Combinations including monoamine antidepressants and short-acting psychedelics

Abstract

The present invention relates to combinations, combinations for use, methods of treatment, kits, dosing regimens, delivery devices, adjunctive treatment methods, short-acting psychedelic agents for use, or parenteral formulations for use, for treating mental disorders in patients. In particular, the present invention relates to administering short-acting psychedelic agents in combination with monoamine antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

Description

Field of Invention

[0001] This invention relates to combinations, combinations for use, methods of treatment, kits, dosing regimens, delivery devices, adjunctive therapies, short-acting psychedelic agents for use, or parenteral formulations for use, for treating mental disorders in patients. In particular, this invention relates to administering short-acting psychedelic agents in combination with monoamine antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). Background of the Invention

[0002] Antidepressants are a broad range of medications used to treat many mental conditions, including depression, anxiety disorders, obsessive-compulsive disorder, and eating disorders. Most antidepressants approved by regulatory authorities are monoamine antidepressants, which are non-psychedelic drugs characterized by a mechanism of action that addresses an imbalance (usually a deficiency) of one or more neurotransmitters: serotonin, norepinephrine, and dopamine. The standard treatment for most target mental conditions is selective serotonin reuptake inhibitors (SSRIs). SSRIs are widely used as antidepressants and are generally used as first-line treatment, and are thought to work by increasing serotonin levels in the brain. SSRIs are usually taken orally, typically in tablet form, and typically need to be taken daily for two to four weeks before any benefit is felt. Examples of SSRIs include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vortioxetine.

[0003] Large-scale meta-analyses have shown that SSRIs are typically effective within three months for about one-third of patients, and another one-third respond within 12 months. The remaining one-third do not respond and commonly continue taking one or more antidepressants for many years without achieving a clinically meaningful response. Furthermore, patients may have difficulty withdrawing from monoamine antidepressants such as SSRIs, and this must be done slowly, with dose reductions over a period of four weeks or more, to prevent withdrawal symptoms (discontinuation syndrome). With over 300 million people worldwide suffering from depression, there remains a widespread medical need to improve the clinical response rates of SSRIs and other monoamine antidepressants.

[0004] Classical psychedelics have also shown promise in preclinical and clinical settings in the treatment of mental disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). For example, psilocybin (also known as psilocybin) showed significant improvements in various depression and anxiety ratings in a randomized, double-blind trial (Griffiths et al. Journal of Psychopharmacology, 30(12), 1181-1197 (2016)). The efficacy of psilocybin 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 RR Griffiths, Am. J. Drug Alcohol Abuse, 2017, 43, 1, 55-60), and it is currently being investigated for several other mental health disorders rooted in psychologically destructive thought processing patterns (anorexia nervosa: NCT# NCT04052568).

[0005] Becker et al. conducted a double-blind, placebo-controlled, crossover clinical trial (clinicaltrials.gov identifier: NCT03912974) to investigate the response to psilocybin (25 mg) in healthy volunteers after pretreatment with escitalopram or placebo. Becker et al. reported that two weeks of daily escitalopram treatment did not reduce the positive mood or psychotropic effects of psilocybin (sufficient dose) 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 was also conducted to investigate the effects of orally administered psilocybin (with a psychedelic experience typically lasting 6 to 8 hours) in participants with treatment-resistant depression. This trial compared participants receiving SSRI treatment with those who had discontinued SSRI treatment before the trial. Compass Pathways, the sponsor of this trial, announced that patients taking psilocybin in combination with SSRIs showed "equivalent treatment outcomes to patients who had discontinued SSRI therapy" (Compass Pathways Press Release dated 13 December 2021: https: / / compasspathways.com / positive-outcome-25mg-comp360-psilocybin-therapy-adjunct-ssri-antidepressants-open-label-treatment-resistant-depression-study / ).

[0006] Cybin has completed the Phase 1 portion of a Phase 1 / 2a clinical trial evaluating a deuterated psilocybin analog (CYB003) in healthy participants with and without major depressive disorder (ClinicalTrials.gov identifier: NCT05385783). In February 2023, Cybin announced that the psychedelic effect of CYB003 was observed within approximately 15 minutes after a single oral dose, with a mean duration of peak effect of approximately 2 hours. This data is based on an interim analysis of CYB003 in healthy volunteers (https: / / cybin.com / cyb003 / ).

[0007] The University of California is conducting a Phase 1 clinical trial (ClinicalTrials.gov identifier: NCT05317689) to compare the physiological and psychological effects of psilocin (also known as psilocin), administered orally as a tablet or sublingually by dissolving the tablet under the tongue, with the effects of psilocybin administered as a tablet in healthy adults. Each participant will receive 15.5 mg of oral psilocin, 25 mg of oral psilocybin, or 2.18 mg to 4.36 mg of sublingual psilocin.

[0008] Reunion Neuroscience has completed a Phase 1 clinical trial of a compound formed by adding a glutarate moiety to the phenolic functional group of 4-hydroxy-N,N-diisopropyltryptamine. The compound was reported to have a mean subjective duration of 3.7 hours at a dose of 33 mg (poster presented at the American Society of 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.

[0009] Short-acting psychedelic agents, such as N,N-dimethyltryptamine (DMT), have been shown to have therapeutic value as rapid-acting antidepressants with a duration of action of more than three months (Small Pharma Inc. Press Release dated 25 January 2023: https: / / smallpharma.com / press-releases / positive-topline-results-from-phase-iia-trial-of-spl026-in-major-depressive-disorder / ).

[0010] To date, no studies have investigated the safety, tolerability, or efficacy of short-acting psychedelics in patients receiving treatment with monoamine antidepressants such as SSRIs. The majority of clinical trials testing the efficacy of psychedelics in the treatment of mental health disorders exclude patients currently receiving SSRIs. Since both SSRIs and serotonergic (or classical) psychedelics exert their primary effects via the serotonergic system, theoretically, there are multiple ways in which these compounds could interact acutely. a) Safety: SSRIs inhibit the reuptake of serotonin (5-hydroxytryptamine [5-HT]). This means that SSRIs increase intrasynaptic serotonin, which in turn increases activity at 5-HT receptors. Classical psychedelics work by activating 5-HT receptors, so the combined effect of these two mechanisms can create a risk of inducing serotonin toxicity. b) Pharmacodynamics / Efficacy: Long-term use of SSRIs leads to homeostatic downregulation of 5-HT receptors. This means that the psychological effects of classic psychedelic drugs may be diminished when administered. c) Pharmacodynamics / Efficacy: Analysis of data from trials evaluating the efficacy of MDMA adjunctive therapy after SSRI discontinuation suggests that patients who have recently discontinued SSRI treatment may experience a decrease in the effectiveness of subsequent serotonergic therapy (Feduccia, AA, Jerome, L., Mithoefer, MC, Holland, J. Discontinuations of medications classified as reuptake inhibitors affects treatment response of MDMA assisted psychotherapy. Psychopharmacology (Berl). 2021; 238: 581-588).

[0011] The present invention addresses these clinical uncertainties and provides evidence of a surprising synergistic effect when using a short-acting psychedelic agent in combination with a monoamine antidepressant, as well as a treatment method, a kit, and an administration schedule for use in the treatment of mental disorders in patients.

Summary of the Invention

[0012] As a first aspect, the present invention provides a combination comprising: (i) a monoamine antidepressant; and (ii) a short-acting psychedelic agent .

[0013] As a second aspect, the present invention provides a method for treating a mental disorder in a patient, preferably, the mental disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders. This treatment method comprises administering to the patient: (i) a monoamine antidepressant; and (ii) a short-acting psychedelic agent .

[0014] As a third aspect, the present invention provides a kit comprising: (i) a formulation of a short-acting psychedelic agent; and (ii) instructions for administering the formulation of the short-acting psychedelic agent to a patient in combination with a monoamine antidepressant .

[0015] As a fourth aspect, the present invention provides an administration schedule (administration regimen) comprising: (i) administration of a monoamine antidepressant; and (ii) administration of a short-acting psychedelic agent .

[0016] In a fifth aspect, the present invention provides a method for adjuvant treatment of a mental disorder in a patient receiving treatment with a monoamine antidepressant, preferably the mental disorder being selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders. This adjuvant treatment involves administering a short-acting psychedelic agent to the patient.

[0017] In a sixth aspect, the present invention provides a short-acting psychedelic agent for use as an adjunct treatment for mental disorders in patients receiving treatment with monoamine antidepressants, preferably the mental disorder being selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0018] In a seventh aspect, the present invention provides the use of a short-acting psychedelic agent for the manufacture of a medicament for the adjunctive treatment of a mental disorder in a patient being treated with a monoamine antidepressant, preferably the mental disorder being selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0019] In an eighth aspect, the present invention provides a parenteral formulation comprising a dose of a short-acting psychedelic agent for use in the treatment of a mental disorder in a patient being treated with a monoamine antidepressant; wherein the treatment comprises administering to the patient a dose of the short-acting psychedelic agent, preferably parenterally; preferably, the mental disorder is selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, and preferably selected from depressive disorders and anxiety disorders.

[0020] In a ninth aspect, the present invention provides a delivery device for use in the treatment of mental disorders in patients being treated with monoamine antidepressants, wherein the delivery device is configured to deliver a parenteral dose, preferably a parenteral dose, of a short-acting psychedelic agent to the patient.

[0021] To avoid any doubt, embodiments relating to each aspect of the present invention are applied with modifications necessary for other aspects of the invention. Further aspects and embodiments of the present invention will become apparent from the discussion herein.

[0022] In the first, second, third, fourth, fifth, sixth, seventh, eighth, and ninth embodiments of the present invention, the short-acting psychedelic agent is preferably selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, psilocine, deuterated psilocine, psilocybin, deuterated psilocybin, psilocine-4-glutarate, deuterated psilocine-4-glutarate, iprosin-4-glutarate, deuterated iprosin-4-glutarate, mixtures thereof, and pharmaceutically acceptable salts thereof.

[0023] In the first, second, third, fourth, fifth, sixth, seventh, eighth, and ninth embodiments of the present invention, the monoamine antidepressant is preferably a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

[0024] definition Throughout this specification, one or more aspects of the present invention may be combined with one or more features described herein to define individual embodiments of the present invention.

[0025] In the detailed explanation, several terms will be mentioned, but unless the context clearly indicates the opposite, these terms should be understood to have the meanings set forth below.

[0026] The nomenclature used herein for short-acting psychedelic agents for use in the present invention is the nomenclature commonly used in the art. The compounds described herein may also be referred to by nomenclature in accordance with the International Union of Pure and Applied Chemistry (IUPAC) rules for chemical compounds, specifically the "IUPAC Compendium of Chemical Terminology (Gold Book)" (AD Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). To avoid doubt, if the rules of the IUPAC organization conflict with the definitions provided herein, the definitions herein shall prevail.

[0027] N,N-dimethyltryptamine (DMT) is also known by the IUPAC name 2-(1H-indole-3-yl)-N,N-dimethylethaneamine and CAS registry number 61-50-7. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is also known by the IUPAC name 2-(5-methoxy-1H-indole-3-yl)-N,N-dimethylethaneamine and CAS registry number 1019-45-0. Psilocybin is also known by the IUPAC name 3-[2-(dimethylamino)ethyl]-1H-indole-4-yl dihydrogen phosphate and CAS registry number 520-52-5. Psilosine is also known by the IUPAC name 3-[2-(dimethylamino)ethyl]-1H-indole-4-ol and CAS registry number 520-53-6. N,N-diisopropyltryptamine (DIPT) is also known by the IUPAC name N-[2-(1H-indole-3-yl)ethyl]-N-propan-2-ylpropan-2-amine. Iprocin is also known as 4-hydroxy-N,N-diisopropyltryptamine, or the IUPAC name 3-[2-(diisopropylamino)ethyl]-1H-indol-4-ol, CAS registration number 132328-45-1.

[0028] As used herein, a "compound of Formula I" is a compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

Chemical formula

[0029] As used herein, the terms “deuterated N,N-dimethyltryptamine,” “deuterated 5-methoxy-N,N-dimethyltryptamine,” “deuterated psilocine,” “deuterated psilocybin,” “deuterated N,N-diisopropyltryptamine,” deuterated psilocine-4-glutarate, and deuterated iprosin-4-glutarate” (collectively, “deuterated analogs” of short-acting psychedelic agents) mean that one or more hydrogen atoms in the structure of a short-acting psychedelic agent are substituted with a deuterium atom, where the deuterium atom is a hydrogen atom having an additional neutron. Deuterium substitution is performed by substituting one or more of the α and β positions in the following formula R 2 and R 3 This can be done on an alkyl group (such as a methyl group) represented by, on an indole ring, and / or on the methoxy group of 5-methoxy-N,N-dimethyltryptamine. In some embodiments, deuteration is performed. - α position, - α-position and β-position, - In the following equation, R 2 and R 3 Alkyl groups represented by (e.g., methyl group), - In the following equation, R 2 and R 3 Alkyl groups (e.g., methyl groups) represented by and at the α-position, - In the following equation, R 2 and R 3 Alkyl group (e.g., methyl group) represented by, α-position, and β-position This can be done in [location].

[0030] Where a compound described herein is described as deuterated or as a deuterated analog, the compound is enriched with deuterium in an amount dependent on the percentage of deuterium available in the reagent from which the compound is derived. For example, the d6-dimethylamino moiety of the compound of formula I (wherein -NR) 2 R 3d6-dimethylamino substituents (which are -N(CD3)2) can be derived from dimethyl-d7-amine or dimethyl-d6-amine (commonly available as HCl salts), which are available from chemical suppliers with deuterium purity ranging from 98% to 99%. As a result, the deuterium purity in the resulting d6-dimethylamino substituents is 98% to 99%. This means that, as those skilled in the art will understand, not all compounds of formula I (e.g.) contain the d6-dimethylamino substituent, and some may contain d0-d5-dimethylamino, but the average deuterium purity is approximately 98% to 99%. The term “deuterated analogs” will be understood to include isotopic mixtures of these compounds, e.g., isotopic mixtures of d0, d1 and d2-deuterated N,N-dimethyltryptamine or deuterated 5-methoxy-N,N-dimethyltryptamine. Such isotopic mixtures are described in the published patent publications WO2022 / 117359 and WO2020 / 245133, the disclosures thereof being incorporated herein in their entirety by reference.

[0031] In some embodiments, short-acting psychedelic agents are substituted with a methoxy group at the 5-position. The term "methoxy" (often abbreviated as OMe) defines a monovalent group obtained by removing a hydrogen atom from the OH moiety of methanol.

[0032] In some embodiments, the short-acting psychedelic agent is substituted at the 4-position with -OH, -OPO3H2, or -OC(O)C1~C3alkyleneCO2H, preferably -OPO3H2 or glutarate (-OC(O)C3alkyleneCO2H). The term "C1~C3 alkylene" refers to a linear saturated divalent hydrocarbon group consisting of one, two, or three carbon atoms, i.e., methylene, ethylene, or propylene.

[0033] To avoid any ambiguity, the 5th position of the short-acting psychedelic agent refers to the labeled position in the following structure (substituents are not shown), where R 2 and R 3Both are methyl, or as defined in any of the following embodiments. [ka]

[0034] In this specification, references to the dose or total dose of short-acting psychedelic agents refer to the dose or total dose of the agent as free base equivalents. For example, when a salt of a short-acting psychedelic agent (such as a fumarate) is used, the dose or total dose is specified as free base equivalents.

[0035] In this specification, "antidepressant" refers to a drug that is an approved pharmacological treatment for depressive disorders in at least one jurisdiction, such as the United States, the European Union, the United Kingdom, Australia, New Zealand, and Japan. In this specification, "monoamine antidepressant" refers to a non-psychedelic drug characterized by a mechanism of action that addresses an imbalance of one or more neurotransmitters selected from serotonin, norepinephrine, and dopamine.

[0036] However, monoamine antidepressants are preferably not monoamine oxidase inhibitor class antidepressants. At certain dose levels, monoamine oxidase inhibitor antidepressants may interfere with short-acting psychedelics and prolong their duration of action. Preferred monoamine antidepressants for use in the present invention are serotonin reuptake inhibitors, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

[0037] Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a type of monoamine antidepressant that inhibits the reuptake of serotonin and norepinephrine and are used to treat many disorders, including depressive disorders, anxiety disorders, and obsessive-compulsive disorder (OCD). SNRIs approved by the U.S. Food and Drug Administration (FDA) include desvenlafaxine, duloxetine, levomilunacipran, milnacipram, and venlafaxine.

[0038] Selective serotonin reuptake inhibitors (SSRIs) are a type of monoamine antidepressant that selectively inhibits the reuptake of serotonin and are used to treat many disorders, including depressive disorders, anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). In the UK, SSRIs are recommended as a first-line treatment for depressive disorders. Fluoxetine is approved by the FDA in the US and by the EMA in Europe for the treatment of bulimia nervosa. Approved SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine.

[0039] As used herein, the term "in combination with" refers to treatment with a short-acting psychedelic administered to a patient receiving treatment with a monoamine antidepressant. This may also be referred to as "adjuvant therapy," "adjunctive treatment," or "combination therapy." Typically, short-acting psychedelics are administered to patients who have received an appropriate course of treatment (appropriate duration and units) with one or more antidepressants and who are continuing treatment with a monoamine antidepressant. That is, the patient receives continuous treatment with a monoamine antidepressant before and during treatment with a short-acting psychedelic. An appropriate course of treatment with a monoamine antidepressant varies depending on the antidepressant, but is typically a course of treatment lasting four weeks or more, preferably six weeks or more. For example, a patient may take a monoamine antidepressant once (or more than twice) daily for a period of four weeks or more, preferably six weeks or more. Typically, the patient has not experienced clinically meaningful symptom improvement after administering an appropriate course of treatment with a monoamine antidepressant. As used herein, the term "in combination with" does not require the simultaneous administration of monoamine antidepressants and short-acting psychedelics. To avoid ambiguity, monoamine antidepressants and short-acting psychedelics may be administered and / or prescribed by different healthcare professionals (e.g., different physicians). Typically, monoamine antidepressants and short-acting psychedelics may be administered separately and sequentially. Optionally, monoamine antidepressants and short-acting psychedelics may be administered simultaneously. Typically, monoamine antidepressants are administered daily over the course of a treatment course, while short-acting psychedelics are administered as a single dose.

[0040] As used herein, the terms “synergistic” or “synergistic” refer to an effect greater than an additive effect.

[0041] As used herein, the terms “parenteral administration” or “administer parenterally” mean administering a dose of a short-acting psychedelic agent in one or more divided doses over a period of administration via any route other than oral. Parenteral administration is preferably substantially continuous for an administration period of up to about 15 minutes, for example, 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, parenteral administration may include an initial bolus dose of a short-acting psychedelic agent, which is a single dose of the drug administered at a rapid rate, typically over about 30 to 60 seconds, providing a fast-onset breakthrough psychedelic experience, followed by substantially continuous administration for a period of about 5 to 15 minutes. In other embodiments, parenteral administration may include a bolus dose of a psychedelic agent, which is a single dose of the drug administered at a rapid rate, typically over about 30 to 60 seconds. In some embodiments, administration includes bolus administration such as intramuscular, intranasal, or intravenous bolus administration.

[0042] As used herein, the term “effective dose” refers to a dose sufficient to induce a psychedelic experience (i.e., a period in which a person experiences one or more of the following: an intense reaction or emotion, an altered state of perception, a hallucination of the visual or other sense, a spiritual experience, ego dissolution, and dissociation). Ego dissolution refers to a state in which the boundary between the individual and the external world disappears (dissolves). Dissociation refers to a state in which an individual experiences a sense of disconnection between different parts of the brain, such as a disconnection between mind and body.

[0043] As used herein, the term “therapeutic dose” refers to the dose of monoamine antidepressants and short-acting psychedelics that, when used in combination, produce a therapeutic effect. Individual doses of each drug may not produce a therapeutic effect on their own.

[0044] As used herein, "month" is defined as a calendar month.

[0045] As used herein, “administration is to be given only once in any three-month period” means that there is an interval of at least 90 days between administrations. Similarly, as used herein, “administration is to be given only once in any six-month period” means that there is an interval of at least 180 days between administrations, and so on.

[0046] "Administration is given at most once every three months" means that at least three months, or 90 days, must pass between administrations. Similarly, "Administration is given at most once every six months" means that at least six months, or 180 days, must pass between administrations, and so on.

[0047] In this specification, any reference to the singular form of a noun includes the plural form of that noun unless the context suggests otherwise, and vice versa.

[0048] Throughout this specification, the word “contains,” or variations such as “contains,” or “includes,” are understood to mean encompassing the elements, integers, or processes, or groups of elements, integers, or processes described herein, but not to exclude any other elements, integers, or processes, or groups of elements, integers, or processes. The term “contains” includes, within its scope, the terms “consisting of only,” or “essentially consisting of only.”

[0049] The term "consisting only of" or its variations thereof is understood to mean encompassing the listed element, integer, or process, or group of elements, integers, or processes, and excluding other elements, integers, or processes, or groups of elements, integers, or processes.

[0050] The term "essentially consisting only of" or variations thereof means the inclusion of the described elements, integers, or processes, or groups of elements, integers, or processes, and is understood to mean that there may be further components, but only those that do not substantially affect the essential features of the embodiments of the present invention.

[0051] In this specification, the term “approximately” is used to refer to a value that is within ±5% of a specified value when modifying a number or value. To avoid ambiguity, where a number or value is specified without the term “approximately” in this specification, that number or value should be understood according to standard numerical rounding conventions with respect to the number of decimal places. For example, an integer such as 6 is understood to include values ​​≥ 5.5 and < 6.5. Similarly, a number specified to one decimal place, such as 5.3, is understood to include values ​​≥ 5.25 and < 5.35.

[0052] When a range of values ​​is given, that range includes the value at the end point. For example, the range 20 to 28, or 20~28, includes the values ​​20, 21, 22, 23, 24, 25, 26, 27, and 28; the range 5 to 15, or 5~15, includes the values ​​5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15.

[0053] As used herein, the term “patient” preferably refers to a mammal. Typically, that mammal is a human, but it may also refer to a domesticated mammal. This term does not include experimental mammals.

[0054] As used herein, the terms “in combination with psychotherapy” or “psychedelic assisted psychotherapy” refer to the treatment of mental disorders by psychological means, which are enhanced by the combination, method, or kit of the present invention. The administration of psychotherapy is provided in parallel with the dose of a short-acting psychedelic agent, which includes, for example, any dose as defined herein.

[0055] The term "treatment" defines therapeutic measures taken by a patient to slow or halt the progression of a disorder, or to improve or cure the disorder. This also includes preventive measures taken by patients with diagnosed mental disorders. Such preventive measures, also called secondary prevention, aim to reduce the effects of the disorder and / or prevent the onset (progression) of the disorder through treatment in accordance with the present invention.

[0056] As used herein, the term “improvement” refers to a clinically meaningful reduction in symptom severity over a period of time, compared to a baseline assessment before administration of a short-acting psychedelic, or as assessed by patient-reported outcomes. Improvement may be assessed by patient-reported outcomes or healthcare professional-reported outcomes, such as structured patient interviews or questionnaires. The term “healthcare professional” refers to a qualified and / or registered physician or healthcare professional, including therapists, psychiatrists, and psychologists.

[0057] Patient-reported outcomes or healthcare worker-reported outcomes may include assessments using rating scales, which include, but are not limited to, the following: The Clinical Global Impression (CGI) is an observer-rated scale consisting of one or more of three different measurement items (severity of the disease (CGI-S), overall improvement (CGI-I), and effectiveness index (CGI-E)); the Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire; the Hamilton Depression Rating Scale (HAMD17) is a 17-item scale; the Beck Depression Inventory-II; the Ruminative Response Scale (RRS-22) is a self-report measurement consisting of 22 items and three factors (depression, worrying, and reflection); and the Beck Anxiety Inventory (BAI) is a self-report questionnaire. Inventory); Hamilton Anxiety Scale (HAM-A); State-Trait Anxiety Inventory (STAI, or STAI-T); General Anxiety Disorder Assessment (GAD-7); Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS); Yale-Brown Obsessive-Compulsive Scale;Suicidal tendency rating scales, such as the Beck Scale for Suicidal Ideation (BSS), the Columbia-Suicide Severity Rating Scale (C-SSRS), the suicidal thoughts item of the MADRS for suicidal ideation, or the Clinical Global Impression of Severity of Suicidality-Revised (CGI-SS-R) scale. Patient-reported outcomes may include: the Beck Depression Inventory (BDI-II); the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), a 16-item self-administered questionnaire; the EQ-5D-5L descriptive system and EQ VAS; the Patient Global Impression of Severity scale (PGI-S); and the Patient Global Impression of Improvement scale (PGI-I). Combinations of assessment scales may also be used. Healthcare professional or patient-reported outcomes may include weight gain in anorexia nervosa; the frequency of binge-eating-purging episodes in bulimia nervosa; or the frequency of binge-eating episodes in binge-eating disorder.

[0058] Measuring clinically meaningful reductions in symptom severity is assessed according to rating scales or other healthcare professional or patient-reported outcomes, including:

[0059] Typically, for the Clinical Global Impression Scale (CGI), a response score of 0, 1, 2, or 3 indicates improvement, preferably 0, 1, or 2.

[0060] Typically, for assessment scales such as the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAMD17), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), Beck Suicidal 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 Obsessive-Compulsive Scale, Quality of Life Pleasure and Satisfaction Questionnaire - Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS, and the Clinician's Post-Traumatic Stress Disorder Scale (CAPS), a reduction of 15% or more in the score compared to the baseline rating indicates improvement, preferably 20% or more, or 30% or more, or 50% or more.

[0061] Alternatively, a clinically meaningful reduction in symptom severity can be assessed by a decrease in scores on assessment scales. For example, improvement is indicated by a decrease in the following scores: a decrease of 6 points or more on the MADRS scale; a decrease of 4 points or more on the HAMD-17 scale; or a decrease of 12 points or more on the Beck Depression Inventory II (BDI-II) scale. Alternatively, a reduction in severity categories, such as a decrease from severe to moderate, indicates improvement.

[0062] Typically, improvement is indicated by a decrease in the number of questions answered "yes" on the Columbia Suicide Severity Rating Scale (C-SSRS). Alternatively, improvement is indicated by a reduction in severity categories, such as a decrease from very severe to severe, or from severe to moderate severe.

[0063] Typically, improvement is indicated by a reduction in the patient's self-assessed severity score on the Patient General Impression Scale (PGI-S). For example, a reduction in severity score from 6 (severe) to 4 (moderate).

[0064] Typically, for the Patient General Impression Scale (PGI-I), a score of 3 (slightly improved) or lower indicates improvement, preferably a score of 2 (considerably improved) or lower. The PGI-I scale is evaluated only after administration, and not in comparison to baseline assessment.

[0065] As used herein, the term “remission” refers to a reduction in the symptoms of a mental disorder to a level of mild symptoms or to a level within the healthy range, i.e., a level in which the patient does not experience symptoms that indicate a clinical state. For depressive disorders, remission is typically considered to be a score of 13 or less on the MADRS rating scale, preferably 10 or less; or a score of 7 or less on the HAMD17 rating scale; or a score of 19 or less on the Beck Depression Scale II; or a score of 15 or less on the Beck Anxiety Scale; or a score of 17 or less on the Hamilton Anxiety Scale; or a score of 15 or less on the Yale-Brown Obsessive-Compulsive Scale; or a score of 3 or less on the Patient’s Global Impression Scale for Severity (PGI-S). Remission is typically considered to be a score of “no” on each question of the Columbia Suicide Severity Rating Scale (C-SSRS), or a score of 10 or less (moderate), preferably 6 or less.

[0066] As used herein, the terms “short-duration psychedelic agent” or “short-duration psychedelic” refer to a psychedelic agent that induces a psychedelic experience with a duration of 4 hours or less, or 3 hours or less, or 2 hours or less, or 1 hour or less. Preferably, a short-duration psychedelic induces a psychedelic experience of 1 hour or less. Preferably, a short-duration psychedelic is administered parenterally. Typical short-duration psychedelic agents are delivered parenterally (i.e., not administered orally). This is because the agent is not orally active (e.g., DMT, 5-MeO-DMT) or because oral administration results in a long-duration psychedelic experience. For example, oral administration of psilocybin induces a psychedelic experience with a duration of about 6 to 8 hours. However, certain orally active psychedelic agents (e.g., deuterated DMT or deuterated psilocybin) can induce psychedelic experiences with shorter durations, for example, three hours or less, preferably one hour or less. Therefore, the present invention provides psychedelic experiences with a duration of three hours or less, preferably one hour or less, more preferably 45 minutes or less, and even more preferably 30 minutes or less, and in any aspect or preferred example of any embodiment of the present invention, the short-acting psychedelic agent is provided in a dosage form suitable for parenteral administration, preferably by injection, inhalation, insulation, transdermal or transmucosal administration.

[0067] As used herein, the term “mental disorder” is characterized by a clinically significant impairment in an individual’s cognition, emotional regulation, or behavior and is associated with present distress (e.g., painful symptoms) or impairment (i.e., impairment in one or more significant areas of function), or with a significant increased risk of death, pain, impairment, or loss of significant freedom. The diagnostic criteria for mental disorders as referred herein are set forth in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

[0068] As used herein, the term “obsessive-compulsive disorder” (OCD) is defined by the presence of either an obsession or a compulsion, though generally both are present. Its symptoms can cause significant functional impairment and / or distress. An obsession is defined as an unwanted, intrusive thought, image, or urge that repeatedly enters a person’s mind. A compulsion is a repetitive behavior or mental act that a person feels compelled to perform. Typically, OCD manifests as one or more obsessions that trigger a compulsion. For example, an obsession with germs may trigger a compulsion to clean, or an obsession with food may trigger a compulsion to overeat, undereat, or vomit after eating (i.e., an obsession with food may manifest as an eating disorder). Compulsions can be obvious and observable to others, such as checking that a door is locked, or they can be inconspicuous and unobservable mental acts, such as repeating a specific phrase in one’s mind. The Yale-Brown Obsessive-Compulsive Rating Scale (Y-BOCS) can be used to assess OCD.

[0069] As used herein, the term “eating disorder” is defined as a severe and persistent disturbance in eating behavior, and the distressing thoughts and feelings associated therewith. The term “eating disorder” includes, but is not limited to, anorexia nervosa and bulimia nervosa, bulimia nervosa, avoidant restrictive food intake disorder, other specified eating and eating disorders, pica and rumination disorders.

[0070] Eating disorders often coexist with anxiety disorders and obsessive-compulsive disorders. Neziroglu and Sandler distinguish between OCD and eating disorders as follows: "Patients with eating disorders are primarily motivated by concerns about their physical appearance and consequently alter their eating patterns to lose weight. In contrast, patients with OCD may restrict their eating for reasons entirely unrelated to concerns about their body image" (https: / / iocdf.org / expert-opinions / expert-opinion-eating-disorders-and-ocd / ).

[0071] The term "eating disorder" includes anorexia nervosa, bulimia nervosa, and binge eating disorder (BED; also known as binge eating disorder). Symptoms of anorexia nervosa include eating too little and / or exercising too much in an attempt to keep weight as low as possible. Symptoms of bulimia nervosa include consuming large amounts of food in a very short period of time (i.e., binging), followed by intentionally becoming ill, using laxatives, eating too little, and / or exercising too much to prevent weight gain. Symptoms of BED include regularly consuming large amounts of food until one is uncomfortably full, resulting in distress and feelings of guilt.

[0072] As used herein, 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.

[0073] As used herein, the term “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 a period of two weeks or longer, for most of the day, or nearly every day (also known herein as a “major depressive episode”): • Depressed mood, such as feeling sad, empty, or tearful (in children and teenagers, depressed mood can manifest as persistent irritability (irritability)); • No significant loss of interest or pleasure in all or most activities; • Significant weight loss, weight gain, or decreased or increased appetite despite not dieting (in children, failure to achieve expected weight gain); • Insomnia or increased need for sleep; • Restlessness or slowness of movement that may be observed by others; • Fatigue or loss of energy; • Feelings of worthlessness, or excessive or inappropriate guilt; Difficulty making decisions, or a decline in thinking ability or concentration; • Recurrent thoughts about death or suicide, or suicide attempts. At least one of the symptoms must be either a depressed mood or a loss of interest or pleasure.

[0074] Persistent depressive disorder, also known as dysthymia, is defined as a condition in which patients exhibit the following two characteristics: A. Depressed mood for at least two years, almost every day, for most of the time. Children and adolescents may also experience irritability for at least one year. B. While experiencing depression, you experience at least two of the following symptoms: • Overeating or loss of appetite • Excessive sleepiness or difficulty sleeping • Fatigue, lack of energy • Low self-esteem Difficulty concentrating or making decisions

[0075] As used herein, the term “treatment-resistant major depressive disorder” refers to MDD that does not achieve an adequate response to standard treatment.

[0076] As used herein, “bipolar disorder” (also known as manic-depressive illness) is a disorder characterized by abnormal fluctuations in mood, energy levels, activity levels, and ability to perform routine tasks.

[0077] Bipolar disorder has two defined subcategories, both characterized by distinct fluctuations in mood, energy, and activity levels. These moods range from periods of extreme upbeat, euphoric, and energetic behavior (known as manic episodes, further defined below) to periods of extreme sadness, depression, or despair (known as depressive episodes). Milder manic periods are known as hypomanic episodes.

[0078] Bipolar I disorder is defined by a manic episode lasting at least seven days, or manic symptoms so severe that the person requires immediate hospitalization. Depressive episodes also usually occur, typically lasting at least two weeks. Mixed depressive episodes (where depressive and manic symptoms are present simultaneously) can also occur.

[0079] Bipolar II disorder is defined by a pattern of depressive and hypomanic episodes, but not by a full-blown manic episode like those described above.

[0080] As used herein, “bipolar depression” is defined as an individual who has experienced depressive symptoms accompanied by a past or co-occurring episode of manic symptoms, but who does not meet the clinical criteria for bipolar disorder.

[0081] Depressive disorders are typically assessed using assessment scales selected from combinations of the following: the Clinical Global Impression Scale (CGI); the Montgomery-Asberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD-17); the Beck Depression Inventory II; the Beck Anxiety Inventory (BAI); suicidal ideation rating scales, such as the Beck Scale for Suicidal Ideation (BSS), the Columbia Suicide Severity Rating Scale (C-SSRS), the suicidal thoughts item of the MADRS for suicidal ideation, the Revised Clinical Global Impression Rating Scale for Suicidal Ideation Severity (CGI-SS-R), or the Columbia Suicide Severity Rating Scale (C-SSRS), etc. Depressive disorders can also be assessed using the Beck Depression Inventory (BDI-II); the Quality of Life Pleasure and Satisfaction Questionnaire - Short Version (Q-LES-Q-SF); the EQ-5D-5L Descriptive System and EQ VAS; the Patient Global Impression Scale for Severity (PGI-S); and patient-reported outcomes selected from combinations of these outcome assessments.

[0082] Depressive disorders are preferably assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), the Beck Depression Scale II, the Beck Suicidal Ideation Scale (BSS), the Montgomery-Asberg Depression Rating Scale (MADRS), and / or the 17-item Hamilton Depression Rating Scale (HAMD-17).

[0083] 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 assessment scales selected from the Beck Anxiety Inventory (BAI), Hamilton Anxiety Scale (HAM-A), State-Trait Anxiety Inventory (STAI or STAI-T), Generalized Anxiety Disorder Assessment (GAD-7), and combinations thereof. Anxiety disorders may also be assessed using patient-reported outcomes, as described above.

[0084] As used herein, “Generalized anxiety disorder” (GAD) refers to a chronic disorder characterized by persistent anxiety that is not focused on any single object or situation. Individuals with GAD experience nonspecific, persistent fears and worries and become overly concerned with everyday matters. GAD is characterized by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability (irritability, anger), muscle tension, and sleep disturbances.

[0085] A phobia is defined as a persistent fear of a particular object or situation, in which the affected person makes great efforts to avoid it (usually to an extent that does not reflect the actual danger). If it is not possible to completely avoid the object or situation that is feared, the affected person endures it with significant distress, causing substantial impairment to their social or occupational activities.

[0086] Patients suffering from "panic disorder" are defined as those who experience one or more short episodes of intense fear and anxiety (also called panic attacks) that are 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 in less than 10 minutes.

[0087] Social anxiety disorder is defined as a strong fear and avoidance of negative public perception, embarrassment, humiliation, or social interaction. Social anxiety often manifests as certain physical symptoms, including blushing, sweating, and difficulty speaking.

[0088] Post-traumatic stress disorder (PTSD) is an anxiety disorder that arises from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, natural disasters, rape, hostage situations, child abuse, bullying, and even serious accidents. Common symptoms include hyperarousal, flashbacks, avoidance behavior, anxiety, anger, and depression.

[0089] The Post-Traumatic Stress Disorder Scale (CAPS), administered by clinicians, can be used to assess PTSD symptoms.

[0090] As used herein, the term “postpartum depression” (PPD; also known as postpartum depression) is a form of depression experienced by either parent of a newborn. Symptoms typically appear within four weeks of birth and often include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleep or eating patterns. (See detailed description below.)

[0091] The present invention relates to a combination, treatment method, kit, administration plan, delivery device, parenteral formulation, or adjunctive treatment method based on the remarkable finding that administering a single effective dose of a short-acting psychedelic, such as N,N-dimethyltryptamine, to patients receiving treatment with monoamine antidepressants resulted in greater symptom improvement compared to administration of the short-acting psychedelic without monoamine antidepressant treatment (such as SSRI treatment). This greater symptom improvement may offer numerous benefits, including improved response rates, improved remission rates, reduced doses of one or both drugs, and reduced or more effective withdrawal from monoamine antidepressants after administration of the short-acting psychedelic.

[0092] Therefore, a first aspect of the present invention provides a combination, as Embodiment 1, that includes the following: (i) Monoamine antidepressants; and (ii) Short-acting psychedelic agents.

[0093] A second aspect of the present invention provides, as Embodiment 2, a method for treating a mental disorder in a patient, preferably the mental disorder being selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, and the treatment method comprises administering to the patient the following: (i) Monoamine antidepressants; and (ii) Short-acting psychedelic agents.

[0094] A third aspect of the present invention provides a kit, as Embodiment 3, that includes the following: (i) Formulations of short-acting psychedelic agents; and (ii) Instructions for administering a short-acting psychedelic preparation to a patient in combination with a monoamine antidepressant.

[0095] A fourth aspect of the present invention provides, as Embodiment 4, a dosage plan comprising the following: (i) Administration of monoamine antidepressants; and (ii) Administration of short-acting psychedelic drugs.

[0096] A fifth aspect of the present invention provides, as Embodiment 5, a method for adjunct treatment of a mental disorder in a patient receiving treatment with a monoamine antidepressant, preferably the mental disorder being selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders; this adjunct treatment comprises administering a short-acting psychedelic agent to the patient.

[0097] A sixth aspect of the present invention provides, as Embodiment 6, a short-acting psychedelic agent for use as an adjunct treatment for mental disorders in patients receiving treatment with monoamine antidepressants, preferably the mental disorder being selected from at least one of depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0098] The present invention further provides, as Embodiment 7, a combination described in Embodiment 1, wherein the combination is synergistic; or a therapeutic method, kit, administration plan, adjunct therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 2 to 6, wherein (i) Monoamine antidepressants; and (ii) Short-acting psychedelic agents The administration of these drugs produces a synergistic effect.

[0099] The present invention further provides, as Embodiment 8, a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use as described in any of the preceding embodiments, wherein the monoamine antidepressant is selected from selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

[0100] The present invention further provides, as Embodiment 9, a combination, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any of the preceding embodiments, wherein the short-acting psychedelic agent is N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, psilocine, deuterated psilocine, psilocybin, deuterated psilocybin, psilocine-4-glucan The short-acting psychedelic agent is selected from talate, deuterated psilocin-4-glutarate, iprosin-4-glutarate, deuterated iprosin-4-glutarate, mixtures thereof, and pharmaceutically acceptable salts thereof, and preferably, the short-acting psychedelic agent 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.

[0101] The present invention further provides, as Embodiment 10, a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use described in any of the preceding embodiments, wherein the monoamine antidepressant is selected from at least one of desvenlafaxine, duloxetine, levomirunacipran, milnacipran, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, as well as pharmaceutically acceptable salts thereof.

[0102] The present invention further includes an embodiment 11, which is a combination of any one of embodiments 1 to 10, (i) A suitable course of monoamine antidepressants; and (ii) Single dose of short-acting psychedelic agents A combination including; or (i) Administration of an appropriate course of monoamine antidepressants; and (ii) Administration of a single dose of a short-acting psychedelic agent The present invention provides a therapeutic method, kit, administration plan, adjunct therapeutic method, or short-acting psychedelic agent for use, including, as described in any of the preceding embodiments.

[0103] The present invention further provides, as Embodiment 12, a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use as described in Embodiment 11, wherein a suitable course of treatment includes a treatment period of four weeks or more.

[0104] The present invention further provides, as Embodiment 13, a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use as described in any one of Embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered only once in any three-month period, or the single dose of the short-acting psychedelic agent is for administration only once in any three-month period. In a further embodiment, the present invention provides a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use as described in any one of Embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered at most once every three months, or the single dose of the short-acting psychedelic agent is for administration at most once every three months.

[0105] The present invention further provides, as Embodiment 14, a treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use according to any one of Embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered only once in any six-month period, or the single dose of the short-acting psychedelic agent is for administration only once in any six-month period; or provides a combination according to any one of Embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is for administration only once in any six-month period. In further embodiments, the present invention provides a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use according to any one of Embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered up to once in six months, or the single dose of the short-acting psychedelic agent is for administration up to once in six months.

[0106] The present invention further provides, as Embodiment 15, a treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use as described in any one of Embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered only once in any nine-month period, or the single dose of the short-acting psychedelic agent is for administration only once in any nine-month period; or further provides a combination as described in any one of Embodiments 11 and 12, wherein the single dose of the short-acting psychedelic agent is for administration only once in any nine-month period. In further embodiments, the present invention provides a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use as described in any one of embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered up to once every nine months, or the single dose of the short-acting psychedelic agent is for administration up to once every nine months.

[0107] The present invention further provides, as Embodiment 16, a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use described in any one of Embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered only once in any 12-month period, or the single dose of the short-acting psychedelic agent is for administration only once in any 12-month period; or further provides a combination described in any one of Embodiments 11 and 12, wherein the single dose of the short-acting psychedelic agent is for administration only once in any 12-month period. In further embodiments, the present invention provides a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use as described in any one of embodiments 11 and 12, wherein a single dose of the short-acting psychedelic agent is administered up to once every 12 months, or the single dose of the short-acting psychedelic agent is for administration up to once every 12 months.

[0108] The present invention further provides, as Embodiment 17, a combination, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any of the earlier embodiments, which are, (i) Oral formulations of monoamine antidepressants; and (ii) Parenteral formulations of short-acting psychedelic drugs Includes.

[0109] Embodiment 18 further provides a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use in the treatment of a mental disorder, preferably selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, and preferably selected from depressive disorders and anxiety disorders.

[0110] Embodiment 19 further provides a combination, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use in the treatment of a depressive disorder selected from major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, depression in terminally ill patients, and treatment-resistant depression, as described in any of the earlier embodiments.

[0111] As Embodiment 20, the present invention further provides a combination, treatment method, kit, dosing regimen, adjunctive treatment method, or short-acting psychedelic agent for use in the treatment of anxiety disorders selected from generalized anxiety disorder, phobias, panic disorder, social anxiety disorder, and post-traumatic stress disorder, as described in any of the earlier embodiments.

[0112] The present invention further provides, as Embodiment 21, a combination for use, a therapeutic method, a kit, a dosing regimen, an adjunct therapeutic method, or a short-acting psychedelic agent for use described in any one of Embodiments 18 to 20, which are, Prior to administration of short-acting psychedelics, assess the patient using baseline assessments with rating scales and / or healthcare worker-reported outcomes and / or patient-reported outcomes; and Patients are evaluated in a post-administration assessment after administration of a short-acting psychedelic. Further includes processes and / or instructions for doing so.

[0113] The present invention further provides, as Embodiment 22, a combination for use, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use described in Embodiment 21, wherein baseline assessments include: Clinical Global Impression Scale (CGI); Montgomery-Asberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD17); Beck Depression Inventory II; Beck Anxiety Inventory (BAI); Hamilton Anxiety Scale (HAM-A); State-Trait Anxiety Inventory (STAI or STAI-T); General Anxiety Disorder Assessment (GAD-7); Clinician Post-Traumatic Stress Disorder Scale (CAPS); Yale-Brown Obsessive-Compulsive Scale; Beck Scale for Suicidal Ideation (BSS); Columbia Suicide Severity Rating Scale (C-SSRS); Suicidal Thought Item of MADRS for Suicidal Ideation; Clinical Global Impression Revised (CGI-SS-R) Scale for Suicidal Tendency Severity; Beck Depression Inventory (BDI-II); Quality of Life The assessment is based on a selection of evaluation scales, including the Pleasure and Satisfaction Questionnaire - Short Version (Q-LES-Q-SF), the EQ-5D-5L Descriptive System and EQ VAS, the Patient's General Impression Scale for Severity (PGI-S), and combinations thereof.

[0114] The present invention further provides, as Embodiment 23, a combination for use, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use described in Embodiment 21 or 22, wherein post-administration evaluation is performed using the following: Clinical Global Impression Scale (CGI); Montgomery-Asberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD17); Beck Depression Inventory II; Beck Anxiety Inventory (BAI); Hamilton Anxiety Scale (HAM-A); State-Trait Anxiety Inventory (STAI or STAI-T); General Anxiety Disorder Assessment (GAD-7); Clinician Post-Traumatic Stress Disorder Scale (CAPS); Yale-Brown Obsessive-Compulsive Scale; Beck Scale for Suicidal Ideation (BSS); Columbia Suicide Severity Rating Scale (C-SSRS); MADRS Suicidal Thought Item for Suicidal Ideation; Clinical Global Impression Revised (CGI-SS-R) Scale for Suicidal Tendency Severity; Beck Depression Inventory (BDI-II); Quality of Life The assessment is based on the following scales: the Enjoyment and Satisfaction Questionnaire - Short Version (Q-LES-Q-SF); the EQ-5D-5L Descriptive System and EQ VAS; the Patient's General Impression Scale for Severity (PGI-S); the Clinical General Improvement Scale (CGI-I); the Patient's General Impression Scale for Improvement (PGI-I); and assessment scales selected from combinations thereof.

[0115] The present invention further provides, as Embodiment 24, a combination for use, a treatment method, a kit, a dosing regimen, an adjunct treatment method, or a short-acting psychedelic agent for use described in any one of Embodiments 21 to 23, wherein the mental disorder is a depressive disorder, and baseline and post-dosing assessments are performed using a depression rating scale selected from the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD17), the Beck Depression Scale II, and combinations thereof.

[0116] The present invention further provides, as Embodiment 25, a combination for use, a treatment method, a kit, a dosing regimen, an adjunct treatment method, or a short-acting psychedelic agent for use described in any one of Embodiments 18 to 24, which result in remission from mental disorders in patients.

[0117] The present invention further provides, as Embodiment 26, a combination for use, a treatment method, a kit, a dosage schedule, an adjunct treatment method, or a short-acting psychedelic agent for use as described in Embodiment 25, wherein remission is evaluated at a time of 6 to 10 days, preferably 6 to 8 days, after administration of the short-acting psychedelic agent.

[0118] The present invention further provides, as Embodiment 27, a combination for use, a treatment method, a kit, a dosage plan, an adjunct treatment method, or a short-acting psychedelic agent for use as described in any of the earlier embodiments, wherein the administration or instructions for administration of the short-acting psychedelic agent include: Administering a dose of a short-acting psychedelic agent parenterally to the patient for a maximum duration of approximately 15 minutes, preferably from approximately 5 minutes to approximately 15 minutes, and In this context, parenteral administration is essentially continuous.

[0119] The present invention further provides, as Embodiment 28, a combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in Embodiments 11 to 27, wherein the administration of the short-acting psychedelic agent is parenteral administration selected from the group consisting of intravenous, intramuscular, intranasal, transmucosal, and transdermal administration, and inhalation, preferably selected from intravenous and intramuscular administration.

[0120] The present invention further provides, as Embodiment 29, a combination for use, a therapeutic method, a kit, a dosing regimen, an adjunctive therapeutic method, or a short-acting psychedelic agent for use as described in Embodiment 28, wherein parenteral administration is by intravenous infusion, preferably by using a syringe pump.

[0121] The present invention further provides, as Embodiment 30, a combination for use, a therapeutic method, a kit, a dosing regimen, an adjunctive therapeutic method, or a short-acting psychedelic agent for use as described in Embodiment 29, wherein parenteral administration is by biphasic intravenous infusion.

[0122] The present invention further provides, as Embodiment 31, a combination for use, a treatment method, a kit, a dosing regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use as described in Embodiment 29, wherein parenteral administration is by monophasic intravenous infusion.

[0123] The present invention further provides, as Embodiment 32, a combination for use, a treatment method, a kit, a dosing plan, an adjunct treatment method, or a short-acting psychedelic agent for use as described in any one of Embodiments 28 to 31, wherein the dosing period is approximately 8 minutes to approximately 12 minutes.

[0124] The present invention further provides, as Embodiment 33, a combination for use, a treatment method, a kit, a dosing schedule, an adjunct treatment method, or a short-acting psychedelic agent for use as described in Embodiment 30, wherein the dosing period is approximately 9 minutes to approximately 11 minutes, or approximately 10 minutes.

[0125] As Embodiment 34, the present invention further provides a combination or combination for use, treatment method, kit, administration plan, adjunctive treatment method, or short-acting psychedelic agent for use described in any of the earlier embodiments, wherein the dose of the short-acting psychedelic agent is selected from the group consisting of: - Approximately 20 mg to 80 mg of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; - Approximately 20 mg to 80 mg of deuterated N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; - Approximately 15 mg to 30 mg of deuterated N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; - Approximately 10 mg to 30 mg of 5-methoxy-N,N-dimethyltryptamine, its deuterated analogues, or pharmaceutically acceptable salts thereof; - Approximately 10 mg to 30 mg of deuterated 5-methoxy-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; Alternatively, the dose of a short-acting psychedelic is selected from the following group: - Approximately 10 mg to 30 mg of psilocybin, or a pharmaceutically acceptable salt thereof; - Approximately 10 mg to 20 mg of deuterated psilocybin, or a pharmaceutically acceptable salt thereof; - Approximately 1 mg to 20 mg of psilocin, or a pharmaceutically acceptable salt thereof; - Approximately 1 mg to approximately 20 mg of deuterated psilocine, or a pharmaceutically acceptable salt thereof; and - Approximately 20 mg to 50 mg of psilocin-4-glutarate, deuterated psilocin-4-glutarate, iprosin-4-glutarate, or deuterated iprosin-4-glutarate, or pharmaceutically acceptable salts thereof.

[0126] To avoid any ambiguity, when salts of short-acting psychedelics are used, the specified dose is the dose of free base equivalents.

[0127] The present invention further provides, as Embodiment 35, a combination for use described in any one of Embodiments 11 to 34, or a therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any of the earlier embodiments, which include parenteral administration of a total dose of about 20 mg 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.

[0128] The present invention further provides, as Embodiment 36, a combination for use described in any one of Embodiments 11 to 35, or a therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any of the earlier embodiments, which include parenteral administration of N,N-dimethyltryptamine, a deuterated analog, a pharmaceutically acceptable salt thereof, or a mixture thereof in a total dose of about 20 mg to about 23 mg, or a total dose of about 26 mg to about 29 mg.

[0129] The present invention further provides, as Embodiment 37, a combination for use described in any one of Embodiments 11 to 34, or a therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 2 to 34, wherein the short-acting psychedelic agent 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, with a total dose of about 7 mg to about 10 mg.

[0130] The present invention further provides, as Embodiment 38, a combination for use, a method of treatment, a kit, a dosage plan, an adjunct treatment method, or a short-acting psychedelic agent for use as described in any one of Embodiments 34 to 36, wherein the administration is by intravenous infusion, and the short-acting psychedelic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine, a mixture thereof, or a pharmaceutically acceptable salt thereof, with a total dose of about 20 mg to about 23 mg.

[0131] The present invention further provides, as Embodiment 39, a combination for use, a method of treatment, a kit, a dosage plan, an adjunct treatment method, or a short-acting psychedelic agent for use as described in any one of Embodiments 34 to 36, wherein the administration is by intravenous infusion, and the short-acting psychedelic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, or deuterated N,N-dimethyltryptamine, a mixture thereof, or a pharmaceutically acceptable salt thereof, with a total dose of approximately 26 mg to approximately 29 mg.

[0132] The present invention further provides, as Embodiment 40, a combination for use, a treatment method, a kit, a dosage plan, an adjunct treatment method, or a short-acting psychedelic agent for use as described in Embodiments 27, 28, and 34, wherein the administration is by intramuscular administration.

[0133] The present invention further provides, as Embodiment 41, a combination for use, a treatment method, a kit, a dosage plan, an adjunct treatment method, or a short-acting psychedelic agent for use as described in Embodiment 40, wherein the short-acting psychedelic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, with a total dose of about 20 mg to about 70 mg, preferably about 50 mg to about 70 mg; or the short-acting psychedelic agent is N,N-dimethyltryptamine or deuterated N,N-dimethyltryptamine, or a mixture thereof, or a pharmaceutically acceptable salt thereof, with a total dose of about 20 mg to about 60 mg, or about 15 mg to about 30 mg.

[0134] The present invention further provides, as Embodiment 42, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any of the preceding embodiments, wherein the short-acting psychedelic agent is a compound of formula I or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Ra is selected from H and D; or Ra is selected from -OH, -OPO3H2, and -OC(O)C1~C3 alkylenes CO2H; Rb is selected from H, D, -OCH3, and -OCD3; R 2 and R 3 Each of them is independent of C(H z ) Selected from 3; or R 2 and R 3 Each of them operates independently, C2(H z )5 and C3(H z ) Selected from 7; and Each H x H y and H z These are independently selected from protium and deuterium.

[0135] The present invention further provides, as Embodiment 43, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use as described in Embodiment 42, where R 2 and R 3 These are selected independently from CH3 and CD3.

[0136] The present invention further provides, as Embodiment 44, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use as described in Embodiment 42, where R 2 and R 3 Both are CH3, or R 2 and R 3 Both are CD3, or R 2 CH3 is R 3 It is CD3.

[0137] The present invention further provides, as Embodiment 45, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 42 to 44, where each Hx is H, or each H x It is D.

[0138] The present invention further provides, as Embodiment 46, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 42 to 45, where each H y is H, or each H y is D, or one of H y H is the other H y It is D.

[0139] The present invention further provides, as Embodiment 47, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 43 to 44 and 46, where each H x H y and H z It is deuterium.

[0140] The present invention further provides, as Embodiment 48, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any of the earlier embodiments, wherein the short-acting psychedelic agent is a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, or a mixture thereof; wherein Ra and Rb are as defined in Embodiment 42. [ka]

[0141] The present invention further provides, as Embodiment 49, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 42 to 48, where Ra is H.

[0142] The present invention further provides, as Embodiment 50, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 42 to 49, where Rb is H.

[0143] The present invention further provides, as Embodiment 51, a combination, combination for use, therapeutic method, kit, administration plan, adjunctive therapeutic method, or short-acting psychedelic agent for use described in any one of Embodiments 42 to 50, wherein the compound is selected from the following: N,N-dimethyltryptamine; α-Prothio,α-Deutero-N,N-dimethyltryptamine; α,α-didutero-N,N-dimethyltryptamine; α,α,β,β-tetraduetero-N,N-dimethyltryptamine; N,N-di(triduteromethyl)tryptamine; α-Prothio,α-Deutero-N,N-Di(trideuteromethyl)tryptamine; α,α-didutero-N,N-di(triduteromethyl)tryptamine; α,α,β,β-tetraduetero-N,N-di(tridueteromethyl)tryptamine; 5-Methoxy-N,N-dimethyltryptamine; 5-Methoxy-α-Prothio,α-Deutero-N,N-dimethyltryptamine; 5-Methoxy-α,α-didutero-N,N-dimethyltryptamine; 5-Methoxy-α,α,β,β-tetraduetero-N,N-dimethyltryptamine; 5-Methoxy-N,N-di(trideuteromethyl)tryptamine; 5-Methoxy-α-Prothio,α-Deutero-N,N-Di(trideuteromethyl)tryptamine; 5-Methoxy-α,α-didutero-N,N-di(triduteromethyl)tryptamine; 5-Methoxy-α,α,β,β-tetraduetero-N,N-di(tridueteromethyl)tryptamine; and Pharmacologically acceptable salts thereof, and mixtures thereof; Alternatively, the compound is selected from the following group: Psilocybin; α-Prothio,α-Deuteropsilocybin; α,α-diduteropsilocybin; α,α,β,β-tetradueteropsilocybin; 4-(dihydrogen phosphate)-N,N-di(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α-prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α,α,β,β-tetraduetero-N,N-di(tridueteromethyl)tryptamine; Psilocine; α-Prothio, α-Deuterosilosin; α,α-diduterosilosine; α,α,β,β-tetradueterosilosine; 4-Hydroxy-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-α-prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 4-Hydroxy-α,α,β,β-tetraduetero-N,N-di(tridueteromethyl)tryptamine; Psilosin-4-glutarate; α-Prothio,α-Deuterosilosin-4-Glutarate; α,α-diduterosilosin-4-glutarate; α,α,β,β-tetradueterosilosin-4-glutarate; 4-Hydroxy-N,N-di(trideuteromethyl)tryptamine-4-glutarate; 4-Hydroxy-α-Prothio,α-Deutero-N,N-Di(Triduteromethyl)tryptamine-4-Glutarate; 4-hydroxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine-4-glutarate; 4-Hydroxy-α,α,β,β-tetraduetero-N,N-di(tridueteromethyl)tryptamine-4-glutarate; Iprosin-4-glutarate; α-Prothio,α-Deutero-Iprosin-4-Glutarate; α,α-didutero-iprosin-4-glutarate; α,α,β,β-tetraduetero-iprosin-4-glutarate; 4-Hydroxy-N,N-di(heptaduteroisopropyl)tryptamine-4-glutarate; 4-Hydroxy-α-Prothio,α-Deutero-N,N-Di(Heptaduteroisopropyl)tryptamine-4-Glutarate; 4-Hydroxy-α,α-didutero-N,N-di(heptaduteroisopropyl)tryptamine-4-glutarate; 4-Hydroxy-α,α,β,β-tetraduetero-N,N-di(heptaduteroisopropyl)tryptamine-4-glutarate; and Pharmacopoeially acceptable salts thereof, and mixtures thereof.

[0144] The present invention further provides, as Embodiment 52, a combination for use, a therapeutic method, a kit, a dosing regimen, an adjunct therapeutic method, or a short-acting psychedelic agent for use described in any one of Embodiments 18 to 51, which include the following: administration to a patient or instructions for administration to a patient: (i) Oral administration of selective serotonin reuptake inhibitors to the patient for a period of four weeks or more; (ii) Parenteral administration to patients of short-acting psychedelic agents selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, their deuterated analogs, and pharmaceutically acceptable salts thereof. Steps (i) and (ii) of Embodiment 52 may be administered by different healthcare professionals.

[0145] The present invention further provides, as Embodiment 53, a combination for use, a treatment method, a kit, a dosing regimen, an adjunct treatment method, or a short-acting psychedelic agent for use as described in Embodiment 52, wherein oral administration of a selective serotonin reuptake inhibitor to a patient is performed over a period of six weeks or more.

[0146] As Embodiment 54, the present invention further provides a combination, combination for use, treatment method, kit, administration plan, adjunct treatment method, or short-acting psychedelic agent for use in the treatment of mental disorders in patients, wherein the treatment includes psychedelic-assisted psychotherapy.

[0147] The present invention further provides, in Embodiment 55, the kit described in Embodiment 54, which includes instructions for psychedelic supportive psychotherapy.

[0148] The present invention further provides, as Embodiment 56, a therapeutic method, administration plan, combination for use, adjunctive therapeutic method, or short-acting psychedelic agent for use described in Embodiment 54, which include: A. The following administrations to the patient (i) monoamine antidepressants, and (ii) Parenteral formulations of short-acting psychedelic agents, preferably selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, psilocine, deuterated psilocine, psilocybin, deuterated psilocybin, psilocine-4-glutarate, deuterated psilocybin, iprosin-4-glutarate, deuterated iprosin-4-glutarate and pharmaceutically acceptable salts thereof; and B. Psychotherapy sessions. Steps (i) and (ii) of Embodiment 56 may be administered by different healthcare professionals.

[0149] The present invention further provides, as Embodiment 57, a treatment method, administration plan, combination for use, adjunct treatment method, or short-acting psychedelic agent for use as described in Embodiment 54 or 56, wherein a psychotherapy session includes: a. Preparation Stage, which includes preparing the patient for a psychedelic experience; b. Administration Stage, comprising the administration of a short-acting psychedelic agent according to any of the embodiments described above; and c. Integration Stage, including interviews or discussions with the patient led by a psychiatrist or therapist, focusing on the psychedelic experience.

[0150] The present invention further provides, as Embodiment 58, the kit described in Embodiment 55, which further includes instructions for: a. Preparation phase, including preparing the patient for a psychedelic experience; b. Administration step, comprising administration of a short-acting psychedelic agent according to any of the preceding embodiments; and c. The integration phase includes interviews or discussions with the patient, led by a psychiatrist or therapist, that focus on the psychedelic experience.

[0151] The present invention further provides, in Embodiment 59, the auxiliary treatment method described in Embodiment 5, wherein a short-acting psychedelic agent is administered to a patient who has received an appropriate course of monoamine antidepressants.

[0152] The present invention further provides, as Embodiment 60, the auxiliary treatment method described in Embodiment 5 or 59, in which a short-acting psychedelic agent and a monoamine antidepressant are administered separately.

[0153] The present invention further provides, as Embodiment 61, the auxiliary treatment method described in Embodiments 5, 59, or 60, where, (i) Short-acting psychedelic agents are selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof; and (ii) The monoamine antidepressant is a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and pharmaceutically acceptable salts thereof.

[0154] The present invention further provides, in Embodiment 62, a short-acting psychedelic agent for use as described in Embodiment 6, wherein the short-acting psychedelic agent is administered to a patient receiving an appropriate course of monoamine antidepressants.

[0155] The present invention further provides, as Embodiment 63, a short-acting psychedelic agent for use as described in Embodiment 6 or 62, wherein the short-acting psychedelic agent and the monoamine antidepressant are administered to the patient separately.

[0156] The present invention further provides, as Embodiment 64, a short-acting psychedelic agent for use as described in Embodiments 6, 62, or 63, where, (i) Short-acting psychedelic agents are selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof; and (ii) The monoamine antidepressant is a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and pharmaceutically acceptable salts thereof.

[0157] The present invention further provides, as Embodiment 65, a combination including the following: (i) Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and pharmaceutically acceptable salts thereof; and (ii) Short-acting psychedelic agents selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof; These are intended for simultaneous, sequential, or separate use in the treatment of mental disorders in patients, and preferably the mental disorders are selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0158] The present invention further provides, as Embodiment 66, a combination for use described in Embodiment 65, for separate use in the treatment of mental disorders in patients, preferably, the mental disorder being selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0159] The present invention further provides, as Embodiment 67, a combination for use described in Embodiment 65 or 66, wherein the short-acting psychedelic agent is administered to a patient who has received an appropriate course of selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

[0160] The present invention further provides, as Embodiment 68, a combination for use described in Embodiments 65 to 67, which comprises SSRIs selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, as well as pharmaceutically acceptable salts thereof.

[0161] In a seventh aspect, the present invention further provides the use of short-acting psychedelic agents for the manufacture of pharmaceuticals for the adjunctive treatment of mental disorders in patients receiving treatment with monoamine antidepressants, preferably the mental disorder being selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders.

[0162] In an eighth aspect, the present invention provides a parenteral formulation comprising a dose of a short-acting psychedelic agent for use in the treatment of a mental disorder in a patient receiving treatment with a monoamine antidepressant; wherein the treatment comprises administering a dose of the short-acting psychedelic agent to the patient, preferably parenterally; preferably, the mental disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, and eating disorders, and preferably selected 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.

[0163] In a ninth aspect, the present invention further provides a delivery device for use in the treatment of mental disorders in patients being treated with monoamine antidepressants, wherein the delivery device is configured to deliver a parenteral dose, preferably a parenteral dose, of a short-acting psychedelic agent to the patient.

[0164] To avoid any doubt, all embodiments and aspects disclosed herein with respect to the first to sixth aspects shall apply mutatis mutandis to the seventh to ninth aspects of the present invention.

[0165] A combination of a monoamine antidepressant and a short-acting psychedelic, as defined in any aspect or embodiment of the present invention, preferably provides simultaneously detectable plasma concentrations of the monoamine antidepressant and the short-acting psychedelic when administered to a patient.

[0166] The combinations of the present invention, combinations for use, dosage plans, therapeutic methods, adjunctive therapeutic methods, short-acting psychedelic agents for use in kits, delivery devices, or parenteral formulations may be prepared according to the synthesis processes described in WO2021 / 089873, US20210395201, WO2022 / 117359 and US20220202775, the disclosures thereof being incorporated herein in their entirety by reference.

[0167] The dose of a short-acting psychedelic agent for use in the combinations, combinations for use, administration plans, therapeutic methods, adjunctive therapeutic methods, short-acting psychedelic agents for use, kits, delivery devices, or parenteral formulations of the present invention may preferably be in the form of a pharmaceutically acceptable salt, where the salt comprises an acid and a free base of a short-acting psychedelic agent selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, psilocybin, psilocin, psilocin-4-glutarate, iprosin-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. In "Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich:Wiley-VCH / VHCA, 2002," P.H. Stahl and C.G. Wermuth provide an overview of pharmaceutical salts and the acids they contain. The acids listed in this review are suitable for inclusion in salts of pharmaceutical formulations.

[0168] The salts include fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, gluconic acid, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphor acid, camphor (camphor)-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid (gentisic acid), and gluten. It may contain acids selected from the group consisting of coheptonic acid, glucuronic acid, glutamic acid, 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, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, toluenesulfonic acid, and undecylenic acid.

[0169] Preferably, the pharmaceutically acceptable salt is selected from fumarate, tartrate, citrate, succinate, benzoate, and hydrochloride. More preferably, the pharmaceutically acceptable salt is fumarate.

[0170] More preferably, the pharmaceutically acceptable salt of a short-acting psychedelic is a fumarate.

[0171] Parenteral administration routes include intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, and transdermal administration, as well as inhalation. Any parenteral route capable of administration over a period of up to about 15 minutes, preferably from about 5 minutes to about 15 minutes, is suitable for use in the present invention. Preferred parenteral administration routes according to any aspect of the present invention are selected from intravenous infusion, intramuscular infusion, subcutaneous infusion, intranasal, transmucosal, and transdermal administration, as well as inhalation. Intravenous infusion is a particularly preferred route of administration. Intramuscular administration is a particularly preferred route of administration.

[0172] If the parenteral administration route is intravenous, the delivery device may include an infusion bag or syringe, and preferably further include a syringe pump. When administering intravenous infusion using two syringe pumps, the syringe pumps may be connected to a single cannula via a three-way tap. If the parenteral administration route is intramuscular, the delivery device may include a syringe. If the parenteral route is intranasal, the delivery device may include a pump-action spray means. If the parenteral route is transmucosal, the delivery device may include an oromucosal film. If the parenteral route is transdermal, the delivery device may include a transdermal patch. If the administration route is inhalation, the delivery device may include a metered-dose inhaler, vaporizer, or nebulizer.

[0173] Formulations suitable for parenteral administration have a pH of approximately 3 to 9, and liquid formulations have an osmotic pressure (osmolality) of approximately 250 to 600 mOsm / Kg. pH values ​​above 9 have been reported by I. Usach et al. in "Adv. Ther., 36, 2986-2996 (2019)" to be associated with tissue necrosis (death of cells in tissue), while values ​​below 3 have been reported to cause pain and phlebitis (inflammation of veins). Osmotic pressures above 600 mOsm / Kg have also been reported to cause pain. Usach et al. also recommend that parenteral formulations should be formulated as isotonic solutions (osmotic pressure of approximately 300 mOsm / Kg), and suggest an upper limit of 600 mOsm / Kg to minimize pain.

[0174] Osmotic pressure is formally defined as the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water, and is expressed by the following formula:

number

[0175] In this specification, when a first solution is defined as isotonic with a second solution, those solutions have the same osmotic pressure. For example, when a formulation is defined as isotonic with human serum, that formulation has the same osmotic pressure as human serum. Human serum typically has an osmotic pressure of about 275 to about 300 mOsm / Kg (L. Hooper et al., BMJ Open, 2015; 5(10): e008846).

[0176] Formulations suitable for injection according to the present invention are described in WO2022 / 043227 and US11406619. Formulations suitable for inhalation according to the present invention are described in WO2022 / 117640. Formulations suitable for transdermal administration are described in US2021 / 0346347 and US17 / 866,477. Formulations suitable for buccal administration are described in WO2022 / 232179. Other suitable formulations according to the present invention are described in concurrently pending patent application US17 / 574,424. The entire disclosures of each of these patent applications are incorporated herein by reference.

[0177] In some embodiments, the parenteral formulation for use in the present invention comprises a salt of a short-acting psychedelic agent, a base agent, water, and optionally a buffer other than the salt, wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg / ml or more as free base, and an osmotic pressure of about 250 to about 350 mOsm / Kg; and wherein the formulation comprises a dose of the short-acting psychedelic agent in a volume of 5 ml or less.

[0178] A base agent adjusts the pH of the formulation to the required pH range, for example, from pH 5 to pH 6. Since the pH of formulations containing salts of short-acting psychedelic agents, water, and buffers is often low (e.g., less than pH 5), pH adjustment with a base agent may be necessary. Those skilled in the art can evaluate suitable base agents for adjusting the pH of a solution without the risk of decomposition of the salts of short-acting psychedelic agents. The base agent may be sodium hydroxide or potassium hydroxide.

[0179] Parenteral formulations may optionally contain a buffer in addition to the salt, i.e., the buffer is not simply a counterion for the short-acting psychedelic agent. For example, if the salt is N,N-dimethyltryptamine fumarate (i.e., the fumarate of N,N-dimethyltryptamine), then in addition to the buffering effect provided by the fumarate, a certain amount of buffer may be required. The term “buffer” is well known in the art and refers to a chemical substance that, when included in a formulation, resists changes in pH due to the addition of an acid or base to the formulation. As used herein, the term “buffer” refers to a buffering system or buffering agent. In a formulation, a buffer contains a weak acid and its conjugate base. A suitable buffer contains an acid having a pKa value within ±1 of the desired pH of the formulation. For example, if the desired pH of the formulation is about 5.0, a suitable buffer contains a weak acid having a pKa value between about 4.0 and about 6.0. If the acid in the buffer has multiple pKa values ​​(i.e., each molecule of the acid can donate multiple protons), then for the buffer to be suitable, at least one of the pKa values ​​must be within the desired pH range.

[0180] The weak acid and conjugate base in the buffer are in equilibrium with each other. According to Le Chatelier's principle (when a constraint (such as a change in the concentration of reactants) is applied to a system in equilibrium, the equilibrium shifts to counteract the effect of that constraint), the addition of an acid or base to the formulation shifts the equilibrium position in a direction favorable to the conjugate base or weak acid, respectively. As a result, the concentration of free protons in the formulation (and therefore the pH) remains relatively unchanged.

[0181] Suitable buffer systems include acetates and acetic acid (pKa=4.75); citrates 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 reported in water at 25°C. Typically, the buffer contains only one of the above pairs, i.e., one acid and its conjugate base.

[0182] 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.

[0183] The buffer concentration in the formulation is typically sufficient to withstand significant pH changes in the formulation when stored for two weeks (i.e., the pH typically fluctuates by less than about 0.1 pH units). Those skilled in the art can assess and achieve an appropriate buffer concentration. Often, the buffer concentration is about 15 mM to about 75 mM, for example, about 20 mM to about 30 mM. In some embodiments, the buffer concentration is about 25 mM.

[0184] As used herein, the term “buffer” refers to a weak acid or weak base. Any pharmaceutically acceptable buffer, including phosphoric acid, citric acid, acetic acid, phosphates, citrates, and acetates, may be used in the formulations of the present invention. In some embodiments, the buffer comprises sodium phosphate, sodium citrate, or sodium acetate.

[0185] Sometimes, the concentration of a short-acting psychedelic agent and any buffer in a formulation results in a desired osmotic pressure. Alternatively, the desired osmotic pressure can be achieved by including one or more isotonic agents in the formulation. Therefore, in some embodiments, the formulation further includes an isotonic agent. In this specification, an isotonic agent is defined as a chemical substance that, when included in a formulation, increases the osmotic pressure of the formulation. As described above, osmotic pressure is the number of osmotically active particles (number of solute particles) contained in 1 kg of solution. Therefore, a chemical substance that acts as a solute when incorporated into a formulation is included in the definition of an isotonic agent.

[0186] In some embodiments, the formulation includes an isotonic agent. The concentration of the isotonic agent depends on the concentrations of other components in the formulation, such as short-acting psychedelics and buffers. For example, if a formulation without an isotonic agent has an osmotic pressure of about 60 mOsm / kg, at least about 190 mOsm / kg is provided by the isotonic agent (e.g., 95 mM sodium chloride). MF Powell, T. Nguyen, and L. Baloian provide a review of excipients suitable for parenteral administration (administration by means other than the mouth or gastrointestinal tract) in "PDA J. Pharm. Sci. Technol., 52, 238-311 (1998)". All soluble excipients that can be administered intravenously, as described in this review, can be considered isotonic agents because they contribute to the osmotic pressure when added to a formulation.

[0187] Suitable excipients for use in the dosage of short-acting psychedelic agents when used according to the present invention may be selected from the group comprising ethanol, citric acid, trisodium citrate, benzalkonium chloride, microcrystalline cellulose, sodium carboxymethylcellulose, chlorobutanol, disodium edetate, glycerin, hydrochloric acid, methylparaben, polyethylene glycol, propylene glycol, propylparaben, sodium saccharin, sodium bicarbonate, sodium bisulfite, sodium bisulfite, sodium chloride, sodium hydroxide, sodium metabisulfite, sodium phosphate, sodium citrate, sulfuric acid, trisodium citrate, tromethamine, and mixtures thereof.

[0188] Some excipients can act as co-solvents. Suitable solvents or co-solvents for use in the formulations of the present invention may be selected from ethanol, polyethylene glycol, propylene glycol, and mixtures thereof. In some embodiments, the formulations contain a co-solvent. In some embodiments, the formulations do not contain a co-solvent. In particular, when the salt of the short-acting psychedelic agent is a fumarate, for example, N,N-dimethyltryptamine fumarate or α,α-didutero-N,N-dimethyltryptamine fumarate, the formulations do not contain a co-solvent.

[0189] Therapeutic improvement can be assessed using assessment scales commonly used in the field. For patients with depressive disorders such as MDD or TRD, the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAMD-17) may be used. The assessment scales are used to perform a baseline assessment before administration of the short-acting psychedelic and again to assess the therapeutic effect after administration of the short-acting psychedelic (post-administration). Preferably, post-administration assessments are performed about 24 hours to about 1 month after administration of the short-acting psychedelic, preferably about 1 week, about 2 weeks, about 3 weeks and / or about 4 weeks after administration of the short-acting psychedelic. A reduction in symptoms to a substantially asymptomatic level is considered to indicate remission. Remission can be assessed by a MADRS score of 13 or less, or 10 or less, a HAMD-17 score of 10 or less, preferably 8 or less, or a BDI-II score of 13 or less, preferably 11 or less.

[0190] In some embodiments, a short-acting psychedelic agent may be administered as a biphasic IV infusion via an intravenous cannula over a period of 6 to 11 minutes. In some embodiments, the short-acting psychedelic agent may be administered as a biphasic IV infusion via an intravenous cannula, where each phase comprises a 5-minute infusion. In some embodiments, the short-acting psychedelic agent may be administered as a monophasic IV infusion via an intravenous cannula over a period of 6 to 11 minutes, preferably about 10 minutes. When a biphasic IV infusion is used, preferably, a syringe pump is connected to a single cannula via a three-way stopcock: once the infusion from the first pump is complete, the three-way stopcock is switched, and the infusion from the second pump continues.

[0191] The term "monophasal" IV infusion refers to the administration of an IV infusion using a single syringe pump, where the short-acting psychedelic is administered from a single syringe pump. The term "biphasic" IV infusion refers to the administration of an IV infusion using two syringe pumps, where the first phase involves the administration of a short-acting psychedelic from the first syringe pump, followed by the second phase involving the administration of a short-acting psychedelic from the second syringe pump. Biphasic IV infusion is essentially continuous (with a non-substantial interruption in the infusion to switch administration from the first syringe pump to the second syringe pump).

[0192] In some embodiments, short-acting psychedelic agents may be administered by intramuscular injection.

[0193] In some embodiments, the kit is a kit for treating a patient's mental disorder according to one of the preceding embodiments, and the kit is a) A container containing parenteral doses of short-acting psychedelic agents 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 accompanying leaflet on or associated with the container that includes instructions for administering the parenteral formulation, indicating that the administration to the patient is to be used in combination with the administration of a monoamine antidepressant, preferably a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor; Includes.

[0194] In some embodiments, parenteral formulations, combinations, combinations for use, methods of treatment, adjunctive treatments, short-acting psychedelic agents for use, kits, delivery devices, or administration plans according to any of the preceding embodiments are intended for use in treating patients who have not responded to an appropriate course of treatment with at least one antidepressant, preferably at least one monoamine antidepressant, or at least two different antidepressants.

[0195] As used herein, the term "unresponsive" refers to the absence of clinically meaningful improvement in symptoms, as measured, for example, by one or more of the rating scales described above. A lack of response to an appropriate course of treatment with monoamine antidepressants may be determined retrospectively or proactively. A proactive determination of unresponsiveness refers to a determination made by the prescribing physician or therapist after the administration of part of the course of treatment. A retrospective determination refers to a determination made by the prescribing physician or therapist after the administration of the entire appropriate course of treatment.

[0196] This invention relates to the treatment of disorders with a combination of drugs: a monoamine antidepressant and a short-acting psychedelic. The “therapeutic” dose of the two drugs refers to the amount of the monoamine antidepressant and the short-acting psychedelic that, when administered in combination, elicits a clinically meaningful response in a patient. The dose of each drug may not be therapeutically effective when administered alone. For example, the dose of a monoamine antidepressant may be less than a therapeutically effective dose when administered alone, but may be therapeutically effective when administered in combination with a short-acting psychedelic according to this invention. To avoid doubt, the doses of (i) a monoamine antidepressant and (ii) a short-acting psychedelic as defined in any of the preceding embodiments include a therapeutically effective dose when administered together.

[0197] The combination therapy according to the present invention can be achieved by administering a monoamine antidepressant and a short-acting psychedelic agent simultaneously, sequentially, or separately. The monoamine antidepressant and the short-acting psychedelic agent are preferably formulated and administered separately. The monoamine antidepressant and the short-acting psychedelic agent are often prescribed and / or administered by different healthcare professionals (such as physicians). The present invention also provides the administration of these two in a single formulation. Other combinations may also be included in combination therapy. For example, the two drugs may be formulated together and administered in combination with a further dose of either drug or another formulation containing a third drug. Two or more drugs in combination therapy may be administered simultaneously, but this is not mandatory. For example, the administration of the first drug (or combination of drugs) may precede the administration of the second drug (or combination of drugs) by several minutes, several hours, several days, or several weeks. Therefore, two or more drugs can be administered to each other within minutes, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days, or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks (for example, when monoamine antidepressants are administered as controlled-release formulations). In some cases, longer intervals are also possible. Often, it is desirable, though not required, that the two or more drugs used in combination therapy be present in the patient's body simultaneously, i.e., the administration schedules for monoamine antidepressants and short-acting psychedelics provide simultaneously detectable plasma concentrations. Combination therapy may also involve two or more doses of one or more of the drugs used in combination. The two drugs may be administered according to different dosing schedules and by different healthcare providers. For example, monoamine antidepressants may be delivered on a daily schedule, and single doses of short-acting psychedelics may be administered separately over any 3-month, 6-month, 9-month, or 12-month period.For example, a monoamine antidepressant may be delivered on a daily schedule, and a single dose of a short-acting psychedelic may be administered separately, up to once every three months, or up to once every six months, or up to once every nine months, or up to once every twelve months. The two agents of the present invention may be administered sequentially one or more times in any combination. Preferably, the combination therapy according to the present invention is achieved by a dosing schedule of an antidepressant and a short-acting psychedelic that simultaneously provides concurrently detectable plasma concentrations of the two agents. [Examples]

[0198] Currently, an open-label trial of a single dose of N,N-dimethyltryptamine [DMT] fumarate is underway in patients taking selective serotonin reuptake inhibitors (SSRIs) for depression, but whose depression has not been completely relieved by the SSRIs (ClinicalTrials.gov identifier: NCT05553691). This trial includes two groups: "Study cohort": Patients currently receiving a stable course of treatment with SSRIs but whose depressive symptoms have not been completely relieved (SSRIs prescribed outside the study). Patients were given a single dose of DMT fumarate via intravenous infusion; and "Control cohort": Patients currently receiving no pharmacological treatment for depression (control group). Patients received a single dose of DMT fumarate via intravenous infusion.

[0199] Patients were recruited with moderate to severe major depressive disorder (MDD), defined by a Hamilton Depression Rating Scale (HAM-D) score of 14 or higher. Efficacy was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) to measure the change in patients' depressive symptoms from baseline (day 0). Additional exploratory outcome measures included the Beck Depression Inventory (BDI) for patient self-report depression assessments and the State-Trait Anxiety Inventory (STAI-T) for patient self-report anxiety assessments. DMT fumarate is administered intravenously on day 1. Effectiveness MADRS

[0200] The results using the MADRS scale are shown in Table 1 below. [Table 1]

[0201] Table 1 In the study cohort treated with DMT fumarate in combination with an SSRI, the mean percentage change from baseline (day 0) in the cohort participants (n=12) was -78.1% on day 8 to -90.2% on day 29. The response rate was 100% on day 29 in the study cohort. Remarkably, complete remission was observed in 11 participants (92%) in this cohort on day 29, while 10 participants showed remission at all other time points. One participant was observed to have a MADRS score of 11 on day 29, just short of the remission criterion (score 10).

[0202] In comparison, the control cohort (n=5) showed a mean rate of change from baseline of -53.1% on day 8 and -54.8% on day 29, with a response rate of 80% on day 29. One participant in the control cohort achieved remission on day 29 (20%).

[0203] It was surprising to observe such a significant difference in the effectiveness of DMT treatment for antidepressant effects between the study cohort and the control cohort. These data suggest that the effectiveness of DMT fumarate may be enhanced when administered in combination with an SSRI.

[0204] BDI-II These data were supported by assessments on the Beck (BDI-II) scale at days 15 and 29, as shown in Table 2 below: [Table 2]

[0205] Table 2 Here again, treatment with dimethyl fumarate resulted in a significant mean change rate of -84% at day 15 to -88% at day 29 from baseline (day 0) in the participants of the test cohort (n = 12). In contrast, in the participants of the control cohort (n = 5), the mean change rate from baseline was -54% at day 15 to -59% at day 29. STAI-T

[0206] The results according to the STAI-T scale are shown below.

Table 3

[0207] Table 3 From the data shown in Table 3, it can be seen that treatment with dimethyl fumarate resulted in a significant mean change rate of -41.0% from baseline (day 0) at day 29 in the participants of the test cohort (n = 12). In contrast, in the participants of the control cohort (n = 5), the mean change rate from baseline at day 29 was -27.2%.

[0208] The data shown in Tables 1 to 3 above indicate that in patients who are taking selective serotonin reuptake inhibitors (SSRI) for depression but whose depression has not been completely alleviated by SSRI, the symptoms of both depression and anxiety were significantly reduced after treatment with dimethyl fumarate.

[0209] Safety and tolerance DMT fumarate was well-tolerated in all patients in both the study cohort and the control cohort, with no significant differences between the two groups. No serious drug-related adverse events were reported. A small number of drug-related adverse events (AEs) were reported (8 in the study cohort and 3 in the control cohort), all of which were considered mild or moderate in severity. The majority of drug-related AEs resolved during hospital visits for administration.

Claims

1. (i) monoamine antidepressants; and (ii) Short-acting psychedelic agents A combination that includes this.

2. The combination according to claim 1, wherein the combination is synergistic.

3. The combination according to any of the preceding claims, wherein the monoamine antidepressant is selected from a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor.

4. The aforementioned short-acting psychedelic agents include N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, psilocin, deuterated psilocin, psilocybin, deuterated psilocybin, psilocin-4-glutarate, deuterated psilocin-4-glutarate, iprosin-4-glutarate, deuterated iprosin-4-glutarate, mixtures thereof, and pharmaceutically acceptable salts thereof. A combination selected from any of the preceding claims.

5. The monoamine antidepressants include desvenlafaxine, duloxetine, levomirunacipran, milnacipran, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, as well as pharmaceutically acceptable salts thereof. A combination selected from any of the preceding claims.

6. (i) an appropriate course of monoamine antidepressants; and (ii) Single dose of short-acting psychedelic agents A combination of any of the preceding claims, including the combination of any of the preceding claims.

7. The combination according to claim 6, wherein the appropriate treatment course includes a treatment period of four weeks or more.

8. The combination according to any one of claims 6 and 7, wherein the single dose of the short-acting psychedelic agent is for administration only once during any three-month period.

9. The combination according to any one of claims 6 to 7, wherein the single dose of the short-acting psychedelic agent is for administration at most once every three months.

10. The combination according to any one of claims 6 to 7, wherein the single dose of the short-acting psychedelic agent is for administration only once during any six-month period.

11. The combination according to any one of claims 6 to 7, wherein the single dose of the short-acting psychedelic agent is for administration at most once every six months.

12. The combination according to any one of claims 6 to 7, wherein the single dose of the short-acting psychedelic agent is for administration only once during any nine-month period.

13. The combination according to any one of claims 6 to 7, wherein the single dose of the short-acting psychedelic agent is for administration at most once every nine months.

14. The combination according to any one of claims 6 to 7, wherein the single dose of the short-acting psychedelic agent is for administration only once during any 12-month period.

15. The combination according to any one of claims 6 to 7, wherein the single dose of the short-acting psychedelic agent is for administration at most once every 12 months.

16. (i) Oral formulations of the monoamine antidepressant; and (ii) Parenteral formulations of the short-acting psychedelic agent A combination of any of the preceding claims, including the combination of any of the preceding claims.

17. A combination according to any of the preceding claims for use in the treatment of mental disorders, Preferably, the mental disorder is a combination selected from depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, panic disorder, and eating disorder.

18. A combination of any of the preceding claims for use in the treatment of a depressive disorder, 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 for use in the treatment of an anxiety disorder selected from generalized anxiety disorder, phobias, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

20. A combination for use according to any one of claims 17 to 19, further comprising the following steps: a. Baseline assessment of patients using assessment scales and / or healthcare professional-reported outcomes and / or patient-reported outcomes; and b. Post-administration evaluation of the patient after administration of the short-acting psychedelic agent.

21. The baseline assessments include: Clinical Global Impression Scale (CGI); Montgomery-Asberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD-17); Beck Depression Inventory II; Beck Anxiety Inventory (BAI); Hamilton Anxiety Scale (HAM-A); State-Trait Anxiety Inventory (STAI or STAI-T); Generalized Anxiety Disorder Assessment (GAD-7); Clinician Post-Traumatic Stress Disorder Scale (CAPS); Yale-Brown Obsessive-Compulsive Scale; Beck Scale for Suicidal Ideation (BSS); Columbia Suicide Severity Rating Scale (C-SSRS); Suicidal Thought Item of MADRS for Suicidal Ideation; Clinical Global Impression, Revised (CGI-SS-R) Scale for Suicidal Tendency Severity; Beck Depression Inventory (BDI-II); Quality of Life Questionnaire on Enjoyment and Satisfaction - Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS; Patient General Impression Scale for Severity (PGI-S); and combinations thereof. A combination for use according to claim 20, which is based on an evaluation scale selected from the following.

22. The post-administration evaluations mentioned above include: Clinical Global Impression Scale (CGI); Montgomery-Asberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD-17); Beck Depression Inventory II; Beck Anxiety Inventory (BAI); Hamilton Anxiety Scale (HAM-A); State-Trait Anxiety Inventory (STAI or STAI-T); Generalized Anxiety Disorder Assessment (GAD-7); Clinician Post-Traumatic Stress Disorder Scale (CAPS); Yale-Brown Obsessive-Compulsive Scale; Beck Scale for Suicidal Ideation (BSS); Columbia Suicide Severity Rating Scale (C-SSRS); Suicidal Thought Item of MADRS for Suicidal Ideation; Revised Clinical Global Impression for Suicidal Tendency Severity (CGI-SS-R); Beck Depression Inventory (BDI-II); Quality of Life Questionnaire on Enjoyment and Satisfaction - Short Version (Q-LES-Q-SF); EQ-5D-5L Descriptive System and EQ VAS; Patient Global Impression Scale (PGI-S); Clinical Global Improvement Scale (CGI-I); Patient Global Impression Scale (PGI-I); and combinations thereof A combination for use according to claim 20 or 21, which is based on an evaluation scale selected from the following.

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

24. A combination for use according to any one of claims 13 to 23, which brings about remission of the patient from the mental disorder.

25. The combination for use according to any one of claims 17 to 24, wherein remission is evaluated 6 to 10 days, preferably 6 to 8 days, after administration of the short-acting psychedelic agent.

26. The administration of the aforementioned short-acting psychedelic agent The procedure involves administering the patient a dose of the short-acting psychedelic agent parenterally, with the administration duration being up to about 15 minutes, preferably from about 5 minutes to about 15 minutes. The parenteral administration is substantially continuous. A combination for use according to any one of claims 17 to 25.

27. The administration of the aforementioned short-acting psychedelic agent Parenteral administration is selected from the group consisting of intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, and transdermal administration, and inhalation, and preferably, parenteral administration is selected from the group consisting of intravenous, intramuscular, intranasal, transmucosal, and transdermal administration, and inhalation. A combination for use according to any one of claims 17 to 26.

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

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

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

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

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

33. The dose of the aforementioned short-acting psychedelic agent is - Approximately 20 mg to 80 mg of N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - Approximately 20 mg to 80 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - Approximately 15 mg to 30 mg of deuterated N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; - Approximately 10 mg to approximately 30 mg of 5-methoxy-N,N-dimethyltryptamine, its deuterated analogue, or pharmaceutically acceptable salts thereof; and - Approximately 10 mg to 30 mg of deuterated 5-methoxy-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; Selected from the group consisting of, The dose of the aforementioned short-acting psychedelic agent is - Approximately 10 mg to 30 mg of psilocybin, or a pharmaceutically acceptable salt thereof; - Approximately 10 mg to 20 mg of deuterated psilocybin, or a pharmaceutically acceptable salt thereof; - Approximately 1 mg to 20 mg of psilocine, or a pharmaceutically acceptable salt thereof; - Approximately 1 mg to approximately 20 mg of deuterated psilocine, or a pharmaceutically acceptable salt thereof; and - Approximately 20 mg to 50 mg of psilocin-4-glutarate, deuterated psilocin-4-glutarate, iprosin-4-glutarate, deuterated iprosin-4-glutarate, or pharmaceutically acceptable salts thereof. A combination or combination for use according to any one of claims 6 to 32, selected from the group consisting of the following:

34. A combination for use according to any one of claims 17 to 33, comprising parenteral administration of a total dose of approximately 20 mg to approximately 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. A combination for use according to any one of claims 17 to 33, comprising parenteral administration of N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, or pharmaceutically acceptable salts thereof, or mixtures thereof, in a total dose of approximately 20 mg to approximately 23 mg, or approximately 26 mg to approximately 29 mg.

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

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

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

39. The combination for use according to claim 27, wherein the administration is by intramuscular administration.

40. The short-acting psychedelic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and the total dose is about 20 mg to about 70 mg, preferably about 50 mg to about 70 mg; or, The short-acting psychedelic agent 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 approximately 20 mg to approximately 60 mg, or approximately 15 mg to approximately 30 mg. The combination for use described in claim 39.

41. The combination or combination for use described in any of the preceding claims, wherein the short-acting psychedelic agent is a compound of formula I or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, Ra is selected from H and D; or Ra is -OH, -OPO ３ H ２ and -OC(O)C1-C ３ Alkylene CO2 ２ Selected from H; Rb is H, D, -OCH ３ and -OCD ３ Selected from; R ２ and R ３ are each independently selected from C(Hz) ３ ; or R ２ and R ３ Each of them is independent of C ２ (Hz) ５ and C ３ (Hz) ７ Selected from; and Each H ｘ , H ｙ and H ｚ (These are independently selected from protium and deuterium.)

42. R ２ and R ３ However, each is independent of CH ３ and CD ３ A combination or combination for use as described in claim 41, selected from the above.

43. R ２ and R ３ Both CH ３ R ２ and R ３ Both are on CD ３ is or R ２ ga CH ３ And R ３ is CD ３ The combination or combination for use described in claim 42.

44. Each H ｘ is H, or each H ｘ The combination or combination for use according to any one of claims 41 to 43, wherein D is the combination for use.

45. Each H ｙ Is H, or each H ｙ Is D, or is H ｙ H is the other H ｙ The combination or combination for use according to any one of claims 41 to 44, wherein D is the combination for use.

46. Each H ｘ , H ｙ and H ｚ The combination or combination for use according to any one of claims 41 to 45, wherein is deuterium.

47. The aforementioned short-acting psychedelic agent is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof, or mixtures thereof: 【Chemistry 2】 The combination or combination for use according to any of the preceding claims, wherein Ra and Rb are as defined in claim 41.

48. The combination or combination for use according to any one of claims 41 to 47, wherein Ra is H or Ra is D.

49. The combination or combination for use according to any one of claims 41 to 48, wherein Rb is H or Rb is D.

50. The aforementioned short-acting psychedelic agent N,N-dimethyltryptamine; α-prothio,α-deutero-N,N-dimethyltryptamine; α,α-dideutero-N,N-dimethyltryptamine; α,α,β,β-tetradeutero-N,N-dimethyltryptamine; N,N-di(trideuteromethyl)tryptamine; α-prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine; α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; 5-methoxy-N,N-dimethyltryptamine; 5-methoxy-α-prothio, α-Deutero-N,N-dimethyltryptamine; 5-Methoxy-α,α-didutero-N,N-dimethyltryptamine; 5-Methoxy-α,α,β,β-tetradutero-N,N-dimethyltryptamine; 5-Methoxy-N,N-di(triduteromethyl)tryptamine; 5-Methoxy-α-prothio,α-Deutero-N,N-di(triduteromethyl)tryptamine; 5-Methoxy-α,α-didutero-N,N-di(triduteromethyl)tryptamine; 5-Methoxy-α,α,β,β-tetradutero-N,N-di(triduteromethyl)tryptamine; and pharmaceutically acceptable salts thereof Selected from the group consisting of, The aforementioned compounds are: psilocybin; α-prothio,α-deuteropsilocybin; α,α-dideuteropsilocybin; α,α,β,β-tetradeuteropsilocybin; 4-(dihydrogen phosphate)-N,N-di(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α-prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α,α,β,β-tetradeutero-N,N -di(triduteromethyl)tryptamine; silosine; α-prothio,α-duterosilosine; α,α-diduterosilosine; α,α,β,β-tetraduterosiloin; 4-hydroxy-N,N-di(triduteromethyl)tryptamine; 4-hydroxy-α-prothio,α-dutero-N,N-di(triduteromethyl)tryptamine; 4-hydroxy-α,α-didutero-N,N-di(triduteromethyl)tryptamine; 4-hydroxy-α,α,β,β-tetradutero-N,N-di (triduteromethyl)tryptamine; psilocin-4-glutarate; α-prothio,α-dutero-psilocinate; α,α-didutero-psilocinate; α,α,β,β-tetradutero-psilocinate; 4-hydroxy-N,N-di(triduteromethyl)tryptamine-4-glutarate; 4-hydroxy-α-prothio,α-dutero-N,N-di(triduteromethyl)tryptamine-4-glutarate; 4-hydroxy-α,α-didutero-N, N-di(triduteromethyl)tryptamine-4-glutarate; 4-hydroxy-α,α,β,β-tetradutero-N,N-di(triduteromethyl)tryptamine-4-glutarate; iprosin-4-glutarate; α-prothio,α-dutero-iprosin-4-glutarate; α,α-didutero-iprosin-4-glutarate; α,α,β,β-tetradutero-iprosin-4-glutarate; 4-hydroxy-N,N-di(heptaduteroisopropyl)tryptamine-4-glutarate;4-hydroxy-α-prothio,α-deutero-N,N-di(heptaduteroisopropyl)tryptamine-4-glutarate; 4-hydroxy-α,α-dideutero-N,N-di(heptaduteroisopropyl)tryptamine-4-glutarate; 4-hydroxy-α,α,β,β-tetradeutero-N,N-di(heptaduteroisopropyl)tryptamine-4-glutarate; and pharmaceutically acceptable salts thereof; A combination or combination for use according to any one of claims 41 to 48, selected from the group consisting of the following:

51. (i) Oral administration of selective serotonin reuptake inhibitors to patients for a period of four weeks or more; and (ii) Parenteral administration to patients of short-acting psychedelic agents selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, their deuterated analogs, and pharmaceutically acceptable salts thereof. A combination for use according to any one of claims 17 to 46, including the combination described in any one of claims 17 to 46.

52. The combination for use according to claim 51, wherein the oral administration of the selective serotonin reuptake inhibitor to the patient is over a period of six weeks or more.

53. A combination for use according to any one of claims 17 to 52, wherein the treatment of a mental disorder in a patient includes psychedelic support psychotherapy.

54. A. The following administrations to the aforementioned patient (i) monoamine antidepressants, and (ii) Parenteral formulations of short-acting psychedelic agents, preferably selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, psilocine, deuterated psilocine, psilocybin, deuterated psilocybin, psilocine-4-glutarate, deuterated psilocybin, iprosin-4-glutarate, deuterated iprosin-4-glutarate, and pharmaceutically acceptable salts thereof; and B. Psychotherapy sessions A combination for use according to claim 53, including the combination described in claim 53.

55. a. Preparation phase: This includes preparing the patient for a psychedelic experience; b. Administration stage: comprising administration of the short-acting psychedelic agent according to any of the preceding claims; and c. Integration phase: Includes interviews or discussions with the patient, led by a psychiatrist or therapist, focusing on the psychedelic experience. A combination for use according to claim 53 or 54, further comprising:

56. A short-acting psychedelic agent for use as an adjunct treatment for mental disorders in patients receiving treatment with monoamine antidepressants, wherein the mental disorder is selected from depressive disorders, anxiety disorders, obsessive-compulsive disorders, post-traumatic stress disorders, panic disorders, and eating disorders.

57. The short-acting psychedelic agent for use according to claim 56, wherein the short-acting psychedelic agent is administered to a patient receiving an appropriate course of monoamine antidepressants.

58. The short-acting psychedelic agent and the monoamine antidepressant are administered to the patient separately, the short-acting psychedelic agent for use according to claim 56 or 57.

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

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

61. R ２ and R ３ Both CH ３ is or R ２ and R ３ Both are on CD ３ A short-acting psychedelic agent for use according to any one of claims 56 to 60.

62. Each H ｙ is H, or each H ｙ A short-acting psychedelic agent for use according to any one of claims 56 to 61, wherein D is

63. Each H ｘ , H ｙ and H ｚ A short-acting psychedelic agent for use according to any one of claims 56 to 62, wherein the active ingredient is deuterium.

64. The aforementioned short-acting psychedelic agent is selected from the group consisting of the following compounds, or pharmaceutically acceptable salts thereof, or mixtures thereof: 【Chemistry 4】 A short-acting psychedelic agent for use according to any one of claims 56 to 63, wherein Ra and Rb are as defined in claim 60.

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

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

67. (i) Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and pharmaceutically acceptable salts thereof; and (ii) Short-acting psychedelic agents selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof. A combination of methods, including, for simultaneous, sequential, or separate use in the treatment of mental disorders in patients.

68. These are intended for separate use in the treatment of mental disorders in patients. The combination for use according to claim 67, wherein the mental disorder is selected from depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, panic disorder, and eating disorder.

69. The combination for use according to claim 67 or 68, wherein the short-acting psychedelic agent is administered to a patient who has received an appropriate course of treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI).

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

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