Combinations comprising monoamine antidepressant and short-acting magical agent

Abstract

The present invention relates to a combination, a combination for treating a psychiatric disorder in a patient, a method for treating a psychiatric disorder in a patient, a kit, a dosing regimen, a delivery device, a method of adjuvant therapy, a short-acting magical agent for treating a psychiatric disorder in a patient or a parenteral formulation for treating a psychiatric disorder in a patient. In particular, the present invention relates to the combined administration of a short acting magical agent with a monoamine antidepressant, such as a selective serotonin reuptake inhibitor (SSRI).

Description

Invention Field

[0001] This invention relates to combinations for treating psychiatric disorders in patients, methods for treating psychiatric disorders in patients, kits for treating psychiatric disorders in patients, administration regimens, delivery devices, methods of adjunctive therapy, short-acting hallucinogens for treating psychiatric disorders in patients, or parenteral preparations for treating psychiatric disorders in patients. Specifically, this invention relates to the combined administration of short-acting hallucinogens with monoamine antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Background of the Invention

[0003] Antidepressants are a large class of medications used to treat a variety of psychiatric conditions, such as depression, anxiety, obsessive-compulsive disorder, and eating disorders. Most regulatory-approved antidepressants are monoamine antidepressants: non-hallucinogens characterized by their mode of action that addresses an imbalance (or deficiency) in one or more neurotransmitters, serotonin, norepinephrine, and dopamine. In most applicable psychiatric conditions, the standard of care is a selective serotonin reuptake inhibitor (SSRI). SSRIs are widely used as antidepressants, often as first-line treatment, and are thought to work by increasing serotonin levels in the brain. SSRIs are generally taken orally, usually in tablet form, and typically require daily administration for 2 to 4 weeks before any benefit is felt. SSRIs include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vortioxetine.

[0004] Large meta-analyses have shown that SSRIs typically respond within three months in about one-third of patients, and another third within 12 months. The remaining third do not respond and will often remain on one or more antidepressants for many years without ever achieving a clinically meaningful response. Furthermore, discontinuing monoamine antidepressants (such as SSRIs) is difficult and should be done slowly, reducing the dose over a period of four weeks or longer to prevent withdrawal symptoms (withdrawal syndrome). With over 300 million people suffering from depression globally, there remains a significant medical need to improve the clinical response rates of SSRIs and other monoamine antidepressants.

[0005] Typical hallucinogens have also shown preclinical and clinical potential in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). For example, psilocybin has been shown to significantly improve a range of depression and anxiety rating scales in randomized, double-blind studies (Griffiths et al. Journal of Psychopharmacology, 30(12), 1181-1197 (2016)). The efficacy of seroxipen has been demonstrated in depression (RL Carhart-Harris et al., Psychopharmacology, 2018, 235, 399-408), end-of-life anxiety (RR Griffiths et al., J. Psychopharmacol., 2016, 30, 12, 1181-1197) and addiction (MW Johnson, A. Garcia-Romeu and RRGriffiths, Am. J. Drug Alcohol Abuse, 2017, 43, 1, 55-60), and is currently being investigated for several other mental health disorders that originate from a destructive pattern of thought processing (anorexia nervosa: NCT#NCT04052568).

[0006] Becker et al. conducted a double-blind, placebo-controlled, crossover clinical trial (clinicaltrials.gov ID NCT03912974) to investigate the response of healthy volunteers to selocillin (25 mg) after pretreatment with escitalopram or placebo. Becker et al. reported that two weeks of daily escitalopram treatment did not reduce the positive mood or mental changes of full-dose selocillin in healthy subjects (Clin Pharmacol Ther. 2022 Apr; 111(4); 886-895. Published online 2021 Nov 22. doi: 10.1002 / cpt.2487). An open-label clinical trial has also been conducted to investigate the effect of oral administration of selocillin (where hallucinogenic experiences typically last six to eight hours) in participants with treatment-resistant depression, comparing participants receiving SSRIs with those who had discontinued their SSRIs before the start of the trial. The trial’s sponsor, Compass Pathways, announced that patients receiving psilocybin and a concomitant SSRI showed “treatment outcomes comparable to those of patients who opted out of their SSRI therapy” (Compass Pathways press release, December 13, 2021: https: / / compasspathways.com / positive-outcome-25mg-comp360-psilocybin-therapy-adjunct-ssri-antidepressants-open-label-treatment-resistant-depression-study / ).

[0007] Cybin Inc. has completed the Phase 1 portion of a Phase 1 / 2a clinical trial evaluating a deuterated selocillin analogue (CYB003) in healthy participants with and without major depressive disorder (ClinicalTrials.gov ID: NCT05385783). In February 2023, Cybin announced that hallucinogenic effects were observed within approximately 15 minutes following a single oral dose of CYB003, with a mean duration of peak effect of approximately 2 hours, based on an interim analysis of CYB003 in healthy volunteers (https: / / cybin.com / cyb003 / ).

[0008] The University of California is conducting a Phase 1 clinical trial to compare the physiological and psychological effects of psilocin (orally administered as a pill or sublingually dissolved tablet) and psilocin (administered as a pill) in healthy adults (ClinicalTrials.gov ID: NCT05317689). Each participant will be administered 15.5 mg of psilocin orally, 25 mg of psilocin orally, or 2.18 mg–4.36 mg of psilocin sublingually.

[0009] Reunion Neuroscience has completed a Phase 1 clinical trial of a compound consisting of a glutarate moiety attached to a phenolic functional group of 4-hydroxy-N,N-diisopropyltryptamine. The compound reportedly had a mean duration of subjective experience of 3.7 hours at 33 mg (poster presented at the American Society for Clinical Psychopharmacology Annual Meeting, May 30–June 2, 2023: https: / / reunionneuro.com / wp-content / uploads / 2023 / 06 / 23-RNR-3851_ASCP23_RE104_Poster_M1-3.pdf). The compound, N,N-diisopropyltryptamine-4-glutarate, is also known as iprocin-4-glutarate, isoprocin-4-glutarate, or 4-glutarate-DIPT.

[0010] Short-acting hallucinogens, such as N,N-dimethyltryptamine (DMT), have been shown to have therapeutic value as rapid-acting antidepressants with a duration of three months or more (SmallPharma Inc. press release, January 25, 2023: https: / / smallpharma.com / press-releases / positive-topline-results-from-phase-iia-trial-of-spl026-in-major-depressive-disorder / ).

[0011] To date, no studies have investigated the safety, tolerability, or efficacy of short-acting hallucinogens in patients receiving monoamine antidepressants (such as SSRIs). Most clinical trials testing the efficacy of hallucinogens in treating mental health disorders exclude patients currently taking SSRIs. Since both SSRIs and serotonin-containing (or typical) hallucinogens exert their primary effects through the serotonin system, theoretically, these compounds could interact violently through multiple pathways:

[0012] a) Safety: SSRIs inhibit the reuptake of serotonin (5-hydroxytryptamine [5-HT]), meaning they increase intrasynaptic serotonin and thus enhance activity at 5-HT receptors. Since typical hallucinogens act by activating 5-HT receptors, these two activities together can create a risk of inducing serotonin toxicity.

[0013] b) Pharmacodynamics / Efficacy: Long-term use of SSRIs leads to homeostatic downregulation of 5-HT receptors, meaning that the psychological effects may be diminished when typical hallucinogens are administered.

[0014] c) Pharmacodynamics / Efficacy: Data analysis from trials evaluating the efficacy of MDMA-assisted psychotherapy after SSRI discontinuation suggests that patients who recently discontinued SSRIs may experience a decline in the efficacy of subsequent serotonin-containing therapy (Feduccia, AA, Jerome, L., Mithoefer, MC, Holland, J. Discontinuations of medications classified as reuptake inhibitors affect treatment response of MDMA assisted psychotherapy. Psychopharmacology (Berl). 2021; 238:581-588).

[0015] This invention addresses these clinical uncertainties and provides evidence of surprising synergistic effects when short-acting hallucinogens are used in combination with monoamine antidepressants, including methods, kits, or dosing regimens for treating psychiatric disorders in patients. Invention Overview

[0017] As a first aspect, the present invention provides a combination comprising:

[0018] (i) monoamine antidepressants; and

[0019] (ii) Short-acting hallucinogens.

[0020] As a second aspect, the present invention provides a method for treating a patient’s psychiatric disorder, preferably wherein the psychiatric disorder is selected from at least one of depressive disorder, anxiety disorder, obsessive-compulsive disorder and eating disorder;

[0021] The method of treatment includes administering the following to the patient:

[0022] (i) monoamine antidepressants; and

[0023] (ii) Short-acting hallucinogens.

[0024] As a third aspect, the present invention provides a kit comprising:

[0025] (i) Dosage forms of short-acting hallucinogens; and

[0026] (ii) Instructions for use of short-acting hallucinogen formulations administered to patients in combination with monoamine antidepressants.

[0027] As a fourth aspect, the present invention provides a dosing regimen comprising:

[0028] (i) administration of monoamine antidepressants; and

[0029] (ii) Administration of short-acting hallucinogens.

[0030] As a fifth aspect, the present invention provides a method for adjunctive treatment of psychiatric disorders in patients receiving monoamine antidepressant therapy, preferably wherein the psychiatric disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders; the adjunctive treatment method includes administering a short-acting hallucinogen to the patient.

[0031] As a sixth aspect, the present invention provides a short-acting hallucinogen for adjunctive treatment of psychiatric disorders in patients receiving monoamine antidepressant therapy, preferably wherein the psychiatric disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0032] As a seventh aspect, the present invention provides the use of a short-acting hallucinogen in the manufacture of a medicament for adjunctive treatment of psychiatric disorders in patients receiving monoamine antidepressant therapy, preferably wherein the psychiatric disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0033] As an eighth aspect, the present invention provides a parenteral preparation comprising a dose of a short-acting hallucinogen for treating a psychiatric disorder in a patient receiving monoamine antidepressant treatment; wherein the treatment comprises administering, preferably parenterally, the dose of the short-acting hallucinogen to the patient; preferably wherein the psychiatric disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, and more preferably from depressive disorders and anxiety disorders.

[0034] As a ninth aspect, the present invention provides a delivery device for treating psychiatric disorders in patients receiving monoamine antidepressant treatment, wherein the delivery device is configured to deliver to the patient a parenteral dose of a short-acting hallucinogen, preferably parenteral administration.

[0035] To avoid ambiguity, embodiments relating to various aspects of the invention are adapted to other aspects of the invention with necessary modifications. Further aspects and embodiments of the invention will become apparent from the discussion herein.

[0036] In the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth aspects of the present invention, the short-acting hallucinogen is preferably selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, cyprotinin, deuterated cyprotinin, cyprosiben, deuterated cyprosiben, cyprotinin-4-pentanediol ester, deuterated cyprotinin-4-pentanediol ester, iprocin-4-pentanediol ester, deuterated iprocin-4-pentanediol ester, mixtures thereof and pharmaceutically acceptable salts thereof.

[0037] In the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth aspects of the present invention, the monoamine antidepressant is preferably a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

[0038] definition

[0039] In this specification, one or more aspects of the invention may be combined with one or more features described herein to define different embodiments of the invention.

[0040] In the detailed description of the invention, many terms are mentioned, which should be understood to have the meanings provided below, unless the context clearly indicates the opposite meaning.

[0041] The nomenclature used herein for the short-acting hallucinogens used in this invention is that commonly used in the art. The compounds described herein may also be named according to the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC) rules for chemical compounds, specifically “IUPAC Compendium of Chemical Terminology (Gold Book)” (see AD Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). For the avoidance of doubt, if the IUPAC rules conflict with the definitions provided herein, the definitions herein shall prevail.

[0042] N,N-Dimethyltryptamine (DMT), also known as IUPAC name 2-(1H-indol-3-yl)-N,N-dimethylethylamine, CAS registry number 61-50-7.

[0043] 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), also known by the IUPAC name 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, CAS Registry No. 1019-45-0.

[0044] Xelosine is also known by the IUPAC name 3-[2-(dimethylamino)ethyl]-1H-indole-4-yl dihydrophosphate, CAS registry number 520-52-5.

[0045] Xyloxane is also known by the IUPAC name 3-[2-(dimethylamino)ethyl]-1H-indole-4-ol, CAS registry number 520-53-6.

[0046] N,N-Diisopropyltryptamine (DIPT), also known by the IUPAC name N-[2-(1H-indol-3-yl)ethyl]-N-propyl-2-propyl-2-amine.

[0047] Iprocin is also known as 4-hydroxy-N,N-diisopropyltryptamine or IUPAC name 3-[2-(diisopropylamino)ethyl]-1H-indole-4-ol, CAS registry number 132328-45-1.

[0048] The "compound of formula I" described herein refers to a compound of the formula shown below or a pharmaceutically acceptable salt thereof:

[0049]

[0050] in:

[0051] Ra is selected from H and D; or

[0052] Ra is selected from -OH, -OPO3H2 and -OC(O)C1-C3 alkyleneCO2H;

[0053] Rb is selected from H, D, -OCH3, and -OCD3;

[0054] R 2 and R 3 Each is independently selected from C(H) z )3; or

[0055] R 2 and R 3 Each is independently selected from C2(H) z )5 and C3(H z )7; and

[0056] H x H y and H z Each is independently selected from protium and deuterium.

[0057] As used herein, the terms “deuterated N,N-dimethyltryptamine,” “deuterated 5-methoxy-N,N-dimethyltryptamine,” “deuterated cyclophosphine,” “deuterated cyclophosphine,” “deuterated N,N-diisopropyltryptamine,” deuterated cyclophosphine-4-glutarate, and deuterated iprocin-4-glutarate, collectively referred to as “deuterated analogues” of short-acting hallucinogens, refer to the substitution of one or more hydrogen atoms in the structure of a short-acting hallucinogen by a deuterium atom, wherein the deuterium atom is a hydrogen atom with an additional neutron. The deuterium substitution can occur at one or more of the α and β positions, in the following formula R 2 and R 3 This can be on an alkyl group (such as a methyl group), on an indole ring, and / or on a methoxy group of 5-methoxy-N,N-dimethyltryptamine. In some embodiments, deuteration can be performed...

[0058] -α position.

[0059] -α and β positions,

[0060] - In the following formula, R 2 and R 3 The alkyl group (e.g., methyl group) is represented.

[0061] - In the following formula, R 2 and R 3 The alkyl group (e.g., methyl group) and α-position are represented.

[0062] - In the following formula, R 2 and R 3 The alkyl group (e.g., methyl group) and the α and β positions are represented.

[0063] When the compounds described herein are indicated as or described as deuterated or deuterated analogues, the compounds are enriched with deuterium, the amount of which depends on the percentage of deuterium available in the reagent from which the compound is derived. For example, the d6-dimethylamino moiety of compounds of formula I (wherein -NR) 2 R 3-N(CD3)2) can be derived from dimethyl-d7-amine or dimethyl-d6-amine (usually obtained as HCl salts), and these reagents can be obtained from chemical suppliers with a deuterium purity ranging from 98% to 99%. The purity of deuterium in the resulting d6-dimethylamino-substituted compounds is therefore between 98% and 99%. This means that, as those skilled in the art will understand, not all compounds of formula I (used as examples) will include d6-dimethylamino substitution; some may include d0-d5-dimethylamino, but the average purity of deuterium is about 98% to 99%. It should be understood that the term deuterated analogues includes isotopic mixtures of these compounds, such as isotopic mixtures of d0, d1, and d2-deuterated N,N-dimethyltryptamine or deuterated 5-methoxy-N,N-dimethyltryptamine. The mixture of isotopes is described in published patent applications WO2022 / 117359 and WO2020 / 245133, the disclosures of which are incorporated herein by reference in their entirety.

[0064] In some implementations, the short-acting hallucinogen is substituted with a methoxy group at the 5-position. The term "methoxy" (usually abbreviated as OMe) is defined as a monovalent group obtained by removing a hydrogen atom from the OH moiety of methanol.

[0065] In some embodiments, the short-acting hallucinogen is substituted at the 4-position with -OH, -OPO3H2, or -OC(O)C1-C3 alkylene CO2H, preferably with -OPO3H2 or glutarate (-OC(O)C3 alkylene CO2H). The term "C1-C3 alkylene" refers to a straight-chain saturated divalent hydrocarbon group having one, two, or three carbon atoms, i.e., methylene, ethylene, or propylene.

[0066] To avoid ambiguity, the 5th position of a short-acting hallucinogen refers to the position marked in the following structure (substitution not shown), where R 2 and R 3 All are methyl or as defined in any of the following implementation schemes.

[0067]

[0068] In this document, references to the dosage or total dose of a short-acting hallucinogen refer to the dosage or total dose of the agent as a free base equivalent. For example, when a salt of a short-acting hallucinogen (such as fumarate) is used, the dosage or total dose is specified as an equivalent dose of free base.

[0069] In this document, the term "antidepressant" refers to a medicine approved for the pharmacological treatment of depressive disorders in at least one jurisdiction, such as the United States of America, the European Union, the United Kingdom, Australia, New Zealand, and Japan. The term "monoamine antidepressant" refers to a non-hallucinogenic agent characterized by resolving imbalances in one or more neurotransmitters selected from serotonin, norepinephrine, and dopamine.

[0070] As an addendum, the monoamine antidepressant is preferably not a monoamine oxidase-inhibitor (MAOI). At certain dose levels, MAOIs can interfere with and prolong the duration of short-acting hallucinogens. Preferred monoamine antidepressants for use in this invention are serotonin reuptake inhibitors, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

[0071] Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of monoamine antidepressants that inhibit the reuptake of serotonin and norepinephrine and are used to treat a variety of disorders, including depressive disorders, anxiety disorders, and obsessive-compulsive disorder (OCD). SNRIs approved by the U.S. Food and Drug Administration (FDA) include divenlafaxine, duloxetine, levomirnazepine, mirnazepine, and venlafaxine.

[0072] Selective serotonin reuptake inhibitors (SSRIs) are a class of monoamine antidepressants that selectively inhibit the reuptake of serotonin and are used to treat a variety of disorders, including depressive disorders, anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). In the UK, SSRIs are recommended as first-line treatment for depressive disorders. Fluoxetine is approved by the US FDA and the European EMA for the treatment of bulimia nervosa. Approved SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine.

[0073] As used herein, the term "in combination with" refers to the administration of a short-acting hallucinogen to a patient receiving monoamine antidepressant therapy. This may also be referred to as "adjunctive therapy," "additional therapy," or "combination therapy." Typically, a short-acting hallucinogen is administered to a patient who has received an adequate course of treatment with one or more antidepressants and continues to receive monoamine antidepressant therapy; that is, the patient receives continuous treatment with a monoamine antidepressant before and during treatment with the short-acting hallucinogen. An adequate course of treatment with the monoamine antidepressant will vary depending on the specific antidepressant, but will generally be a course of treatment for a period of 4 weeks or longer, preferably 6 weeks or longer. For example, a patient may receive a once-daily (or twice- or more-than-daily) dose of the monoamine antidepressant for a period of 4 weeks or longer, preferably 6 weeks or longer. Typically, after an adequate course of treatment with the monoamine antidepressant, the patient does not experience clinically meaningful symptom improvement. As used herein, the term "in combination with" does not require the simultaneous administration of a monoamine antidepressant and a short-acting hallucinogen. To avoid ambiguity, monoamine antidepressants and short-acting hallucinogens may be administered and / or prescribed by different healthcare practitioners, such as different physicians. Typically, monoamine antidepressants and short-acting hallucinogens are administered separately, and may be administered sequentially. Optionally, monoamine antidepressants and short-acting hallucinogens may be administered concurrently. Typically, during the course of treatment, monoamine antidepressants are administered daily, while short-acting hallucinogens are administered in a single dose.

[0074] As used in this article, the term "synergistic" or "synergistic" refers to an effect greater than the sum of its parts.

[0075] As used herein, the terms "parenteral administration" or "extragastric administration" mean the administration of a dose of a short-acting hallucinogen once or multiple times over a period of time by any route other than oral administration. The parenteral administration is preferably substantially continuous over a period of up to about 15 minutes, such as about 5 to about 15 minutes, or about 5 to about 15 minutes, or about 8 to about 12 minutes, or about 9 to about 11 minutes, or about 6 to about 14 minutes, or about 7 to about 13 minutes, or about 8 to about 11 minutes, or about 9 minutes, or about 10 minutes, or about 11 minutes. In other embodiments, the parenteral administration may comprise an initial bolus administration of a short-acting hallucinogen, followed by substantially continuous administration over a period of about 5 to about 15 minutes, the bolus administration being a single dose of the agent administered at a rapid rate (typically within about 30 to about 60 seconds), the single dose providing a rapidly onset breakthrough hallucinogenic experience. In other embodiments, the parenteral administration may include bolus administration of the hallucinogen, which is the administration of a single dose of the agent at a rapid rate (typically within about 30 to about 60 seconds). In some embodiments, the administration includes bolus administration, such as intramuscular, intranasal, or intravenous bolus administration.

[0076] As used in this article, the term "effective dose" refers to a dose sufficient to induce a hallucinatory experience, i.e., during which the patient experiences one or more intense reactions or emotions, altered perceptual states, visual or other sensory hallucinations, psychic experiences, self-dissolution, and dissociation. Self-dissolution describes the state of the erosion of the boundary between the individual and the external world. Dissociation describes the state in which the individual experiences a feeling of disconnection between different parts of the brain, such as a break in the connection between mind and body.

[0077] As used herein, the term "therapeuticly effective dose" refers to the dose at which a monoamine antidepressant and a short-acting hallucinogen provide therapeutic efficacy in combination. The dose of any single agent may not be sufficient to provide therapeutic efficacy on its own.

[0078] As used in this article, "month" is defined as a calendar month.

[0079] As used herein, “only one application in any three-month period” means an interval of at least 90 days between two applications. Similarly, as used herein, “only one application in any six-month period” means an interval of at least 180 days between two applications, and so on.

[0080] "Administer at most once every three months" means that at least three months, or 90 days, must pass between two applications. Similarly, "Administer at most once every six months" means that at least six months, or 180 days, must pass between two applications, and so on.

[0081] In this text, references to the singular form of a noun include the plural form, and vice versa, unless the context otherwise suggests otherwise.

[0082] In this specification, the word "comprise," or variations such as "comprises" or "comprising," will be understood to imply inclusion of the stated element, integer, or step, or a group of elements, integers, or steps, but does not exclude any other element, integer, or step, or a group of elements, integers, or steps. The term "comprising" includes the terms "consisting of" or "substantially consisting of" within its scope.

[0083] The term “consisting of” or variations thereof is to be understood as implying inclusion of the said element, integer or step, or group of elements, integers or steps, and excluding any other element, integer or step or group of elements, integers or steps.

[0084] The term “consistently composed of” or variations thereof is to be understood to imply the inclusion of the stated elements, integers or steps, or groups of elements, integers or steps, and additional components may be present, but only those that do not substantially affect the essential characteristics of embodiments of the invention.

[0085] When quantifying numbers or values, the term "about" is used herein to refer to values ​​within ±5% of a specified value. For the avoidance of ambiguity, if the term "about" is not used when specifying a number or value herein, the number or value should be understood according to standard rounding conventions based on the number of decimal places. For example, an integer such as 6 is understood to contain values ​​≥5.5 and <6.5. Similarly, a number specified with one decimal place, such as 5.3, is understood to contain values ​​≥5.25 and <5.35.

[0086] When a range of values ​​is provided, the range includes endpoint values. For example, a range of 20 to 28 or from 20 to 28 would include values ​​20, 21, 22, 23, 24, 25, 26, 27, and 28; a range of 5 to 15 or from 5 to 15 would include values ​​5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15.

[0087] As used herein, the term "patient" preferably refers to a mammal. Generally, the mammal is human, but also refers to domesticated mammals. This term does not include laboratory animals.

[0088] As used herein, the terms "in conjunction with psychotherapy" or "psychotherapy-assisted psychotherapy" refer to the treatment of psychiatric disorders by psychological means, enhanced by the combination, method of treatment, or kit of the present invention. Psychotherapy practices are provided with a dose (including, for example, any dose defined herein) of a short-acting hallucinogen.

[0089] The term "treatment" defines therapeutic care for a patient in order to slow or halt the rate of progression of the disorder, or to improve or cure the disorder. It also includes preventative treatment for patients diagnosed with a psychiatric disorder. This preventative treatment, also referring to secondary prevention, aims to reduce the impact of the disorder and / or hinder its development through treatment according to the invention.

[0090] As used herein, the term “improvement” refers to a clinically significant reduction in symptom severity over a period of time compared to a baseline assessment prior to administration of the short-acting hallucinogen or, as assessed by patient-reported outcomes. Improvement can be assessed by patient-reported outcomes or clinician-reported outcomes such as structured patient interviews or questionnaires. The term “clinician” refers to a qualified and / or registered physician or healthcare professional, including therapists, psychiatrists, and psychologists.

[0091] Patient-reported outcomes or clinician-reported outcomes may include assessments using rating scales, including, but not limited to, the Clinical Global Impression Scale (CGI), an observer rating scale consisting of one or more of three different measures—Disease Severity (CGI-S), Overall Improvement (CGI-I), and Efficacy Index (CGI-E); the Montgomery-Esenberg Depression Rating Scale (MADRS), a 10-item diagnostic questionnaire; the 17-item Hamilton Depression Rating Scale (HAMD17); the Beck Depression Questionnaire-II; and the Ruminant Thought Scale (RRS-22). Self-reported measures consisting of 22 items and three factors (depression, rumination, and reflection); the Beck Anxiety Inventory (BAI); the Hamilton Anxiety Scale (HAM-A); the State-Trait Anxiety Inventory (STAI or STAI-T); the Generalized Anxiety Disorder Assessment (GAD-7); the Clinical Post-Traumatic Stress Disorder Scale (CAPS); the Yale-Brown Compulsive Scale; and suicidal ideation rating scales, such as the Beck Suicide Ideation Scale (BSS), the Columbia Suicide Severity Rating Scale (C-SSRS), and the suicidal thoughtsite of the MADRS for suicidal ideation or the Clinical Global Impression of Suicidal Ideation-Revised (CGI-SS-R) scale. Patient-reported results may also include the Beck Depression Inventory-II (BDI-II); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Version (Q-LES-Q-SF), 16-Item Self-Administered Questionnaire; EQ-5D-5L Descriptive System and EQ VAS; Patient Global Impression Severity Scale (PGI-S); and Patient Global Impression Improvement Scale (PGI-I). Combinations of these rating scales may be used. Clinician- or patient-reported results may include weight gain (for anorexia nervosa); frequency of binge-clearing episodes (for bulimia nervosa); or frequency of binge-eating episodes (for bulimia disorder).

[0092] A clinically meaningful decrease in symptom severity will be assessed based on rating scales or other clinician or patient-reported results, including:

[0093] For the Clinical Global Impression Scale (CGI), a response score of 0, 1, 2, or 3 generally indicates improvement, with 0, 1, or 2 being preferred.

[0094] Typically, for rating scales such as the Montgomery-Esenberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAMD17), Beck Depression Questionnaire-II (BDI-II), Beck Anxiety Questionnaire (BAI), Beck Suicide Ideation Scale (BSS), Columbia Suicide Severity Rating Scale (C-SSRS), Hamilton Anxiety Scale (HAM-A), State-Trait Anxiety Inventory (STAI or STAI-T), Generalized Anxiety Disorder Assessment (GAD-7), Yale-Brown Compulsive Scale, Quality of Life Enjoyment and Satisfaction Questionnaire-Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS, and Clinical Post-Traumatic Stress Disorder Scale (CAPS); a 15% or greater decrease in score compared to baseline indicates improvement, preferably 20% or more, or 30% or more, or 50% or more.

[0095] Alternatively, a clinically meaningful decrease in symptom severity can be assessed by a decrease in scores on rating scales. For example, a decrease in scores of 6 or more on the MADRS scale; a decrease of 4 or more on the HAMD-17 scale; and a decrease of 12 or more on the Beck Depression Questionnaire-II (BDI-II) scale. Alternatively, a decrease in severity classification indicates improvement, such as from severe to moderate.

[0096] Generally, a decrease in the number of "yes" answers to questions on the Columbia Suicide Severity Rating Scale (C-SSRS) indicates improvement. Alternatively, a decrease in the intensity category indicates improvement, such as a drop from extremely severe to severe, or from severe to moderately severe.

[0097] Generally, for the Patient Global Impression Severity Scale (PGI-S), a decrease in the severity rating assessed by the patient indicates improvement, for example, a decrease in severity rating from 6 (severe illness) to 4 (moderate illness).

[0098] Generally, for the Patient Global Impression Improvement Scale (PGI-I), a rating of 3 (minimum improvement) or less indicates improvement, with a score of 2 (significant improvement) or less preferred. The PGI-I scale is not used to assess baseline, but only post-drug administration.

[0099] As used herein, the term “remission” refers to a decrease in symptoms of the psychiatric disorder to a level indicating mild symptoms or that the patient is within the healthy range, i.e., the patient is not experiencing symptoms indicating a clinical disorder. For depressive disorders, remission is generally considered to be a score of 13 or less on the MADRS, preferably 10 or less; or 7 or less on the HAMD17 rating scale; or 19 or less on the Beck Depression Questionnaire-II; or 15 or less on the Beck Anxiety Questionnaire; or 17 or less on the Hamilton Anxiety Scale; or 15 or less on the Yale-Brown Compulsive Disorder Scale; or 3 or less on the Patient General Impression Severity Scale (PGI-S). Remission is generally considered to be for patients who answer “no” to every question on the Columbia Suicide Severity Rating Scale (C-SSRS) or a score of 10 or less (moderate), preferably 6 or less.

[0100] As used herein, the term "short-acting hallucinogen" or "short-acting hallucinogenic drug" refers to a hallucinogen that induces a hallucinogenic experience lasting 4 hours or less, or 3 hours or less, or 2 hours or less, or 1 hour or less. Preferably, the short-acting hallucinogen induces a hallucinogenic experience lasting 1 hour or less. Preferably, the short-acting hallucinogen is administered parenterally. Typical short-acting hallucinogens are delivered parenterally, i.e., not orally, because the agent does not have oral activity (e.g., DMT, 5-MeO-DMT) or because oral administration would result in a long-lasting hallucinogenic experience. For example, oral administration of psilocybin induces a hallucinogenic experience lasting approximately 6 to 8 hours. However, hallucinogens with specific oral activity (e.g., deuterated DMT or deuterated psilocybin) can induce a shorter duration of hallucinogenic experience, such as 3 hours or less, preferably 1 hour or less. Therefore, the present invention provides a duration of hallucinogenic experience of 3 hours or less, preferably 1 hour or less, more preferably 45 minutes or less, and even more preferably 30 minutes or less, and in any preferred embodiment or embodiment of the present invention, the short-acting hallucinogen is provided in a dosage form suitable for parenteral administration, preferably by injection, inhalation, inhalation, transdermal or transmucosal administration.

[0101] As used herein, the term “psychiatric disorder” is characterized by clinically significant disturbances in an individual’s cognition, emotional regulation, or behavior, and is associated with present distress (e.g., pain symptoms) or disability (i.e., impairment in one or more vital functional areas) or with a significantly increased risk of death, pain, disability, or significant loss of freedom. The diagnostic criteria for psychiatric disorders referenced herein are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

[0102] As used in this article, the term "obsessive-compulsive disorder" (OCD) is defined as the presence of obsessive thoughts or compulsive behaviors, but often both. Symptoms can cause significant functional impairment and / or distress. Obsessive thoughts are defined as unwanted, intrusive ideas, images, or impulses that repeatedly enter a person's mind. Compulsive behaviors are repetitive actions or mental activities that a person feels compelled to perform. Typically, OCD manifests as one or more obsessive thoughts that drive the acceptance of compulsive behaviors. For example, obsessive thoughts about germs can drive compulsive behaviors related to cleaning, or obsessive thoughts about food can drive compulsive behaviors such as overeating, eating too little, or vomiting after eating (i.e., obsessive thoughts about food can manifest as an eating disorder). Compulsive behaviors can be overt and visible to others, such as checking if a door is locked, or covert mental activities that cannot be observed, such as repeating specific phrases in someone's mind. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) can be used to assess OCD.

[0103] As used herein, the term “eating disorder” is defined as a severe and persistent disturbance of eating behavior and associated distressing thoughts and feelings. The term “eating disorder” includes, but is not limited to, anorexia nervosa and bulimia nervosa, binge eating disorder, avoidance of restrictive food intake disorder, other designated feeding and eating disorders, pica, and rumination disorder.

[0104] Eating disorders often occur alongside anxiety disorders and obsessive-compulsive disorders. Neziroglu and Sandler distinguish between OCD and eating disorders: "However, patients with eating disorders are primarily driven by concerns about their appearance and thus alter their eating patterns to correspondingly lose weight. Patients with OCD may restrict their eating due to concerns that are very different from their body image." https: / / iocdf.org / expert-opinions / expert-opinion-eating-disorders-and-ocd / ).

[0105] The term "eating disorder" includes anorexia nervosa, bulimia nervosa, and binge eating disorder (BED). Symptoms of anorexia nervosa include eating too little and / or exercising too much to maintain the lowest possible weight. Symptoms of bulimia nervosa include eating large amounts of food in a very short period of time (i.e., binge eating) and then feigning illness, using laxatives, eating too little, and / or exercising too much to prevent weight gain. Symptoms of BED include regularly eating large amounts of food until uncomfortablely full and feeling unhappy or guilty as a result.

[0106] As used in this article, the term “depressive disorder” includes, but is not limited to, major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, depression in terminally ill patients, and treatment-resistant depression.

[0107] As used in this article, “major depressive disorder” (MDD, also known as major depression or clinical depression) is defined as the presence of five or more of the following symptoms for most of the day, almost every day, over a period of two weeks or longer (also referred to as a “major depressive episode” in this article):

[0108] • Depressive mood, such as feeling sad, empty, or tearful (in children and adolescents, depressive mood can manifest as persistent irritability);

[0109] • Significantly reduced interest or a lack of pleasure in all or most activities;

[0110] • Significant weight loss, weight gain, or decreased or increased appetite without dieting (in children, failure to gain weight as expected);

[0111] • Insomnia or increased urge to sleep;

[0112] • Restlessness or slowed behavior that can be observed by others;

[0113] • Fatigue or loss of energy;

[0114] • Feelings of guilt that are worthless, excessive, or inappropriate;

[0115] • Difficulty making decisions, or difficulty thinking or concentrating;

[0116] • Periodic thoughts of death or suicide, or attempted suicide.

[0117] At least one of the symptoms must be a depressed mood or loss of interest or pleasure.

[0118] Persistent depressive disorder, also known as dysthymia, is defined as a condition in which the patient exhibits the following two characteristics:

[0119] A. Having a depressive mood for most of the day, almost every day, for at least two years. Children and adolescents may have irritability for at least one year.

[0120] B. When depressed, a person experiences at least two of the following symptoms:

[0121] Overeating or lack of appetite.

[0122] • Excessive sleep or difficulty sleeping.

[0123] • Fatigue and lack of energy.

[0124] Low self-esteem.

[0125] • Difficulty concentrating or making decisions.

[0126] As used in this article, the term “treatment-resistant major depressive disorder” describes MDD that has failed to achieve an adequate response to standard treatment therapies.

[0127] As used in this article, "bipolar disorder," also known as manic-depressive disorder, is a disorder that causes abnormal shifts in mood, energy, activity levels, and the ability to perform daily tasks.

[0128] Bipolar disorder has two distinct subcategories; both involve clear alterations in mood, energy, and activity levels. These moods range from periods of extreme “elation,” euphoria, and enthusiastic behavior (called manic episodes, further defined below) to periods of deep sadness, “depression,” or hopelessness (called depressive episodes). Less severe manic periods are called hypomanic episodes.

[0129] Bipolar I disorder is defined by a manic episode lasting at least 7 days or by manic symptoms severe enough to require immediate hospitalization. Depressive episodes often occur as well, typically lasting at least 2 weeks. Mixed-feature depressive episodes (combining depressive and manic symptoms) are also possible.

[0130] Bipolar II disorder is defined by a pattern of depressive episodes and hypomanic episodes, but not the full-blown manic episodes described above.

[0131] As used in this article, “bipolar depression” is defined as an individual who is experiencing depressive symptoms and has had or is currently experiencing episodes of manic symptoms, but does not meet the clinical criteria for bipolar disorder.

[0132] Depressive disorders are typically assessed using rating scales selected from the following: Clinical Global Impression Scale (CGI); Montgomery-Esenberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD-17); Beck Depression Questionnaire-II; Beck Anxiety Questionnaire (BAI); suicide propensity rating scales such as the Beck Suicide Ideation Scale (BSS), Columbia Suicide Severity Rating Scale (C-SSRS), the suicidal ideation item in the MADRS, the Clinical Global Impression-Revised (CGI-SS-R) scale for the severity of suicide propensity, or the Columbia Suicide Severity Rating Scale (C-SSRS); and combinations of these scales. Depressive disorders may also be assessed using patient-reported outcomes selected from the following: Beck Depression Questionnaire-II; Quality of Life Enjoyment and Satisfaction Questionnaire-Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS; Patient Global Impression Severity Scale (PGI-S); and combinations of these outcome assessments.

[0133] Depressive disorders are preferably assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), the Beck Depression Questionnaire-II, the Beck Suicide Ideology Scale (BSS), the Montgomery-Esenberg Depression Rating Scale (MADRS), and / or the 17-item Hamilton Depression Rating Scale (HAMD-17).

[0134] As used herein, the term “anxiety disorder” includes, but is not limited to, generalized anxiety disorder, phobias, panic disorder, social anxiety disorder, and post-traumatic stress disorder. Anxiety disorders are typically assessed using rating scales selected from the following: the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the State-Trait Anxiety Inventory (STAI or STAI-T), the Generalized Anxiety Disorder Assessment (GAD-7), and combinations of these scales. Anxiety disorders may also be assessed using patient-reported outcomes, as described above.

[0135] As used in this article, "generalized anxiety disorder" (GAD) refers to a chronic disorder characterized by persistent anxiety that is not focused on any single object or situation. Those with GAD experience nonspecific, persistent fears and worries and become excessively preoccupied with everyday matters. GAD is characterized by chronic excessive worry, accompanied by three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbances.

[0136] Phobias are defined as a persistent fear of an object or situation in which the affected person will try every possible means to avoid it, often disproportionate to the actual danger. If the feared object or situation cannot be completely avoided, the affected person will suffer from it with significant distress and it will significantly interfere with their social or professional activities.

[0137] Patients suffering from "panic disorder" are defined as those who experience one or more brief episodes of intense fear and anxiety (also known as panic attacks), often characterized by trembling, shaking, confusion, dizziness, nausea, and / or difficulty breathing. A panic attack is defined as a sudden onset of fear or discomfort that peaks within ten minutes.

[0138] Social anxiety disorder is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests as specific physical symptoms, including blushing, sweating, and difficulty speaking.

[0139] Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by traumatic experiences. PTSD can be triggered by extreme situations such as combat, natural disasters, rape, hostage situations, child abuse, bullying, or even serious accidents. Common symptoms include hypervigilance, flashbacks, avoidance behavior, anxiety, anger, and depression.

[0140] The Clinical Post-Traumatic Stress Disorder Scale (CAPS) can be used to assess PTSD symptoms.

[0141] As used in this article, the term "postpartum depression" (PPD, also known as postnatal depression) is a form of depression experienced by one of the parents of a newborn. Symptoms typically develop within four weeks of the baby's birth and often include extreme sadness, fatigue, anxiety, loss of interest in or pleasure from hobbies and activities, irritability, and changes in sleep or eating patterns. Invention Details

[0143] The combinations, methods of treatment, kits, administration regimens, delivery devices, parenteral formulations, or adjunctive treatments of the present invention are based on the surprising finding that administering a single effective dose of a short-acting hallucinogen (such as N,N-dimethyltryptamine) to a patient receiving monoamine antidepressant treatment provides greater symptom improvement compared to administering the short-acting hallucinogen in the absence of monoamine antidepressant treatment (such as SSRI treatment). This greater symptom improvement can provide a variety of advantages. These advantages may include increased response rates to the monoamine antidepressant after administration of the short-acting hallucinogen, increased remission rates, dose reduction of one or both agents, and reduced or more effective discontinuation of monoamine antidepressants.

[0144] Therefore, a first aspect of the present invention is provided, as embodiment 1, a combination comprising:

[0145] (i) monoamine antidepressants; and

[0146] (ii) Short-acting hallucinogens.

[0147] A second aspect of the invention is provided, as embodiment 2,

[0148] A method for treating a patient with a psychiatric disorder, preferably wherein the psychiatric disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, the method of treatment comprising administering to the patient:

[0149] (i) monoamine antidepressants; and

[0150] (ii) Short-acting hallucinogens.

[0151] A third aspect of the present invention is provided, as embodiment 3, a reagent kit comprising:

[0152] (i) Dosage forms of short-acting hallucinogens; and

[0153] (ii) Instructions for use of dosage forms of short-acting hallucinogens administered to patients in combination with monoamine antidepressants.

[0154] A fourth aspect of the present invention is provided, as embodiment 4, a dosing regimen comprising:

[0155] (i) administration of monoamine antidepressants; and

[0156] (ii) Administration of short-acting hallucinogens.

[0157] A fifth aspect of the invention provides, as embodiment 5, a method for adjunctive treatment of a psychiatric disorder in a patient receiving monoamine antidepressant treatment, preferably wherein the psychiatric disorder is selected from at least one of depressive disorder, anxiety disorder, obsessive-compulsive disorder, and eating disorder; the adjunctive treatment method includes administering a short-acting hallucinogen to the patient.

[0158] A sixth aspect of the invention provides, as embodiment 6, a short-acting hallucinogen for adjunctive treatment of psychiatric disorders in patients receiving monoamine antidepressant therapy, preferably wherein the psychiatric disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0159] The present invention further provides, as embodiment 7, a combination of embodiments 1, wherein the combination is synergistic; or a method, kit, administration regimen, adjunctive therapy method, or short-acting hallucinogen for treatment according to any one of embodiments 2 to 6, wherein the administration of...

[0160] (i) monoamine antidepressants; and

[0161] (ii) Short-acting hallucinogens

[0162] Provide synergy.

[0163] The present invention further provides, as embodiment 8, a combination of any of the foregoing embodiments, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purposes described herein, wherein the monoamine antidepressant is selected from selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

[0164] The present invention further provides, as embodiment 9, a combination of any of the foregoing embodiments, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the short-acting hallucinogen is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, serotonin, deuterated serotonin, seroceline, and deuterated seroceline. The short-acting hallucinogen is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine and deuterated 5-methoxy-N,N-dimethyltryptamine, mixtures thereof and pharmaceutically acceptable salts thereof, preferably N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine and deuterated 5-methoxy-N,N-dimethyltryptamine, mixtures thereof and pharmaceutically acceptable salts thereof.

[0165] The present invention further provides, as embodiment 10, a combination of any of the foregoing embodiments, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the monoamine antidepressant is selected from at least one of the following: divenlafaxine, duloxetine, levamisole, mirtazapine, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and pharmaceutically acceptable salts thereof.

[0166] The present invention further provides, as embodiment 11, a combination of any one of embodiments 1 to 10, comprising:

[0167] (i) Adequate treatment duration with monoamine antidepressants; and

[0168] (ii) A single dose of a short-acting hallucinogen; or

[0169] The treatment method, kit, administration regimen, adjunctive treatment method, or short-acting hallucinogen for the stated purpose according to any of the foregoing embodiments includes:

[0170] (i) Administer a sufficient course of monoamine antidepressants; and

[0171] (ii) Administering a single dose of a short-acting hallucinogen.

[0172] The present invention further provides, as embodiment 12, a combination of embodiments 11, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purposes described herein, wherein the sufficient course of treatment includes a treatment period of 4 weeks or longer.

[0173] The present invention further provides, as embodiment 13, a combination of embodiments 11 and 12, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said purpose, wherein the administration of a single dose of the short-acting hallucinogen is performed only once in any three-month period, or wherein the single dose of the short-acting hallucinogen is administered only once in any three-month period. As another embodiment, the present invention provides, a combination of embodiments 11 and 12, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said purpose, wherein the administration of a single dose of the short-acting hallucinogen is performed at most once every three months, or wherein the single dose of the short-acting hallucinogen is administered at most once every three months.

[0174] The present invention further provides, as embodiment 14, a method, kit, administration regimen, method of adjunctive therapy, or short-acting hallucinogen for the purpose of treatment according to any one of embodiments 11 and 12, wherein the administration of a single dose of the short-acting hallucinogen is performed only once in any six-month period, or wherein the single dose of the short-acting hallucinogen is administered only once in any six-month period; or a combination of any one of embodiments 11 and 12, wherein the single dose of the short-acting hallucinogen is administered only once in any six-month period. As another embodiment, the present invention provides a method, kit, administration regimen, method of adjunctive therapy, or short-acting hallucinogen for the purpose of treatment according to any combination of embodiments 11 and 12, wherein the administration of a single dose of the short-acting hallucinogen is performed at most once every six months, or wherein the single dose of the short-acting hallucinogen is administered at most once every six months.

[0175] The present invention further provides, as embodiment 15, a method, kit, administration regimen, adjunctive therapy method, or short-acting hallucinogen for treatment according to any one of embodiments 11 and 12, wherein the administration of a single dose of the short-acting hallucinogen is performed only once in any nine-month period, or wherein the single dose of the short-acting hallucinogen is administered only once in any nine-month period; or a combination of any one of embodiments 11 and 12, wherein the single dose of the short-acting hallucinogen is administered only once in any nine-month period. As another embodiment, the present invention provides a method, kit, administration regimen, adjunctive therapy method, or short-acting hallucinogen for treatment according to any combination of embodiments 11 and 12, wherein the administration of a single dose of the short-acting hallucinogen is performed at most once every nine months, or wherein the single dose of the short-acting hallucinogen is administered at most once every nine months.

[0176] The present invention further provides, as embodiment 16, a combination of embodiments 11 and 12, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said purpose, wherein the administration of a single dose of the short-acting hallucinogen is performed only once in any twelve-month period, or wherein the single dose of the short-acting hallucinogen is administered only once in any twelve-month period; or a combination of embodiments 11 and 12, wherein the single dose of the short-acting hallucinogen is administered only once in any twelve-month period. As another embodiment, the present invention provides, a combination of embodiments 11 and 12, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said purpose, wherein the administration of a single dose of the short-acting hallucinogen is performed at most once every twelve months, or wherein the single dose of the short-acting hallucinogen is administered at most once every twelve months.

[0177] The present invention further provides, as embodiment 17, a combination of any of the foregoing embodiments, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, comprising,

[0178] (i) the oral dosage form of the monoamine antidepressant; and

[0179] (ii) The parenteral formulation of the short-acting hallucinogen.

[0180] The present invention further provides, as embodiment 18, a combination of any of the foregoing embodiments, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purpose thereof, for the treatment of psychiatric disorders, preferably, wherein the psychiatric disorders are selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, and more preferably from depressive disorders and anxiety disorders.

[0181] The present invention further provides, as embodiment 19, a combination of any of the foregoing embodiments, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purpose thereof, for the treatment of depressive disorders selected from the following: major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, depression in terminally ill patients, and treatment-resistant depression.

[0182] The present invention further provides, as embodiment 20, a combination of any of the foregoing embodiments, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purpose thereof, for the treatment of anxiety disorders selected from the following: generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

[0183] The present invention further provides, as embodiment 21, a combination, method of treatment, kit, administration regimen, method of adjunctive treatment, or short-acting hallucinogen for the stated purpose according to any one of embodiments 18 to 20, further comprising the following steps and / or instructions for use:

[0184] Prior to administration of short-acting hallucinogens, a baseline assessment of the patient should be performed using rating scales and / or clinician-reported and / or patient-reported outcomes; and

[0185] Post-administration assessment of patients following administration of short-acting hallucinogens.

[0186] The present invention further provides, as embodiment 22, a combination, method of treatment, kit, administration regimen, method of adjunctive treatment, or short-acting hallucinogen for the stated purpose according to embodiment 21, wherein the baseline assessment is performed by a rating scale selected from the following: Clinical Global Impression Scale (CGI); Montgomery-Esenberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD17); Beck Depression Questionnaire-II; Beck Anxiety Questionnaire (BAI); Hamilton Anxiety Scale (HAM-A); State-Trait Anxiety Questionnaire (ST). AI or STAI-T); Generalized Anxiety Disorder Assessment (GAD-7); Clinical Post-Traumatic Stress Disorder Scale (CAPS); Yale-Brown Compulsive Scale; Beck Suicidal Ideation Scale (BSS); Columbia Suicide Severity Rating Scale (C-SSRS); Suicidal Ideation Item in MADRS; Clinical Global Impression of Suicidal Tendency Severity - Revised Version (CGI-SS-R) Scale; Beck Depression Questionnaire-II (BDI-II); Quality of Life Enjoyment and Satisfaction Questionnaire - Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS; Patient Global Impression Severity Scale (PGI-S); and combinations thereof.

[0187] The present invention further provides, as embodiment 23, a combination, method of treatment, kit, administration regimen, method of adjunctive treatment, or short-acting hallucinogen for the stated purpose according to embodiment 21 or 22, wherein the post-administration assessment is performed by a rating scale selected from the following: Clinical Global Impression Scale (CGI); Montgomery-Esenberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD17); Beck Depression Questionnaire-II; Beck Anxiety Questionnaire (BAI); Hamilton Anxiety Scale (HAM-A); State-Trait Anxiety Questionnaire (STI-A). STAI or STAI-T); Generalized Anxiety Disorder Assessment (GAD-7); Clinical Post-Traumatic Stress Disorder Scale (CAPS); Yale-Brown Obsessive-Compulsive Scale; Beck Suicidal Ideation Scale (BSS); Columbia Suicide Severity Rating Scale (C-SSRS); Suicidal Ideation Item in MADRS; Clinical Global Impression of Suicidal Tendency Severity - Revised Version (CGI-SS-R); Beck Depression Questionnaire (BDI-II); Quality of Life Enjoyment and Satisfaction Questionnaire - Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS; Patient Global Impression Severity Scale (PGI-S); Clinical Global Impression Improvement Scale (CGI-I); Patient Global Impression Improvement Scale (PGI-I); and combinations thereof.

[0188] The present invention further provides, as embodiment 24, a combination of embodiments 21 to 23 for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the psychiatric disorder is a depressive disorder, and wherein the baseline assessment and post-dosing assessment are performed using a depression rating scale selected from the following: Montgomery-Esenberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAMD17), Baker Depression Questionnaire-II, and combinations thereof.

[0189] The present invention further provides, as embodiment 25, a combination of embodiments 18 to 24 for the purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purpose, which provides relief from the psychotic disorder to the patient.

[0190] The present invention further provides, as embodiment 26, a combination of embodiments 25 for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein relief is assessed at a time point of 6 to 10 days, preferably 6 to 8 days, after administration of the short-acting hallucinogen.

[0191] The present invention further provides, as embodiment 27, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose according to any of the foregoing embodiments, wherein the administration or instructions for use of the short-acting hallucinogen include:

[0192] During a dosing period of up to about 15 minutes, preferably about 5 to about 15 minutes, a certain dose of the short-acting hallucinogen is administered parenterally to the patient, and

[0193] The parenteral administration described therein is essentially continuous.

[0194] The present invention further provides, as embodiment 28, a combination of embodiments 11 to 27 for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the administration of the short-acting hallucinogen is parenteral administration, the parenteral administration being selected from the group consisting of intravenous, intramuscular, intranasal, transmucosal, and transdermal administration and inhalation, preferably selected from intravenous and intramuscular administration.

[0195] The present invention further provides, as embodiment 29, a combination for the purpose of said use, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said use according to embodiment 28, wherein said parenteral administration is by intravenous infusion, preferably wherein said intravenous administration is performed using an infusion pump.

[0196] The present invention further provides, as embodiment 30, a combination for the purpose of said use, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said use according to embodiment 29, wherein the parenteral administration is by biphasic intravenous infusion.

[0197] The present invention further provides, as embodiment 31, a combination for the purpose of said use, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said use according to embodiment 29, wherein said parenteral administration is by monophasic intravenous infusion.

[0198] The present invention further provides, as embodiment 32, a combination for the purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purpose according to any one of embodiments 28 to 31, wherein the dosing period is about 8 to about 12 minutes.

[0199] The present invention further provides, as embodiment 33, a combination for said use, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said use according to embodiment 30, wherein said dosing period is about 9 to about 11 minutes or about 10 minutes.

[0200] The present invention further provides, as embodiment 34, a combination of any of the foregoing embodiments or a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the dose of the short-acting hallucinogen is selected from the group consisting of:

[0201] - Approximately 20 to approximately 80 mg of N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof;

[0202] - Approximately 20 to approximately 80 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof;

[0203] - Approximately 15 to approximately 30 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof;

[0204] - Approximately 10 to approximately 30 mg of 5-methoxy-N,N-dimethyltryptamine, a deuterated analogue, or a pharmaceutically acceptable salt thereof; and

[0205] - Approximately 10 to approximately 30 mg of deuterated 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof;

[0206] Alternatively, the dosage of the short-acting hallucinogen may be selected from the group consisting of:

[0207] - Approximately 10 to approximately 30 mg of serocepin or a pharmaceutically acceptable salt thereof;

[0208] - Approximately 10 to approximately 20 mg of deuterated thelosibine or a pharmaceutically acceptable salt thereof;

[0209] - Approximately 1 to approximately 20 mg of cyclophosphamide or a pharmaceutically acceptable salt thereof;

[0210] - Approximately 1 to approximately 20 mg of deuterated cyproheptadine or a pharmaceutically acceptable salt thereof; and

[0211] - Approximately 20 to approximately 50 mg of cyclophosphamide-4-glutarate, deuterated cyclophosphamide-4-glutarate, iprocin-4-glutarate, deuterated iprocin-4-glutarate, or a pharmaceutically acceptable salt thereof.

[0212] To avoid ambiguity, when using the salt of the aforementioned short-acting hallucinogen, the specified dose is the dose of free base equivalent.

[0213] The present invention further provides, as embodiment 35, a combination of embodiments 11 to 34 for the stated purpose, or a method of treatment, kit, administration regimen, adjunctive treatment method, or short-acting hallucinogen for the stated purpose according to any of the foregoing embodiments, comprising parenteral administration of about 20 to about 29 mg of N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or a mixture thereof.

[0214] The present invention further provides, as embodiment 36, a combination of embodiments 11 to 35 for the stated purpose, or a method of treatment, kit, administration regimen, adjunctive treatment method, or short-acting hallucinogen for the stated purpose according to any of the foregoing embodiments, comprising parenteral administration of N,N-dimethyltryptamine, its deuterated analogue, its pharmaceutically acceptable salt, or mixtures thereof in a total dose of about 20 to about 23 mg or a total dose of about 26 to about 29 mg.

[0215] The present invention further provides, as embodiment 37, a combination of embodiments 11 to 34 for the stated purpose, or a method of treatment, kit, administration regimen, adjunctive treatment method, or short-acting hallucinogen for the stated purpose according to embodiments 2 to 34, wherein the short-acting hallucinogen is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or a mixture thereof, and the total dose is about 7 to about 10 mg.

[0216] The present invention further provides, as embodiment 38, a combination, method of treatment, kit, administration regimen, method of adjunctive treatment, or short-acting hallucinogen for the stated purpose according to any one of embodiments 34 to 36, wherein the administration is by intravenous infusion, the short-acting hallucinogen being N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine, a mixture thereof, or a pharmaceutically acceptable salt thereof, and the total dose being about 20 to about 23 mg.

[0217] The present invention further provides, as embodiment 39, a combination, method of treatment, kit, administration regimen, method of adjunctive treatment, or short-acting hallucinogen for the stated purpose according to any one of embodiments 34 to 36, wherein the administration is by intravenous infusion, the short-acting hallucinogen being N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine, a mixture thereof, or a pharmaceutically acceptable salt thereof, and the total dose being about 26 to about 29 mg.

[0218] The present invention further provides, as embodiment 40, combinations for the stated purpose, methods for treatment, kits, administration regimens, adjunctive treatment methods, or short-acting hallucinogens for the stated purpose according to embodiments 27, 28, and 34, wherein the administration is by intramuscular administration.

[0219] The present invention further provides, as embodiment 41, a combination, method of treatment, kit, administration regimen, method of adjunctive treatment, or short-acting hallucinogen for the stated purpose according to embodiment 40, wherein the short-acting hallucinogen is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and the total dose is about 20 to about 70 mg, preferably about 50 to about 70 mg; or the short-acting hallucinogen is N,N-dimethyltryptamine or deuterated N,N-dimethyltryptamine or a mixture thereof or a pharmaceutically acceptable salt thereof, and the total dose is about 20 to about 60 mg or about 15 to about 30 mg.

[0220] The present invention further provides, as embodiment 42, a combination of any of the foregoing embodiments, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the short-acting hallucinogen is a compound of formula I or a pharmaceutically acceptable salt thereof:

[0221]

[0222] in:

[0223] Ra is selected from H and D; or

[0224] Ra is selected from -OH, -OPO3H2 and -OC(O)C1-C3 alkyleneCO2H;

[0225] Rb is selected from H, D, -OCH3, and -OCD3;

[0226] R 2 and R 3 Each is independently selected from C(H) z )3; or

[0227] R 2 and R 3 Each is independently selected from C2(H) z )5 and C3(H z )7; and

[0228] H x H y and H z Each is independently selected from protium and deuterium.

[0229] The present invention further provides, as embodiment 43, a combination of embodiments 42, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein R 2 and R 3 They are each independently selected from CH3 and CD3.

[0230] The present invention further provides, as embodiment 44, a combination of embodiments 42, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein R 2 and R 3 They are all CH3 or R 2 and R 3 Both are CD3 or R 2 It is CH3 and R 3 It's CD3.

[0231] The present invention further provides, as embodiment 45, a combination of any one of embodiments 42 to 44, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein each H x All are H or each H x All are D.

[0232] The present invention further provides, as embodiment 46, a combination of any one of embodiments 42 to 45, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein each H y All are H or each H y Both are D or one H y It is H and one H y It is D.

[0233] The present invention further provides, as embodiment 47, a combination of any one of embodiments 43 to 44 and 46, a combination for said purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for said purpose, wherein each H x H y and H z It is deuterium.

[0234] The present invention further provides, as embodiment 48, a combination of any of the foregoing embodiments, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the short-acting hallucinogen is selected from the group consisting of:

[0235]

[0236] Or a pharmaceutically acceptable salt thereof or a mixture thereof; wherein Ra and Rb are as defined in embodiment 42.

[0237] The present invention further provides, as embodiment 49, a combination of any one of embodiments 42 to 48, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein Ra is H.

[0238] The present invention further provides, as embodiment 50, a combination of any one of embodiments 42 to 49, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein Rb is H.

[0239] The present invention further provides, as embodiment 51, a combination of any one of embodiments 42 to 50, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, wherein the compound is selected from:

[0240] N,N-Dimethyltryptamine;

[0241] α-Protamine, α-Deuterated-N,N-Dimethyltryptamine;

[0242] α,α-Dideuterated-N,N-dimethyltryptamine;

[0243] α,α,β,β-Tetradeuterated-N,N-dimethyltryptamine;

[0244] N,N-Di(trideuterated methyl)tryptamine;

[0245] α-Protyl, α-Deuterated-N,N-Di(trideuterated methyl)tryptamine;

[0246] α,α-Dideuterated-N,N-Di(trideuterated methyl)tryptamine;

[0247] α,α,β,β-Tetradeuterated-N,N-Di(trideuterated methyl)tryptamine;

[0248] 5-Methoxy-N,N-Dimethyltryptamine;

[0249] 5-Methoxy-α-protyl,α-deuteryl-N,N-dimethyltryptamine;

[0250] 5-Methoxy-α,α-Dideuterated-N,N-Dimethyltryptamine;

[0251] 5-Methoxy-α,α,β,β-Tetradeuterated-N,N-Dimethyltryptamine;

[0252] 5-Methoxy-N,N-Di(trideuterated methyl)tryptamine;

[0253] 5-Methoxy-α-protyl,α-deuteryl-N,N-di(trideuterated methyl)tryptamine;

[0254] 5-Methoxy-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine;

[0255] 5-Methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and

[0256] Its pharmaceutically acceptable salts and mixtures thereof; or

[0257] The compound is selected from the group consisting of the following.

[0258] Selosibin;

[0259] α-Protyl, α-Deuteryl-xelospin;

[0260] α,α-dideuterium-selosibin;

[0261] α,α,β,β-tetradeuterium-selosibin;

[0262] 4-(dihydrophosphate)-N,N-bis(trideuterated methyl)tryptamine;

[0263] 4-(dihydrophosphate)-α-protyl,α-deuteryl-N,N-bis(trideuterated methyl)tryptamine;

[0264] 4-(dihydrophosphate)-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine;

[0265] 4-(dihydrophosphate)-α,α,β,β-tetradeuter-N,N-di(trideuterated methyl)tryptamine;

[0266] Celosia;

[0267] α-Protyl, α-Deuteryl-Xyloxine;

[0268] α,α-dideuterium-xellotin;

[0269] α,α,β,β-tetradeuterium-xeloxin;

[0270] 4-Hydroxy-N,N-Di(trideuterated methyl)tryptamine;

[0271] 4-Hydroxy-α-protyl,α-deuterium-N,N-di(trideuterated methyl)tryptamine;

[0272] 4-Hydroxy-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine;

[0273] 4-Hydroxy-α,α,β,β-Tetradeuterated-N,N-Di(trideuterated methyl)tryptamine;

[0274] Xyloxane-4-glutaric acid ester;

[0275] α-Protyl, α-Deuterated-xelocin-4-pentanediol ester;

[0276] α,α-Dideuterated-xellotin-4-pentanediol ester;

[0277] α,α,β,β-Tetradeuterated-xellotin-4-pentanediol ester;

[0278] 4-Hydroxy-N,N-Di(trideuterated methyl)tryptamine-4-pentanediol ester;

[0279] 4-Hydroxy-α-protyl,α-deuteryl-N,N-bis(trideuterated methyl)tryptamine-4-pentanediol ester;

[0280] 4-Hydroxy-α,α-Dideuterated-N,N-Di(trideuterated methyl)tryptamine-4-pentanediol ester;

[0281] 4-Hydroxy-α,α,β,β-Tetradeuterated-N,N-Di(trideuterated methyl)tryptamine-4-pentanediol ester;

[0282] iprocin-4-glutarate;

[0283] α-Protyl, α-deuteryl-iprocin-4-glutarate;

[0284] α,α-Dideuterated-iprocin-4-glutarate;

[0285] α,α,β,β-tetradeuterated-iprocin-4-glutaric acid ester;

[0286] 4-Hydroxy-N,N-Di(heptadeuterated isopropyl)tryptamine-4-pentanediol ester;

[0287] 4-Hydroxy-α-protyl,α-deuteryl-N,N-di(heptadeuteroisopropyl)tryptamine-4-pentanediol;

[0288] 4-Hydroxy-α,α-Dideuterated-N,N-Di(heptadeuterated isopropyl)tryptamine-4-pentanediol ester;

[0289] 4-Hydroxy-α,α,β,β-Tetradeuterated-N,N-Di(heptadeuterated isopropyl)tryptamine-4-pentanediol; and

[0290] Its pharmaceutically acceptable salts and mixtures thereof.

[0291] The present invention further provides, as embodiment 52, a combination, method of treatment, kit, administration regimen, method of adjunctive treatment, or short-acting hallucinogen for the stated purpose according to any one of embodiments 18 to 51, comprising administering the following to a patient or administering the following to a patient:

[0292] (i) Administer a selective serotonin reuptake inhibitor orally to the patient over a period of 4 weeks or longer.

[0293] (ii) administering a short-acting hallucinogen to the patient parenterally, said short-acting hallucinogen being selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, its deuterated analogues and pharmaceutically acceptable salts thereof.

[0294] Steps (i) and (ii) of implementation scheme 52 can be applied by different healthcare practitioners.

[0295] The present invention further provides, as embodiment 53, a combination of embodiments 52 for the purposes described, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the purposes described, wherein the oral administration of a selective serotonin reuptake inhibitor to the patient is over a period of 6 weeks or longer.

[0296] The present invention further provides, as embodiment 54, a combination of any of the foregoing embodiments, a combination for the stated purpose, a method for treatment, a kit, a dosing regimen, a method for adjunctive treatment, or a short-acting hallucinogen for the stated purpose, for treating a patient’s psychiatric disorder, wherein said treatment includes hallucinogenic-adjunctive psychotherapy.

[0297] The present invention further provides, as embodiment 55, a kit according to claim 54, which includes instructions for use of hallucinogenic-assisted psychotherapy.

[0298] The present invention further provides, as embodiment 56, a method for treatment, administration regimen, combination for said use, administration regimen, method for adjunctive treatment, or short-acting hallucinogen for said use according to embodiment 54, comprising:

[0299] A. Administer to the patient

[0300] (i) Monoamine antidepressants, and

[0301] (ii) A short-acting hallucinogen, preferably selected from the parenteral form of the following short-acting hallucinogens: N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, ciprotin, deuterated ciprotin, ciprocil, deuterated ciprocil, ciprotin-4-glutaric acid ester, deuterated ciprotin-4-glutaric acid ester, iprocin-4-glutaric acid ester, deuterated iprocin-4-glutaric acid ester and pharmaceutically acceptable salts thereof; and

[0302] B. Psychotherapy session.

[0303] Steps (i) and (ii) of implementation scheme 56 can be applied by different healthcare practitioners.

[0304] The present invention further provides, as embodiment 57, a method of treatment, a dosage regimen, a combination for said purpose, a method of adjunctive treatment, or a short-acting hallucinogen for said purpose according to embodiment 54 or 56, wherein said psychotherapy session includes:

[0305] a. Preparation phase, including preparing the patient for the hallucinogenic experience;

[0306] b. The administration phase, including the administration of a short-acting hallucinogen as described in any of the foregoing embodiments; and

[0307] c. The integration phase, which includes interviews or discussions with the patient led by a psychiatrist or therapist, focusing on the hallucinogenic experience.

[0308] The present invention further provides, as embodiment 58, the kit according to embodiment 55, to further include the following instructions for use:

[0309] a. Preparation phase, including preparing the patient for the hallucinogenic experience;

[0310] b. The administration phase, including the administration of a short-acting hallucinogen as described in any of the foregoing embodiments; and

[0311] c. The integration phase, which includes interviews or discussions with the patient led by a psychiatrist or therapist, focusing on the hallucinogenic experience.

[0312] The present invention further provides, as embodiment 59, a method of adjunctive treatment according to embodiment 5, wherein the short-acting hallucinogen is administered to a patient who has received a sufficient course of monoamine antidepressant.

[0313] The present invention further provides, as embodiment 60, a method of adjunctive treatment according to embodiment 5 or 59, wherein the short-acting hallucinogen and the monoamine antidepressant are administered separately.

[0314] The present invention further provides, as embodiment 61, a method for adjunctive treatment according to embodiments 5, 59, or 60, wherein...

[0315] (i) The short-acting hallucinogen is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof; and

[0316] (ii) The monoamine antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine and their pharmaceutically acceptable salts.

[0317] The present invention further provides, as embodiment 62, a short-acting hallucinogen for the stated purpose according to embodiment 6, wherein the short-acting hallucinogen is administered to a patient who has received a sufficient course of treatment with a monoamine antidepressant.

[0318] The present invention further provides, as embodiment 63, a short-acting hallucinogen for the stated purpose according to embodiment 6 or 62, wherein the short-acting hallucinogen and the monoamine antidepressant are administered to the patient separately.

[0319] The present invention further provides, as embodiment 64, a short-acting hallucinogen for the stated purpose according to embodiments 6, 62 or 63, wherein...

[0320] (i) The short-acting hallucinogen is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof; and

[0321] (ii) The monoamine antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine and their pharmaceutically acceptable salts.

[0322] The present invention further provides, as embodiment 65, a combination of the following:

[0323] (i) a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine and their pharmaceutically acceptable salts; and

[0324] (ii) Short-acting hallucinogens selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and their pharmaceutically acceptable salts;

[0325] For use simultaneously, sequentially, or separately in the treatment of a patient’s psychiatric disorder, preferably wherein the psychiatric disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0326] The present invention further provides, as embodiment 66, a combination of embodiments 65 for the purposes described, for use in the treatment of psychiatric disorders of patients, preferably wherein the psychiatric disorders are selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders and eating disorders.

[0327] The present invention further provides, as embodiment 67, a combination of embodiments 65 or 66 for the said use, wherein the short-acting hallucinogen is administered to a patient who has received a sufficient course of selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

[0328] The present invention further provides, as embodiment 68, a combination of embodiments 65 to 67 for the stated purpose, comprising an SSRI selected from the following: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine and pharmaceutically acceptable salts thereof.

[0329] The present invention further provides, as a seventh aspect, the use of a short-acting hallucinogen in the manufacture of a medicament for adjunctive treatment of psychiatric disorders in patients receiving monoamine antidepressant treatment, preferably wherein the psychiatric disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0330] This invention provides, as an eighth aspect, a parenteral preparation comprising a dose of a short-acting hallucinogen for treating psychiatric disorders in patients receiving monoamine antidepressant therapy; wherein the treatment comprises administration, preferably parenteral, of the dose of the short-acting hallucinogen to the patient; preferably wherein the psychiatric disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, and more preferably from depressive disorders and anxiety disorders. The depressive disorder may be selected from major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, depression in terminally ill patients, and treatment-resistant depression. The anxiety disorder may be selected from generalized anxiety disorder, phobias, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

[0331] The invention further provides, as a ninth aspect, a delivery device for treating psychiatric disorders in patients receiving monoamine antidepressant treatment, wherein the delivery device is configured to deliver to the patient a parenteral dose of a short-acting hallucinogen, preferably parenteral.

[0332] To avoid any doubt, all embodiments and aspects disclosed herein with respect to the first to sixth aspects are applied to the seventh to ninth aspects of the present invention with necessary modifications.

[0333] When a patient is given a combination of a monoamine antidepressant and a short-acting hallucinogen as defined in any aspect or embodiment of the invention, the combination preferably provides simultaneously detectable plasma levels of both the monoamine antidepressant and the short-acting hallucinogen.

[0334] The short-acting hallucinogens for the said combinations, combinations for the said uses, dosing regimens, methods for treatment, methods for adjunctive treatment, short-acting hallucinogens for the said uses, kits, delivery devices, or parenteral preparations for the said uses of the present invention can be prepared according to the synthetic methods described in WO2021 / 089873, US20210395201, WO2022 / 117359, and US20220202775, the disclosures of which are hereby incorporated herein by reference in their entirety.

[0335] The administration of the short-acting hallucinogen for the stated combination, the combination for the stated purpose, the administration regimen, the method of treatment, the method of adjunctive treatment, the short-acting hallucinogen for the stated purpose, the kit, the delivery device, or the parenteral preparation for the stated purpose is preferably in the form of a pharmaceutically acceptable salt, wherein the salt comprises an acid and a free base of the short-acting hallucinogen selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, xelosipin, xelosin, xelosin-4-glutarate, iprocin-4-glutarate, and their deuterated analogs. An example of a salt comprising an acid and a dimethyltryptamine compound is N,N-dimethyltryptamine fumarate, which is the fumarate of N,N-dimethyltryptamine. PHStahl and CGWermuth provide an overview of pharmaceutical salts and the acids contained therein in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. The acids described in this review are those suitable for inclusion in the salts of said preparations.

[0336] The salt may include acids selected from the group consisting of: fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, gluconic acid, 1-hydroxy-2-naphthylcarboxylic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetaminobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid... Acids, formic acid, galactoic acid, gentic acid, glucoheponic acid, glucuronic acid, glutamic acid, glutamate, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pyruvic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanate, toluenesulfonic acid, and undecenoic acid.

[0337] Preferably, the pharmaceutically acceptable salt is selected from fumarate, tartrate, citrate, succinate, benzoate, and hydrochloride. More preferably, the pharmaceutically acceptable salt is fumarate.

[0338] More preferably, the pharmaceutically acceptable salt of the short-acting hallucinogen is a fumarate.

[0339] Parenteral administration routes include intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, and percutaneous administration, as well as inhalation. Any parenteral route capable of administration over a period of up to about 15 minutes, preferably from about 5 to about 15 minutes, is suitable for use in this invention. Preferred parenteral administration routes according to any aspect of the invention are selected from intravenous infusion, intramuscular infusion, subcutaneous infusion, intranasal, transmucosal, and percutaneous administration, as well as inhalation. Intravenous infusion is a particularly preferred route of administration. Intramuscular administration is a particularly preferred route of administration.

[0340] When the parenteral administration route is intravenous, the delivery device may include an infusion bag or syringe, and may preferably further include an infusion pump. When two infusion pumps are used for intravenous infusion, the infusion pumps are connected to a single cannula via a three-way valve. When the parenteral administration route is intramuscular, the delivery device may include a syringe. When the parenteral route is intranasal, the delivery device may include a pump-driven spray. When the parenteral route is transmucosal, the delivery device may include an oral mucosal film. When the parenteral route is percutaneous, the delivery device may include a percutaneous patch. When the administration route is inhalation, the delivery device may include a metered-dose inhaler, vaporizer, or nebulizer.

[0341] Dosage forms suitable for parenteral administration have a pH of approximately 3 to 9, and for liquid formulations, an osmolarity of approximately 250 to approximately 600 mOsm / kg. I. Usach et al. reported in Adv. Ther., 36, 2986-2996 (2019) that pH values ​​above 9 were associated with tissue necrosis (intra-tissue cell death), while values ​​below 3 caused pain and phlebitis (phlebitis). Osmolar concentrations above 600 mOsm / kg have also been reported to cause pain. Usach et al. also recommended that parenteral formulations should be formulated as isotonic solutions (approximately 300 mOsm / kg osmolar concentration) and proposed an upper limit of 600 mOsm / kg to minimize pain.

[0342] The gravimetric osmolarity is formally defined as the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water, as expressed by the following formula:

[0343]

[0344] Where p is the partial vapor pressure of water in the solution and p * It is the partial vapor pressure of pure water. In simpler terms, gravimetric osmolarity is the number of active particles (the number of solute particles) that permeate 1 kg of solution. Therefore, gravimetric osmolarity is only a function of the number of particles and is independent of the molecular weight, size, shape, or charge of the particles (see DKFaria et al., MEMendes and NMSumita, J. Bras. Patol. Med. Lab., 53, 1, 38-45 (2017), a review on the measurement of serum gravimetric osmolarity). For example, one mole of a non-dissociated substance dissolved in 1 kg of water (e.g., DMT as a free base) has a gravimetric osmolarity of 1 Osm / kg (1000 mOsm / kg), while one mole of a substance that dissociates into two separate species in solution (e.g., DMT fumarate) dissolved in 1 kg of water has a gravimetric osmolarity of 2 Osm / kg (2000 mOsm / kg).

[0345] When the first solution is defined as isotonic with the second solution in this document, the solutions have the same weight osmotic concentration. For example, when a formulation is defined as isotonic with human serum, the formulation has the same weight osmotic concentration as human serum. Human serum typically has a weight osmotic concentration of about 275 to about 300 mOsm / kg (L. Hooper et al., BMJ Open, 2015; 5(10):e008846).

[0346] Formulations suitable for injection according to the invention are described in WO2022 / 043227 and US11406619. Formulations suitable for inhalation administration according to the invention are described in WO2022 / 117640. Formulations suitable for transdermal administration are described in US20210346347 and US17 / 866,477. Formulations suitable for buccal administration are described in WO2022 / 232179. Other suitable formulations according to the invention are described in co-pending patent application US17 / 574,424. The entire disclosure of each of these patent applications is hereby incorporated herein by reference in its entirety.

[0347] In some embodiments, the parenteral preparations used in the present invention comprise a salt of a short-acting hallucinogen, an alkaline reagent, water, and optionally a buffer distinct from the salt, wherein the preparation has a pH of about 5 to about 6, a concentration of about 10 mg / ml or higher as free base, and a weight osmotic pressure concentration of about 250 to about 350 mOsm / Kg; and wherein the preparation contains a dose of the short-acting hallucinogen in a volume of 5 ml or less.

[0348] The alkaline reagent adjusts the pH of the formulation to the desired pH range, such as pH 5 to pH 6. Formulations containing the short-acting hallucinogen salt, water, and a buffer often have a low pH, such as below pH 5, and therefore require pH adjustment using an alkaline reagent. A skilled technician can assess suitable alkaline reagents to adjust the pH of the solution without the risk of degradation of the short-acting hallucinogen salt. The alkaline reagent may be sodium hydroxide or potassium hydroxide.

[0349] The parenteral formulation optionally includes a buffer, distinct from a salt, i.e., the buffer is not merely an antiion of the short-acting hallucinogen. For example, when the salt is N,N-dimethyltryptamine fumarate (i.e., fumarate of N,N-dimethyltryptamine), the amount of buffer required exceeds the buffering effect provided by the fumarate. The term "buffer" is well known in the art and refers to a chemical that, when added to a formulation, resists changes in pH when an acid or base is added to the formulation. As used herein, the term "buffer" refers to a buffer system or buffering agent. In the formulation, the buffer comprises a weak acid and its conjugate base. Suitable buffers comprise an acid having a pKa value within a desired pH ± 1 range of the formulation. For example, if the desired pH of the formulation is about 5.0, a suitable buffer comprises a weak acid having a pKa value of about 4.0 to about 6.0. If the acid in the buffer has more than one pKa value (i.e., each molecule of the acid is capable of providing more than one proton), then for the buffer to be suitable, at least one of the pKa values ​​must be within the desired pH range.

[0350] The weak acid and conjugate base of a buffer are in equilibrium. According to Le Chatelier's principle (if a constraint is imposed on a system in equilibrium (such as changing the concentration of reactants), the equilibrium will shift to counteract the effect of the constraint), adding an acid or a base to the formulation shifts the equilibrium in favor of the conjugate base or the weak acid, respectively. Therefore, the concentration of free protons in the formulation (and thus the pH value) remains relatively constant.

[0351] Suitable buffer systems comprise acetate and acetic acid (pKa = 4.75); citrate and citric acid (pKa = 3.13, 4.76, and 6.40); and phosphoric acid (pKa = 2.14, 7.20, and 12.37); or mixtures thereof. The pKa values ​​cited herein are those reported in water at 25°C. Typically, the buffer contains only one pair of the above-listed combinations, i.e., an acid and its conjugate base.

[0352] In some embodiments, the buffer comprises acetate and acetic acid; citrate and citric acid; or phosphate and phosphoric acid. Sometimes, the buffer comprises acetate and acetic acid; or citrate and citric acid. In some embodiments, the buffer comprises acetate and acetic acid, often sodium acetate and acetic acid, or potassium acetate and acetic acid.

[0353] The concentration of the buffer in the formulation is typically sufficient to resist significant pH changes in the formulation during two weeks of storage (i.e., typically pH fluctuations are less than about 0.1 pH units), and those skilled in the art can assess and achieve a suitable buffer concentration. Typically, the buffer concentration is from about 15 mM to about 75 mM, such as from about 20 mM to about 30 mM. In some embodiments, the buffer concentration is about 25 mM.

[0354] As used herein, the term "buffer agent" refers to a weak acid or weak base. Any pharmaceutically acceptable buffer agent may be used in the formulations of the present invention, including phosphoric acid, citric acid, acetic acid, phosphates, citrates, and acetates. In some embodiments, the buffer agent comprises sodium phosphate, sodium citrate, or sodium acetate.

[0355] Sometimes, the concentrations of short-acting hallucinogens and optional buffers in a formulation produce a desired gravimetric osmolarity. Alternatively, this desired gravimetric osmolarity can be achieved by including one or more tonic agents in the formulation. Therefore, in some embodiments, the formulation further includes a tonic agent. Herein, a tonic agent is defined as a chemical that, when included in a formulation, increases the gravimetric osmolarity of the formulation. As described above, gravimetric osmolarity is the number of active particles (solute particles) that permeate 1 kg of solution. Therefore, chemicals that act as solutes when incorporated into a formulation fall within the definition of a tonic agent.

[0356] In some embodiments, the formulation contains a tonic agent. The concentration of the tonic agent depends on the concentration of other components in the formulation, such as short-acting hallucinogens and buffers. For example, when a formulation without a tonic agent has a weight osmolality of about 60 mOsm / kg, the tonic agent will provide a weight osmolality of at least about 190 mOsm / kg (e.g., 95 mM sodium chloride). M.M. Powell, T. Nguyen, and L. Baloian provide a review of excipients suitable for parenteral administration (administered via a route other than the oral cavity or digestive tract) in PDA J. Pharm. Sci. Technol., 52, 238-311 (1998). All soluble excipients listed in that review article that can be administered intravenously will contribute to the weight osmolality when added to the formulation and can therefore be considered tonic agents.

[0357] When using short-acting hallucinogens according to the present invention, the excipients used in the dosage of said short-acting hallucinogens may be selected from the group consisting of: ethanol, citric acid, trisodium citrate, benzalkonium chloride, microcrystalline cellulose, sodium carboxymethyl cellulose, chlorobutanol, disodium edetate, glycerol, hydrochloric acid, methylparaben, polyethylene glycol, propylene glycol, propylparaben, sodium saccharin, sodium bicarbonate, sodium bisulfite, sodium chloride, sodium hydroxide, sodium metabisulfite, sodium phosphate, sodium citrate, sulfuric acid, trisodium citrate, tromethamine, and mixtures thereof.

[0358] Some excipients can be used as co-solvents. Suitable solvents or co-solvents in the formulations used in this invention may be selected from ethanol, polyethylene glycol, propylene glycol, and mixtures thereof. In some embodiments, the formulation comprises a co-solvent. In some embodiments, the formulation does not contain a co-solvent. Specifically, when the salt of the short-acting hallucinogen is a fumarate, such as N,N-dimethyltryptamine fumarate or α,α-dideuterated-N,N-dimethyltryptamine fumarate, the formulation does not contain a co-solvent.

[0359] Treatment improvement can be assessed using rating scales commonly used in the art. For patients with depressive disorders such as MDD or TRD, the Montgomery-Essenberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAMD-17) can be used. These rating scales are used before administration of the short-acting hallucinogen to provide a baseline assessment, and are used again after administration (post-dose) to assess treatment efficacy. Post-dose assessment is preferably performed approximately 24 hours to approximately one month after administration of the short-acting hallucinogen, preferably approximately one week, two weeks, three weeks, and / or four weeks after administration. Symptom reduction to a essentially symptom-free level is considered indicative of remission. Remission can be assessed by an MADRS score of 13 or less, or 10 or less; an HAMD-17 score of 10 or less, preferably 8 or less; or a BDI-II score of 13 or less, preferably 11 or less.

[0360] In some embodiments, the short-acting hallucinogen is administered via intravenous cannulation as a biphasic IV infusion over 6-11 minutes. In some embodiments, the short-acting hallucinogen is administered via intravenous cannulation as a biphasic IV infusion, wherein each phase comprises a 5-minute infusion. In some embodiments, the short-acting hallucinogen is administered via intravenous cannulation as a monophasic IV infusion over 6-11 minutes, preferably about 10 minutes. When using biphasic IV infusion, the infusion pump is suitably connected to a single cannula via a three-way valve: after the first pump infusion is completed, the three-way valve switches to allow infusion to continue from the second pump.

[0361] The term "single-phase" IV infusion refers to the administration of an IV infusion via a single infusion pump, wherein the short-acting hallucinogen is administered from a single infusion pump. The term "biphasic" IV infusion refers to the administration of an IV infusion via two infusion pumps, wherein a first phase comprises the administration of a short-acting hallucinogen from a first infusion pump, followed by a second phase comprising the administration of a short-acting hallucinogen from a second infusion pump. The biphasic IV infusion is substantially continuous, with a non-substantial interruption in the infusion to change the administration from the first infusion pump to the second infusion pump.

[0362] In some implementations, the short-acting hallucinogen can be administered via intramuscular injection.

[0363] In some embodiments, the kit is a kit for treating a patient with a psychiatric disorder according to any of the foregoing embodiments, and the kit comprises a) a container containing a parenteral dose of a short-acting hallucinogen selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof; and b) a label or package insert on or associated with the container containing instructions for use of the parenteral preparation indicating that administration to the patient is in conjunction with administration of a monoamine antidepressant, preferably a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor.

[0364] In some embodiments, the parenteral preparation, combination, combination for the purpose, method of treatment, method of adjunctive treatment, short-acting hallucinogen for the purpose, kit, delivery device or administration regimen according to any of the foregoing embodiments is used to treat a patient who does not respond to treatment with at least one antidepressant for a sufficient duration, said at least one antidepressant preferably being at least one monoamine antidepressant, or at least two different antidepressants.

[0365] As used herein, “non-response” refers to the absence of clinically meaningful improvement in symptoms, such as as measured by one or more rating scales described above. A lack of response to a sufficient course of monoamine antidepressants can be determined retrospectively or prospectively. Prospective determination of lack of response refers to a judgment made by the prescribing clinician or therapist after a partial course of treatment. Retrospective determination refers to a judgment made by the prescribing clinician or therapist after a full, sufficient course of treatment.

[0366] This invention relates to the treatment of disorders using a combination of a monoamine antidepressant and a short-acting hallucinogen. The “therapeuticly effective” dose of the two agents refers to the amount of the monoamine antidepressant and the short-acting hallucinogen that, when administered in combination, induce a clinically meaningful response in the patient. The dose of each agent may not be therapeutically effective when administered as a single agent. For example, the dose of the monoamine antidepressant may be lower than the therapeutically effective amount when administered as a single agent, but is therapeutically effective when administered in combination with the short-acting hallucinogen according to the invention. For the avoidance of doubt, the doses of (i) the monoamine antidepressant and (ii) the short-acting hallucinogen as defined in any of the foregoing embodiments include the combined therapeutically effective dose.

[0367] According to the present invention, combination therapy can be achieved by administering a monoamine antidepressant and a short-acting hallucinogen simultaneously, sequentially, or separately. Preferably, the monoamine antidepressant and the short-acting hallucinogen are formulated and administered separately. Monoamine antidepressants and short-acting hallucinogens are often prescribed and / or administered by different healthcare practitioners (such as physicians). The present invention also provides for administration of both in a single dosage form. Other combinations can also be included through combination therapy. For example, two agents can be formulated together and administered in combination with a different formulation containing an additional dose of one of the agents or a third agent. Although two or more agents can be administered simultaneously in combination therapy, they do not need to be administered simultaneously. For example, the first agent (or combination of agents) can be administered minutes, hours, days, or weeks before the administration of the second agent (or combination of agents). Therefore, it is possible to administer the two or more of these agents within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other, for example, when a monoamine antidepressant is administered as a controlled-release formulation. In some cases, even longer intervals are possible. However, in many cases, it is desirable for the two or more of these agents used in combination therapy to be present in the patient's body simultaneously; that is, the administration regimen of the monoamine antidepressant and the short-acting hallucinogen provides simultaneously detectable plasma levels, which is not necessary. Combination therapy can also include two or more administrations of one or more agents used in the combination. The administration of the two agents can be based on different dosing schedules and performed by different healthcare practitioners. For example, a monoamine antidepressant can be delivered on a daily schedule, while a single dose of a short-acting hallucinogen can be administered alone for any three-month, six-month, nine-month, or twelve-month period. Alternatively, a monoamine antidepressant can be delivered on a daily schedule, while a single dose of a short-acting hallucinogen can be administered alone at most once every three months, or at most once every six months, or at most once every nine months, or at most once every twelve months. The two agents described in this invention can be administered sequentially, once or multiple times, in any combination. Preferably, the combined treatment according to this invention is achieved through a regimen of administration of an antidepressant and a short-acting hallucinogen, which simultaneously provides detectable plasma levels of both agents. Example

[0368] A nonblinded study of a single dose of N,N-dimethyltryptamine [DMT] fumarate is being conducted in patients currently receiving selective serotonin reuptake inhibitors (SSRIs) for their depression but whose depression is not fully relieved by the SSRIs (ClinicalTrials.gov ID: NCT05553691). The study includes two groups:

[0369] - "Trial Group": Patients currently on a stable SSRI regimen but whose depressive symptoms are not fully relieved by the SSRI (SSRIs prescribed outside the study). Patients were administered a single dose of DMT fumarate via intravenous infusion; and

[0370] - "Control group": Patients who are not currently receiving any pharmacological treatment for their depression (control group). Patients were administered a single dose of DMT fumarate via intravenous infusion.

[0371] Recruited patients had moderate to severe major depressive disorder (“MDD”) as defined by a Hamilton Depression Rating Scale (HAM-D) score ≥14. The Montgomery-Esenberg Depression Rating Scale (MADRS) was used to assess efficacy in measuring any change in depressive symptoms compared to baseline (day 0). Additional exploratory endpoints included the Beck Depression Questionnaire (BDI) to assess patients’ self-reported depression and the State-Trait Anxiety Inventory-T (STAI-T) to assess patients’ self-reported anxiety.

[0372] DMT fumarate was administered via intravenous infusion on day 1.

[0373] effect

[0374] MADRS

[0375] The results on the MADRS scale are shown in Table 1 below.

[0376]

[0377]

[0378] *A response is defined as a decrease of ≥50% in the MADRS score compared to baseline; remission is defined as a MADRS score ≤1.

[0379] Table 1

[0380] For participants in the experimental cohort (n=12), treatment with DMT fumarate in combination with an SSRI (experimental cohort) resulted in a mean percentage change from baseline (day 0) of -78.1% on day 8 to -90.2% on day 29. The response rate was 100% on day 29 for the experimental cohort. Surprisingly, complete remission (92%) was observed in 11 participants in this experimental cohort on day 29, while 10 participants showed remission at all other time points. One participant was observed on day 29 with a MADRS score of 11, although this did not meet the criteria for remission at 10.

[0381] In contrast, the control group (n=5) showed a mean change of -53.1% from baseline on day 8 and a mean change of -54.8% from baseline on day 29, with a response rate of 80% on day 29. One participant in the control group showed remission on day 29 (20%).

[0382] Surprisingly, there was such a significant difference in the antidepressant effects of DMT treatment between the experimental and control groups. These data suggest a potential synergistic effect when DMT fumarate is administered in combination with SSRIs.

[0383] BDI-II

[0384] These data were confirmed by assessments on the Becks (BDI-II) scale on days 15 and 29, as shown in Table 2 below;

[0385]

[0386]

[0387] Table 2

[0388] Furthermore, for participants in the experimental cohort (n=12), treatment with DMT fumarate resulted in a significant mean % change compared to baseline (day 0), from -84% on day 15 to -88% on day 29. In contrast, for participants in the control cohort (n=5), the mean % change compared to baseline was -54% on day 15 to -59% on day 29.

[0389] STAI-T

[0390] The results on the STAI-T scale are shown below.

[0391]

[0392]

[0393] Table 3

[0394] As can be seen from the data presented in Table 3, for participants in the experimental group (n=12), treatment with DMT fumarate resulted in a significant mean % change of -41.0% from baseline (day 0) on day 29. In contrast, for participants in the control group (n=5), the mean % change from baseline on day 29 was -27.2%.

[0395] The data presented in Tables 1 to 3 above show that in patients who were receiving selective serotonin reuptake inhibitors (SSRIs) for their depression but whose depression was not fully relieved by SSRIs, the symptoms of depression and anxiety were significantly reduced after receiving DMT fumarate treatment.

[0396] Safety & Tolerance

[0397] All patients in both the experimental and control groups tolerated DMT fumarate administration well, with no significant differences between the two groups. No drug-related serious adverse events were reported. A small number of drug-related adverse events (“AEs”) were reported (8 in the experimental group and 3 in the control group), all of which were classified as mild or moderate in severity. Most drug-related AEs were resolved during the administration visit.

Claims

1. Combinations, which include: (i) Monoamine antidepressants; and (ii) Short-acting hallucinogens.

2. The combination of claims 1, wherein the combination is synergistic.

3. A combination of any of the preceding claims, wherein the monoamine antidepressant is selected from selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

4. A combination of any of the preceding claims, wherein the short-acting hallucinogen is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, cyprotinin, deuterated cyprotinin, cyprosiben, deuterated cyprosiben, cyprotinin-4-glutaric acid ester, deuterated cyprotinin-4-glutaric acid ester, iprocin-4-glutaric acid ester, deuterated iprocin-4-glutaric acid ester, mixtures thereof, and pharmaceutically acceptable salts thereof.

5. A combination of any of the preceding claims, wherein the monoamine antidepressant is selected from divenlafaxine, duloxetine, levomirnazepine, mirnazepine, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, as well as pharmaceutically acceptable salts thereof.

6. A combination of any one of the preceding claims, comprising: (i) Adequate treatment duration with monoamine antidepressants; and (ii) A single dose of a short-acting hallucinogen.

7. The combination of claims 6, wherein the sufficient course of treatment comprises a treatment period of 4 weeks or longer.

8. The combination of any one of claims 6 and 7, wherein the single dose of the short-acting hallucinogen is administered only once within any three-month period.

9. The combination of any one of claims 6 to 7, wherein the single dose of the short-acting hallucinogen is administered at most once every three months.

10. The combination of any one of claims 6 to 7, wherein the single dose of the short-acting hallucinogen is administered only once within any six-month period.

11. The combination of any one of claims 6 to 7, wherein the single dose of the short-acting hallucinogen is administered at most once every six months.

12. The combination of any one of claims 6 to 7, wherein the single dose of the short-acting hallucinogen is administered only once during any nine-month period.

13. The combination of any one of claims 6 to 7, wherein the single dose of the short-acting hallucinogen is administered at most once every nine months.

14. The combination of any one of claims 6 to 7, wherein the single dose of the short-acting hallucinogen is administered only once during any twelve-month period.

15. The combination of any one of claims 6 to 7, wherein the single dose of the short-acting hallucinogen is administered at most once every twelve months.

16. A combination of any one of the preceding claims, comprising: (i) the oral dosage form of the monoamine antidepressant; and (ii) The parenteral formulation of the short-acting hallucinogen.

17. A combination of any of the preceding claims for treating a psychiatric disorder, preferably wherein the psychiatric disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, post-traumatic stress disorder, panic disorder, and eating disorders.

18. A combination of any of the preceding claims for treating a depressive disorder, said depressive disorder being selected from major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients.

19. A combination of any of the preceding claims, used for treating anxiety disorders selected from generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

20. The combination for said use according to any one of claims 17 to 19, further comprising the following steps: a. Baseline assessment of patients using rating scales and / or clinician-reported outcomes and / or patient-reported outcomes; and b. Post-administration assessment of patients after administration of short-acting hallucinogens.

21. The combination of claims 20 for the stated use, wherein the baseline assessment is performed using a rating scale selected from: the Clinical Global Impression Scale (CGI); the Montgomery-Esenberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD17); the Beck Depression Questionnaire-II; the Beck Anxiety Questionnaire (BAI); the Hamilton Anxiety Scale (HAM-A); the State-Trait Anxiety Questionnaire (STAI or STAI-T); the Generalized Anxiety Disorder Assessment (GAD-7); the Clinical Post-Traumatic Stress Disorder Scale (CAPS); the Yale-Brown Compulsive Scale; the Beck Suicide Ideation Scale (BSS); the Columbia Suicide Severity Rating Scale (C-SSRS); the suicidal ideation item in the MADRS; the Clinical Global Impression-Revised (CGI-SS-R) scale for suicidal tendency severity; the Beck Depression Questionnaire-II; the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Version (Q-LES-Q-SF); the EQ-5D-5L Descriptive System and EQ VAS; Patient Global Impression Severity Scale (PGI-S); and combinations thereof.

22. The combination of claim 20 or 21 for the stated use, wherein the post-drug assessment is performed using a rating scale selected from: the Clinical Global Impression Scale (CGI); the Montgomery-Esenberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD17); the Beck Depression Questionnaire-II; the Beck Anxiety Questionnaire (BAI); the Hamilton Anxiety Rating Scale (HAM-A); the State-Trait Anxiety Questionnaire (STAI or STAI-T); and the Generalized Anxiety Disorder Assessment (GAD). -7); Clinical Post-Traumatic Stress Disorder Scale (CAPS); Yale-Brown Compulsive Disorder Scale; Baker Suicide Ideation Scale (BSS); Columbia Suicide Severity Rating Scale (C-SSRS); Suicidal Ideation Item in MADRS; Clinical Global Impression of Suicidal Tendency Severity - Revised Version (CGI-SS-R) Scale; Baker Depression Questionnaire-II; Quality of Life Enjoyment and Satisfaction Questionnaire - Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS; Patient Global Impression Severity Scale (PGI-S); Clinical Global Impression Improvement Scale (CGI-I); Patient Global Impression Improvement Scale (PGI-I); and combinations thereof.

23. The combination of any one of claims 17, 18, and 20 to 22 for the said use, wherein the psychiatric disorder is a depressive disorder, and wherein the baseline assessment and post-drug assessment are performed using a depression rating scale selected from the Montgomery-Esenberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD17), the Beck Depression Questionnaire-II, and combinations thereof.

24. A combination of claims 13 to 23 for the stated purpose, which provides relief to the patient from the said psychiatric disorder.

25. The combination of any one of claims 17 to 24 for the said use, wherein relief is assessed 6 to 10 days, preferably 6 to 8 days, after administration of the short-acting hallucinogen.

26. The combination of any one of claims 17 to 25 for the said use, wherein the administration of said short-acting hallucinogen comprises: The short-acting hallucinogen is administered parenterally to the patient for a duration of up to about 15 minutes, preferably within a period of about 5 to about 15 minutes. The parenteral administration described therein is essentially continuous.

27. The combination of any one of claims 17 to 26 for the stated purpose, wherein the administration of the short-acting hallucinogen is parenteral administration, the parenteral administration being selected from the group consisting of intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, and transdermal administration as well as inhalation, preferably the group consisting of intravenous, intramuscular, intranasal, transmucosal, and transdermal administration as well as inhalation.

28. The combination for the said use according to claim 27, wherein the parenteral administration is by intravenous infusion, preferably wherein the intravenous administration is performed using an infusion pump.

29. The combination for the said use according to claim 28, wherein the parenteral administration is via biphasic intravenous infusion.

30. The combination for the said use according to claim 28, wherein the parenteral administration is via monophasic intravenous infusion.

31. The combination for the said use according to any one of claims 28 to 30, wherein the administration period is about 8 to about 12 minutes.

32. The combination for the said use according to claim 31, wherein the administration period is about 9 to about 11 minutes or about 10 minutes.

33. The combination of any one of claims 6 to 32, or the combination for the stated purpose, wherein the dose of the short-acting hallucinogen is selected from the group consisting of: - Approximately 20 to approximately 80 mg of N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - Approximately 20 to approximately 80 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - Approximately 15 to approximately 30 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - Approximately 10 to approximately 30 mg of 5-methoxy-N,N-dimethyltryptamine, a deuterated analogue, or a pharmaceutically acceptable salt thereof; and - Approximately 10 to approximately 30 mg of deuterated 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; Alternatively, the dosage of the short-acting hallucinogen may be selected from the group consisting of: - Approximately 10 to approximately 30 mg of serocepin or a pharmaceutically acceptable salt thereof; - Approximately 10 to approximately 20 mg of deuterated thelosibine or a pharmaceutically acceptable salt thereof; - Approximately 1 to approximately 20 mg of cyclophosphamide or a pharmaceutically acceptable salt thereof; - Approximately 1 to approximately 20 mg of deuterated cyproheptadine or a pharmaceutically acceptable salt thereof; and - Approximately 20 to approximately 50 mg of cyclophosphamide-4-glutarate, deuterated cyclophosphamide-4-glutarate, iprocin-4-glutarate, deuterated iprocin-4-glutarate, or a pharmaceutically acceptable salt thereof.

34. The combination for the said use according to any one of claims 17 to 33, comprising parenteral administration of a total dose of about 20 to about 29 mg of N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or a mixture thereof.

35. The combination for the said use according to any one of claims 17 to 33, comprising parenteral administration of N,N-dimethyltryptamine or deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof or a mixture thereof in a total dose of about 20 to about 23 mg or a total dose of about 26 to about 29 mg.

36. The combination for the stated use according to any one of claims 17 to 33, wherein the short-acting hallucinogen is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or a mixture thereof, and the total dose is about 7 to about 10 mg.

37. The combination for the stated use according to any one of claims 26 to 33, wherein the administration is by intravenous infusion, the short-acting hallucinogen is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or a mixture thereof, and the total dose is about 20 to about 23 mg.

38. The combination for the stated use according to any one of claims 26 to 33, wherein the administration is by intravenous infusion, the short-acting hallucinogen is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or a mixture thereof, and the total dose is about 26 to about 29 mg.

39. The combination for the purpose of claim 27, wherein the application is by intramuscular administration.

40. The combination for the stated use according to claim 39, wherein the short-acting hallucinogen is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and the total dose is about 20 to about 70 mg, preferably about 50 to about 70 mg; or the short-acting hallucinogen is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or a mixture thereof, and the total dose is about 20 to about 60 mg or about 15 to about 30 mg.

41. A combination of any one of the preceding claims or a combination for the stated purpose, wherein the short-acting hallucinogen is a compound of formula I or a pharmaceutically acceptable salt thereof: Ra is selected from H and D; or Ra is selected from -OH, -OPO3H2 and -OC(O)C1-C3 alkyleneCO2H; Rb is selected from H, D, -OCH3, and -OCD3; R 2 and R 3 Each is independently selected from C(H) z )3; or R 2 and R 3 Each is independently selected from C2(H) z )5 and C3(H z )7; and H x H y and H z Each is independently selected from protium and deuterium.

42. The combination of claims 41 or the combination for the said purpose, wherein R 2 and R 3 Each is independently selected from CH3 and CD3.

43. The combination of claims 42 or the combination for the said purpose, wherein R 2 and R 3 They are all CH3 or R 2 and R 3 Both are CD3 or R 2 It is CH3 and R 3 It's CD3.

44. A combination of any one of claims 41 to 43, or a combination for the stated purpose, wherein each H x All are H or each H x All are D.

45. A combination of any one of claims 41 to 44, or a combination for the stated purpose, wherein each H y All are H or each H y Both are D or one H y It is H and one H y It is D.

46. ​​A combination of any one of claims 41 to 45, or a combination for the stated purpose, wherein each H x H y and H z They are all deuterium.

47. A combination of any one of the preceding claims or a combination for the stated purpose, wherein the short-acting hallucinogen is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof or a mixture thereof; wherein Ra and Rb are as defined in claim 41.

48. A combination of any one of claims 41 to 47 or a combination for the said purpose, wherein Ra is H or Ra is D.

49. A combination of any one of claims 41 to 48 or a combination for the said purpose, wherein Rb is H or Rb is D.

50. A combination of any one of claims 41 to 48, or a combination for the stated purpose, wherein the short-acting hallucinogen is selected from the group consisting of: N,N-Dimethyltryptamine; α-Protamine, α-Deuterated-N,N-Dimethyltryptamine; α,α-Dideuterated-N,N-dimethyltryptamine; α,α,β,β-Tetradeuterated-N,N-dimethyltryptamine; N,N-Di(trideuterated methyl)tryptamine; α-Protyl, α-Deuterated-N,N-Di(trideuterated methyl)tryptamine; α,α-Dideuterated-N,N-Di(trideuterated methyl)tryptamine; α,α,β,β-Tetradeuterated-N,N-Di(trideuterated methyl)tryptamine; 5-Methoxy-N,N-Dimethyltryptamine; 5-Methoxy-α-protyl,α-deuteryl-N,N-dimethyltryptamine; 5-Methoxy-α,α-Dideuterated-N,N-Dimethyltryptamine; 5-Methoxy-α,α,β,β-Tetradeuterated-N,N-Dimethyltryptamine; 5-Methoxy-N,N-Di(trideuterated methyl)tryptamine; 5-Methoxy-α-protyl,α-deuteryl-N,N-di(trideuterated methyl)tryptamine; 5-Methoxy-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine; 5-Methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and Its pharmaceutically acceptable salt; or The compound is selected from the group consisting of the following. Selosibin; α-Protyl, α-Deuteryl-xelospin; α,α-dideuterium-selosibin; α,α,β,β-tetradeuterium-selosibin; 4-(dihydrophosphate)-N,N-bis(trideuterated methyl)tryptamine; 4-(dihydrophosphate)-α-protyl,α-deuteryl-N,N-bis(trideuterated methyl)tryptamine; 4-(dihydrophosphate)-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine; 4-(dihydrophosphate)-α,α,β,β-tetradeuter-N,N-di(trideuterated methyl)tryptamine; Celosia; α-Protyl, α-Deuteryl-Xyloxine; α,α-dideuterium-xellotin; α,α,β,β-tetradeuterated psiloin; 4-Hydroxy-N,N-Di(trideuterated methyl)tryptamine; 4-Hydroxy-α-protyl,α-deuterium-N,N-di(trideuterated methyl)tryptamine; 4-Hydroxy-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine; 4-Hydroxy-α,α,β,β-Tetradeuterated-N,N-Di(trideuterated methyl)tryptamine; Xyloxane-4-glutaric acid ester; α-Protyl, α-Deuterated-xelocin-4-pentanediol ester; α,α-Dideuterated-xellotin-4-pentanediol ester; α,α,β,β-Tetradeuterated-xellotin-4-pentanediol ester; 4-Hydroxy-N,N-Di(trideuterated methyl)tryptamine-4-pentanediol ester; 4-Hydroxy-α-protyl,α-deuteryl-N,N-bis(trideuterated methyl)tryptamine-4-pentanediol ester; 4-Hydroxy-α,α-Dideuterated-N,N-Di(trideuterated methyl)tryptamine-4-pentanediol ester; 4-Hydroxy-α,α,β,β-Tetradeuterated-N,N-Di(trideuterated methyl)tryptamine-4-pentanediol ester; iprocin-4-glutarate; α-Protyl, α-deuteryl-iprocin-4-glutarate; α,α-Dideuterated-iprocin-4-glutarate; α,α,β,β-tetradeuterated-iprocin-4-glutaric acid ester; 4-Hydroxy-N,N-Di(heptadeuterated isopropyl)tryptamine-4-pentanediol ester; 4-Hydroxy-α-protyl,α-deuteryl-N,N-di(heptadeuteroisopropyl)tryptamine-4-pentanediol; 4-Hydroxy-α,α-Dideuterated-N,N-Di(heptadeuterated isopropyl)tryptamine-4-pentanediol ester; 4-Hydroxy-α,α,β,β-Tetradeuterated-N,N-Di(heptadeuterated isopropyl)tryptamine-4-pentanediol; and Its pharmaceutically acceptable salt.

51. The combination for said use according to any one of claims 17 to 46, comprising: (i) Administer a selective serotonin reuptake inhibitor orally to the patient over a period of 4 weeks or longer. and (ii) administering a short-acting hallucinogen to the patient parenterally, said short-acting hallucinogen being selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, its deuterated analogues and pharmaceutically acceptable salts thereof.

52. The combination of claim 51 for the said use, wherein the course of oral administration of the selective serotonin reuptake inhibitor to the patient is 6 weeks or longer.

53. A combination of any one of claims 17 to 52 for the said use, wherein the treatment of the patient's psychiatric disorder comprises hallucinogenic-assisted psychotherapy.

54. The combination for said purpose according to claim 53, comprising: A. Administer to the patient (i) Monoamine antidepressants, and (ii) A short-acting hallucinogen, preferably selected from the parenteral form of the following short-acting hallucinogens: N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, ciprotin, deuterated ciprotin, ciprocil, deuterated ciprocil, ciprotin-4-glutaric acid ester, deuterated ciprotin-4-glutaric acid ester, iprocin-4-glutaric acid ester, deuterated iprocin-4-glutaric acid ester and pharmaceutically acceptable salts thereof; and B. Psychotherapy session.

55. The combination of claim 53 or 54 for the said purpose, further comprising: a. Preparation phase, including preparing the patient for the hallucinogenic experience; b. The administration phase, comprising administering a short-acting hallucinogen according to any one of the preceding claims; and c. Integration phase, including patient interviews or discussions led by psychiatrists or therapists, focusing on hallucinogenic experiences.

56. A short-acting hallucinogen for adjunctive treatment of psychiatric disorders in patients receiving monoamine antidepressant therapy, preferably wherein the psychiatric disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, post-traumatic stress disorder, panic disorder, and eating disorders.

57. The short-acting hallucinogen for the stated purpose according to claim 56, wherein the short-acting hallucinogen is administered to a patient who has received a sufficient course of treatment with a monoamine antidepressant.

58. The short-acting hallucinogen for the stated purpose according to claim 56 or 57, wherein the short-acting hallucinogen and the monoamine antidepressant are administered to the patient separately.

59. A short-acting hallucinogen for the said use according to any one of claims 56 to 58, wherein... (i) The monoamine antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine and their pharmaceutically acceptable salts; and (ii) The short-acting hallucinogen is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and its pharmaceutically acceptable salts.

60. A short-acting hallucinogen for the said use according to any one of claims 56 to 59, wherein said short-acting hallucinogen is a compound of formula I or a pharmaceutically acceptable salt thereof: Ra is selected from H and D; or Rb is selected from H and D; R 2 and R 3 Each is independently selected from C(H) z )3; and Each H x H y and H z Both are independently selected from protium and deuterium.

61. A short-acting hallucinogen for the said use according to any one of claims 56 to 60, wherein R 2 and R 3 Both are CH3 or R 2 and R 3 They are all CD3.

62. A short-acting hallucinogen for the said purpose according to any one of claims 56 to 61, wherein each H y All are H or each H y All are D.

63. A short-acting hallucinogen for the said purpose according to any one of claims 56 to 62, wherein each H x H y and H z They are all deuterium.

64. A short-acting hallucinogen for the said purpose according to any one of claims 56 to 63, wherein the short-acting hallucinogen is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof or a mixture thereof; wherein Ra and Rb are as defined in claim 60.

65. A short-acting hallucinogen for the said use according to any one of claims 56 to 64, wherein Ra is H.

66. A short-acting hallucinogen for the said use according to any one of claims 56 to 65, wherein Rb is H.

67. Combinations, which include: (i) a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine and their pharmaceutically acceptable salts; and (ii) Short-acting hallucinogens selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and their pharmaceutically acceptable salts; It is used simultaneously, sequentially, or separately in the treatment of a patient's psychiatric disorders.

68. The combination of claims 67 for the stated uses, wherein the combination is used in the treatment of a patient’s psychiatric disorder, wherein the psychiatric disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, post-traumatic stress disorder, panic disorder, and eating disorders.

69. The combination of claims 67 or 68 for the stated purpose, wherein the short-acting hallucinogen is administered to a patient who has received a sufficient course of selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

70. The combination for the stated use according to any one of claims 67 to 69, wherein the combination comprises an SSRI selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine and pharmaceutically acceptable salts thereof.

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