,397, filed March 3, 2014, U.S. Provisional Application No.
61/952,718, filed March 13, 2014, U.S. Provisional Application No. 61/952,740, filed March 13, 2014, U.S. Provisional Application No. 61/952,736, filed March 13, 2014, U.S. Provisional Application No. 61/952,743, filed March 13, 2014, and U.S. Provisional Application No.
62/049,968, filed September 12, 2014.
FIELD OF THE INVENTION
[0002] This invention relates generally to the use of each of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof at a dosage that provides a therapeutic serum concentration for treating or preventing a disease or disorder in a patient.
STATE OF THE ART
Nicotine Addiction
STATE OF THE ART
Nicotine Addiction
[0003] Nicotine addiction relates generally to smoking, although other forms of nicotine addiction are common (e.g., chewing tobacco). Smoking and other forms of nicotine use pose a serious threat to global health. In the United States alone, annual mortality from smoking (including environmental exposure, i.e. "second-hand smoke") is greater than 440,000. Costs associated with smoking-related illness in the United States total $96 billion in medical costs and $97 billion in lost productivity each year. Furthermore, smoking significantly increases the risk of a number of diseases, including coronary artery disease, stroke, lung cancer and other cancers, and chronic obstructive pulmonary disease. An estimated 46 million people in the United States are smokers, 20.6 percent of the US population.
[0004] More than 40 percent of existing smokers attempt to quit smoking annually. Various approved therapies (varenicline, bupropion, nicotine patch/gum, nicotine nasal spray/inhaler, hypnotherapy, biofeedback) have long been in clinical use to treat nicotine dependence.
Date Recue/Date Received 2021-07-21
Date Recue/Date Received 2021-07-21
5 PCT/US2015/018356 Current therapies directed toward smoking cessation tend to focus on counseling, behavioral treatment such as hypnosis, and/or pharmaceutical therapies. Quitting smoking is difficult and may require multiple attempts, with success rates of 4% to 25% depending on the technique used. Users often relapse because of stress, weight gain, and withdrawal symptoms.
Furthermore, nicotine replacement therapies (e.g., nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler) do not directly treat nicotine addiction, as the patient remains addicted to nicotine throughout treatment.
[0005] A nicotine addict in remission may exhibit psychological symptoms of nicotine addiction long after the physical symptoms of nicotine addiction are gone.
Many ex-smokers relapse due to a trigger, such as stress or environmental cues. For example, approximately 50% of relapses occur when the ex-smoker has been drinking alcohol.
Alcohol Dependence
Furthermore, nicotine replacement therapies (e.g., nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler) do not directly treat nicotine addiction, as the patient remains addicted to nicotine throughout treatment.
[0005] A nicotine addict in remission may exhibit psychological symptoms of nicotine addiction long after the physical symptoms of nicotine addiction are gone.
Many ex-smokers relapse due to a trigger, such as stress or environmental cues. For example, approximately 50% of relapses occur when the ex-smoker has been drinking alcohol.
Alcohol Dependence
[0006] Alcohol dependence (also referred to alcohol abuse, alcohol addiction, or alcoholism) is a serious public health problem throughout the world. As many as 140 million people worldwide have an alcohol abuse problem, although only a small fraction of those receive treatment. Alcohol abuse can cause damage to almost every organ in the body, including the brain. Long-term alcohol abuse is known to cause or contribute to numerous diseases, including cirrhosis of the liver, pancreatitis, epilepsy, dementia, heart disease, peptic ulcers, damage to the central and/or peripheral nervous system, cancer, polyneuropathy, nutritional deficiencies, and death.
[0007] Complicating the treatment of alcohol dependence, alcohol-dependent patients generally experience significant, potentially fatal, withdrawal symptoms while attempting to quit using alcohol. Acute withdrawal lasts one to three weeks after cessation of alcohol consumption. Acute withdrawal symptoms include anxiety, seizures, delirium tremens (DTs), hallucinations, shakes, and heart failure. Post-acute withdrawal can last significantly longer, with symptoms such as anxiety, depression, sleep disturbance, fatigue, and tension being common.
[0008] Treatment for alcohol dependence generally includes detoxification followed by individual and/or group therapy. Detoxification may include treatment with medications (such as benzodiazepines) that reduce the symptoms of withdrawal. However, drugs such as benzodiazepines have numerous negative side effects, including adverse psychological effects and physical dependence. Benzodiazepines are also known to increase alcohol cravings in alcohol dependent people, and are thus not suitable for long-term treatment of alcohol dependence/addiction.
Substance or Drug Addiction 100091 Substance or drug addiction is a serious public health problem throughout the world.
Heroin and other opioids, including prescription painkillers, are widely abused and account for a large percentage of illicit drug use. Opioid use is also linked to approximately 50% of violent crimes in the United States and costs the U.S. economy billions of dollars per year.
As many as 23.5 million people in the US (almost 10%) have a drug or alcohol abuse problem, although only a small fraction of those receive treatment.
[0010] Complicating the treatment of drug addiction, drug-addicted patients generally experience significant withdrawal symptoms while attempting to quit using the drug. Acute withdrawal from drug dependence is characterized by dramatic and traumatic symptoms, including sweating, racing heart, palpitations, muscle tension, tightness in the chest, difficulty breathing, tremor, nausea, vomiting, diarrhea, grand mal seizures, heart attacks, strokes, hallucinations and DTs. Withdrawal can also include severe cravings for the drug, fatigue, lack of pleasure, anxiety, irritability, sleepiness, suicidal thoughts, and sometimes agitation or extreme suspicion or paranoia. Once acute withdrawal symptoms have subsided, post-acute withdrawal syndrome can last for months or years. Post-acute withdrawal symptoms include fatigue, depression, lack of motivation, and increased pain sensitivity. Acute and post-acute withdrawal symptoms are the primary reason drug-addicted patients return to using the drug after treatment, even when the patient has been drug-free for a significant amount of time.
100111 Although treatments have been developed in attempts to ameliorate acute and post-acute withdrawal symptoms, such treatments do not work for all types of drugs.
In addition, treatment of withdrawal may require use of other addictive substances (e.g., morphine or methadone) and that the addict attend a clinic daily for an extended amount of time. Due to the severity and duration of withdrawal symptoms, addicted patients have a high rate of relapse. There is a significant need for effective, non-addictive treatment for acute and post-acute withdrawal symptoms.
Depression [00121 Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b). Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes. A major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it can include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
[0013] Post-traumatic stress disorder (PTSD), as defined by DSM-III-R/IV
(American Psychiatric Association, 1987; American Psychiatric Association, 1994a), requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Although PTSD is classified as an anxiety disorder, PTSD is unique from other anxiety disorders because of the requirement of exposure to a traumatic event.
[0014] Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event;
avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
[0015] The CDC estimates that about 1 in 10 adults in the United States suffer from depression. High levels of depression correlate with high rates of other diseases, including obesity, heart disease, and stroke. Similarly, PTSD affects approximately 8%
of Americans at some point in their lives. More strikingly, up to 30% of people, including veterans, who spend time in war zones develop PTSD. PTSD is increasingly recognized as a major issue for U.S. troops returning from Iraq and Afghanistan, as well as those who served in previous wars, and is a potential contributor to the high rate of suicide among veterans.
[0016] Given the prevalence and impact of depression and PTSD, there is a need for treatments that address these issues. Prior to the embodiments described herein, the therapeutic dosing of ibogaine and its derivatives for treating depression and/or PTSD in humans at an acceptable QT interval prolongation has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe.
Tolerance To Opioid Analgesics [0017] Addictive opioid analgesic agents such as morphine are well-characterized and exceptionally potent analgesics. As is well known, continued use of many such opioids (especially at high doses) carries a significant risk of dependency/addiction.
Indeed, potential addiction to such opioids is a serious issue that limits the therapeutic use of addictive opioids as analgesic agents. For example, the use of morphine as an analgesic is common among end stage patients suffering from serious pain where addiction is no longer a concern.
[0018] Drug tolerance to opioid analgesics is common, and may be psychological and/or physiological. A patient who has developed tolerance to the opioid analgesic is not necessarily addicted to or misusing the analgesic. Drug tolerance occurs when the patient's reaction to the drug is reduced, requiring an increase in dose to achieve the same desired effect.
100191 Drug tolerance requires that the dosage of analgesic be increased in order to provide sustained analgesic effect. However, high doses of opioids may lead to serious complications and side effects, including physical dependence, addiction, respiratory depression, nausea, sedation, euphoria or dysphoria, decreased gastrointestinal motility, and itching.
100201 It would be beneficial to provide a method for modulating opioid analgesic tolerance in a patient taking one or more opioid analgesics for the treatment of pain.
Impulse Control Disorder, Anxiety-Related Disorders, Violence And/Or Anger, Or Regulating Food Intake [0021] Obsessive compulsive disorder (OCD) is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, and/or significantly interfere with social or occupational functioning.
100221 Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a). A panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
100231 Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) intµerferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
[0024] Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM-IV
(American Psychiatric Association, 1994a).
[0025] Impulse control disorder is a class of psychiatric disorders involving the failure to resist a temptation, urge, or impulse (impulsivity) where such impulse is potentially harmful to the patient and/or others. The American Psychiatric Association's DSM-5 (May 2013) includes impulse control disorders "characterized by problems in emotional and behavioral self-control".
These include borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, intemet addiction, trichotillomania, pathological skin picking, and compulsive shopping. Impulse control disorder may be related to anxiety disorder and/or OCD.
[0026] Violence and anger, particularly when out of proportion to a stimulus and/or a result of pathological anger, are associated with a number of mental disorders. These include oppositional defiant disorder, attention-deficit/hyperactivity disorder and conduct disorder (in children and adolescents), psychotic disorder, bipolar disorder, antisocial, borderline, paranoid and narcissistic personality disorders, adjustment disorder with disturbance of conduct, and intermittent explosive disorder. Pathological anger and violence account for a significant portion of violent crimes, including many high-profile crimes involving multiple victims.
Highly volatile individuals are over-represented in the prison system in the United States.
[0027] Over 2/3 of adults in the U.S. are overweight, with about half of those being obese. The U.S. weight loss market is estimated to be worth over $60 billion; diet pills alone account for around $1 billion. However, many diet pills contain ingredients that are at best of dubious efficacy and at worst dangerous. Obesity greatly increases a person's risk for a variety of diseases, including coronary heart disease, high blood pressure, stioke, type 2 diabetes, abnormal levels of blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, reproductive issues, and gallstones.
[0028] Given the prevalence and impact of anxiety disorders, impulse control disorder, anger/violence-related disorders, and overweight/obesity, there is a need for treatments that address these issues. Prior to the embodiments described herein, the therapeutic dosing of ibogaine and its derivatives for treating anxiety disorders, impulse control disorder, Date Recue/Date Received 2021-07-21 anger/violence-related disorders, or regulation of food intake in humans at an acceptable QT
interval prolongation has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe.
SUMMARY OF THE INVENTION
100011 Ibogaine has been used as a botanical preparation from the root bark of iboga tabernathe for over 100 years both as a crude preparation and as semisynthetic ibogaine, which was marketed in France until about 1970. The therapeutic use of ibogaine is limited due to potentially adverse side effects. For example, ibogaine exhibits undesirable stimulant and hallucinogenic properties, and in addition, can induce tremors. At conventional doses, ibogaine causes adverse side effects in a majority of patients receiving treatment.
100021 hi the United States, ibogaine is classified as a Schedule I controlled substance. The use of ibogaine in humans is complicated by the fact that the ranges in the prior art are exceptionally broad (0.01 to 1000 mg/kg body weight). Furthermore, the ranges generally used to treat addiction (e.g., 15 mg/kg to 20 mg/kg) cause hallucinations and may be fatal. Lotsof and Wachtel, Manual for lbogaine Therapy: Screening, Safety, Monitoring &
Aftercare (2d revision, 2003), accessed at www.ibogaine.desk.nl/manual.html; Hoelen, et al.
New Engl. J.
Med. 360(3), 308 (2009).
[0003] Further, prior to the embodiments described herein, the therapeutic dosing of ibogaine and its derivatives for treating opioid or opioid-like drug addiction in humans at an acceptable QT interval prolongation has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe. A prolonged QT interval is a marker of potential ventricular tachyarrhythmia which, and can result in death. Serious complications, including ventricular tachyarrhythmia and death, can result from prolongation of the treated patient's QT
interval by ibogaine, rendering high doses of ibogaine unacceptable.
[0004] Heretofore, it was unclear whether a therapeutic dose of ibogaine could be found that resulted in QT interval prolongation within an acceptable range. It is expected that other compounds that share ibogaine's core structure will have a similar prolongation effect on QT
interval. See, U.S. Provisional Patent Application No. 61/945,746 filed February 27, 2014 Date Recue/Date Received 2021-07-21 entitled METHOD FOR ACUTE AND LONG-TERM TREATMENT OF DRUG
ADDICTION.
Nicotine [0033] This invention is based, in part, on the discovery that at very low doses, direct blood stream delivery of ibogaine will reduce the desire to smoke. Such dosing is well below that previously described. Direct blood stream delivery of ibogaine is contemplated to enhance the amount of ibogaine delivered to the brain, because ibogaine so administered does not initially pass through the liver before reaching the brain as it does when ingested. Direct blood stream delivery of ibogaine includes sublingual, pulmonary and intranasal delivery where the ibogaine is absorbed directly into the blood stream and then into the brain. The rapid delivery of ibogaine into the brain causes a significant reduction in the craving to smoke on a rapid basis, typically less than 15 minutes after administration.
The very low doses and direct delivery from the blood stream to the brain is also contemplated to avoid significant QT prolongation or to keep the QT prolongation within the acceptable range.
[0034] Ibogaine is believed to bind to several receptors in the brain, including nicotinic acetylcholine receptors (nAChRs) and opiod receptors (e.g., ii-opiod receptors). Without being bound by theory, it is believed that the nAChR has a greater binding affinity for ibogaine than other receptors in the brain. This allows treatment of nicotine addiction and/or nicotine cravings using much lower doses of ibogaine than are currently used for the treatment of other conditions, such as opioid withdrawal. Furthermore, a nicotine addict in remission may not exhibit physical symptoms of addiction, but rather may have psychological cravings for cigarettes or other forms of nicotine, or may anticipate such cravings in certain situations. As such, and without being bound by theory, it is expected that lower amounts of ibogaine are required to treat or prevent nicotine cravings in such situations than would be required in a patient who is currently addicted to nicotine.
[0035] In one aspect, this invention relates to methods of treating nicotine addiction or preventing relapse of nicotine use, comprising administration of a therapeutic amount of ibogaine, an ibogainc derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
[0036] In one aspect, this invention relates to treating nicotine addiction in a patient in need thereof comprising administering to the patient by direct blood stream delivery a
Substance or Drug Addiction 100091 Substance or drug addiction is a serious public health problem throughout the world.
Heroin and other opioids, including prescription painkillers, are widely abused and account for a large percentage of illicit drug use. Opioid use is also linked to approximately 50% of violent crimes in the United States and costs the U.S. economy billions of dollars per year.
As many as 23.5 million people in the US (almost 10%) have a drug or alcohol abuse problem, although only a small fraction of those receive treatment.
[0010] Complicating the treatment of drug addiction, drug-addicted patients generally experience significant withdrawal symptoms while attempting to quit using the drug. Acute withdrawal from drug dependence is characterized by dramatic and traumatic symptoms, including sweating, racing heart, palpitations, muscle tension, tightness in the chest, difficulty breathing, tremor, nausea, vomiting, diarrhea, grand mal seizures, heart attacks, strokes, hallucinations and DTs. Withdrawal can also include severe cravings for the drug, fatigue, lack of pleasure, anxiety, irritability, sleepiness, suicidal thoughts, and sometimes agitation or extreme suspicion or paranoia. Once acute withdrawal symptoms have subsided, post-acute withdrawal syndrome can last for months or years. Post-acute withdrawal symptoms include fatigue, depression, lack of motivation, and increased pain sensitivity. Acute and post-acute withdrawal symptoms are the primary reason drug-addicted patients return to using the drug after treatment, even when the patient has been drug-free for a significant amount of time.
100111 Although treatments have been developed in attempts to ameliorate acute and post-acute withdrawal symptoms, such treatments do not work for all types of drugs.
In addition, treatment of withdrawal may require use of other addictive substances (e.g., morphine or methadone) and that the addict attend a clinic daily for an extended amount of time. Due to the severity and duration of withdrawal symptoms, addicted patients have a high rate of relapse. There is a significant need for effective, non-addictive treatment for acute and post-acute withdrawal symptoms.
Depression [00121 Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b). Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes. A major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it can include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
[0013] Post-traumatic stress disorder (PTSD), as defined by DSM-III-R/IV
(American Psychiatric Association, 1987; American Psychiatric Association, 1994a), requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Although PTSD is classified as an anxiety disorder, PTSD is unique from other anxiety disorders because of the requirement of exposure to a traumatic event.
[0014] Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event;
avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
[0015] The CDC estimates that about 1 in 10 adults in the United States suffer from depression. High levels of depression correlate with high rates of other diseases, including obesity, heart disease, and stroke. Similarly, PTSD affects approximately 8%
of Americans at some point in their lives. More strikingly, up to 30% of people, including veterans, who spend time in war zones develop PTSD. PTSD is increasingly recognized as a major issue for U.S. troops returning from Iraq and Afghanistan, as well as those who served in previous wars, and is a potential contributor to the high rate of suicide among veterans.
[0016] Given the prevalence and impact of depression and PTSD, there is a need for treatments that address these issues. Prior to the embodiments described herein, the therapeutic dosing of ibogaine and its derivatives for treating depression and/or PTSD in humans at an acceptable QT interval prolongation has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe.
Tolerance To Opioid Analgesics [0017] Addictive opioid analgesic agents such as morphine are well-characterized and exceptionally potent analgesics. As is well known, continued use of many such opioids (especially at high doses) carries a significant risk of dependency/addiction.
Indeed, potential addiction to such opioids is a serious issue that limits the therapeutic use of addictive opioids as analgesic agents. For example, the use of morphine as an analgesic is common among end stage patients suffering from serious pain where addiction is no longer a concern.
[0018] Drug tolerance to opioid analgesics is common, and may be psychological and/or physiological. A patient who has developed tolerance to the opioid analgesic is not necessarily addicted to or misusing the analgesic. Drug tolerance occurs when the patient's reaction to the drug is reduced, requiring an increase in dose to achieve the same desired effect.
100191 Drug tolerance requires that the dosage of analgesic be increased in order to provide sustained analgesic effect. However, high doses of opioids may lead to serious complications and side effects, including physical dependence, addiction, respiratory depression, nausea, sedation, euphoria or dysphoria, decreased gastrointestinal motility, and itching.
100201 It would be beneficial to provide a method for modulating opioid analgesic tolerance in a patient taking one or more opioid analgesics for the treatment of pain.
Impulse Control Disorder, Anxiety-Related Disorders, Violence And/Or Anger, Or Regulating Food Intake [0021] Obsessive compulsive disorder (OCD) is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, and/or significantly interfere with social or occupational functioning.
100221 Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a). A panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
100231 Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) intµerferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
[0024] Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM-IV
(American Psychiatric Association, 1994a).
[0025] Impulse control disorder is a class of psychiatric disorders involving the failure to resist a temptation, urge, or impulse (impulsivity) where such impulse is potentially harmful to the patient and/or others. The American Psychiatric Association's DSM-5 (May 2013) includes impulse control disorders "characterized by problems in emotional and behavioral self-control".
These include borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, intemet addiction, trichotillomania, pathological skin picking, and compulsive shopping. Impulse control disorder may be related to anxiety disorder and/or OCD.
[0026] Violence and anger, particularly when out of proportion to a stimulus and/or a result of pathological anger, are associated with a number of mental disorders. These include oppositional defiant disorder, attention-deficit/hyperactivity disorder and conduct disorder (in children and adolescents), psychotic disorder, bipolar disorder, antisocial, borderline, paranoid and narcissistic personality disorders, adjustment disorder with disturbance of conduct, and intermittent explosive disorder. Pathological anger and violence account for a significant portion of violent crimes, including many high-profile crimes involving multiple victims.
Highly volatile individuals are over-represented in the prison system in the United States.
[0027] Over 2/3 of adults in the U.S. are overweight, with about half of those being obese. The U.S. weight loss market is estimated to be worth over $60 billion; diet pills alone account for around $1 billion. However, many diet pills contain ingredients that are at best of dubious efficacy and at worst dangerous. Obesity greatly increases a person's risk for a variety of diseases, including coronary heart disease, high blood pressure, stioke, type 2 diabetes, abnormal levels of blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, reproductive issues, and gallstones.
[0028] Given the prevalence and impact of anxiety disorders, impulse control disorder, anger/violence-related disorders, and overweight/obesity, there is a need for treatments that address these issues. Prior to the embodiments described herein, the therapeutic dosing of ibogaine and its derivatives for treating anxiety disorders, impulse control disorder, Date Recue/Date Received 2021-07-21 anger/violence-related disorders, or regulation of food intake in humans at an acceptable QT
interval prolongation has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe.
SUMMARY OF THE INVENTION
100011 Ibogaine has been used as a botanical preparation from the root bark of iboga tabernathe for over 100 years both as a crude preparation and as semisynthetic ibogaine, which was marketed in France until about 1970. The therapeutic use of ibogaine is limited due to potentially adverse side effects. For example, ibogaine exhibits undesirable stimulant and hallucinogenic properties, and in addition, can induce tremors. At conventional doses, ibogaine causes adverse side effects in a majority of patients receiving treatment.
100021 hi the United States, ibogaine is classified as a Schedule I controlled substance. The use of ibogaine in humans is complicated by the fact that the ranges in the prior art are exceptionally broad (0.01 to 1000 mg/kg body weight). Furthermore, the ranges generally used to treat addiction (e.g., 15 mg/kg to 20 mg/kg) cause hallucinations and may be fatal. Lotsof and Wachtel, Manual for lbogaine Therapy: Screening, Safety, Monitoring &
Aftercare (2d revision, 2003), accessed at www.ibogaine.desk.nl/manual.html; Hoelen, et al.
New Engl. J.
Med. 360(3), 308 (2009).
[0003] Further, prior to the embodiments described herein, the therapeutic dosing of ibogaine and its derivatives for treating opioid or opioid-like drug addiction in humans at an acceptable QT interval prolongation has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe. A prolonged QT interval is a marker of potential ventricular tachyarrhythmia which, and can result in death. Serious complications, including ventricular tachyarrhythmia and death, can result from prolongation of the treated patient's QT
interval by ibogaine, rendering high doses of ibogaine unacceptable.
[0004] Heretofore, it was unclear whether a therapeutic dose of ibogaine could be found that resulted in QT interval prolongation within an acceptable range. It is expected that other compounds that share ibogaine's core structure will have a similar prolongation effect on QT
interval. See, U.S. Provisional Patent Application No. 61/945,746 filed February 27, 2014 Date Recue/Date Received 2021-07-21 entitled METHOD FOR ACUTE AND LONG-TERM TREATMENT OF DRUG
ADDICTION.
Nicotine [0033] This invention is based, in part, on the discovery that at very low doses, direct blood stream delivery of ibogaine will reduce the desire to smoke. Such dosing is well below that previously described. Direct blood stream delivery of ibogaine is contemplated to enhance the amount of ibogaine delivered to the brain, because ibogaine so administered does not initially pass through the liver before reaching the brain as it does when ingested. Direct blood stream delivery of ibogaine includes sublingual, pulmonary and intranasal delivery where the ibogaine is absorbed directly into the blood stream and then into the brain. The rapid delivery of ibogaine into the brain causes a significant reduction in the craving to smoke on a rapid basis, typically less than 15 minutes after administration.
The very low doses and direct delivery from the blood stream to the brain is also contemplated to avoid significant QT prolongation or to keep the QT prolongation within the acceptable range.
[0034] Ibogaine is believed to bind to several receptors in the brain, including nicotinic acetylcholine receptors (nAChRs) and opiod receptors (e.g., ii-opiod receptors). Without being bound by theory, it is believed that the nAChR has a greater binding affinity for ibogaine than other receptors in the brain. This allows treatment of nicotine addiction and/or nicotine cravings using much lower doses of ibogaine than are currently used for the treatment of other conditions, such as opioid withdrawal. Furthermore, a nicotine addict in remission may not exhibit physical symptoms of addiction, but rather may have psychological cravings for cigarettes or other forms of nicotine, or may anticipate such cravings in certain situations. As such, and without being bound by theory, it is expected that lower amounts of ibogaine are required to treat or prevent nicotine cravings in such situations than would be required in a patient who is currently addicted to nicotine.
[0035] In one aspect, this invention relates to methods of treating nicotine addiction or preventing relapse of nicotine use, comprising administration of a therapeutic amount of ibogaine, an ibogainc derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
[0036] In one aspect, this invention relates to treating nicotine addiction in a patient in need thereof comprising administering to the patient by direct blood stream delivery a
9 therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof. In one aspect, a therapeutically effective amount of ibogaine or derivative is from about 50 ng to less than 10 lig per kg of body weight. In some embodiments, the therapeutically effective amount of ibogaine or ibogaine derivative is administered once a day, twice a day, or more than twice a day.
[0037] In another aspect, this invention provides a method for treating nicotine addiction in a patient in need thereof comprising administering to the patient a therapeutic amount of ibogaine or an ibogaine derivative or pharmaceutically acceptable salt and/or solvate thereof, wherein the ibogaine or derivative or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
[0038] In another aspect, relates to methods of preventing relapse of nicotine use, comprising administration of a prophylactic amount of ibogainc, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof to inhibit a behavioral craving for nicotine.
[0039] In one aspect, this invention relates to preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient by direct blood stream delivery a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof. In one aspect, a prophylactically effective amount of ibogaine or derivative is from about 50 ng to less than 10 t.ig per kg of body weight. In some embodiments, the prophylactically effective amount of ibogaine or ibogaine derivative is administered once a day, twice a day, or more than twice a day.
In some embodiments, the prophylactically effective amount is administered when the patient feels a craving, or anticipates feeling a craving, for nicotine.
[0040] In another aspect, this invention provides a method for preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt andVor solvate thereof, wherein the ibogaine, derivative, or salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
[0041] In one aspect, provided herein is a method for treating nicotine addiction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein said therapeutically effective amount is from about 50 ng to less than
[0037] In another aspect, this invention provides a method for treating nicotine addiction in a patient in need thereof comprising administering to the patient a therapeutic amount of ibogaine or an ibogaine derivative or pharmaceutically acceptable salt and/or solvate thereof, wherein the ibogaine or derivative or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
[0038] In another aspect, relates to methods of preventing relapse of nicotine use, comprising administration of a prophylactic amount of ibogainc, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof to inhibit a behavioral craving for nicotine.
[0039] In one aspect, this invention relates to preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient by direct blood stream delivery a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof. In one aspect, a prophylactically effective amount of ibogaine or derivative is from about 50 ng to less than 10 t.ig per kg of body weight. In some embodiments, the prophylactically effective amount of ibogaine or ibogaine derivative is administered once a day, twice a day, or more than twice a day.
In some embodiments, the prophylactically effective amount is administered when the patient feels a craving, or anticipates feeling a craving, for nicotine.
[0040] In another aspect, this invention provides a method for preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt andVor solvate thereof, wherein the ibogaine, derivative, or salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
[0041] In one aspect, provided herein is a method for treating nicotine addiction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein said therapeutically effective amount is from about 50 ng to less than
10 lig per kg body weight per day.
[0042] In one embodiment, the therapeutically effective amount is from about 50 ng to about 1 ps per kg body weight per day. hi another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the therapeutically effective amount is administered once a day. In another embodiment, the therapeutically effective amount is administered two or more times per day.
[0043] In another aspect, provided herein is a method for preventing a nicotine craving in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein said prophylactically effective amount is from about 50 ng to less than 101.tg per kg body weight per day.
[0044] In one embodiment, the patient is no longer physically addicted to nicotine. In another embodiment, the prophylactically effective amount is from about 50 ng to about 1 i.tg per kg body weight per day. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered on an as-needed basis as determined by the subject. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered before the nicotine craving occurs. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered after the nicotine craving occurs.
Alcohol [0045] One aspect of the current invention is predicated, at least in part, on the surprising discovery that treatment of alcohol dependence with ibogaine and derivatives thereof can be achieved with an acceptable QT interval prolongation when such compounds are administered within a narrow dosage range. Specifically, dosing an addicted patient with greater than about 1 mg/kg body weight to about 8 mg/kg body weight, provides a therapeutic reduction in withdrawal symptoms in alcohol dependent patients. Preferably, the dose range that provide both therapeutic results and an acceptable QT interval prolongation of less than
[0042] In one embodiment, the therapeutically effective amount is from about 50 ng to about 1 ps per kg body weight per day. hi another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the therapeutically effective amount is administered once a day. In another embodiment, the therapeutically effective amount is administered two or more times per day.
[0043] In another aspect, provided herein is a method for preventing a nicotine craving in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein said prophylactically effective amount is from about 50 ng to less than 101.tg per kg body weight per day.
[0044] In one embodiment, the patient is no longer physically addicted to nicotine. In another embodiment, the prophylactically effective amount is from about 50 ng to about 1 i.tg per kg body weight per day. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered on an as-needed basis as determined by the subject. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered before the nicotine craving occurs. In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered after the nicotine craving occurs.
Alcohol [0045] One aspect of the current invention is predicated, at least in part, on the surprising discovery that treatment of alcohol dependence with ibogaine and derivatives thereof can be achieved with an acceptable QT interval prolongation when such compounds are administered within a narrow dosage range. Specifically, dosing an addicted patient with greater than about 1 mg/kg body weight to about 8 mg/kg body weight, provides a therapeutic reduction in withdrawal symptoms in alcohol dependent patients. Preferably, the dose range that provide both therapeutic results and an acceptable QT interval prolongation of less than
11 50 milliseconds in addicted humans is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1.3 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
100461 In one aspect of the invention, the narrow therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate described above do not prolong the QT interval to unacceptable levels in human patients. It is expected that alcohol dependent patients will be administered therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval e.g., to determine whether the patient has any pre-existing cardiac conditions or other indicators which would disqualify them from treatment with ibogaine. In one embodiment, a patient who exhibits a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof will not require further clinical monitoring.
[0047] Some aspects of the current invention are further predicated on the discovery that even lower doses of ibogaine, ibogaine derivative, or phaimaceutically acceptable salt and/or solvate thereof, for example approximately 80% or less of the therapeutic dose, may be effective for prevention of relapse of alcohol use in an addicted patient treated to ameliorate their alcohol dependence. That is, a lower dose of ibogaine can prevent a patient who is no longer physically dependent on alcohol from relapsing to use thereof. Without being bound by theory, it is believed that a patient who is no longer physically dependent on alcohol requires less ibogaine to prevent relapse at least in part because the changes made to the brain by alcohol dependence at least partially reverse when the patient detoxifies from alcohol.
This lower, maintenance dose of ibogaine results in a QT interval prolongation that does not require clinical cardiac monitoring.
[0048] In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mI, to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered
100461 In one aspect of the invention, the narrow therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate described above do not prolong the QT interval to unacceptable levels in human patients. It is expected that alcohol dependent patients will be administered therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval e.g., to determine whether the patient has any pre-existing cardiac conditions or other indicators which would disqualify them from treatment with ibogaine. In one embodiment, a patient who exhibits a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof will not require further clinical monitoring.
[0047] Some aspects of the current invention are further predicated on the discovery that even lower doses of ibogaine, ibogaine derivative, or phaimaceutically acceptable salt and/or solvate thereof, for example approximately 80% or less of the therapeutic dose, may be effective for prevention of relapse of alcohol use in an addicted patient treated to ameliorate their alcohol dependence. That is, a lower dose of ibogaine can prevent a patient who is no longer physically dependent on alcohol from relapsing to use thereof. Without being bound by theory, it is believed that a patient who is no longer physically dependent on alcohol requires less ibogaine to prevent relapse at least in part because the changes made to the brain by alcohol dependence at least partially reverse when the patient detoxifies from alcohol.
This lower, maintenance dose of ibogaine results in a QT interval prolongation that does not require clinical cardiac monitoring.
[0048] In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mI, to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered
12 to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
[0049] In some embodiments, the patient is administered a high (therapeutic) dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to alcohol use. In some embodiments, the patient is administered a therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof over time until the maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose. In some embodiments, the dose of ibogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
[0050] In some embodiments, the dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 8 mg/kg. In a preferred embodiment, the aggregate dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 4 mg/kg. In another preferred embodiment, the aggregate dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to 3 mg/kg.
[0051] In some embodiments, the serum concentration of ibogaine is sufficient to inhibit or ameliorate said dependence while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 80 ms. In one embodiment, the maintenance dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 50 ms. In some embodiments, the maintenance
[0049] In some embodiments, the patient is administered a high (therapeutic) dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to alcohol use. In some embodiments, the patient is administered a therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof over time until the maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose. In some embodiments, the dose of ibogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
[0050] In some embodiments, the dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 8 mg/kg. In a preferred embodiment, the aggregate dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 4 mg/kg. In another preferred embodiment, the aggregate dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to 3 mg/kg.
[0051] In some embodiments, the serum concentration of ibogaine is sufficient to inhibit or ameliorate said dependence while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 80 ms. In one embodiment, the maintenance dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 50 ms. In some embodiments, the maintenance
13 dose or therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 30 ms. In a preferred embodiment, the maintenance dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT
interval of less than 20 ms. In a preferred embodiment, the patient is tested to determine QT
interval before treatment with ibogaine, and if clinician determines that the QT prolongation would be unacceptable risk, ibogaine therapy will be contraindicated.
[0052] In one aspect, provided herein is amethod for treating alcohol dependence in a human patient suffering therefrom, comprising administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.
[0053] In one embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
[0054] In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine, ibogainc derivative, or pharmaceutically acceptable salt and/or solvate thereof provides an average serum concentration of about 50 ng/mL to about 200 ng/mL.
[0055] In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
interval of less than 20 ms. In a preferred embodiment, the patient is tested to determine QT
interval before treatment with ibogaine, and if clinician determines that the QT prolongation would be unacceptable risk, ibogaine therapy will be contraindicated.
[0052] In one aspect, provided herein is amethod for treating alcohol dependence in a human patient suffering therefrom, comprising administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.
[0053] In one embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
[0054] In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine, ibogainc derivative, or pharmaceutically acceptable salt and/or solvate thereof provides an average serum concentration of about 50 ng/mL to about 200 ng/mL.
[0055] In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
14 [0056] In another embodiment, the method further comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT
interval greater than about 470 ms. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT interval ?pater than about 450 ms.
[0057] In another aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of ibogaine, ibogaine derivative, or phai tnaceutically acceptable salt ancUor solvate thereof that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0058] In one embodiment, the withdrawal symptoms are due to acute withdrawal.
In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0059] In another aspect, provided herein is a method to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is no longer physically dependent on alcohol.
[0060] In one embodiment, the maintenance dosage is less than about 70% of a therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 30 ms.
In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 20 ms.
Drug Addiction [0061] This invention is predicated, at least in part, on the surprising discovery that treatment of addiction with ibogaine can be achieved with an acceptable QT
interval prolongation when such compounds are administered within a narrow dosage range.
Specifically, dosing an addicted patient with from greater than about 1 mg/kg body weight to about 4 rag/kg body weight, ibogaine will provide a therapeutic reduction in withdrawal symptoms and/or an increase in time to resumption of substance use in addicted patients without unacceptable prolongation of the patient's QT interval.
[0062] In some aspects of the invention, the dose range of ibogaine that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in substance-addicted humans is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1.3 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0063] In some embodiments, the narrow therapeutic doses of ibogaine unexpectedly do not prolong the QT interval to unacceptable levels in human addicted patients. It is expected that drug addicted patients will be administered therapeutic doses of ibogaine in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with ibogaine.
[0064] Some aspects of the current invention are further predicated on the discovery that even lower doses of ibogaine, for example approximately 80% or less of the therapeutic dose, may be effective for prevention of relapse of drug use in an addicted patient treated to ameliorate their drug use. That is, a lower dose of the compound can prevent a patient who is no longer physically addicted to a substance from relapsing to use of that substance. Without being bound by theory, it is believed that a patient who is no longer physically addicted to the drug requires less compound to prevent relapse because the drug does not compete with the compound for receptor binding, and/or because desensitization of one or more receptors in the brain by the drug is reversed when the patient ceases to take the drug.
This lower, maintenance dose results in a QT interval prolongation that does not require clinical cardiac monitoring.
[0065] In some embodiments, the therapeutic dose of ibogaine administered to the patient is sufficient to provide an average serum concentration of the compound of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
100661 In some embodiments, the patient is administered a high (therapeutic) dose of ibogaine for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to drug use. In some embodiments, the patient is administered a therapeutic dose of ibogaine for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of ibogaine over time until the maintenance dose is reached.
In some embodiments, a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose. In some embodiments, the dose of the compound is tapered over time from the high therapeutic dose to a lower therapeutic dose.
[0067] In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of ibogaine is from greater than about 1 mg/kg to about 8 mg/kg. In a preferred embodiment, the aggregate dose of ibogaine is from greater than about 1 mg/kg to about 4 mg/kg. In another preferred embodiment, the aggregate dose of ibogaine is from greater than about 1 mg/kg to 3 mg/kg.
100681 In some embodiments, the serum concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, the therapeutic dose of ibogaine provides prolongation of the QT interval of less than 80 ms. In a preferred embodiment, the maintenance dose of ibogaine provides prolongation of the QT interval of less than 50 ms. In some embodiments, the maintenance dose or therapeutic dose of ibogaine provides prolongation of the QT interval of less than 30 ms. In a preferred embodiment, the maintenance dose of ibogaine provides prolongation of the QT interval of less than 20 ms. In one embodiment, the QT prolongation is equivalent to or less than that observed in patient receiving methadone treatment. In a preferred embodiment, the patient is tested to determine QT interval before treatment with the compound, and if clinician determines that the QT prolongation would be unacceptable risk, therapy will be contraindicated.
Substance Abuse [0069] In one aspect, provided herein is a method for treating substance abuse in a human patient addicted thereto, comprising administering to the patient a dosage of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, preferably ibogaine, wherein the dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0070] In one embodiment, the ibogaine is administered as a single dose or multiple doses.
In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0071] In one aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to Date Recue/Date Received 2021-07-21 attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0072] In one embodiment, the the withdrawal symptoms are due to acute withdrawal.
[0073] In another embodiment, the ibogaine is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 3 mg/kg per day.
In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT
interval is less than about 450 ms.
[0074] In another aspect, provided herein is a method to prevent relapse of substance abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine, wherein the patient is no longer abusing the substance.
[0075] In one embodiment, the dosage is less than about 70% of a therapeutic dose of ibogaine, and further wherein the prolongation of the QT interval is no greater than about 30 ins. In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 20 ms.
[0076] In one embodiment, the unit dose of ibogaine is administered in one or more dosings.
[0077] In another aspect, provided herein is a method for treating substance abuse in a patient addicted thereto, comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0078] In one embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT interval greater than about 470 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT
interval greater than about 450 ms.
[0079] In another embodiment, the addictive substance is selected from the group consisting of benzodiazepines, cannabinoids and synthetic cannabinoids, stimulants, barbiturates, gamma-hydroxybutyrate (GHB), ketamine, PCP, dextromethorphan (DXM), lysergic acid diethylamide (LSD), mescaline, anabolic steroids, and derivatives of each thereof.
Opioid Or Opioid¨Like Drug Abuse [0080] In one aspect, provided herein is a method for treating opioid or opioid-like drug abuse in a human patient addicted thereto, comprising administering to the patient a dosage of ibogaine wherein the dosage provides an average serum concentration of about 50 ng/mL
to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0081] In another embodiment, the ibogaine is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0082] In another aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0083] In another embodiment, the withdrawal symptoms are due to acute withdrawal. In another embodiment, the ibogaine is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the QT
interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0084] In another aspect, provided herein is a method to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine wherein the patient is no longer abusing the opioid or opioid-like drug.
[0085] In one embodiment, the dosage is less than about 70% of a therapeutic dose of ibogaine and further wherein the prolongation of the QT interval is no greater than about 30 ms. In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 20 ms.
[0086] In one embodiment, the unit dose of ibogaine is administered in one or more dosings.
100871 In one aspect, provided herein is a method for treating opioid or opioid-like drug abuse in a patient addicted thereto, comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0088] In one embodiment, the prescreening step comprises ascertaining that treatment with ibogainc, ibogaine derivative, or pharmaceutically acceptable salt thereof will not result in a QT interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT
interval greater than about 470 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT interval greater than about 450 ms.
Pain [0089] Pain is broadly defined as an unpleasant sensory experience associated with actual or potential tissue damage, or described in terms of such damage. The interpretation of sensory pain occurs when peripheral nerve endings called nociceptors are stimulated and subsequently transmit signals through sensory neurons in the spinal cord. The signals are then transmitted to the brain, at which point the individual becomes aware of the pain.
[0090] There are a number of pain categories and classifications, which for example, can be grouped into four categories according to the source and related nociceptors:
(1) cutaneous pain; (2) somatic pain; (3) visceral pain; and (4) neuropathic pain. Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain indicates present damage to tissue or disease and may be "fast" and "sharp" followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. Acute pain generally responds well to medications (e.g., morphine).
[0091] Chronic pain may be medically defined as pain that has lasted six months or longer.
This constant or intermittent pain has often outlived its purpose because it does not help the body to prevent injury. It is often more difficult to treat than acute pain.
Expert care is generally necessary to treat any pain that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to control the pain. This can lead to drug dependency. For example, opioids are used in some instances for prolonged periods to control chronic pain. Drug tolerance, chemical dependency, and even psychological addiction may occur.
[0092] Debilitating chronic pain affects tens of millions of people annually.
Accordingly, this costs hundreds of millions of dollars in terms of medication, physical therapy, and lost production. The current methods for treating chronic pain have a limited success rate and in some cases may result in chemical dependency.
[0093] Numerous treatments have been developed in attempts to ameliorate pain in its various categories. However, in many cases, treatment requires the use of addictive or habit-forming substances (e.g., morphine or methadone). Accordingly, there is a significant need for an effective, non-addictive treatment for pain, such as chronic, debilitating, nociceptive pain, that reduces the need for habit-fointing pain relieving drugs.
[0094] Furthermore, human clinical studies demonstrate that the lower dosing of ibogaine has minimal impact on the alleviation of pain in patients. Thus, the previously disclosed broad range has now been found to be insufficient for at least some human therapies at the lower end of this range.
[0095] In some embodiments, the current invention is predicated on the surprising discovery that treatment with a narrow dosage range of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, preferably of ibogaine, between greater than about 0.1 mg/kg body weight and about 8 mg/kg body weight, provides a therapeutic alleviation of pain. Preferably, the dose range that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in humans is between about 0.1 mg per kg body weight and no more than about 3 mg per kg body weight and, more preferably between about 0.7 mg per kg body weight and no more than about 2 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0096] In some embodiments, the narrow therapeutic doses of ibogaine described above do not prolong the QT interval to unacceptable levels in human patients. In some embodiments, patients are administered therapeutic doses of ibogaine in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with ibogaine.
In one embodiment, a patient who exhibits a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of ibogaine will not require further clinical monitoring. In one embodiment, the patient is not monitored after administration of ibogaine.
[0097] In some embodiments, the therapeutic dose of ibogaine administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
[0098] In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of ibogaine is from about 0.1 mg/kg to about 8 mg/kg. In one embodiment, the aggregate dose of ibogaine is from about 0.1 mg/kg to about 3 mg/kg.
In another embodiment, the aggregate dose of ibogaine is from about 0.7 mg/kg to 1.5 mg/kg.
[0099] In one aspect, provided herein is a method for treating pain in a patient, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to alleviate and/or inhibit said pain while maintaining a QT interval of less than about 500 ms during said treatment.
[0100] In one embodiment, the ibogaine is administered as a single dose or multiple doses.
In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage ibogainc is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine thereof is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine provides an average serum concentration of about 50 ng/mL
to about 200 ng/mL.
[0101] In one aspect, provided herein is a method for alleviating pain symptoms in a human patient susceptible to such symptoms, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to alleviate said pain symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0102] In one embodiment, the pain symptoms are due to chronic pain. In another embodiment, the ibogaine is administered as a single dose or multiple doses.
In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day.
[0103] In one embodiment, the unit dose of ibogaine is administered in one or more dosings.
Depression [0104] The current invention is predicated on the surprising discovery that treatment with a narrow dosage range of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, between greater than about 1 mg/kg body weight and about 8 mg/kg body weight, provides a therapeutic reduction in symptoms of depression and/or PTSD in affected patients. Preferably, the dose range that provide both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1.3 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0105] In one aspect, this invention relates to treating depression and/or PTSD in a patient in need thereof comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, this invention treats depression. In another embodiment, this invention treats PTSD. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
[0106] In some embodiments, the therapeutic dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient is sufficient to provide an average scrum concentration of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL. In one embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 200 ng/mL.
[0107] In a preferred embodiment, the narrow therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate described above unexpectedly do not prolong the QT interval to unacceptable levels in human patients. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT
interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify him/her from treatment with ibogaine or ibogaine derivative.
[0108] In some embodiments, the serum concentration is sufficient to inhibit or ameliorate symptoms of depression and/or PTSD while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment.
101091 In another aspect, this invention provides a method for treating depression and/or PTSD in a patient in need thereof comprising administering to the patient ibogaine, ibogaine derivative, or salt and/or solvate thereof in a sustained release manner such that the serum concentration of ibogaine or ibogaine derivative is maintained at a therapeutically effective amount for a period of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, or a period of time between any two of these durations.
[0110] In one aspect, provided herein is a method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine or ibogaine derivative serum level of between about 50 ng/mL
and about 400 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0111] In one embodiment, the therapeutically effective amount is between about 1 mg to about 4 mg per kg of body weight. In another embodiment, the therapeutically effective amount is between about 50 ng to less than 100 tg per kg of body weight. In another embodiment, the dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms. In another embodiment, the QT interval is less than about 420 ms. In another embodiment, the method further comprising selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
[0112] In another embodiment, depression is treated. In another embodiment, posttraumatic stress disorder is treated.
[0113] In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, ibogaine or ibogaine derivative or a pharmaceutically acceptable salt and/or solvate thereof is administered.
Reducing Tolerance To Opioid Analgesics [0114] This invention is directed, in part, to the use of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, preferably ibogaine, to modulate tolerance to addictive opioid analgesic agents in a patient who has developed or is at risk of developing a tolerance for the analgesic. In such methods, effective analgesia can be achieved in a patient while resensitizing the patient to the addictive opioid analgesic. The term "resensitizing the patient" is used herein to refer to reducing, relieving, attenuating, and/or reversing tolerance to the analgesic. In one aspect, the resensitized patient obtains therapeutic effect from a lower dose of the opioid analgesic than before resensitization.
In one aspect, the resensitized patient obtains improved therapeutic effect from the same dose of the opioid analgesic compared to before resensitization.
[0115] The use of ibogaine for the modulation of tolerance to opioid analgesic agents is limited due to potentially adverse side effects. The use of ibogaine to modulate opioid tolerance is generally not favored due to the adverse side effects that can result from receiving a therapeutic dose according to conventional known methods.
101161 In one embodiment, ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered concurrently with the opioid analgesic. In one embodiment, ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered after administration of the analgesic, for example one, two, three, four, eight, ten, twelve, 24 hours or more after administration of the analgesic. In one embodiment, one dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered. In one embodiment, two or more doses of ibogainc, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof are administered. In one embodiment, the opioid analgesic is interrupted for a period of time while ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered. In one embodiment, a non-opioid analgesic is administered while the opioid analgesic is interrupted. In one embodiment, ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof acts as an analgesic.
In one embodiment, the opioid analgesic is not interrupted during ibogaine treatment.
[0117] In one aspect, provided herein is a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic therapy an amount of ibogaine, ibogaine derivative or phaunaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
[0118] In one embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method further comprises interrupting the dosage of the analgesic.
In another embodiment, the method further comprises administering ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof concurrently with the analgesic. In another embodiment, during concurrent administration, the dose of opioid analgesic is reduced.
[0119] In another embodiment, the dose or aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day.
[0120] In another embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT
interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0121] In another embodiment, the method further comprises selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT
interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT interval greater than about 470 ms.
In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT interval greater than about 450 ms.
[0122] In another embodiment, the opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, oxymorphone. In another embodiment, the opioid analgesic is morphine.
Impulse Control [0123] The current invention is also predicated on the surprising discovery that treatment with a narrow dosage range of ibogaine or pharmaceutically acceptable salt and/or solvate thereof, between greater than about 1 mg/kg body weight and about 4 mg/kg body weight, provides a therapeutic reduction in symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders in affected patients, or provides a therapeutic reduction in food consumption. Preferably, the dose range that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0124] In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is between about 60 mg and about 150 mg. In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 100 mg. In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 120 mg.
In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 1.5 mg/kg body weight. In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 2 mg/kg body weight.
[0125] In some embodiments, the patient is administered an initial dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, the initial dose is from about 50 mg to about 120 mg. In one embodiment, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from about 5 mg to about 50 mg. In one embodiment, such a dosing regimen provides an average serum concentration of ibogaine of about 50 ng/mL to about 180 ng/mL. In one embodiment, the one or more additional doses maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL
over a period of time. In one embodiment, the one or more additional doses are administered periodically.
[0126] Furthermore, at very low doses, direct blood stream delivery of ibogaine may reduce symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders, or provide regulation of food intake. Such dosing is well below that previously described.
Direct blood stream delivery of ibogaine enhances the amount of ibogaine delivered to the brain, because ibogaine does not pass through the liver as it does when ingested. Direct blood stream delivery of ibogaine includes sublingual, pulmonary and intranasal delivery where the ibogaine is absorbed directly into the blood stream and then into the brain.
The rapid delivery of ibogaine into the brain, e.g. less than about 15 minutes, may cause a significant reduction in symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders, or food cravings.
[0127] In one aspect, this invention relates to treating anxiety disorders, impulse control disorder, anger/violence-related disorders, or regulation of food intake in a patient in need thereof comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, solvate, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, this invention treats an anxiety disorder. In one embodiment, this invention treats OCD. In one embodiment, this invention treats generalized anxiety disorder. In one embodiment, this invention treats social anxiety disorder. In one embodiment, this invention treats panic disorder. In another embodiment, this invention treats impulse control disorder. In another embodiment, this invention treats pathological anger and/or violence. In another embodiment, this invention treats anger/violence-related disorders. In another embodiment, this invention reduces pathological anger in a patient. In another embodiment, this invention reduces violent outbursts in a patient. In another embodiment, this invention regulates food intake. In one embodiment, food consumption is reduced. In one embodiment, food cravings are reduced. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
[0128] In some embodiments, the therapeutic dose of ibogaine or pharmaceutically acceptable salt ancUor solvate thereof administered to the patient is sufficient to provide a serum concentration of about 1000 to about 6000 ng*hour/mL. In some embodiments the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide a maximum serum concentration (Cmax) of less than about 250 ng/mL. In a preferred embodiment, the therapeutic dose provides a Cmax of about 100 ng/mL to about 200 ng/mL.
[0129] In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 180 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 110 ng/mL. In one embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 100 ng/mL. In one embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of less than about 50 ng/mL.
[0130] In one aspect, provided herein is a method for treating an anxiety-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0131] In one embodiment, the anxiety-related disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and social anxiety disorder.
[0132] In another aspect, provided herein is a method for treating an impulse control disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine scrum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT
interval of less than about 500 ms during said treatment.
[0133] In one embodiment, the impulse control disorder is selected from the group consisting of borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder, attention deficit disorder, schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, internet addiction, trichotillomania, pathological skin picking, and compulsive shopping.
[0134] In another aspect, provided herein is a method for regulating food intake and/or attenuating food craving in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt ancUor solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine serum level of between about 50 ng/mL and about 180 ng/mL
while maintaining a QT interval of less than about 500 ms during said treatment.
[0135] In another aspect, provided herein is a method for treating an anger-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, and further wherein the therapeutically effective amount provides an efficacious average ibogaine serum level of between about 50 ng/mL and about 180 ng/mL
while maintaining a QT interval of less than about 500 ms during said treatment.
[0136] In one embodiment, the method comprises:
a) administering an initial dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng/mL to about 180 ng/mL; and b) administering at least one additional dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of about 50 ng/mL to about 180 ng/mL
for a period of time.
101371 In one embodiment, the initial dose is from about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from about 6 hours to about 24 hours after the previous dose.
[0138] In another embodiment, the QT interval is less than about 450 ins. In another embodiment, the method further comprises selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
[0139] In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery.
101401 In another embodiment, ibogaine or a pharmaceutically acceptable salt and/or solvate thereof is administered.
101411 In some embodiments, the maintenance dose of ibogaine is 5 mg to 100 mg. In some embodiments, the maintenance dose of ibogaine is about 1.5 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 1 mg/kg body weight. In some embodiments, the maintenance dose of ibogaine is about 0.9 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.8 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.7 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.6 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.5 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.4 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.3 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.2 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.1 mg/kg body weight.
Compounds Administered [0142] In the various method, formulation and kit aspects and embodiments, in one embodiment a compound utilized herein is represented by, or ibogaine as used herein is replaced by, a compound Formula 1:
X
wherein R is hydrogen or Ci-C3-alkoxy, RI is hydrogen, Ci-C3-alkyl, C1-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH, and X is H, COOH, or COOR2, where R2 is C1-C6 alkyl or (CH2CH20).CH3, where n = 1 to 3.
[0143] In another embodiment, ibogaine or a pharmaceutically acceptable salt and/or solvate thereof is utilized. In another embodiment, ibogaine or a pharmaceutically acceptable salt and/or solvate thereof is utilized. In another embodiment, the ibogaine, ibogaine derivative, is chosen from the group consisting of ibogaine, coronaridine, ibogamine, voacangine, 18-methoxycoronaridine, 2-methoxyethy1-18-methoxycoronaridinate, methylaminocoronatidine or a pharmaceutically acceptable salt and/or solvate thereof.
[0144] In another embodiment, the compound utilized herein is chosen from the group consisting of ibogaine, coronaridine, ibogamine, voacangine, 18-methoxycoronaridine, 2-methoxyethyl-18-methoxycoronaridinate, 18-methylaminocoronaridine and a pharmaceutically acceptable salt and/or solvate.
[0145] In another embodiment, the compound utilized herein is selected from the group consisting of 16-hydroxymethy1-18-hydroxyibogaline, 16-hydroxymethy1-18-methoxyibogaline, 16-ethoxycarbony1-18-hydroxyibogaline laurate, and 16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxymethyl ether and a pharmaceutically acceptable salt and/or solvate thereof.
[0146] In one embodiment, the ibogaine derivative is represented by Formula II:
II
ss, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is hydrogen or C1-C3 alkoxy;
RI is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, (CH2)õ,0C(0)alkyl, (CH2)OH, (CH2).0a1kyl, (CH2).,0(CH2)p0(CH2),P(CH2),CH3 or CH2-Y-CH3 where each of m, p and q is 1,2 or 3; and r is 0, 1 or 2,Y is 0 or NH; and R2 is H, (CH2)õOH, COOH, or COOR4, where R4 is C1-C6 alkyl or (CH2CH20)õCH3, where n is 1, 2, or 3.
[0147] In one embodiment, the ibogaine derivative is selected from the group consisting of coronaridine, ibogamine, voacangine, 18-methoxycoronaridinc, 2-Methoxycthy1-18-methoxycoronaridinate, and 18-Methylaminocoronaridine.
[0148] In one embodiment, the ibogaine derivative is selected from the group consisting of 16-hydroxymethy1-18-hydroxyibogaline, 16-hydroxymethy1-18-methoxyibogaline, 16-ethoxycarbony1-18-hydroxyibogaline laurate, and 16-ethoxycarbony1-18-hydroxyibogaline methoxyethoxymethyl ether.
[0149] In one embodiment, the compound is of Formula IA:
X
IA
wherein R is hydrogen or CI-C3-alkoxy, RI is hydrogen, Ci-C3-alkyl, Ci-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH, and X is H, COOH, or COOR2, where R2 is Cl-C6 alkyl or (CH2CH20),CH3, where n = 1 to 3.
[0150] In another embodiment, the ibogaine derivative is represented by Formula II:
s, II
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is OCH3;
RI is CH2CH3; and R2 is COOR4, where R4 is (CH2CH20)nCH3, where n is 1.
[0151] When replacing ibogaine, the compounds of formula I, It and subformulas thereof as utilized herein exclude ibogaine.
[0152] In a preferred embodiment, the compound utilized herein is:
a pharmaceutically acceptable salt thereof, or a solvate of each thereof.
[0152A] In another aspect, provided herein is a use of a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating nicotine addiction in a patient in need thereof, wherein said therapeutically effective amount is from about 50 ng to less than 10 jig per kg body weight per day.
Date Recue/Date Received 2021-07-21 [0152B] In another aspect, provided herein is a use of a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating nicotine addiction in a patient in need thereof, wherein said therapeutically effective amount is from about 50 ng to less than 10 pg per kg body weight per day.
[0152C] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating alcohol dependence in a human patient suffering therefrom, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.
[0152D] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating alcohol dependence in a human patient suffering therefrom, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.
[0152E] In another aspect, provided herein is a use of a therapeutic dose of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, wherein said therapeutic dose provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
10152F1I In another aspect, provided herein is a use of a therapeutic dose of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, wherein said therapeutic dose provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
36a Date Recue/Date Received 2021-07-21 [0152G] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer physically dependent on alcohol.
[0152H] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer physically dependent on alcohol.
[01521] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
10152J1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152K] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mI, to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
36b Date Recue/Date Received 2021-07-21 [0152L1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0152M] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
[0152N] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
[01520] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating opioid or opioid-like drug abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152P1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating opioid or opioid-like drug abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic 36c Date Recue/Date Received 2021-07-21 dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0152Q] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating substance abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0152R] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating substance abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL
to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152S] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
10152T1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mI, to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
36d Date Recue/Date Received 2021-07-21 [0152U1 In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of substance abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the substance.
[0152V1 In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of substance abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the substance.
10152W1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating substance abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152X1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating substance abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0152Y] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, wherein said therapeutic dosage is formulated for interruption or concurrent administration with said opioid analgesic 36e Date Recue/Date Received 2021-07-21 therapy to provide an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
10152Z] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, wherein said therapeutic dosage is formulated for interruption or concurrent administration with said opioid analgesic therapy to provide an average serum concentration of about 50 ng/mL to about 500 ng/mI ., said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
10152AA1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152B1311 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152CC] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, 36f Date Recue/Date Received 2022-05-30 said dosage being sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 500 ms during said treatment.
[0152DDI In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[1:1152EE] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is about 70% or less than the therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt, where the therapeutic dosage is the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt of from about 1 mg/kg to about 4 mg/kg body weight per day, said maintenance dosage being formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
[0152FF1 In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is about 70% or less than the therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt, where the therapeutic dosage is the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt of from about 1 mg/kg to about 4 mg/kg body weight per day, said maintenance dosage being formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
36g Date Recue/Date Received 2022-11-07 DETAILED DESCRIPTION
[0153] It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of this invention will be limited only by the appended claims.
[0154] The detailed description of the invention is divided into various sections only for the reader's convenience and disclosure found in any section may be combined with that in another section. Unless defined otherwise, all technical and scientific terms used herein have 36h Date Recue/Date Received 2022-05-30 the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
101551 It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes a plurality of compounds.
Definitions [0156] Unless defined otherwise, all technical and scientific tet Ins used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings.
[0157] The term "about" when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( +) or ( - ) 10 %, 5 % or 1 % or any subrange or subvalue there between.
[0158] "Administration" refers to introducing an agent, such as ibogainc, into a patient.
Typically, an effective amount is administered, which amount can be determined by the treating physician or the like. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used. The agent may be administered by direct blood stream delivery, e.g. sublingual, intranasal, or intrapulmonary administration.
[0159] The related terms and phrases "administering" and "administration of", when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
[0160] "Periodic administration" or "periodically administering" refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of ibogainc or salt and/or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.
[0161] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of' when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of' shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
[0162] As used herein, is a single bond or a double bond.
[0163] As used herein, the term "alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((C113)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CI3)2CHCH2-), sec-butyl ((CH3)(C113CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). The term "Cx alkyl" refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C3 refers to an alkyl group having 3 carbon atoms.
[0164] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, R20_c(0)_, _ NR2 C(0)R2 , R20_C(0)¨u_, _ NR2 R20, _C(0)NR20R20 , -C(S)NR20R20, -NR20C(0)NR20R20, _met (S)NR2 R2 0, -0-C(0)NR20R20 , S(0)2NR20R20, _o_s(0)2NR20R20, _N¨K 20 _ S(0) 2NR2 R 20, _ C (=NR2 ) NR20K 20, aryl, aryloxy, arylthio, azido, carboxyl, -C(0)0-R21, -NR20-C(0)0-R21, -0-C(0)0-R21, cyano, cycloalkyl, 2, cycloalkyloxy, cycloalkylthio, _NR2OceNR20)N(R20) halo, hydroxy, hydroxyamino, _NR2o-NR2o¨K2o, alkoxyamino, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl, SO3H, -0S(0)2-R21, -s(o)2-R21, _c (s)--K 21, thiocyanate, thiol, and alkylthio; each R2 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R2 groups attached to a common atom are optionally joined together with the atom bound thereto to form a heterocycle; and each R21 is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle.
[0165] "Alkoxy" refers to the group -0-alkyl wherein alkyl is defined herein.
Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
[0166] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(41-1)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
101671 "Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, -C(0)-R20, _NR20c(0)R20, R20-C(0)0-, - ONR2 K20, C(0 )NR20K- 20, _ C(S)NR2oR20, _NR20c(o)NR20R20, _N.-.K 20-U(S)NR213R2 o, -0-C(0)NR20R20, -S(0)2NR2o-K, _ 20 O-S (0)2NR
20R20, _N¨K 20_ S(0)2NR2 R20, _G(=NR20)NR20-K 20, aryl, aryloxy, arylthio, azido, carboxyl, -C(0)0_R21, _NR20 _ C(0)0-R21, -0-C(0)0-R21, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, -NR20c(=NR20)N)(R20, 2, halo, hydroxy, hydroxyamino, alkoxyamino, -NR2ONR20¨ 20, K heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl, S011-1, -0S(0)2-R21, -S(0)2_R21, -C(S)-R21, thiocyanate, thiol, and alkylthio; each R2 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R2 groups attached to a common atom are optionally joined together with the atom bound thereto to form a heterocycle; and each R21 is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle.
[0168] "Cyano" refers to the group -CN.
[0169] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 or 3 to 8 carbon atoms having single or multiple cyclic rings including fused, bridged, and Spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicycle[2,2,2doctanyl, norbomyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl.
[0170] "Substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkoxy, -C(0)-R20, -NR2oc(o)R2o, R20-C(0)0_, _NR20R20, _ C(0)NR2 R20, _C(S)NR2()R20, -NR20c(0)NR2oR2o, _N.-.K 20¨
U(S)NR2 R2 o, -0-C(0)NR20R20, ¨
S(0)2NR20 R20, _o_s(0)2NR2OR20, _N¨K 20_ S(0) 2NR2 R 20, _ C(=NR20)NR20¨x 20, aryl, aryloxy, arylthio, azido, carboxyl, -C(0)0-R21, _NR 20 -C(0)0-R21, -0-C(0)0-R21, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, -NR20C(=NR20)N(R20, ) halo, hydroxy, hydroxyamino, alkoxyamino, -NR20NR20¨K 20, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, hetcrocyclylthio, nitro, spirocycloalkyl, SO3H, -0S(0)2-R21, -S(0)2-R21, -C(S)-R21, thiocyanate, thiol, and alkylthio;
each R2 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R2 groups attached to a common atom are optionally joined together with the atom bound thereto to form a heterocycle; and each R21 is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle.
[0171] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
[0172] "Haloalkyl" refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein.
[0173] "Heteroaryl" refers to an aromatic group of from 5 to 14 ring atoms, including from 1 to 10 carbon atoms and 1 to 4 heteroatorns selected from the group consisting of oxygen, nitrogen and sulfur. In some embodiments, heteroaryl comprises 5, 6, or 7 ring atoms, including 1 to 4 heteroatoms. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N¨>0), sulfinyl, and/or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and fiiranyl.
[0174] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
101751 "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyr refers to a saturated or partially saturated, but not aromatic, group having from 3 to 14 ring atoms, including from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. In some embodiments, heteroaryl comprises 3, 4, 5, 6 or 7 ring atoms, including 1 to 4 heteroatoms. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and Spiro ring systems.
In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfmyl, and/or sulfonyl moieties.
[0176] "Substituted heterocyclic" or "substituted hetcrocycloalkyl" or "substituted heterocycly1" refers to heterocycly1 groups that are substituted with flbm 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
[01771 "Ibogaine" refers to the compound:
It should be understood that where "ibogaine" is mentioned herein, one more polymorphs of ibogaine can be utilized and are contemplated. lbogaine is isolated from Tabernanth iboga, a shrub of West Africa. lbogaine can also be synthesized using known methods.
See, e.g., Biichi, etal. (1966), J. Am. Chem Society, 88(13), 3099-3109 Unless specified otherwise, "ibogaine" as used herein refers to ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
[0178] In some embodiments, the ibogaine or ibogaine derivative is represented by Formula or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is H, halo, C1-C3 alkyl, substituted C1-C3 alkyl, OR1 , NH2, NHR1 , NR10R11, NHC(0)R10, or NR1 C(0)R11;
R1 is H, C1-C3 alkyl, substituted CI-C3 alkyl, C1-C3 alkoxy, CH2-X-CH, or (CH2),,,,R3;
R2 is H, COOH, COOR4, (CH2).0H, CH(OH)R5, CH2OR5, C(0)NH2, C(0)NHR5, C(0)NR5R6, C(0)NHNH2, C(0)NHNHR5, C(0)NHNR5R6, C(0)NR5NH2, C(0)NR5NHR6, C(0)NR5NR6R7, C(0)NHNH(C(0)R5), C(0)NHNR5(C(0)R6), C(0)NR5NH(C(0)R6), C(0)NR5NR6(C(0)R7), CN, or C(0)R5;
RI is C1-C3 alkyl, benzyl, substituted Ci-C3alkyl, YH, YR8, YC(0)R8, C(0)YR8, C(0)NH2, C(0)NHR8, C(0)NR8R9, NH2, NHR8, NR8R9, NHC(0)R8, 0(CH2)p0(CH2),10(CH2)rCH3 or NR8C(0)R9;
R4 is C1-C6 alkyl or (CH2CH20)na-13;
R5, R6, R7, R8, R9, R1 , and Ri 1 are independently alkyl or substituted alkyl;
K is H, alkyl, or substituted alkyl;
R13 is H, OR1 , alkyl, or substituted alkyl;
Xis 0 or NH;
YisOorS;
m is an integer selected from 0-8;
each of n, p and q is 1, 2 or 3; and ris0,1or2.
[0179] In some embodiments, the ibogaine or ibogaine derivative is represented by Formula or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is hydrogen or CI-C:3 alkoxy, RI is hydrogen, Ci-C3 alkyl, Ci-C3 alkoxy, (CH2).0C(0)alkyl, (CH2).0H, (CH2)mOalkyl, (CH2),,,O(CH2)p0(CH2)0(CH2)1CH3 or CH2-Y-CH3 where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is 0 or NH, and R2 is H, (CH2)õ0H, COOH, or COOR4, where R4 is C1-C6 alkyl or (CH2CH20)11CH3, where n is 1, 2, or 3.
[0180] In one embodiment, R is methoxy. In one embodiment, RI- is ethyl. In one embodiment, RI is methoxy. In one embodiment, RI is CH2-Y-CH3 where Y is 0. In one embodiment, Itt is CH2-Y-CH3 where Y is NH. In one embodiment, R2 is hydrogen.
In one embodiment, In one embodiment, R2 is COOR4 and R4 is methyl. In one embodiment, n = 1.
In a preferred embodiment, R, RI and R2 are all not hydrogen. In one embodiment, when R is methoxy and R1 is hydrogen, then R2 is COOH or COOR4. In another embodiment, when R
is methoxy and RI is hydrogen, then X is COOR4 where R4 is (CH2CH20)CH3.
[0181] In one embodiment, R12 is hydrogen.
[0182] In one embodiment, le is H. In one embodiment, RI is C1-C3 alkyl, such as ethyl.
In one embodiment, RI is CH2CH2OH. In one embodiment, RI is CH2CH2OCH3. In one embodiment, RI is CH2CH20CH2Ph. In one embodiment, Rl is CH2CH20C(0)alkyl. In one embodiment, RI is CH2CH20(CH2)p0(CH2)40(CH2),CH3.
[0183] In one embodiment, R2 is CH2OH and CH(OH)R5. In one embodiment, R2 is CH2OR5. In one embodiment, R2 is CO2R5. In one embodiment, R2 is C(0)NH2, C(0)NHR5, or C(0)NR5R6. In one embodiment, R2 is C(0)NHNH2, C(0)NHNHR5, C(0)NR5NH2, C(0)NHNR5R6, C(0)NH5NHR6, or C(0)NR5NR6R7. In one embodiment, R2 is C(0)NHNH(C(0)R5), C(0)NHNR5(C(0)R6), C(0)NR5NH(C(0)R6), or C(0)NR5NR6(C(0)R7). In one embodiment, R2 is C(0)R5.
[0184] In some embodiments, the ibogaine or ibogaine derivative is selected from:
Name Structure coronaridine 1 8-hydroxycoronaridine OH
1 8-methoxycoronaridine OCH3 18-benzyloxycoronaridine 18-hydroxycoronaridine laurate 0 (CH2)ioCH3 18-hydroxycoronaridine methoxyethoxymethyl ether 18-hydroxycoronatidine acetate voacangine 18-hydroxyvoacangine OH
18-methoxyvoacangine OCH3 18-benzyloxyvoacangine 18-hydroxyvoacangine laurate (CH2)10CH3 18-hydroxyvoacangine acetate 18-hydroxyvoacangine methoxyethoxyrnethyl ether conopharyngine 18-hydroxyconopharyngine OH
18-methoxyconopharyngine OCH3 18-benzyloxyconopharyngine 18-hydroxyconopharyngine laurate (CH2)1oCH3 18-hydroxyconopharyngine acetate 18-hydroxyconopharyngine methoxyethoxymethyl ether 0 ibogamine 16-ethoxycarbony1-18- OH
hydroxyibogamine = 02CH2CH3 16-hydroxymethy1-18- OH
hydroxyibogamine = H2OH
16-ethoxycarbony1-18- OCH3 methoxyibogamine = 020H2CH3 16-hydroxyrnethyl- 18-methoxyibogamine = H2OH
16-ethoxycarbony1-18-benzyloxyibogamine 0 .3 16-ethoxycarbony1-18- 0 (CH2)10CH3 hydroxyibogamine latuate = 02CH2CH3 16-ethoxycarbony1-18-hydroxyibogamine acetate = 02CH2CH3 16-ethoxycarbony1-18-hydroxyibogamine methoxyethoxymethyl ether ibogaine 16-ethoxycarbony1-18- OH
hydroxyibogaine = 02CH2CH3 1 6-hydroxymethy1-1 8- OH
hydroxyibogaine = H2OH
16-ethoxycarbony1-18- 0, methoxyibogaine 16-hydroxyrnethyl- 18-methoxyibogaine 16-ethoxycarbony1-18-benzyloxyibogaine 0 16-ethoxycarbony1-18-)1111 hydroxyibogainelaurate 16-ethoxycarbony1-18-hydroxyibogaine acetate 16-ethoxycarbony1-18-hydroxyibogaine methoxyethoxymethyl ether ibogaline 16-ethoxycarbony1-18- OH
hydroxyibogaline '0 16-hydroxymethy1-18- OH
hydroxyibogaline 16-ethoxycarbony1-18- OCH3 methoxyibogaline "0 16-hydroxymethy1-18- OCH3 methoxyibogaline 16-ethoxycarbony1-18-benzyloxyibogaline 0 16-ethoxycarbony1-18- (CH2)1oCH3 hydroxyibogalinc lauratc 16-ethoxycarbony1-18-hydroxyibogaline acetate 16-ethoxycarbony1-18-hydroxyibogaline 0 methoxyethoxymethyl ether "0 and pharmaceutically acceptable salts and/or solvates thereof.
101851 This invention is not limited to any particular chemical form of the compounds, and the drug may be given to patients either as a free base, solvate, or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used.
Examples of such acids include, without limitation, those described below as "pharmaceutically acceptable salts" and the like.
101861 In one embodiment, the ibogaine derivative is:
(coronaridine), (ibogamine), (voacangine), 0, (18-methoxycoronaridine, 18-MC), 0, (2-Methoxyethyl- 1 8-methoxycoronaridinate, ME-1 8-MC), or N, (18-Methylaminocoronaridine, 18-MAC).
[0187] "Pharmaceutically acceptable composition" refers to a composition that is suitable for administration to a mammal, particularly, a human. Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.
[0188] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
[0189] A "pharmaceutically acceptable solvate" or "hydrate" of a compound of the invention means a solvate or hydrate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, and includes, but is not limited to, complexes of a compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
[0190] As used herein the term "solvate" is taken to mean that a solid-form of a compound that crystallizes with one or more molecules of solvent trapped inside. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but arc certainly not limited to, water, methanol, ethanol, isopropanol, butanol, Cl-C6 alcohols in general (and optionally substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention. Additionally, various organic and inorganic acids and bases can be added or even used alone as the solvent to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate. Further, by being left in the atmosphere or recrystallized, the compounds of the present invention may absorb moisture, may include one or more molecules of water in the formed crystal, and thus become a hydrate.
Even when such hydrates are formed, they are included in the term "solvate". Solvate also is meant to include such compositions where another compoi id or complex co-crystallizes with the compound of interest.
[0191] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate, or derivative of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of ibogaine, in the context of treating nicotine dependency, refers to an amount of the ibogaine that attenuates the dependency and/or statistically presents little or no risk of relapse to nicotine use. For example, and without limitation, a therapeutically effective amount of ibogaine, in the context of treating alcohol dependency, refers to an amount of ibogaine that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of ibogaine in the context of treating opioid or opioid-like drug dependency, refers to an amount of compound that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of ibogaine in the context of treating drug dependency, refers to an amount of compound that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of ibogaine, in the context of treating pain, refers to an amount of ibogaine that provides immediate and/or sustained pain relief for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of an agent, in the context of treating anxiety disorders, impulse control disorder, and/or anger/violence-related disorders, refers to an amount of the agent that attenuates the anxiety disorder, impulse control disorder, or anger/violence-related disorders, and/or symptoms thereof, in the patient.
A therapeutically effective amount of an agent, in the context of regulating food intake and/or controlling food cravings, refers to an amount of the agent that reduces the patient's food intake and/or reduces food cravings in the patient.
[0192] A "therapeutic level" of a drug is an amount of ibogaine that is sufficient to treat a disease or disorder or symptoms of a disease or disorder or to heat, prevent, or attenuate a disease or disorder or symptoms of a disease or disorder, but not high enough to pose any significant risk to the patient. Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient.
This concentration is referred to as the "serum concentration." Where the serum concentration of ibogaine is mentioned, it is to be understood that the term "ibogaine"
encompasses any form of ibogaine, including derivatives thereof.
101931 As defined herein, a "prophylactically effective amount" of a drug is an amount, typically less than the therapeutically effective amount, that provides attenuation and/or prevention of a disease or disorder or symptoms of a disease or disorder in a patient. For example, the prophylactically effective amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer physically addicted to nicotine. For example, a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount. However, a prophylactically effective amount may be the same as the therapeutically effective amount, for example when a patient who is physically addicted to nicotine is administered ibogaine to attenuate cravings for a period of time when nicotine use is not feasible. The prophylactically effective amount may vary for different a diseases or disorders or symptoms of different diseases or disorders.
[0194] As defined herein, a "maintenance amount" of a drug is an amount, typically less than the therapeutically effective amount that provides attenuation and/or prevention of a disease or disorder or symptoms of a disease or disorder in a patient. The maintenance amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer manifests a disease or disorder or symptoms of a disease or disorder. For example, a maintenance amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount. However, a prophylactically effective amount may be the same as the therapeutically effective amount, for example when a patient who is physically addicted to nicotine is administered ibogaine to attenuate cravings for a period of time when nicotine use is not feasible., or any subvalue or subrange there between.
[0195] "Treatment", "treating", and "treat" are defined as acting upon a disease, disorder, or condition with ibogaine to reduce or ameliorate harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. "Treatment," as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the condition but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition. "Treating" or "treatment of' a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to: treating nicotine addiction; treating, preventing, and/or attenuating cravings for nicotine; and preventing relapse of nicotine use. This includes reducing or eliminating smoking in the patient, and/or reducing or eliminating symptoms of withdrawal, cravings, and the like. For some purposes of this invention, beneficial or desired clinical results include, but arc not limited to: treating substance addiction;
treating, preventing, and/or attenuating acute withdrawal symptoms; treating, preventing, and/or attenuating long-term (post-acute) withdrawal symptoms; and preventing relapse of substance use. For purposes of certain aspects of this invention, beneficial or desired clinical results include, but are not limited to: pain relief in all categories and classifications of pain;
treating, alleviating and/or preventing acute and/or chronic pain; treating, alleviating and/or preventing cutaneous, somatic, visceral and/or neuropathic pain; and preventing the recurrence of long-term pain.
[0196] "Periodic administration" or "periodically administering" refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.
[0197] As used herein, the terms "addiction", "abuse", and "dependence" are used interchangeably to refer to the patient's inability to stop using nicotine, alcohol, a drug, or the like, even when it would be in his/her best interest to stop. A patient may be physically and/or behaviorally addicted to a substance. The DSMIV-TR criteria for dependency include:
Dependence or significant impairment or distress, as manifested by 3 or more of the following during a 12 month period:
1. Tolerance or markedly increased amounts of the substance to achieve intoxication or desired effect or markedly diminished effect with continued use of the same amount of substance 2. Withdrawal symptoms or the use of certain substances to avoid withdrawal symptoms 3. Use of a substance in larger amounts or over a longer period than was intended 4. Persistent desire or unsuccessful efforts to cut down or control substance use 5. Involvement in chronic behavior to obtain the substance, use the substance, or recover from its effects 6. Reduction or abandonment of social, occupational or recreational activities because of substance use 7. Use of substances even though there is a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance [0198] As used herein, the term "nicotine addict in remission" refers to any patient who has quit using nicotine for a period of time. As used herein, a nicotine addict in remission includes any person who was previously addicted to nicotine in any form, including but not limited to cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. The period of time since the nicotine addict in remission quit using nicotine may be short, for example one day to a few weeks, or longer-term, for example months or years. Preferably, the patient has quit using nicotine long enough to no longer exhibit physical symptoms of nicotine addiction. The patient may exhibit psychological symptoms of nicotine addiction. In some embodiments, the patient does not exhibit psychological symptoms of nicotine addiction.
101991 As used herein, the term "patient" refers to mammals and includes humans and non-human mammals.
[0200] As used herein, the terms "addictive substance", "drug", "addictive drug" and the like refer to drugs and other substances whose use results in addiction in at least a subset of individuals who use them. Addictive substances include, without limitation, benzodiazepines (including chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, and midazolam), cannabinoids and synthetic cannabinoids, stimulants (including amphetamine, methylphenidate, dexmethylphenidate, dextroamphetamine, mixed amphetamine salts, dextromethamphetamine, lisdexamfetamine, modafinil, adrafinil, armodafinil, caffeine, ephedrine, methylenedioxymethamphetamine, methylenedioxypyrovalerone, mephedrone, phenylpropanolamine, propylhexachine, pseudo ephedrine, and khat), barbiturates (including allobarbital, amobarbital, aprobarbital, alphenal, barbital, brallobarbital, pentobarbital, phenobarbital, and secobarbital), gamma-hydroxybutyrate (GHB), ketamine, opiate, opioid, opioid-like drug, PCP, dextromethorphan (DXM), lysergic acid diethytamide (LSD), mescaline, anabolic steroids, and derivatives of each thereof Addictive substances may be illicit drugs, prescription drugs prone to abuse, or other legal drugs prone to abuse."
[0201] As used herein, the term "opiate" refers to naturally-occurring alkaloids found in the opium poppy. These include codeine, morphine, oripavirte, pseudomorphine, and thebaine.
Also included are opium, opium poppy, poppy straw, and extracts and concentrates thereof.
[0202] As used herein, the term "opioid" refers to naturally-occurring opiates and synthetic or semi-synthetic opioids that have psychoactive effects. Non-limiting examples include acetyl-alpha-methylphentanyl, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprodine, anileridine, benzylmorphine, benzethidine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butorphanol, earfentanil, clonitazene, codeine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diethylthiambutene, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethyl-thiambutene, dioxaphetyl butyrate, diphenoxylate, difenoxin, dipipanone, eptazocine, ethohcptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levo-alphacetylmethadol, levomethorphan, levorphanol, levophenacylmorphan, levomoramide, lofentani1, loperamide, laudanum, mepeiidine, meptazinol, metazocine, methadone, 3-methylfentanyl, 3-methylthiofentanyl, metopon, morphine, morpheridine, MPPP (1-methyl-4-phenyl-4-propionoxypiperidine), myrophine, narceine, nicomorphine, noracymethadol, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, para-fluorofentanyl, paregoric, PEPAP (14-2-phenethyl)-4-phenyl-4-acetoxypiperidine), pentazocine, phenadoxone, phenampromide, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, racemoramide, racemethorphan, racemorphan, remifentanil, sufentanil, tapentadol, thebaine, thiofentanyl, tilidine, tramadol, trimeperidine, mixtures of any of the foregoing, salts of any of the foregoing, derivatives of any of the foregoing, and the like. The term opioids also encompasses opioid intermediates, including 4-cyano-2-dimethylamino-4,4-diphenyl butane, 2-methy1-3-morpholino-1,1-diphenylpropane-carboxylic acid, 4-cyano-1-methyl-4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate, and 1-methy1-4-phenylpiperidine-4-carboxylic acid. Many opioids are Schedulel or Schedule II drugs in the US.
102031 As used herein, the term "opioid-like drug" refers to any illicit drug that binds to one or more opioid receptor and causes opioid-like addiction. Acute and long-term withdrawal symptoms from cessation of use of such drugs may be similar to those from cessation of opioids. Opioid-like drugs include amphetamine, methamphetamine, ketamine, and cocaine.
[0204] Obsessive compulsive disorder (OCD) is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic ancUor repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, and/or significantly interfere with social or occupational functioning.
[0205] Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a). A panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
102061 Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a).
Exposure to the feared situation almost invariably provokes anxiety, which may appioach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) int erferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
102071 Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM-IV
(American Psychiatric Association, 1994a).
[0208] Impulse control disorder is a class of psychiatric disorders involving the failure to resist a temptation, urge, or impulse (impulsivity) where such impulse is potentially harmful to the patient and/or others. The American Psychiatric Association's DSM-5 (May 2013) includes impulse control disorders "characterized by problems in emotional and behavioral self-control".
These include borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, intemet addiction, trichotillomania, pathological skin picking, and compulsive shopping. Impulse control disorder may be related to anxiety disorder and/or OCD.
[0209] Violence and anger, particularly when out of proportion to a stimulus and/or a result of pathological anger, are associated with a number of mental disorders. These include oppositional defiant disorder, attention-deficit/hyperactivity disorder and conduct disorder (in Date Recue/Date Received 2021-07-21 children and adolescents), psychotic disorder, bipolar disorder, antisocial, borderline, paranoid and narcissistic personality disorders, adjustment disorder with disturbance of conduct, and intermittent explosive disorder. Pathological anger and violence account for a significant portion of violent crimes, including many high-profile crimes involving multiple victims. Hidhly volatile individuals are over-represented in the prison system in the United States.
[0210] As used herein, the term "pain" refers to all categories and classifications of pain, which are summarized below for purposes of illustration. First, cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localized pain of short duration. Example injuries that produce cutaneous pain include paper cuts, minor burns (e.g., first degree burns) and superficial lacerations.
[0211] Second, somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves, and is detected with somatic nociceptors. The scarcity of nociceptors in these areas produces a sharp, aching, pain of longer duration than cutaneous pain and somewhat less localized. Examples include a sprained ankle or broken bones.
[0212] Third, visceral pain originates from body organs. Visceral nociceptors are located within body organs and internal cavities. Similar to somatic pain, a scarcity of nociceptors in these areas produces a pain usually more aching and of a longer duration than somatic pain.
Visceral pain may be more difficult to localize. Injuries to visceral tissue may exhibit "referred" pain, where the sensation is localized to an area completely unrelated to the site of injury. Myocardial ischaemia (i.e., the loss of blood flow to a part of the heart muscle tissue) is an example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm, or hand. Another example of referred pain is phantom limb pain. Phantom limb pain is the sensation of pain from a limb that a person no longer has or from which the person no longer receives physical signals. This phenomena¨
also known as deafferentation pain is almost universally reported by amputees and quadriplegics.
[0213] Fourth, neuropathic pain (e.g., "neuralgia") can occur as a result of injury or disease to the nerve tissue itself. The injury or disease can disrupt the ability of the sensory nerves to transmit correct information to the thalamus or cortex. Consequently, the brain interprets painful stimuli even though there is no obvious or documented physiologic cause for the pain.
[0214] Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain indicates present damage to tissue or disease and may be "fast" and "sharp" followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. Acute pain generally responds well to medications (e.g., morphine).
[0215] Chronic pain may be medically defined as pain that has lasted six months or longer.
This constant or intermittent pain has often outlived its purpose because it does not help the body to prevent injury. It is often more difficult to treat than acute pain.
Expert care is generally necessary to treat any pain that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to control the pain. This can lead to drug dependency. For example, opioids are used in some instances for prolonged periods to control chronic pain. Drug tolerance, chemical dependency, and even psychological addiction may occur.
[0216] The therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood administration (e.g., sublingual, pulmonary and intfanasal delivery) is used, a lower dose of the compound is administered. In one aspect, a therapeutically effective amount of ibogaine or derivative is from about 50 ng to less than 100 pg per kg of body weight.
Where other routes of administration are used, a higher dose of the compound is administered. In one embodiment, the therapeutically effective amount of the compound is from greater than about 1 mg to about 8 mg per kg of body weight per day.
[0217] As used herein, the term "QT interval" refers to the measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. Prolongation of the QT interval refers to an increase in the QT interval.
[0218] "Nociceptive pain" refers to pain that is sensed by nociceptors, which are the nerves that sense and respond to parts of the body suffering from a damage. The nociceptors can signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.
Nociceptive pain is typically well localized, constant, and often has an aching or throbbing quality. A subtype of nociceptive pain includes visceral pain and involves the internal organs.
Visceral pain tends to be episodic and poorly localized. Nociceptive pain may be time limited;
when the tissue damage heals, the pain typically resolves. However, nociceptive pain related to arthritis or cancer may not be time limited. Nociceptive pain tends to respond to treatment with opiate analgesics, such as, for example, buprenorphin, codeine, hydrocodone, oxycodone, morphine, and the like. Examples of nociceptive pain include, without limitation, pains from sprains, bone fractures, burns, bumps, bruises, inflammatory pain from an infection or arthritic disorder, pains from obstructions, cancer pain, and myofascial pain related to abnormal muscle stresses.
[0219] "Neuropathic pain" refers to chronic pain, often due to tissue injury.
Neuropathic pain is generally caused by injury or damage to nerve fibers. It may include burning or coldness, "pins and needles" sensations, numbness and/or itching. It may be continuous and/or episodic. Neuropathic pain is difficult to treat, but opioids, including, without limitation, methadone, tramadol, tapentadol, oxycodone, methadone, morphine, levorphanol, and the like. Causes of neuropathic pain include, without limitation, alcoholism; amputation;
back, leg, and hip problems; chemotherapy; diabetes; facial nerve problems;
HIV/AIDS;
multiple sclerosis; shingles; spine surgery; trigeminal neuralgia;
fibromyalgia; and the like. In some cases, the cause of neuropathic pain may be unclear or unknown.
[0220] "Addictive" refers to a compound that, when administered to a mammal over a period of time, creates dependency in the mammal to that compound. The dependence can be physiological and/or psychological. A therapeutic effect of an addictive compound on a mammal may decrease with prolonged administration of the addictive compound, which is a non-limiting example of a physiological dependence. When administered to a mammal, an addictive compound may also create a craving in the mammal for more of it, which is a non-limiting example of a psychological dependence. Examples of addictive compounds include, without limitation, addictive opioids, and the like.
[0221] "Analgesic" and "analgesic agent" refer to a compound that is capable of inhibiting and/or reducing pain in mammals. Pain may be inhibited and/or reduced in the mammal by the binding of the opioid analgesic agent to the mu receptor. When analgesia is effected through the mu receptor, the analgesic agent is referred to as a mu receptor agonist. Certain analgesic agents are capable of inhibiting nociceptive and/or neuropathic pain including, by way of example, morphine, codeine, hydromorphone, oxycodone, hydrocodone, buprenorphin, and the like.
[0222] The term "tolerance" as used herein refers to the psychological and/or physiologic process wherein the patient adjusts to the frequent presence of a substance such that a higher dose of the substance is required to achieve the same effect. Tolerance may develop at different times for different effects of the same drug (e.g., analgesic effect versus side effects). The mechanisms of tolerance are not entirely understood, but they may include receptor down-regulation or desensitization, inhibitory pathway up-regulation, increased metabolism, and/or changes in receptor processing (e.g., phosphorylation).
[0223] The therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood administration (e.g., sublingual, pulmonary, buccal, or intranasal delivery) is used, a lower dose of the compound is administered. In one aspect, a therapeutically effective amount of ibogaine or derivative is from about 50 ng to less than about 100 gg per kg of body weight.
Where other routes of administration are used, a higher dose of the compound is administered. In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 4 mg per kg of body weight per day.
[0224] The term "dose" refers to a range of ibogaine, ibogaine derivative, or pharmaceutical salt or solvate thereof that provides a therapeutic serum level of ibogaine when given to a patient in need thereof. The dose is recited in a range, for example from about 20 mg to about 120 mg, and can be expressed either as milligrams or as mg/kg body weight. The attending clinician will select an appropriate dose florin the range based on the patient's weight, age, degree of addiction, health, and other relevant factors, all of which are well within the skill of the art.
[0225] The term "unit dose" refers to a dose of drug that is given to the patient to provide therapeutic results, independent of the weight of the patient. In such an instance, the unit dose is sold in a standard form (e.g., 20 mg tablet). The unit dose may be administered as a single dose or a series of subdoses. In some embodiments, the unit dose provides a standardized level of drug to the patient, independent of weight of patient. Many medications are sold based on a dose that is therapeutic to all patients based on a therapeutic window. In such cases, it is not necessary to titrate the dosage amount based on the weight of the patient.
Compositions [0226] As will be apparent to the skilled artisan upon reading this disclosure, in one aspect this invention provides compositions for treating a disease or disorder as described herein in a subject, comprising ibogaine. In another aspect this invention further provides compositions for treating, attenuating, or preventing a disease or disorder or symptoms of a disease or disorder as described herein in a subject, comprising ibogaine.
[0227] This invention is not limited to any particular chemical form of the compounds, and the drug may be given to patients either as a free base, solvate, or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used.
Examples of such acids include, without limitation, those described below as "pharmaceutically acceptable salts" and the like.
102281 In one aspect, the invention provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of ibogaine and a pharmaceutically acceptable excipient, wherein the therapeutically or prophylactically effective amount of ibogainc is an amount that delivers an aggregate amount of ibogaine of about 50 ng to less than 10 lag per kg body weight per day. In some aspects, the therapeutically or prophylactically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 10 jig per kg body weight per day.. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day. Dosing schemes are discussed in further detail below in the subsection titled "Dosing and Routes of Administration."
[0229] In some embodiments, the composition is formulated for sublingual, intranasal, or intrapulmonary delivery. These routes of administration are discussed in further detail below in the subsection titled "Dosing and Routes of Administration."
102301 In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of ibogaine, derivative, or salt and/or solvate thereof and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to less than 100 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogainc is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 50 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 10 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 1 1.1,g per kg body weight per day. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day. The ranges include both extremes as well as any subranges there between.
102311 In some embodiments, the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 8 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 6 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.7 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg per kg body weight per day. The ranges include both extremes as well as any subranges there between.
[0232] In one embodiment, the therapeutically effective amount of the compound is about 8 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 7 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 6 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg/kg body weight per day.
[0233] In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof is an amount that delivers an aggregate amount of ibogaine of about 50 ng to less than 10 'g per kg body weight per day.
[0234] In one embodiment, the therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt thereof is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 1 jig per kg body weight per day.
[0235] In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.7 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about about 2 mg per kg body weight per day. The ranges include both extremes as well as any subrange or subvalue there between.
[0236] In one embodiment, the therapeutically effective amount of the compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg per kg body weight per day.
[0237] In another aspect, provided herein is a pharmaceutically acceptable formulation comprising a unit dose of ibogaine, wherein the amount of ibogaine is sufficient to provide a serum concentration of about 50 ng/mL to about 500 ng/mL when administered to a patient.
Methods of the Invention [0238] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating nicotine addiction, alcohol dependence, drug addiction,pain, depression, impulse control, anxiety, violence/anger, food intake, or tolerance to opioids in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof. This invention further provides a method for treating, attenuating, or preventing a disease or disorder or symptoms of a disease or disorder in a subject amenable to treatment with the compounds utilized herein, comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
a. Treating Nicotine Addiction 102391 In some embodiments, the invention provides, in certain aspect, a method for treating nicotine addiction in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
[0240] The subject or patient may be any patient who uses nicotine in any form, including cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. In some embodiments, the patient is addicted to nicotine. In some embodiments, the patient is physically addicted to nicotine. In some embodiments, the patient is psychologically addicted to nicotine.
[0241] In some embodiments, the therapeutically effective amount of the compound is from about 50 ng to less than 10 g per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 g per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 500 ng to less than 10 lag per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 1 lag to less than 10 ps per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 g, about 2 g, about 3 g, about 3 g, about 4 jug, about 5 g, about 6 g, about 7 g, about 8 g, about 9 jug, about 10 jig per kilogram body weight per day. The therapeutically effective amount of the compound may be any amount within any of these ranges, including endpoints.
[0242] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0243] Where the therapeutically effective amount is administered more than one time per day, a portion of the total therapeutically effective amount is administered at each time. For example, an 90 kg patient taking 1 jig ibogaine per kg body weight per day would take 90 jig once a day, 45 1.1g twice a day, or 30 jig three times a day, etc.
[0244] In some embodiments, the therapeutically effective amount of ibogaine, derivative, or salt and/or solvate thereof is administered once when needed, e.g., when the patient has a craving for nicotine or anticipates to have a craving for nicotine as described herein.
[0245] An ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, suitable for administration in accordance with the methods provide herein, can be suitable for a variety of delivery modes including, without limitation, oral and transdermal delivery. Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutancous and subcutaneous routes may also be used. Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980). In some embodiments, the ibogaine or ibogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
[0246] In a preferred embodiment, ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule foim. In certain embodiments, the compound is provided as a pharmaceutically acceptable salt, for example ibogaine HC1, with dosages reported as the amount of free base compound. In some embodiments, the pharmaceutically acceptable salt is provided in hard gelatin capsules containing only the salt with no excipients.
b. Preventing Relapse Of Nicotine Use [0247] In some embodiments, the invention provides for a method for treating, preventing, or attenuating nicotine cravings in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof. In some embodiments, the invention provides for a method for preventing recurrence of nicotine addiction in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
[0248] In some situations, a patient who has not ceased nicotine use nonetheless is unable to use nicotine for an extended amount of time. For example, most airplane flights no longer allow smoking, and have banned vaporizers and e-cigarettes, as well. Other places and situations where nicotine use is not feasible or is difficult include movie theaters, other entertainment venues (including theater, opera, concerts, and the like), and even workplaces, notably hospitals and schools where smoking may not be allowed anywhere on the property.
In some embodiments, a prophylactically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered before and/or during a period of time when the patient expects to be unable to use nicotine, wherein the ibogaine, derivative, or salt and/or solvate prevents, interrupts, or attenuates cravings for nicotine. In some embodiments, nicotine cravings are attenuated, interrupted, or prevented for at least 2, 3,4, 5, 6, 7, 8, 10, 15, or 24 hours.
[0249] In some embodiments, the ibogaine, derivative, or salt and/or solvate is administered on an as-needed basis by the patient. In some embodiments, the ibogaine, derivative, or salt and/or solvate may be administered before the nicotine craving occurs. For example, the patient may take a dose of ibogaine, derivative, or salt and/or solvate in anticipation of cravings, such as before drinking alcohol, before a stressful situation occurs, or when facing another trigger for nicotine use. In some embodiments, the patient takes a dose of ibogaine, derivative, or salt and/or solvate after the nicotine craving occurs, for example during the craving, in order to reduce or eliminate the craving. In some embodiments, the dose of ibogaine, derivative, or salt and/or solvate is low enough that a patient can take one dose before a craving occurs, and another later the same day if he/she feels or anticipates another craving.
[0250] In one embodiment, the prophylactically effective amount of the compound is from about 50 rig to less than 10 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is film about 50 ng to about 1 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 500 ng per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 100 lag per kilogram body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges, including endpoints.
[0251] In some embodiments, the prophylactically effective amount of ibogaine, derivative, or salt and/or solvate thereof is administered once a day. In some embodiments, the prophylactically effective amount is administered twice per day. In some embodiments, the prophylactically effective amount is administered more than two times per day.
[0252] Where the prophylactically effective amount of ibogaine, derivative, or salt and/or solvate thereof is administered more than one time per day, a portion of the total prophylactically effective amount is administered at each time. For example, an 90 kg patient taking 1 jig ibogaine derivative, or salt and/or solvate per kg body weight per day would take 90 jig once a day, 45 pig twice a day, or 30 ps three times a day, etc.
102531 In some embodiments, the ibogaine or ibogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
c. Alcohol Dependence [0254] In one aspect, this invention relates to treatment of acute withdrawal horn alcohol in an alcohol dependent patient comprising administration of a therapeutically effective amount of ibogaine.
[0255] In one aspect, this invention relates to a method for treating alcohol abuse in an alcohol-dependent patient, comprising administering to the patient a dosage of ibogaine, thereof that piovides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0256] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 60 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
102571 In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of ibogaine that provides an average scrum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
102581 In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about ng/mL. In a preferred embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0259] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0260] In some embodiments, the ibogaine or ibogainc derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
[0261] In some embodiments, the therapeutically effective amount of ibogaine is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule Patin. In certain embodiments, the ibogaine is provided as ibogaine HO, with dosages reported as the amount of free base ibogaine. In some embodiments, the ibogaine HC1 is provided in hard gelatin capsules containing only ibogaine HCl with no excipients.
[0262] In one aspect, this invention relates to treatment or attenuation of post-acute withdrawal from alcohol dependence, and/or symptoms of withdrawal, in an addicted patient by administering a maintenance amount of ibogaine. In some aspects, this invention relates to a method to prevent relapse of alcohol abuse and/or use in an addicted patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine.
[0263] These dosing amounts, including administration of a maintenance amount of ibogaine, are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
d. Drug Addiction [0264] In some aspects, the present invention provides a method for treating substance abuse or addiction, including acute and post-acute withdrawal symptoms, in an addicted patient, comprising administering to the patient a dosage ibogaine.
[0265] In one aspect, this invention relates to treatment of acute withdrawal from an addictive substance in an addicted patient comprising administration of a therapeutically effective amount of ibogaine.
[0266] In one aspect, this invention relates to a method for treating substance abuse in an addicted patient, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL,said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0267] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0268] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0269] In some embodiments, the therapeutic dose of ibogaine is a tapered dosing over a period of time, during which the patient is detoxified, for example, without suffering significant acute withdrawal symptoms. Without being bound by theory, it is believed that tapering will allow the full therapeutic effect of the compound with less prolongation of the QT interval. Tapering involves administration of one or more subsequently lower doses of the compound over time.
[0270] In one aspect, this invention relates to treatment or attenuation of post-acute withdrawal from an addictive substance in an addicted patient with a maintenance amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
[0271] In some aspects, this invention relates to a method to prevent relapse of substance abuse in an addicted patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine.
[0272] In some embodiments, the patient undergoes long-term (e.g., one year or longer) treatment with maintenance doses of ibogaine. In some embodiments, the patient is treated for acute withdrawal with therapeutic doses of ibogaine and then the amount of compound is reduced to maintenance levels after acute withdrawal symptoms would be expected to have subsided. Acute withdrawal symptoms generally are the most pronounced in the first 48 to 72 hours after cessation of the drug of addiction, although acute withdrawal may last as long as a week or more.
e. Pain [0273] In one aspect, this invention relates to treatment of pain in a patient suffering from pain comprising administration of a therapeutically effective amount of ibogaine.
[0274] In one aspect, this invention relates to a method for treating pain in a patient suffering from pain, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient to inhibit or ameliorate said pain. In one embodiment, the dosage of ibogaine results in prolongation of the QT interval of less than about 50 ms. In one embodiment, the dosage of ibogainc results in a QT interval of less than about 500 ms [0275] In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 800 ng/mL or about 20 ng/mL to about 800 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 nWtnL to about 700 ng/mL or about 20 ng/mL to about 700 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 600 ng/mL, or about 2Ong/mL to about 600 ng/mL.
In a preferred embodiment, the average serum concentration of is from about 50 ng/mL to about 500 ng/mL, or about 2Ong/mL to about 500 ng/mL. In one embodiment, the average serum concentration of ibogainc is from about 50 ng/mL to about 400 ng/mL, or about 20ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 300 ng/mL, or about 20ng/mL to about 300 ng/mL.
In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 200 ng/mt., or about 2Ong/mL to about 200 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 100 ng/mL, or about 20ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0276] In one embodiment, the dosage or aggregate dosage of ibogaine is from greater than about 1 mg/kg to about 8 mg/kg body weight per day.
1. Depression [0277] The following description of depressive disorders and PTSD is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of this invention.
The definitions of depressive disorders and PTSD given below are those listed in American Psychiatric Association, 1994a or American Psychiatric Association, 1987.
Additional information regarding these disorders can be found in this reference, as well as other references cited below.
[0278] In some embodiments, it is contemplated that the compounds of this invention will be effective in treating depression in patients who have been diagnosed as having depression based upon the administration of any of the following tests: Hamilton Depression Rating Scale (MRS), Hamilton depressed mood item, Clinical Global Impressions (CGI)-Severity of Illness. It is further contemplated that the compounds of the invention will be effective in improving certain of the factors measured in these tests, such as the HDRS
subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGI-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
[0279] This invention provides, in certain embodiments, a method of treating a patient suffering from major depressive disorder, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein effective to treat the subject's major depressive disorder.
[0280] The invention also provides a method of treating a patient suffering from dysthymic disorder, bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
Date Recue/Date Received 2021-07-21 [0281] It is contemplated that the compounds utilized herein can be effective in treating PTSD in patients who have been diagnosed as having PTSD based upon the administration of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-rated Impact of Event Scale (IES). It is further contemplated that the compounds described herein will be effective in inducing improvements in the scores of the CAPS, IFS, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds described herein will be effective in preventing relapse of PTSD.
[0282] This invention provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's post-traumatic stress disorder.
[0283] Another aspect of the current invention provides a method for treating depression and/or PTSD in a patient in need thereof, which method comprises administering ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof to the patient, wherein the amount of the ibogaine or ibogaine derivative is sufficient to treat depression and/or PTSD in the patient.
102841 In a preferred embodiment, the invention provides a method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides average ibogaine or ibogaine derivative serum levels of between about 50 to about 800 ng/ml In some embodiments, the average ibogaine or ibogaine derivative serum level provided by the dosage is less than about 50 ng/mL. In one embodiment, the therapeutically effective amount is between about 1 mg to about 8 mg per kg of body weight. In one embodiment, the therapeutically effective amount is between about 50 ng to less than 100 ug per kg of body weight. In one embodiment, depression is treated. In one embodiment, posttraumatic stress disorder is treated. In one embodiment, the ibogaine, ibogainc derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
g. Reduced Tolerance To Opioid Analgesics [0285] As will be apparent to the skilled artisan upon reading this disclosure, the present invention provides a method for modulating tolerance to opioids in a patient undergoing opioid analgesic therapy, comprising administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0286] In one aspect of this invention, patient is being treated with an addictive opioid analgesic to relieve the patient's pain. The pain may be of any type and from any source. In one embodiment, the patient is treated for acute pain. In one embodiment, the patient is treated for chronic pain. In one embodiment, the patient is treated for nociceptive pain. In one embodiment, the patient is treated for neuropathic pain. In some embodiments, the pain is caused by surgery, diabetes, trigeminal neuralgia, fibromyalgia, cancer, central pain syndrome, tissue damage, physical injury, and the like. In some embodiments, the source of the pain is unknown or unclear.
[0287] In one aspect, this invention relates to a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic an amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient resensitize the patient to the opioid as an analgesic while maintaining a QT
interval of less than about 500 ms during said treatment.
[0288] In one aspect, this invention relates to a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic an amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 60 ng/mL to about 400 ng/mL, said concentration being sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 420 ms during treatment.
[0289] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five limes daily with ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week.
The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, opioid analgesic to which tolerance is being modulated, length of time of analgesic treatment, and the like, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0290] The patient may be receiving any addictive opioid analgesic for the treatment of pain.
In a preferred embodiment, the opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, heroin, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, oxymorphone, and derivatives of each thereof.
h.
Impulse Control Disorder, Anxiety-Related Disorders, Violence And/Or Anger, Or Regulating Food Intake [0291] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating anxiety disorder, impulse control disorder, anger/violence-related disorders, or regulating food intake in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
[0292] The following description of anxiety disorders and impulse control disorders is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of this invention. Disorders associated with violence and/or anger are included in these descriptions.The definitions of anxiety disorders and impulse control disorders given below are those listed in American Psychiatric Association, 2013, American Psychiatric Association, 1994a, or American Psychiatric Association, 1987. Additional information regarding these disorders can be found in these references, as well as other references cited below.
Date Recue/Date Received 2021-07-21 [0293] Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating these disorders in patients who have been diagnosed as having such disorders.
[0294] This invention provides for a method of treating a patient suffering from anxiety which comprises administering to the patient an amount of any of the compounds described herein effective to treat the subject's anxiety.
[0295] It is contemplated that the compounds described herein will be effective in treating obsessions and compulsions in patients who have been diagnosed as having obsessive compulsive disorder based upon administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (for adults), National Institute of Mental Health Global OCD Scale (NIMH
GOCS), CGI-Severity of Illness scale. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds described herein will be effective in preventing relapse of obsessive compulsive disorder and/or symptoms thereof.
[0296] This invention provides a method of treating obsessions and/or compulsions in a patient with obsessive compulsive disorder, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein effective to treat the subject's obsessions and/or compulsions.
[0297] It is contemplated that the compounds described herein will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGI-Severity of Illness scale. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of the factors measured in these evaluations, such as a reduction in frequency or elimination of panic attacks, an improvement in the CGI-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds described herein will be effective in preventing relapse of panic disorder.
[0298] This invention provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's panic disorder.
[0299] It is contemplated that the compounds described herein can be effective in treating social anxiety disorder in patients who have been diagnosed as having social anxiety disorder based upon the administration of any of the following tests: the Liebowitz Social Anxiety Scale (LSAS), the CGI-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the axis V Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability Scales, the Schneier Disability Profile, the World Health Organization Quality of Life-100 (WH000L-100), or other tests as described in Bobes, 1998. It is further contemplated that the compounds described herein will be effective in inducing improvements as measured by these tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds described herein will be effective in preventing relapse of social anxiety disorder.
[0300] This invention provides a method of treating social anxiety disorder in a patient which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's social anxiety disorder.
[0301] It is contemplated that the compounds utilized herein can be effective in treating generalized anxiety disorder in patients who have been diagnosed as having this disorder based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds described herein will be effective in preventing relapse of general anxiety disorder.
Date Recue/Date Received 2021-07-21 [0302] The invention provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the patient an amount of any of the compounds described herein effective to treat the subject's generalized anxiety disorder.
[0303] Impulse control disorders include pathological gambling (PG), kleptomania, trichotillomania (TTM), intermittent explosive disorder (1ED), and pyromania.
Impulse control disorders may also include pathological skin picking (PSP), compulsive sexual behavior (CSB), compulsive buying (CB), conduct disorder, antisocial personality disorder, oppositional defiant disorder, borderline personality disorder, attention deficit/hyperactivity disorder (ADHD, which includes attention deficit disorder, ADD), schizophrenia, mood disorders, paraphilia, and intern& addiction. Symptoms of impulse control disorders include:
repetitive participation in behavior despite adverse consequences, diminished control over the behavior, an urge/impulse to engage in the behavior, and feelings of pleasure while participating in the behavior.
[0304] It is contemplated that the compounds utilized herein can be effective in treating impulse control disorders in patients who have at least one impulse control disorder based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, including impulsivity or lack of self-control. It is also contemplated that the compounds described herein will be effective in preventing relapse of the impulse control disorder.
[0305] It is contemplated that the compounds utilized herein can be effective in treating ADHD or ADD in patients who have the disorder, based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, including impulsivity or lack of self-control. It is also contemplated that the compounds described herein will be effective in preventing relapse of ADD or ADHD.
[0306] It is contemplated that the compounds utilized herein can be effective in treating schizophrenia in patients who have the disorder, based upon the diagnostic criteria described in DSM-1V or DSM-5. Schizophrenia is characterized by delusions, hallucinations, disorganized speech and behavior, and other symptoms that cause social or occupational dysfunction. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder. It is also contemplated that the compounds described herein will be effective in preventing relapse of schizophrenia.
[0307] It is contemplated that the compounds described herein will be effective in treating non-suicidal self injury disorder in patients who have been diagnosed with this disorder based on the patient's exhibition of symptoms including deliberate tissue injury without suicidal intent (e.g., cutting, burning, self-poisoning, or self-mutilation). It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of self injury.
It is also contemplated that the compounds described herein will be effective in preventing relapse of non-suicidal self injury disorder.
[0308] This invention provides a method of treating non-suicidal self injury disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's non-suicidal self injury disorder.
[0309] It is contemplated that the compounds described herein will be effective in treating Miinchausen syndrome in patients who have been diagnosed with this disorder based on the patient's propensity for feigning disease, illness, or psychological trauma to draw attention, sympathy, or reassurance to themselves. Symptoms may include frequent hospitalizations, knowledge of several illnesses, frequent requests for medication (e.g., pain killers), willingness to undergo extensive surgery, few to no visitors during hospitalizations, and exaggerated or fabricated stories about multiple medical problems. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of one or more symptoms. It is also contemplated that the compounds described herein will be effective in preventing relapse of Miinchausen syndrome. Manchausen syndrome also includes Miinchausen syndrome by proxy, in which a caregiver exaggerates, fabricates, or induces illness in someone in his/her care.
[0310] This invention provides a method of treating Miinchausen syndrome in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's Miinchausen syndrome.
[0311] It is contemplated that the compounds described herein will be effective in treating disruptive mood dysregulation disorder in patients who have been diagnosed with this disorder on the basis of severe and recurrent temper outbursts, grossly out of proportion to the stimulus or situation, as well as a persistent irritable/angry mood most of the time. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of tember outbursts and/or an improvement in mood. It is also contemplated that the compounds described herein will be effective in preventing relapse of disruptive mood dysregulation disorder disorder.
[0312] This invention provides a method of treating disruptive mood dysregulation disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's disruptive mood dysregulation disorder.
[0313] It is contemplated that the compounds utilized herein can be effective in reducing the frequency, intensity, and duration of anger and/or violence in individuals prone to one or both. Although anger and violence disorders other than those associated with other disorders (e.g., as described above) are not outlined in DSM IV or DSM 5, many health professionals recognize that such disorders are associated with significant dysfunction.
Anger management training and other psychosocial treatments are often used in an effort to treat these individuals.
[0314] This invention provides a method of treating anger- and/or violence-related disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's anger- and/or violence-related disorder.
[0315] It is contemplated that the compounds utilized herein can be effective in regulating food intake and/or reducing food cravings in patients in need thereof. In some embodiments, the patient is overweight. In some embodiments, the patient is obese. In some embodiments, the patient exhibits comorbidities associated with overweight/obesity, for example coronary heart disease, high blood pressure, stroke, type 2 diabetes, abnormal levels of blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, reproductive issues, and/or gallstones.
[0316] This invention provides a method of regulating food intake and/or reducing food cravings in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to regulate/reduce the subject's food intake and/or food cravings.
[0317] In a preferred embodiment, the invention provides a method for treating anxiety disorders, impulse control disorders, OCD, and/or anger/violence-related disorders, or regulating food intake and/or food cravings, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides average ibogaine serum levels of between about 50 to about 180 ng/ml.
hi some embodiments, the average ibogainc serum level provided by the dosage is less than about 50 ng/mL. In one embodiment, the therapeutically effective amount is between about 1 mg to about 4 mg per kg of body weight. In one embodiment, the therapeutically effective amount is between about 50 ng to about 100 g per kg of body weight. In one embodiment, an anxiety disorder is treated. In one embodiment, OCD is treated. In one embodiment, an impulse control disorder is treated. On one embodiment, an anger-related disorder is treated.
in one embodiment, a violence-related disorder is treated. In one embodiment, symptoms of anger are reduced or eliminated. In one embodiment, violent outbursts are reduced or eliminated. In one embodiment, food intake is regulated. In one embodiment, food cravings are attenuated. In one embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery.
[0318] In one aspect, this invention relates to a method for attenuating symptoms of anxiety disorder, impulse control disorder, or an anger and/or violence-related disorder in a human patient, comprising administering to the patient a dosage of ibogaine or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
103191 In one aspect, this invention relates to a method for attenuating food cravings in a human patient, comprising administering to the patient a dosage of ibogaine or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 250 ng/mL, said concentration being sufficient to attenuate said cravings while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said cravings while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 420 ms during treatment.
[03201 In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In a preferred embodiment, the QT
interval is not prolonged more than about 20 ms. In one embodiment, the QT
interval is not prolonged more than about 10 ms.
[03211 In one aspect, this invention relates to a method for treating an anxiety disorder, an impulse control disorder, or an anger/violence-related disorder, and/or treating or attenuating the symptoms thereof in a patient, comprising selecting a patient exhibiting symptoms of an anxiety disorder, impulse control disorder, or anger/violence-related disorder who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to inhibit or ameliorate said disorder or symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0322] in one aspect, this invention relates to a method for regulating food intake, and/or treating or attenuating food cravings, in a patient, comprising selecting an overweight or obese patient who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said disorder or symptoms while maintaining a QT
interval of less than about 500 ms during said treatment.
IV. Dosage and Routes of Administration Therapeutic Dose [0323] In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the average serum concentration of ibogaine is ftom about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about ng/mL. In a preferred embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0324] In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 80 ng/mL to about 150 ng/mL. In one embodiment, the average scrum concentration of ibogaine is from about 80 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subrange or subvalue there between.
103251 In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1000 ng*hr/mL and about 6000 ng*hr/mL. In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng*hr/mL and about 5800 nehr/mL.
In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng*hr/mL and about 5500 ng*hr/mL. The ranges include both extremes as well as any subrange or subvalue there between.
[0326] In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 250 ng/mL. In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 40 ng/mL and about 250 ng/mL. In a preferred embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and about 200 ng/mL. In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 100 ng/mL and about 180 ng/mL. The ranges include both extremes as well as any subrange or subvalue there between.
[0327] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 8 mg/kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 7 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogainc derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 6 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 5 mg/kg body weight. In a preferred embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 2 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.7 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 2 mg/kg body weight. The ranges include both extremes as well as any subranges there between.
[0328] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 8 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 6 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1.7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1.5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1 mg/kg body weight per day.
[0329] In one aspect, the invention provides administering a pharmaceutical composition comprising a pharmaceutically effective amount of ibogaine and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 100 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 50 g per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 10 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 1 fig per kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is administered two or more times per day. In some embodiments, the composition is administered less than once a day, for example once every two days, once every three days, once every four days, once a week, etc.
[0330] In one embodiment, the dosage or aggregate dosage of compound is from about 1 mg to about 4 mg per kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day.
[0331] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 70 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 75 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 90 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of ibogainc, ibogaine derivative, or salt or solvate thereof is between about 90 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 100 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 110 mg and about 130 mg.
The ranges include both extremes as well as any subrange or subvalue there between.
[0332] In another embodiment, there is provided a unit dose of ibogaine, ibogaine derivative, or salt or solvate thereof which is about 50 mg to about 200 mg per dose. In one embodiment, the unit dose is about 50 to about 120 mg per dose. In one embodiment, the unit dose is about 120 mg per dose. It being understood that the term "unit dose"
means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.
[0333] In some embodiments, the patient is administered an initial dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, such a dosing regimen provides an average serum concentration of ibogaine of about 50 ng/mL to about 180 ng/nrtL. In one embodiment, the one or more additional doses maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL over a period of time.
[0334] In some embodiments, the initial dose of ibogainc, ibogaine derivative, or salt or solvate thereof is from about 75 mg to about 120 mg. In one embodiment, the initial dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment, the initial dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment, the initial dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In one embodiment, the initial dose is about 110 mg. In one embodiment, the initial dose is about 115 mg. In one embodiment, the initial dose is about 120 mg.
[0335] In some embodiments, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from about 5 mg to about 50 mg. In one embodiment, the one or more additional doses may or may not comprise the same amount of ibogaine, ibogaine derivative, or salt or solvate thereof. In one embodiment, at least one additional dose is about 5 mg. In one embodiment, at least one additional dose is about 10 mg. In one embodiment, at least one additional dose is about 15 mg.
In one embodiment, at least one additional dose is about 20 mg. In one embodiment, at least one additional dose is about 25 mg. In one embodiment, at least one additional dose is about 30 mg. In one embodiment, at least one additional dose is about 35 mg. In one embodiment, at least one additional dose is about 40 mg. In one embodiment, at least one additional dose is about 45 mg. In one embodiment, at least one additional dose is about 50 mg.
[0336] In one embodiment, the one or more additional doses are administered periodically.
In one embodiment, the one or more additional doses are administered approximately every 4 hours. In one embodiment, the one or more additional doses are administered every 6 hours.
In one embodiment, the one or more additional doses are administered approximately every 8 hours. In one embodiment, the one or more additional doses are administered approximately every 10 hours. In one embodiment, the one or more additional doses are administered approximately every 12 hours. In one embodiment, the one or more additional doses are administered approximately every 18 hours. In one embodiment, the one or more additional doses are administered approximately every 24 hours. In one embodiment, the one or more additional doses are administered approximately every 36 hours. In one embodiment, the one or more additional doses are administered approximately every 48 hours.
103371 In some embodiments, the patient is administered a high (therapeutic) dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant symptoms of a disease or disorder, and then is administered a lower (maintenance) dose to prevent relapse. In some embodiments, the patient is administered a therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant symptoms, and then is administered a decreasing (tapered) amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof over time until the maintenance dose is reached.
[0338] For treating pain the following dosages are contemplated as useful.
[0339] In one embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.7 mg to about 1.5 mg per kg body weight per day. The ranges include both extremes as well as any subrangcs there between.
[0340] In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.1 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.9 mg/kg body weigjht per day. In one embodiment, the therapeutically effective amount of the compound is about 0.8 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.7 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.6 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.1 mg/kg body weight per day.
[0341] In one embodiment, lbogaine is administered at an amount by weight that is twice that administered for noiibogaine for treating a same or similar condition.
For example, and without limitation, an administration of a dose 80 mg ibogaine approximates a dose of 40 mg noribogaine.
Maintenance Dose [0342] In some embodiments, the maintenance dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 10% to about 80% of the therapeutic dose. In some embodiments, the maintenance dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof is about 70% of the therapeutic dose.
In some embodiments, the maintenance dose is about 60% of the therapeutic dose. In some embodiments, the maintenance dose is about 50% of the therapeutic dose. In some embodiments, the maintenance dose is about 40% of the therapeutic dose. In some embodiments, the maintenance dose is about 30% of the therapeutic dose. In some embodiments, the maintenance dose is about 20% of the therapeutic dose. In some embodiments, the maintenance dose is about 10% of the therapeutic dose.
[0343] In some embodiments, the maintenance average serum level of ibogaine is about 10% to about 80% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 70% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 60% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 50% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 40% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 30%
of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 20% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 10%
of the therapeutic average serum level of ibogaine.
Tapered Dosing [0344] In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or salt and/or solvate thereof is a tapered dosing over a period of time, during which the patient is detoxified, for example, without suffering significant acute withdrawal symptoms. Without being bound by theory, it is believed that tapering will allow the full therapeutic effect of ibogaine with less prolongation of the QT interval. Tapering involves administration of one or more subsequently lower doses of ibogaine over time. For example, in some embodiments, the first tapered dose is about 50% to about 95% of the first or original dose. In some embodiments, the second tapered dose is about 40% to about 90% of the first or original dose. In some embodiments, the third tapered dose is about 30% to about 85% of the first or original dose. In some embodiments, the fourth tapered dose is about 20% to about 80% of the first or original dose. In some embodiments, the fifth tapered dose is about 10% to about 75% of the first or original dose.
[0345] In some embodiments, the first tapered dose is given after the first dose of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the first tapered dose is given after the second, third, or a subsequent dose of compound. The first tapered dose may be administered at any time after the previous dose of compound.
[0346] In one embodiment, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate is tapered over time until the desired maintenance dose is reached. For example, in some embodiments, the first tapered dose is about 50% to about 95% of the therapeutic dose. In some embodiments, the second tapered dose is about 40% to about 90% of the therapeutic dose. In some embodiments, the third tapered dose is about 30% to about 85% of the therapeutic dose. In some embodiments, the fourth tapered dose is about 20% to about 80% of the therapeutic dose. In some embodiments, the fifth tapered dose is about 10% to about 75% of the therapeutic dose. In some embodiments, one tapered dose is given to achieve the maintenance dose.
In some embodiments, two tapered doses are given to achieve the maintenance dose. In some embodiments, three tapered doses are given to achieve the maintenance dose. In some embodiments, four or more tapered doses are given to achieve the maintenance dose.
Determination of the tapered doses, number of tapered doses, and the like can be readily made a qualified clinician.
103471 The first tapered dose may be administered at any time after the previous dose of ibogaine. The first tapered dose can be given once, for example, followed by subsequent further tapered doses, or it can be given multiple times with or without subsequent, further tapered doses (e.g., second, third, fourth, etc. tapered doses), which likewise can be given once or over multiple administrations, for example. In some embodiments, the first tapered dose is given after the first dose of ibogaine. In some embodiments, the first tapered dose is given after the second, third, or a subsequent dose of ibogaine. In some embodiments, the first tapered dose is administered one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of ibogaine. Similarly, second, third, fourth, etc.
tapered doses, if given, can be given one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of ibogaine.
[0348] In some embodiments, one tapered dose is given to achieve the desired lower therapeutic dose. In some embodiments, two tapered doses are given to achieve the desired lower therapeutic dose. In some embodiments, three tapered doses are given to achieve the desired lower therapeutic dose. In some embodiments, four or more tapered doses are given to achieve the desired lower therapeutic dose. Determination of the tapered doses, number of tapered doses, and the like can be readily made a qualified clinician.
[0349] In some embodiments, the patient undergoes long-term (e.g., one month, three months, six months, one year or longer) treatment with maintenance doses of ibogaine, ibogaine derivative, or salt and/or solvate thereof. In some embodiments, the patient is treated for acute withdrawal with therapeutic doses of ibogaine as described above, and then the amount of ibogaine is reduced to maintenance levels after acute withdrawal symptoms would be expected to have subsided. Acute withdrawal symptoms generally are the most pronounced in the first week after cessation of alcohol use, although acute withdrawal may last as long as six weeks or more.
[0350] In some embodiments, the composition is administered via sublingual, intranasal, or intrapulmonary delivery. In one aspect, the invention provides administering a pharmaceutical composition comprising a pharmaceutically effective amount of ibogaine or ibogaine derivative and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to less than 100 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to about 50 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to about 10 litg per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to about 1 p.g per kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is administered two or more times per day. In some embodiments, the composition is administered less than once a day, for example once every two days, once every three days, once every four days, once a week, etc.
[0351] In some embodiments, the composition is administered via oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery.
[0352] A particularly suitable composition comprises a composition suitable for a transdermal route of delivery in which the ibogaine or ibogaine derivative is applied as part of a cream, gel or, preferably, patch (for examples of transdermal formulations, see U.S. Pat. Nos.
4,806,341; 5,149,538; and 4,626,539).
[0353] In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In one embodiment, the QT
interval is not prolonged more than about 20 ms. In one embodiment, the QT interval is not prolonged more than about 10 ms.
Formulations [0354] This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the amount of ibogaine is sufficient to provide an average serum concentration of about 50 ng/mL to about 850 ng/mL when administered to a patient. In other embodiments, the amount of ibogaine is sufficient to provide an average serum concentration of about 50 ng/mL to about 400 ng/mL when administered to a patient.
[0355] In some embodiments, the unit dose of ibogaine is administered in one or more dosings.
[0356] In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the amount of ibogaine is sufficient to Date Recue/Date Received 2021-07-21 provide an average serum concentration of ibogaine from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about 600 ng/mL. In a preferred embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 400 ng/mL, or about 60 ng/mL to about ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average scrum concentration of ibogaine from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/m.L. The ranges include both eximmes as well as any subranges between.
[0357] In some embodiments, the formulation is designed for periodic administration, such as once, twice, three time, four times or five time daily with ibogaine or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
Delivery method [0358] The compositions, provided herein or known, suitable for administration in accordance with the methods provided herein, can be suitable for a variety of delivery modes including, without limitation, sublingual, intrapulmonary, or intranasal delivery.
Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intra-peritoneal, intra-cutaneous and subcutaneous routes may also be used. Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions.
Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
[0359] The compositions provided herein can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing ibogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
[0360] The compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal administration.
The compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient may be provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), (for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide or other suitable gases. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve.
Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine. In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler.
[0361] In some embodiments, ibogaine is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. In certain embodiments, the ibogaine is provided as ibogaine HC1, with dosages reported as the amount of free base ibogaine. In some embodiments, the ibogaine HC1 is provided in hard gelatin capsules containing only ibogaine HC1 with no excipients.
[0362] The compositions utilized herein may be formulated for sublingual administration, for example as sublingual tablets. Sublingual tablets are designed to dissolve very rapidly.
The formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol.
[03631 It has been discovered that ibogaine has a bitter taste to at least some patients.
Accordingly, compositions for oral use (including sublingual, inhaled, and other oral formulations) may be formulated to utilize taste-masking technologies. A
number of ways to mask the taste of bitter drugs are known in the art, including addition of sugars, flavors, sweeteners, or coatings; use of lipoproteins, vesicles, and/or liposomes;
granulation;
microencapsulation; numbing of taste buds; multiple emulsion; modification of viscosity; or salt fot _________________________________________________________ 'nation;
inclusion or molecular complexes; ion exchange resins; and solid dispersion.
Any method of masking the bitterness of the compound of the invention may be used.
Patient Pre-screening and Monitoring [0364] Pre-screening of patients before treatment with ibogaine and/or monitoring of patients during ibogaine treatment may be required to ensure that QT interval is not prolonged beyond a certain value. For example, QT interval greater than 500 ms can be considered dangerous for individual patients. Pre-screening and/or monitoring may be necessary at high levels of ibogaine treatment.
[0365] In some embodiments, a patient receiving ibogaine is monitored in a clinical setting.
Monitoring may be necessary to ensure the QT interval is not prolonged to an unacceptable degree. A "clinical setting" refers to an inpatient setting (e.g., inpatient clinic, hospital, rehabilitation facility) or an outpatient setting with frequent, regular monitoring (e.g., outpatient clinic that is visited daily to receive dose and monitoring).
Monitoring includes monitoring of QT interval. Methods for monitoring of QT interval are well-known in the art, for example by ECG.
[0366] In one embodiment, a patient receiving ibogaine is not monitored in a clinical setting. ln one embodiment, a patient receiving ibogaine is monitored periodically, for example daily, weekly, monthly, or occasionally.
[0367] In one aspect, this invention relates to a method for treating a disease or disorder or symptoms of a disease or disorder, comprising selecting addicted dependent patient who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse or symptoms while maintaining a QT interval of less than 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0368] In one embodiment, prescreening of the patient comprises ascertaining that ibogaine treatment will not result in a QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that ibogaine treatment will not result in a QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that ibogaine treatment will not result in a QT interval over about 450 ms. In one embodiment, prescreening comprises ascertaining that ibogaine treatment will not result in a QT interval over about 420 ms. In one embodiment, prescreening comprises determining the patient's pre-treatment QT interval.
[0369] As it relates to pre-screening or pre-selection of patients, patients may be selected based on any criteria as determined by the skilled clinician. Such criteria may include, by way of non-limiting example, pre-treatment QT interval, pre-existing cardiac conditions, risk of cardiac conditions, age, sex, general health, and the like. The following are examples of selection criteria for disallowing ibogaine treatment or restricting dose of ibogaine administered to the patient: high QT interval before treatment (e.g., such that there is a risk of the patient's QT interval exceeding 500 ms during treatment); congenital long QT syndrome;
bradycardia; hypokalemia or hypornagnesemia; recent acute myocardial infarction;
uncompensated heart failure; and taking other drugs that increase QT interval.
In some embodiments, the methods can include selecting and/or administering/providing ibogaine to a patient that lacks one more of such criteria.
[0370] In one embodiment, this invention relates to pre-screening a patient to determine if the patient is at risk for prolongation of the QT interval beyond a safe level. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is not administered ibogaine. In one embodiment, a patient at risk for prolongation of the QT
interval beyond a safe level is administered ibogaine at a limited dosage.
[0371] In one embodiment, this invention relates to monitoring a patient who is administered a therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, the dose of ibogaine is reduced if the patient has one or more adverse side effects. In one embodiment, the ibogaine treatment is discontinued if the patient has one or more adverse side effects. In one embodiment, the adverse side effect is a QT interval that is prolonged beyond a safe level.
The determination of a safe level of prolongation is within the skill of a qualified clinician.
Kit of Parts [0372] One aspect of this invention is directed to a kit of parts for the treatment of a disease or disorder and/or symptoms of a disease or disorder as described herein in a patient, wherein the kit comprises a composition comprising ibogaine, ibogaine derivative, or salt and/or solvate thereof and a means for administering the composition to a patient in need thereof.
The means for administration to a patient can include, for example, any one or combination of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, a transdermal patch, a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, an inhaler comprising the composition, etc. In one embodiment, the kit of parts further comprises instructions for dosing and/or administration of the composition.
[0373] In some aspects, the invention is directed to a kit of parts for administration of ibogaine, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, and further wherein each delivery vehicle is identified by the amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provided therein; and optionally further comprising a dosing treatment schedule in a readable medium. In some embodiments, the dosing treatment schedule includes the amount of ibogaine required to achieve each average serum level is provided. In some embodiments, the kit of parts includes a dosing treatment schedule that provides an attending clinician the ability to select a dosing regimen of ibogaine based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve. In some embodiments, the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight (or mass) and sex of the patient. In an embodiment, the storage medium can include an accompanying pamphlet or similar written information that accompanies the unit dose form in the kit. In an embodiment, the storage medium can include electronic, optical, or other data storage, such as a non-volatile memory, for example, to store a digitally-encoded machine-readable representation of such information.
103741 The term "delivery vehicle" as used herein refers to any formulation that can be used for administration of ibogaine to a patient. Non-limiting, exemplary delivery vehicles include caplets, pills, capsules, tablets, powder, liquid, or any other form by which the drug can be administered. Delivery vehicles may be intended for administration by oral, inhaled, injected, or any other means.
[0375] The term "readable medium" as used herein refers to a representation of data that can be read, for example, by a human or by a machine. Non-limiting examples of human-readable formats include pamphlets, inserts, or other written fauns. Non-limiting examples of machine-readable formats include any mechanism that provides (i.e., stores and/or transmits) information in a form readable by a machine (e.g., a computer, tablet, and/or smartphone).
For example, a machine-readable medium includes read-only memory (ROM); random access memory (RAM); magnetic disk storage media; optical storage media; and flash memory devices. In one embodiment, the machine-readable medium is a CD-ROM. In one embodiment, the machine-readable medium is a USB drive. In one embodiment, the machine-readable medium is a Quick Response Code (QR Code) or other matrix barcode.
[0376] In some aspects, the machine-readable medium comprises software that contains information regarding dosing schedules for the unit dose form of ibogaine and optionally other drug information. In some embodiments, the software may be interactive, such that the attending clinician or other medical professional can enter patient information. In a non-limiting example, the medical professional may enter the weight and sex of the patient to be treated, and the software program provides a recommended dosing regimen based on the information entered. The amount and timing of ibogaine recommended to be delivered will be within the dosages that result in the serum concentrations as provided herein.
[0377] In some embodiments, the kit of parts comprises multiple delivery vehicles in a variety of dosing options. For example, the kit of parts may comprise pills or tablets in multiple dosages, such as 240 mg, 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, and/or 10 mg of ibogaine per pill. Each pill is labeled such that the medical professional and/or patient can easily distinguish different dosages. Labeling may be based on printing or embossing on the pill, shape of the pill, color of pill, the location of the pill in a separate, labeled compartment within the kit, and/or any other distinguishing features of the pill. In some embodiments, all of the delivery vehicles within a kit are intended for one patient. In some embodiments, the delivery vehicles within a kit arc intended for multiple patients.
[0378] One aspect of this invention is directed to a kit of parts for the treatment of a disease or disorder described herein, wherein the kit comprises a unit dose form of ibogaine, ibogaine derivative, or salt and/or solvate thereof. The unit dose form provides a patient with an average serum level of ibogaine of from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the unit dose form provides a patient with an average serum level of ibogaine of from about 50 ng/mL to about 400 ng/mL or about 60 ng/mL to about 400 ng/mL.
[0379] In some embodiments, the unit dose form comprises one or multiple dosages to be administered periodically, such as once, twice, three time, four times or five time daily with ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.
[0380] These dose ranges may be achieved by transdermal, oral, or parenteral administration of ibogaine or a pharmaceutically acceptable salt and/or solvate thereof in unit dose form. Such unit dose form may conveniently be provided in transdermal patch, tablet, caplet, liquid or capsule form. In certain embodiments, the ibogaine is provided as ibogaine HC1, with dosages reported as the amount of free base ibogaine. In some embodiments, the ibogaine HC1 is provided in hard gelatin capsules containing only ibogaine HC1 with no excipients. In some embodiments, ibogaine is provided in saline for intravenous administration.
103811 In another aspect, provided herein is a kit of parts for administration of ibogaine, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of ibogaine and further wherein each delivery vehicle is identified by the amount of ibogaine provided therein; and optionally further comprising a dosing treatment schedule in a readable medium.
103821 In one embodiment, the amount of ibogaine required to achieve each maximum serum level is provided in the readable medium. In another embodiment, the readable medium is a computer-readable medium. In another embodiment, the multiple delivery vehicles contain different amounts of ibogaine. In another embodiment, the dosing treatment schedule provides an attending clinician the ability to select a dosing regimen of ibogaine based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve. In another embodiment, the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight and sex of the patient.
EXAMPLES
[0383] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
Example I: Effect Of Low Dose Of Ibogaine On Smoking Cessation [0384] A female habitual smoker intranasally absorbs a milligram amount of ibogainc hydrochloride. During a period of several hours, any craving to smoke is measured periodically.
Example 2. Efficacy Of Ibogaine, Ibogaine Derivative, Or A Pharmaceutically Acceptable Salt Thereof In Humans [0385] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in alcohol-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured.
Example 3. Efficacy Of Ibogaine In Treating Substance Dependency [0386] The efficacy of ibogaine is evaluated in substance-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients are administered 60 mg or 120 mg of the compound and QT interval is measured.
Example 4. Use Of Ibogaine To Treat Chronic Pain In Humans [0387] Six patients experiencing chronic pain are screened and selected to receive administration of ibogaine. Four patients intranasally absorb a milligram amount of ibogaine hydrochloride and the remaining two patients receiv a placebo. The level of pain and pain relief of the patients are measured.
Example 5. Forced Swim Test (FST) With Rats [0388] Animals: Male Sprague-Dawley rats (Taconic Farms, N.Y.) are used in all experiments. Rats arc housed 5 per cage and maintained on a 12:12-h light-dark cycle. Rats are handled for 1 minute each day for 4 days prior to behavioral testing.
[0389] Drug Administration: Animals are randomly assigned to receive a single intraperitoneal administration of vehicle (2.5% Et0H/2.5% Tween-80), imipramine (positive control; 60 mg/kg), or Test Compound 60 minutes before the start of the 5 minute test period.
All injections are given using 1 cc tuberculin syringe with 26 3/8 gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport, N.J.). The volume of injection is 1 ml/kg.
[0390] Experimental Design: The procedure used in this study employs a water depth of 31 cm. The greater depth in this test prevents the rats from supporting themselves by touching the bottom of the cylinder with their feet. Swim sessions are conducted by placing rats in individual plexiglass cylinders (46 cm tall and 20 cm diameter) containing 23-25 C water.
Swim tests are conducted always between 9:00 and 17:00 hours and included an initial 15-minute conditioning test followed 24 hours later by a 5-minute test. Drug treatments are administered 60 minutes before the 5-minute test period. Following all swim sessions, rats are removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes and returned to their home cages. All test sessions are videotaped using a color video camera and recorded for scoring later.
[0391] Behavioral Scoring: The rat's behavior is rated at 5 second intervals during the 5 minute test by a single individual, who is blind to the treatment condition.
Scored behaviors are: 1. Immobility--rat remains floating in the water without struggling and is only making those movements necessary to keep its head above water; 2. Climbing--rat is making active movements with its forepaws in and out of the water, usually directed against the walls; 3.
Swimming--rat is making active swimming motions, more than necessary to merely maintain its head above water, e.g. moving around in the cylinder; and 4. Diving--entire body of the rat is submerged.
[0392] Data Analysis: The forced swim test data (immobility, swimming, climbing, diving) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test. The data are analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).
Example 6. Forced Swim Test (FST) With Mice [0393] Animals: DBA/2 mice (Taconic Farms, N.Y.) are used in all experiments.
Animals are housed 5 per cage in a controlled environment under a 12:12 hour light:dark cycle.
Animals are handled 1 min each day for 4 days prior to the experiment. This procedure includes a mock gavage with a 1.5 inch feeding tube.
[0394] Drug Administration: Animals are randomly assigned to receive a single administration of vehicle (5% Et0H/5% Tween-80), Test Compound, or imipramine (60 mg/kg) by oral gavage 1 hour before the swim test.
[0395] Experimental Design: The procedure for the forced swim test in the mouse is similar to that described above for the rat, with the following modifications. The cylinder used for the test is a 1 liter beaker (10.5 cm diameter and 15 cm height) filled to 800 ml (10 cm depth) with 23 25 C. water. Only one 5-minute swim test is conducted for each mouse, between 13:00 and 17:00 hours. Drug treatments are administered 30-60 minutes before the 5-minute test period. Following all swim sessions, mice are removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes. All test sessions are videotaped using a Sony color video camera and recorder for scoring later.
[0396] Behavioral Scoring: The behavior during minutes 2-5 of the test is played back on a TV monitor and scored by the investigator. The total time spent immobile (animal floating with only minimal movements to remain afloat) and mobile (swimming and movements beyond those required to remain afloat) are recorded.
103971 Data Analysis: The forced swim test data (time exhibiting immobility, mobility;
seconds) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test. The data are analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).
Example 7. Effect of ibogaine on QT interval in humans [0398] The safety of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof is evaluated in patients in a randomized, placebo-controlled, double-blind trial. Patients are administered 60 mg or 120 mg of the compound and QT
interval is measured.
Example 8. Effect of ibogaine on depression in humans [0399] A male patient, age 55, suffering from depression unrelated to the use of any illicit substance, is treated with ibogainc hydrochloride at a dose of about 1 mg/kg/day for a period of four weeks. During the treatment period, his depression is determined by the patient's self-reporting of a decrease in symptoms and/or changes in one or more of the following tests:
HDRS, Hamilton depressed mood item, and CGI-Severity of Illness.
Example 9. Efficacy of ibogaine to modulate opioid tolerance in humans [0400] A female patient, age 59, undergoing opioid analgesic therapy for chronic back pain, is treated with ibogaine hydrochloride at a dose of about 2 mg/kg concurrently with the opioid. The amount of opioid required to treat her back pain after ibogaine treatment is measured.
Example 10. Social Interaction Test (SIT) [0401] Animals: Male albino Sprague-Dawley rats (Taconic Farms, N.Y.) are housed in pairs under a 12 hr light dark cycle (lights on at 0700 hrs.) with free access to food and water.
[0402] Rats are allowed to acclimate to the animal care facility for 5 days and are housed singly for 5 days prior to testing. Animals are handled for 5 minutes per day.
On the test day, weight matched pairs of rats ( 5%), unfamiliar to each other, are given identical treatments and returned to their home cages. Animals are randomly divided into 5 treatment groups, with pairs per group, and are given one of the following i.p. treatments: Test Compound (1, 2 or 4 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg). Dosing is done 1 hour prior to testing. Rats are subsequently placed in a white perspex test box or arena (54x37x26 cm), whose floor is divided up into 24 equal squares, for 15 minutes. An air conditioner is used to generate background noise and to keep the room at approximately 74 F. All sessions are videotaped using a JVC camcorder (model GR-SZ I, Elmwood Park, N.J.) with either TDK
(HG ultimate brand) or Sony 30 minute videocassettes. All sessions are conducted between 13:00 and 16:30 hours. Active social interaction, defined as grooming, sniffing, biting, boxing, wrestling, following and crawling over or under, is scored using a stopwatch (Sportsline model no. 226, 1/100 sec. discriminability). The number of episodes of rearing (animal completely raises up its body on its hind limbs), grooming (licking, biting, scratching of body), and face ishing (i.e. hands are moved repeatedly over face), and number of squares crossed are scored. Passive social interaction (animals are lying beside or on top of each other) is not scored. All behaviors are assessed later by an observer who is blind as to the treatment of each pair. At the end of each test, the box is thoroughly wiped with moistened paper towels.
[0403] Data Analysis: The social interaction data (time interacting, rearing and squares crossed) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Student-Newman-Keuls test. The data are subjected to a test of normality (Shapiro-Wilk test). The data are analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, Md., 1997).
Example 11. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on anxiety-related disorders in humans [0404] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for an anxiety-related disorder in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured.
Example 12. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on impulse control disorders in humans [0405] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for an impulse control disorder in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured.
Example 13. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on violence-related disorders in humans [0406] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for a violence-related disorder in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured. Mean prolongation of the QT interval and/or the severity of violent outbursts, are determined by self-evaluation and clinical evaluation.
Example 14. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on food intake in humans [0407] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for obesity related to over-eating in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured. Mean prolongation of the QT interval, weight loss and food intake and/or cravings, are determined by self-evaluation and clinical evaluation.
interval greater than about 470 ms. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT interval ?pater than about 450 ms.
[0057] In another aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of ibogaine, ibogaine derivative, or phai tnaceutically acceptable salt ancUor solvate thereof that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0058] In one embodiment, the withdrawal symptoms are due to acute withdrawal.
In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0059] In another aspect, provided herein is a method to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is no longer physically dependent on alcohol.
[0060] In one embodiment, the maintenance dosage is less than about 70% of a therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 30 ms.
In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 20 ms.
Drug Addiction [0061] This invention is predicated, at least in part, on the surprising discovery that treatment of addiction with ibogaine can be achieved with an acceptable QT
interval prolongation when such compounds are administered within a narrow dosage range.
Specifically, dosing an addicted patient with from greater than about 1 mg/kg body weight to about 4 rag/kg body weight, ibogaine will provide a therapeutic reduction in withdrawal symptoms and/or an increase in time to resumption of substance use in addicted patients without unacceptable prolongation of the patient's QT interval.
[0062] In some aspects of the invention, the dose range of ibogaine that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in substance-addicted humans is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1.3 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0063] In some embodiments, the narrow therapeutic doses of ibogaine unexpectedly do not prolong the QT interval to unacceptable levels in human addicted patients. It is expected that drug addicted patients will be administered therapeutic doses of ibogaine in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with ibogaine.
[0064] Some aspects of the current invention are further predicated on the discovery that even lower doses of ibogaine, for example approximately 80% or less of the therapeutic dose, may be effective for prevention of relapse of drug use in an addicted patient treated to ameliorate their drug use. That is, a lower dose of the compound can prevent a patient who is no longer physically addicted to a substance from relapsing to use of that substance. Without being bound by theory, it is believed that a patient who is no longer physically addicted to the drug requires less compound to prevent relapse because the drug does not compete with the compound for receptor binding, and/or because desensitization of one or more receptors in the brain by the drug is reversed when the patient ceases to take the drug.
This lower, maintenance dose results in a QT interval prolongation that does not require clinical cardiac monitoring.
[0065] In some embodiments, the therapeutic dose of ibogaine administered to the patient is sufficient to provide an average serum concentration of the compound of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
100661 In some embodiments, the patient is administered a high (therapeutic) dose of ibogaine for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to drug use. In some embodiments, the patient is administered a therapeutic dose of ibogaine for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of ibogaine over time until the maintenance dose is reached.
In some embodiments, a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose. In some embodiments, the dose of the compound is tapered over time from the high therapeutic dose to a lower therapeutic dose.
[0067] In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of ibogaine is from greater than about 1 mg/kg to about 8 mg/kg. In a preferred embodiment, the aggregate dose of ibogaine is from greater than about 1 mg/kg to about 4 mg/kg. In another preferred embodiment, the aggregate dose of ibogaine is from greater than about 1 mg/kg to 3 mg/kg.
100681 In some embodiments, the serum concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, the therapeutic dose of ibogaine provides prolongation of the QT interval of less than 80 ms. In a preferred embodiment, the maintenance dose of ibogaine provides prolongation of the QT interval of less than 50 ms. In some embodiments, the maintenance dose or therapeutic dose of ibogaine provides prolongation of the QT interval of less than 30 ms. In a preferred embodiment, the maintenance dose of ibogaine provides prolongation of the QT interval of less than 20 ms. In one embodiment, the QT prolongation is equivalent to or less than that observed in patient receiving methadone treatment. In a preferred embodiment, the patient is tested to determine QT interval before treatment with the compound, and if clinician determines that the QT prolongation would be unacceptable risk, therapy will be contraindicated.
Substance Abuse [0069] In one aspect, provided herein is a method for treating substance abuse in a human patient addicted thereto, comprising administering to the patient a dosage of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, preferably ibogaine, wherein the dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0070] In one embodiment, the ibogaine is administered as a single dose or multiple doses.
In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0071] In one aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to Date Recue/Date Received 2021-07-21 attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0072] In one embodiment, the the withdrawal symptoms are due to acute withdrawal.
[0073] In another embodiment, the ibogaine is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 3 mg/kg per day.
In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT
interval is less than about 450 ms.
[0074] In another aspect, provided herein is a method to prevent relapse of substance abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine, wherein the patient is no longer abusing the substance.
[0075] In one embodiment, the dosage is less than about 70% of a therapeutic dose of ibogaine, and further wherein the prolongation of the QT interval is no greater than about 30 ins. In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 20 ms.
[0076] In one embodiment, the unit dose of ibogaine is administered in one or more dosings.
[0077] In another aspect, provided herein is a method for treating substance abuse in a patient addicted thereto, comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0078] In one embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT interval greater than about 470 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT
interval greater than about 450 ms.
[0079] In another embodiment, the addictive substance is selected from the group consisting of benzodiazepines, cannabinoids and synthetic cannabinoids, stimulants, barbiturates, gamma-hydroxybutyrate (GHB), ketamine, PCP, dextromethorphan (DXM), lysergic acid diethylamide (LSD), mescaline, anabolic steroids, and derivatives of each thereof.
Opioid Or Opioid¨Like Drug Abuse [0080] In one aspect, provided herein is a method for treating opioid or opioid-like drug abuse in a human patient addicted thereto, comprising administering to the patient a dosage of ibogaine wherein the dosage provides an average serum concentration of about 50 ng/mL
to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0081] In another embodiment, the ibogaine is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0082] In another aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0083] In another embodiment, the withdrawal symptoms are due to acute withdrawal. In another embodiment, the ibogaine is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In another embodiment, the QT
interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0084] In another aspect, provided herein is a method to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine wherein the patient is no longer abusing the opioid or opioid-like drug.
[0085] In one embodiment, the dosage is less than about 70% of a therapeutic dose of ibogaine and further wherein the prolongation of the QT interval is no greater than about 30 ms. In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 20 ms.
[0086] In one embodiment, the unit dose of ibogaine is administered in one or more dosings.
100871 In one aspect, provided herein is a method for treating opioid or opioid-like drug abuse in a patient addicted thereto, comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0088] In one embodiment, the prescreening step comprises ascertaining that treatment with ibogainc, ibogaine derivative, or pharmaceutically acceptable salt thereof will not result in a QT interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT
interval greater than about 470 ms. In another embodiment, the prescreening step comprises ascertaining that treatment with ibogaine will not result in a QT interval greater than about 450 ms.
Pain [0089] Pain is broadly defined as an unpleasant sensory experience associated with actual or potential tissue damage, or described in terms of such damage. The interpretation of sensory pain occurs when peripheral nerve endings called nociceptors are stimulated and subsequently transmit signals through sensory neurons in the spinal cord. The signals are then transmitted to the brain, at which point the individual becomes aware of the pain.
[0090] There are a number of pain categories and classifications, which for example, can be grouped into four categories according to the source and related nociceptors:
(1) cutaneous pain; (2) somatic pain; (3) visceral pain; and (4) neuropathic pain. Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain indicates present damage to tissue or disease and may be "fast" and "sharp" followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. Acute pain generally responds well to medications (e.g., morphine).
[0091] Chronic pain may be medically defined as pain that has lasted six months or longer.
This constant or intermittent pain has often outlived its purpose because it does not help the body to prevent injury. It is often more difficult to treat than acute pain.
Expert care is generally necessary to treat any pain that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to control the pain. This can lead to drug dependency. For example, opioids are used in some instances for prolonged periods to control chronic pain. Drug tolerance, chemical dependency, and even psychological addiction may occur.
[0092] Debilitating chronic pain affects tens of millions of people annually.
Accordingly, this costs hundreds of millions of dollars in terms of medication, physical therapy, and lost production. The current methods for treating chronic pain have a limited success rate and in some cases may result in chemical dependency.
[0093] Numerous treatments have been developed in attempts to ameliorate pain in its various categories. However, in many cases, treatment requires the use of addictive or habit-forming substances (e.g., morphine or methadone). Accordingly, there is a significant need for an effective, non-addictive treatment for pain, such as chronic, debilitating, nociceptive pain, that reduces the need for habit-fointing pain relieving drugs.
[0094] Furthermore, human clinical studies demonstrate that the lower dosing of ibogaine has minimal impact on the alleviation of pain in patients. Thus, the previously disclosed broad range has now been found to be insufficient for at least some human therapies at the lower end of this range.
[0095] In some embodiments, the current invention is predicated on the surprising discovery that treatment with a narrow dosage range of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, preferably of ibogaine, between greater than about 0.1 mg/kg body weight and about 8 mg/kg body weight, provides a therapeutic alleviation of pain. Preferably, the dose range that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in humans is between about 0.1 mg per kg body weight and no more than about 3 mg per kg body weight and, more preferably between about 0.7 mg per kg body weight and no more than about 2 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0096] In some embodiments, the narrow therapeutic doses of ibogaine described above do not prolong the QT interval to unacceptable levels in human patients. In some embodiments, patients are administered therapeutic doses of ibogaine in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with ibogaine.
In one embodiment, a patient who exhibits a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of ibogaine will not require further clinical monitoring. In one embodiment, the patient is not monitored after administration of ibogaine.
[0097] In some embodiments, the therapeutic dose of ibogaine administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
[0098] In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of ibogaine is from about 0.1 mg/kg to about 8 mg/kg. In one embodiment, the aggregate dose of ibogaine is from about 0.1 mg/kg to about 3 mg/kg.
In another embodiment, the aggregate dose of ibogaine is from about 0.7 mg/kg to 1.5 mg/kg.
[0099] In one aspect, provided herein is a method for treating pain in a patient, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to alleviate and/or inhibit said pain while maintaining a QT interval of less than about 500 ms during said treatment.
[0100] In one embodiment, the ibogaine is administered as a single dose or multiple doses.
In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage ibogainc is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine thereof is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine provides an average serum concentration of about 50 ng/mL
to about 200 ng/mL.
[0101] In one aspect, provided herein is a method for alleviating pain symptoms in a human patient susceptible to such symptoms, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to alleviate said pain symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0102] In one embodiment, the pain symptoms are due to chronic pain. In another embodiment, the ibogaine is administered as a single dose or multiple doses.
In another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day.
[0103] In one embodiment, the unit dose of ibogaine is administered in one or more dosings.
Depression [0104] The current invention is predicated on the surprising discovery that treatment with a narrow dosage range of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, between greater than about 1 mg/kg body weight and about 8 mg/kg body weight, provides a therapeutic reduction in symptoms of depression and/or PTSD in affected patients. Preferably, the dose range that provide both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1.3 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0105] In one aspect, this invention relates to treating depression and/or PTSD in a patient in need thereof comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, this invention treats depression. In another embodiment, this invention treats PTSD. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
[0106] In some embodiments, the therapeutic dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient is sufficient to provide an average scrum concentration of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL. In one embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 200 ng/mL.
[0107] In a preferred embodiment, the narrow therapeutic doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate described above unexpectedly do not prolong the QT interval to unacceptable levels in human patients. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT
interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify him/her from treatment with ibogaine or ibogaine derivative.
[0108] In some embodiments, the serum concentration is sufficient to inhibit or ameliorate symptoms of depression and/or PTSD while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment.
101091 In another aspect, this invention provides a method for treating depression and/or PTSD in a patient in need thereof comprising administering to the patient ibogaine, ibogaine derivative, or salt and/or solvate thereof in a sustained release manner such that the serum concentration of ibogaine or ibogaine derivative is maintained at a therapeutically effective amount for a period of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, or a period of time between any two of these durations.
[0110] In one aspect, provided herein is a method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine or ibogaine derivative serum level of between about 50 ng/mL
and about 400 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0111] In one embodiment, the therapeutically effective amount is between about 1 mg to about 4 mg per kg of body weight. In another embodiment, the therapeutically effective amount is between about 50 ng to less than 100 tg per kg of body weight. In another embodiment, the dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms. In another embodiment, the QT interval is less than about 420 ms. In another embodiment, the method further comprising selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
[0112] In another embodiment, depression is treated. In another embodiment, posttraumatic stress disorder is treated.
[0113] In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, ibogaine or ibogaine derivative or a pharmaceutically acceptable salt and/or solvate thereof is administered.
Reducing Tolerance To Opioid Analgesics [0114] This invention is directed, in part, to the use of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, preferably ibogaine, to modulate tolerance to addictive opioid analgesic agents in a patient who has developed or is at risk of developing a tolerance for the analgesic. In such methods, effective analgesia can be achieved in a patient while resensitizing the patient to the addictive opioid analgesic. The term "resensitizing the patient" is used herein to refer to reducing, relieving, attenuating, and/or reversing tolerance to the analgesic. In one aspect, the resensitized patient obtains therapeutic effect from a lower dose of the opioid analgesic than before resensitization.
In one aspect, the resensitized patient obtains improved therapeutic effect from the same dose of the opioid analgesic compared to before resensitization.
[0115] The use of ibogaine for the modulation of tolerance to opioid analgesic agents is limited due to potentially adverse side effects. The use of ibogaine to modulate opioid tolerance is generally not favored due to the adverse side effects that can result from receiving a therapeutic dose according to conventional known methods.
101161 In one embodiment, ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered concurrently with the opioid analgesic. In one embodiment, ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered after administration of the analgesic, for example one, two, three, four, eight, ten, twelve, 24 hours or more after administration of the analgesic. In one embodiment, one dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered. In one embodiment, two or more doses of ibogainc, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof are administered. In one embodiment, the opioid analgesic is interrupted for a period of time while ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered. In one embodiment, a non-opioid analgesic is administered while the opioid analgesic is interrupted. In one embodiment, ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof acts as an analgesic.
In one embodiment, the opioid analgesic is not interrupted during ibogaine treatment.
[0117] In one aspect, provided herein is a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic therapy an amount of ibogaine, ibogaine derivative or phaunaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
[0118] In one embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method further comprises interrupting the dosage of the analgesic.
In another embodiment, the method further comprises administering ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof concurrently with the analgesic. In another embodiment, during concurrent administration, the dose of opioid analgesic is reduced.
[0119] In another embodiment, the dose or aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day.
[0120] In another embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT
interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0121] In another embodiment, the method further comprises selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT
interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT interval greater than about 470 ms.
In another embodiment, the prescreening step comprises ascertaining that ibogaine treatment will not result in a QT interval greater than about 450 ms.
[0122] In another embodiment, the opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, oxymorphone. In another embodiment, the opioid analgesic is morphine.
Impulse Control [0123] The current invention is also predicated on the surprising discovery that treatment with a narrow dosage range of ibogaine or pharmaceutically acceptable salt and/or solvate thereof, between greater than about 1 mg/kg body weight and about 4 mg/kg body weight, provides a therapeutic reduction in symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders in affected patients, or provides a therapeutic reduction in food consumption. Preferably, the dose range that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0124] In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is between about 60 mg and about 150 mg. In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 100 mg. In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 120 mg.
In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 1.5 mg/kg body weight. In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds is about 2 mg/kg body weight.
[0125] In some embodiments, the patient is administered an initial dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, the initial dose is from about 50 mg to about 120 mg. In one embodiment, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from about 5 mg to about 50 mg. In one embodiment, such a dosing regimen provides an average serum concentration of ibogaine of about 50 ng/mL to about 180 ng/mL. In one embodiment, the one or more additional doses maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL
over a period of time. In one embodiment, the one or more additional doses are administered periodically.
[0126] Furthermore, at very low doses, direct blood stream delivery of ibogaine may reduce symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders, or provide regulation of food intake. Such dosing is well below that previously described.
Direct blood stream delivery of ibogaine enhances the amount of ibogaine delivered to the brain, because ibogaine does not pass through the liver as it does when ingested. Direct blood stream delivery of ibogaine includes sublingual, pulmonary and intranasal delivery where the ibogaine is absorbed directly into the blood stream and then into the brain.
The rapid delivery of ibogaine into the brain, e.g. less than about 15 minutes, may cause a significant reduction in symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders, or food cravings.
[0127] In one aspect, this invention relates to treating anxiety disorders, impulse control disorder, anger/violence-related disorders, or regulation of food intake in a patient in need thereof comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, solvate, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, this invention treats an anxiety disorder. In one embodiment, this invention treats OCD. In one embodiment, this invention treats generalized anxiety disorder. In one embodiment, this invention treats social anxiety disorder. In one embodiment, this invention treats panic disorder. In another embodiment, this invention treats impulse control disorder. In another embodiment, this invention treats pathological anger and/or violence. In another embodiment, this invention treats anger/violence-related disorders. In another embodiment, this invention reduces pathological anger in a patient. In another embodiment, this invention reduces violent outbursts in a patient. In another embodiment, this invention regulates food intake. In one embodiment, food consumption is reduced. In one embodiment, food cravings are reduced. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
[0128] In some embodiments, the therapeutic dose of ibogaine or pharmaceutically acceptable salt ancUor solvate thereof administered to the patient is sufficient to provide a serum concentration of about 1000 to about 6000 ng*hour/mL. In some embodiments the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide a maximum serum concentration (Cmax) of less than about 250 ng/mL. In a preferred embodiment, the therapeutic dose provides a Cmax of about 100 ng/mL to about 200 ng/mL.
[0129] In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 180 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 110 ng/mL. In one embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 100 ng/mL. In one embodiment, the dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of less than about 50 ng/mL.
[0130] In one aspect, provided herein is a method for treating an anxiety-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0131] In one embodiment, the anxiety-related disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and social anxiety disorder.
[0132] In another aspect, provided herein is a method for treating an impulse control disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine scrum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT
interval of less than about 500 ms during said treatment.
[0133] In one embodiment, the impulse control disorder is selected from the group consisting of borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder, attention deficit disorder, schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, internet addiction, trichotillomania, pathological skin picking, and compulsive shopping.
[0134] In another aspect, provided herein is a method for regulating food intake and/or attenuating food craving in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt ancUor solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average ibogaine serum level of between about 50 ng/mL and about 180 ng/mL
while maintaining a QT interval of less than about 500 ms during said treatment.
[0135] In another aspect, provided herein is a method for treating an anger-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, and further wherein the therapeutically effective amount provides an efficacious average ibogaine serum level of between about 50 ng/mL and about 180 ng/mL
while maintaining a QT interval of less than about 500 ms during said treatment.
[0136] In one embodiment, the method comprises:
a) administering an initial dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng/mL to about 180 ng/mL; and b) administering at least one additional dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of about 50 ng/mL to about 180 ng/mL
for a period of time.
101371 In one embodiment, the initial dose is from about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from about 6 hours to about 24 hours after the previous dose.
[0138] In another embodiment, the QT interval is less than about 450 ins. In another embodiment, the method further comprises selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
[0139] In another embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery.
101401 In another embodiment, ibogaine or a pharmaceutically acceptable salt and/or solvate thereof is administered.
101411 In some embodiments, the maintenance dose of ibogaine is 5 mg to 100 mg. In some embodiments, the maintenance dose of ibogaine is about 1.5 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 1 mg/kg body weight. In some embodiments, the maintenance dose of ibogaine is about 0.9 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.8 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.7 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.6 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.5 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.4 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.3 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.2 mg/kg body weight.
In some embodiments, the maintenance dose of ibogaine is about 0.1 mg/kg body weight.
Compounds Administered [0142] In the various method, formulation and kit aspects and embodiments, in one embodiment a compound utilized herein is represented by, or ibogaine as used herein is replaced by, a compound Formula 1:
X
wherein R is hydrogen or Ci-C3-alkoxy, RI is hydrogen, Ci-C3-alkyl, C1-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH, and X is H, COOH, or COOR2, where R2 is C1-C6 alkyl or (CH2CH20).CH3, where n = 1 to 3.
[0143] In another embodiment, ibogaine or a pharmaceutically acceptable salt and/or solvate thereof is utilized. In another embodiment, ibogaine or a pharmaceutically acceptable salt and/or solvate thereof is utilized. In another embodiment, the ibogaine, ibogaine derivative, is chosen from the group consisting of ibogaine, coronaridine, ibogamine, voacangine, 18-methoxycoronaridine, 2-methoxyethy1-18-methoxycoronaridinate, methylaminocoronatidine or a pharmaceutically acceptable salt and/or solvate thereof.
[0144] In another embodiment, the compound utilized herein is chosen from the group consisting of ibogaine, coronaridine, ibogamine, voacangine, 18-methoxycoronaridine, 2-methoxyethyl-18-methoxycoronaridinate, 18-methylaminocoronaridine and a pharmaceutically acceptable salt and/or solvate.
[0145] In another embodiment, the compound utilized herein is selected from the group consisting of 16-hydroxymethy1-18-hydroxyibogaline, 16-hydroxymethy1-18-methoxyibogaline, 16-ethoxycarbony1-18-hydroxyibogaline laurate, and 16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxymethyl ether and a pharmaceutically acceptable salt and/or solvate thereof.
[0146] In one embodiment, the ibogaine derivative is represented by Formula II:
II
ss, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is hydrogen or C1-C3 alkoxy;
RI is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, (CH2)õ,0C(0)alkyl, (CH2)OH, (CH2).0a1kyl, (CH2).,0(CH2)p0(CH2),P(CH2),CH3 or CH2-Y-CH3 where each of m, p and q is 1,2 or 3; and r is 0, 1 or 2,Y is 0 or NH; and R2 is H, (CH2)õOH, COOH, or COOR4, where R4 is C1-C6 alkyl or (CH2CH20)õCH3, where n is 1, 2, or 3.
[0147] In one embodiment, the ibogaine derivative is selected from the group consisting of coronaridine, ibogamine, voacangine, 18-methoxycoronaridinc, 2-Methoxycthy1-18-methoxycoronaridinate, and 18-Methylaminocoronaridine.
[0148] In one embodiment, the ibogaine derivative is selected from the group consisting of 16-hydroxymethy1-18-hydroxyibogaline, 16-hydroxymethy1-18-methoxyibogaline, 16-ethoxycarbony1-18-hydroxyibogaline laurate, and 16-ethoxycarbony1-18-hydroxyibogaline methoxyethoxymethyl ether.
[0149] In one embodiment, the compound is of Formula IA:
X
IA
wherein R is hydrogen or CI-C3-alkoxy, RI is hydrogen, Ci-C3-alkyl, Ci-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH, and X is H, COOH, or COOR2, where R2 is Cl-C6 alkyl or (CH2CH20),CH3, where n = 1 to 3.
[0150] In another embodiment, the ibogaine derivative is represented by Formula II:
s, II
or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is OCH3;
RI is CH2CH3; and R2 is COOR4, where R4 is (CH2CH20)nCH3, where n is 1.
[0151] When replacing ibogaine, the compounds of formula I, It and subformulas thereof as utilized herein exclude ibogaine.
[0152] In a preferred embodiment, the compound utilized herein is:
a pharmaceutically acceptable salt thereof, or a solvate of each thereof.
[0152A] In another aspect, provided herein is a use of a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating nicotine addiction in a patient in need thereof, wherein said therapeutically effective amount is from about 50 ng to less than 10 jig per kg body weight per day.
Date Recue/Date Received 2021-07-21 [0152B] In another aspect, provided herein is a use of a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating nicotine addiction in a patient in need thereof, wherein said therapeutically effective amount is from about 50 ng to less than 10 pg per kg body weight per day.
[0152C] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating alcohol dependence in a human patient suffering therefrom, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.
[0152D] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating alcohol dependence in a human patient suffering therefrom, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.
[0152E] In another aspect, provided herein is a use of a therapeutic dose of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, wherein said therapeutic dose provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
10152F1I In another aspect, provided herein is a use of a therapeutic dose of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, wherein said therapeutic dose provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
36a Date Recue/Date Received 2021-07-21 [0152G] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer physically dependent on alcohol.
[0152H] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer physically dependent on alcohol.
[01521] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
10152J1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152K] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mI, to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
36b Date Recue/Date Received 2021-07-21 [0152L1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0152M] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
[0152N] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
[01520] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating opioid or opioid-like drug abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152P1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating opioid or opioid-like drug abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic 36c Date Recue/Date Received 2021-07-21 dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0152Q] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating substance abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0152R] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating substance abuse in a human patient addicted thereto, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL
to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152S] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
10152T1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mI, to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
36d Date Recue/Date Received 2021-07-21 [0152U1 In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of substance abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the substance.
[0152V1 In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of substance abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is formulated for periodic administration to said patient who is no longer abusing the substance.
10152W1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating substance abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152X1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating substance abuse in a patient addicted thereto who is prescreened to evaluate tolerance for prolongation of QT interval, wherein said therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0152Y] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, wherein said therapeutic dosage is formulated for interruption or concurrent administration with said opioid analgesic 36e Date Recue/Date Received 2021-07-21 therapy to provide an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
10152Z] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, wherein said therapeutic dosage is formulated for interruption or concurrent administration with said opioid analgesic therapy to provide an average serum concentration of about 50 ng/mL to about 500 ng/mI ., said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
10152AA1 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152B1311 In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
10152CC] In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, 36f Date Recue/Date Received 2022-05-30 said dosage being sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 500 ms during said treatment.
[0152DDI In another aspect, provided herein is a use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[1:1152EE] In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is about 70% or less than the therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt, where the therapeutic dosage is the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt of from about 1 mg/kg to about 4 mg/kg body weight per day, said maintenance dosage being formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
[0152FF1 In another aspect, provided herein is a use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is about 70% or less than the therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt, where the therapeutic dosage is the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt of from about 1 mg/kg to about 4 mg/kg body weight per day, said maintenance dosage being formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
36g Date Recue/Date Received 2022-11-07 DETAILED DESCRIPTION
[0153] It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of this invention will be limited only by the appended claims.
[0154] The detailed description of the invention is divided into various sections only for the reader's convenience and disclosure found in any section may be combined with that in another section. Unless defined otherwise, all technical and scientific terms used herein have 36h Date Recue/Date Received 2022-05-30 the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
101551 It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes a plurality of compounds.
Definitions [0156] Unless defined otherwise, all technical and scientific tet Ins used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings.
[0157] The term "about" when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( +) or ( - ) 10 %, 5 % or 1 % or any subrange or subvalue there between.
[0158] "Administration" refers to introducing an agent, such as ibogainc, into a patient.
Typically, an effective amount is administered, which amount can be determined by the treating physician or the like. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used. The agent may be administered by direct blood stream delivery, e.g. sublingual, intranasal, or intrapulmonary administration.
[0159] The related terms and phrases "administering" and "administration of", when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
[0160] "Periodic administration" or "periodically administering" refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of ibogainc or salt and/or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.
[0161] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of' when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of' shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
[0162] As used herein, is a single bond or a double bond.
[0163] As used herein, the term "alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((C113)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CI3)2CHCH2-), sec-butyl ((CH3)(C113CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). The term "Cx alkyl" refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C3 refers to an alkyl group having 3 carbon atoms.
[0164] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, R20_c(0)_, _ NR2 C(0)R2 , R20_C(0)¨u_, _ NR2 R20, _C(0)NR20R20 , -C(S)NR20R20, -NR20C(0)NR20R20, _met (S)NR2 R2 0, -0-C(0)NR20R20 , S(0)2NR20R20, _o_s(0)2NR20R20, _N¨K 20 _ S(0) 2NR2 R 20, _ C (=NR2 ) NR20K 20, aryl, aryloxy, arylthio, azido, carboxyl, -C(0)0-R21, -NR20-C(0)0-R21, -0-C(0)0-R21, cyano, cycloalkyl, 2, cycloalkyloxy, cycloalkylthio, _NR2OceNR20)N(R20) halo, hydroxy, hydroxyamino, _NR2o-NR2o¨K2o, alkoxyamino, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl, SO3H, -0S(0)2-R21, -s(o)2-R21, _c (s)--K 21, thiocyanate, thiol, and alkylthio; each R2 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R2 groups attached to a common atom are optionally joined together with the atom bound thereto to form a heterocycle; and each R21 is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle.
[0165] "Alkoxy" refers to the group -0-alkyl wherein alkyl is defined herein.
Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
[0166] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(41-1)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
101671 "Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, -C(0)-R20, _NR20c(0)R20, R20-C(0)0-, - ONR2 K20, C(0 )NR20K- 20, _ C(S)NR2oR20, _NR20c(o)NR20R20, _N.-.K 20-U(S)NR213R2 o, -0-C(0)NR20R20, -S(0)2NR2o-K, _ 20 O-S (0)2NR
20R20, _N¨K 20_ S(0)2NR2 R20, _G(=NR20)NR20-K 20, aryl, aryloxy, arylthio, azido, carboxyl, -C(0)0_R21, _NR20 _ C(0)0-R21, -0-C(0)0-R21, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, -NR20c(=NR20)N)(R20, 2, halo, hydroxy, hydroxyamino, alkoxyamino, -NR2ONR20¨ 20, K heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl, S011-1, -0S(0)2-R21, -S(0)2_R21, -C(S)-R21, thiocyanate, thiol, and alkylthio; each R2 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R2 groups attached to a common atom are optionally joined together with the atom bound thereto to form a heterocycle; and each R21 is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle.
[0168] "Cyano" refers to the group -CN.
[0169] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 or 3 to 8 carbon atoms having single or multiple cyclic rings including fused, bridged, and Spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicycle[2,2,2doctanyl, norbomyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl.
[0170] "Substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkoxy, -C(0)-R20, -NR2oc(o)R2o, R20-C(0)0_, _NR20R20, _ C(0)NR2 R20, _C(S)NR2()R20, -NR20c(0)NR2oR2o, _N.-.K 20¨
U(S)NR2 R2 o, -0-C(0)NR20R20, ¨
S(0)2NR20 R20, _o_s(0)2NR2OR20, _N¨K 20_ S(0) 2NR2 R 20, _ C(=NR20)NR20¨x 20, aryl, aryloxy, arylthio, azido, carboxyl, -C(0)0-R21, _NR 20 -C(0)0-R21, -0-C(0)0-R21, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, -NR20C(=NR20)N(R20, ) halo, hydroxy, hydroxyamino, alkoxyamino, -NR20NR20¨K 20, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, hetcrocyclylthio, nitro, spirocycloalkyl, SO3H, -0S(0)2-R21, -S(0)2-R21, -C(S)-R21, thiocyanate, thiol, and alkylthio;
each R2 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R2 groups attached to a common atom are optionally joined together with the atom bound thereto to form a heterocycle; and each R21 is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle.
[0171] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
[0172] "Haloalkyl" refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein.
[0173] "Heteroaryl" refers to an aromatic group of from 5 to 14 ring atoms, including from 1 to 10 carbon atoms and 1 to 4 heteroatorns selected from the group consisting of oxygen, nitrogen and sulfur. In some embodiments, heteroaryl comprises 5, 6, or 7 ring atoms, including 1 to 4 heteroatoms. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N¨>0), sulfinyl, and/or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and fiiranyl.
[0174] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
101751 "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyr refers to a saturated or partially saturated, but not aromatic, group having from 3 to 14 ring atoms, including from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. In some embodiments, heteroaryl comprises 3, 4, 5, 6 or 7 ring atoms, including 1 to 4 heteroatoms. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and Spiro ring systems.
In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfmyl, and/or sulfonyl moieties.
[0176] "Substituted heterocyclic" or "substituted hetcrocycloalkyl" or "substituted heterocycly1" refers to heterocycly1 groups that are substituted with flbm 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
[01771 "Ibogaine" refers to the compound:
It should be understood that where "ibogaine" is mentioned herein, one more polymorphs of ibogaine can be utilized and are contemplated. lbogaine is isolated from Tabernanth iboga, a shrub of West Africa. lbogaine can also be synthesized using known methods.
See, e.g., Biichi, etal. (1966), J. Am. Chem Society, 88(13), 3099-3109 Unless specified otherwise, "ibogaine" as used herein refers to ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
[0178] In some embodiments, the ibogaine or ibogaine derivative is represented by Formula or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is H, halo, C1-C3 alkyl, substituted C1-C3 alkyl, OR1 , NH2, NHR1 , NR10R11, NHC(0)R10, or NR1 C(0)R11;
R1 is H, C1-C3 alkyl, substituted CI-C3 alkyl, C1-C3 alkoxy, CH2-X-CH, or (CH2),,,,R3;
R2 is H, COOH, COOR4, (CH2).0H, CH(OH)R5, CH2OR5, C(0)NH2, C(0)NHR5, C(0)NR5R6, C(0)NHNH2, C(0)NHNHR5, C(0)NHNR5R6, C(0)NR5NH2, C(0)NR5NHR6, C(0)NR5NR6R7, C(0)NHNH(C(0)R5), C(0)NHNR5(C(0)R6), C(0)NR5NH(C(0)R6), C(0)NR5NR6(C(0)R7), CN, or C(0)R5;
RI is C1-C3 alkyl, benzyl, substituted Ci-C3alkyl, YH, YR8, YC(0)R8, C(0)YR8, C(0)NH2, C(0)NHR8, C(0)NR8R9, NH2, NHR8, NR8R9, NHC(0)R8, 0(CH2)p0(CH2),10(CH2)rCH3 or NR8C(0)R9;
R4 is C1-C6 alkyl or (CH2CH20)na-13;
R5, R6, R7, R8, R9, R1 , and Ri 1 are independently alkyl or substituted alkyl;
K is H, alkyl, or substituted alkyl;
R13 is H, OR1 , alkyl, or substituted alkyl;
Xis 0 or NH;
YisOorS;
m is an integer selected from 0-8;
each of n, p and q is 1, 2 or 3; and ris0,1or2.
[0179] In some embodiments, the ibogaine or ibogaine derivative is represented by Formula or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is hydrogen or CI-C:3 alkoxy, RI is hydrogen, Ci-C3 alkyl, Ci-C3 alkoxy, (CH2).0C(0)alkyl, (CH2).0H, (CH2)mOalkyl, (CH2),,,O(CH2)p0(CH2)0(CH2)1CH3 or CH2-Y-CH3 where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is 0 or NH, and R2 is H, (CH2)õ0H, COOH, or COOR4, where R4 is C1-C6 alkyl or (CH2CH20)11CH3, where n is 1, 2, or 3.
[0180] In one embodiment, R is methoxy. In one embodiment, RI- is ethyl. In one embodiment, RI is methoxy. In one embodiment, RI is CH2-Y-CH3 where Y is 0. In one embodiment, Itt is CH2-Y-CH3 where Y is NH. In one embodiment, R2 is hydrogen.
In one embodiment, In one embodiment, R2 is COOR4 and R4 is methyl. In one embodiment, n = 1.
In a preferred embodiment, R, RI and R2 are all not hydrogen. In one embodiment, when R is methoxy and R1 is hydrogen, then R2 is COOH or COOR4. In another embodiment, when R
is methoxy and RI is hydrogen, then X is COOR4 where R4 is (CH2CH20)CH3.
[0181] In one embodiment, R12 is hydrogen.
[0182] In one embodiment, le is H. In one embodiment, RI is C1-C3 alkyl, such as ethyl.
In one embodiment, RI is CH2CH2OH. In one embodiment, RI is CH2CH2OCH3. In one embodiment, RI is CH2CH20CH2Ph. In one embodiment, Rl is CH2CH20C(0)alkyl. In one embodiment, RI is CH2CH20(CH2)p0(CH2)40(CH2),CH3.
[0183] In one embodiment, R2 is CH2OH and CH(OH)R5. In one embodiment, R2 is CH2OR5. In one embodiment, R2 is CO2R5. In one embodiment, R2 is C(0)NH2, C(0)NHR5, or C(0)NR5R6. In one embodiment, R2 is C(0)NHNH2, C(0)NHNHR5, C(0)NR5NH2, C(0)NHNR5R6, C(0)NH5NHR6, or C(0)NR5NR6R7. In one embodiment, R2 is C(0)NHNH(C(0)R5), C(0)NHNR5(C(0)R6), C(0)NR5NH(C(0)R6), or C(0)NR5NR6(C(0)R7). In one embodiment, R2 is C(0)R5.
[0184] In some embodiments, the ibogaine or ibogaine derivative is selected from:
Name Structure coronaridine 1 8-hydroxycoronaridine OH
1 8-methoxycoronaridine OCH3 18-benzyloxycoronaridine 18-hydroxycoronaridine laurate 0 (CH2)ioCH3 18-hydroxycoronaridine methoxyethoxymethyl ether 18-hydroxycoronatidine acetate voacangine 18-hydroxyvoacangine OH
18-methoxyvoacangine OCH3 18-benzyloxyvoacangine 18-hydroxyvoacangine laurate (CH2)10CH3 18-hydroxyvoacangine acetate 18-hydroxyvoacangine methoxyethoxyrnethyl ether conopharyngine 18-hydroxyconopharyngine OH
18-methoxyconopharyngine OCH3 18-benzyloxyconopharyngine 18-hydroxyconopharyngine laurate (CH2)1oCH3 18-hydroxyconopharyngine acetate 18-hydroxyconopharyngine methoxyethoxymethyl ether 0 ibogamine 16-ethoxycarbony1-18- OH
hydroxyibogamine = 02CH2CH3 16-hydroxymethy1-18- OH
hydroxyibogamine = H2OH
16-ethoxycarbony1-18- OCH3 methoxyibogamine = 020H2CH3 16-hydroxyrnethyl- 18-methoxyibogamine = H2OH
16-ethoxycarbony1-18-benzyloxyibogamine 0 .3 16-ethoxycarbony1-18- 0 (CH2)10CH3 hydroxyibogamine latuate = 02CH2CH3 16-ethoxycarbony1-18-hydroxyibogamine acetate = 02CH2CH3 16-ethoxycarbony1-18-hydroxyibogamine methoxyethoxymethyl ether ibogaine 16-ethoxycarbony1-18- OH
hydroxyibogaine = 02CH2CH3 1 6-hydroxymethy1-1 8- OH
hydroxyibogaine = H2OH
16-ethoxycarbony1-18- 0, methoxyibogaine 16-hydroxyrnethyl- 18-methoxyibogaine 16-ethoxycarbony1-18-benzyloxyibogaine 0 16-ethoxycarbony1-18-)1111 hydroxyibogainelaurate 16-ethoxycarbony1-18-hydroxyibogaine acetate 16-ethoxycarbony1-18-hydroxyibogaine methoxyethoxymethyl ether ibogaline 16-ethoxycarbony1-18- OH
hydroxyibogaline '0 16-hydroxymethy1-18- OH
hydroxyibogaline 16-ethoxycarbony1-18- OCH3 methoxyibogaline "0 16-hydroxymethy1-18- OCH3 methoxyibogaline 16-ethoxycarbony1-18-benzyloxyibogaline 0 16-ethoxycarbony1-18- (CH2)1oCH3 hydroxyibogalinc lauratc 16-ethoxycarbony1-18-hydroxyibogaline acetate 16-ethoxycarbony1-18-hydroxyibogaline 0 methoxyethoxymethyl ether "0 and pharmaceutically acceptable salts and/or solvates thereof.
101851 This invention is not limited to any particular chemical form of the compounds, and the drug may be given to patients either as a free base, solvate, or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used.
Examples of such acids include, without limitation, those described below as "pharmaceutically acceptable salts" and the like.
101861 In one embodiment, the ibogaine derivative is:
(coronaridine), (ibogamine), (voacangine), 0, (18-methoxycoronaridine, 18-MC), 0, (2-Methoxyethyl- 1 8-methoxycoronaridinate, ME-1 8-MC), or N, (18-Methylaminocoronaridine, 18-MAC).
[0187] "Pharmaceutically acceptable composition" refers to a composition that is suitable for administration to a mammal, particularly, a human. Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.
[0188] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
[0189] A "pharmaceutically acceptable solvate" or "hydrate" of a compound of the invention means a solvate or hydrate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, and includes, but is not limited to, complexes of a compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
[0190] As used herein the term "solvate" is taken to mean that a solid-form of a compound that crystallizes with one or more molecules of solvent trapped inside. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but arc certainly not limited to, water, methanol, ethanol, isopropanol, butanol, Cl-C6 alcohols in general (and optionally substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention. Additionally, various organic and inorganic acids and bases can be added or even used alone as the solvent to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate. Further, by being left in the atmosphere or recrystallized, the compounds of the present invention may absorb moisture, may include one or more molecules of water in the formed crystal, and thus become a hydrate.
Even when such hydrates are formed, they are included in the term "solvate". Solvate also is meant to include such compositions where another compoi id or complex co-crystallizes with the compound of interest.
[0191] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate, or derivative of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of ibogaine, in the context of treating nicotine dependency, refers to an amount of the ibogaine that attenuates the dependency and/or statistically presents little or no risk of relapse to nicotine use. For example, and without limitation, a therapeutically effective amount of ibogaine, in the context of treating alcohol dependency, refers to an amount of ibogaine that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of ibogaine in the context of treating opioid or opioid-like drug dependency, refers to an amount of compound that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of ibogaine in the context of treating drug dependency, refers to an amount of compound that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of ibogaine, in the context of treating pain, refers to an amount of ibogaine that provides immediate and/or sustained pain relief for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of an agent, in the context of treating anxiety disorders, impulse control disorder, and/or anger/violence-related disorders, refers to an amount of the agent that attenuates the anxiety disorder, impulse control disorder, or anger/violence-related disorders, and/or symptoms thereof, in the patient.
A therapeutically effective amount of an agent, in the context of regulating food intake and/or controlling food cravings, refers to an amount of the agent that reduces the patient's food intake and/or reduces food cravings in the patient.
[0192] A "therapeutic level" of a drug is an amount of ibogaine that is sufficient to treat a disease or disorder or symptoms of a disease or disorder or to heat, prevent, or attenuate a disease or disorder or symptoms of a disease or disorder, but not high enough to pose any significant risk to the patient. Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient.
This concentration is referred to as the "serum concentration." Where the serum concentration of ibogaine is mentioned, it is to be understood that the term "ibogaine"
encompasses any form of ibogaine, including derivatives thereof.
101931 As defined herein, a "prophylactically effective amount" of a drug is an amount, typically less than the therapeutically effective amount, that provides attenuation and/or prevention of a disease or disorder or symptoms of a disease or disorder in a patient. For example, the prophylactically effective amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer physically addicted to nicotine. For example, a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount. However, a prophylactically effective amount may be the same as the therapeutically effective amount, for example when a patient who is physically addicted to nicotine is administered ibogaine to attenuate cravings for a period of time when nicotine use is not feasible. The prophylactically effective amount may vary for different a diseases or disorders or symptoms of different diseases or disorders.
[0194] As defined herein, a "maintenance amount" of a drug is an amount, typically less than the therapeutically effective amount that provides attenuation and/or prevention of a disease or disorder or symptoms of a disease or disorder in a patient. The maintenance amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer manifests a disease or disorder or symptoms of a disease or disorder. For example, a maintenance amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount. However, a prophylactically effective amount may be the same as the therapeutically effective amount, for example when a patient who is physically addicted to nicotine is administered ibogaine to attenuate cravings for a period of time when nicotine use is not feasible., or any subvalue or subrange there between.
[0195] "Treatment", "treating", and "treat" are defined as acting upon a disease, disorder, or condition with ibogaine to reduce or ameliorate harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. "Treatment," as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the condition but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition. "Treating" or "treatment of' a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to: treating nicotine addiction; treating, preventing, and/or attenuating cravings for nicotine; and preventing relapse of nicotine use. This includes reducing or eliminating smoking in the patient, and/or reducing or eliminating symptoms of withdrawal, cravings, and the like. For some purposes of this invention, beneficial or desired clinical results include, but arc not limited to: treating substance addiction;
treating, preventing, and/or attenuating acute withdrawal symptoms; treating, preventing, and/or attenuating long-term (post-acute) withdrawal symptoms; and preventing relapse of substance use. For purposes of certain aspects of this invention, beneficial or desired clinical results include, but are not limited to: pain relief in all categories and classifications of pain;
treating, alleviating and/or preventing acute and/or chronic pain; treating, alleviating and/or preventing cutaneous, somatic, visceral and/or neuropathic pain; and preventing the recurrence of long-term pain.
[0196] "Periodic administration" or "periodically administering" refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.
[0197] As used herein, the terms "addiction", "abuse", and "dependence" are used interchangeably to refer to the patient's inability to stop using nicotine, alcohol, a drug, or the like, even when it would be in his/her best interest to stop. A patient may be physically and/or behaviorally addicted to a substance. The DSMIV-TR criteria for dependency include:
Dependence or significant impairment or distress, as manifested by 3 or more of the following during a 12 month period:
1. Tolerance or markedly increased amounts of the substance to achieve intoxication or desired effect or markedly diminished effect with continued use of the same amount of substance 2. Withdrawal symptoms or the use of certain substances to avoid withdrawal symptoms 3. Use of a substance in larger amounts or over a longer period than was intended 4. Persistent desire or unsuccessful efforts to cut down or control substance use 5. Involvement in chronic behavior to obtain the substance, use the substance, or recover from its effects 6. Reduction or abandonment of social, occupational or recreational activities because of substance use 7. Use of substances even though there is a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance [0198] As used herein, the term "nicotine addict in remission" refers to any patient who has quit using nicotine for a period of time. As used herein, a nicotine addict in remission includes any person who was previously addicted to nicotine in any form, including but not limited to cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. The period of time since the nicotine addict in remission quit using nicotine may be short, for example one day to a few weeks, or longer-term, for example months or years. Preferably, the patient has quit using nicotine long enough to no longer exhibit physical symptoms of nicotine addiction. The patient may exhibit psychological symptoms of nicotine addiction. In some embodiments, the patient does not exhibit psychological symptoms of nicotine addiction.
101991 As used herein, the term "patient" refers to mammals and includes humans and non-human mammals.
[0200] As used herein, the terms "addictive substance", "drug", "addictive drug" and the like refer to drugs and other substances whose use results in addiction in at least a subset of individuals who use them. Addictive substances include, without limitation, benzodiazepines (including chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, and midazolam), cannabinoids and synthetic cannabinoids, stimulants (including amphetamine, methylphenidate, dexmethylphenidate, dextroamphetamine, mixed amphetamine salts, dextromethamphetamine, lisdexamfetamine, modafinil, adrafinil, armodafinil, caffeine, ephedrine, methylenedioxymethamphetamine, methylenedioxypyrovalerone, mephedrone, phenylpropanolamine, propylhexachine, pseudo ephedrine, and khat), barbiturates (including allobarbital, amobarbital, aprobarbital, alphenal, barbital, brallobarbital, pentobarbital, phenobarbital, and secobarbital), gamma-hydroxybutyrate (GHB), ketamine, opiate, opioid, opioid-like drug, PCP, dextromethorphan (DXM), lysergic acid diethytamide (LSD), mescaline, anabolic steroids, and derivatives of each thereof Addictive substances may be illicit drugs, prescription drugs prone to abuse, or other legal drugs prone to abuse."
[0201] As used herein, the term "opiate" refers to naturally-occurring alkaloids found in the opium poppy. These include codeine, morphine, oripavirte, pseudomorphine, and thebaine.
Also included are opium, opium poppy, poppy straw, and extracts and concentrates thereof.
[0202] As used herein, the term "opioid" refers to naturally-occurring opiates and synthetic or semi-synthetic opioids that have psychoactive effects. Non-limiting examples include acetyl-alpha-methylphentanyl, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprodine, anileridine, benzylmorphine, benzethidine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butorphanol, earfentanil, clonitazene, codeine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diethylthiambutene, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethyl-thiambutene, dioxaphetyl butyrate, diphenoxylate, difenoxin, dipipanone, eptazocine, ethohcptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levo-alphacetylmethadol, levomethorphan, levorphanol, levophenacylmorphan, levomoramide, lofentani1, loperamide, laudanum, mepeiidine, meptazinol, metazocine, methadone, 3-methylfentanyl, 3-methylthiofentanyl, metopon, morphine, morpheridine, MPPP (1-methyl-4-phenyl-4-propionoxypiperidine), myrophine, narceine, nicomorphine, noracymethadol, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, para-fluorofentanyl, paregoric, PEPAP (14-2-phenethyl)-4-phenyl-4-acetoxypiperidine), pentazocine, phenadoxone, phenampromide, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, racemoramide, racemethorphan, racemorphan, remifentanil, sufentanil, tapentadol, thebaine, thiofentanyl, tilidine, tramadol, trimeperidine, mixtures of any of the foregoing, salts of any of the foregoing, derivatives of any of the foregoing, and the like. The term opioids also encompasses opioid intermediates, including 4-cyano-2-dimethylamino-4,4-diphenyl butane, 2-methy1-3-morpholino-1,1-diphenylpropane-carboxylic acid, 4-cyano-1-methyl-4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate, and 1-methy1-4-phenylpiperidine-4-carboxylic acid. Many opioids are Schedulel or Schedule II drugs in the US.
102031 As used herein, the term "opioid-like drug" refers to any illicit drug that binds to one or more opioid receptor and causes opioid-like addiction. Acute and long-term withdrawal symptoms from cessation of use of such drugs may be similar to those from cessation of opioids. Opioid-like drugs include amphetamine, methamphetamine, ketamine, and cocaine.
[0204] Obsessive compulsive disorder (OCD) is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic ancUor repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, and/or significantly interfere with social or occupational functioning.
[0205] Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a). A panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
102061 Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a).
Exposure to the feared situation almost invariably provokes anxiety, which may appioach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) int erferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
102071 Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM-IV
(American Psychiatric Association, 1994a).
[0208] Impulse control disorder is a class of psychiatric disorders involving the failure to resist a temptation, urge, or impulse (impulsivity) where such impulse is potentially harmful to the patient and/or others. The American Psychiatric Association's DSM-5 (May 2013) includes impulse control disorders "characterized by problems in emotional and behavioral self-control".
These include borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, intemet addiction, trichotillomania, pathological skin picking, and compulsive shopping. Impulse control disorder may be related to anxiety disorder and/or OCD.
[0209] Violence and anger, particularly when out of proportion to a stimulus and/or a result of pathological anger, are associated with a number of mental disorders. These include oppositional defiant disorder, attention-deficit/hyperactivity disorder and conduct disorder (in Date Recue/Date Received 2021-07-21 children and adolescents), psychotic disorder, bipolar disorder, antisocial, borderline, paranoid and narcissistic personality disorders, adjustment disorder with disturbance of conduct, and intermittent explosive disorder. Pathological anger and violence account for a significant portion of violent crimes, including many high-profile crimes involving multiple victims. Hidhly volatile individuals are over-represented in the prison system in the United States.
[0210] As used herein, the term "pain" refers to all categories and classifications of pain, which are summarized below for purposes of illustration. First, cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localized pain of short duration. Example injuries that produce cutaneous pain include paper cuts, minor burns (e.g., first degree burns) and superficial lacerations.
[0211] Second, somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves, and is detected with somatic nociceptors. The scarcity of nociceptors in these areas produces a sharp, aching, pain of longer duration than cutaneous pain and somewhat less localized. Examples include a sprained ankle or broken bones.
[0212] Third, visceral pain originates from body organs. Visceral nociceptors are located within body organs and internal cavities. Similar to somatic pain, a scarcity of nociceptors in these areas produces a pain usually more aching and of a longer duration than somatic pain.
Visceral pain may be more difficult to localize. Injuries to visceral tissue may exhibit "referred" pain, where the sensation is localized to an area completely unrelated to the site of injury. Myocardial ischaemia (i.e., the loss of blood flow to a part of the heart muscle tissue) is an example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm, or hand. Another example of referred pain is phantom limb pain. Phantom limb pain is the sensation of pain from a limb that a person no longer has or from which the person no longer receives physical signals. This phenomena¨
also known as deafferentation pain is almost universally reported by amputees and quadriplegics.
[0213] Fourth, neuropathic pain (e.g., "neuralgia") can occur as a result of injury or disease to the nerve tissue itself. The injury or disease can disrupt the ability of the sensory nerves to transmit correct information to the thalamus or cortex. Consequently, the brain interprets painful stimuli even though there is no obvious or documented physiologic cause for the pain.
[0214] Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain indicates present damage to tissue or disease and may be "fast" and "sharp" followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. Acute pain generally responds well to medications (e.g., morphine).
[0215] Chronic pain may be medically defined as pain that has lasted six months or longer.
This constant or intermittent pain has often outlived its purpose because it does not help the body to prevent injury. It is often more difficult to treat than acute pain.
Expert care is generally necessary to treat any pain that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to control the pain. This can lead to drug dependency. For example, opioids are used in some instances for prolonged periods to control chronic pain. Drug tolerance, chemical dependency, and even psychological addiction may occur.
[0216] The therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood administration (e.g., sublingual, pulmonary and intfanasal delivery) is used, a lower dose of the compound is administered. In one aspect, a therapeutically effective amount of ibogaine or derivative is from about 50 ng to less than 100 pg per kg of body weight.
Where other routes of administration are used, a higher dose of the compound is administered. In one embodiment, the therapeutically effective amount of the compound is from greater than about 1 mg to about 8 mg per kg of body weight per day.
[0217] As used herein, the term "QT interval" refers to the measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. Prolongation of the QT interval refers to an increase in the QT interval.
[0218] "Nociceptive pain" refers to pain that is sensed by nociceptors, which are the nerves that sense and respond to parts of the body suffering from a damage. The nociceptors can signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.
Nociceptive pain is typically well localized, constant, and often has an aching or throbbing quality. A subtype of nociceptive pain includes visceral pain and involves the internal organs.
Visceral pain tends to be episodic and poorly localized. Nociceptive pain may be time limited;
when the tissue damage heals, the pain typically resolves. However, nociceptive pain related to arthritis or cancer may not be time limited. Nociceptive pain tends to respond to treatment with opiate analgesics, such as, for example, buprenorphin, codeine, hydrocodone, oxycodone, morphine, and the like. Examples of nociceptive pain include, without limitation, pains from sprains, bone fractures, burns, bumps, bruises, inflammatory pain from an infection or arthritic disorder, pains from obstructions, cancer pain, and myofascial pain related to abnormal muscle stresses.
[0219] "Neuropathic pain" refers to chronic pain, often due to tissue injury.
Neuropathic pain is generally caused by injury or damage to nerve fibers. It may include burning or coldness, "pins and needles" sensations, numbness and/or itching. It may be continuous and/or episodic. Neuropathic pain is difficult to treat, but opioids, including, without limitation, methadone, tramadol, tapentadol, oxycodone, methadone, morphine, levorphanol, and the like. Causes of neuropathic pain include, without limitation, alcoholism; amputation;
back, leg, and hip problems; chemotherapy; diabetes; facial nerve problems;
HIV/AIDS;
multiple sclerosis; shingles; spine surgery; trigeminal neuralgia;
fibromyalgia; and the like. In some cases, the cause of neuropathic pain may be unclear or unknown.
[0220] "Addictive" refers to a compound that, when administered to a mammal over a period of time, creates dependency in the mammal to that compound. The dependence can be physiological and/or psychological. A therapeutic effect of an addictive compound on a mammal may decrease with prolonged administration of the addictive compound, which is a non-limiting example of a physiological dependence. When administered to a mammal, an addictive compound may also create a craving in the mammal for more of it, which is a non-limiting example of a psychological dependence. Examples of addictive compounds include, without limitation, addictive opioids, and the like.
[0221] "Analgesic" and "analgesic agent" refer to a compound that is capable of inhibiting and/or reducing pain in mammals. Pain may be inhibited and/or reduced in the mammal by the binding of the opioid analgesic agent to the mu receptor. When analgesia is effected through the mu receptor, the analgesic agent is referred to as a mu receptor agonist. Certain analgesic agents are capable of inhibiting nociceptive and/or neuropathic pain including, by way of example, morphine, codeine, hydromorphone, oxycodone, hydrocodone, buprenorphin, and the like.
[0222] The term "tolerance" as used herein refers to the psychological and/or physiologic process wherein the patient adjusts to the frequent presence of a substance such that a higher dose of the substance is required to achieve the same effect. Tolerance may develop at different times for different effects of the same drug (e.g., analgesic effect versus side effects). The mechanisms of tolerance are not entirely understood, but they may include receptor down-regulation or desensitization, inhibitory pathway up-regulation, increased metabolism, and/or changes in receptor processing (e.g., phosphorylation).
[0223] The therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood administration (e.g., sublingual, pulmonary, buccal, or intranasal delivery) is used, a lower dose of the compound is administered. In one aspect, a therapeutically effective amount of ibogaine or derivative is from about 50 ng to less than about 100 gg per kg of body weight.
Where other routes of administration are used, a higher dose of the compound is administered. In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 4 mg per kg of body weight per day.
[0224] The term "dose" refers to a range of ibogaine, ibogaine derivative, or pharmaceutical salt or solvate thereof that provides a therapeutic serum level of ibogaine when given to a patient in need thereof. The dose is recited in a range, for example from about 20 mg to about 120 mg, and can be expressed either as milligrams or as mg/kg body weight. The attending clinician will select an appropriate dose florin the range based on the patient's weight, age, degree of addiction, health, and other relevant factors, all of which are well within the skill of the art.
[0225] The term "unit dose" refers to a dose of drug that is given to the patient to provide therapeutic results, independent of the weight of the patient. In such an instance, the unit dose is sold in a standard form (e.g., 20 mg tablet). The unit dose may be administered as a single dose or a series of subdoses. In some embodiments, the unit dose provides a standardized level of drug to the patient, independent of weight of patient. Many medications are sold based on a dose that is therapeutic to all patients based on a therapeutic window. In such cases, it is not necessary to titrate the dosage amount based on the weight of the patient.
Compositions [0226] As will be apparent to the skilled artisan upon reading this disclosure, in one aspect this invention provides compositions for treating a disease or disorder as described herein in a subject, comprising ibogaine. In another aspect this invention further provides compositions for treating, attenuating, or preventing a disease or disorder or symptoms of a disease or disorder as described herein in a subject, comprising ibogaine.
[0227] This invention is not limited to any particular chemical form of the compounds, and the drug may be given to patients either as a free base, solvate, or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used.
Examples of such acids include, without limitation, those described below as "pharmaceutically acceptable salts" and the like.
102281 In one aspect, the invention provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of ibogaine and a pharmaceutically acceptable excipient, wherein the therapeutically or prophylactically effective amount of ibogainc is an amount that delivers an aggregate amount of ibogaine of about 50 ng to less than 10 lag per kg body weight per day. In some aspects, the therapeutically or prophylactically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 10 jig per kg body weight per day.. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day. Dosing schemes are discussed in further detail below in the subsection titled "Dosing and Routes of Administration."
[0229] In some embodiments, the composition is formulated for sublingual, intranasal, or intrapulmonary delivery. These routes of administration are discussed in further detail below in the subsection titled "Dosing and Routes of Administration."
102301 In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of ibogaine, derivative, or salt and/or solvate thereof and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to less than 100 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogainc is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 50 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 10 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 1 1.1,g per kg body weight per day. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day. The ranges include both extremes as well as any subranges there between.
102311 In some embodiments, the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 8 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 6 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.7 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg per kg body weight per day. The ranges include both extremes as well as any subranges there between.
[0232] In one embodiment, the therapeutically effective amount of the compound is about 8 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 7 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 6 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg/kg body weight per day.
[0233] In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof is an amount that delivers an aggregate amount of ibogaine of about 50 ng to less than 10 'g per kg body weight per day.
[0234] In one embodiment, the therapeutically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt thereof is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 1 jig per kg body weight per day.
[0235] In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.7 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about about 2 mg per kg body weight per day. The ranges include both extremes as well as any subrange or subvalue there between.
[0236] In one embodiment, the therapeutically effective amount of the compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg per kg body weight per day.
[0237] In another aspect, provided herein is a pharmaceutically acceptable formulation comprising a unit dose of ibogaine, wherein the amount of ibogaine is sufficient to provide a serum concentration of about 50 ng/mL to about 500 ng/mL when administered to a patient.
Methods of the Invention [0238] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating nicotine addiction, alcohol dependence, drug addiction,pain, depression, impulse control, anxiety, violence/anger, food intake, or tolerance to opioids in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof. This invention further provides a method for treating, attenuating, or preventing a disease or disorder or symptoms of a disease or disorder in a subject amenable to treatment with the compounds utilized herein, comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
a. Treating Nicotine Addiction 102391 In some embodiments, the invention provides, in certain aspect, a method for treating nicotine addiction in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
[0240] The subject or patient may be any patient who uses nicotine in any form, including cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. In some embodiments, the patient is addicted to nicotine. In some embodiments, the patient is physically addicted to nicotine. In some embodiments, the patient is psychologically addicted to nicotine.
[0241] In some embodiments, the therapeutically effective amount of the compound is from about 50 ng to less than 10 g per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 g per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 500 ng to less than 10 lag per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 1 lag to less than 10 ps per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 g, about 2 g, about 3 g, about 3 g, about 4 jug, about 5 g, about 6 g, about 7 g, about 8 g, about 9 jug, about 10 jig per kilogram body weight per day. The therapeutically effective amount of the compound may be any amount within any of these ranges, including endpoints.
[0242] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0243] Where the therapeutically effective amount is administered more than one time per day, a portion of the total therapeutically effective amount is administered at each time. For example, an 90 kg patient taking 1 jig ibogaine per kg body weight per day would take 90 jig once a day, 45 1.1g twice a day, or 30 jig three times a day, etc.
[0244] In some embodiments, the therapeutically effective amount of ibogaine, derivative, or salt and/or solvate thereof is administered once when needed, e.g., when the patient has a craving for nicotine or anticipates to have a craving for nicotine as described herein.
[0245] An ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, suitable for administration in accordance with the methods provide herein, can be suitable for a variety of delivery modes including, without limitation, oral and transdermal delivery. Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutancous and subcutaneous routes may also be used. Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980). In some embodiments, the ibogaine or ibogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
[0246] In a preferred embodiment, ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule foim. In certain embodiments, the compound is provided as a pharmaceutically acceptable salt, for example ibogaine HC1, with dosages reported as the amount of free base compound. In some embodiments, the pharmaceutically acceptable salt is provided in hard gelatin capsules containing only the salt with no excipients.
b. Preventing Relapse Of Nicotine Use [0247] In some embodiments, the invention provides for a method for treating, preventing, or attenuating nicotine cravings in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof. In some embodiments, the invention provides for a method for preventing recurrence of nicotine addiction in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate of each thereof.
[0248] In some situations, a patient who has not ceased nicotine use nonetheless is unable to use nicotine for an extended amount of time. For example, most airplane flights no longer allow smoking, and have banned vaporizers and e-cigarettes, as well. Other places and situations where nicotine use is not feasible or is difficult include movie theaters, other entertainment venues (including theater, opera, concerts, and the like), and even workplaces, notably hospitals and schools where smoking may not be allowed anywhere on the property.
In some embodiments, a prophylactically effective amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered before and/or during a period of time when the patient expects to be unable to use nicotine, wherein the ibogaine, derivative, or salt and/or solvate prevents, interrupts, or attenuates cravings for nicotine. In some embodiments, nicotine cravings are attenuated, interrupted, or prevented for at least 2, 3,4, 5, 6, 7, 8, 10, 15, or 24 hours.
[0249] In some embodiments, the ibogaine, derivative, or salt and/or solvate is administered on an as-needed basis by the patient. In some embodiments, the ibogaine, derivative, or salt and/or solvate may be administered before the nicotine craving occurs. For example, the patient may take a dose of ibogaine, derivative, or salt and/or solvate in anticipation of cravings, such as before drinking alcohol, before a stressful situation occurs, or when facing another trigger for nicotine use. In some embodiments, the patient takes a dose of ibogaine, derivative, or salt and/or solvate after the nicotine craving occurs, for example during the craving, in order to reduce or eliminate the craving. In some embodiments, the dose of ibogaine, derivative, or salt and/or solvate is low enough that a patient can take one dose before a craving occurs, and another later the same day if he/she feels or anticipates another craving.
[0250] In one embodiment, the prophylactically effective amount of the compound is from about 50 rig to less than 10 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is film about 50 ng to about 1 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 500 ng per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 100 lag per kilogram body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges, including endpoints.
[0251] In some embodiments, the prophylactically effective amount of ibogaine, derivative, or salt and/or solvate thereof is administered once a day. In some embodiments, the prophylactically effective amount is administered twice per day. In some embodiments, the prophylactically effective amount is administered more than two times per day.
[0252] Where the prophylactically effective amount of ibogaine, derivative, or salt and/or solvate thereof is administered more than one time per day, a portion of the total prophylactically effective amount is administered at each time. For example, an 90 kg patient taking 1 jig ibogaine derivative, or salt and/or solvate per kg body weight per day would take 90 jig once a day, 45 pig twice a day, or 30 ps three times a day, etc.
102531 In some embodiments, the ibogaine or ibogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
c. Alcohol Dependence [0254] In one aspect, this invention relates to treatment of acute withdrawal horn alcohol in an alcohol dependent patient comprising administration of a therapeutically effective amount of ibogaine.
[0255] In one aspect, this invention relates to a method for treating alcohol abuse in an alcohol-dependent patient, comprising administering to the patient a dosage of ibogaine, thereof that piovides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0256] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 60 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
102571 In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of ibogaine that provides an average scrum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
102581 In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about ng/mL. In a preferred embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0259] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0260] In some embodiments, the ibogaine or ibogainc derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
[0261] In some embodiments, the therapeutically effective amount of ibogaine is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule Patin. In certain embodiments, the ibogaine is provided as ibogaine HO, with dosages reported as the amount of free base ibogaine. In some embodiments, the ibogaine HC1 is provided in hard gelatin capsules containing only ibogaine HCl with no excipients.
[0262] In one aspect, this invention relates to treatment or attenuation of post-acute withdrawal from alcohol dependence, and/or symptoms of withdrawal, in an addicted patient by administering a maintenance amount of ibogaine. In some aspects, this invention relates to a method to prevent relapse of alcohol abuse and/or use in an addicted patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine.
[0263] These dosing amounts, including administration of a maintenance amount of ibogaine, are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
d. Drug Addiction [0264] In some aspects, the present invention provides a method for treating substance abuse or addiction, including acute and post-acute withdrawal symptoms, in an addicted patient, comprising administering to the patient a dosage ibogaine.
[0265] In one aspect, this invention relates to treatment of acute withdrawal from an addictive substance in an addicted patient comprising administration of a therapeutically effective amount of ibogaine.
[0266] In one aspect, this invention relates to a method for treating substance abuse in an addicted patient, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL,said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0267] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0268] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0269] In some embodiments, the therapeutic dose of ibogaine is a tapered dosing over a period of time, during which the patient is detoxified, for example, without suffering significant acute withdrawal symptoms. Without being bound by theory, it is believed that tapering will allow the full therapeutic effect of the compound with less prolongation of the QT interval. Tapering involves administration of one or more subsequently lower doses of the compound over time.
[0270] In one aspect, this invention relates to treatment or attenuation of post-acute withdrawal from an addictive substance in an addicted patient with a maintenance amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
[0271] In some aspects, this invention relates to a method to prevent relapse of substance abuse in an addicted patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of ibogaine.
[0272] In some embodiments, the patient undergoes long-term (e.g., one year or longer) treatment with maintenance doses of ibogaine. In some embodiments, the patient is treated for acute withdrawal with therapeutic doses of ibogaine and then the amount of compound is reduced to maintenance levels after acute withdrawal symptoms would be expected to have subsided. Acute withdrawal symptoms generally are the most pronounced in the first 48 to 72 hours after cessation of the drug of addiction, although acute withdrawal may last as long as a week or more.
e. Pain [0273] In one aspect, this invention relates to treatment of pain in a patient suffering from pain comprising administration of a therapeutically effective amount of ibogaine.
[0274] In one aspect, this invention relates to a method for treating pain in a patient suffering from pain, comprising administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient to inhibit or ameliorate said pain. In one embodiment, the dosage of ibogaine results in prolongation of the QT interval of less than about 50 ms. In one embodiment, the dosage of ibogainc results in a QT interval of less than about 500 ms [0275] In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 800 ng/mL or about 20 ng/mL to about 800 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 nWtnL to about 700 ng/mL or about 20 ng/mL to about 700 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 600 ng/mL, or about 2Ong/mL to about 600 ng/mL.
In a preferred embodiment, the average serum concentration of is from about 50 ng/mL to about 500 ng/mL, or about 2Ong/mL to about 500 ng/mL. In one embodiment, the average serum concentration of ibogainc is from about 50 ng/mL to about 400 ng/mL, or about 20ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 300 ng/mL, or about 20ng/mL to about 300 ng/mL.
In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 200 ng/mt., or about 2Ong/mL to about 200 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 100 ng/mL, or about 20ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0276] In one embodiment, the dosage or aggregate dosage of ibogaine is from greater than about 1 mg/kg to about 8 mg/kg body weight per day.
1. Depression [0277] The following description of depressive disorders and PTSD is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of this invention.
The definitions of depressive disorders and PTSD given below are those listed in American Psychiatric Association, 1994a or American Psychiatric Association, 1987.
Additional information regarding these disorders can be found in this reference, as well as other references cited below.
[0278] In some embodiments, it is contemplated that the compounds of this invention will be effective in treating depression in patients who have been diagnosed as having depression based upon the administration of any of the following tests: Hamilton Depression Rating Scale (MRS), Hamilton depressed mood item, Clinical Global Impressions (CGI)-Severity of Illness. It is further contemplated that the compounds of the invention will be effective in improving certain of the factors measured in these tests, such as the HDRS
subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGI-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
[0279] This invention provides, in certain embodiments, a method of treating a patient suffering from major depressive disorder, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein effective to treat the subject's major depressive disorder.
[0280] The invention also provides a method of treating a patient suffering from dysthymic disorder, bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
Date Recue/Date Received 2021-07-21 [0281] It is contemplated that the compounds utilized herein can be effective in treating PTSD in patients who have been diagnosed as having PTSD based upon the administration of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-rated Impact of Event Scale (IES). It is further contemplated that the compounds described herein will be effective in inducing improvements in the scores of the CAPS, IFS, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds described herein will be effective in preventing relapse of PTSD.
[0282] This invention provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's post-traumatic stress disorder.
[0283] Another aspect of the current invention provides a method for treating depression and/or PTSD in a patient in need thereof, which method comprises administering ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof to the patient, wherein the amount of the ibogaine or ibogaine derivative is sufficient to treat depression and/or PTSD in the patient.
102841 In a preferred embodiment, the invention provides a method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides average ibogaine or ibogaine derivative serum levels of between about 50 to about 800 ng/ml In some embodiments, the average ibogaine or ibogaine derivative serum level provided by the dosage is less than about 50 ng/mL. In one embodiment, the therapeutically effective amount is between about 1 mg to about 8 mg per kg of body weight. In one embodiment, the therapeutically effective amount is between about 50 ng to less than 100 ug per kg of body weight. In one embodiment, depression is treated. In one embodiment, posttraumatic stress disorder is treated. In one embodiment, the ibogaine, ibogainc derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
g. Reduced Tolerance To Opioid Analgesics [0285] As will be apparent to the skilled artisan upon reading this disclosure, the present invention provides a method for modulating tolerance to opioids in a patient undergoing opioid analgesic therapy, comprising administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0286] In one aspect of this invention, patient is being treated with an addictive opioid analgesic to relieve the patient's pain. The pain may be of any type and from any source. In one embodiment, the patient is treated for acute pain. In one embodiment, the patient is treated for chronic pain. In one embodiment, the patient is treated for nociceptive pain. In one embodiment, the patient is treated for neuropathic pain. In some embodiments, the pain is caused by surgery, diabetes, trigeminal neuralgia, fibromyalgia, cancer, central pain syndrome, tissue damage, physical injury, and the like. In some embodiments, the source of the pain is unknown or unclear.
[0287] In one aspect, this invention relates to a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic an amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient resensitize the patient to the opioid as an analgesic while maintaining a QT
interval of less than about 500 ms during said treatment.
[0288] In one aspect, this invention relates to a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic an amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 60 ng/mL to about 400 ng/mL, said concentration being sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 420 ms during treatment.
[0289] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five limes daily with ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week.
The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, opioid analgesic to which tolerance is being modulated, length of time of analgesic treatment, and the like, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0290] The patient may be receiving any addictive opioid analgesic for the treatment of pain.
In a preferred embodiment, the opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, heroin, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, oxymorphone, and derivatives of each thereof.
h.
Impulse Control Disorder, Anxiety-Related Disorders, Violence And/Or Anger, Or Regulating Food Intake [0291] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating anxiety disorder, impulse control disorder, anger/violence-related disorders, or regulating food intake in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
[0292] The following description of anxiety disorders and impulse control disorders is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of this invention. Disorders associated with violence and/or anger are included in these descriptions.The definitions of anxiety disorders and impulse control disorders given below are those listed in American Psychiatric Association, 2013, American Psychiatric Association, 1994a, or American Psychiatric Association, 1987. Additional information regarding these disorders can be found in these references, as well as other references cited below.
Date Recue/Date Received 2021-07-21 [0293] Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating these disorders in patients who have been diagnosed as having such disorders.
[0294] This invention provides for a method of treating a patient suffering from anxiety which comprises administering to the patient an amount of any of the compounds described herein effective to treat the subject's anxiety.
[0295] It is contemplated that the compounds described herein will be effective in treating obsessions and compulsions in patients who have been diagnosed as having obsessive compulsive disorder based upon administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (for adults), National Institute of Mental Health Global OCD Scale (NIMH
GOCS), CGI-Severity of Illness scale. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds described herein will be effective in preventing relapse of obsessive compulsive disorder and/or symptoms thereof.
[0296] This invention provides a method of treating obsessions and/or compulsions in a patient with obsessive compulsive disorder, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein effective to treat the subject's obsessions and/or compulsions.
[0297] It is contemplated that the compounds described herein will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGI-Severity of Illness scale. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of the factors measured in these evaluations, such as a reduction in frequency or elimination of panic attacks, an improvement in the CGI-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds described herein will be effective in preventing relapse of panic disorder.
[0298] This invention provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's panic disorder.
[0299] It is contemplated that the compounds described herein can be effective in treating social anxiety disorder in patients who have been diagnosed as having social anxiety disorder based upon the administration of any of the following tests: the Liebowitz Social Anxiety Scale (LSAS), the CGI-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the axis V Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability Scales, the Schneier Disability Profile, the World Health Organization Quality of Life-100 (WH000L-100), or other tests as described in Bobes, 1998. It is further contemplated that the compounds described herein will be effective in inducing improvements as measured by these tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds described herein will be effective in preventing relapse of social anxiety disorder.
[0300] This invention provides a method of treating social anxiety disorder in a patient which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's social anxiety disorder.
[0301] It is contemplated that the compounds utilized herein can be effective in treating generalized anxiety disorder in patients who have been diagnosed as having this disorder based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds described herein will be effective in preventing relapse of general anxiety disorder.
Date Recue/Date Received 2021-07-21 [0302] The invention provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the patient an amount of any of the compounds described herein effective to treat the subject's generalized anxiety disorder.
[0303] Impulse control disorders include pathological gambling (PG), kleptomania, trichotillomania (TTM), intermittent explosive disorder (1ED), and pyromania.
Impulse control disorders may also include pathological skin picking (PSP), compulsive sexual behavior (CSB), compulsive buying (CB), conduct disorder, antisocial personality disorder, oppositional defiant disorder, borderline personality disorder, attention deficit/hyperactivity disorder (ADHD, which includes attention deficit disorder, ADD), schizophrenia, mood disorders, paraphilia, and intern& addiction. Symptoms of impulse control disorders include:
repetitive participation in behavior despite adverse consequences, diminished control over the behavior, an urge/impulse to engage in the behavior, and feelings of pleasure while participating in the behavior.
[0304] It is contemplated that the compounds utilized herein can be effective in treating impulse control disorders in patients who have at least one impulse control disorder based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, including impulsivity or lack of self-control. It is also contemplated that the compounds described herein will be effective in preventing relapse of the impulse control disorder.
[0305] It is contemplated that the compounds utilized herein can be effective in treating ADHD or ADD in patients who have the disorder, based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, including impulsivity or lack of self-control. It is also contemplated that the compounds described herein will be effective in preventing relapse of ADD or ADHD.
[0306] It is contemplated that the compounds utilized herein can be effective in treating schizophrenia in patients who have the disorder, based upon the diagnostic criteria described in DSM-1V or DSM-5. Schizophrenia is characterized by delusions, hallucinations, disorganized speech and behavior, and other symptoms that cause social or occupational dysfunction. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder. It is also contemplated that the compounds described herein will be effective in preventing relapse of schizophrenia.
[0307] It is contemplated that the compounds described herein will be effective in treating non-suicidal self injury disorder in patients who have been diagnosed with this disorder based on the patient's exhibition of symptoms including deliberate tissue injury without suicidal intent (e.g., cutting, burning, self-poisoning, or self-mutilation). It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of self injury.
It is also contemplated that the compounds described herein will be effective in preventing relapse of non-suicidal self injury disorder.
[0308] This invention provides a method of treating non-suicidal self injury disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's non-suicidal self injury disorder.
[0309] It is contemplated that the compounds described herein will be effective in treating Miinchausen syndrome in patients who have been diagnosed with this disorder based on the patient's propensity for feigning disease, illness, or psychological trauma to draw attention, sympathy, or reassurance to themselves. Symptoms may include frequent hospitalizations, knowledge of several illnesses, frequent requests for medication (e.g., pain killers), willingness to undergo extensive surgery, few to no visitors during hospitalizations, and exaggerated or fabricated stories about multiple medical problems. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of one or more symptoms. It is also contemplated that the compounds described herein will be effective in preventing relapse of Miinchausen syndrome. Manchausen syndrome also includes Miinchausen syndrome by proxy, in which a caregiver exaggerates, fabricates, or induces illness in someone in his/her care.
[0310] This invention provides a method of treating Miinchausen syndrome in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's Miinchausen syndrome.
[0311] It is contemplated that the compounds described herein will be effective in treating disruptive mood dysregulation disorder in patients who have been diagnosed with this disorder on the basis of severe and recurrent temper outbursts, grossly out of proportion to the stimulus or situation, as well as a persistent irritable/angry mood most of the time. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of tember outbursts and/or an improvement in mood. It is also contemplated that the compounds described herein will be effective in preventing relapse of disruptive mood dysregulation disorder disorder.
[0312] This invention provides a method of treating disruptive mood dysregulation disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's disruptive mood dysregulation disorder.
[0313] It is contemplated that the compounds utilized herein can be effective in reducing the frequency, intensity, and duration of anger and/or violence in individuals prone to one or both. Although anger and violence disorders other than those associated with other disorders (e.g., as described above) are not outlined in DSM IV or DSM 5, many health professionals recognize that such disorders are associated with significant dysfunction.
Anger management training and other psychosocial treatments are often used in an effort to treat these individuals.
[0314] This invention provides a method of treating anger- and/or violence-related disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's anger- and/or violence-related disorder.
[0315] It is contemplated that the compounds utilized herein can be effective in regulating food intake and/or reducing food cravings in patients in need thereof. In some embodiments, the patient is overweight. In some embodiments, the patient is obese. In some embodiments, the patient exhibits comorbidities associated with overweight/obesity, for example coronary heart disease, high blood pressure, stroke, type 2 diabetes, abnormal levels of blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, reproductive issues, and/or gallstones.
[0316] This invention provides a method of regulating food intake and/or reducing food cravings in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to regulate/reduce the subject's food intake and/or food cravings.
[0317] In a preferred embodiment, the invention provides a method for treating anxiety disorders, impulse control disorders, OCD, and/or anger/violence-related disorders, or regulating food intake and/or food cravings, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides average ibogaine serum levels of between about 50 to about 180 ng/ml.
hi some embodiments, the average ibogainc serum level provided by the dosage is less than about 50 ng/mL. In one embodiment, the therapeutically effective amount is between about 1 mg to about 4 mg per kg of body weight. In one embodiment, the therapeutically effective amount is between about 50 ng to about 100 g per kg of body weight. In one embodiment, an anxiety disorder is treated. In one embodiment, OCD is treated. In one embodiment, an impulse control disorder is treated. On one embodiment, an anger-related disorder is treated.
in one embodiment, a violence-related disorder is treated. In one embodiment, symptoms of anger are reduced or eliminated. In one embodiment, violent outbursts are reduced or eliminated. In one embodiment, food intake is regulated. In one embodiment, food cravings are attenuated. In one embodiment, the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery.
[0318] In one aspect, this invention relates to a method for attenuating symptoms of anxiety disorder, impulse control disorder, or an anger and/or violence-related disorder in a human patient, comprising administering to the patient a dosage of ibogaine or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
103191 In one aspect, this invention relates to a method for attenuating food cravings in a human patient, comprising administering to the patient a dosage of ibogaine or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 250 ng/mL, said concentration being sufficient to attenuate said cravings while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said cravings while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 420 ms during treatment.
[03201 In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In a preferred embodiment, the QT
interval is not prolonged more than about 20 ms. In one embodiment, the QT
interval is not prolonged more than about 10 ms.
[03211 In one aspect, this invention relates to a method for treating an anxiety disorder, an impulse control disorder, or an anger/violence-related disorder, and/or treating or attenuating the symptoms thereof in a patient, comprising selecting a patient exhibiting symptoms of an anxiety disorder, impulse control disorder, or anger/violence-related disorder who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to inhibit or ameliorate said disorder or symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0322] in one aspect, this invention relates to a method for regulating food intake, and/or treating or attenuating food cravings, in a patient, comprising selecting an overweight or obese patient who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said disorder or symptoms while maintaining a QT
interval of less than about 500 ms during said treatment.
IV. Dosage and Routes of Administration Therapeutic Dose [0323] In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the average serum concentration of ibogaine is ftom about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about ng/mL. In a preferred embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL
to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0324] In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about ng/mL. In one embodiment, the average serum concentration of ibogaine is from about 80 ng/mL to about 150 ng/mL. In one embodiment, the average scrum concentration of ibogaine is from about 80 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subrange or subvalue there between.
103251 In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1000 ng*hr/mL and about 6000 ng*hr/mL. In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng*hr/mL and about 5800 nehr/mL.
In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng*hr/mL and about 5500 ng*hr/mL. The ranges include both extremes as well as any subrange or subvalue there between.
[0326] In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 250 ng/mL. In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 40 ng/mL and about 250 ng/mL. In a preferred embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and about 200 ng/mL. In one embodiment, the dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 100 ng/mL and about 180 ng/mL. The ranges include both extremes as well as any subrange or subvalue there between.
[0327] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 8 mg/kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 7 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogainc derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 6 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 5 mg/kg body weight. In a preferred embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 2 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 1.7 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 2 mg/kg body weight. The ranges include both extremes as well as any subranges there between.
[0328] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 8 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 6 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1.7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1.5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt and/or solvate thereof is about 1 mg/kg body weight per day.
[0329] In one aspect, the invention provides administering a pharmaceutical composition comprising a pharmaceutically effective amount of ibogaine and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 100 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 50 g per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 10 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine is an amount that delivers an aggregate amount of ibogaine of about 50 ng to about 1 fig per kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is administered two or more times per day. In some embodiments, the composition is administered less than once a day, for example once every two days, once every three days, once every four days, once a week, etc.
[0330] In one embodiment, the dosage or aggregate dosage of compound is from about 1 mg to about 4 mg per kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day.
[0331] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 70 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 75 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 90 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of ibogainc, ibogaine derivative, or salt or solvate thereof is between about 90 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 100 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof is between about 110 mg and about 130 mg.
The ranges include both extremes as well as any subrange or subvalue there between.
[0332] In another embodiment, there is provided a unit dose of ibogaine, ibogaine derivative, or salt or solvate thereof which is about 50 mg to about 200 mg per dose. In one embodiment, the unit dose is about 50 to about 120 mg per dose. In one embodiment, the unit dose is about 120 mg per dose. It being understood that the term "unit dose"
means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.
[0333] In some embodiments, the patient is administered an initial dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, such a dosing regimen provides an average serum concentration of ibogaine of about 50 ng/mL to about 180 ng/nrtL. In one embodiment, the one or more additional doses maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL over a period of time.
[0334] In some embodiments, the initial dose of ibogainc, ibogaine derivative, or salt or solvate thereof is from about 75 mg to about 120 mg. In one embodiment, the initial dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment, the initial dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment, the initial dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In one embodiment, the initial dose is about 110 mg. In one embodiment, the initial dose is about 115 mg. In one embodiment, the initial dose is about 120 mg.
[0335] In some embodiments, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from about 5 mg to about 50 mg. In one embodiment, the one or more additional doses may or may not comprise the same amount of ibogaine, ibogaine derivative, or salt or solvate thereof. In one embodiment, at least one additional dose is about 5 mg. In one embodiment, at least one additional dose is about 10 mg. In one embodiment, at least one additional dose is about 15 mg.
In one embodiment, at least one additional dose is about 20 mg. In one embodiment, at least one additional dose is about 25 mg. In one embodiment, at least one additional dose is about 30 mg. In one embodiment, at least one additional dose is about 35 mg. In one embodiment, at least one additional dose is about 40 mg. In one embodiment, at least one additional dose is about 45 mg. In one embodiment, at least one additional dose is about 50 mg.
[0336] In one embodiment, the one or more additional doses are administered periodically.
In one embodiment, the one or more additional doses are administered approximately every 4 hours. In one embodiment, the one or more additional doses are administered every 6 hours.
In one embodiment, the one or more additional doses are administered approximately every 8 hours. In one embodiment, the one or more additional doses are administered approximately every 10 hours. In one embodiment, the one or more additional doses are administered approximately every 12 hours. In one embodiment, the one or more additional doses are administered approximately every 18 hours. In one embodiment, the one or more additional doses are administered approximately every 24 hours. In one embodiment, the one or more additional doses are administered approximately every 36 hours. In one embodiment, the one or more additional doses are administered approximately every 48 hours.
103371 In some embodiments, the patient is administered a high (therapeutic) dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant symptoms of a disease or disorder, and then is administered a lower (maintenance) dose to prevent relapse. In some embodiments, the patient is administered a therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant symptoms, and then is administered a decreasing (tapered) amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof over time until the maintenance dose is reached.
[0338] For treating pain the following dosages are contemplated as useful.
[0339] In one embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.7 mg to about 1.5 mg per kg body weight per day. The ranges include both extremes as well as any subrangcs there between.
[0340] In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.1 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.9 mg/kg body weigjht per day. In one embodiment, the therapeutically effective amount of the compound is about 0.8 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.7 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.6 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.1 mg/kg body weight per day.
[0341] In one embodiment, lbogaine is administered at an amount by weight that is twice that administered for noiibogaine for treating a same or similar condition.
For example, and without limitation, an administration of a dose 80 mg ibogaine approximates a dose of 40 mg noribogaine.
Maintenance Dose [0342] In some embodiments, the maintenance dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 10% to about 80% of the therapeutic dose. In some embodiments, the maintenance dose of ibogaine or pharmaceutically acceptable salt and/or solvate thereof is about 70% of the therapeutic dose.
In some embodiments, the maintenance dose is about 60% of the therapeutic dose. In some embodiments, the maintenance dose is about 50% of the therapeutic dose. In some embodiments, the maintenance dose is about 40% of the therapeutic dose. In some embodiments, the maintenance dose is about 30% of the therapeutic dose. In some embodiments, the maintenance dose is about 20% of the therapeutic dose. In some embodiments, the maintenance dose is about 10% of the therapeutic dose.
[0343] In some embodiments, the maintenance average serum level of ibogaine is about 10% to about 80% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 70% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 60% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 50% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 40% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 30%
of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 20% of the therapeutic average serum level of ibogaine. In some embodiments, the maintenance average serum level of ibogaine is about 10%
of the therapeutic average serum level of ibogaine.
Tapered Dosing [0344] In some embodiments, the therapeutic dose of ibogaine, ibogaine derivative, or salt and/or solvate thereof is a tapered dosing over a period of time, during which the patient is detoxified, for example, without suffering significant acute withdrawal symptoms. Without being bound by theory, it is believed that tapering will allow the full therapeutic effect of ibogaine with less prolongation of the QT interval. Tapering involves administration of one or more subsequently lower doses of ibogaine over time. For example, in some embodiments, the first tapered dose is about 50% to about 95% of the first or original dose. In some embodiments, the second tapered dose is about 40% to about 90% of the first or original dose. In some embodiments, the third tapered dose is about 30% to about 85% of the first or original dose. In some embodiments, the fourth tapered dose is about 20% to about 80% of the first or original dose. In some embodiments, the fifth tapered dose is about 10% to about 75% of the first or original dose.
[0345] In some embodiments, the first tapered dose is given after the first dose of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the first tapered dose is given after the second, third, or a subsequent dose of compound. The first tapered dose may be administered at any time after the previous dose of compound.
[0346] In one embodiment, the therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate is tapered over time until the desired maintenance dose is reached. For example, in some embodiments, the first tapered dose is about 50% to about 95% of the therapeutic dose. In some embodiments, the second tapered dose is about 40% to about 90% of the therapeutic dose. In some embodiments, the third tapered dose is about 30% to about 85% of the therapeutic dose. In some embodiments, the fourth tapered dose is about 20% to about 80% of the therapeutic dose. In some embodiments, the fifth tapered dose is about 10% to about 75% of the therapeutic dose. In some embodiments, one tapered dose is given to achieve the maintenance dose.
In some embodiments, two tapered doses are given to achieve the maintenance dose. In some embodiments, three tapered doses are given to achieve the maintenance dose. In some embodiments, four or more tapered doses are given to achieve the maintenance dose.
Determination of the tapered doses, number of tapered doses, and the like can be readily made a qualified clinician.
103471 The first tapered dose may be administered at any time after the previous dose of ibogaine. The first tapered dose can be given once, for example, followed by subsequent further tapered doses, or it can be given multiple times with or without subsequent, further tapered doses (e.g., second, third, fourth, etc. tapered doses), which likewise can be given once or over multiple administrations, for example. In some embodiments, the first tapered dose is given after the first dose of ibogaine. In some embodiments, the first tapered dose is given after the second, third, or a subsequent dose of ibogaine. In some embodiments, the first tapered dose is administered one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of ibogaine. Similarly, second, third, fourth, etc.
tapered doses, if given, can be given one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of ibogaine.
[0348] In some embodiments, one tapered dose is given to achieve the desired lower therapeutic dose. In some embodiments, two tapered doses are given to achieve the desired lower therapeutic dose. In some embodiments, three tapered doses are given to achieve the desired lower therapeutic dose. In some embodiments, four or more tapered doses are given to achieve the desired lower therapeutic dose. Determination of the tapered doses, number of tapered doses, and the like can be readily made a qualified clinician.
[0349] In some embodiments, the patient undergoes long-term (e.g., one month, three months, six months, one year or longer) treatment with maintenance doses of ibogaine, ibogaine derivative, or salt and/or solvate thereof. In some embodiments, the patient is treated for acute withdrawal with therapeutic doses of ibogaine as described above, and then the amount of ibogaine is reduced to maintenance levels after acute withdrawal symptoms would be expected to have subsided. Acute withdrawal symptoms generally are the most pronounced in the first week after cessation of alcohol use, although acute withdrawal may last as long as six weeks or more.
[0350] In some embodiments, the composition is administered via sublingual, intranasal, or intrapulmonary delivery. In one aspect, the invention provides administering a pharmaceutical composition comprising a pharmaceutically effective amount of ibogaine or ibogaine derivative and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to less than 100 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to about 50 jig per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to about 10 litg per kg body weight per day. In some aspects, the therapeutically effective amount of ibogaine or ibogaine derivative is an amount that delivers an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to about 1 p.g per kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is administered two or more times per day. In some embodiments, the composition is administered less than once a day, for example once every two days, once every three days, once every four days, once a week, etc.
[0351] In some embodiments, the composition is administered via oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery.
[0352] A particularly suitable composition comprises a composition suitable for a transdermal route of delivery in which the ibogaine or ibogaine derivative is applied as part of a cream, gel or, preferably, patch (for examples of transdermal formulations, see U.S. Pat. Nos.
4,806,341; 5,149,538; and 4,626,539).
[0353] In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In one embodiment, the QT
interval is not prolonged more than about 20 ms. In one embodiment, the QT interval is not prolonged more than about 10 ms.
Formulations [0354] This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the amount of ibogaine is sufficient to provide an average serum concentration of about 50 ng/mL to about 850 ng/mL when administered to a patient. In other embodiments, the amount of ibogaine is sufficient to provide an average serum concentration of about 50 ng/mL to about 400 ng/mL when administered to a patient.
[0355] In some embodiments, the unit dose of ibogaine is administered in one or more dosings.
[0356] In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the amount of ibogaine is sufficient to Date Recue/Date Received 2021-07-21 provide an average serum concentration of ibogaine from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about 600 ng/mL. In a preferred embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 400 ng/mL, or about 60 ng/mL to about ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average scrum concentration of ibogaine from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the amount of ibogaine is sufficient to provide an average serum concentration of ibogaine from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/m.L. The ranges include both eximmes as well as any subranges between.
[0357] In some embodiments, the formulation is designed for periodic administration, such as once, twice, three time, four times or five time daily with ibogaine or a pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
Delivery method [0358] The compositions, provided herein or known, suitable for administration in accordance with the methods provided herein, can be suitable for a variety of delivery modes including, without limitation, sublingual, intrapulmonary, or intranasal delivery.
Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intra-peritoneal, intra-cutaneous and subcutaneous routes may also be used. Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions.
Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
[0359] The compositions provided herein can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing ibogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
[0360] The compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal administration.
The compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient may be provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), (for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide or other suitable gases. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve.
Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine. In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler.
[0361] In some embodiments, ibogaine is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. In certain embodiments, the ibogaine is provided as ibogaine HC1, with dosages reported as the amount of free base ibogaine. In some embodiments, the ibogaine HC1 is provided in hard gelatin capsules containing only ibogaine HC1 with no excipients.
[0362] The compositions utilized herein may be formulated for sublingual administration, for example as sublingual tablets. Sublingual tablets are designed to dissolve very rapidly.
The formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol.
[03631 It has been discovered that ibogaine has a bitter taste to at least some patients.
Accordingly, compositions for oral use (including sublingual, inhaled, and other oral formulations) may be formulated to utilize taste-masking technologies. A
number of ways to mask the taste of bitter drugs are known in the art, including addition of sugars, flavors, sweeteners, or coatings; use of lipoproteins, vesicles, and/or liposomes;
granulation;
microencapsulation; numbing of taste buds; multiple emulsion; modification of viscosity; or salt fot _________________________________________________________ 'nation;
inclusion or molecular complexes; ion exchange resins; and solid dispersion.
Any method of masking the bitterness of the compound of the invention may be used.
Patient Pre-screening and Monitoring [0364] Pre-screening of patients before treatment with ibogaine and/or monitoring of patients during ibogaine treatment may be required to ensure that QT interval is not prolonged beyond a certain value. For example, QT interval greater than 500 ms can be considered dangerous for individual patients. Pre-screening and/or monitoring may be necessary at high levels of ibogaine treatment.
[0365] In some embodiments, a patient receiving ibogaine is monitored in a clinical setting.
Monitoring may be necessary to ensure the QT interval is not prolonged to an unacceptable degree. A "clinical setting" refers to an inpatient setting (e.g., inpatient clinic, hospital, rehabilitation facility) or an outpatient setting with frequent, regular monitoring (e.g., outpatient clinic that is visited daily to receive dose and monitoring).
Monitoring includes monitoring of QT interval. Methods for monitoring of QT interval are well-known in the art, for example by ECG.
[0366] In one embodiment, a patient receiving ibogaine is not monitored in a clinical setting. ln one embodiment, a patient receiving ibogaine is monitored periodically, for example daily, weekly, monthly, or occasionally.
[0367] In one aspect, this invention relates to a method for treating a disease or disorder or symptoms of a disease or disorder, comprising selecting addicted dependent patient who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse or symptoms while maintaining a QT interval of less than 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0368] In one embodiment, prescreening of the patient comprises ascertaining that ibogaine treatment will not result in a QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that ibogaine treatment will not result in a QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that ibogaine treatment will not result in a QT interval over about 450 ms. In one embodiment, prescreening comprises ascertaining that ibogaine treatment will not result in a QT interval over about 420 ms. In one embodiment, prescreening comprises determining the patient's pre-treatment QT interval.
[0369] As it relates to pre-screening or pre-selection of patients, patients may be selected based on any criteria as determined by the skilled clinician. Such criteria may include, by way of non-limiting example, pre-treatment QT interval, pre-existing cardiac conditions, risk of cardiac conditions, age, sex, general health, and the like. The following are examples of selection criteria for disallowing ibogaine treatment or restricting dose of ibogaine administered to the patient: high QT interval before treatment (e.g., such that there is a risk of the patient's QT interval exceeding 500 ms during treatment); congenital long QT syndrome;
bradycardia; hypokalemia or hypornagnesemia; recent acute myocardial infarction;
uncompensated heart failure; and taking other drugs that increase QT interval.
In some embodiments, the methods can include selecting and/or administering/providing ibogaine to a patient that lacks one more of such criteria.
[0370] In one embodiment, this invention relates to pre-screening a patient to determine if the patient is at risk for prolongation of the QT interval beyond a safe level. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is not administered ibogaine. In one embodiment, a patient at risk for prolongation of the QT
interval beyond a safe level is administered ibogaine at a limited dosage.
[0371] In one embodiment, this invention relates to monitoring a patient who is administered a therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, the dose of ibogaine is reduced if the patient has one or more adverse side effects. In one embodiment, the ibogaine treatment is discontinued if the patient has one or more adverse side effects. In one embodiment, the adverse side effect is a QT interval that is prolonged beyond a safe level.
The determination of a safe level of prolongation is within the skill of a qualified clinician.
Kit of Parts [0372] One aspect of this invention is directed to a kit of parts for the treatment of a disease or disorder and/or symptoms of a disease or disorder as described herein in a patient, wherein the kit comprises a composition comprising ibogaine, ibogaine derivative, or salt and/or solvate thereof and a means for administering the composition to a patient in need thereof.
The means for administration to a patient can include, for example, any one or combination of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, a transdermal patch, a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, an inhaler comprising the composition, etc. In one embodiment, the kit of parts further comprises instructions for dosing and/or administration of the composition.
[0373] In some aspects, the invention is directed to a kit of parts for administration of ibogaine, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, and further wherein each delivery vehicle is identified by the amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provided therein; and optionally further comprising a dosing treatment schedule in a readable medium. In some embodiments, the dosing treatment schedule includes the amount of ibogaine required to achieve each average serum level is provided. In some embodiments, the kit of parts includes a dosing treatment schedule that provides an attending clinician the ability to select a dosing regimen of ibogaine based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve. In some embodiments, the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight (or mass) and sex of the patient. In an embodiment, the storage medium can include an accompanying pamphlet or similar written information that accompanies the unit dose form in the kit. In an embodiment, the storage medium can include electronic, optical, or other data storage, such as a non-volatile memory, for example, to store a digitally-encoded machine-readable representation of such information.
103741 The term "delivery vehicle" as used herein refers to any formulation that can be used for administration of ibogaine to a patient. Non-limiting, exemplary delivery vehicles include caplets, pills, capsules, tablets, powder, liquid, or any other form by which the drug can be administered. Delivery vehicles may be intended for administration by oral, inhaled, injected, or any other means.
[0375] The term "readable medium" as used herein refers to a representation of data that can be read, for example, by a human or by a machine. Non-limiting examples of human-readable formats include pamphlets, inserts, or other written fauns. Non-limiting examples of machine-readable formats include any mechanism that provides (i.e., stores and/or transmits) information in a form readable by a machine (e.g., a computer, tablet, and/or smartphone).
For example, a machine-readable medium includes read-only memory (ROM); random access memory (RAM); magnetic disk storage media; optical storage media; and flash memory devices. In one embodiment, the machine-readable medium is a CD-ROM. In one embodiment, the machine-readable medium is a USB drive. In one embodiment, the machine-readable medium is a Quick Response Code (QR Code) or other matrix barcode.
[0376] In some aspects, the machine-readable medium comprises software that contains information regarding dosing schedules for the unit dose form of ibogaine and optionally other drug information. In some embodiments, the software may be interactive, such that the attending clinician or other medical professional can enter patient information. In a non-limiting example, the medical professional may enter the weight and sex of the patient to be treated, and the software program provides a recommended dosing regimen based on the information entered. The amount and timing of ibogaine recommended to be delivered will be within the dosages that result in the serum concentrations as provided herein.
[0377] In some embodiments, the kit of parts comprises multiple delivery vehicles in a variety of dosing options. For example, the kit of parts may comprise pills or tablets in multiple dosages, such as 240 mg, 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, and/or 10 mg of ibogaine per pill. Each pill is labeled such that the medical professional and/or patient can easily distinguish different dosages. Labeling may be based on printing or embossing on the pill, shape of the pill, color of pill, the location of the pill in a separate, labeled compartment within the kit, and/or any other distinguishing features of the pill. In some embodiments, all of the delivery vehicles within a kit are intended for one patient. In some embodiments, the delivery vehicles within a kit arc intended for multiple patients.
[0378] One aspect of this invention is directed to a kit of parts for the treatment of a disease or disorder described herein, wherein the kit comprises a unit dose form of ibogaine, ibogaine derivative, or salt and/or solvate thereof. The unit dose form provides a patient with an average serum level of ibogaine of from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the unit dose form provides a patient with an average serum level of ibogaine of from about 50 ng/mL to about 400 ng/mL or about 60 ng/mL to about 400 ng/mL.
[0379] In some embodiments, the unit dose form comprises one or multiple dosages to be administered periodically, such as once, twice, three time, four times or five time daily with ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.
[0380] These dose ranges may be achieved by transdermal, oral, or parenteral administration of ibogaine or a pharmaceutically acceptable salt and/or solvate thereof in unit dose form. Such unit dose form may conveniently be provided in transdermal patch, tablet, caplet, liquid or capsule form. In certain embodiments, the ibogaine is provided as ibogaine HC1, with dosages reported as the amount of free base ibogaine. In some embodiments, the ibogaine HC1 is provided in hard gelatin capsules containing only ibogaine HC1 with no excipients. In some embodiments, ibogaine is provided in saline for intravenous administration.
103811 In another aspect, provided herein is a kit of parts for administration of ibogaine, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of ibogaine and further wherein each delivery vehicle is identified by the amount of ibogaine provided therein; and optionally further comprising a dosing treatment schedule in a readable medium.
103821 In one embodiment, the amount of ibogaine required to achieve each maximum serum level is provided in the readable medium. In another embodiment, the readable medium is a computer-readable medium. In another embodiment, the multiple delivery vehicles contain different amounts of ibogaine. In another embodiment, the dosing treatment schedule provides an attending clinician the ability to select a dosing regimen of ibogaine based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve. In another embodiment, the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight and sex of the patient.
EXAMPLES
[0383] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
Example I: Effect Of Low Dose Of Ibogaine On Smoking Cessation [0384] A female habitual smoker intranasally absorbs a milligram amount of ibogainc hydrochloride. During a period of several hours, any craving to smoke is measured periodically.
Example 2. Efficacy Of Ibogaine, Ibogaine Derivative, Or A Pharmaceutically Acceptable Salt Thereof In Humans [0385] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in alcohol-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured.
Example 3. Efficacy Of Ibogaine In Treating Substance Dependency [0386] The efficacy of ibogaine is evaluated in substance-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients are administered 60 mg or 120 mg of the compound and QT interval is measured.
Example 4. Use Of Ibogaine To Treat Chronic Pain In Humans [0387] Six patients experiencing chronic pain are screened and selected to receive administration of ibogaine. Four patients intranasally absorb a milligram amount of ibogaine hydrochloride and the remaining two patients receiv a placebo. The level of pain and pain relief of the patients are measured.
Example 5. Forced Swim Test (FST) With Rats [0388] Animals: Male Sprague-Dawley rats (Taconic Farms, N.Y.) are used in all experiments. Rats arc housed 5 per cage and maintained on a 12:12-h light-dark cycle. Rats are handled for 1 minute each day for 4 days prior to behavioral testing.
[0389] Drug Administration: Animals are randomly assigned to receive a single intraperitoneal administration of vehicle (2.5% Et0H/2.5% Tween-80), imipramine (positive control; 60 mg/kg), or Test Compound 60 minutes before the start of the 5 minute test period.
All injections are given using 1 cc tuberculin syringe with 26 3/8 gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport, N.J.). The volume of injection is 1 ml/kg.
[0390] Experimental Design: The procedure used in this study employs a water depth of 31 cm. The greater depth in this test prevents the rats from supporting themselves by touching the bottom of the cylinder with their feet. Swim sessions are conducted by placing rats in individual plexiglass cylinders (46 cm tall and 20 cm diameter) containing 23-25 C water.
Swim tests are conducted always between 9:00 and 17:00 hours and included an initial 15-minute conditioning test followed 24 hours later by a 5-minute test. Drug treatments are administered 60 minutes before the 5-minute test period. Following all swim sessions, rats are removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes and returned to their home cages. All test sessions are videotaped using a color video camera and recorded for scoring later.
[0391] Behavioral Scoring: The rat's behavior is rated at 5 second intervals during the 5 minute test by a single individual, who is blind to the treatment condition.
Scored behaviors are: 1. Immobility--rat remains floating in the water without struggling and is only making those movements necessary to keep its head above water; 2. Climbing--rat is making active movements with its forepaws in and out of the water, usually directed against the walls; 3.
Swimming--rat is making active swimming motions, more than necessary to merely maintain its head above water, e.g. moving around in the cylinder; and 4. Diving--entire body of the rat is submerged.
[0392] Data Analysis: The forced swim test data (immobility, swimming, climbing, diving) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test. The data are analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).
Example 6. Forced Swim Test (FST) With Mice [0393] Animals: DBA/2 mice (Taconic Farms, N.Y.) are used in all experiments.
Animals are housed 5 per cage in a controlled environment under a 12:12 hour light:dark cycle.
Animals are handled 1 min each day for 4 days prior to the experiment. This procedure includes a mock gavage with a 1.5 inch feeding tube.
[0394] Drug Administration: Animals are randomly assigned to receive a single administration of vehicle (5% Et0H/5% Tween-80), Test Compound, or imipramine (60 mg/kg) by oral gavage 1 hour before the swim test.
[0395] Experimental Design: The procedure for the forced swim test in the mouse is similar to that described above for the rat, with the following modifications. The cylinder used for the test is a 1 liter beaker (10.5 cm diameter and 15 cm height) filled to 800 ml (10 cm depth) with 23 25 C. water. Only one 5-minute swim test is conducted for each mouse, between 13:00 and 17:00 hours. Drug treatments are administered 30-60 minutes before the 5-minute test period. Following all swim sessions, mice are removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes. All test sessions are videotaped using a Sony color video camera and recorder for scoring later.
[0396] Behavioral Scoring: The behavior during minutes 2-5 of the test is played back on a TV monitor and scored by the investigator. The total time spent immobile (animal floating with only minimal movements to remain afloat) and mobile (swimming and movements beyond those required to remain afloat) are recorded.
103971 Data Analysis: The forced swim test data (time exhibiting immobility, mobility;
seconds) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test. The data are analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).
Example 7. Effect of ibogaine on QT interval in humans [0398] The safety of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof is evaluated in patients in a randomized, placebo-controlled, double-blind trial. Patients are administered 60 mg or 120 mg of the compound and QT
interval is measured.
Example 8. Effect of ibogaine on depression in humans [0399] A male patient, age 55, suffering from depression unrelated to the use of any illicit substance, is treated with ibogainc hydrochloride at a dose of about 1 mg/kg/day for a period of four weeks. During the treatment period, his depression is determined by the patient's self-reporting of a decrease in symptoms and/or changes in one or more of the following tests:
HDRS, Hamilton depressed mood item, and CGI-Severity of Illness.
Example 9. Efficacy of ibogaine to modulate opioid tolerance in humans [0400] A female patient, age 59, undergoing opioid analgesic therapy for chronic back pain, is treated with ibogaine hydrochloride at a dose of about 2 mg/kg concurrently with the opioid. The amount of opioid required to treat her back pain after ibogaine treatment is measured.
Example 10. Social Interaction Test (SIT) [0401] Animals: Male albino Sprague-Dawley rats (Taconic Farms, N.Y.) are housed in pairs under a 12 hr light dark cycle (lights on at 0700 hrs.) with free access to food and water.
[0402] Rats are allowed to acclimate to the animal care facility for 5 days and are housed singly for 5 days prior to testing. Animals are handled for 5 minutes per day.
On the test day, weight matched pairs of rats ( 5%), unfamiliar to each other, are given identical treatments and returned to their home cages. Animals are randomly divided into 5 treatment groups, with pairs per group, and are given one of the following i.p. treatments: Test Compound (1, 2 or 4 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg). Dosing is done 1 hour prior to testing. Rats are subsequently placed in a white perspex test box or arena (54x37x26 cm), whose floor is divided up into 24 equal squares, for 15 minutes. An air conditioner is used to generate background noise and to keep the room at approximately 74 F. All sessions are videotaped using a JVC camcorder (model GR-SZ I, Elmwood Park, N.J.) with either TDK
(HG ultimate brand) or Sony 30 minute videocassettes. All sessions are conducted between 13:00 and 16:30 hours. Active social interaction, defined as grooming, sniffing, biting, boxing, wrestling, following and crawling over or under, is scored using a stopwatch (Sportsline model no. 226, 1/100 sec. discriminability). The number of episodes of rearing (animal completely raises up its body on its hind limbs), grooming (licking, biting, scratching of body), and face ishing (i.e. hands are moved repeatedly over face), and number of squares crossed are scored. Passive social interaction (animals are lying beside or on top of each other) is not scored. All behaviors are assessed later by an observer who is blind as to the treatment of each pair. At the end of each test, the box is thoroughly wiped with moistened paper towels.
[0403] Data Analysis: The social interaction data (time interacting, rearing and squares crossed) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Student-Newman-Keuls test. The data are subjected to a test of normality (Shapiro-Wilk test). The data are analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, Md., 1997).
Example 11. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on anxiety-related disorders in humans [0404] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for an anxiety-related disorder in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured.
Example 12. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on impulse control disorders in humans [0405] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for an impulse control disorder in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured.
Example 13. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on violence-related disorders in humans [0406] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for a violence-related disorder in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured. Mean prolongation of the QT interval and/or the severity of violent outbursts, are determined by self-evaluation and clinical evaluation.
Example 14. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof on food intake in humans [0407] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt thereof is evaluated in participants undergoing treatment for obesity related to over-eating in a randomized, placebo-controlled, double-blind trial. Patients are not taking any other medications to treat anxiety. Patients are administered placebo or 60 mg or 120 mg of the compound and QT interval is measured. Mean prolongation of the QT interval, weight loss and food intake and/or cravings, are determined by self-evaluation and clinical evaluation.
Claims (28)
1. Use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
2. Use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for treating opioid or opioid-like drug abuse in a human patient addicted thereto, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
3. The use according to claim 1 in a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
4. The use according to claim 2 in a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
5. The use according to claim 3 or 4, wherein the prescreening ascertained that treatment with ibogaine, ibogaine derivative, or pharmaceutically acceptable salt thereof, will not result in a QT interval greater than about 500 ms.
6. The use according to claim 5, wherein the prescreening ascertained that treatment with ibogaine will not result in a QT interval greater than about 470 ms.
Date Recue/Date Received 2022-11-07
Date Recue/Date Received 2022-11-07
7. The use according to claim 5, wherein the prescreening ascertained that treatment with ibogaine will not result in a QT interval greater than about 450 ms.
8. The use according to any one of claims 1 to 7, wherein the QT interval is less than about 450 ms.
9. The use according to any one of claims 1 to 8, wherein the dosage provides an average serum concentration of about 50 ng/mL to about 500 ng/mL.
10. Use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
11. Use of a therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, wherein the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt is from about 1 mg/kg to about 4 mg/kg body weight per day, said dosage being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
12. The use according to any one of claims 1 to 11, wherein the dosage provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
13. The use according to any one of claims 1 to 11, wherein the dosage provides a maximum serum concentration (Cmax) of less than about 250 ng/mL.
Date Recue/Date Received 2022-11-07
Date Recue/Date Received 2022-11-07
14. The use according to any one of claims 1 to 13, wherein the dosage is about 1 mg/kg to about 2 mg/kg body weight per day.
15. The use according to any one of claims 1 to 14, wherein the QT interval is not prolonged more than about 50 ms.
16. Use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is about 70%
or less than the therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt, where the therapeutic dosage is the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt of from about 1 mg/kg to about 4 mg/kg body weight per day, said maintenance dosage being formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
or less than the therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt, where the therapeutic dosage is the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt of from about 1 mg/kg to about 4 mg/kg body weight per day, said maintenance dosage being formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
17. Use of a maintenance dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, for preparation of a medicament to prevent relapse of opioid or opioid-like drug abuse in a patient treated to ameliorate said abuse, wherein said maintenance dosage is about 70% or less than the therapeutic dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt, where the therapeutic dosage is the aggregate dosage of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt of from about 1 mg/kg to about 4 mg/kg body weight per day, said maintenance dosage being formulated for periodic administration to said patient who is no longer abusing the opioid or opioid-like drug.
18. The use according to claim 16 or claim 17, wherein the maintenance dosage is about 1.5 mg/kg body weight per day.
Date Recue/Date Received 2022-11-07
Date Recue/Date Received 2022-11-07
19. The use according to claim 16 or claim 17, wherein the maintenance dosage is about 1 mg/kg body weight per day.
20. The use according to claim 16 or claim 17, wherein the maintenance dosage is about 0.1 mg/kg body weight per day.
21. The use according to any one of claims 1 to 20, wherein the ibogaine or ibogaine derivative is represented by Formula I:
<EviG>
or a pharmaceutically acceptable salt and/or solvate thereof, wherein is a single or double bond;
R is H, halo, C1-C3 alkyl, substituted C1-C3 alkyl, 0R10, NH2, MIR1 , NR10R11, NHC(0)R16, or NR10C(0)R11;
le is H, C1-C3 alkyl, substituted C1-C3alkyl, C1-C3alkoxy, CH2-X-CH3, or (CH2),,,R3;
R2 is H, COOH, COOR4, (CH2)n0H, CH(OH)R5, CH2OR5, C(0)NH2, C(0)NHR5, C(0)NR5R6, C(0)NHNH2, C(0)NHNHR5, C(0)NHNR5R6, C(0)NR5NH2, C(0)NR5NHR6, C(0)NR5NR6R7, C(0)NHNH(C(0)R5), C(0)NHNR5(C(0)R6), C(0)NR5NH(C(0)R6), C(0)NR5NR6(C(0)R7), CN, or C(0)R5;
R3 is CI-C3 alkyl, benzyl, substituted Ci-C3 alkyl, YH, YR8, YC(0)1e, C(0)YR8, C(0)NH2, C(0)NHR8, C(0)NR8R9, NH2, NHR8, NR8R9, NHC(0)R8, 0(CH2)p0(CH2)q0(CH2),CH3 or NR8C(0)R9;
le is Cl-C6 alkyl or (CH2CH20)nCH3;
R5, R6, R7, R8, R9, R10, and R11 are independently alkyl or substituted alkyl;
R12 is H, alkyl, or substituted alkyl;
R13 is H, 0R10, alkyl, or substituted alkyl;
X is 0 or NH;
Date Recue/Date Received 2022-11-07 Y is 0 or S;
m is an integer selected from 0-8;
each of n, p and q is 1, 2 or 3; and r is 0, 1 or 2.
<EviG>
or a pharmaceutically acceptable salt and/or solvate thereof, wherein is a single or double bond;
R is H, halo, C1-C3 alkyl, substituted C1-C3 alkyl, 0R10, NH2, MIR1 , NR10R11, NHC(0)R16, or NR10C(0)R11;
le is H, C1-C3 alkyl, substituted C1-C3alkyl, C1-C3alkoxy, CH2-X-CH3, or (CH2),,,R3;
R2 is H, COOH, COOR4, (CH2)n0H, CH(OH)R5, CH2OR5, C(0)NH2, C(0)NHR5, C(0)NR5R6, C(0)NHNH2, C(0)NHNHR5, C(0)NHNR5R6, C(0)NR5NH2, C(0)NR5NHR6, C(0)NR5NR6R7, C(0)NHNH(C(0)R5), C(0)NHNR5(C(0)R6), C(0)NR5NH(C(0)R6), C(0)NR5NR6(C(0)R7), CN, or C(0)R5;
R3 is CI-C3 alkyl, benzyl, substituted Ci-C3 alkyl, YH, YR8, YC(0)1e, C(0)YR8, C(0)NH2, C(0)NHR8, C(0)NR8R9, NH2, NHR8, NR8R9, NHC(0)R8, 0(CH2)p0(CH2)q0(CH2),CH3 or NR8C(0)R9;
le is Cl-C6 alkyl or (CH2CH20)nCH3;
R5, R6, R7, R8, R9, R10, and R11 are independently alkyl or substituted alkyl;
R12 is H, alkyl, or substituted alkyl;
R13 is H, 0R10, alkyl, or substituted alkyl;
X is 0 or NH;
Date Recue/Date Received 2022-11-07 Y is 0 or S;
m is an integer selected from 0-8;
each of n, p and q is 1, 2 or 3; and r is 0, 1 or 2.
22. The use according to any one of claims 1 to 20, wherein the ibogaine or ibogaine derivative is represented by Formula II:
or a pharmaceutically acceptable salt and/or solvate thereof, wherein is a single or double bond;
R is hydrogen or C1-C3 alkoxy;
It' is hydrogen, Ci-C3 alkyl, Ci-C3 alkoxy, (CH2).0C(0)alkyl, (CH2).0H, (CH2)mOalkyl, (CH2)m0(CH2)pO(CH2),10(CH2),CH3 or CH2-Y-CH3 where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is 0 or NH; and R2 is H, (CH2)n0H, COOH, or COOR4, where le is Ci-C6 alkyl or (CH2CH20)nCH3, where n is 1, 2, or 3.
or a pharmaceutically acceptable salt and/or solvate thereof, wherein is a single or double bond;
R is hydrogen or C1-C3 alkoxy;
It' is hydrogen, Ci-C3 alkyl, Ci-C3 alkoxy, (CH2).0C(0)alkyl, (CH2).0H, (CH2)mOalkyl, (CH2)m0(CH2)pO(CH2),10(CH2),CH3 or CH2-Y-CH3 where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is 0 or NH; and R2 is H, (CH2)n0H, COOH, or COOR4, where le is Ci-C6 alkyl or (CH2CH20)nCH3, where n is 1, 2, or 3.
23. The use according to claim 22, wherein R is OCH3; It' is CH2CH3; and R2 is COOR4, where R4 is (CH2CH20)nCH3, where n is 1.
24. The use according to any one of claims 1 to 20, wherein the ibogaine or ibogaine derivative is represented by Formula IA:
Date Recue/Date Received 2022-11-07 wherein is a single or double bond;
R is hydrogen or Ci-C3-alkoxy;
RI is hydrogen, Cl-C3-alkyl, C1-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH;
and X is H, COOH, or COOR2, where R2 is C1-C6 alkyl or (CH2CH20)nCH3, where n = 1 to 3.
Date Recue/Date Received 2022-11-07 wherein is a single or double bond;
R is hydrogen or Ci-C3-alkoxy;
RI is hydrogen, Cl-C3-alkyl, C1-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH;
and X is H, COOH, or COOR2, where R2 is C1-C6 alkyl or (CH2CH20)nCH3, where n = 1 to 3.
25. The use according to any one of claims 1 to 20, wherein the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is ibogaine.
26. The use according to any one of claims 1 to 20, wherein the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is an ibogaine derivative, wherein the ibogaine derivative is selected from the group consisting of coronaridine, ibogamine, voacangine, 18-methoxycoronaridine, 2-methoxyethy1-18-methoxycoronaridinate, and 18-methylaminocoronaridine.
27. The use according to any one of claims 1 to 20, wherein the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is an ibogaine derivative, wherein the ibogaine derivative is selected from the group consisting of 16-hydroxymethy1-18-hydroxyibogaline, 16-hydroxymethy1-18-methoxyibogaline, 16-ethoxycarbony1-18-hydroxyibogaline laurate, and 16-ethoxycarbony1-18-hydroxyibogaline methoxyethoxymethyl ether.
28. The use according to any one of claims 1 to 20, wherein the ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is an ibogaine derivative, wherein the ibogaine derivative is 18-methoxycoronaridine.
Date Recue/Date Received 2022-11-07
Date Recue/Date Received 2022-11-07
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3212001A CA3212001A1 (en) | 2014-03-03 | 2015-03-02 | Therapeutic uses of ibogaine and related compounds |
Applications Claiming Priority (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461947397P | 2014-03-03 | 2014-03-03 | |
US61/947,397 | 2014-03-03 | ||
US201461952743P | 2014-03-13 | 2014-03-13 | |
US201461952725P | 2014-03-13 | 2014-03-13 | |
US201461952724P | 2014-03-13 | 2014-03-13 | |
US201461952718P | 2014-03-13 | 2014-03-13 | |
US201461952736P | 2014-03-13 | 2014-03-13 | |
US201461952740P | 2014-03-13 | 2014-03-13 | |
US61/952,740 | 2014-03-13 | ||
US61/952,724 | 2014-03-13 | ||
US61/952,725 | 2014-03-13 | ||
US61/952,743 | 2014-03-13 | ||
US61/952,718 | 2014-03-13 | ||
US61/952,736 | 2014-03-13 | ||
US201462049968P | 2014-09-12 | 2014-09-12 | |
US62/049,968 | 2014-09-12 | ||
PCT/US2015/018356 WO2015134405A1 (en) | 2014-03-03 | 2015-03-02 | Therapeutic uses of ibogaine and related compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3212001A Division CA3212001A1 (en) | 2014-03-03 | 2015-03-02 | Therapeutic uses of ibogaine and related compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2978537A1 CA2978537A1 (en) | 2015-09-11 |
CA2978537C true CA2978537C (en) | 2023-10-24 |
Family
ID=54055765
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2978537A Active CA2978537C (en) | 2014-03-03 | 2015-03-02 | Therapeutic uses of ibogaine and related compounds |
CA3212001A Pending CA3212001A1 (en) | 2014-03-03 | 2015-03-02 | Therapeutic uses of ibogaine and related compounds |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3212001A Pending CA3212001A1 (en) | 2014-03-03 | 2015-03-02 | Therapeutic uses of ibogaine and related compounds |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP3113771A4 (en) |
AU (2) | AU2015225442A1 (en) |
CA (2) | CA2978537C (en) |
WO (1) | WO2015134405A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9561233B2 (en) | 2014-03-13 | 2017-02-07 | Demerx, Inc. | Use of ibogaine for the treatment of pain |
US9592239B2 (en) | 2014-09-12 | 2017-03-14 | Demerx, Inc. | Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake |
GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
WO2020212948A1 (en) | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Methods of treating neurocognitive disorders, chronic pain and reducing inflammation |
CN114786677A (en) * | 2019-10-01 | 2022-07-22 | 思维医学股份有限公司 | 18-MC for the treatment of substance use disorders |
AU2021254855A1 (en) * | 2020-04-16 | 2022-09-15 | Pike Therapeutics, Inc. | Transdermal micro-dosing delivery of psychedelics derivatives |
WO2023278108A1 (en) * | 2021-06-29 | 2023-01-05 | Mind Medicine, Inc. | 18-mc for treating obesity |
WO2024171075A1 (en) * | 2023-02-15 | 2024-08-22 | Clearmind Medicine Inc. | Compositions comprising ibogaine, optionally in combination with n-acylethanolamines, and uses thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4857523A (en) * | 1988-07-18 | 1989-08-15 | Nda International, Inc. | Rapid method for attenuating the alcohol dependency syndrome |
US5629307A (en) * | 1989-10-20 | 1997-05-13 | Olney; John W. | Use of ibogaine in reducing excitotoxic brain damage |
WO2008039179A1 (en) * | 2006-09-26 | 2008-04-03 | Addiction Research Institute, Inc. | Compositions for the treatment of hepatitis c and methods for using compositions for the treatment of hepatitis c |
-
2015
- 2015-03-02 WO PCT/US2015/018356 patent/WO2015134405A1/en active Application Filing
- 2015-03-02 CA CA2978537A patent/CA2978537C/en active Active
- 2015-03-02 CA CA3212001A patent/CA3212001A1/en active Pending
- 2015-03-02 AU AU2015225442A patent/AU2015225442A1/en not_active Abandoned
- 2015-03-02 EP EP15758129.9A patent/EP3113771A4/en not_active Withdrawn
-
2020
- 2020-11-18 AU AU2020273281A patent/AU2020273281B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
EP3113771A1 (en) | 2017-01-11 |
AU2020273281A1 (en) | 2020-12-17 |
AU2020273281B2 (en) | 2024-05-02 |
CA2978537A1 (en) | 2015-09-11 |
EP3113771A4 (en) | 2017-10-25 |
AU2015225442A1 (en) | 2016-10-20 |
WO2015134405A1 (en) | 2015-09-11 |
CA3212001A1 (en) | 2015-09-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2020273281B2 (en) | Therapeutic uses of ibogaine and related compounds | |
AU2020267217B2 (en) | Therapeutic methods employing noribogaine and related compounds | |
US10653700B2 (en) | Composition comprising a therapeutic agent and a respiratory stimulant and methods for the use thereof | |
US20220023310A1 (en) | Methods for acute and long-term treatment of opioid and opioid-like drug addiction | |
US11077118B2 (en) | Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake | |
AU2002342533B2 (en) | Prevention of addiction in pain management | |
CA2994150A1 (en) | Antitussive compositions and methods | |
JP2021530557A (en) | Treatment method using tradipitant | |
WO2021063387A1 (en) | Use of composition of imatinib and derivative thereof in preparation of drug for preventing, treating and controlling addiction relapse | |
CA3024081A1 (en) | Methods for treatment of opioid dependency and withdrawal using noribogaine | |
CA3142755A1 (en) | Composition comprising a therapeutic agent and a respiratory stimulant | |
In | Materials preparation to the practical classes for the students of pharmaceutical faculty LESSON № 21 Theme 29. Condensed heterocyclic systems. Purine. Notion about alkaloids. | |
CN104666305A (en) | Novel application of high-selectivity 5-hydroxytryptamine 5-HT2C receptor agonist WAY163909 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |
|
EEER | Examination request |
Effective date: 20200225 |