WO2022082058A1 - Méthode de traitement par alcaloïdes tryptamines - Google Patents

Méthode de traitement par alcaloïdes tryptamines Download PDF

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WO2022082058A1
WO2022082058A1 PCT/US2021/055301 US2021055301W WO2022082058A1 WO 2022082058 A1 WO2022082058 A1 WO 2022082058A1 US 2021055301 W US2021055301 W US 2021055301W WO 2022082058 A1 WO2022082058 A1 WO 2022082058A1
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tryptamine
alkaloid
minutes
subject
pharmaceutically acceptable
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PCT/US2021/055301
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English (en)
Inventor
Ryan Steven BRIDGES
J. Cannon CLIFTON
John Bryan CLIFTON
Neiloufar FAMILY
Emeline L. MAILLET
Shlomi RAZ
David E. Nichols
Maria Rosario
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Eleusis Therapeutics Us, Inc.
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Publication of WO2022082058A1 publication Critical patent/WO2022082058A1/fr

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    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • tryptamine alkaloids Significant interest in the therapeutic application of tryptamine alkaloids has developed, based upon evidence of possible therapeutic effects in a wide array of clinical applications, including psychiatric conditions, pain disorders, and neurological conditions.
  • harnessing the full therapeutic utility of tryptamine alkaloids requires new methods to mitigate side effects while enhancing safety and efficacy associated with tryptamine alkaloid administration.
  • the invention features a method of treating a disease or condition in a subject in need thereof, the method including intravenously administering to the subject a continuous infusion of an aqueous solution including an pharmacologically effective amount of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, wherein the continuous infusion is administered at a rate of between 0.7 mg/hr and 30 mg/hr (e.g., 0.7 ⁇ 0.1 mg/hr, 0.8 ⁇ 0.1 mg/hr, 0.9 ⁇ 0.1 mg/hr, 1 ⁇ 0.1 mg/hr, 2 ⁇ 1 mg/hr, 3 ⁇ 1 mg/hr, 4 ⁇ 1 mg/hr, 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 1 mg/hr, 11 ⁇ 1 mg/hr, 12 ⁇ 1 mg/hr, 13 ⁇ 1 mg/hr, 14 ⁇ 1
  • the pharmacologically effective amount of the tryptamine alkaloid is administered as a saline solution.
  • the tryptamine alkaloid is selected from from N,N-dimethyl tryptamine (DMT), 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N, N-Diethyltryptamine (DET), 4-hydroxy-N, N- diethyltryptamine (4-HO-DET), 4-Hydroxy-N,N"diisopropyUryptamine (4-OH-DiPT), 4-hydroxy-N-methyi-N- isopropyl tryptamine (4-OH-MiPT), O-acetylpsilocin (4-AcO-DMT), and phosphates, acetate esters, or pharmaceutically acceptable salts thereof.
  • the invention features a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject a free base equivalent of from 1 mg to 200 mg of a tryptamine alkaloid (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, over a period of between 1 and 60 minutes (e.g., a continuous in
  • the invention features a method of treating a disease or condition in a subject in need thereof, the method comprising intranasally administering to the subject an aqueous solution including a free base equivalent of from 1 mg to 200 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.
  • a tryptamine alkaloid or
  • the tryptamine alkaloid is selected from N,N-dimethyl tryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N, N-Diethyltryptamine (DET), 4-hydroxy-N, N- diethyltryptamine (4-HO-DET), O-acetylpsilocin (4-AcO-DMT), and pharmaceutically acceptable salts thereof.
  • DMT N,N-dimethyl tryptamine
  • 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • DET N, N-Diethyltryptamine
  • O-acetylpsilocin 4-AcO-DMT
  • the tryptamine alkaloid is DMT or 5-MeO-DMT.
  • a free base equivalent of from 30 mg to 200 mg e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg
  • the tryptamine alkaloid is administered to the subject over a period of 20 to 60 minutes (e.g., a continuous infusion over about 20 minutes, 30 minutes, 45 minutes, 50 minutes, and 60 minutes).
  • a free base equivalent of 56 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over a period of 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
  • a free base equivalent of 70 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over a period of 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
  • a free base equivalent of from 15 mg to 160 mg e.g., 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg. 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, and 160 ⁇ 10 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of 2 to 20 minutes (e.g., a continuous infusion over a period of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • 15 mg to 160 mg e.g., 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg. 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg
  • a free base equivalent of 28 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • a free base equivalent of 42 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • a free base equivalent of 56 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion over a period of about 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • the tryptamine alkaloid is DET, 4-OH-DET, or 4-AcO-DMT.
  • a free base equivalent of from 4 mg to 15 mg e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg
  • 4 mg to 15 mg e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg
  • the tryptamine alkaloid is administered to the subject over a period of 20 to 60 minutes (e.g., a continuous infusion over about 25 minutes, 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
  • a free base equivalent of 5.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
  • a free base equivalent of 7.5 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
  • a free base equivalent of 10.0 ⁇ 2.0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 30 to 60 minutes (e.g., a continuous infusion over about 30 minute, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
  • a free base equivalent of from 1 mg to 5 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered to the subject over a period of 2 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • a free base equivalent of 4.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • a free base equivalent of 3.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • a free base equivalent of 2.0 ⁇ 1 .0 mg of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is administered over a period of 5 to 20 minutes (e.g., a continuous infusion of about 2 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes).
  • the invention features a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject a pharmacologically effective amount of (i) a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, and (ii) a benzodiazepine, each in an amount that together is effective for the treatment of the disease or condition.
  • the invention features, a method of treating a disease or condition in a subject in need thereof, including administering to the subject a timed intravenous infusion of a tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, wherein (i) the timed intravenous infusion is administered at a free base equivalent rate of between 5 mg/hr and 250 mg/hr (e.g., 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 5 mg/hr, 15 ⁇ 5 mg/hr, 20 ⁇ 5 mg/hr, 25 ⁇ 5 mg/hr, 30 ⁇ 5 mg/hr, 40 ⁇ 5 mg/hr, 45 ⁇ 5 mg/hr, 50 ⁇ 10 mg/hr, 60 ⁇ 10 mg/hr, 70 ⁇ 10 mg/hr, 80 ⁇ 10 mg/hr, 90 ⁇ 10 mg/hr, 100 ⁇ 10 mg/hr, 1 10 ⁇ 10 mg/hr,
  • the tryptamine alkaloid infusion or intranasal preparation may be administered in combination with an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic.
  • additional agents such as an antiemetic, and/or benzodiazepine are also administered.
  • described herein specifically are methods of treating a disease or condition where the disease or condition is chronic pain.
  • the method includes administering to the subject a first preparation, the first preparation including a pharmacologically effective amount of an antiemetic agent.
  • the antiemetic agent of the first preparation includes a non-selective 5-HT antagonist, 5- HT3 receptor antagonist, 5-HT4 receptor agonist, CB1 agonist, D2 receptor antagonist, D3 receptor antagonist, GABA receptor agonist, H1 receptor antagonist, muscarinic acetylcholine receptor antagonist, NK1 receptor antagonist, or a combination thereof.
  • the first preparation includes an intravenous infusion or intranasal preparation of ondansetron.
  • the intravenous infusion includes a pharmacologically effective amount of a benzodiazepine.
  • the benzodiazepine is 1 ,4-benzodiazepine, 1 ,5- benzodiazepine, 2,3-benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine, pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, or a combination thereof.
  • the benzodiazepine includes lorazepam.
  • the benzodiazepine is administered in a dosage of between 2 mg and 40 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, 15 ⁇ 1 mg, 16 ⁇ 1 mg, 17 ⁇ 1 mg, 18 ⁇ 1 mg, 19 ⁇ 1 mg, 20 ⁇ 1 mg, 21 ⁇ 1 mg, 22 ⁇ 1 mg, 23 ⁇ 1 mg, 24 ⁇ 1 mg, 25 ⁇ 1 mg, 26 ⁇ 1 mg, 27 ⁇ 1 mg, 28 ⁇ 1 mg, 29 ⁇ 1 mg, 30 ⁇ 1 mg, 31 ⁇ 1 mg, 32 ⁇ 1 mg, 33 ⁇ 1 mg, 34 ⁇ 1 mg, 35 ⁇ 1 mg, 36 ⁇ 1 mg, 37 ⁇ 1 mg, 38 ⁇ 1 mg, and 39 ⁇ 1 mg).
  • the lorazepam is administered in a dosage between 2 mg and 4 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, and 4 ⁇ 1 mg).
  • the benzodiazepine is diazepam.
  • the diazepam is administered in a dosage between 5 mg and 10 mg (e.g., 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, and 10 ⁇ 1 mg).
  • the ratio of the tryptamine alkaloid to benzodiazepine is between 10:1 and 1 :5 by weight (e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight) by weight.
  • the intravenous infusion or intranasal preparation includes a pharmacologically effective amount of an anesthetic, a sedative, an antiemetic, an anticonvulsant, an antidepressant, an antimigraine, an antipsychotic, an anxiolytic, and/or an antiparkinson.
  • intravenous infusion or intranasal preparation includes ondansetron or a pharmaceutically acceptable salt thereof.
  • the subject s plasma concentration of 5-MeO-DMT is monitored.
  • the intravenous infusion or intranasal preparation including a pharmacologically effective amount of the tryptamine alkaloid is administered at least twice over the course of a month. In some embodiments, the intravenous infusion or intranasal preparation including a pharmacologically effective amount of the tryptamine alkaloid is administered between 2 and 10 times (e.g., 3, 4, 5, 6, 7, 8, and 9 times) over the course of a year.
  • the disease or condition being treated a psychological condition.
  • the psychological condition is evaluated 1 -8 weeks (e.g., 2, 3, 4, 5, 6, and 7 weeks) after treatment.
  • the psychological condition is evaluated 1 week after treatment.
  • the psychological condition is evaluated 4 weeks after treatment.
  • the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder, an eating disorder, or compulsive behavior.
  • the psychological condition is depression.
  • the depression is evaluated using the Hamilton Depression Rating Scale (HAM-D).
  • the HAM-D score decreases compared to the score before treatment. In particular embodiments, the HAM-D score decreases by 50% compared to the score before treatment.
  • the depression is evaluated using the Beck Depression Inventory Scale (BDI).
  • BDI Beck Depression Inventory Scale
  • the BDI score decreases compared to the score before treatment.
  • the BDI score decreases by 50% compared to the score before treatment.
  • the depression is evaluated using the Quick Inventory of Depressive Symptomatology (QIDS) score.
  • QIDS Quick Inventory of Depressive Symptomatology
  • the QIDS score decreases compared to the score before treatment.
  • the QIDS score decreases by 50% compared to the score before treatment.
  • the depression is evaluated using a Montgomery-Asberg Depression Rating Scale.
  • the Montgomery-Asberg Depression Rating Scale score decreases compared to the score before treatment.
  • the Montgomery-Asberg Depression Rating Scale score decreases by 50% compared to the score before treatment. In particular embodiments, the Montgomery-Asberg Depression Rating Scale score is less than 10 after treatment.
  • the psychological condition is anxiety. In certain embodiments, the anxiety is end of life anxiety, or anxiety of a subject receiving palliative care.
  • the disease or condition is a neurological injury, an inflammatory condition, or chronic pain.
  • the disease or condition is an inflammatory condition.
  • the inflammatory condition is lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
  • the inflammatory condition is chronic obstructive pulmonary disease (COPD)), or Alzheimer’s disease.
  • the disease or condition is a neurological injury.
  • the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury.
  • the disease or condition is a chronic pain condition.
  • the chronic pain condition results from postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica.
  • the chronic pain condition results from trigeminal autonomic cephalalgia.
  • trigeminal autonomic cephalalgia is selected from the group consisting of episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).
  • the trigeminal autonomic cephalalgia is episodic or chronic CH.
  • the method further includes administering to the subject one or more medications for pain relief, including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
  • the tryptamine alkaloid is DMT, or a pharmaceutically acceptable salt thereof.
  • the tryptamine alkaloid is 4-AcO-DMT, or a pharmaceutically acceptable salt thereof.
  • the tryptamine alkaloid is 5-MeO-DMT, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, the tryptamine alkaloid is 4-OH-DiPT or 4- OH-MiPT, or a phosphate, acetate ester, or pharmaceutically acceptable salt thereof.
  • the method further includes monitoring the intensity rating by the subject, and in response to the intensity rating further administering to the subject a benzodiazepine to reduce the intensity rating.
  • the benzodiazepine can be lorazepam, or any other benzodiazepine described herein.
  • the term “about” refers to a value that is within 10% above or below the value being described.
  • acute stress disorder and “ASD” refer to a condition that arises as a response to a stressful event or situation of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime).
  • acute stress disorder is an anxiety disorder that involves a very specific reaction following exposure to a traumatic event or stressor.
  • the duration of acute stress disorder is shorter than that for PTSD, such that the symptoms are present for at least one, two, or three days, but no more than four, five, or six weeks. For individuals exhibiting symptoms persisting for a longer period of time, a diagnosis of PTSD may be warranted.
  • administering refers to a method of giving a dosage of a compound or pharmaceutical composition to a subject.
  • tryptamine alkaloid refers to N,N-dimethyl tryptamine (DMT), and its derivatives, including O-acetylpsilocin (4-AcO-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), diethyltryptamine (4-OH-DET), 4-hydroxy-N-methyl-N-isopropyltryptamine (4OH-MiPT), and 4-hydroxy- N,N-di-isopropyltryptamine (4-OH-DIPT) as phosphates or acetate esters or as a pharmaceutically acceptable salts thereof.
  • continuous infusion refers to an infusion of a drug (e.g., the tryptamine alkaloid or a pharmaceutically acceptable salt thereof) such that the plasma concentration of the drug and/or metabolite does not vary by more than ⁇ 10% for at least 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, or 15 minutes unless the rate of infusion is altered in response to the subject’s intensity rating.
  • a drug e.g., the tryptamine alkaloid or a pharmaceutically acceptable salt thereof
  • the terms “dosage” and “unit dose” when used in reference to a therapeutic composition refer to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent, i.e., carrier, or vehicle.
  • dysthymia or “dysthymic disorder” is meant a chronically depressed mood that occurs for most of the day, more days than not, for at least two years. In children and adolescents, the mood may be irritable rather than depressed, and the required minimum duration is one year. During the two year period (one year for children or adolescents), any symptom-free intervals last no longer than 2 months.
  • dysthymia During periods of depressed mood, at least two of the following additional symptoms are present: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration, or difficulty making decisions, and feelings of hopelessness.
  • the symptoms cause clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning.
  • the diagnosis of dysthymia is not made if: the individual has ever had a manic episode, a mixed episode, a hypomanic episode; has ever met the criteria for a cyclothymic disorder; the depressive symptoms occur exclusively during the course of a chronic psychotic disorder (e.g., schizophrenia); or if the disturbance is due to the direct physiological effects of a substance or a general medical condition.
  • a chronic psychotic disorder e.g., schizophrenia
  • free base equivalent an amount corresponding to a free base equivalent in a mass of a tryptamine alkaloid salt form.
  • a free base equivalent of 1 mg of N,N-dimethyl- tryptamine is equal to 1 mg of N,N-dimethyl-tryptamine in its free base form and equal to 1 .28 mg of N,N- dimethyl-tryptamine in its hydrochloride salt form (e.g., 1 ,0x(240.728/188.269) to account for the mass contribution of the hydrochloride).
  • generalized anxiety disorder refers to a condition characterized by excessive anxiety and worry (i.e., apprehensive expectation). Typically, the excessive anxiety and worry occur on more days than not for a period of time (e.g., one, two, three, or four months or more).
  • the anxiety and worry can be associated with (i) restlessness, feeling keyed up, or on edge; and/or (ii) muscle tension.
  • the anxiety and worry can be associated with (a) a marked avoidance of situations in which a negative outcome could occur; (b) a marked time and effort preparing for situations in which a negative outcome could occur; (c) a marked procrastination in behavior or decision-making due to worries; and (d) repeatedly seeking reassurance due to worries.
  • the anxiety, worry, or physical symptoms can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in many, but not necessarily all individuals with GAD.
  • the term “intensity rating,” “intensity of experience,” and “intensity of acute subjective effects” refer to the intensity of an experience a subject has after being administered a particular drug measured on a scale from 1 to 10 by subjects. An intensity rating of less than 2 may indicate that it is safe for a subject to leave the clinic. The intensity rating described by the subject is used to determine whether the infusion rate of a drug should be increased, decreased, or remain the same.
  • intranasal preparation refers to a tryptamine alkaloid, or pharmaceutically acceptable salt thereof, which may be formulated as a pharmaceutical composition for administration by way of the nasal cavity.
  • Obsessive compulsive disorder As used herein, the terms “obsessive compulsive disorder,” “OCD,” and “anxiety and obsessive- compulsive spectrum disorders” refer to a condition characterized by obsessions and/or compulsions. Obsessions are recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that usually cause marked anxiety or distress in which the appetite individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e. , by performing a compulsion).
  • Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly.
  • the behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive.
  • the obsessions or compulsions are time consuming (for example, take more than 1 hour a day), or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • the term “pharmaceutically acceptable salt” refers to those salts of the compounds described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic or inorganic acid.
  • panic disorder refers to a condition characterized by recurrent and unexpected panic attacks.
  • Panic disorder includes both panic disorder with agoraphobia and panic disorder without agoraphobia.
  • Subjects with this condition can exhibit one or both of the following: (i) a persistent concern or worry about additional panic attacks or their consequences (e.g., losing control, having a heart attack, going crazy); and/or (ii) significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks), which may include agoraphobic avoidance.
  • the terms "pharmacologically effective amount,” “therapeutically effective amount,” and the like, when used in reference to a therapeutic composition refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, such as clinical results.
  • these terms refer to an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition.
  • the quantity of a given composition described herein that will correspond to such an amount may vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like.
  • an “effective amount,” "pharmacologically effective amount,” or the like, of a composition of the present disclosure also include an amount that results in a beneficial or desired result in a subject as compared to a control (e.g., a decrease in the score on the Montgomery-Asberg Depression Rating Scale).
  • post traumatic stress disorder and “PTSD” refer to a condition that arises as a delayed and/or protracted response to a stressful event or situation (either short- or long- lasting) of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime).
  • Predisposing factors such as personality traits (e.g., compulsive, asthenic) or previous history of neurotic illness may lower the threshold for the development of the condition or aggravate its course, but they are neither necessary nor sufficient to explain its occurrence.
  • PTSD is a less frequent and more enduring consequence of psychological trauma than the more frequently seen acute stress response.
  • PTSD has been recognized in the past as railway spine, stress syndrome, shell shock, battle fatigue, traumatic war neurosis, and post-traumatic stress syndrome.
  • Diagnostic symptoms include re-experiencing original trauma(s), by means of flashbacks or nightmares; avoidance of stimuli associated with the trauma; and increased arousal, such as difficulty falling or staying asleep, anger, and hypervigilance.
  • Formal diagnostic criteria DSM-V, DSM-IV, and/or ICD-9 require that the symptoms last more than one month and cause significant impairment in social, occupational, or other important areas of functioning (e.g., problems with work and/or relationships).
  • Formal diagnostic criteria can include: (i) intrusion symptoms that are associated with the traumatic event (e.g., (a) spontaneous or cued recurrent, involuntary, and intrusive distressing memories of the traumatic event; (b) recurrent distressing dreams in which the content and/or effect of the dream is related to the event; (c) dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event were recurring (such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings; (d) intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event; and/or (e) marked physiological reactions to reminders of the traumatic event); (ii) persistent avoidance of stimuli associated with the traumatic event (e.g., (a) thoughts, feelings, or physical sensations that arouse recollections of the traumatic event; (b) activities, places, physical reminders, or times (
  • Formal diagnostic criteria can further include that the duration of disturbance is more than a certain period of time (e.g., one month, three months, or six months) and that the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • the condition may show a chronic course over many years and a transition to an enduring personality change.
  • the three main symptoms associated with PTSD are (1 ) “reliving” the traumatic event, such as flashbacks, nightmares, intrusive thoughts and recollections, (2) avoidance behaviors and emotional numbing, and (3) hypersensitivity such as an inability to sleep, anxious feelings, overactive startle response, hyperarousal, hypervigilance, irritability, and outbursts of anger.
  • psychological disorder and “psychological condition” refer to a condition characterized by a disturbance in one’s emotional or behavioral regulation that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental function.
  • Psychological disorders include, but are not limited to depressive disorders (major depression, treatment resistant depression, melancholic depression, atypical depression, or dysthymia), anxiety disorders (end of life anxiety, generalized anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, or social phobia), addictions (e.g., substance abuse, e.g., alcoholism, tobacco abuse, or drug abuse)), eating disorders (e.g., anorexia nervosa, bulimia nervosa, and binge eating disorder) and compulsive behavior disorders (e.g., primary impulse-control disorders or obsessive-compulsive disorder).
  • depressive disorders major depression, treatment resistant depression, melancholic depression, atypical depression,
  • Psychological disorders can be any psychological condition associated with one or more symptoms, e.g., somatic symptoms (e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause), or psychosomatic symptoms (e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome).
  • somatic symptoms e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause
  • psychosomatic symptoms e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome.
  • Psychological disorders also include repetitive body-focused behaviors, such as tic disorders (e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder).
  • tic disorders e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder.
  • development of a psychological disorder is associated with or characterized by a prodromal symptom, such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self-esteem, irritability, dependency, self-pity, somatic complaints, decreased effectiveness, helplessness, and decreased initiation of voluntary responses.
  • a prodromal symptom such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self-esteem, irritability, dependency
  • social phobia and “social anxiety disorder” refer to a condition characterized by fear or anxiety associated with one or more social situations. Subjects with this condition typically exhibit a marked fear or anxiety about one or more social situations in which the person is exposed to possible scrutiny by others. Examples include social interactions (e.g., having a conversation), being observed (e.g., eating or drinking), or performance in front of others (e.g., giving a speech).
  • an individual with this condition (i) fears that he or she will act in a way, or show anxiety symptoms that will be negatively evaluated (i.e., be humiliating, embarrassing, lead to rejection, or offend others); (ii) the social situations almost invariably provoke immediate fear or anxiety; (iii) the social situations are avoided or endured with intense fear or anxiety; and (iv) the fear or anxiety is out of proportion to the danger posed by the social situation.
  • the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking or refusal to speak in social situations.
  • the fear, anxiety, and avoidance can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • the terms “treat,” “treating,” or “treatment” refer to administration of a compound or pharmaceutical composition for a therapeutic purpose.
  • To “treat a disorder” or use for “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease to ameliorate the disease or one or more symptoms thereof to improve the subject’s condition (e.g., by reducing one or more symptoms of inflammation).
  • the term “therapeutic” includes the effect of mitigating deleterious clinical effects of certain inflammatory processes (i.e., consequences of the inflammation, rather than the symptoms of inflammation).
  • the methods of the invention can be used as a primary prevention measure, i.e., to prevent a condition or to reduce the risk of developing a condition.
  • Prevention refers to prophylactic treatment of a subject who may not have fully developed a condition or disorder, but who is susceptible to, or otherwise at risk of, the condition.
  • the methods of the invention can be used either for therapeutic or prophylactic purposes.
  • unipolar depression or “major depressive disorder” is meant a clinical course that is characterized by one or more major depressive episodes in an individual without a history of manic, mixed, or hypomanic episodes.
  • the diagnosis of unipolar depression is not made if: manic, mixed, or hypomanic episodes develop during the course of depression; if the depression is due to the direct physiological effects of a substance; if the depression is due to the direct physiological effects of a general medical condition; if the depression is due to a bereavement or other significant loss (“reactive depression”); or if the episodes are better accounted for by schizoaffective disorder and are not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder.
  • depression may be associated with chronic general medical conditions (e.g., diabetes, myocardial infarction, carcinoma, and stroke). Generally, unipolar depression is more severe than dysthymia.
  • the essential feature of a major depressive episode is a period of at least two15 weeks during which there is either depressed mood or loss of interest or pleasure in nearly all activities. In children and adolescents, the mood may be irritable rather than sad. The episode may be a single episode or may be recurrent.
  • the individual also experiences at least four additional symptoms drawn from a list that includes changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts.
  • Each symptom must be newly present or must have clearly worsened compared with the person's pre-episode status.
  • the symptoms must persist for most of the day, nearly every day, for at least two consecutive weeks, and the episode must be accompanied by clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, 1994).
  • FIG. 1 is a graph showing a simulation for pharmacokinetic data measured as the concentration of N,N-dimethyl tryptamine (DMT) in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 15 minute infusion.
  • FIG. 2 is a graph showing a simulation for pharmacokinetic data measured as the concentration of DMT in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 30 minute infusion.
  • DMT N,N-dimethyl tryptamine
  • FIG. 3 is a graph showing a simulation for pharmacokinetic data measured as the concentration of DMT in the plasma in ng/mL for a subject dosed with 0.2 mg, 0.4 mg, or 0.8 mg of DMT over a 45 minute infusion.
  • the disclosure provides new methods of treating psychological conditions, neurological injuries, pain, cephalic pain (e.g., headache), inflammatory conditions, and anxiety in a subject by utilizing intravenous tryptamine alkaloid infusion formulations or intranasal tryptamine alkaloid preparations.
  • the tryptamine alkaloid infusion or intranasal formulation is administered in combination with another therapeutic agent, such as an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic.
  • additional agents such as an antiemetic, and/or benzodiazepine can also be administered.
  • tryptamine alkaloid Treatment with an infusion or intranasal administration of tryptamine alkaloid can cause profound changes in consciousness that may cause acute transient anxiety and subsequent discomfort to the subject during treatment.
  • the psychoactivity of tryptamine alkaloids can include: visual hallucinations and illusions, distortion of the spatial perception and body image, disturbances of the thought and speech, and euphoria.
  • the combination therapies of the invention can ameliorate unwanted side effects associated with tryptamine alkaloid therapy, and permit therapies with increased, reduced, or prolonged treatment times that may be required to achieve a therapeutic effect, or an improved therapeutic effect, in a given subject for a given condition.
  • the psychological condition may be any psychological condition described herein.
  • the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder (PTSD), an eating disorder, or compulsive behavior.
  • the psychological condition may be depression.
  • the psychological condition may also be anxiety.
  • the anxiety may be experienced by a subject who is receiving palliative care or is enrolled in a hospice program.
  • the subject who is experiencing anxiety has symptoms such as hypervigilance, fatigue, racing thoughts, irritability, excessive worry, and/or fear.
  • a subject may be diagnosed with a psychological condition by a clinician, a physician, or a therapist.
  • the subject may be diagnosed with a psychological condition by evaluation of the subject’s symptoms by a physician, clinician, or therapist, based on a physical examination.
  • a blood test may be used to evaluate blood concentration levels of certain biomarkers such as hormones, calcium, vitamin D, electrolytes, and iron in diagnosing depression.
  • a depression screening test may be performed by the physician, clinician, or therapist to aid in the diagnosis of depression.
  • the depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self- Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), or the Montgomery-Asberg Depression Rating Scale (MADRS-C).
  • the methods described herein may be used to treat psychosomatic pain conditions.
  • the psychosomatic pain condition may be fibromyalgia, chronic fatigue, migraines, or back pain.
  • the subject is being treated for depression with the intravenous infusion of the tryptamine alkaloid.
  • the subject is being treated for depression with the intranasal preparation of the tryptamine alkaloid.
  • the subject may have their symptoms of depression evaluated using a depression screening test.
  • the symptoms of depression may be evaluated by a clinician using the Clinical Global Impression (CGI) rating.
  • the depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS).
  • the subject being treated for depression with the intravenous infusion or intranasal preparation of the tryptamine alkaloid may have their symptoms of depression evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS-C).
  • the subject may be evaluated using the MADRS-C by a clinician, physician, or third party rater.
  • the subject may self-evaluate using the MADRS.
  • the subject’s score obtained using the MADRS-C may be decreased compared to the score before treatment.
  • the subject’s score may decreased by at least 50% compared to the score before treatment.
  • the subject’s score obtained using the MADRS-C may be less than 10.
  • the decrease in the subject’s score using the MADRS-C is decreased for 1 week after treatment.
  • the decrease in the subject’s score using the MADRS-C is decreased for 4 weeks after treatment.
  • the subject’s score using the MADRS-C is decreased for more than 4 weeks after treatment.
  • the subject is being treated for anxiety with an intravenous infusion of the tryptamine alkaloid. In some embodiments, the subject is being treated for anxiety with an intranasal preparation of the tryptamine alkaloid.
  • the subject may have their symptoms of anxiety evaluated using an anxiety screening test.
  • the anxiety screening test may be the Zung Self-Rating Anxiety Scale, the Hamilton Anxiety Scale, the Beck Anxiety Inventory, the Social Phobia Inventory, the Penn State Worry Questionnaire, the Yale-Brown Obsessive-Compulsive Scale, or the - General Anxiety Disorder-7.
  • the subject’s anxiety score using any one of these screening tests decreases in comparison to the subject’s score before receiving treatment.
  • the subject’s anxiety score using any one of the above screening tests decreases by 50% in comparison to the subject’s score before receiving treatment.
  • the subject meets fewer criteria for anxiety as described by the Diagnostic and Statistical Manual of Mental Disorders in comparison before receiving treatment.
  • the methods of the invention are used to treat psychological conditions, e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior, by administering an infusion of the tryptamine alkaloid as needed to treat the symptoms associated with the psychological condition.
  • the methods of the invention are used to treat psychological conditions, e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior, by administering an intranasal preparation of the tryptamine alkaloid as needed to treat the symptoms associated with the psychological condition.
  • An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloids e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloids over a period of time of between 10 minutes and 1 hour, spaced at least three days, five days, 10 days, or two weeks apart.
  • the intensity and/or frequency of the symptoms associated with the psychological disorder can be reduced following treatment with the infused tryptamine alkaloids.
  • Another example of this method of treatment is when a subject is being treated with four intranasal administrations of the tryptamine alkaloids, e.g., each administration with a dose of between 1 mg and 200 mg spaced at least two days, five days, seven days, 10 days, or two weeks apart.
  • the intensity and/or frequency of the symptoms associated with the psychological disorder can be reduced following treatment with the intranasal tryptamine alkaloids.
  • the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
  • the neurological injury may be any neurological injury.
  • the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury.
  • the methods of treating a neurological injury described herein may reduce acute inflammation.
  • hippocampal hyperactivity is reduced.
  • the methods described herein for treating a neurological injury may be administered in combination with a behavioral, physical, or speech therapy.
  • the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury, by administering an infusion of the tryptamine alkaloid as needed to treat pain, inflammation, and/or other symptoms associated with the neurological injury.
  • a neurological injury e.g., stroke, traumatic brain injury, and spinal cord injury
  • an infusion of the tryptamine alkaloid as needed to treat pain, inflammation, and/or other symptoms associated with the neurological injury.
  • An example of this method of treatment is when a subject is being treated with five infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid over a period of time of between 10 minutes and 1 hour, spaced at least two days, five days, seven days, 10 days, or two weeks apart.
  • the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
  • the intensity and/or frequency of the symptoms associated with the neurological injury can be reduced following treatment with infused the tryptamine alkaloid.
  • the treatment can be used to promote neurogenesis and improve cognitive function following a neurological injury.
  • the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury, by administering an intranasal preparation of the tryptamine alkaloid as needed to pain, inflammation, and/or other symptoms associated with the neurological injury.
  • this method of treatment is when a subject is being treated with four intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage of between 1 mg and 200 mg, spaced at least two days, five days, seven days, 10 days, or two weeks apart.
  • the intensity and/or frequency of the symptoms associated with the neurological injury can be reduced following treatment with the intranasal tryptamine alkaloid.
  • An inflammatory condition in a subject can be treated with an infusion or intranasal administration of the tryptamine alkaloid using the methods of the invention.
  • the inflammatory condition to be treated can be a lung inflammation (e.g., chronic obstructive pulmonary disease (COPD)), neuroinflammation (e.g., Alzheimer’s disease), chronic inflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
  • COPD chronic obstructive pulmonary disease
  • neuroinflammation e.g., Alzheimer’s disease
  • chronic inflammation e.g., rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and/or septicemia.
  • inflammation is treated by administering an infusion of the tryptamine alkaloid as needed to treat (i) acute attacks of inflammation (e.g., inflammatory bowel disease), or (ii) chronic inflammatory conditions (e.g., arthritis).
  • An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid or an over a period of time of between 30 minutes and 4 hours, spaced at least three days, five days, 10 days, or two weeks apart.
  • the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
  • the intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the infused tryptamine alkaloid.
  • inflammation is treated by administering an intranasal preparation of the tryptamine alkaloid as needed to treat (i) acute attacks of inflammation (e.g., inflammatory bowel disease), or (ii) chronic inflammatory conditions (e.g., arthritis).
  • this method of treatment is when a subject is being treated with three intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage between 1 mg and 200 mg of the tryptamine alkaloid, spaced at least three days, five days, 10 days, or two weeks apart.
  • the intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the intranasal tryptamine alkaloid.
  • a disorder or condition associated with pain can be treated with an infusion or intranasal preparation of the tryptamine alkaloid using the methods of the invention.
  • the pain can be chronic pain, which may result, e.g., from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica.
  • the chronic pain may arise from an operation.
  • the chronic pain may also be pain associated with a particular disease or condition such as nephropathy, multiple sclerosis, shingles, or complex regional pain syndrome.
  • a disorder or condition associated with cephalic pain can be treated with an infusion of the tryptamine alkaloid using the methods of the invention.
  • a disorder or condition associated with cephalic pain is a disorder or condition which has as one of its symptoms cephalic/head pain (e.g., headache).
  • examples of such disorders or conditions include trigeminal autonomic cephalalgias such as episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).
  • CH episodic and chronic cluster headache
  • PH episodic and chronic paroxysmal hemicrania
  • SUNCT short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing
  • vascular headaches e.g., migraine headaches
  • tension headaches e.g., headaches associated with the use of a substance (e.g., triptans such as sumatriptan, benzodiazepines such as alprazolam, analgesics such as ibuprofen, ergots such as ergotamine, opioids such as morphine, recreational drugs such as caffeine, nicotine, alcohol, and hormone replacement therapy containing, for example, estrogen) or its
  • disorders or conditions associated with cephalic pain include miscellaneous headache unassociated with a structural lesion, headache associated with a nonvascular intracranial disorder, headache associated with a non-cephalic infection, headache associated with a metabolic disorder, headache associated with a disorder of the cranium, neck, eyes, nose, sinuses, teeth, mouth, or other facial or cranial structure, nerve trunk pain and deafferentiation pain.
  • the methods of the invention are used to treat chronic pain, e.g., postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica, by administering an infusion or intranasal preparation of the tryptamine alkaloid as needed to treat acute attacks of cephalic pain during the period in which the tryptamine alkaloid is being administered.
  • chronic pain e.g., postoperative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica
  • An example of this method of treatment is when a subject is being treated with three infusions of the tryptamine alkaloid, e.g., each administration at a free base equivalent rate of between 5 mg/hr and 600 mg/hr of the tryptamine alkaloid over a period of time of between 30 minutes and 1 hour, spaced at least three days, five days, 10 days, or two weeks apart.
  • the subject can be treated with a free base equivalent of 10.0 ⁇ 1 .0 mg of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, administered over a period of 10 to 60 minutes.
  • the intensity and/or frequency of the chronic pain can be reduced following treatment with infused the tryptamine alkaloid.
  • the subject being treated for chronic pain is also administered a medication for pain relief including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
  • a medication for pain relief including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
  • Another example of this method of treatment is when a subject is being treated with three intranasal administrations of the tryptamine alkaloid, e.g., each administration at a dosage between 1 mg and 200 mg of the tryptamine alkaloid, spaced at least three days, five days, 10 days, or two weeks apart.
  • the intensity and/or frequency of the inflammation or pain associated with inflammation can be reduced following treatment with the intranasal tryptamine alkaloid.
  • the tryptamine alkaloids that can be used in the methods of the invention include DMT, 4-AcO- DMT, 5-MeO-DMT, 4-OH-DET, 4-OH-DIPT and phosphates, acetate esters, or pharmaceutically acceptable salts thereof.
  • Tryptamine alkaloids have a high affinity for 5-HT2A receptor, also known as the serotonin 2A receptor, which plays a key role in regulating mood, sexual behavior, aggression, impulsivity, cognitive function, appetite, pain, sleep, and memory along with other behaviors. As result, tryptamine alkaloids bind to the 5-HT2A receptor mimicking the binding of serotonin.
  • This disclosure provides methods for treating a subject having a psychological condition or a neurological injury using an intravenous infusion or intranasal preparation of the tryptamine alkaloid.
  • the disclosure provides a method for treating a subject with a psychological condition using an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof.
  • the tryptamine alkaloid may be administered as an infusion described herein.
  • the rate of infusion may be adjusted so as to minimize adverse side effects and maximize the effectiveness of treatment on the subject’s psychological condition.
  • the subject’s plasma concentration of 5- MeO-DMT may be monitored over the course of the infusion.
  • the disclosure provides a method for treating a subject with a neurological injury, inflammation, or pain using an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof.
  • the tryptamine alkaloid may be administered as an infusion described herein.
  • the rate of infusion may be adjusted so as to minimize adverse side effects and maximize the effectiveness of treatment on the subject’s psychological condition.
  • the subject’s plasma concentration of 5-MeO-DMT may be monitored over the course of the infusion.
  • the disclosure provides a method for treating a subject with a psychological condition using an intranasal preparation of tryptamine alkaloid.
  • the tryptamine alkaloid may be administered at a dosage of between 5 mg/hr and 600 mg/hr (e.g., 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 1 mg/hr, 11 ⁇ 1 mg/hr, 12 ⁇ 1 mg/hr, 13 ⁇ 1 mg/hr, 14 ⁇ 1 mg/hr, 15 ⁇ 5 mg/hr, 20 ⁇ 5 mg/hr, 25 ⁇ 5 mg/hr, 30 ⁇ 5 mg/hr, 40 ⁇ 20 mg/hr, 60 ⁇ 20 mg/hr, 80 ⁇ 20 mg/hr, 100 ⁇ 50 mg/hr, 150 ⁇ 50 mg/hr, 200 ⁇ 50 mg/hr, 250 ⁇ 50 mg/hr, 300 ⁇ 50 mg/hr, 350 ⁇ 50 mg/hr
  • the tryptamine alkaloid may be administered in a dosage of the free base equivalent of between 1 mg and 200 mg (e.g., (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5 mg, 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg).
  • 1 mg and 200 mg e.g., (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 5
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 30 mg and 200 mg (e.g., (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) over a period of 20 to 60 minutes.
  • 30 mg and 200 mg e.g., (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 30 mg and 100 mg (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, and 100 ⁇ 10 mg) over a period of 20 to 60 minutes.
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 100 mg and 200 mg (e.g., 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) over a period of 20 to 60 minutes.
  • 100 mg and 200 mg e.g., 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 15 mg and 160 mg (e.g., 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, and 160 ⁇ 10 mg) over a period of 10 to 20 minutes.
  • 15 mg and 160 mg e.g., 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 1 10 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, and 160 ⁇ 10 mg
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 15 mg and 50 mg (e.g., 15 ⁇ 5 mg, 20 ⁇ 5 mg, 25 ⁇ 5 mg, 30 ⁇ 10 mg, 40 ⁇ 10 mg, and 50 ⁇ 10 mg) over a period of 10 to 20 minutes.
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 50 mg and 100 mg (e.g., 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, and 100 ⁇ 10 mg) over a period of 10 to 20 minutes.
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 4 mg and 15 mg (e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg) over a period of 20 to 60 minutes.
  • 4 mg and 15 mg e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg , 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 4 mg and 10 mg (e.g., 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 mg, 9 ⁇ 1 mg, and 10 ⁇ 1 mg) over a period of 20 to 60 minutes.
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 10 mg and 15 mg (e.g., 10 ⁇ 1 mg, 1 1 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, and 15 ⁇ 1 mg) over a period of 20 to 60 minutes.
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 1 mg and 5 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) over a period of 10 to 20 minutes.
  • the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be administered in a dosage of the free base equivalent of between 1 mg and 3 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) over a period of 10 to 20 minutes. In some embodiments, the free base equivalent of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, may be administered in a dosage of the free base equivalent of between 3 mg and 5 mg (e.g., 3 ⁇ 1 mg, 4 ⁇ 1 mg, and 5 ⁇ 1 mg) over a period of 10 to 20 minutes.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid for the treatment of a disease or condition may be administered at once or twice.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered between 2 and 10 times (e.g., 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, and 10 times).
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered weekly.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered multiple times in one week (e.g., 2 times a week, 3 times a week, 4 times a week, and 5 times a week).
  • the infusion or intranasal preparation of tryptamine alkaloid may be administered 2 times a week.
  • the infusion or intranasal preparation of tryptamine alkaloid may be administered 3 times a week.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered every two weeks.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered monthly.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may also be administered every 3 months and the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered every 4 months.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered once a year.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered until the subject’s symptoms of their disease or condition are improved compared the subject’s symptoms of depression before being administered treatment.
  • the methods for treating a disease or condition described herein include administering to a subject an intravenous infusion or intranasal preparation of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.
  • the tryptamine alkaloid infusion or intranasal may be administered in combination with an anxiolytic, an antihistamine, a beta-blocker, an alpha blocker, a sedative, or an anesthetic.
  • additional agents such as an antiemetic, and/or benzodiazepine are also administered.
  • described herein specifically are methods of treating a disease or condition where the disease or condition is chronic pain.
  • the subject When the subject is being treated for chronic pain with the tryptamine alkaloid infusion or intranasal the subject may also be administered one or more medications for pain relief, including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
  • medications for pain relief including morphine, hydromorphone, hydrocodone, meperidine, and fentanyl.
  • the intravenous tryptamine alkaloid infusion may be administered to a subject in combination with a pharmacologically effective amount of an anxiolytic (e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine).
  • anxiolytic e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine
  • the intranasal tryptamine alkaloid preparation may be administered to a subject in combination with a pharmacologically effective amount of an anxiolytic (e.g., a serotonin 5-HTIA receptor agonist, such a benzodiazepine).
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a benzodiazepine.
  • the benzodiazepine may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the benzopiazepine may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
  • the benzodiazepine and the tryptamine alkaloid infusion or intranasal are administered concurrently.
  • the tryptamine alkaloid infusion or intranasal and the benzodiazepine are administered separately.
  • the benzodiazepine may be 1 ,4-benzodiazepine, 1 ,5-benzodiazepine, 2,3-benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine, pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, diazepam, midazolam, alprazolam, temazepam, clonazepam or a combination thereof.
  • the benzodiazepine is lorazepam.
  • Lorazepam is a benzodiazepine medication sold under various trade names including ATIVAN®, ALMAZINE®, and TAVOR®. Lorazepam has various properties, including acting as a sedative, a hypnotic, an amnesiac, and an anxiolytic. Like other benzodiazepines, lorazepam is generally understood to act primarily by enhancing the effect of gamma-aminobutyric acid (GABA) at the GABAA receptor. As the primary inhibitory neurotransmitter, GABA acts to reduce neuronal excitability throughout the nervous system. Compared to other benzodiazepines such as diazepam (valium), lorazepam is substantially more potent and longer acting.
  • GABA gamma-aminobutyric acid
  • the benzodiazepine is administered in combination with the tryptamine alkaloid infusion or intranasal preparation such that the ratio of tryptamine alkaloid to benzodiazepine is between 10:1 and 1 :5 by weight (e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight).
  • 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1 :3, 1 :4 and 1 :5 by weight e.g., 10:1 , 9:1 , 8:1 , 7:1 , 6:1 , 5:1 , 4:1 , 3:1 , 2:1 , 1 :1 , 1 :2, 1
  • the benzodiazepine may be administered in a dosage of between 2 mg and 40 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, 4 ⁇ 1 mg, 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, 10 ⁇ 1 mg, 11 ⁇ 1 mg, 12 ⁇ 1 mg, 13 ⁇ 1 mg, 14 ⁇ 1 mg, 15 ⁇ 1 mg, 16 ⁇ 1 mg, 17 ⁇ 1 mg, 18 ⁇ 1 mg, 19 ⁇ 1 mg, 20 ⁇ 1 mg, 21 ⁇ 1 mg, 22 ⁇ 1 mg, 23 ⁇ 1 mg, 24 ⁇ 1 mg, 25 ⁇ 1 mg, 26 ⁇ 1 mg, 27 ⁇ 1 mg, 28 ⁇ 1 mg, 29 ⁇ 1 mg, 30 ⁇ 1 mg, 31 ⁇ 1 mg, 32 ⁇ 1 mg, 33 ⁇ 1 mg, 34 ⁇ 1 mg, 35 ⁇ 1 mg, 36 ⁇ 1 mg, 37 ⁇ 1 mg, 38 ⁇ 1 mg, and 39 ⁇ 1 mg) in combination with the tryptamine alkaloid infusion or intranasal preparation.
  • the benzodiazepine administered may be lorazepam.
  • the lorazepam may be administered in a dosage between 2 mg and 4 mg (e.g., 2 ⁇ 1 mg, 3 ⁇ 1 mg, and 4 ⁇ 1 mg).
  • the benzodiazepine administered in combination with the tryptamine alkaloid may be diazepam.
  • the diazepam may be administered in a dosage between 5 mg and 10 mg (e.g., 5 ⁇ 1 mg, 6 ⁇ 1 mg, 7 ⁇ 1 mg, 8 ⁇ 1 , 9 ⁇ 1 mg, and 10 ⁇ 1 mg).
  • the benzodiazepine may be administered orally, transmucosally (e.g. nasally, buccally, sublingually, vaginally, ocularly, rectally, etc.) intravenously, by inhalation, intramuscular injection, and any other form of delivery
  • the benzodiazepine may be administered to the subject to dampen the effects of the tryptamine alkaloid. As a result, the benzodiazepine may decrease the intensity of the experience of the subject being administered the tryptamine alkaloid. Therefore, benzodiazepine may be administered in order to limited, stop, or prevent any negative side effects (such as tryptamine alkaloid-induced anxiety) from the tryptamine alkaloid that the subject may experience.
  • any negative side effects such as tryptamine alkaloid-induced anxiety
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an antihistamine, which produce sedative effects by blocking the H1 receptor.
  • the antihistamine may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the antihistamine may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
  • the antihistamine and the tryptamine alkaloid infusion or intranasal are administered concurrently.
  • the tryptamine alkaloid infusion or intranasal and the antihistamine are administered separately.
  • the antihistamine used in combination with the intravenous tryptamine alkaloid infusion or intranasal may be carbinoxamine, clemastine, dimenhydrinate, pyrilamine, tripelennamine, chlorpheniramine, brompheniramine, hydroxyzine, cyclizine, acrivastine, cetririzine, azelastine, loratadine, fexofenadine, doxepin, diphenhydramine, or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • the benzodiazepine is hydroxyzine or a pharmaceutically acceptable salt thereof.
  • the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a beta-blocker (e.g., an amount that ameliorates anxiety).
  • a beta-blocker e.g., an amount that ameliorates anxiety.
  • the beta-blocker may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the beta-blocker may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
  • the beta-blocker and the tryptamine alkaloid infusion or intranasal are administered concurrently.
  • the tryptamine alkaloid infusion or intranasal and the beta-blocker are administered separately.
  • the beta-blocker used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be propranolol, nadolol, timolol, pindolol, labetalol, metroprolol, atenolol, esmolol, and acebutolol, or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • the beta-blocker is propranolol, atenolol, or a pharmaceutically acceptable salt thereof.
  • the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an alpha blocker (e.g., an amount that ameliorates hypertension).
  • the alpha blocker may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the alpha blocker may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
  • the alpha blocker and the tryptamine alkaloid infusion or intranasal are administered concurrently.
  • the tryptamine alkaloid infusion or intranasal and the alpha blocker are administered separately.
  • the alpha blocker used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, clonidine, lofexidine, dexmedetomidine, guanfacine, myrcene, or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • the alpha blocker is prazosin, clonidine, guanfacine, or a pharmaceutically acceptable salt thereof.
  • the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of a sedative (e.g., a sedating amount of a barbiturate, a hypnotic, or a benzodiazepine (described above)).
  • a sedative e.g., a sedating amount of a barbiturate, a hypnotic, or a benzodiazepine (described above)
  • the sedative may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the sedative may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
  • the sedative and the tryptamine alkaloid infusion or intranasal are administered concurrently.
  • the sedative used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be a barbituate selected from benzylbutylbarbiturate, butalbital, amobarbital, pentobarbital, secobarbital, sodium thiopental, or phenobarbital; or a hypnotic selected from eszopiclone, zaleplon, zolpidem, or zopiclone, or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject in combination with a pharmacologically effective amount of an anesthetic (e.g., an amount that produces anesthesia).
  • the anesthetic may be formulated in the same composition as the tryptamine alkaloid infusion or intranasal, or the anesthetic may be formulated in a separate compositon from the tryptamine alkaloid infusion or intranasal.
  • the anesthetic and the tryptamine alkaloid infusion or intranasal are administered concurrently.
  • the tryptamine alkaloid infusion or intranasal and the anesthetic are administered separately.
  • the anesthetic used in combination with the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be chloral hydrate, ketamine, esketamine, etomidate, propofol, fospropofol, chlorobutanol, or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • the anesthetic is propofol or a pharmaceutically acceptable salt thereof.
  • the intravenous infusion or intranasal preparation of a tryptamine alkaloid may be administered to a subject having a disease or condition in need of treatment in combination with a pharmacologically effective amount of an antiemetic agent.
  • the antiemetic agent may be administered to the subject prior to the tryptamine alkaloid infusion or intranasal.
  • the antiemetic agent may be a non-selective 5-HT antagonist, 5-HT3 receptor antagonist, 5-HT4 receptor agonist, CB1 agonist, D2 receptor antagonist, D3 receptor antagonist, GABA receptor agonist, H1 receptor antagonist, muscarinic acetylcholine receptor antagonist, NK1 receptor antagonist, or a combination thereof.
  • the antiemetic agent is ondansetron.
  • Ondansetron is an antiemetic medication sold under the trade names ZOFRAN® and ONDISSOLVE® in various markets.
  • Ondansetron is a 5-HT3 receptor antagonist (a “setron”) generally used in controlling nausea and vomiting in post-operative conditions and in chemotherapy subjects, and as well as for various off-label uses.
  • 5-HT3 receptor antagonists bind to and block the 5-HT3 receptor, which is a ligand-gated ion channel found in the vagus nerve and in the area postrema, as well as the in the vomiting center in the medulla oblongata of the brainstem. Synaptic transmission initiated via the 5- HT3 receptor directly mediates the nausea and vomiting reflex.
  • a pharmacologically effective amount of an antiemetic agent may be administered to the subject.
  • the antiemetic agent may be ondansetron.
  • the ondansetron may be administered in a dosage between 4 mg and 8 mg.
  • the antiemetic agent is administered as a 4 mg intravenous infusion of ondansetron prior to the tryptamine alkaloid infusion.
  • the ondansetron may be administered as a 4 mg intranasal dosage prior to the tryptamine alkaloid intranasal preparation.
  • other preparations may be administered to the subject which may vary in dosage form.
  • methods of delivery of the antiemetic agent other than intravenous infusion may be utilized, including but not limited to oral delivery, transmucosal (e.g. nasal, buccal, sublingual, vaginal, ocular, rectal, etc.) delivery, inhalatory delivery, intramuscular injection, and any other form of delivery that may achieve administration to the subject of a pharmacologically effective amount of the antiemetic agent.
  • transmucosal e.g. nasal, buccal, sublingual, vaginal, ocular, rectal, etc.
  • inhalatory delivery e.g., intramuscular injection
  • intramuscular injection e.g., intramuscular injection
  • antiemetic agents other than ondansetron may be utilized, including but not limited to other setrons, or other antiemetic compounds or preparations.
  • the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be contained in any appropriate amount in any suitable carrier substance formulated for intravenous infusion or intranasal administration and is generally present in an amount of 1 -95% by weight of the total weight of the composition. In particular embodiments, the tryptamine alkaloid is present in an amount of 65-95% by weight of the of the total weight of the composition.
  • the tryptamine alkaloid for intravenous infusion may be formulated in a saline solution. In certain embodiments, the tryptamine alkaloid for intranasal administration may be formulated in a saline solution.
  • compositions for infusion or intranasal use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added.
  • the composition may be in the form of a solution, a suspension, an emulsion, an infusion device, a dropper, a pipette, a spray, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • dosing may be achieved by the subject administering an appropriate, predetermined volume of the solution.
  • a spray this may be achieved, for example, by means of a metering atomizing spray pump.
  • the composition may include suitable carriers and/or excipients.
  • the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release.
  • the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents.
  • the pharmaceutical compositions of tryptamine alkaloid according to the invention may be in a form suitable for sterile infusion.
  • the pharmaceutical compositions of tryptamine alkaloid according to the invention may be in the form of a suitable intranasal preparation.
  • the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof is dissolved or suspended in a parenterally acceptable liquid vehicle.
  • acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution, and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate).
  • preservatives e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate.
  • a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like.
  • Administration of an intravenous infusion of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be controlled by a rate of infusion.
  • administration of an intranasal preparation of tryptamine alkaloid, or a pharmaceutically acceptable salt thereof may be controlled by a spray device. This is especially preferred in cases in which the subject receives a dosing regimen that at peak plasma levels can result in side effects.
  • the rate of tryptamine alkaloid infusion may be between 5 mg/hr and 600 mg/hr (e.g., 5 ⁇ 1 mg/hr, 6 ⁇ 1 mg/hr, 7 ⁇ 1 mg/hr, 8 ⁇ 1 mg/hr, 9 ⁇ 1 mg/hr, 10 ⁇ 1 mg/hr, 11 ⁇ 1 mg/hr, 12 ⁇ 1 mg/hr, 13 ⁇ 1 mg/hr, 14 ⁇ 1 mg/hr, 15 ⁇ 5 mg/hr, 20 ⁇ 5 mg/hr, 25 ⁇ 5 mg/hr, 30 ⁇ 5 mg/hr, 40 ⁇ 20 mg/hr, 60 ⁇ 20 mg/hr, 80 ⁇ 20 mg/hr, 100 ⁇ 50 mg/hr, 150 ⁇ 50 mg/hr, 200 ⁇ 50 mg/hr, 250 ⁇ 50 mg/hr, 300 ⁇ 50 mg/hr, 350 ⁇ 50 mg/hr, 400 ⁇ 50 mg/hr, 450 ⁇ 50 mg/hr, 500 ⁇ 50
  • the tryptamine alkaloid infusion may administered in an amount of between from 30 mg to 200 mg (e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg, 130 ⁇ 10 mg, 140 ⁇ 10 mg, 150 ⁇ 10 mg, 160 ⁇ 10 mg, 170 ⁇ 10 mg, 180 ⁇ 10 mg, 190 ⁇ 10 mg, and 200 ⁇ 10 mg) of the tryptamine alkaloid, or a pharmaceutically acceptable salt thereof, over a period of 20 to 60 minutes (e.g., a continuous infusion over about 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, and 60 minutes).
  • 30 mg to 200 mg e.g., 30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, 100 ⁇ 10 mg, 110 ⁇ 10 mg, 120 ⁇ 10 mg,
  • the free base equivalent of the tryptamine alkaloid may be administered to the subject in an amount of between 30 mg and 100 mg (30 ⁇ 10 mg, 40 ⁇ 10 mg, 50 ⁇ 10 mg, 60 ⁇ 10 mg, 70 ⁇ 10 mg, 80 ⁇ 10 mg, 90 ⁇ 10 mg, and 100 ⁇ 10 mg) over a period of 30 to 60 minutes.
  • the intravenous infusion or intranasal preparation of tryptamine alkaloid is administered in combination with an anxiolytic agent (e.g., benzodiazepine) which may result in a dampening and/or shortening of the intensity of the experience of the subject in comparison to when tryptamine alkaloid alone is administered.
  • an anxiolytic agent e.g., benzodiazepine
  • the intravenous tryptamine alkaloid infusion is administered in combination with an anxiolytic agent (e.g., benzodiazepine) which may result in intensity rating falling below 2 more quickly than the time the intensity rating takes to fall below 2 when only the tryptamine alkaloid is administered.
  • the antiemetic, anxiolytic agent, or pharmaceutically acceptable salt thereof which may be administered in combination with the tryptamine alkaloid infusion may be formulated in any suitable carrier substance and is generally present in an amount of 1 -95% by weight of the total weight of the composition.
  • the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof are formulated in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • Pharmaceutical compositions according to the invention may be formulated to release the antiemetic, anxiolytic, or pharmaceutically acceptable salt thereof, substantially immediately upon administration or at any predetermined time or time period after administration.
  • any of the antiemetic and anxiolytic agents described herein may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • the antiemetic and anxiolytic agents may also be administered parenterally by injection, infusion, or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • Example 1 Treatment of patients having depression with intravenous infusion of DMT in combination with lorazepam
  • Subjects suffering from depression are treated with an intravenous infusion of N,N- dimethyltryptamine (DMT) and lorazepam.
  • DMT N,N- dimethyltryptamine
  • the subject is first diagnosed with depression by a clinician by using a physical exam, using the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), or conducting an depression screening test such as the Patient Health Questionnaire- 9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS).
  • PHQ-9 Patient Health Questionnaire- 9
  • BDI Beck Depression Inventory
  • CES-D the Zung Self-Rating Depression Scale
  • CES-D Center for Epidemiological Studies Depression Scale
  • HRSD Hamilton Rating Scale for Depression
  • MADRS Montgomery-Asberg Depression Rating Scale
  • the subjects are administered a continuous intravenous dosage of DMT with an infusion rate of between 5 mg/hr and 250 mg/hr over a time period of no more than one hour.
  • the DMT is co-infused with lorazepam at an infusion rate of between 75 mg/hr and 115 mg/hr.
  • the subject is administered a dosage of the DMT and lorazepam combination up to 3 to 4 times a week for a period of 2 weeks.
  • DMT/lorazepam infusions can reduce depression in subjects suffering from depression or a condition associated with depression.
  • Example 2 Administration of Acetylpsilocin to treat post-traumatic stress disorder with lorazepam
  • Subjects suffering from post-traumatic stress disorder are treated with an intravenous infusion of acetylpsilocin (4-AcO-DMT) and lorazepam.
  • the subject is first diagnosed by a clinician with post-traumatic stress disorder using a physical exam and the criteria listed in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).
  • the subjects are administered a continuous intravenous dosage of 4-AcO-DMT.
  • the intensity of the 4-AcO-DMT experienced by the subject is rated by the subject and is monitored throughout administration of the tryptamine alkaloid infusion using the Drug Effects Questionnaire (DEQ).
  • DEQ Drug Effects Questionnaire
  • the subjects are simultaneously administered the benzodiazepine lorazepam in the same intravenous formulation as the 4-AcO-DMT in a dosage of 2 mg to 4 mg. In other embodiments, the subjects are simultaneously administered the benzodiazepine diazepam in the same intravenous formulation as the 4-AcO-DMT in a dosage of 5 mg to 10 mg.
  • the subject is administered the intravenous infusion of 4-AcO-DMT and lorazepam up to 3 times a week for one week.
  • the subject’s symptoms associated with post-traumatic stress disorder are evaluated by a clinician using the criteria listed in the DSM-5.
  • the subject’s anxiety level is assessed using an anxiety screening test such as the Zung Self-Rating Anxiety Scale, the Hamilton Anxiety Scale, the Beck Anxiety Inventory, or the General Anxiety Disorder-7.
  • the subject is capable of adaptive reconsolidation of the subject’s traumatic memory, resulting in a reduction in anxiety, depression, aggression, and/or hypervigilance.
  • the subject can experience less anxiety in comparison the amount of anxiety experienced before treatment.
  • the clinician may recommend continued treatment.
  • the 4-AcO-DMT infusions can reduce the intensity and frequency of PTSD symptoms (e.g., anxiety or depression) in subjects suffering from PTSD.
  • Example 3 Administration of 5-methoxy-N,N-dimethyltryptamine to treat eating disorders
  • Subjects suffering from an eating disorder are treated with an intravenous infusion of 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT) in combination with the anxiolytic lorazepam.
  • the subjects are first diagnosed by a clinician with an eating disorder including anorexia nervosa, bulimia nervosa, and binge eating disorder as having met the criteria listed in the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).
  • the subjects are administered an intravenous dosage of 5-MeO-DMT.
  • the intensity of the 5-MeO-DMT experienced by the subject is rated by the subject and is monitored throughout administration of the 5-MeO-DMT infusion.
  • the 5-MeO-DMT infusion is stopped when the patient experiences a negative side effect including vomiting, muscle weakness, dizziness, paranoia, or frightening hallucinations.
  • a negative side effect including vomiting, muscle weakness, dizziness, paranoia, or frightening hallucinations.
  • the intensity experienced by the subject drops quickly resulting in ending the negative side effects in less than 10 minutes.
  • intravenous administration of 5-MeO-DMT is restarted but now with co-administration of an anxiolytic (e.g., lorazepam).
  • the subject is administered the intravenous infusion of 5-MeO-DMT and lorazepam up to 3 times a week for two weeks.
  • the subject is evaluated by a clinician to identify any changes in the subject’s symptoms associated with an eating disorder.
  • the subject may experience fewer of the symptoms described by the criteria for being diagnosed with an eating disorder as described in the DSM- 5 in comparison to the subject’s symptoms before receiving treatment.
  • the subject may experience weight gain, fewer purging events per week, fewer binging events per week, or an increase in daily caloric intake as a result of receiving the intravenous 5-MeO-DMT infusion.
  • the mean concentration-time profiles of dimethyltryptamine (DMT) was determined from 10 subjects administered an intravenous bolus dose of DMT ranging from 0.05 mg/kg to 0.2 mg/kg and placebo (see, e.g., Strassman RJ and Qualls CR. Arch Gen Psychiatry. 1994; 51 : 85-97). These concentration time profiles were used to simulate concentration-time profiles of several doses of DMT administered as an intravenous infusion at concentrations of 0.2 mg, 0.4 mg, and 0.8 mg over an intravenous infusion time of 15 minutes (FIG. 1 ), 30 minutes (FIG. 2), or 45 minutes (FIG. 3). The relationship between DMT concentration and subjective effects were also derived from this publication. The simulated dosing regimens were selected to maintain concentrations between minimum and maximum efficacious DMT concentration.
  • DMT dimethyltryptamine
  • Analogous simulations can be performed for other tryptamine alkaloids to assess appropriate dosing levels based upon the PK and PD performance of a particular tryptamine alkaloid.

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Abstract

L'invention concerne des méthodes de traitement destinées à des patients souffrant d'une maladie ou d'un état, consistant à administrer par perfusion intraveineuse ou préparation intranasale d'une quantité pharmaceutiquement efficace d'un alcaloïde tryptamine en combinaison avec un second agent. Par exemple, la perfusion intraveineuse ou la préparation intranasale de l'alcaloïde tryptamine peut comprendre un composé supplémentaire tel qu'une benzodiazépine, de préférence le lorazépam, administré par perfusion intraveineuse continue. De telles méthodes peuvent être observées pour mieux soulager les symptômes d'états psychologiques, de lésions neurologiques, de douleur chronique ou d'états inflammatoires, et peuvent conduire à un besoin réduit pour d'autres médicaments.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023230303A1 (fr) * 2022-05-27 2023-11-30 Lerer Leonard Traitement de déclin cognitif lié à l'anesthésie et à la sédation
US11905535B2 (en) 2019-10-01 2024-02-20 Empyrean Nueroscience, Inc. Genetic engineering of fungi to modulate tryptamine expression
US12012381B2 (en) 2021-12-30 2024-06-18 Atai Therapeutics, Inc. Dimethyltryptamine analogues as nitric oxide delivery drugs

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571395A (en) * 1980-01-21 1986-02-18 Burroughs Wellcome Co. Lorazepam and bupropion, compositions and methods
US20130302357A1 (en) * 2009-02-05 2013-11-14 Wei Li Novel benzodiazepine derivatives
US20190350949A1 (en) * 2017-01-18 2019-11-21 Procare Beheer B.V. Psilocybin and/or psilocin in combination with cannabinoids and/or terpenes
WO2020169850A1 (fr) * 2019-02-22 2020-08-27 Gh Research Limited 5-méthoxy-n,n-diméthyltryptamine (5-méo-dmt) pour la traitement de la dépression

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571395A (en) * 1980-01-21 1986-02-18 Burroughs Wellcome Co. Lorazepam and bupropion, compositions and methods
US20130302357A1 (en) * 2009-02-05 2013-11-14 Wei Li Novel benzodiazepine derivatives
US20190350949A1 (en) * 2017-01-18 2019-11-21 Procare Beheer B.V. Psilocybin and/or psilocin in combination with cannabinoids and/or terpenes
WO2020169850A1 (fr) * 2019-02-22 2020-08-27 Gh Research Limited 5-méthoxy-n,n-diméthyltryptamine (5-méo-dmt) pour la traitement de la dépression

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11905535B2 (en) 2019-10-01 2024-02-20 Empyrean Nueroscience, Inc. Genetic engineering of fungi to modulate tryptamine expression
US12012381B2 (en) 2021-12-30 2024-06-18 Atai Therapeutics, Inc. Dimethyltryptamine analogues as nitric oxide delivery drugs
WO2023230303A1 (fr) * 2022-05-27 2023-11-30 Lerer Leonard Traitement de déclin cognitif lié à l'anesthésie et à la sédation

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