WO2022159507A1 - Combination of cannabinoids with additional therapeutic agents for treating diseases or disorders - Google Patents

Combination of cannabinoids with additional therapeutic agents for treating diseases or disorders Download PDF

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Publication number
WO2022159507A1
WO2022159507A1 PCT/US2022/013000 US2022013000W WO2022159507A1 WO 2022159507 A1 WO2022159507 A1 WO 2022159507A1 US 2022013000 W US2022013000 W US 2022013000W WO 2022159507 A1 WO2022159507 A1 WO 2022159507A1
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agent
disorder
disease
subject
alkyl
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PCT/US2022/013000
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French (fr)
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Ralph Laufer
Vincenzo Summa
Caroline J HELLER
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Merit Therapeutics, Inc.
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Publication of WO2022159507A1 publication Critical patent/WO2022159507A1/en

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    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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

Definitions

  • This invention relates to methods comprising administration of cannabinoid compounds and at least one additional therapeutic agent for the treatment or prevention of diseases or disorders including, but not limited to, fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (e.g., Parkinson's disease, Huntington's disease, , Alzheimer's disease), seizures, epilepsy, aggression, fear, phobias, anxiety, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
  • diseases or disorders including, but not limited to, fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (e.g.
  • Cannabinoids include more than 80 known chemical compounds found in all parts of the cannabis plant, Cannabis indica and Cannabis sativa. These compounds include CBD (Cannabidiol), CBDV (Cannabidivarin), CBDA (Cannabidiol - Acid), CBDVA (Cannabidivarin - Acid), CBC (Cannabichromene), CBG (Cannabigerol), CBGA (Cannabigerol - Acid), CBGV (Cannabigerovarin), CBN (Cannabinol), CBNV (Cannabinovarin), D9-THC (Delta-9 Tetrahydrocannabinol), THCA (Tetrahydrocannabinol-Acid), THCV (Tetrahydrocannabivarin), THCVA (Tetrahydrocannabivarin-Acid), and D8-THC (Delta-8 Tetrahydrocannabinol).
  • CBD CBD
  • CBDV CBDV
  • CBDA CBDA
  • Cannabinoids have a wide variety of both psychotropic and non-psychotropic effects on humans. For example, cannabinoids may stimulate appetite and relieve nausea in patients receiving chemotherapy. It has been used to treat conditions such as chronic pain and glaucoma. Cannabinoids are also believed to be effective in suppressing muscle spasticity, spasms, bladder dysfunction, and pain symptoms of MS.
  • a combination of cannabinoid compounds and additional therapeutic agents may exhibit a therapeutic synergistic or additive effect and allow for an improved safety profile of said therapeutic agents.
  • the required therapeutically effective amount of the therapeutic agent may also be less than current recommended and approved dosages, thus minimizing the toxicity during treatments.
  • Such a combination therapy may also prevent or delay the onset of drug resistance and reduce potentially the side effects that arise from the use of the additional therapeutic agents alone.
  • the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emes
  • the cannabinoid compound is any one that is known or available in the art.
  • the cannabinoid compound is tetrahydrocannabinol (THC), tetrahydrocannabinol acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin acid (THCV A), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiol acid (CBDA), cannabidivarin acid (CBDV A), cannabichromene (CBC), cannabigerol (CBG), cannabigerol acid (CBGA), cannabigerovarin (CBGV), cannabinol (CBN), or cannabinovarin (CBNV), or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product
  • CBD cannabidivarin acid
  • the additional therapeutic agent is an analgesic agent, an antianxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti-convulsive agent, antiepileptics, an anti-inflammatory agent, an anti-depressant agent, an anti-emetic agent, an anti- ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti-dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an anti-osteoporosis agent, or a cardiovascular agent.
  • an analgesic agent an antianxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti-convulsive agent, antiepileptics, an anti-inflammatory agent, an anti-depressant agent, an anti-
  • the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.
  • Figure 1 depicts an experiment design for study of NSAID and CBD combination effects on mouse Carrageenan-induced paw inflammation.
  • FIG. 1 depicts an acute test article dosing result (ACB-1).
  • Figure 3 depicts ACB-1 at the 4 hour time point snapshot.
  • FIG 4 depicts an acute test article dosing result (ACB-2).
  • Figure 5 depicts ACB-2 at the 4 hour time point snapshot.
  • Figure 6 depicts improved efficacy when combing CBD and Carprofen in ACB-3.
  • Figure 7 depicts ACB-3 at the 4 hour time point snapshot.
  • Figure 8 depicts the left ankle caliper change from baseline in ACB-4.
  • Figure 9 depicts ACB-4 data at the 4 hour time point.
  • Figure 10 depicts ACB-5 data at the 4 hour time point.
  • Figure 11 depicts a good combo effect with CBC at the 6 hour time point in ACB-5.
  • Figure 12 depicts combo effects with CBG, CBN, and CBC at the 8 hour point in ACB- 5.
  • Figure 13 depicts the result of a forced swim test.
  • Figure 14 depicts the anti-depressive effect of combo (fluoxetine + CBD) in early time points of forced swim test.
  • the present invention relates to a novel method for the treatment of a disease or disorder in a subject currently receiving a therapeutic agent by administration a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, in combination with the therapeutic agent.
  • a combination therapy that includes a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and at least one additional therapeutic agent as described herein may exhibit a therapeutic synergistic or additive effect.
  • the therapeutically effective amount of the therapeutic agent administered to the subject is much less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • a combination of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, with at least one additional therapeutic agent as described herein may allow for an improved safety profile of either the cannabinoid compound or the additional therapeutic agent during treatments and result in a decrease in the onset of resistance development.
  • the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emes
  • the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia nervosa, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.
  • the disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency.
  • the disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
  • the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia.
  • the disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures.
  • the disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma.
  • the cannabinoid compound is any one that is known or available in the art.
  • the cannabinoid compound is tetrahydrocannabinol (THC), tetrahydrocannabinol acid (THC A), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin acid (THCV A), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiol acid (CBDA), cannabidivarin acid (CBDVA), cannabichromene (CBC), cannabigerol (CBG), cannabigerol acid (CBGA), cannabigerovarin (CBGV), cannabinol (CBN), or cannabinovarin (CBNV), or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product
  • the cannabinoid compound is THC or THCV. In some embodiments, the cannabinoid compound is THC. In some embodiments, the THC is delta-9 tetrahydrocannabinol or delta- 8 tetrahydrocannabinol. In other embodiments, the cannabinoid compound is THCV.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof is represented by a compound of formula (A) or a compound of formula (B)
  • R1-R25 and R29-R31 are each independently H, alkyl, OH, alkoxy, C00R m , or CONRmRn,
  • R26 and R27 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy,
  • R28 is H, alkyl, R P CO, or R q OCO
  • R m and R n are each independently H or alkyl
  • R p and R q are each independently alkyl.
  • the cannabinoid compound is CBD.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof is represented by a compound of formula (C)
  • Xi-Xie and X19-X26 are each independently H, alkyl, OH, alkoxy, COOX m , or CONXmXn,
  • X17 and Xis are each independently H, alkyl, X P CO, or X q OCO,
  • X27 and X28 are each independently H, alkyl, halogen, NO2, CN, COOX m , or CONX m Xn,
  • X29 and X30 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NX m X n , COOX m , or CONX m X n ,
  • X m and X n are each independently H or alkyl.
  • X p and X q are each independently alkyl.
  • the cannabinoid compound is CBG.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof is represented by a compound of formula (D)
  • Y1-Y20, Y25, Y26, and Y28- Y31 are each independently H, alkyl, OH, alkoxy, COOY m , or CONYmYn,
  • Y21 and Y22 are each independently H, alkyl, Y P CO, or Y q OCO,
  • Y23 and Y24 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NY m Y n , COOY m , or CONY m Y n ,
  • Y27 and Y32 are each independently H, alkyl, halogen, NO2, CN, COOY m , or CONY m Yn, and
  • Y m and Y n are each independently H or alkyl.
  • Y p and Y q are each independently alkyl.
  • the cannabinoid compound is CBC.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof is represented by a compound of formula (E)
  • Z1-Z24 are each independently H, alkyl, OH, alkoxy, COOZ m , or CONZ m Z n ,
  • Z25-Z27 are each independently H, alkyl, halogen, NO2, CN, COOZ m , or CONZ m Z n ,
  • Z28 and Z29 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NZ m Z n , COOZ m , or CONZ m Z n ,
  • Z30 is H, alkyl, Z P CO, or Z q OCO,
  • Z m , and Z n are each independently H or alkyl.
  • Z p , and Z q are each independently alkyl.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof is represented by any one of the compounds below:
  • the term “analog” refers to a compound or synthetic cannabinoid that has the same basic chemical structure as a naturally occurring cannabinoid, such as ring structures and unsaturated bonds.
  • the chemical, biological, and pharmacological properties of the analog may be the same as or similar to the naturally occurring cannabinoid.
  • the analog of a cannabinoid compound refers to a compound that may not exhibit one or more unwanted side effects of a naturally occurring cannabinoid.
  • the analog of the cannabinoid compound may be obtained by chemical modifications or biological reactions on the naturally occurring cannabinoid or prepared from commercially available materials.
  • derivative includes, but is not limited to, acid derivatives, amide derivatives, ester derivatives and the like.
  • the term “metabolite” refers to any substance produced from another substance by metabolism or a metabolic process.
  • the term “pharmaceutical product” means a composition suitable for pharmaceutical use (pharmaceutical composition).
  • the term “prodrug” means a substance which can be converted in vivo into a biologically active agent by such reactions as hydrolysis, esterification, de-esterification, activation, salt formation and the like.
  • alkyl refers to a saturated aliphatic hydrocarbon, including straight-chained and branched-chained. Typically, the alkyl group has 1- 12 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 carbons atoms.
  • Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl ( ⁇ ?.g., n- propyl and isopropyl), butyl ( ⁇ ?.g., n-butyl, iso-butyl, /-butyl), pentyl (e.g., n-penlyl, iso-pentyl, neo-pentyl), and the like.
  • the alkyl group may be optionally substituted by at least one of halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, CN, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • halogen or “halo” or “halide” refers to F, Cl, Br, or I.
  • haloalky 1 refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCI2, C2CI5, and the like.
  • the term “compound,” as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopomers of the structures depicted. All compounds are also meant to include solvated or hydrated forms.
  • the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound and at least one additional therapeutic agent.
  • the disease or disorder is pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia.
  • the disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
  • the neurodegenerative disorder is Parkinson's disease, Huntington's disease, or Alzheimer's disease.
  • the disease or disorder is pain or inflammation.
  • the disease or disorder is osteoarthritis, musculoskeletal disorders, anorexia, emesis, or glaucoma.
  • the disease or disorder is osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, or a metabolic syndrome-related disorder.
  • the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid compound or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and at least an additional therapeutic agent.
  • the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy- induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.
  • the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
  • the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid compound or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and at least one additional therapeutic agent.
  • the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof.
  • the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above.
  • the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
  • the present invention provides a method of treating or preventing fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, or Rett syndrome in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism,
  • the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia.
  • the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism.
  • the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency.
  • the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder.
  • the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
  • the present invention provides a method for treating or preventing pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein.
  • the pain is chronic pain.
  • the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (a)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
  • the pain is chronic pain.
  • the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
  • the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
  • the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
  • the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above.
  • the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder.
  • the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a nonhuman animal.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
  • a cannabinoid compound or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof
  • the disease or disorder is osteoarthritis. In other embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington's disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma.
  • the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder.
  • the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein the disease or disorder is pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia. In some embodiments, the disease or disorder is pain.
  • the pain is chronic pain. In other embodiments, the pain is acute pain. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is chemo-related nausea, vomiting, and anorexia. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein the disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety.
  • the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder.
  • the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is aggression. In some embodiments, the disease or disorder is fear. In some embodiments, the disease or disorder is phobias, e.g., noise phobias. In some embodiments, the disease or disorder is generalized anxiety disorder. In some embodiments, the disease or disorder is separation anxiety. In some embodiments, the subject is an animal. In other embodiments, the subject is a dog. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the disease or disorder is anorexia.
  • the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In some embodiments, the causes of anorexia include, but are not limited to, secondary to chemo, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, and iatrogenic problems. [0070] In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is anxiety.
  • the anxiety is separation anxiety or generalized anxiety.
  • the disease or disorder is aggression.
  • the aggression is dominance aggression, fear aggression, intraspecific aggression, or territorial aggression.
  • the disease or disorder is a compulsive disorder.
  • the disease or disorder is noise phobias.
  • the disease or disorder is epilepsy.
  • the disease or disorder is seizures.
  • the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above.
  • the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder.
  • the subject is an animal.
  • the subject is a dog.
  • the subject is a horse, a dog, a cat, or a ferret.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma.
  • the disease or disorder is anorexia.
  • the anorexia is acute anorexia.
  • the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In other embodiments, the anorexia is associated with chronic renal insufficiency.
  • the disease or disorder is anxiety. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above.
  • the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder.
  • the subject is an animal.
  • the subject is a cat.
  • the subject is a horse, a dog, a cat, or a ferret.
  • the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
  • the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of pain or inflammation.
  • the additional therapeutic agent is as described anywhere herein for the treatment and prevention of pain or inflammation.
  • the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery, soft-tissue surgery, or dental surgery.
  • the present invention provides a method of treating or preventing fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
  • the “therapeutic agent” as used herein refers to an agent or a drug that is capable of providing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied.
  • the “therapeutic agent” can be any agent or drug as known in the art or being currently developed.
  • the terms “therapeutic agent” and “therapeutic drug” are used interchangeably.
  • the “therapeutic agent” refers to the “additional therapeutic agent” as used herein.
  • the additional therapeutic agent is an analgesic agent, an anti-anxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti- convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti-depressant agent, an antiemetic agent, an anti-ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti- dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an antiosteoporosis agent, or a cardiovascular agent.
  • the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an analgesic agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an analgesic agent.
  • the disease or disorder is pain such as acute pain or chronic pain.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the analgesic agent is an opioid analgesic agent or a nonopioid analgesic agent.
  • the non-opioid analgesic agent is meloxicam, acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, carbamazepine, gabapentin, or pregabalin.
  • the analgesic agent is naproxen sodium or magnesium.
  • the analgesic is carbamazepine, gabapentin, pregabalin, acetaminophen, ibuprofen, or naproxen. In some embodiments, the analgesic agent is carprofen.
  • the opioid analgesic agent is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol.
  • the opioid analgesic agent is hydrocodone bitartrate or oxycodone hydrochloride.
  • the opioid analgesic agent is a naturally occurring opiate, such as an alkaloid occurring in the opium poppy.
  • the naturally occurring opiate is morphine, codeine, narcotine, papaverine, narceine, or thebaine.
  • the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of CBD and an analgesic agent.
  • the analgesic agent is carprofen.
  • the subject is a human patient or a non-human animal.
  • the subject is a human patient.
  • the subject is a non-human animal.
  • the non-human animal is a dog or a cat.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and a therapeutic agent for treatment of a neurodegenerative disease or disorder.
  • the disease or disorder is a neurodegenerative disease or disorder.
  • the neurodegenerative disease or disorder is Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive, Tourette's syndrome, or progressive muscular atrophy.
  • the neurodegenerative disease or disorder is Parkinson's disease, Alzheimer's disease, or Huntington's disease.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanins (e.g., anthocyanin cyanidin-3-O-glucoside), levodopa, pergolide (PERMAXTM), ephenedrine sulfate (EPHEDRINETM), pemoline CYLERTTM), mazindol (SANOREXTM), d,l-a-methylphenethylamine (ADDERALLTM) methylphenydate (RITALINTM), pramipexole (MIRAPEXTM), modafinil (PROVIGILTM), or ropinirole (REQUIPTM).
  • anthocyanins e.g., anthocyanin cyanidin-3-O-glucoside
  • levodopa e.g., pergolide (PERMAXTM), ephenedrine sulfate (EPHEDRINETM), pemoline CYLERTTM), ma
  • the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanin, levodopa, pergolide, ephenedrine sulfate, pemoline, mazindol, a-methylphenethylamine, methylphenidate, pramipexole, modafinil, or ropinirole.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-dyskensia agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-dyskensia agent.
  • the disease or disorder is a movement disorder or Parkinson disease.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-dyskensia agent is selected from baclofen (LioresalTM), botulinum toxin (BotoxTM), clonazepam (KlonopinTM), and diazepam (ValiumTM).
  • an anti-dyskensia agent is baclofen, botulinum toxin, clonazepam, or diazepam.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an immunosuppressive agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an immunosuppressive agent.
  • the disease or disorder is an autoimmune disease.
  • the autoimmune disease is lupus or rheumatoid arthritis.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the immunosuppressive agent is azathioprine, cyclophosphamide, bromocriptine, glutaraldehyde, cyclosporin A, prednisone, prednisolone, methylprednisone, dexamethasone, heterologous anti-lymphocyte globulin, deoxyspergualin, or rapamycin.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-spasmodic agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-spasmodic agent.
  • the disease or disorder is irritable bowel syndrome, abdominal pain, or bladder dysfunction.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-spasmodic agent is carbamatepine, oxcarbazepine, ferbocate, furboc acid, paroxamine, fibapramine, laxamide, talapanib, retigabine, levethiracetam, tobinamide, zonisamide. barbiturates, benzodiazepines, or hydantoin.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-diabetic agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-diabetic agent.
  • the disease or disorder is diabetes.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-diabetic agent is mefluminine hydrochloride, acarbose, miglitol, human insulin, pig insulin, bovine insulin, nateglinide, reglinide, glimepiride, glibenclamide, chlorpromide, tolazamide, or glipben.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-convulsant agent or an anti-epileptic agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anticonvulsant agent or an anti-epileptic agent.
  • the disease or disorder is seizure, neuropathic pain, or epilepsy.
  • the disease or disorder is a seizure associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-convulsant agent or anti-epileptic agent is phenobarbital, pentobarbital, nitronazapine, clozapine acid salt, diazapine, saigabin, gabapentin, phenytoin, 5,5- diphenylhydantoin, carbamatepine, oxcarbazepine, falbockate, falbock acid, bifarin Pockic acid, paroxamide, fibamay, levethiracetam, tobinamide, zonisamide, lamtidine, mesylamine, ethoxyl , or ruitijiabin.
  • the anti-convulsant agent or anti-epileptic agent is brivaracetam, carbamzepine, clobazam, rancedon, ethosuximide, non-ammonia ester, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin sodium salt, pregabalin, desoxyphenobarbital, rotigotine, rufinamide, seletracetam, talampanel, tiagabine, topiramate, sodium valproate, vigabatrin, or zonisamide.
  • the anticonvulsant agent or anti-epileptic agent is arbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, tiagabine, valproic acid, or zonisamide.
  • the anti-convulsant agent or anti-epileptic agent is Epidiolex®.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-psychotic agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-psychotic agent.
  • the disease or disorder is schizophrenia, psychosis, or bipolar disorder.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-psychotic agent is risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine, or raclopride.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an cholesterol/lipid lowering agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by a cholesterol/lipid lowering agent.
  • the disease or disorder is high cholesterol, lipid abnormalities, obesity, or a metabolic syndrome-related disorder.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the cholesterol/lipid lowering agent is pravastatin, lovastatin, simvastatin, fluvastatin, atorvsatatin, rosuvastatin, cholestyramine, colestipol, gemfibrozil, clofibrate, fenofibrate, benzafibrate, rosiglitazone, or ezetimibe.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-inflammatory agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-inflammatory agent.
  • the disease or disorder is an inflammatory disease.
  • the disease or disorder is severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, headaches, digestive disorders, or a fever.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-inflammatory agent is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, naproxen, ketoprofen, celecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-bacterial agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-bacterial agent.
  • the disease or disorder is a bacterial infection.
  • the disease or disorder is a skin or eye infection, tuberculosis, or a urinary tract infection.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-bacterial agent is selected from the group consisting of erythromycin, aji azithromycin, clarithromycin, telithromycin, penicillin G, penicillin V, methicillin, toluene oxazinmycin, o-chloropenicillin, diclofenac, phenoxypenicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, Piperacillin, azlocillin, temocillin, cepalothin, cefepime, cefacyclohexene, ceftizodine, cefazolin, cefotaxazole, cephalosporin, cephalosporin IV, cefprozil, cloxacromycin, loracarbef, cefotaxime, cefinetazole, ceftazidime cefotaxime, cefizoxime, ceftriaxone, cefoperazone, ceftazidime
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-emetic.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-emetics.
  • the disease or disorder is vomiting, nausea, motion sickness, or the side effects of opioid analgesics, general anesthetics, and/or chemotherapy directed against cancer.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-emetic is dolasetron, granisetron, ondansetron, tropisetron, palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-depressant.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-depressant.
  • the disease or disorder is an obsessive-compulsive disorder (OCD), depression, panic disorder, an anxiety disorder, bipolar disorder, posttraumatic stress disorder (PTSD), phobias, or social anxiety disorder.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-depressants is selected from the group consisting of adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, apelinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprin
  • the present invention provides a method for method for treating or preventing depression in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of CBD and an anti-depressant agent.
  • the anti-depressant agent is a selective serotonin reuptake inhibitor (SSRI).
  • the anti-depressant agent is fluoxetine.
  • the subject is a human patient or a nonhuman animal.
  • the subject is a human patient.
  • the subject is a non-human animal.
  • the non-human animal is a dog or a cat.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-anxiety agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-anxiety agent.
  • the disease or disorder is generalized anxiety disorder, social phobia, anxiety, obsessive-compulsive disorder (OCD), panic disorder, and depression.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-anxiety agent is comipramine hydrochloride, fluoxetine hydrochloride, salprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam prazepam, buspirone, flesinoxan, gepirone and ipsapirone, pindolol, carbamazepine, lamotrigine, valproate, clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol, vigabatrin, or barbiturates.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and a sleeping agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by a sleeping agent.
  • the disease or disorder is insomnia, sleepwalking, night terrors, a movement disorder that interrupts sleep, such as restless legs syndrome (RLS) and periodic limb movement disorder.
  • the cannabinoid compound is any compound of formulas (A)- (E), or any compounds as described herein.
  • the sleeping agent is zolpidem, alpidem, zopiclone, or indiflon.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an orexigenic agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an orexigenic agent.
  • the disease or disorder is anorexia .
  • a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an orexigenic agent can stimulate appetite and produce weight gain in older persons.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the orexigenic agent is megestrol or oxandrolone.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an ocular hypotensive agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an ocular hypotensive agent.
  • the disease or disorder is glaucoma.
  • a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an ocular hypotensive agent can lower intraocular pressure (IOP).
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the ocular hypotensive agent includes, but is not limited to, bimatoprost, latanoprost, travoprost, timolol, betaxolol, dorzolamide, brinzolamide, pilocarpine, brimonidine, latanoprost, travoprost, or bimatoprost.
  • the present invention provides a method for treating or preventing osteoporosis in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-osteoporosis agent.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-osteoporosis agent includes, but is not limited to alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, apeledoxifene, teriparatide, abaloparatide, and denosumab.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-migraine agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by an anti-migraine agent.
  • the disease or disorder is migraine headache or migraine pain.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the anti-migraine agent is sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan, probatriptan, or almotriptan.
  • the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and a cardiovascular agent.
  • the disease or disorder is any one that can be treated or prevented as known in the art by a cardiovascular agent.
  • the disease or disorder includes, but is not limited to, arrhythmias, blood clots, coronary artery disease, high or low blood pressure, high cholesterol, heart failure, and stroke.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the term “cardiovascular agents” refer to medicines that are used to treat medical conditions associated with the heart or the circulatory system (blood vessels).
  • the cardiovascular agent is avasimibe, pactimibe, captopril, enalapril, enalaprilat, tradolapril, moexipril, ramipril, hinapril, perindopril, lisinopril, benazepril, fosinopril, eplerenone, aldactone, doxazosin, methyldofu, clonidine, prazosin, terazosin, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan, adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, mex
  • the present invention provides a method for treating or preventing cancer, comprising administering to a subject in need thereof a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-cancer agent.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the cancer is chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, colon tumors, lung tumors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, or melanoma.
  • the cancer is chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph-i- CML).
  • the anti-cancer agent is a chemotherapeutic agent.
  • the chemotherapeutic agent is adrimycin, doxorubicin, 5 -fluorouracil, cytosine arabinoside(“Ara-C”), cyclophosphamide, thiotepa, taxotere (docetaxel), bulsulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycine, esperamicins, or melphalan.
  • the anti-cancer agent is a cytostatic drug.
  • the cytostatic drug is busulfan, chlorambucil, cyclophosphamide, melphalan, carmustine, lomustine, 5 -fluorouracil, gemcitabine, pemetrexed, doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, paclitaxel, docetaxel, vinblastine, vincristine, etoposide, cisplatin, carboplatin, or oxaliplatin.
  • the anti-cancer agent is an alkylating agent.
  • the alkylating agent includes, but is not limited to, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.
  • the anti-cancer agent is a cancer immunotherapy monoclonal antibody.
  • the cancer immunotherapy monoclonal antibody is rituximab, bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, or trastuzumab.
  • the anti-cancer agent is an anti- tumor antibiotic agent.
  • the anti-tumor antibiotic agent includes, but is not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea.
  • the anti-cancer agent is selected from the group consisting of amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.
  • the anti-cancer agent is an anti-metabolite agent.
  • the anti-metabolite agent includes, but is not limited to, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafur, carmofur, capecitabine, and gemcitabine.
  • the anti-cancer agent is a mitotic inhibitor.
  • the mitotic inhibitor includes, but is not limited to, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.
  • the anti-cancer agent is a tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor includes, but is not limited to, imatinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib.
  • the anti-cancer agent is a topoisomerase inhibitor.
  • the topoisomerase inhibitor includes, but is not limited to, etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan.
  • the additional therapeutic agent is selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, antiatherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antiviral infection, fun
  • an additional therapeutic agent is selected from norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium
  • NRIs norepin
  • squalene synthetase inhibitors include fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta- muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethiazide, polythiazide, benzothiazide, ethacrynic acid,
  • metformin glucosidase inhibitors
  • glucosidase inhibitors e.g., acarbose
  • insulins meglitinides (e.g., repaglinide)
  • meglitinides e.g., repaglinide
  • sulfonylureas e.g., glimepiride, glyburide, and glipizide
  • thiozolidinediones e.g.
  • troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; antibiotics, such as anthracy clines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L- asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocor
  • a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein is administered in combination with an additional therapeutic agent
  • typically a daily dosage may be about 0.1 to about 1 milligrams of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, per kilogram of patient body weight and, in the case of the additional therapeutic agent, the usual dosage of the therapeutic agent when administered alone may be reduced by about 10- 90% when administered with a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described
  • the therapeutically effective amount of the additional therapeutic agent administered to the subject is less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein.
  • the therapeutically effective amount of the therapeutic agent administered to the subject is 0% to 90%, 5% to 90%, or 10% to 90% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is 20% to 80% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the therapeutically effective amount of the therapeutic agent administered to the subject is 20% to 70% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the therapeutically effective amount of the therapeutic agent administered to the subject is at least 10% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein, or any compounds as described herein. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 20% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the therapeutically effective amount of the therapeutic agent administered to the subject is at least 30% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 40% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the therapeutically effective amount of the therapeutic agent administered to the subject is at least 50% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the therapeutically effective amount of the therapeutic agent administered to the subject is at least 5%, or 15%, or 25%, or 35%, or 45%, or 55% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the additional therapeutic agent and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein are administered in combination administered concurrently.
  • the additional therapeutic agent and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof are administered concurrently.
  • the present invention further provides a combination therapy.
  • administered in combination means the administration of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E) as described herein, or any compounds as described herein, and one or more additional therapeutic agents to treat a therapeutic disorder described in the present invention.
  • Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient.
  • such administration also encompasses use of each type of active ingredient in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the diseases or disorders described herein.
  • the therapeutic agent and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof are formulated in the same pharmaceutical composition.
  • the present invention provides a pharmaceutical composition comprising the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, at least one additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
  • the additional therapeutic agent is formulated in a first pharmaceutical composition and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, is formulated in a second pharmaceutical composition.
  • the present invention provides a kit comprising a first compartment containing a first pharmaceutical composition comprising a therapeutic agent as described herein and a second compartment containing a second pharmaceutical composition comprising a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and the additional therapeutic agents are combined in a single dosage unit they may be formulated such that the physical contact between the active ingredients is minimized to reduce a potential chemical interaction between the combined active ingredients.
  • one or both active ingredients may be enteric coated.
  • the active ingredient(s) may be coated with a material that affects a sustained release throughout the gastrointestinal tract.
  • the compound of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof may not be coated.
  • pharmaceutical composition refers to a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and/or a therapeutic agent, together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
  • compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g.; Tris-HCL, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid,
  • a "therapeutically effective amount” as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.
  • Standard references are available that describe procedures for preparing various compositions or formulations suitable for administration of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
  • the mode of administration and dosage form are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.
  • compositions as described herein can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracancerally, transmucosally, transdermally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, intraventricularly, intracranially, intravaginally, by inhalation, rectally, or intratumorally. These methods include any means in which the composition can be delivered to tissue (e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces. Another method of administration is via aerosol formulation.
  • compositions may be administered topically to body surfaces and are thus formulated in a form suitable for topical administration.
  • suitable topical formulations include gels, ointments, creams, lotions, drops and the like.
  • the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • Suitable dosage forms include, but are not limited to, oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for systemic delivery of active ingredients.
  • the formulations are suitable for oral or topical administration.
  • carrier or diluents are well known to those skilled in the art.
  • the carrier or diluent may be a solid carrier or diluent for solid formulations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.
  • Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. com starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • a starch e.g. com starch, pregeletanized starch
  • a sugar e.g., lactose, mannitol, sucrose, dextrose
  • a cellulosic material e.g. microcrystalline cellulose
  • an acrylate e.g. polymethylacrylate
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like.
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
  • the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
  • Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, orally disintegrating tablets or films, or lozenges, each containing a predetermined amount of the active ingredient.
  • a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
  • a tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent.
  • Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
  • a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s).
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
  • flavorings can be added to all dosage forms when needed, including, but not limited to, solid oral forms and liquid oral forms.
  • Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which in some embodiments is isotonic with the blood of the recipient (e.g., physiological saline solution).
  • Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose form.
  • Parenteral administration may comprise any suitable form of systemic delivery.
  • Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.
  • Nasal and other mucosal spray formulations can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are, in some embodiments, adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
  • Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
  • Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
  • a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose
  • compositions of this invention may further include one or more ingredient selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
  • the formulations may be of immediate release, sustained release, delay ed-onset release or any other release profile known to one skilled in the art.
  • the methods of the invention comprise administration of a compound at a therapeutically effective amount.
  • the therapeutically effective amount may include various dosages.
  • a dosage unit of the compounds used in the present invention may comprise a single compound or mixtures thereof with additional therapeutic agents.
  • a “dose” or “dosage unit” or “unit dosage” of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein as measured in milligrams refers to the milligrams of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, present in a preparation, regardless of the form of the preparation.
  • a dosage unit may comprise a single compound or mixtures of compounds thereof.
  • a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof is administered at a dosage of 1-3000 mg per day.
  • a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein is administered at a dosage of 0.01-1.0 mg per day, at a dosage of 0.025-1.0 mg per day, at a dosage of 0.05-1.0 mg per day, at a dosage of 0.075-1.0 mg per day, at a dosage of 0.01-0.075 mg per day, at a dosage of 0.01-0.05 mg per day, at a dosage of 0.01-0.025 mg per day, at a dosage of 0.025-0.05 mg per day, at a dosage of 0.05- 0.075 mg per day, at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 10-100 mg per day, 15-60 mg per day, 15-100 mg per day, 25-100 mg per day, 50-100 mg
  • the methods may comprise administering a compound at various dosages.
  • the compound may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.
  • the compound may be administered at a dosage of 0.1 mg/kg/day.
  • the compound may be administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.
  • a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, liquid suspensions, and granules.
  • the pharmaceutical composition as described herein is in the form of a capsule, a tablet, or a liquid suspension. In other embodiments, the pharmaceutical composition as described herein is in an oral dosage unit form.
  • a pharmaceutical composition is prepared for once daily administration. In another embodiment, a pharmaceutical composition is prepared for more than once daily administration, for example, twice daily, three times daily, four times daily, etc.
  • Plasma levels of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof may be measured using the methods described by Li et al.
  • Examples of cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S 1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1,
  • the inhibition of the cytochrome P450 isoform is measured by the method of Ko et al, British Journal of Clinical Pharmacology 2000, 49, 343-351.
  • the inhibition of the MAOA isoform is measured by the method of Weyler et al, J. Biol Chem. 1985, 260, 13199-13207.
  • the inhibition of the MAOB isoform is measured by the method of Uebelhack et al, Pharmacopsychiatry 1998, 31, 187-192.
  • Examples of polymorphically-expressed cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
  • liver microsomes cytochrome P450 isoforms
  • monoamine oxidase isoforms are measured by the methods described herein.
  • improved disorder-control and/or disorder-eradication endpoints include, but are not limited to, major cytogenetic response, complete cytogenetic response, complete hematologic response, complete molecular remission, improved progression-free survival, increase in overall survival rate, tumor shrinkage, increased median overall survival time, improved overall response rate, and improved disease control rate.
  • hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase ("ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP,” “y-GTP,” or “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5 '-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in "Diagnostic and Laboratory Test Reference", 4 th edition, Mosby, 1999.
  • the formulas also include any and all hydrates and/or solvates of the compound formulas. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulas are to be understood to include and represent those various hydrates and/or solvates.
  • solvate refers to compounds that further include a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. If the solvent is water, the solvate is referred to as "hydrate.” Pharmaceutically acceptable solvates and hydrates are complexes that, for example, may include from 1 to about 100, or from 1 to about 10, or from one to about 2.3 or 4 molecules of water or a solvent. In some embodiments, the hydrate may be a channel hydrate. It should be understood that the term “compound” in this application covers the compound and solvates of the compound, as well as mixtures thereof.
  • hydrate includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and the like.
  • Subject refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, and the like), lagomorphs (e.g., rabbit), swine (e.g., pig, miniature pig), equine, ferrets, parrots, canine, feline, bovine, ovine, caprine, and camelids.
  • a primate e.g., human, monkey, chimpanzee, gorilla, and the like
  • rodents e.g., rats, mice, gerbils, hamsters, and the like
  • lagomorphs e.g., rabbit
  • swine e.g., pig, miniature pig
  • equine ferrets
  • parrots canine, feline, bovine, ovine, caprine, and camelids
  • the subject in the method of the invention is a human patient.
  • the subject is a non-human animal.
  • the subject is a companion animal, an exotic animal, or a farm animal.
  • the subject is a horse, a dog, a cat, or a ferret.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and formulations comprising the same may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • the animals include horses, dogs, and cats.
  • treatment refers to the administering of a therapeutic effective amount of the composition as described herein which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease form occurring or a combination of two or more of the above.
  • the phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof can also prepared in the form of the pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; for example, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • the pharmaceutically acceptable salts of the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof can be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing salt for another ion or suitable ion-exchange resin.
  • a pharmaceutically acceptable salt form of a cannabinoid compound can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base functionality with a suitable organic or inorganic acid.
  • Suitable acids for preparation of the pharmaceutically acceptable salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • Other pharmaceutically acceptable salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, IH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(
  • the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof can be isolated or prepared using methods known in the art, including, for example, by referring to the following Schemes.
  • the following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.
  • Liver microsomal stability assays are conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% sodium bicarbonate (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM magnesium chloride).
  • Test compounds are prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay concentration 5 microgram per mL) and incubated at 37° C. Final concentration of acetonitrile in the assay should be ⁇ 1%.
  • the cytochrome P450 enzymes are expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, Calif.).
  • Monoamine Oxidase A Inhibition and Oxidative Turnover [00205] The procedure is carried out using the methods described by Weyler et al., Journal of Biological Chemistry 1985, 260, 13199-13207, which is hereby incorporated by reference in its entirety. Monoamine oxidase A activity is measured spectrophotometrically by monitoring the increase in absorbance at 314 nm on oxidation of kynuramine with formation of 4- hydroxyquinoline.
  • the measurements are carried out, at 30° C., in 50 rnM sodium phosphate buffer, pH 7.2, containing 0.2% Triton X-100 (monoamine oxidase assay buffer), plus 1 mM kynuramine, and the desired amount of enzyme in 1 mL total volume.
  • Rats or mice receive a single intravenous dose of a compound of the invention at a dose of 1 mg/kg body weight, or a single oral dose of the compound of Invention at a dose of 10- 50 mg/kg body weight.
  • Plasma samples are collected at different times following dosing and the plasma concentrations of the compound of the invention is determined by HPLC-MS/MS analysis using standards methods. Clearance, half-life, volume of distribution and oral bioavailability are calculated from the plasma concentration-time course data using established methods.
  • Example 2 NSAID and CBD combination effects on Mouse Carrageenan- Induced Paw Inflammation
  • Inflammation models induced by carrageenan are frequently used acute inflammation models mainly because they are well-researched and they exhibit a high degree of reproducibility.
  • Carrageenan is a strong chemical that functions in stimulating the release of inflammatory and proinflammatory mediators, including bradykinin, histamine, tachykinins, reactive oxygen, and nitrogen species. Typical signs of inflammation include edema, hyperalgesia, and erythema, which develop immediately following the treatment of carrageenan.
  • animals are injected with a certain concentration (usually 1%) of the irritant substance carrageenan in one hind footpad, usually, half an hour or an hour after they are treated with the test compound while the other footpad is injected with saline as a control (https://www.creative-biolabs.com/drug-discovery/therapeutics/carrageenan-induced-paw- edema-model.htm).
  • saline https://www.creative-biolabs.com/drug-discovery/therapeutics/carrageenan-induced-paw- edema-model.htm).
  • Efficacy was determined by caliper measurement of the ankle diameter at various time points.
  • Figures 2-5 provided acute test article dosing results (ACB-1). At the 4 hour time point, the combo yielded anti-inflammatory effects and performed better than each API alone.
  • Figures 6 and 7 depicts improved efficacy when combing CBD and Carprofen in ACB- 3.
  • Figures 8 and 9 provided that at the 4 hour time point, higher concentration of CBD combined with suboptimal concentration of NS AID appeared to give a combo effect.
  • Figures 10-12 provided acute test article dosing results (ACB-5) for CBG, CBN, and CBC and showed that at the 8 hour time point, combos were yielding anti-inflammatory effects where the single agent APIs were not.
  • Figure 10 indicated no significant combo effect at the 4 hour time point.
  • Figure 11 showed a good combo effect with CBC at the 6 hour time point in ACB-5.
  • Figure 12 provided a significant combo effect with CBG, CBN, and CBC at the 8 hour point in ACB-5.
  • cannabinoids anti-inflammatory/anti-nociceptive activity can be combined with approved NSAID agents in order to create more efficacious and/or safer therapeutic products for treatments in a subject, including companion animals.
  • the forced swim test (FST), which is one of the most commonly used assays for the study of depressive-like behavior in rodents.
  • the FST is based on the assumption that when placing an animal in a container filled with water, it will first make efforts to escape but eventually will exhibit immobility that may be considered to reflect a measure of behavioral despair.
  • This test has been extensively used because it involves the exposure of the animals to stress, which was shown to have a role in the tendency for major depression. Additionally, the FST has been shown to share some of the factors that are influenced or altered by depression in humans, including changes in food consumption, sleep abnormalities and drug-withdrawal-induced anhedonia (J Vis Exp. 2015; (97): 52587).
  • Figures 13 and 14 provided that fluoxetine alone did not show early effect, but CBD alone or in combo with fluoxetine showed significant anti-depressive effect in the forced swim model. Anti-depression signal was observed in early time points of forced swim test, in which combo was better than each API alone.

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Abstract

This invention relates to methods comprising administration of cannabinoid compounds and at least one additional therapeutic agent for the treatment or prevention of diseases or disorders including, but not limited to, fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (e.g., Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, aggression, fear, phobias, anxiety, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.

Description

COMBINATION OF CANNABINOIDS WITH ADDITIONAL THERAPEUTIC AGENTS FOR TREATING DISEASES OR DISORDERS
FIELD OF THE INVENTION
[001] This invention relates to methods comprising administration of cannabinoid compounds and at least one additional therapeutic agent for the treatment or prevention of diseases or disorders including, but not limited to, fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (e.g., Parkinson's disease, Huntington's disease, , Alzheimer's disease), seizures, epilepsy, aggression, fear, phobias, anxiety, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
BACKGROUND OF THE INVENTION
[002] Cannabinoids include more than 80 known chemical compounds found in all parts of the cannabis plant, Cannabis indica and Cannabis sativa. These compounds include CBD (Cannabidiol), CBDV (Cannabidivarin), CBDA (Cannabidiol - Acid), CBDVA (Cannabidivarin - Acid), CBC (Cannabichromene), CBG (Cannabigerol), CBGA (Cannabigerol - Acid), CBGV (Cannabigerovarin), CBN (Cannabinol), CBNV (Cannabinovarin), D9-THC (Delta-9 Tetrahydrocannabinol), THCA (Tetrahydrocannabinol-Acid), THCV (Tetrahydrocannabivarin), THCVA (Tetrahydrocannabivarin-Acid), and D8-THC (Delta-8 Tetrahydrocannabinol).
[003] Cannabinoids have a wide variety of both psychotropic and non-psychotropic effects on humans. For example, cannabinoids may stimulate appetite and relieve nausea in patients receiving chemotherapy. It has been used to treat conditions such as chronic pain and glaucoma. Cannabinoids are also believed to be effective in suppressing muscle spasticity, spasms, bladder dysfunction, and pain symptoms of MS.
[004] A combination of cannabinoid compounds and additional therapeutic agents may exhibit a therapeutic synergistic or additive effect and allow for an improved safety profile of said therapeutic agents. The required therapeutically effective amount of the therapeutic agent may also be less than current recommended and approved dosages, thus minimizing the toxicity during treatments. Such a combination therapy may also prevent or delay the onset of drug resistance and reduce potentially the side effects that arise from the use of the additional therapeutic agents alone.
SUMMARY OF THE INVENTION
[005] In one aspect, the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.
[006] In some embodiments, the cannabinoid compound is any one that is known or available in the art. In some embodiments, the cannabinoid compound is tetrahydrocannabinol (THC), tetrahydrocannabinol acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin acid (THCV A), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiol acid (CBDA), cannabidivarin acid (CBDV A), cannabichromene (CBC), cannabigerol (CBG), cannabigerol acid (CBGA), cannabigerovarin (CBGV), cannabinol (CBN), or cannabinovarin (CBNV), or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
[007] In some embodiments, the additional therapeutic agent is an analgesic agent, an antianxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti-convulsive agent, antiepileptics, an anti-inflammatory agent, an anti-depressant agent, an anti-emetic agent, an anti- ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti-dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an anti-osteoporosis agent, or a cardiovascular agent.
[008] In some embodiments, the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.
[009] The details of one or more embodiments of the invention are set forth in the accompanying the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF THE FIGURES
[0010] Figure 1 depicts an experiment design for study of NSAID and CBD combination effects on mouse Carrageenan-induced paw inflammation.
[0011] Figure 2 depicts an acute test article dosing result (ACB-1).
[0012] Figure 3 depicts ACB-1 at the 4 hour time point snapshot.
[0013] Figure 4 depicts an acute test article dosing result (ACB-2).
[0014] Figure 5 depicts ACB-2 at the 4 hour time point snapshot.
[0015] Figure 6 depicts improved efficacy when combing CBD and Carprofen in ACB-3. [0016] Figure 7 depicts ACB-3 at the 4 hour time point snapshot.
[0017] Figure 8 depicts the left ankle caliper change from baseline in ACB-4.
[0018] Figure 9 depicts ACB-4 data at the 4 hour time point.
[0019] Figure 10 depicts ACB-5 data at the 4 hour time point.
[0020] Figure 11 depicts a good combo effect with CBC at the 6 hour time point in ACB-5.
[0021] Figure 12 depicts combo effects with CBG, CBN, and CBC at the 8 hour point in ACB- 5.
[0022] Figure 13 depicts the result of a forced swim test.
[0023] Figure 14 depicts the anti-depressive effect of combo (fluoxetine + CBD) in early time points of forced swim test.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0024] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.
[0025] The present invention relates to a novel method for the treatment of a disease or disorder in a subject currently receiving a therapeutic agent by administration a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, in combination with the therapeutic agent.
[0026] It is one aspect of the invention that a combination therapy that includes a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and at least one additional therapeutic agent as described herein may exhibit a therapeutic synergistic or additive effect. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is much less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
[0027] It is another aspect of the invention that a combination of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, with at least one additional therapeutic agent as described herein may allow for an improved safety profile of either the cannabinoid compound or the additional therapeutic agent during treatments and result in a decrease in the onset of resistance development.
[0028] In one aspect, the invention provides a method for treating or preventing a diseases or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency; musculoskeletal disorders, Parkinson's disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, compulsive disorders, or any combination thereof.
[0029] In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy-induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia nervosa, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof.
[0030] In some embodiments, the disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency.
[0031] In some embodiments, the disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
[0032] In some embodiments, the disease or disorder is pain, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia.
[0033] In some embodiments, the disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures.
[0034] In some embodiments, the disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma.
[0035] In some embodiments, the cannabinoid compound is any one that is known or available in the art. In some embodiments, the cannabinoid compound is tetrahydrocannabinol (THC), tetrahydrocannabinol acid (THC A), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin acid (THCV A), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiol acid (CBDA), cannabidivarin acid (CBDVA), cannabichromene (CBC), cannabigerol (CBG), cannabigerol acid (CBGA), cannabigerovarin (CBGV), cannabinol (CBN), or cannabinovarin (CBNV), or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
[0036] In some embodiments, the cannabinoid compound is THC or THCV. In some embodiments, the cannabinoid compound is THC. In some embodiments, the THC is delta-9 tetrahydrocannabinol or delta- 8 tetrahydrocannabinol. In other embodiments, the cannabinoid compound is THCV.
[0037] In some embodiments, the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (A) or a compound of formula (B)
Figure imgf000009_0001
Figure imgf000010_0001
wherein
R1-R25 and R29-R31 are each independently H, alkyl, OH, alkoxy, C00Rm, or CONRmRn,
R26 and R27 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy,
SH, S-alkyl, NRmRn, COORm, or CONRmRn,
R28 is H, alkyl, RPCO, or RqOCO,
Rm and Rn are each independently H or alkyl, and
Rp and Rq are each independently alkyl.
[0038] In some embodiments, the cannabinoid compound is CBD.
[0039] In some embodiments, the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (C)
Figure imgf000011_0001
wherein
Xi-Xie and X19-X26 are each independently H, alkyl, OH, alkoxy, COOXm, or CONXmXn,
X17 and Xis are each independently H, alkyl, XPCO, or XqOCO,
X27 and X28 are each independently H, alkyl, halogen, NO2, CN, COOXm, or CONXmXn,
X29 and X30 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NXmXn, COOXm, or CONXmXn,
Xm and Xn are each independently H or alkyl.
Xp and Xq are each independently alkyl.
[0040] In some embodiments, the cannabinoid compound is CBG.
[0041] In some embodiments, the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (D)
Figure imgf000012_0001
wherein
Y1-Y20, Y25, Y26, and Y28- Y31 are each independently H, alkyl, OH, alkoxy, COOYm, or CONYmYn,
Y21 and Y22 are each independently H, alkyl, YPCO, or YqOCO,
Y23 and Y24 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NYmYn, COOYm, or CONYmYn,
Y27 and Y32 are each independently H, alkyl, halogen, NO2, CN, COOYm, or CONYmYn, and
Ym and Yn are each independently H or alkyl.
Yp and Yq are each independently alkyl.
[0042] In some embodiments, the cannabinoid compound is CBC.
[0043] In some embodiments, the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (E)
Figure imgf000013_0001
wherein
Z1-Z24 are each independently H, alkyl, OH, alkoxy, COOZm, or CONZmZn,
Z25-Z27 are each independently H, alkyl, halogen, NO2, CN, COOZm, or CONZmZn,
Z28 and Z29 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NZmZn, COOZm, or CONZmZn,
Z30 is H, alkyl, ZPCO, or ZqOCO,
Zm, and Zn are each independently H or alkyl.
Zp, and Zq are each independently alkyl.
[0044] In some embodiments, the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by any one of the compounds below:
Figure imgf000013_0002
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
[0045] As used herein, in some embodiments, the term “analog” refers to a compound or synthetic cannabinoid that has the same basic chemical structure as a naturally occurring cannabinoid, such as ring structures and unsaturated bonds. In some embodiments, the chemical, biological, and pharmacological properties of the analog may be the same as or similar to the naturally occurring cannabinoid. In some embodiments, the analog of a cannabinoid compound refers to a compound that may not exhibit one or more unwanted side effects of a naturally occurring cannabinoid. In some embodiments, the analog of the cannabinoid compound may be obtained by chemical modifications or biological reactions on the naturally occurring cannabinoid or prepared from commercially available materials.
[0046] As used herein, in some embodiments, the term “derivative” includes, but is not limited to, acid derivatives, amide derivatives, ester derivatives and the like.
[0047] As used herein, in some embodiments, the term “metabolite” refers to any substance produced from another substance by metabolism or a metabolic process.
[0048] As used herein, in some embodiments, the term “pharmaceutical product” means a composition suitable for pharmaceutical use (pharmaceutical composition).
[0049] As used herein, in some embodiments, the term “prodrug” means a substance which can be converted in vivo into a biologically active agent by such reactions as hydrolysis, esterification, de-esterification, activation, salt formation and the like.
[0050] As used herein, in some embodiments, the term “alkyl” refers to a saturated aliphatic hydrocarbon, including straight-chained and branched-chained. Typically, the alkyl group has 1- 12 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 carbons atoms. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (<?.g., n- propyl and isopropyl), butyl (<?.g., n-butyl, iso-butyl, /-butyl), pentyl (e.g., n-penlyl, iso-pentyl, neo-pentyl), and the like. In some embodiments, the alkyl group may be optionally substituted by at least one of halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, CN, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
[0051] As used herein, “alkoxy” refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. [0052] As used herein, “halogen" or "halo" or “halide” refers to F, Cl, Br, or I.
[0001] As used herein, “haloalky 1” refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCI2, C2CI5, and the like.
[0053] As used herein, in some embodiments, the term “compound,” as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopomers of the structures depicted. All compounds are also meant to include solvated or hydrated forms.
[0054] In one aspect, the invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound and at least one additional therapeutic agent.
[0055] In some embodiments, the disease or disorder is pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia.
[0056] In some embodiments, the disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
[0057] In some embodiments, the neurodegenerative disorder is Parkinson's disease, Huntington's disease, or Alzheimer's disease.
[0058] In some embodiments, the disease or disorder is pain or inflammation.
[0059] In certain embodiments, the disease or disorder is osteoarthritis, musculoskeletal disorders, anorexia, emesis, or glaucoma.
[0060] In other embodiments, the disease or disorder is osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, or a metabolic syndrome-related disorder.
[0061] In another aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid compound or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and at least an additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, chemotherapy- induced emesis, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, or emesis, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
[0062] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid compound or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and at least one additional therapeutic agent. In some embodiments, the disease or disorder is fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, or convulsion, or any combination thereof. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. [0063] In another aspect, the present invention provides a method of treating or preventing fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, or Rett syndrome in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
[0064] In a further aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. In some embodiments, the disease or disorder is non-24-hour sleep wake disorder. In other embodiments, the disease or disorder is Smith-Magenis syndrome. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is primary insomnia circadian rhythm-related disorders. In some embodiments, the disease or disorder is depression. In some embodiments, the disease or disorder is jet-lag. In some embodiments, the disease or disorder is work-shift syndrome. In some embodiments, the disease or disorder is a sleep disorder. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is a reproductive disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is benign prostatic hyperplasia. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is a neuroendocrine disorder. In some embodiments, the disease or disorder is dysthymia. In some embodiments, the disease or disorder is bipolar disorder. In some embodiments, the disease or disorder is a delayed sleep phase disorder. In some embodiments, the disease or disorder is a general anxiety disorder. In some embodiments, the disease or disorder is a seasonal affective disorder. In some embodiments, the disease or disorder is an attention deficit hyperactivity disorder. In some embodiments, the disease or disorder is Alzheimer's. In some embodiments, the disease or disorder is Angelman syndrome. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is migraine. In some embodiments, the disease or disorder is night-time hypertension. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a type 2 diabetes. In some embodiments, the disease or disorder is testosterone insufficiency. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
[0065] In another aspect, the present invention provides a method for treating or preventing pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein. In some embodiments, the pain is chronic pain. In some embodiments, the present invention provides a method of treating or preventing pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (a)-(E), or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the pain is chronic pain. In some embodiments, the present invention provides a method of treating or preventing multiple sclerosis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the present invention provides a method of treating or preventing chemo-related nausea, vomiting, and anorexia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a nonhuman animal.
[0066] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease), seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. In some embodiments, the disease or disorder is osteoarthritis. In other embodiments, the disease or disorder is musculoskeletal disorders. In some embodiments, the disease or disorder is anorexia. In some embodiments, the disease or disorder is emesis. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neurodegenerative disorders, for example, Parkinson's disease, Huntington's disease, and/or Alzheimer's disease. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is osteoporosis. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the disease or disorder is a cardiovascular disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic syndrome-related disorder. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
[0067] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein the disease or disorder is pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia. In some embodiments, the disease or disorder is pain. In some embodiments, the pain is chronic pain. In other embodiments, the pain is acute pain. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is chemo-related nausea, vomiting, and anorexia. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal.
[0068] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein the disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the disease or disorder is seizures. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is aggression. In some embodiments, the disease or disorder is fear. In some embodiments, the disease or disorder is phobias, e.g., noise phobias. In some embodiments, the disease or disorder is generalized anxiety disorder. In some embodiments, the disease or disorder is separation anxiety. In some embodiments, the subject is an animal. In other embodiments, the subject is a dog. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.
[0069] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures. In some embodiments, the disease or disorder is anorexia. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In some embodiments, the causes of anorexia include, but are not limited to, secondary to chemo, neoplastic disease, degenerative disorders, auto-immune diseases, allergies, metabolic disorders, infection, inflammation, trauma, toxicity, nutritional imbalance, idiopathic conditions, and iatrogenic problems. [0070] In some embodiments, the disease or disorder is glaucoma. In some embodiments, the disease or disorder is anxiety. In some embodiments, the anxiety is separation anxiety or generalized anxiety. In some embodiments, the disease or disorder is aggression. In some embodiments, the aggression is dominance aggression, fear aggression, intraspecific aggression, or territorial aggression. In some embodiments, the disease or disorder is a compulsive disorder. In some embodiments, the disease or disorder is noise phobias. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is seizures. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In some embodiments, the subject is a dog. In other embodiments, the subject is a horse, a dog, a cat, or a ferret.
[0071] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent, wherein said disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma. In some embodiments, the disease or disorder is anorexia. In some embodiments, the anorexia is acute anorexia. In some embodiments, the anorexia is chronic anorexia. In other embodiments, the anorexia is a primary anorexia. In some embodiments, the anorexia is a secondary anorexia, e.g., secondary to chemo. In other embodiments, the anorexia is associated with chronic renal insufficiency. In some embodiments, the disease or disorder is anxiety. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or disorder is glaucoma. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of the disease or disorder as described above. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of the disease or disorder. In some embodiments, the subject is an animal. In certain embodiments, the subject is a cat. In other embodiments, the subject is a horse, a dog, a cat, or a ferret. [0072] In another aspect, the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is the one as known in the art that can be used for the treatment or prevention of pain or inflammation. In some embodiments, the additional therapeutic agent is as described anywhere herein for the treatment and prevention of pain or inflammation. In some embodiments, the subject in the method of the invention is a mammal. In other embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret. In some embodiments, the subject is a dog. In some embodiments, the pain or inflammation is associated with osteoarthritis. In some embodiments, the pain or inflammation is a postoperative pain or postoperative inflammation. In certain embodiments, the postoperative pain is associated with orthopedic surgery, soft-tissue surgery, or dental surgery. In some embodiments, the postoperative inflammation is associated with orthopedic surgery, soft-tissue surgery, or dental surgery.
[0073] In yet another aspect, the present invention provides a method of treating or preventing fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E), or any compounds as described herein, and at least one additional therapeutic agent.
[0074] In some embodiments, the “therapeutic agent” as used herein refers to an agent or a drug that is capable of providing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied. The “therapeutic agent” can be any agent or drug as known in the art or being currently developed. In some embodiments, the terms “therapeutic agent” and “therapeutic drug” are used interchangeably. In some embodiments, the “therapeutic agent” refers to the “additional therapeutic agent” as used herein. [0075] In some embodiments of the method of the invention, the additional therapeutic agent is an analgesic agent, an anti-anxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti- convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti-depressant agent, an antiemetic agent, an anti-ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for neurodegenerative diseases or disorders, an anti- dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an anti-diabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an antiosteoporosis agent, or a cardiovascular agent.
[0076] In some embodiments, the additional therapeutic agent is an agent for treating fragile X syndrome. In some embodiments, the additional therapeutic agent is an agent for treating autism spectrum disorder. In some embodiments, the additional therapeutic agent is an agent for treating lysosomal storage diseases. In some embodiments, the additional therapeutic agent is an agent for treating leukodystrophies. In some embodiments, the additional therapeutic agent is an agent for treating Rett syndrome.
[0077] In one aspect, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an analgesic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an analgesic agent. In some embodiments, the disease or disorder is pain such as acute pain or chronic pain. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[0078] In some embodiments, the analgesic agent is an opioid analgesic agent or a nonopioid analgesic agent. In some embodiments, the non-opioid analgesic agent is meloxicam, acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, carbamazepine, gabapentin, or pregabalin. In certain embodiments, the analgesic agent is naproxen sodium or magnesium. In some embodiments, the analgesic is carbamazepine, gabapentin, pregabalin, acetaminophen, ibuprofen, or naproxen. In some embodiments, the analgesic agent is carprofen. [0079] In some embodiments, the opioid analgesic agent is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol. In some embodiments, the opioid analgesic agent is hydrocodone bitartrate or oxycodone hydrochloride. In some embodiments, the opioid analgesic agent is a naturally occurring opiate, such as an alkaloid occurring in the opium poppy. In certain embodiments, the naturally occurring opiate is morphine, codeine, narcotine, papaverine, narceine, or thebaine.
[0080] In some embodiments, the present invention provides a method for treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of CBD and an analgesic agent. In some embodiments, the analgesic agent is carprofen. In some embodiments, the subject is a human patient or a non-human animal. In some embodiments, the subject is a human patient. In other embodiments, the subject is a non-human animal. In certain embodiments, the non-human animal is a dog or a cat.
[0081] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and a therapeutic agent for treatment of a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the neurodegenerative disease or disorder is Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive, Tourette's syndrome, or progressive muscular atrophy. In some embodiments, the neurodegenerative disease or disorder is Parkinson's disease, Alzheimer's disease, or Huntington's disease. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[0082] In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanins (e.g., anthocyanin cyanidin-3-O-glucoside), levodopa, pergolide (PERMAX™), ephenedrine sulfate (EPHEDRINE™), pemoline CYLERT™), mazindol (SANOREX™), d,l-a-methylphenethylamine (ADDERALL™) methylphenydate (RITALIN™), pramipexole (MIRAPEX™), modafinil (PROVIGIL™), or ropinirole (REQUIP™). In some embodiments, the therapeutic agent for treatment of a neurodegenerative disease or disorder is resveratrol, anthocyanin, levodopa, pergolide, ephenedrine sulfate, pemoline, mazindol, a-methylphenethylamine, methylphenidate, pramipexole, modafinil, or ropinirole.
[0083] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-dyskensia agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-dyskensia agent. In some embodiments, the disease or disorder is a movement disorder or Parkinson disease. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[0084] In some embodiments, the anti-dyskensia agent is selected from baclofen (Lioresal™), botulinum toxin (Botox™), clonazepam (Klonopin™), and diazepam (Valium™). In other embodiments, an anti-dyskensia agent is baclofen, botulinum toxin, clonazepam, or diazepam.
[0085] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an immunosuppressive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an immunosuppressive agent. In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is lupus or rheumatoid arthritis. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein. [0086] In some embodiments, the immunosuppressive agent is azathioprine, cyclophosphamide, bromocriptine, glutaraldehyde, cyclosporin A, prednisone, prednisolone, methylprednisone, dexamethasone, heterologous anti-lymphocyte globulin, deoxyspergualin, or rapamycin.
[0087] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-spasmodic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-spasmodic agent. In some embodiments, the disease or disorder is irritable bowel syndrome, abdominal pain, or bladder dysfunction. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[0088] In some embodiments, the anti-spasmodic agent is carbamatepine, oxcarbazepine, ferbocate, furboc acid, paroxamine, fibapramine, laxamide, talapanib, retigabine, levethiracetam, tobinamide, zonisamide. barbiturates, benzodiazepines, or hydantoin.
[0089] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-diabetic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-diabetic agent. In some embodiments, the disease or disorder is diabetes. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[0090] In some embodiments, the anti-diabetic agent is mefluminine hydrochloride, acarbose, miglitol, human insulin, pig insulin, bovine insulin, nateglinide, reglinide, glimepiride, glibenclamide, chlorpromide, tolazamide, or glipben.
[0091] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-convulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anticonvulsant agent or an anti-epileptic agent. In some embodiments, the disease or disorder is seizure, neuropathic pain, or epilepsy. In some embodiments, the disease or disorder is a seizure associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[0092] In some embodiments, the anti-convulsant agent or anti-epileptic agent is phenobarbital, pentobarbital, nitronazapine, clozapine acid salt, diazapine, saigabin, gabapentin, phenytoin, 5,5- diphenylhydantoin, carbamatepine, oxcarbazepine, falbockate, falbock acid, bifarin Pockic acid, paroxamide, fibamay, levethiracetam, tobinamide, zonisamide, lamtidine, mesylamine, ethoxyl , or ruitijiabin. In some embodiments, the anti-convulsant agent or anti-epileptic agent is brivaracetam, carbamzepine, clobazam, rancedon, ethosuximide, non-ammonia ester, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin sodium salt, pregabalin, desoxyphenobarbital, rotigotine, rufinamide, seletracetam, talampanel, tiagabine, topiramate, sodium valproate, vigabatrin, or zonisamide. In some embodiments, the anticonvulsant agent or anti-epileptic agent is arbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, tiagabine, valproic acid, or zonisamide. In some embodiments, the anti-convulsant agent or anti-epileptic agent is Epidiolex®.
[0093] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-psychotic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-psychotic agent. In some embodiments, the disease or disorder is schizophrenia, psychosis, or bipolar disorder. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein. [0094] In some embodiments, the anti-psychotic agent is risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine, or raclopride.
[0095] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cholesterol/lipid lowering agent. In some embodiments, the disease or disorder is high cholesterol, lipid abnormalities, obesity, or a metabolic syndrome-related disorder. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[0096] In some embodiments, the cholesterol/lipid lowering agent is pravastatin, lovastatin, simvastatin, fluvastatin, atorvsatatin, rosuvastatin, cholestyramine, colestipol, gemfibrozil, clofibrate, fenofibrate, benzafibrate, rosiglitazone, or ezetimibe.
[0097] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-inflammatory agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-inflammatory agent. In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the disease or disorder is severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, headaches, digestive disorders, or a fever. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein. [0098] In some embodiments, the anti-inflammatory agent is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, naproxen, ketoprofen, celecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, or acetaminophen.
[0099] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-bacterial agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-bacterial agent. In some embodiments, the disease or disorder is a bacterial infection. In some embodiments, the disease or disorder is a skin or eye infection, tuberculosis, or a urinary tract infection. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00100] In some embodiments, the anti-bacterial agent is selected from the group consisting of erythromycin, aji azithromycin, clarithromycin, telithromycin, penicillin G, penicillin V, methicillin, toluene oxazinmycin, o-chloropenicillin, diclofenac, phenoxypenicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, Piperacillin, azlocillin, temocillin, cepalothin, cefepime, cefacyclohexene, ceftizodine, cefazolin, cefotaxazole, cephalosporin, cephalosporin IV, cefprozil, cloxacromycin, loracarbef, cefotaxime, cefinetazole, ceftazidime cefotaxime, cefizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, cetazide, ceftibuten, cefdinir, cefpirome, cefepime, aztreonam, imipenem, meropenem, meropenem penicillin (ertapenem), doricane (doripenem), cephalosporin ceftobiprole and ceftaroline, citric acid, porphyrin, norfloxacin, pefloxacin, enoxacin, oufumycin, levofloxacin, ciprofloxacin, tiproxoxacin temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, and rufosa trovafloxacin), clinafloxacin, gatifloxacin, moxifloxacin, sitar Sitafloxacin, garenoxacin, gemifloxacin, pazufloxacin, p-aminobenzoic acid, sulfadiazine, sulfonamide azole, sulfamethine oxazole and sulfonamide, streptomycin, neomycin, kenmycin, baromycin, gentamicin, tobramycin, butyl Amine kanamycin, netilmicin, spectinomycin, perillamycin, dardamycin and ezeparin, tetracycline, chlortetracycline, chlorotetracycline, go Mechlorin, minocycline, oxytetracycline, methicillin, tigcycline, doxycycline, rifampicin, rifampin, rifapentine, rifabutin, bezoxazinorifamycin and rifaximin, lincomycin, kesendamycin, telavancin, vancomycin, ticlosin, daptomycin, quinupristin and darfapolis Daflopristin, linoleide, polymyxin, colistin, colin, trimethoprim, and bacitracin.
[00101] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-emetic. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-emetics. In some embodiments, the disease or disorder is vomiting, nausea, motion sickness, or the side effects of opioid analgesics, general anesthetics, and/or chemotherapy directed against cancer. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00102] In some embodiments, the anti-emetic is dolasetron, granisetron, ondansetron, tropisetron, palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol.
[00103] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-depressant. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-depressant. In some embodiments, the disease or disorder is an obsessive-compulsive disorder (OCD), depression, panic disorder, an anxiety disorder, bipolar disorder, posttraumatic stress disorder (PTSD), phobias, or social anxiety disorder. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00104] In some embodiments, the anti-depressants is selected from the group consisting of adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, fluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine, and zometapine. In some embodiments, the antidepressant agent is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the anti-depressant agent is fluoxetine.
[00105] In some embodiments, the present invention provides a method for method for treating or preventing depression in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of CBD and an anti-depressant agent. In some embodiments, the anti-depressant agent is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the anti-depressant agent is fluoxetine. In some embodiments, the subject is a human patient or a nonhuman animal. In some embodiments, the subject is a human patient. In other embodiments, the subject is a non-human animal. In certain embodiments, the non-human animal is a dog or a cat.
[00106] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-anxiety agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-anxiety agent. In some embodiments, the disease or disorder is generalized anxiety disorder, social phobia, anxiety, obsessive-compulsive disorder (OCD), panic disorder, and depression. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00107] In some embodiments, the anti-anxiety agent is comipramine hydrochloride, fluoxetine hydrochloride, salprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam prazepam, buspirone, flesinoxan, gepirone and ipsapirone, pindolol, carbamazepine, lamotrigine, valproate, clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol, vigabatrin, or barbiturates.
[00108] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and a sleeping agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a sleeping agent. In some embodiments, the disease or disorder is insomnia, sleepwalking, night terrors, a movement disorder that interrupts sleep, such as restless legs syndrome (RLS) and periodic limb movement disorder. In some embodiments, the cannabinoid compound is any compound of formulas (A)- (E), or any compounds as described herein.
[00109] In some embodiments, the sleeping agent is zolpidem, alpidem, zopiclone, or indiflon.
[00110] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an orexigenic agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an orexigenic agent. In some embodiments, the disease or disorder is anorexia . In some embodiments, a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an orexigenic agent can stimulate appetite and produce weight gain in older persons. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein. [00111] In some embodiments, the orexigenic agent is megestrol or oxandrolone.
[00112] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an ocular hypotensive agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an ocular hypotensive agent. In some embodiments, the disease or disorder is glaucoma. In some embodiments, a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an ocular hypotensive agent can lower intraocular pressure (IOP). In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00113] In some embodiments, the ocular hypotensive agent includes, but is not limited to, bimatoprost, latanoprost, travoprost, timolol, betaxolol, dorzolamide, brinzolamide, pilocarpine, brimonidine, latanoprost, travoprost, or bimatoprost.
[00114] In some embodiments, the present invention provides a method for treating or preventing osteoporosis in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-osteoporosis agent. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00115] In some embodiments, the anti-osteoporosis agent includes, but is not limited to alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, bazedoxifene, teriparatide, abaloparatide, and denosumab.
[00116] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-migraine agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by an anti-migraine agent. In some embodiments, the disease or disorder is migraine headache or migraine pain. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00117] In some embodiments, the anti-migraine agent is sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan, probatriptan, or almotriptan.
[00118] In some embodiments, the present invention provides a method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and a cardiovascular agent. In some embodiments, the disease or disorder is any one that can be treated or prevented as known in the art by a cardiovascular agent. In some embodiments, the disease or disorder includes, but is not limited to, arrhythmias, blood clots, coronary artery disease, high or low blood pressure, high cholesterol, heart failure, and stroke. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00119] As used herein, in some embodiments, the term “cardiovascular agents” refer to medicines that are used to treat medical conditions associated with the heart or the circulatory system (blood vessels). In some embodiments, the cardiovascular agent is avasimibe, pactimibe, captopril, enalapril, enalaprilat, tradolapril, moexipril, ramipril, hinapril, perindopril, lisinopril, benazepril, fosinopril, eplerenone, aldactone, doxazosin, methyldofu, clonidine, prazosin, terazosin, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan, adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride, or tocainide.
[00120] In some embodiments, the present invention provides a method for treating or preventing cancer, comprising administering to a subject in need thereof a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and an anti-cancer agent. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00121] In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, colon tumors, lung tumors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, or melanoma. In some embodiments, the cancer is chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph-i- CML).
[00122] In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is adrimycin, doxorubicin, 5 -fluorouracil, cytosine arabinoside(“Ara-C”), cyclophosphamide, thiotepa, taxotere (docetaxel), bulsulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycine, esperamicins, or melphalan.
[00123] In some embodiments, the anti-cancer agent is a cytostatic drug. In some embodiments, the cytostatic drug is busulfan, chlorambucil, cyclophosphamide, melphalan, carmustine, lomustine, 5 -fluorouracil, gemcitabine, pemetrexed, doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, paclitaxel, docetaxel, vinblastine, vincristine, etoposide, cisplatin, carboplatin, or oxaliplatin.
[00124] In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the alkylating agent includes, but is not limited to, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.
[00125] In some embodiments, the anti-cancer agent is a cancer immunotherapy monoclonal antibody. In some embodiments, the cancer immunotherapy monoclonal antibody is rituximab, bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, or trastuzumab. [00126] In some embodiments, the anti-cancer agent is an anti- tumor antibiotic agent. In some embodiments, the anti-tumor antibiotic agent includes, but is not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea.
[00127] In certain embodiments, the anti-cancer agent is selected from the group consisting of amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.
[00128] In some embodiments, the anti-cancer agent is an anti-metabolite agent. In some embodiments, the anti-metabolite agent includes, but is not limited to, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafur, carmofur, capecitabine, and gemcitabine.
[00129] In some embodiments, the anti-cancer agent is a mitotic inhibitor. In some embodiments, the mitotic inhibitor includes, but is not limited to, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.
[00130] In some embodiments, the anti-cancer agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor includes, but is not limited to, imatinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib.
[00131] In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor includes, but is not limited to, etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan.
[00132] In some embodiments of the method of the invention, the additional therapeutic agent is selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, antiatherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antiviral infection, fungal agents, cholesterol/lipid lowering agents and lipid profile therapies, and agents that mimic ischemic preconditioning and/or myocardial stunning, or a combination thereof.
[00133] In some embodiments, an additional therapeutic agent is selected from norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor Vila Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEPACE inhibitors), such as omapatrilat and gemopatrilat; HMG Co A reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta- muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethiazide, polythiazide, benzothiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; antibiotics, such as anthracy clines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L- asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.
[00134] Where a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein is administered in combination with an additional therapeutic agent, typically a daily dosage may be about 0.1 to about 1 milligrams of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, per kilogram of patient body weight and, in the case of the additional therapeutic agent, the usual dosage of the therapeutic agent when administered alone may be reduced by about 10- 90% when administered with a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00135] In some embodiments of the method of the invention, the therapeutically effective amount of the additional therapeutic agent administered to the subject is less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is 0% to 90%, 5% to 90%, or 10% to 90% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is 20% to 80% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is 20% to 70% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00136] In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 10% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein, or any compounds as described herein. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 20% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 30% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 40% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 50% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the therapeutically effective amount of the therapeutic agent administered to the subject is at least 5%, or 15%, or 25%, or 35%, or 45%, or 55% less than the therapeutically effective amount of the therapeutic agent when administered in the absence of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00137] In some embodiments, the additional therapeutic agent and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein are administered in combination administered concurrently. In other embodiments, the additional therapeutic agent and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, are administered concurrently. [00138] In some embodiments, the present invention further provides a combination therapy. The term “administered in combination” or “combination therapy” means the administration of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E) as described herein, or any compounds as described herein, and one or more additional therapeutic agents to treat a therapeutic disorder described in the present invention. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of active ingredient in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the diseases or disorders described herein.
[00139] It is another aspect of the invention that the therapeutic agent and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, are formulated in the same pharmaceutical composition. Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, at least one additional therapeutic agent, and a pharmaceutically acceptable carrier. In some embodiments, the cannabinoid compound is any compound of formulas (A)-(E), or any compounds as described herein.
[00140] In some embodiments, the additional therapeutic agent is formulated in a first pharmaceutical composition and the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, is formulated in a second pharmaceutical composition.
[00141] In another aspect, the present invention provides a kit comprising a first compartment containing a first pharmaceutical composition comprising a therapeutic agent as described herein and a second compartment containing a second pharmaceutical composition comprising a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. [00142] When the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein and the additional therapeutic agents are combined in a single dosage unit they may be formulated such that the physical contact between the active ingredients is minimized to reduce a potential chemical interaction between the combined active ingredients. For example, one or both active ingredients may be enteric coated. In some embodiments, the active ingredient(s) may be coated with a material that affects a sustained release throughout the gastrointestinal tract. In some embodiments, the compound of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, may not be coated.
[00143] As used herein, "pharmaceutical composition" refers to a therapeutically effective amount of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and/or a therapeutic agent, together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers. Such compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g.; Tris-HCL, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
[00144] A "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen. [00145] Standard references are available that describe procedures for preparing various compositions or formulations suitable for administration of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof. Examples of methods of making formulations and preparations can be found in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).
[00146] The mode of administration and dosage form are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.
[00147] The pharmaceutical compositions as described herein can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracancerally, transmucosally, transdermally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, intraventricularly, intracranially, intravaginally, by inhalation, rectally, or intratumorally. These methods include any means in which the composition can be delivered to tissue (e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces. Another method of administration is via aerosol formulation. The pharmaceutical compositions may be administered topically to body surfaces and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administrations, the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
[00148] Suitable dosage forms include, but are not limited to, oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for systemic delivery of active ingredients. Depending on the indication, in some embodiments, the formulations are suitable for oral or topical administration.
[00149] As used herein "pharmaceutically acceptable carriers or diluents" are well known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for solid formulations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.
[00150] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. com starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
[00151] In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. For solid oral preparations such as, chewable, soft- chew, gummy, powders, capsules, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.
[00152] For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
[00153] In some applications, it may be advantageous to utilize the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
[00154] Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, orally disintegrating tablets or films, or lozenges, each containing a predetermined amount of the active ingredient. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
[00155] A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
[00156] A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
[00157] As used herein, flavorings can be added to all dosage forms when needed, including, but not limited to, solid oral forms and liquid oral forms.
[00158] Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which in some embodiments is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.
[00159] Parenteral administration may comprise any suitable form of systemic delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.
[00160] Nasal and other mucosal spray formulations (e.g. inhalable forms) can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are, in some embodiments, adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
[00161] Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
[00162] Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
[00163] In addition to the aforementioned ingredients, compositions of this invention may further include one or more ingredient selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
[00164] The formulations may be of immediate release, sustained release, delay ed-onset release or any other release profile known to one skilled in the art.
[00165] For administration to mammals, it is expected that the physician will determine the actual dosage and duration of treatment, which will be most suitable for an individual and can vary with the age, weight, genetics and/or response of the particular individual.
[00166] The methods of the invention comprise administration of a compound at a therapeutically effective amount. The therapeutically effective amount may include various dosages.
[00167] A dosage unit of the compounds used in the present invention may comprise a single compound or mixtures thereof with additional therapeutic agents. A “dose” or “dosage unit” or “unit dosage” of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein as measured in milligrams refers to the milligrams of the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, present in a preparation, regardless of the form of the preparation. A dosage unit may comprise a single compound or mixtures of compounds thereof.
[00168] In some embodiments, a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, is administered at a dosage of 1-3000 mg per day. In other embodiments, a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, as described herein is administered at a dosage of 0.01-1.0 mg per day, at a dosage of 0.025-1.0 mg per day, at a dosage of 0.05-1.0 mg per day, at a dosage of 0.075-1.0 mg per day, at a dosage of 0.01-0.075 mg per day, at a dosage of 0.01-0.05 mg per day, at a dosage of 0.01-0.025 mg per day, at a dosage of 0.025-0.05 mg per day, at a dosage of 0.05- 0.075 mg per day, at a dose of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 10-100 mg per day, 15-60 mg per day, 15-100 mg per day, 25-100 mg per day, 50-100 mg per day, 50-200 mg per day, 100-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125- 500 mg per day, 500-1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day.
[00169] The methods may comprise administering a compound at various dosages. For example, the compound may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.
[00170] Alternatively, the compound may be administered at a dosage of 0.1 mg/kg/day. The compound may be administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.
[00171] In some embodiments, a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, liquid suspensions, and granules. [00172] In some embodiments, the pharmaceutical composition as described herein is in the form of a capsule, a tablet, or a liquid suspension. In other embodiments, the pharmaceutical composition as described herein is in an oral dosage unit form.
[00173] The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.
[00174] In another embodiment, a pharmaceutical composition is prepared for once daily administration. In another embodiment, a pharmaceutical composition is prepared for more than once daily administration, for example, twice daily, three times daily, four times daily, etc.
[00175] Plasma levels of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, may be measured using the methods described by Li et al. Rapid Communications in Mass Spectrometry 2005, 19, 1943-1950; De Francia et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(18+19), 1721-1726; Parise et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(20+21), 1894-1900; Pursche et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2007, 852(1- 2), 208-216; Haouala et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(22), 1982-1996; and any references cited therein and any modifications made thereof.
[00176] Examples of cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S 1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51. [00177] Examples of monoamine oxidase isoforms in a mammalian subject include, but are not limited to, MAO A, and MAOB.
[00178] The inhibition of the cytochrome P450 isoform is measured by the method of Ko et al, British Journal of Clinical Pharmacology 2000, 49, 343-351. The inhibition of the MAOA isoform is measured by the method of Weyler et al, J. Biol Chem. 1985, 260, 13199-13207. The inhibition of the MAOB isoform is measured by the method of Uebelhack et al, Pharmacopsychiatry 1998, 31, 187-192.
[00179] Examples of polymorphically-expressed cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
[00180] The metabolic activities of liver microsomes, cytochrome P450 isoforms, and monoamine oxidase isoforms are measured by the methods described herein.
[00181] Examples of improved disorder-control and/or disorder-eradication endpoints, or improved clinical effects include, but are not limited to, major cytogenetic response, complete cytogenetic response, complete hematologic response, complete molecular remission, improved progression-free survival, increase in overall survival rate, tumor shrinkage, increased median overall survival time, improved overall response rate, and improved disease control rate.
[00182] Examples of diagnostic hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST" or "SGOT"), ALT/AST ratios, serum aldolase, alkaline phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP," "y-GTP," or "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5 '-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in "Diagnostic and Laboratory Test Reference", 4th edition, Mosby, 1999.
[00183] As used herein, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.
[00184] In each of the foregoing and each of the following embodiments, it is to be understood that the formulas also include any and all hydrates and/or solvates of the compound formulas. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulas are to be understood to include and represent those various hydrates and/or solvates.
[00185] As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. If the solvent is water, the solvate is referred to as "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that, for example, may include from 1 to about 100, or from 1 to about 10, or from one to about 2.3 or 4 molecules of water or a solvent. In some embodiments, the hydrate may be a channel hydrate. It should be understood that the term “compound” in this application covers the compound and solvates of the compound, as well as mixtures thereof.
[00186] In some embodiments, the term “hydrate” includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and the like.
[00187] "Subject" refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, and the like), lagomorphs (e.g., rabbit), swine (e.g., pig, miniature pig), equine, ferrets, parrots, canine, feline, bovine, ovine, caprine, and camelids. The terms "subject" and "patient" are used interchangeably herein when referencing, for example, a mammalian subject, such as a human patient.
[00188] In some embodiments, the subject in the method of the invention is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a companion animal, an exotic animal, or a farm animal. In certain embodiments, the subject is a horse, a dog, a cat, or a ferret.
[00189] Thus, besides being useful for human treatment, the cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, and formulations comprising the same may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. In some embodiments, the animals include horses, dogs, and cats. [00190] The term “treatment” or “treating” as used herein refers to the administering of a therapeutic effective amount of the composition as described herein which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease form occurring or a combination of two or more of the above.
[00191] In some embodiments, the phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[00192] The cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, can also prepared in the form of the pharmaceutically acceptable salts. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; for example, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. [00193] The pharmaceutically acceptable salts of the cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, can be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing salt for another ion or suitable ion-exchange resin.
[00194] Possible pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977; incorporated herein by reference.
[00195] Typically, a pharmaceutically acceptable salt form of a cannabinoid compound can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base functionality with a suitable organic or inorganic acid.
[00196] Suitable acids for preparation of the pharmaceutically acceptable salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
[00197] Other pharmaceutically acceptable salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[00198] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
[00199] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, IH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2- amino-2-(hydroxymethyl)-l,3-propanediol, and tromethamine.
[00200] It is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable. Further, reference to values stated in ranges includes each and every value within that range. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any combination.
[00201] The cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, can be isolated or prepared using methods known in the art, including, for example, by referring to the following Schemes. [00202] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.
Example 1: Biological Activity Assays
In vitro Liver Microsomal Stability Assay
[00203] Liver microsomal stability assays are conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% sodium bicarbonate (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM magnesium chloride). Test compounds are prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay concentration 5 microgram per mL) and incubated at 37° C. Final concentration of acetonitrile in the assay should be <1%. Aliquots (50 pL) are taken out at times 0, 15, 30, 45, and 60 minutes, and diluted with ice cold acetonitrile (200 pL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 minutes to precipitate proteins. Supernatants are transferred to microcentrifuge tubes and stored for LC/MS/MS analysis of the degradation half-life of the test compounds.
In Vitro Metabolism Using Human Cytochrome P450 Enzymes
[00204] The cytochrome P450 enzymes are expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, Calif.). A 0.25 milliliter reaction mixture containing 0.8 milligrams per milliliter protein, 1.3 millimolar NADP+, 3.3 millimolar glucose-6-phosphate, 0.4 U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a cannabinoid compound, or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof, or any compound of formulas (A)-(E) as described herein, the corresponding non-isotopically enriched compound or standard or control in 100 millimolar potassium phosphate (pH 7.4) is incubated at 37° C. for 20 minutes. After incubation, the reaction is stopped by the addition of an appropriate solvent (e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3 minutes. The supernatant is analyzed by HPLC/MS/MS.
Monoamine Oxidase A Inhibition and Oxidative Turnover [00205] The procedure is carried out using the methods described by Weyler et al., Journal of Biological Chemistry 1985, 260, 13199-13207, which is hereby incorporated by reference in its entirety. Monoamine oxidase A activity is measured spectrophotometrically by monitoring the increase in absorbance at 314 nm on oxidation of kynuramine with formation of 4- hydroxyquinoline. The measurements are carried out, at 30° C., in 50 rnM sodium phosphate buffer, pH 7.2, containing 0.2% Triton X-100 (monoamine oxidase assay buffer), plus 1 mM kynuramine, and the desired amount of enzyme in 1 mL total volume.
Monooamine Oxidase B Inhibition and Oxidative Turnover
[00206] The procedure is carried out as described in Uebelhack et al., Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby incorporated by reference in its entirety.
Quantitation of Compounds of the Invention in Hair Using LC-MS
[00207] The procedure is carried out as described in Coulter et al., Drug Testing and Analysis 2009, 1 (5), 234-239, which is hereby incorporated by reference in its entirety.
Analysis of Compounds of the Invention and Metabolites thereof in Whole Blood by LC- MS
[00208] The procedure is carried out as described in Jagerdeo et al., Rapid Communications in Mass Spectrometry 2009, 23(17), 2697-2705, which is hereby incorporated by reference in its entirety.
Determination of Compounds of the Invention in Whole Blood by GC-MS
[00209] The procedure is carried out as described in Chu et al., Journal of Analytical Toxicology 2002, 26(8), 575-581, which is hereby incorporated by reference in its entirety.
Detection of Compounds of the Invention in Whole Blood by GC-MS
[00210] The procedure is carried out as described in Thomas et al., Journal of Pharmaceutical and Biomedical Analysis 2007, 45(3), 495-503, which is hereby incorporated by reference in its entirety.
CB2 Radioligand Binding Assay
[00211] The procedure is carried out as described in Yao et al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby incorporated by reference in its entirety.
CB 1 Radioligand Binding Assay
[00212] The procedure is carried out as described in Yao et al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby incorporated by reference in its entirety. CB2 Cyclase Functional Assay
[00213] The procedure is carried out as described in Yao et al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby incorporated by reference in its entirety.
CB1 cAMP Assay
[00214] The procedure is carried out as described in Steffens et al., Brit. J. Pharmacol. 2004, (141), 1193-1203, which is hereby incorporated by reference in its entirety.
Pharmacokinetics (PK) In Rats or Mice
[00215] Rats or mice receive a single intravenous dose of a compound of the invention at a dose of 1 mg/kg body weight, or a single oral dose of the compound of Invention at a dose of 10- 50 mg/kg body weight. Plasma samples are collected at different times following dosing and the plasma concentrations of the compound of the invention is determined by HPLC-MS/MS analysis using standards methods. Clearance, half-life, volume of distribution and oral bioavailability are calculated from the plasma concentration-time course data using established methods.
Example 2: NSAID and CBD combination effects on Mouse Carrageenan- Induced Paw Inflammation
[00216] Methods: Carrageenan anti-inflammation model testing
[00217] Inflammation models induced by carrageenan are frequently used acute inflammation models mainly because they are well-researched and they exhibit a high degree of reproducibility. Carrageenan is a strong chemical that functions in stimulating the release of inflammatory and proinflammatory mediators, including bradykinin, histamine, tachykinins, reactive oxygen, and nitrogen species. Typical signs of inflammation include edema, hyperalgesia, and erythema, which develop immediately following the treatment of carrageenan.
[00218] Generally, animals are injected with a certain concentration (usually 1%) of the irritant substance carrageenan in one hind footpad, usually, half an hour or an hour after they are treated with the test compound while the other footpad is injected with saline as a control (https://www.creative-biolabs.com/drug-discovery/therapeutics/carrageenan-induced-paw- edema-model.htm). [00219] On study day -1, animals were weighed and randomized into treatment groups. On study day 0, animals began treatment. On study day 0, one hour post dosing, animals were anesthetized and injected (20pl) with carrageenan into the left hind paw (footpad).
[00220] Efficacy was determined by caliper measurement of the ankle diameter at various time points.
[00221] On study day 0, ~8.5 hours post carrageenan, animals were anesthetized with inhaled isoflurane anesthesia, exsanguinated and then underwent a cervical dislocation to confirm euthanasia.
[00222] Experiments ACB-X consistently demonstrated an increased anti-inflammatory effect at 4 hour time points for the Cannabidiol/Carprofen combination administration. The effect consistently exceeded the anti-inflammatory effect of either active pharmaceutical ingredient alone.
[00223] An example of the Mouse Carrageenan model arms was designed with the following arms as provided in Table 1.
Table 1
Figure imgf000063_0001
[00224] Design: Carrageenan injection into mouse hindpaw causes significant and measurable inflammation in mouse paw and ankle (Table 2 and Figure 1)
Table 2
Figure imgf000064_0002
Figure imgf000064_0001
[00225] Figures 2-5 provided acute test article dosing results (ACB-1). At the 4 hour time point, the combo yielded anti-inflammatory effects and performed better than each API alone.
[00226] Figures 6 and 7 depicts improved efficacy when combing CBD and Carprofen in ACB- 3. Figures 8 and 9 provided that at the 4 hour time point, higher concentration of CBD combined with suboptimal concentration of NS AID appeared to give a combo effect.
[00227] Figures 10-12 provided acute test article dosing results (ACB-5) for CBG, CBN, and CBC and showed that at the 8 hour time point, combos were yielding anti-inflammatory effects where the single agent APIs were not. Figure 10 indicated no significant combo effect at the 4 hour time point. Figure 11 showed a good combo effect with CBC at the 6 hour time point in ACB-5. Figure 12 provided a significant combo effect with CBG, CBN, and CBC at the 8 hour point in ACB-5.
[00228] Accordingly, cannabinoids anti-inflammatory/anti-nociceptive activity can be combined with approved NSAID agents in order to create more efficacious and/or safer therapeutic products for treatments in a subject, including companion animals.
Example 3: Anti-Depressive Effect of Combo in Early Time Points of Forced Swim Test
[00229] Methods: Forced Swim Test as measure of Depression [00230] The forced swim test (FST), which is one of the most commonly used assays for the study of depressive-like behavior in rodents. The FST is based on the assumption that when placing an animal in a container filled with water, it will first make efforts to escape but eventually will exhibit immobility that may be considered to reflect a measure of behavioral despair. This test has been extensively used because it involves the exposure of the animals to stress, which was shown to have a role in the tendency for major depression. Additionally, the FST has been shown to share some of the factors that are influenced or altered by depression in humans, including changes in food consumption, sleep abnormalities and drug-withdrawal-induced anhedonia (J Vis Exp. 2015; (97): 52587).
[00231 ] Method - Animals were given immediate ad libitum access to water and chow and were acclimate to the facility for 7 days prior to any further intervention. On day -3 animals were weighed, randomized by weight. After 7 days of acclimatization (day 0) animals underwent OFA (Open Field) to increase the dynamic range of subsequent assays. Cohort 1, groups 1-4 were injected intraperitoneal (IP) with test article starting at 09:00 on study day 2. Animals were injected in 8-minute intervals to allow for testing to occur exactly 30 minutes after injections. Beginning at 09:30 on study day 2, groups 1-4 underwent testing in the elevated plus maze (EPM).
[00232] On study day 7 for each cohort behavioral analysis started. Prior to each behavioral assay, mice were acclimated to the testing room for 1 hour. OFA, EPM, and FST will be performed.
[00233] Testing groups for this experiment are provided in Table 3
Table 3
Figure imgf000065_0001
[00234] Forced swim test: the concept is rodent that keeps trying to swim is energetic, trying to live. Rodents that just float have given up. Prozac was discovered based on this model.
[00235] Figures 13 and 14 provided that fluoxetine alone did not show early effect, but CBD alone or in combo with fluoxetine showed significant anti-depressive effect in the forced swim model. Anti-depression signal was observed in early time points of forced swim test, in which combo was better than each API alone.
[00236] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMS What is claimed is:
1. A method for preventing or treating a disease or disorder in a subject in need thereof, comprising administering to the subject a cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical product thereof, and at least one additional therapeutic agent, wherein said disease or disorder is selected from the group consisting of fragile X syndrome, autism spectrum disorder, lysosomal storage diseases, leukodystrophies, Rett syndrome, anxiety, migraine, viral infection, fungal infection, bacterial infection, cancer, depression, inflammation, ischemia, psychiatric disorder, spasm, bone degradation, neurodegenerative disorder, pain, convulsion, neuropathic pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, spasticity, Alzheimer's disease, nausea, vomiting, affective disorders, anorexia, dementia, cachexia, HIV wasting syndrome, Tourette's syndrome, and emesis, non-24-hour sleep wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia, circadian rhythm-related disorders, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, attention deficit hyperactivity disorder, Angelman syndrome, schizophrenia, autism, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency, musculoskeletal disorders, Parkinson's disease, Huntington's disease, seizures, epilepsy, osteoporosis, cardiovascular disorders, and metabolic syndrome-related disorders, fear, phobias, aggression, or compulsive disorders, or any combination thereof.
2. The method according to claim 1, wherein said additional therapeutic agent is an analgesic agent, an anti-anxiety agent, an anti-cancer agent, an anti-bacterial agent, an anti- convulsive agent, anti-epileptics, an anti-inflammatory agent, an anti-depressant agent, an antiemetic agent, an anti-ischemic agent, an anti-psychotic agent, an anti-spasmodic agent, an immunosuppressive agent, an agent for treatment of neurodegenerative diseases or disorders, an anti-dyskensia agent, a chemotherapeutic agent, an immunosuppressive agent, an antidiabetic agent, a cholesterol/lipid lowering agent, an orexigenic agent, an ocular hypotensive agent, an anti-osteoporosis agent, or a cardiovascular agent.
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3. The method according to claim 1 or claim 2, wherein said cannabinoid compound is tetrahydrocannabinol (THC), tetrahydrocannabinol acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin acid (THCVA), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiol acid (CBDA), cannabidivarin acid (CBDVA), cannabichromene (CBC), cannabigerol (CBG), cannabigerol acid (CBGA), cannabigerovarin (CBGV), cannabinol (CBN), or cannabinovarin (CBNV), or an analog thereof, a derivative thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or a pharmaceutical product thereof.
4. The method according to any one of claims 1-3, wherein said cannabinoid compound is THC or THCV.
5. The method according to claim 4, wherein said THC is D9-THC (delta-9 tetrahydrocannabinol) or D8-THC (delta-8 tetrahydrocannabinol).
6. The method according to any one of claims 1-3, wherein said cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (A) or a compound of formula (B)
Figure imgf000068_0001
Figure imgf000069_0001
wherein
R1-R25 and R29-R31 are each independently H, alkyl, OH, alkoxy, COORm, or CONRmRn,
R26 and R27 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy,
SH, S-alkyl, NRmRn, COORm, or CONRmRn,
R28 is H, alkyl, RPCO, or RqOCO,
Rm and Rn are each independently H or alkyl, and
Rp and Rq are each independently alkyl.
7. The method according to any one of claims 1-3, wherein said cannabinoid compound is CBD.
8. The method according to any one of claims 1-3, wherein said cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (C)
67
Figure imgf000070_0001
wherein
Xi-Xie and X19-X26 are each independently H, alkyl, OH, alkoxy, COOXm, or
CONXmXn,
X17 and Xis are each independently H, alkyl, XPCO, or XqOCO,
X27 and X28 are each independently H, alkyl, halogen, NO2, CN, COOXm, or CONXmXn,
X29 and X30 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NXmXn, COOXm, or CONXmXn,
Xm and Xn are each independently H or alkyl.
Xp and Xq are each independently alkyl.
9. The method according to any one of claims 1-3, wherein said cannabinoid compound is CBG.
10. The method according to any one of claims 1-3, wherein said cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (D)
Figure imgf000071_0001
wherein
Y1-Y20, Y25, Y26, and Y28- Y31 are each independently H, alkyl, OH, alkoxy, COOYm, or CONYmYn,
Y21 and Y22 are each independently H, alkyl, YPCO, or YqOCO,
Y23 and Y24 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NYmYn, COOYm, or CONYmYn,
Y27 and Y32 are each independently H, alkyl, halogen, NO2, CN, COOYm, or CONYmYn, and
Ym and Yn are each independently H or alkyl.
Yp and Yq are each independently alkyl.
11. The method according to any one of claims 1-3, wherein said cannabinoid compound is CBC.
12. The method according to any one of claims 1-3, wherein said cannabinoid compound, or an analog thereof, a derivative thereof, a metabolite thereof, or a prodrug thereof, is represented by a compound of formula (E)
Figure imgf000072_0001
wherein
Z1-Z24 are each independently H, alkyl, OH, alkoxy, COOZm, or CONZmZn,
Z25-Z27 are each independently H, alkyl, halogen, NO2, CN, COOZm, or CONZmZn,
Z28 and Z29 are each independently H, alkyl, halogen, haloalkyl, NO2, CN, OH, alkoxy, SH, S -alkyl, NZmZn, COOZm, or CONZmZn,
Z30 is H, alkyl, ZPCO, or ZqOCO,
Zm, and Zn are each independently H or alkyl.
Zp, and Zq are each independently alkyl.
13. The method according to any one of claims 1-12, wherein said disease or disorder is pain, musculoskeletal pain, osteoarthritis, multiple sclerosis, epilepsy, or chemo-related nausea, vomiting, and anorexia.
14. The method according to any one of claims 1-12, wherein said disease or disorder is selected from the group consisting of osteoarthritis, musculoskeletal disorders, anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, seizures, epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
15. The method according to claim 14, wherein said neurodegenerative disorder is Parkinson's disease, Huntington's disease, or Alzheimer's disease.
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16. The method according to claim 14, wherein said disease or disorder is pain or inflammation.
17. The method according to claim 14, wherein said disease or disorder is osteoarthritis, musculoskeletal disorders, anorexia, emesis, or glaucoma.
18. The method according to any one of claims 1-12, wherein said disease or disorder is osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, or a metabolic syndrome-related disorder.
19. The method according to any one of claims 1-12, wherein said analgesic agent is an opioid analgesic agent or a non-opioid analgesic agent.
20. The method according to claim 19, wherein said non-opioid analgesic agent is meloxicam, acetaminophen, aspirin, ibuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen, carbamazepine, gabapentin, or pregabalin.
21. The method according to claim 19, wherein said opioid analgesic agent is hydrocodone, oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol.
22. The method according to any one of claims 1-12, wherein said agent for treatment of neurodegenerative diseases or disorder is resveratrol, anthocyanin, levodopa, pergolide, ephenedrine sulfate, pemoline, mazindol, a-methylphenethylamine, methylphenidate, pramipexole, modafinil, or ropinirole.
23. The method according to any one of claims 1-12, wherein said anti-dyskensia agent is baclofen, botulinum toxin, clonazepam, or diazepam.
24. The method according to any one of claims 1-12, wherein said anti-cancer agent is an chemotherapeutic agent, wherein said chemotherapeutic agent is adrimycin, doxorubicin, 5- fluorouracil, cytosine arabinoside (“Ara-C”), cyclophosphamide, thiotepa, taxotere (docetaxel), bulsulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, daunomycin, carminomycin, aminopterin, dactinomycin, mitomycine, esperamicins, or melphalan.
25. The method according to any one of claims 1-12, wherein said anti-cancer agent is a cytostatic drug, selected from busulfan, chlorambucil, cyclophosphamide, melphalan, carmustine, lomustine, 5-fluorouracil, gemcitabine, pemetrexed, doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, paclitaxel, docetaxel, vinblastine, vincristine, etoposide, cisplatin, carboplatin, and oxaliplatin.
26. The method according to any one of claims 1-12, wherein said immunosuppressive agent is azathioprine, cyclophosphamide, bromocriptine, glutaraldehyde, cyclosporin A, prednisone, prednisolone, methylprednisone, dexamethasone, heterologous anti-lymphocyte globulin, deoxyspergualin, or rapamycin.
27. The method according to any one of claims 1-12, wherein said anti-spasmodic agent is carbamatepine, oxcarbazepine, ferbocate, furboc acid, paroxamine, fibapramine, laxamide, talapanib, retigabine, levethiracetam, tobinamide, zonisamide. barbiturates, benzodiazepines, or hydantoin.
28. The method according to any one of claims 1-12, wherein said anti-diabetic agent is mefluminine hydrochloride, acarbose, miglitol, human insulin, pig insulin, bovine insulin, nateglinide, reglinide, glimepiride, glibenclamide, chlorpromide, tolazamide, or glipben.
29. The method according to any one of claims 1-12, wherein said anti-convulsant agent and/or anti-epileptics is phenobarbital, pentobarbital, nitronazapine, clozapine acid salt, diazapine, saigabin, gabapentin, phenytoin, 5,5-diphenylhydantoin, carbamatepine, oxcarbazepine, falbockate, falbock acid, bifarin Pockic acid, paroxamide, fibamay, levethiracetam, tobinamide, zonisamide, lamtidine, mesylamine, ethoxyl , or ruitijiabin.
30. The method according to any one of claims 1-12, wherein anticonvulsive agent and/or anti-epileptics is brivaracetam, carbamzepine, clobazam, rancedon, ethosuximide, nonammonia ester, gabapentin, lacosamide, lamotrigine, Levetiracetam, oxcarbazepine, phenobarbital, phenytoin sodium salt, pregabalin, desoxyphenobarbital, rotigotine, rufinamide, seletracetam, talampanel, tiagabine, topiramate, sodium valproate, vigabatrin, or zonis amide.
31. The method according to any one of claims 1-12, wherein said anti-psychotic agent is risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine, or raclopride.
32. The method according to any one of claims 1-12, wherein said cholesterol/lipid lowering agent is pravastatin, lovastatin, simvastatin, fluvastatin, atorvsatatin, rosuvastatin, cholestyramine, colestipol, gemfibrozil, clofibrate, fenofibrate, benzafibrate, rosiglitazone, or ezetimibe.
33. The method according to any one of claims 1-12, wherein said anti-inflammatory agent is meloxicam, carprofen, tepoxalin, firocoxib, deracoxib, etodolac, ibuprofen, naproxen, ketoprofen, celecoxib, rofecoxib, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, or acetaminophen.
34. The method according to any one of claims 1-12, wherein said anti-bacterial agent is selected from the group consisting of erythromycin, aji azithromycin, clarithromycin, telithromycin, penicillin G, penicillin V, methicillin, toluene oxazinmycin, o-chloropenicillin, diclofenac, phenoxypenicillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, Piperacillin, azlocillin, temocillin, cepalothin, cefepime, cefacyclohexene, ceftizodine, cefazolin, cefotaxazole, cephalosporin, cephalosporin IV, cefprozil, cloxacromycin, loracarbef, cefotaxime, cefinetazole, ceftazidime cefotaxime, cefizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, cetazide, ceftibuten, cefdinir, cefpirome, cefepime, aztreonam, imipenem, meropenem, meropenem penicillin (ertapenem), doricane (doripenem), cephalosporin ceftobiprole and ceftaroline, citric acid, porphyrin, norfloxacin,
73 pefloxacin, enoxacin, oufumycin, levofloxacin, ciprofloxacin, tiproxoxacin temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, and rufosa trovafloxacin), clinafloxacin, gatifloxacin, moxifloxacin, sitar Sitafloxacin, garenoxacin, gemifloxacin, pazufloxacin, p-aminobenzoic acid, sulfadiazine, sulfonamide azole, sulfamethine oxazole and sulfonamide, streptomycin, neomycin, kenmycin, baromycin, gentamicin, tobramycin, butyl Amine kanamycin, netilmicin, spectinomycin, perillamycin, dardamycin and ezeparin, tetracycline, chlortetracycline, chlorotetracycline, go Mechlorin, minocycline, oxytetracycline, methicillin, tigcycline, doxycycline, rifampicin, rifampin, rifapentine, rifabutin, bezoxazinorifamycin and rifaximin, lincomycin, kesendamycin, telavancin, vancomycin, ticlosin, daptomycin, quinupristin and darfapolis Daflopristin, linoleide, polymyxin, colistin, colin, trimethoprim, and bacitracin.
35. The method according to any one of claims 1-12, wherein said anti-emetics is dolasetron, granisetron, ondansetron, tropisetron, palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, dronabinol, midazolam, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, trimethobenzamide, or propofol.
36. The method according to any one of claims 1-12, wherein said anti-depressant is selected from the group consisting of adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine, and zometapine.
74
37. The method according to any one of claims 1-12, wherein said anti-anxiety agent is comipramine hydrochloride, fluoxetine hydrochloride, salprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam prazepam, buspirone, flesinoxan, gepirone and ipsapirone, pindolol, carbamazepine, lamotrigine, valproate, clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol, vigabatrin, or barbiturates.
38. The method according to any one of claims 1-12, wherein said sleeping agent is zolpidem, alpidem, zopiclone, or indiflon.
39. The method according to any one of claims 1-12, wherein said anti-migraine agent is sumatriptan, naratriptan, rizatriptan, zolmitriptan, eletriptan, probatriptan, or almotriptan.
40. The method according to any one of claims 1-12, the orexigenic agent is megestrol or oxandrolone.
41. The method according to any one of claims 1-12, the ocular hypotensive agent is bimatoprost, latanoprost, travoprost, timolol, betaxolol, dorzolamide, brinzolamide, pilocarpine, brimonidine, latanoprost, travoprost, or bimatoprost.
42. The method according to any one of claims 1-12, the anti-osteoporosis agent is alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, bazedoxifene, teriparatide, abaloparatide, or denosumab.
43. The method according to any one of claims 1-12, wherein said cardiovascular agent is avasimibe, pactimibe, captopril, enalapril, enalaprilat, tradolapril, moexipril, ramipril, hinapril, perindopril, lisinopril, benazepril, fosinopril, eplerenone, aldactone, doxazosin, methyldofu, clonidine, prazosin, terazosin, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan, adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride, or tocainide.
44. The method according to any one of claims 1-43, wherein the therapeutically effective amount of said additional therapeutic agent administered to the subject is less than the
75 therapeutically effective amount of said additional therapeutic agent when administered in the absence of the cannabinoid compound.
45. The method according to any one of claims 1-43, wherein the therapeutically effective amount of said additional therapeutic agent administered to the subject is 0% to 90%, 5% to 90%, or 10% to 90% less than the therapeutically effective amount of said additional therapeutic agent when administered in the absence of the cannabinoid compound.
46. The method according to any one of claims 1-43, wherein the therapeutically effective amount of said additional therapeutic agent administered to the subject is at least 20% less than the therapeutically effective amount of said additional therapeutic agent when administered in the absence of the cannabinoid compound.
47. The method according to any one of claims 1-43, wherein the therapeutically effective amount of said additional therapeutic agent administered to the subject is at least 40% less than the therapeutically effective amount of said additional therapeutic agent when administered in the absence of the cannabinoid compound.
48. The method according to any one of claims 1-43, wherein the therapeutically effective amount of said additional therapeutic agent is at least 50% less than the therapeutically effective amount of said additional therapeutic agent when administered in the absence of the cannabinoid compound.
49. The method according to any one of claims 1-48, wherein said additional therapeutic agent and the cannabinoid compound are administered concurrently.
50. The method according to any one of claims 1-48, wherein the additional therapeutic agent and the cannabinoid compound are formulated in the same pharmaceutical composition.
51. The method according to any one of claims 1-48, wherein said additional therapeutic agent is formulated in a first pharmaceutical composition and the cannabinoid compound is formulated in a second pharmaceutical composition.
52. The method according to any one of claims 1-51, wherein said subject is a human patient.
76
53. The method according to any one of claims 1-51, wherein said subject is a non-human animal.
54. The method according to any one of claims 1-51, wherein the disease or disorder is seizures, epilepsy, aggression, fear, phobias, generalized anxiety disorder, or separation anxiety.
55. The method according to claim 54, wherein said subject is an animal.
56. The method according to claim 54, wherein said subject is a dog.
57. The method according to any one of claims 1-51, wherein said disease or disorder is anorexia, glaucoma, anxiety, aggression, compulsive disorders, noise phobias, epilepsy, or seizures.
58. The method according to claim 57, wherein said subject is an animal.
59. The method of claim 57, wherein said subject is a dog.
60. The method according to any one of claims 1-51, wherein said disease or disorder is anorexia, anxiety, epilepsy, osteoarthritis, or glaucoma.
61. The method according to claim 60, wherein said subject is an animal.
62. The method of claim 60, wherein said subject is a cat.
63. A method for treating or preventing pain or inflammation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of CBD and an analgesic agent.
64. The method of claim 63, wherein the analgesic agent is carprofen.
65. A method for treating or preventing depression in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of CBD and an anti-depressant agent.
66. The method of claim 65, wherein the anti-depressant agent is fluoxetine.
77
67. The method of any one of claims 63-66, wherein said subject is a human patient or a non-human animal.
68. The method of claim 67, wherein said subject is a human patient.
69. The method of claim 68, wherein said subject is a non-human animal.
70. The method of claim 69, wherein said non-human animal is a dog or a cat.
71. The method according to claim 1, wherein said additional therapeutic agent is an agent for treating fragile X syndrome.
72. The method according to claim 1, wherein said additional therapeutic agent is an agent for treating autism spectrum disorder.
73. The method according to claim 1, wherein said additional therapeutic agent is an agent for treating lysosomal storage diseases.
74. The method according to claim 1, wherein said additional therapeutic agent is an agent for treating leukodystrophies.
75. The method according to claim 1, wherein said additional therapeutic agent is an agent for treating Rett syndrome.
78
PCT/US2022/013000 2021-01-19 2022-01-19 Combination of cannabinoids with additional therapeutic agents for treating diseases or disorders WO2022159507A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023285072A1 (en) * 2021-07-13 2023-01-19 Receptorpharma Inc S-Corp Esters of 7-cooh cbd derivatives and their use as prevention, prophylaxis of progression, and/or treatment of neurogenerative diseases.

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190224140A1 (en) * 2006-06-23 2019-07-25 Gw Pharma Limited Cannabinoids for use in the treatment of neuropathic pain
WO2020183456A1 (en) * 2019-03-10 2020-09-17 Bol Pharma Ltd. Cannabinoid combinations for treating chronic pain in dialysis patients
WO2021177940A1 (en) * 2020-03-03 2021-09-10 Babak Ghalili Cannabinoid and menthol gel compositions, patches and methods
WO2022016160A1 (en) * 2020-07-17 2022-01-20 India Globalization Capital, Inc. Cannabidiol (cbd) based composition and method for treating pain

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190224140A1 (en) * 2006-06-23 2019-07-25 Gw Pharma Limited Cannabinoids for use in the treatment of neuropathic pain
WO2020183456A1 (en) * 2019-03-10 2020-09-17 Bol Pharma Ltd. Cannabinoid combinations for treating chronic pain in dialysis patients
WO2021177940A1 (en) * 2020-03-03 2021-09-10 Babak Ghalili Cannabinoid and menthol gel compositions, patches and methods
WO2022016160A1 (en) * 2020-07-17 2022-01-20 India Globalization Capital, Inc. Cannabidiol (cbd) based composition and method for treating pain

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023285072A1 (en) * 2021-07-13 2023-01-19 Receptorpharma Inc S-Corp Esters of 7-cooh cbd derivatives and their use as prevention, prophylaxis of progression, and/or treatment of neurogenerative diseases.

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