A combination comprising a monoamine antidepressant and a short-acting psychedelic agent.

Description

1 / 69 “COMBINATION COMPRISING A MONOAMINE ANTIDEPRESSANT AND A SHORT-ACTING PSYCHEDELIC AGENT” FIELD OF THE INVENTION

[0001] The invention relates to a combination, combination for use, method for treating, kit for, dosage regimen, delivery device, adjunctive treatment method, short-acting psychedelic agent for use, or parenteral formulation for use in the treatment of a psychiatric disorder in a patient. In particular, the invention relates to the administration of a short-acting psychedelic agent in combination with a monoamine antidepressant agent, for example, a selective serotonin reuptake inhibitor (SSRI). BACKGROUND OF THE INVENTION

[0002] Antidepressants are a broad class of pharmaceutical agents used to treat various psychiatric conditions, such as depression, anxiety, obsessive-compulsive disorder, and eating disorders. Many of the antidepressant agents approved by regulatory bodies are monoamine antidepressants: non-psychedelic agents characterized by a mode of action that addresses one or more imbalances (usually a deficiency) of the neurotransmitters serotonin, norepinephrine, and dopamine. The standard of care for most applicable psychiatric conditions is selective serotonin reuptake inhibitors (SSRIs). SSRIs are widely used as antidepressants, generally as first-line treatment, and are believed to work by increasing serotonin levels in the brain.SSRIs are generally taken orally, usually in tablet form, and need to be taken daily for 2 to 4 weeks before any benefit is felt. SSRIs include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vortioxetine.

[0003] Large meta-analyses have shown that SSRIs are typically Petition 870250088636, dated 09 / 30 / 2025, page 13 / 403 2 / 69 are effective in approximately one-third of patients within three months, and an additional third of patients respond within 12 months. The remaining third of patients do not respond and generally remain on one or more antidepressant agents for many years without ever achieving a clinically significant response. Furthermore, patient withdrawal from monoamine antidepressant agents, such as SSRIs, can be difficult and should be done slowly, with dose reduction over a period of 4 weeks or more to avoid withdrawal symptoms (discontinuation syndrome). With over 300 million people suffering from depression worldwide, there remains a predominant medical need to increase the clinical response rate of SSRIs and other monoamine antidepressant agents.

[0004] Classic psychedelics have also demonstrated preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). For example, psilocybin has demonstrated significant improvement on a range of depression and anxiety rating scales in randomized double-blind studies (Griffiths et al. Journal of Psychopharmacology, 30(12), 1181-1197 (2016)). The efficacy of 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 is currently being investigated for several other mental health disorders that are 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. report that daily treatment with escitalopram for 2 weeks did not reduce positive mood. Petition 870250088636, dated 09 / 30 / 2025, p. 14 / 403 3 / 69 or the mind-altering effects of a full dose of psilocybin in healthy individuals (Clin Pharmacol Ther. April 2022; 111(4): 886-895. Published online November 22, 2021. doi: 10.1002 / cpt.2487). An open-label clinical trial was also conducted to investigate the effects of orally administered psilocybin (where the duration of the psychedelic experience is typically six to eight hours) in participants with treatment-resistant depression, comparing participants who were receiving treatment with an SSRI with participants who had discontinued SSRI treatment prior to the study. The study sponsor, Compass Pathways, announced that patients who took psilocybin with concomitant SSRIs showed 'comparable treatment outcomes to those of patients withdrawn from their SSRI therapy' (Compass Pathways press release dated December 13, 2021: https: / / compasspathways.com / positive-outcome-25mg-comp360-psilocybintherapy-adjunct-ssri-antidepressants-open-label-treatment-resistant-depressionstudy / )).

[0006] Cybin Inc. 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 Inc. announced that, following a single oral dose of CYB003, psychedelic effects were observed within «15 minutes» and the median duration of peak effects lasted «2 hours», data 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 to compare the physiological and psychological effects of psilocybin taken orally or sublingually, by dissolving a tablet under the tongue, with those of psilocybin taken by tablet in healthy adults (ClinicalTrials.gov Identifier: NCT05317689). Each participant will receive 15.5 mg of oral psilocin, 25 mg of oral psilocybin, or 2.18 mg–4.36 mg of sublingual psilocin. Petition 870250088636, dated 09 / 30 / 2025, p. 15 / 403 4 / 69

[0008] Reunion Neuroscience has completed a Phase 1 clinical study of a compound that is composed of a glutarate moiety attached to the phenolic functional group of 4-hydroxy-N,N-diisopropyltryptamine. The compound is stated to have a mean duration of subjective experience of 33 mg of 3.7 hours (poster presented at the Annual Meeting of the American Society of Clinical Psychopharmacology, May 30–June 2, 2023: https: / / reunionneuro.com / wp-content / uploads / 2023 / 06 / 23-RNR3851_ASCP23_RE104_Poster_M1-3.pdf). The compound N,N-diisopropyltryptamine-4-glutarate is also known as iprocine-4-glutarate, isoprocine-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 fast-acting antidepressants with a duration of three months or more (Small Pharma Inc press release dated January 25, 2023: https: / / smallpharma.com / press-releases / positive-topline-results-from-phase-iiatrial-of-spl026-in-major-depressive-disorder / ).

[0010] To date, no one has investigated the safety, tolerability, or efficacy of short-acting psychedelics in patients undergoing treatment with monoamine antidepressant agents, such as SSRIs. Most clinical trials testing the efficacy of psychedelics in treating mental disorders exclude patients taking SSRI medication. Since both SSRIs and serotonergic (or classic) psychedelics exert their primary effects through the serotonin system, theoretically, there are several ways in which these compounds could acutely interact: a) Safety: SSRIs inhibit the reuptake of serotonin (5-hydroxytryptamine [5-HT]), which means they increase intrasynaptic serotonin and therefore increase the activity of 5-HT receptors. Since classic psychedelics work by activating 5-HT receptors, these two activities together can induce serotonin toxicity. b) Pharmacodynamics / efficacy: prolonged use of SSRIs results in a Petition 870250088636, dated 09 / 30 / 2025, page 16 / 403 5 / 69 homeostatic dysregulation of 5-HT receptors, which means that when a classic psychedelic is administered, the psychological effect may be attenuated. c) Pharmacodynamics / efficacy: analysis of data from studies evaluating the efficacy of MDMA-assisted therapy after discontinuation of SSRIs suggests that patients who have recently discontinued SSRI treatment may experience reduced efficacy of subsequent serotonergic treatments (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 a short-acting psychedelic agent is used in combination with a monoamine antidepressant agent, including methods for treatment, kits or dosage regimens for use in the treatment of a psychiatric disorder in a patient. SUMMARY OF THE INVENTION

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

[0013] In a second aspect, the invention provides a method for treating a psychiatric disorder in a patient, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, and an eating disorder; The method for treating involves administering the following to the patient: (i) a monoamine antidepressant; and (ii) a short-acting psychedelic agent.

[0014] In a third aspect, the invention provides a kit comprising: (i) a dosing form of a short-acting psychedelic agent; and Petition 870250088636, dated 09 / 30 / 2025, page 17 / 403 6 / 69 (ii) instructions for administering the dosage form of a short-acting psychedelic agent to a patient in conjunction with a monoamine antidepressant.

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

[0016] In a fifth aspect, the invention provides a method of adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, and an eating disorder; the adjunctive treatment method comprising administering to the patient a short-acting psychedelic agent.

[0017] In a sixth aspect, the invention provides a short-acting psychedelic agent for use in the adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, and an eating disorder.

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

[0019] In an eighth aspect, the invention provides a parenteral formulation comprising a dose of a short-acting psychedelic agent for use in the treatment of a psychiatric disorder in a patient undergoing treatment with Petition 870250088636, dated 09 / 30 / 2025, page 18 / 403 7 / 69 a monoamine antidepressant agent; wherein the treatment comprises the administration, preferably parenterally, to the patient of a dose of the short-acting psychedelic agent; preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder and an eating disorder, preferably selected from a depressive disorder and an anxiety disorder.

[0020] In a ninth aspect, the invention provides a delivery device for use in the treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, wherein the delivery device is configured to deliver the administration, preferably parenteral administration, to the patient of a parenteral dose of a short-acting psychedelic agent.

[0021] For the avoidance of doubt, the embodiments relating to each aspect of the invention apply mutatis mutandis to the other aspects of the invention. Other aspects and embodiments of the present invention will become apparent from the discussion presented herein.

[0022] In the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth aspects 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, 5-methoxy-N,N-dimethyltryptamine, psilocin, deuterated psilocin, psilocybin, deuterated psilocybin, psilocin-4-glutarate, deuterated psilocin-4-glutarate, iprocin-4-glutarate, deuterated iprocin-4-glutarate, mixtures thereof and pharmaceutically acceptable salts thereof.

[0023] In the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth aspects of the present invention, the monoamine antidepressant agent is preferably a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Petition 870250088636, dated 09 / 30 / 2025, page 19 / 403 8 / 69 DEFINITIONS

[0024] Throughout this descriptive report, one or more aspects of the invention may be combined with one or more features described in the descriptive report to define different embodiments of the invention.

[0025] In the detailed description, reference is made to various terms, which should be understood as having the meanings given below, unless the context expressly indicates otherwise.

[0026] The nomenclature used in this document for the short-acting psychedelic agents for use in the invention is that commonly used in the field. The compounds described in this document may also be referred to by the nomenclature according to the rules of the International Union of Pure and Applied Chemistry (IUPAC) for chemical compounds, specifically the 'IUPAC Compendium of Chemical Terminology (Gold Book)' (see AD Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). For the avoidance of doubt, if a rule of the IUPAC organization is contrary to a definition provided in this document, the definition contained herein shall prevail.

[0027] N,N-dimethyltryptamine (DMT) is also known by the IUPAC name 2-(1H-indol-3-yl)-N,N-dimethylethanamine, CAS registry number 61-50-7.

[0028] 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is also known by the IUPAC name 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, CAS registry number 1019-45-0.

[0029] Psilocybin is also known by the IUPAC name 3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate, CAS registry number 520-52-5.

[0030] Psilocin is also known by the IUPAC name 3-[2(Dimethylamino)ethyl]-1H-indol-4-ol, CAS registry number 520-53-6.

[0031] AN,N-diisopropyltryptamine (DIPT) is also known by the IUPAC name N-[2-(1H-indol-3-yl)ethyl]-N-propan-2-ylpropan-2-amine.

[0032] Iprocin is also known as 4-hydroxy-N,N-di Petition 870250088636, dated 09 / 30 / 2025, page 20 / 403 9 / 69 isopropyltryptamine or by the IUPAC name 3-[2-(Di-isopropylamino)ethyl]-1H-indol-4-ol, CAS registry number 132328-45-1.

[0033] The compound of formula I described in this document is a compound, or a pharmaceutically acceptable salt, of the formula shown below: formula I where: Ra is selected from between H and D; or Ra is selected from -OH, -OPO3H2 and -OC(O)C1-C3alkyleneCO2H; Rb is selected from H, D, -OCH3, and -OCD3; R2 and R3 are each selected independently from C(Hz)3; or R2 and R3 are selected independently from C2(Hz)5 and C3(Hz)7; and each Hx, Hy, and Hz is selected independently from protium and deuterium.

[0034] As used in this document, the terms deuterated N,N-dimethyltryptamine, deuterated 5-methoxy-N,N-dimethyltryptamine, deuterated psilocin, deuterated psilocybin, 'deuterated N,N-diisopropyltryptamine', deuterated psilocin-4-glutarate and deuterated iprocin-4-glutarate, collectively, deuterated analogs of the short-acting psychedelic agent, means that one or more hydrogen atoms in the structure of the short-acting psychedelic agent are replaced with a deuterium atom, wherein a deuterium atom is a hydrogen atom with an additional neutron. The deuterium substitution may be made at one or more of the α and β positions in the alkyl groups represented Petition 870250088636, dated 09 / 30 / 2025, page 21 / 403 10 / 69 by R2 and R3 in the formulas below (as methyl groups), on the indole ring and / or on the methoxy group of 5-methoxy-N,N-dimethyltryptamine. In some embodiments, deuteration can be done in - positions α, - the α positions and the β positions, - the alkyl groups represented by R2 and R3 in the formulas below (for example, methyl groups), - the alkyl groups represented by R2 and R3 in the formulas below (e.g., methyl groups) and the α positions, - the alkyl groups represented by R2 and R3 in the formulas below (e.g., methyl groups) and the α and β positions.

[0035] When the compounds described in this document are indicated as being or described as deuterated or deuterated analogues, the compound in question is enriched with deuterium in an amount that depends on the percentage of deuterium available in the reagents from which the compounds are derived. For example, the d6-dimethylamino moieties of the compounds of formula I, wherein -NR2R3 is -N(CD3)2, may be derived from dimethyl-d7-amine or dimethyld6-amine (commonly available as HCl salts), which are available from chemical suppliers in deuterium purities ranging from 98% to 99%. The purity of deuterium in the resulting d6-dimethylamino substituents is, consequently, between 98% and 99%. This means, as a qualified person will understand, that not all compounds of formula I (for example) will comprise d6-dimethylamino substituents – some may include d0-d5-dimethylamino, but the average purity of deuterium is about 98% to 99%.It should be understood that the term deuterated analogues includes isotopic mixtures of these compounds, for example, an isotopic mixture of deuterated d0, d1 and d2-N,N-dimethyltryptamine or deuterated 5-methoxy-N,N-dimethyltryptamine. These isotopic mixtures are described in published patent applications WO2022 / 117359 and WO2020 / 245133, the disclosures of which are incorporated herein by reference in their entirety. Petition 870250088636, dated 09 / 30 / 2025, page 22 / 403 11 / 69

[0036] In some embodiments, the short-acting psychedelic agent is replaced at position 5 with methoxy. The term methoxy (often abbreviated as OMe) defines a univalent group derived from methanol by the removal of a hydrogen atom from the OH moiety.

[0037] In some embodiments, the short-acting psychedelic agent is substituted at position 4 with -OH, -OPO3H2 or -OC(O)C1-C3alkyleneCO2H, preferably -OPO3H2 or glutarate (-OC(O)C3alkyleneCO2H). The term C1-C3alkylene refers to a linear saturated divalent hydrocarbon radical with one, two or three carbon atoms, i.e. methylene, ethylene or propylene.

[0038] For the avoidance of doubt, position 5 of the short-acting psychedelic agent refers to the positions marked in the structure below (substitution not shown), where R2 and R3 are both methyl, or as defined in any of the embodiments below.

[0039] References herein to the dose or total dose of a short-acting psychedelic agent refer to the dose or total dose as the free base equivalent of that agent. For example, when the salt (such as fumarate salt) of the short-acting psychedelic agent is used, the dose or total dose is specified as the free base equivalent dose.

[0040] References herein to an antidepressant agent refer to an agent that is an approved pharmacological treatment for a depressive disorder in at least one jurisdiction, such as the United States of America. Petition 870250088636, dated 09 / 30 / 2025, p. 23 / 403 12 / 69 the European Union, United Kingdom, Australia, New Zealand and Japan. References herein to a monoamine antidepressant agent refer to a non-psychedelic agent characterized by a mode of action that addresses one or more neurotransmitter imbalances selected from serotonin, norepinephrine and dopamine.

[0041] As a caveat, the monoamine antidepressant agent is not preferably an antidepressant of the monoamine oxidase inhibitor class. At certain dosage levels, monoamine oxidase inhibitor antidepressants may interfere with and prolong the duration of the short-acting psychedelic effect. The preferred monoamine antidepressant agents for use in the present invention are serotonin reuptake inhibitors, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

[0042] Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of monoamine antidepressant agents that inhibit the reuptake of serotonin and norepinephrine and are used to treat various 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, levomilnacipram, milnacipram, and venlafaxine.

[0043] Selective serotonin reuptake inhibitors (SSRIs) are a class of monoamine antidepressant agents that selectively inhibit serotonin reuptake and are used to treat various disorders, including depressive disorders, anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). In the UK, SSRIs are recommended as first-line treatment for depressive disorders. Fluoxetine is approved by the 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. Petition 870250088636, dated 09 / 30 / 2025, page 24 / 403 13 / 69

[0044] The term "in conjunction with," as used in this document, refers to treatment with a short-acting psychedelic administered to a patient receiving treatment with a monoamine antidepressant. This may also be called adjunctive treatment, supplemental treatment, or combination therapy. Typically, the short-acting psychedelic agent is administered to a patient who has received adequate treatment with one or more antidepressant agents and continues to receive treatment with a monoamine antidepressant; that is, the patient receives continuous treatment with the monoamine antidepressant agent before and during treatment with the short-acting psychedelic agent. An adequate course of a monoamine antidepressant agent varies depending on the specific antidepressant agent, but is typically a course of treatment over a period of 4 weeks or more, preferably a period of 6 weeks or more.For example, the patient may take one daily dose (or two or more) of a monoamine antidepressant agent for a period of 4 weeks or more, preferably a period of 6 weeks or more. In general, the patient did not experience a clinically significant improvement in symptoms after administration of an appropriate course of treatment with the monoamine antidepressant agent. The term "in conjunction with," as used in this document, does not require the simultaneous administration of the monoamine antidepressant agent and the short-acting psychedelic agent. For the avoidance of doubt, the monoamine antidepressant agent and the short-acting psychedelic agent may be administered and / or prescribed by different healthcare professionals, such as different physicians. Typically, the monoamine antidepressant agent and the short-acting psychedelic agent are administered separately and may be administered sequentially.Optionally, the monoamine antidepressant and the short-acting psychedelic agent may be administered simultaneously. Typically, the monoamine antidepressant is administered daily for the duration of a treatment course, while the short-acting psychedelic agent... Petition 870250088636, dated 09 / 30 / 2025, page 25 / 403 14 / 69 duration is administered in a single dose.

[0045] As used in this document, the term synergy or synergistic refers to an effect greater than the additive effect.

[0046] As used in this document, the term parenteral administration or parenteral administration means the administration of a dose of a short-acting psychedelic agent by any route other than oral, in one or more portions during the dosing period. Preferably, parenteral administration is essentially continuous for a dosing period of up to about 15 minutes, such as from about 5 to about 15 minutes, or from about 5 to about 15 minutes, or from about 8 to about 12 minutes, or from about 9 to about 11 minutes, or from about 6 to about 14 minutes, or from about 7 to about 13 minutes, or from about 8 to about 11 minutes, or about 9 minutes, or about 10 minutes, or about 11 minutes.In other embodiments, parenteral administration may comprise an initial bolus administration of a short-acting psychedelic agent, i.e., a single dose of an agent administered at a rapid rate, typically over about 30 to about 60 seconds, the single dose providing a rapid onset psychedelic experience, followed by essentially continuous administration for a period of about 5 to about 15 minutes. In other embodiments, parenteral administration may comprise a bolus administration of a psychedelic agent, i.e., a single dose of an agent administered at a rapid rate, typically over about 30 to about 60 seconds. In some embodiments, administration comprises a bolus, such as intramuscular, intranasal, or intravenous bolus administration.

[0047] As used in this document, the term effective dose refers to a dose sufficient to induce a psychedelic experience, that is, a period in which the patient experiences one or more intense reactions or emotions, altered states of perception, visual hallucinations or other sensory hallucinations, spiritual experiences, ego dissolution, and dissociation. Petition 870250088636, dated 09 / 30 / 2025, page 26 / 403 15 / 69 Ego dissolution describes a state in which the boundary between an individual and the outside world dissolves. Dissociation describes a state in which the individual has the sensation that different parts of the brain are not connected, like a disconnection between mind and body.

[0048] As used in this document, the term therapeutically effective dose refers to a dose of the monoamine antidepressant agent and the short-acting psychedelic agent that, combined, provide therapeutic efficacy. The dose of each agent separately may not provide therapeutic efficacy individually.

[0049] A month, as used in this document, is defined as a calendar month.

[0050] Administration occurring only once in any three-month period, as used in this document, means that there is an interval of at least 90 days between administrations. Similarly, administration occurring only once in any six-month period, as used in this document, means that there is an interval of at least 180 days between administrations, and so on.

[0051] Administration occurring at most once every three months means at least three months, i.e., 90 days pass between administrations. Similarly, administration occurring at most once every six months means at least six months, i.e., 180 days pass between administrations, and so on.

[0052] References here to the singular of a noun include the plural of the noun and vice versa, unless the context indicates otherwise.

[0053] Throughout this descriptive report, the word includes, or variations such as includes or comprising, shall be understood as implying the inclusion of an element, whole number or step, or group of elements, whole numbers or steps, but not the exclusion of any other element, whole number or step, or group of elements, whole numbers or steps. The term comprising includes within its scope the term consisting of or Petition 870250088636, dated 09 / 30 / 2025, page 27 / 403 16 / 69 consisting essentially of.

[0054] The term consisting or variants thereof should be understood as implying the inclusion of an element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step or group of elements, integers or steps.

[0055] The term consisting essentially of or variants thereof should be understood as implying the inclusion of an element, whole number or step, or group of elements, whole numbers or steps, and that other components may be present, but only those that do not materially affect the essential characteristics of the embodiment of the invention.

[0056] The term "about" in this document, when qualifying a number or value, is used to refer to values ​​that are within ± 5% of the specified value. For the avoidance of doubt, when a number or value is specified in this document in the absence of the term "about," the number or value should be understood according to standard numerical rounding conventions, according to the number of decimal places. For example, an integer, such as 6, is understood as encompassing values ​​> 5.5 and < 6.5. Similarly, a number specified with one decimal place, such as 5.3, is understood as encompassing values ​​> 5.25 and < 5.35.

[0057] When a range of values ​​is provided, the range includes endpoint values. For example, the range 20 to 28, or 20 to 28, would include the values ​​20, 21, 22, 23, 24, 25, 26, 27, and 28; the range 5 to 15, or 5 to 15, would include the values ​​5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15.

[0058] As used in this document, the term patient preferably refers to a mammal. Typically, the mammal is a human being, but it can also refer to a domestic mammal. The term does not cover laboratory mammals.

[0059] As used in this document, the term in combination with psychotherapy or psychedelic-assisted psychotherapy refers to the treatment of Petition 870250088636, dated 09 / 30 / 2025, page 28 / 403 17 / 69 a psychiatric disorder by psychological means, which are enhanced by the combination, treatment method or kit of the invention. The psychotherapeutic practice is provided together with a dose of the short-acting psychedelic agent, including, for example, any dose defined in the present invention.

[0060] The term treatment defines the therapeutic treatment of a patient in order to reduce or halt the rate of progression of a disorder, or to improve or cure the disorder. Prophylactic treatment of a patient with a diagnosed psychiatric disorder is also included. Such prophylactic treatment, also called secondary prevention, aims to reduce the impact of the disorder and / or prevent the development of the disorder through treatment according to the invention.

[0061] As used in this document, the term improvement refers to a clinically significant reduction in symptom severity over a period of time, compared to a baseline assessment prior to administration of the short-acting psychedelic agent, or as assessed by patient-reported outcomes. Improvement may be assessed by patient-reported outcomes or by physician-reported outcomes, such as an interview or a structured questionnaire with the patient. The term clinician refers to a qualified and / or registered physician or healthcare professional, including therapists, psychiatrists, and psychologists.

[0062] Patient- or physician-reported outcomes may include assessments using rating scales, which include, but are not limited to, the Clinical Global Impression (CGI) scale, an observer-rated scale consisting of one or more of three different measures—disease severity (CGI-S), overall improvement (CGI-I), and effectiveness index (CGI-E); the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-point diagnostic questionnaire; the 17-item Hamilton Depression Rating Scale (HAMD17); the Beck Depression Inventory-II; the Ruminative Response Scale (RRS-22), a measure Petition 870250088636, dated 09 / 30 / 2025, page 29 / 403 The 18 / 69 self-report questionnaire, consisting of 22 items and three factors—depression, worry, and reflection; the Beck Anxiety Inventory (BAI); the Hamilton Anxiety Scale (HAM-A); the State-Trait Anxiety Inventory (STAI or STAI-T); the Generalized Anxiety Disorder Assessment (GAD-7); the Clinician-Administered Post-Traumatic Stress Disorder Scale (CAPS); the Yale-Brown Obsessive-Compulsive Scale; and suicidality assessment scales, such as the Beck Scale for Suicidal Ideation (BSS), the Columbia Suicide Severity Rating Scale (C-SSRS), and the MADRS suicidal thoughts item for suicidal ideation or the scale of Clinical Global Impression of Suicidality Severity - Revised (CGI-SSR). Patient-reported outcomes may also 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 and EQ VAS descriptive systems; the Patient Global Impression of Severity (PGI-S) scale; and the Patient Global Impression of Improvement (PGI-I) scale. A combination of rating scales may be used. Physician- or patient-reported outcomes may include weight gain for anorexia nervosa; frequency of binge-eating / purging episodes for bulimia nervosa; or frequency of binge-eating episodes for binge eating disorder.

[0063] The measurement of a clinically significant reduction in symptom severity will be assessed according to the rating scale or other outcomes reported by the physician or patient, including:

[0064] Typically, for the Clinical Global Impression (CGI) scale, a response score of 0, 1, 2, or 3 indicates improvement, preferably 0, 1, or 2.

[0065] Typically, for rating 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 Scale for Suicidal Ideation (BSS), Columbia Suicide Severity Rating Scale (C-SSRS), Petition 870250088636, dated 09 / 30 / 2025, page 30 / 403 19 / 69 Hamilton Anxiety Scale (HAM-A), State-Trait Anxiety Inventory (STAI or STAI-T), Assessment of Generalized Anxiety Disorder (GAD-7), Yale-Brown Obsessive-Compulsive Scale, Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF); EQ-5D-5L and EQ VAS descriptive systems, and Physician-Administered Post-Traumatic Stress Disorder Scale (CAPS); a 15% or greater reduction in score compared to baseline indicates improvement, preferably 20% or more, 30% or more, or 50% or more.

[0066] Alternatively, a clinically significant reduction in symptom severity can be assessed by a reduction in points on the rating scale. For example, improvement is indicated by the following point reductions: for the MADRS scale, a reduction of 6 or more points; for the HAMD-17 scale, a reduction of 4 or more points; for the Beck Depression Inventory-II (BDI-II) scale, a reduction of 12 or more points. Alternatively, a reduction in the severity category indicates improvement, for example, from severe to moderate.

[0067] Typically, for the Columbia Suicide Severity Rating Scale (C-SSRS), a reduction in the number of questions answered yes indicates improvement. Alternatively, a reduction in the severity category indicates improvement, for example, a reduction from very severe to severe or from severe to moderately severe.

[0068] Typically, for the Patient Global Impression of Severity (PGI-S) scale, a reduction in the patient-assessed severity rating indicates improvement, for example, a reduction in the severity rating from 6 (severely ill) to 4 (moderately ill).

[0069] Typically, for the Patient Global Impression of Improvement (PGI-I) scale, a score of 3 (minimally improved) or below indicates improvement, preferably a score of 2 (much improved) or below. The PGI-I scale is not evaluated in comparison to the baseline assessment, but is a post-dose assessment only. Petition 870250088636, dated 09 / 30 / 2025, page 31 / 403 20 / 69

[0070] As used in this document, the term remission refers to a reduction in the symptoms of a psychiatric disorder to a level that indicates mild symptoms or that the patient is in the healthy range, i.e., the patient is not exhibiting symptoms indicative of a clinical condition. In the case of depressive disorders, remission is typically considered to be a score of 13 or less on the MADRS rating scale, preferably 10 or less; or 7 or less on the HAMD rating scale; or 19 or less on the Beck Depression Inventory-II scale; or 15 or less on the Beck Anxiety Inventory scale; or 17 or less on the Hamilton Anxiety Scale; or 15 or less on the Yale-Brown Obsessive-Compulsive Scale; or 3 or less on the Patient Global Impression-Severity Scale (PGI-S).In general, remission is considered to apply to a patient who answers "no" to every question on the Columbia Suicide Severity Rating Scale (C-SSRS), or scores 10 or less (moderate), preferably 6 or less.

[0071] As used in this document, the term short-acting psychedelic agent or short-duration psychedelic refers to a psychedelic agent that produces a psychedelic experience lasting 4 hours or less, or 3 hours or less, or 2 hours or less, or 1 hour or less. Preferably, the short-acting psychedelic produces a psychedelic experience lasting 1 hour or less. Preferably, the short-acting psychedelic is administered parenterally. Typical short-acting psychedelic agents are administered parenterally, i.e., not orally, either because the agent is not orally active (e.g., DMT, 5MeO-DMT) or because oral administration leads to a long-duration psychedelic experience. For example, oral administration of psilocybin produces a psychedelic experience lasting about 6 to 8 hours.However, certain orally active psychedelics (e.g., deuterated DMT or deuterated psilocybin) can produce a psychedelic experience of shorter duration, for example, 3 hours or less, preferably 1 hour or less. Petition 870250088636, dated 09 / 30 / 2025, page 32 / 403 21 / 69 Therefore, the present invention provides a duration of psychedelic experience of 3 hours or less, preferably 1 hour or less, more preferably 45 minutes or less, and even more preferably 30 minutes or less, and, in the preferred embodiments of any aspect or embodiment of the invention, the short-acting psychedelic agent is provided in a dosage form suitable for parenteral administration, preferably by injection, inhalation, insufflation, transdermal or transmucosal administration.

[0072] As used in this document, the term psychiatric disorder is characterized by a clinically significant disturbance in an individual’s cognition, emotional regulation, or behavior, and which is associated with current distress (e.g., a painful symptom) or disability (i.e., impairment in one or more important areas of functioning) or a significantly increased risk of death, pain, disability, or a significant loss of freedom. The diagnostic criteria for the psychiatric disorders mentioned in this document are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

[0073] As used in this document, the term obsessive-compulsive disorder (OCD) is defined by the presence of obsessions or compulsions, but usually both. Symptoms can cause significant functional impairment and / or distress. An obsession is defined as an unwanted, intrusive thought, image, or impulse that repeatedly enters a person's mind. Compulsions are repetitive behaviors or mental acts that a person feels compelled to perform. Typically, OCD manifests as one or more obsessions, which lead to the adoption of a compulsion. For example, an obsession with germs may lead to a compulsion for cleaning, or an obsession with food may lead to a compulsion to overeat, undereat, or vomit after eating (i.e., an obsession with food may manifest as an eating disorder). A compulsion may be Petition 870250088636, dated 09 / 30 / 2025, page 33 / 403 22 / 69 is an obvious and observable behavior by others, such as checking if a door is locked, or a hidden mental act that cannot be observed, such as repeating a certain phrase in one's mind. The Yale-Brown Obsessive-Compulsive Disorder (Y-BOCS) rating scale can be used to assess OCD.

[0074] As used in this document, the term eating disorder is defined as a severe and persistent disorder in eating behaviors and associated distressing thoughts and emotions. The term eating disorder includes, but is not limited to, anorexia nervosa and bulimia nervosa, binge eating disorder, avoidant / restrictive food intake disorder, other specified eating and feeding disorders, pica, and rumination disorder.

[0075] Eating disorders often occur in conjunction with anxiety disorders and obsessive-compulsive disorder. Neziroglu and Sandler differentiate between OCD and an eating disorder: 'While patients with eating disorders are primarily motivated by concerns about physical appearance and consequently alter their eating patterns to lose weight accordingly, patients with OCD may be restricting their eating for reasons quite different from concerns about body image' (https: / / iocdf.org / expert-opinions / expert-opinion-eating-disorders-and-ocd / ).

[0076] The term eating disorder includes anorexia nervosa, bulimia, and binge eating disorder (BED). Symptoms of anorexia nervosa include eating very little and / or exercising excessively to maintain the lowest possible weight. Symptoms of bulimia include eating a large amount of food in a very short period of time (i.e., binge eating) and then deliberately becoming ill, using laxatives, eating very little, and / or exercising excessively to avoid weight gain. Symptoms of BED include regularly eating large portions of food until feeling uncomfortably full and consequently feeling... Petition 870250088636, dated 09 / 30 / 2025, p. 34 / 403 23 / 69 upset or guilty.

[0077] As used in this document, the term depressive disorder includes, among others, major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, terminal depression, and treatment-resistant depression.

[0078] As used herein, the term major depressive disorder (MDD, also called major depression or clinical depression) is defined as the presence of five or more of the following symptoms during a period of two weeks or more (also called herein a major depressive episode), for most of the day, nearly every day: • Depressed mood, such as sadness, emptiness, or crying (in children and adolescents, depressed mood may appear as constant irritability); • Significantly reduced interest in, or lack of pleasure in, all or most activities; • Significant weight loss when not dieting, weight gain, or decreased or increased appetite (in children, failure to gain weight as expected); • Insomnia or increased desire to sleep; • Restlessness or sluggish behavior that can be observed by other people; • fatigue or loss of energy; • feelings of worthlessness or excessive or inappropriate guilt; • Difficulty making decisions, thinking, or concentrating; • recurring thoughts of death or suicide, or a suicide attempt. [ 0079] At least one of the symptoms must be a depressed mood or a loss of interest or pleasure. [ 0080] Persistent depressive disorder, also known as dysthymia, is defined as a patient who presents with both characteristics of Petition 870250088636, dated 09 / 30 / 2025, page 35 / 403 24 / 69 follow: A. Presents with depressed mood most of the time, nearly every day, for at least two years. Children and adolescents may present with irritable mood, and the time period is at least one year. B. When depressed, the person exhibits at least two of the following symptoms: • Overeating or lack of appetite. • Sleeping too much or having difficulty sleeping. • Fatigue, lack of energy. • Low self-esteem. • Difficulty concentrating or making decisions.

[0081] As used in this document, the term treatment-resistant major depressive disorder describes MDD that fails to achieve an adequate response to treatment with standard therapy.

[0082] As used in this document, bipolar disorder, also known as manic-depressive illness, is a disorder that causes unusual changes in mood, energy, activity levels, and the ability to perform daily tasks.

[0083] There are two defined subcategories of bipolar disorder; both involve clear changes in mood, energy, and activity levels. These mood states range from periods of extremely upbeat, euphoric, and energized behavior (known as manic episodes and defined further below) to periods of very sad, down, or hopeless feelings (known as depressive episodes). The less severe manic periods are known as hypomanic episodes.

[0084] Bipolar I Disorder - defined by manic episodes lasting at least 7 days or by manic symptoms so severe that the person requires immediate hospital care. Depressive episodes, lasting at least 2 weeks, also typically occur. Depressive episodes with mixed features (having both depressive and manic symptoms at the same time) Petition 870250088636, dated 09 / 30 / 2025, page 36 / 403 25 / 69 time) are also possible.

[0085] Bipolar II disorder - defined by a pattern of depressive episodes and hypomanic episodes, but not by full manic episodes as described above.

[0086] As used in this document, bipolar depression is defined as an individual who is experiencing depressive symptoms with a prior or coexisting episode of manic symptoms, but who does not meet the clinical criteria for bipolar disorder.

[0087] Typically, depressive disorders are assessed using a rating scale selected from the Clinical Global Impression (CGI) scale; the Montgomery-Asberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD-17); the Beck Depression Inventory-II; the Beck Anxiety Inventory (BAI); suicidality rating scales such as the Beck Scale for Suicidal Ideation (BSS), the Columbia Suicide Severity Rating Scale (C-SSRS), the MADRS suicidal thoughts item for suicidal ideation, the Clinical Global Impression of Suicidality Severity - Revised (CGI-SSR) or the Columbia Suicide Severity Rating Scale (C-SSRS); and combinations of these scales.Depressive disorders can also be assessed using selected patient-reported outcomes from the Beck Depression Inventory (BDI-II); the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF); the EQ5D-5L and EQ VAS descriptive systems; the Patient Global Impression of Severity scale (PGIS); and combinations of these outcome assessments.

[0088] Preferably, depressive disorders are assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), the Beck Depression Inventory-II, the Beck Scale for Suicidal Ideation (BSS), the Montgomery-Asberg Depression Rating Scale (MADRS), and / or the 17-item Hamilton Depression Rating Scale (HAMD-17).

[0089] As used in this document, the term anxiety disorder Petition 870250088636, dated 09 / 30 / 2025, page 37 / 403 26 / 69 includes, but is not limited to, generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder. Anxiety disorders are typically assessed using a rating scale selected from the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Scale (HAM-A), the State-Trait Anxiety Inventory (STAI or STAI-T), the Assessment of Generalized Anxiety Disorder (GAD-7), and combinations of these scales. Anxiety disorders may also be assessed using patient-reported outcomes, as described above.

[0090] Generalized anxiety disorder (GAD), as used in this document, means a chronic disorder characterized by enduring anxiety that is not focused on any one object or situation. People with GAD experience persistent, nonspecific fear and worry and become excessively preoccupied with everyday matters. GAD is characterized by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbances.

[0091] A phobia is defined as a persistent fear of an object or situation that the affected person tries to avoid as much as possible, usually disproportionate to the actual danger it represents. If the feared object or situation cannot be completely avoided, the affected person will endure it with great distress and significant interference in social or occupational activities.

[0092] A patient suffering from panic disorder is defined as someone who experiences one or more brief attacks (also called panic attacks) of intense terror and apprehension, often marked by trembling, agitation, confusion, dizziness, nausea, and / or difficulty breathing. A panic attack is defined as a fear or discomfort that arises abruptly and reaches its peak in less than ten minutes.

[0093] Social anxiety disorder is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation Petition 870250088636, dated 09 / 30 / 2025, pp. 38 / 403 27 / 69 or social interaction. Social anxiety often manifests as specific physical symptoms, including blushing, sweating, and difficulty speaking.

[0094] Post-traumatic stress disorder (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from an extreme situation such as combat, natural disaster, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidance behaviors, anxiety, anger, and depression.

[0095] The Clinician-Administered Post-Traumatic Stress Disorder (CAPS) Scale can be used to assess PTSD symptoms.

[0096] As used in this document, the term postpartum depression (PPD, also known as postnatal depression) is a form of depression experienced by either parent of a newborn baby. Symptoms typically develop within 4 weeks of the baby's birth and usually include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleep or eating patterns. DETAILED DESCRIPTION

[0097] The combination, method for treating, kit, dosage regimen, delivery device, parenteral formulation, or adjunctive treatment method of the invention is based on the surprising finding that administering a single, effective dose of a short-acting psychedelic, such as N,N-dimethyltryptamine, to a patient undergoing treatment with a monoamine antidepressant provided greater symptom improvement compared to administering the short-acting psychedelic agent in the absence of monoamine antidepressant treatment, such as SSRI treatment. The greater symptom improvement may provide several advantages. Advantages may include an improved response rate, an improved remission rate, reduced dosage of one or both agents, and reduced use or more effective withdrawal of the monoamine antidepressant after treatment. Petition 870250088636, dated 09 / 30 / 2025, pp. 39 / 403 28 / 69 administration of the short-acting psychedelic agent.

[0098] Consequently, the first aspect of the invention provides, as embodiment 1, a combination comprising: (i) A monoamine antidepressant agent; and (ii) a short-acting psychedelic agent.

[0099] The second aspect of the invention provides, as embodiment 2, a method for treating a psychiatric disorder in a patient, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, and an eating disorder, wherein the method for treatment comprises administering to the patient: (i) a monoamine antidepressant; and (ii) a short-acting psychedelic agent.

[0100] The third aspect of the invention provides, as embodiment 3, a kit comprising: (i) a dosage form of a short-acting psychedelic agent; and (ii) instructions for administering the dosage form of a short-acting psychedelic agent to a patient in conjunction with a monoamine antidepressant.

[0101] The fourth aspect of the invention provides, like embodiment 4, a dosing regimen comprising: (i) administration of a monoamine antidepressant; and (ii) administration of a short-acting psychedelic agent.

[0102] The fifth aspect of the invention provides, as embodiment 5, a method of adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, and an eating disorder; the adjunctive treatment method comprising administering to the patient an agent Petition 870250088636, dated 09 / 30 / 2025, page 40 / 403 29 / 69 short-lived psychedelic.

[0103] The sixth aspect of the invention provides, as embodiment 6, a short-acting psychedelic agent for use in the adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, and an eating disorder.

[0104] The invention further provides, as embodiment 7, a combination according to embodiment 1, in which the combination is synergistic; or a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use according to any of embodiments 2 to 6, in which the administration of (i) a monoamine antidepressant agent; and (ii) a short-acting psychedelic agent provides a synergistic effect.

[0105] The invention also provides, as embodiment 8, a combination, treatment method, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use in accordance with any previous embodiment, wherein the monoamine antidepressant agent is selected from a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor.

[0106] The invention further provides, as embodiment 9, a combination, treatment method, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use in accordance with any previous embodiment, wherein the short-acting psychedelic agent is selected from 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, iprocin-4-glutarate, deuterated iprocin-4-glutarate, mixtures thereof and pharmaceutically acceptable salts Petition 870250088636, dated 09 / 30 / 2025, page 41 / 403 30 / 69 of the same, 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.

[0107] The invention also provides, as embodiment 10, a combination, treatment method, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, in accordance with any previous embodiment, wherein the monoamine antidepressant agent is selected from at least one of the following: desvenlafaxine, duloxetine, levomilnacipram, milnacipram, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof.

[0108] The invention also provides, as embodiment 11, a combination according to any of embodiments 1 to 10, comprising (i) a suitable course of treatment with a monoamine antidepressant agent; and (ii) a single dose of a short-acting psychedelic agent; or a method for treatment, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to any previous embodiment, comprising: (i) administration of an appropriate course of a monoamine antidepressant; and (ii) administration of a single dose of a short-acting psychedelic agent.

[0109] The invention also provides, as embodiment 12, a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-duration psychedelic agent for use in accordance with embodiment 11, wherein the appropriate course of treatment comprises a treatment period of 4 weeks or more.

[0110] The invention also provides, as embodiment 13, a combination, Petition 870250088636, dated 09 / 30 / 2025, page 42 / 403 31 / 69 a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to any of embodiments 11 and 12, wherein the administration of a single dose of a short-acting psychedelic agent occurs only once in any three-month period, or wherein the single dose of a short-acting psychedelic agent is for administration only once in any three-month period. As another embodiment, the invention provides a combination, a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to any of embodiments 11 and 12, wherein the administration of a single dose of a short-acting psychedelic agent occurs at most once every three months, or wherein the single dose of a short-acting psychedelic agent is for administration at most once every three months.

[0111] The invention also provides, as embodiment 14, a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to either embodiment 11 and 12, wherein the administration of the single dose of short-acting psychedelic agent occurs only once in any six-month period, or wherein said single dose of a short-acting psychedelic agent is for administration only once in any six-month period; or a combination according to either embodiment 11 and 12, wherein the single dose of a short-acting psychedelic agent is to be administered only once in any six-month period.As another embodiment, the invention provides a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to either embodiment 11 and 12, wherein the administration of a single dose of a short-acting psychedelic agent occurs at most once every three months, or wherein the single dose of a short-acting psychedelic agent is for administration at most once every six months. Petition 870250088636, dated 09 / 30 / 2025, pp. 43 / 403 32 / 69

[0112] The invention further provides, as embodiment 15, a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to either embodiment 11 and 12, wherein the administration of a single dose of a short-acting psychedelic agent occurs only once in any nine-month period, or wherein the single dose of a short-acting psychedelic agent is for administration only once in any nine-month period; or a combination according to either embodiment 11 and 12, wherein the single dose of a short-acting psychedelic agent is to be administered only once in any nine-month period.As another embodiment, the invention provides a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to either embodiment 11 and 12, wherein the administration of a single dose of a short-acting psychedelic agent occurs at most once every nine months, or wherein the single dose of a short-acting psychedelic agent is for administration at most once every nine months.

[0113] The invention also provides, as embodiment 16, a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to any of embodiments 11 and 12, wherein the administration of a single dose of a short-acting psychedelic agent occurs only once in any twelve-month period, or wherein the single dose of a short-acting psychedelic agent is for administration only once in any twelve-month period; or a combination according to any of embodiments 11 and 12, wherein the single dose of a short-acting psychedelic agent is to be administered only once in any twelve-month period. As another embodiment, the invention provides a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to any of embodiments 11 and 12, Petition 870250088636, dated 09 / 30 / 2025, page 44 / 403 33 / 69 where the administration of a single dose of a short-acting psychedelic agent occurs at most once every twelve months, or where the single dose of a short-acting psychedelic agent is for administration at most once every twelve months.

[0114] The invention also provides, as embodiment 17, a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, in accordance with any previous embodiment, comprising (i) an oral dosage form of the monoamine antidepressant agent; and (ii) a parenteral dosage form of the short-acting psychedelic agent.

[0115] The invention also provides, as embodiment 18, a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method or a short-duration psychedelic agent for use, according to any previous embodiment, for use in the treatment of a psychiatric disorder, preferably wherein the psychiatric disorder is selected from among a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder and an eating disorder, preferably selected from among a depressive disorder and an anxiety disorder.

[0116] The invention also provides, as embodiment 19, a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method or a short-acting psychedelic agent for use, according to any previous embodiment, 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.

[0117] The invention also provides, as embodiment 20, a combination, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to any prior embodiment, for use in the treatment of an anxiety disorder. Petition 870250088636, dated 09 / 30 / 2025, page 45 / 403 34 / 69 selected from generalized anxiety disorder, phobia, panic disorder, social anxiety disorder and post-traumatic stress disorder.

[0118] The invention further provides, as embodiment 21, a combination for use, a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to any of embodiments 18 to 20, which further comprises the steps and / or instructions for evaluating the patient with a baseline assessment using a rating scale and / or physician-reported results and / or patient-reported results prior to administration of the short-acting psychedelic agent; and evaluating the patient with a post-dosage assessment after administration of the short-acting psychedelic agent.

[0119] The invention also provides, as embodiment 22, a combination for use, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to embodiment 21, wherein the baseline assessment is made by a rating scale selected from the Clinical Global Impression (CGI) scale; the Montgomery-Asberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD17); the Beck Depression Inventory-II; the Beck Anxiety Inventory (BAI); the Hamilton Anxiety Scale (HAM-A); the State-Trait Anxiety Inventory (STAI or STAI-T); the Generalized Anxiety Disorder Assessment (GAD-7); the Clinician-Administered Post-Traumatic Stress Disorder Scale (CAPS); the Yale-Brown Obsessive-Compulsive Scale; Beck Scale for Suicidal Ideation (BSS); Columbia Suicide Risk Assessment Scale (C-SSRS);The MADRS suicidal thoughts item for suicidal ideation; the Clinical Global Impression of Suicidality Severity Scale - Revised (CGI-SS-R); the Beck Depression Inventory (BDI-II); the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF); the EQ-5D-5L and EQ VAS descriptive systems; the Global Impression of Suicidality scale; Petition 870250088636, dated 09 / 30 / 2025, page 46 / 403 35 / 69 Patient Severity Index (PGI-S); and combinations thereof.

[0120] The invention also provides, as embodiment 23, a combination for use, a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to embodiment 21 or 22, wherein the post-dosage assessment is made by a rating scale selected from the Clinical Global Impression (CGI) scale; the Montgomery-Asberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD17); the Beck Depression Inventory-II; the Beck Anxiety Inventory (BAI); the Hamilton Anxiety Scale (HAM-A); the State-Trait Anxiety Inventory (STAI or STAI-T); the Generalized Anxiety Disorder Assessment (GAD-7); the Clinician-Administered Post-Traumatic Stress Disorder Scale (CAPS); the Yale-Brown Obsessive-Compulsive Scale; Beck Scale for Suicidal Ideation (BSS); Columbia Suicide Risk Assessment Scale (C-SSRS);The MADRS suicidal thoughts item for suicidal ideation; the Clinical Global Impression of Suicidality Severity Scale - Revised (CGI-SS-R); the Beck Depression Inventory (BDI-II); the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF); the EQ-5D-5L and EQ VAS descriptive systems; the Patient Global Impression of Severity Scale (PGI-S); the Clinical Global Improvement Scale (CGI-I); the Patient Global Impression of Improvement Scale (PGI-I); and combinations thereof.

[0121] The invention also provides, as embodiment 24, a combination for use, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to any of embodiments 21 to 23, wherein the psychiatric disorder is a depressive disorder, and wherein the initial and post-dosage assessment is performed using a depression rating scale selected from the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD17), the Depression Inventory of Petition 870250088636, dated 09 / 30 / 2025, page 47 / 403 36 / 69 Beck-II and combinations thereof.

[0122] The invention also provides, as embodiment 25, a combination for use, a method for treating, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to any of embodiments 18 to 24, which provides a patient with remission of the psychiatric disorder.

[0123] The invention further provides, as embodiment 26, a combination for use, a method for treatment, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to embodiment 25, wherein remission is assessed at a time of 6 to 10 days after administration of the short-acting psychedelic agent, preferably 6 to 8 days.

[0124] The invention also provides, as embodiment 27, a combination for use, a method for treatment, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to any previous embodiment, wherein the administration or instructions for administration of the short-acting psychedelic agent comprise: to administer parenterally to the patient a dose of the short-acting psychedelic agent over a dosing period of up to about 15 minutes, preferably from about 5 to about 15 minutes, and in which parenteral administration is essentially continuous.

[0125] The invention also provides, as embodiment 28, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to embodiments 11 to 27, wherein the administration of the short-acting psychedelic agent is a parenteral administration selected from the group consisting of intravenous, intramuscular, intranasal, transmucosal and transdermal administration and inhalation, preferably selected from intravenous and intramuscular administration.

[0126] The invention also provides, as embodiment 29, a combination Petition 870250088636, dated 09 / 30 / 2025, pp. 48 / 403 37 / 69 for use, a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to embodiment 28, wherein parenteral administration is by intravenous infusion, preferably wherein intravenous administration is conducted using a syringe pump.

[0127] The invention also provides, as embodiment 30, a combination for use, a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to embodiment 29, wherein parenteral administration is by two-phase intravenous infusion.

[0128] The invention also provides, embodiment 31, a combination for use, a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to embodiment 29, wherein parenteral administration is by single-phase intravenous infusion.

[0129] The invention also provides, as embodiment 32, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to any of embodiments 28 to 31, wherein the dosage period is from about 8 to about 12 minutes.

[0130] The invention also provides, as embodiment 33, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to embodiment 30, wherein the dosage period is about 9 to about 11 minutes, or about 10 minutes.

[0131] The invention also provides, as embodiment 34, a combination or blend for use, a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to any previous embodiment, wherein the dose of the short-acting psychedelic agent is selected from the group consisting of: Petition 870250088636, dated 09 / 30 / 2025, pp. 49 / 403 38 / 69 - approximately 20 to approximately 80 mg of N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - approximately 20 to approximately 80 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - approximately 15 to approximately 30 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - approximately 10 to approximately 30 mg of 5-methoxy-N,N-dimethyltryptamine, a deuterated analogue or a pharmaceutically acceptable salt thereof; and - approximately 10 to approximately 30 mg of deuterated 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; or the dose of the short-acting psychedelic agent is selected from the group consisting of: - approximately 10 to approximately 30 mg of psilocybin or a pharmaceutically acceptable salt thereof; - approximately 10 to approximately 20 mg of deuterated psilocybin or a pharmaceutically acceptable salt thereof; - approximately 1 to approximately 20 mg of psilocin or a pharmaceutically acceptable salt thereof; - approximately 1 to approximately 20 mg of deuterated psilocin or a pharmaceutically acceptable salt thereof; and - approximately 20 to approximately 50 mg of psilocin-4-glutarate, deuterated psilocin-4-glutarate, iprocin-4-glutarate or deuterated iprocin-4-glutarate or a pharmaceutically acceptable salt thereof.

[0132] To avoid doubt, when a salt of the short-acting psychedelic agent is used, the dose specified is the dose of the free base equivalent.

[0133] The invention further provides, as embodiment 35, a combination for use, according to any of embodiments 11 to 34, or a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to any previous embodiment, comprising the parenteral administration of a total dose of approximately Petition 870250088636, dated 09 / 30 / 2025, p. 50 / 403 39 / 69 from 20 to about 29 mg of N,N-dimethyltryptamine, or of a pharmaceutically acceptable salt thereof, or of deuterated N,N-dimethyltryptamine, or of a pharmaceutically acceptable salt thereof, or of a mixture thereof.

[0134] The invention further provides, as embodiment 36, a combination for use, according to any of embodiments 11 to 35, or a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to any previous embodiment, comprising the parenteral administration of a total dose of about 20 to about 23 mg, or a total dose of about 26 to about 29 mg of N,N-dimethyltryptamine, a deuterated analogue, a pharmaceutically acceptable salt thereof or a mixture thereof.

[0135] The invention further provides, as embodiment 37, a combination for use, according to any of embodiments 11 to 34, or a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to any 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, and the total dose is from about 7 to about 10 mg.

[0136] The invention further provides, as embodiment 38, a combination for use, a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to any of embodiments 34 to 36, wherein administration is by intravenous infusion, 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, and the total dose is from about 20 to about 23 mg.

[0137] The invention also provides, as embodiment 39, a combination for use, a method for treating, a kit, a dosage regimen, a treatment method. Petition 870250088636, dated 09 / 30 / 2025, p. 51 / 403 40 / 69 adjuvant or short-acting psychedelic agent for use, according to any of the embodiments 34 to 36, wherein administration is by intravenous infusion, 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, and the total dose is about 26 to about 29 mg.

[0138] The invention also provides, as embodiment 40, a combination for use, a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to embodiments 27, 28 and 34, wherein administration is by intramuscular administration.

[0139] The invention also provides, as embodiment 41, a combination for use, a method for treating, kit, dosage regimen, adjuvant treatment method or short-acting psychedelic agent for use, according to embodiment 40, wherein the short-acting psychedelic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and the total dose is from about 20 to about 70 mg, preferably from about 50 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, and the total dose is from about 20 to about 60 mg, or from about 15 to about 30 mg.

[0140] The invention also provides, as embodiment 42, a combination, a combination for use, a method for treating, a kit, a dosage regimen, an adjuvant treatment method, or a short-acting psychedelic agent for use, according to any previous embodiment, wherein the short-acting psychedelic agent is a compound of formula I or a pharmaceutically acceptable salt thereof: Petition 870250088636, dated 09 / 30 / 2025, page 52 / 403 41 / 69 formula I where: Ra is selected from between H and D; or Ra is selected from -OH, -OPO3H2 and -OC(O)C1-C3alkyleneCO2H; Rb is selected from H, D, -OCH3, and -OCD3; R2 and R3 are each selected independently from C(Hz)3; or R2 and R3 are selected independently from C2(Hz)5 and C3(Hz)7; and each Hx, Hy, and Hz is selected independently from protium and deuterium.

[0141] The invention further provides, as embodiment 43, a combination, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to embodiment 42, wherein R2 and R3 are each selected independently of CH3 and CD3.

[0142] The invention further provides, as embodiment 44, a combination, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to embodiment 42, wherein R2 and R3 are both CH3, or R2 and R3 are both CD3, or R2 is CH3 and R3 is CD3.

[0143] The invention further provides, as embodiment 45, a combination, a combination for use, a method for treating, a kit, a dosage regimen, an adjuvant treatment method or a short-duration psychedelic agent for Petition 870250088636, dated 09 / 30 / 2025, page 53 / 403 42 / 69 usage, according to any of the modalities 42 to 44, in which each Hxé H, or each Hxé D.

[0144] The invention further provides, as embodiment 46, a combination, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to any of embodiments 42 to 45, wherein each Hy is H, or each Hy is D, or one Hy is H and one Hy is D.

[0145] The invention further provides, as embodiment 47, a combination, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to any of embodiments 43 to 44 and 46, wherein each Hx, Hy and Hz is deuterium.

[0146] The invention also provides, as embodiment 48, a combination, a combination for use, a method for treatment, a kit, a dosage regimen, an adjuvant treatment method, or a short-acting psychedelic agent for use, according to any previous embodiment, wherein the short-acting psychedelic agent is selected from the group consisting of: Petition 870250088636, dated 09 / 30 / 2025, page 54 / 403 43 / 69 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; wherein Ra and Rb are as defined in embodiment 42.

[0147] The invention further provides, as embodiment 49, a combination, a combination for use, a method for treatment, kit, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, according to any of embodiments 42 to 48, wherein Ra is H.

[0148] The invention also provides, as embodiment 50, a combination, a combination for use, a method for treating, a kit, a dosage regimen, an adjuvant treatment method or a short-duration psychedelic agent for use, according to any of embodiments 42 to 49, wherein Rb is H.

[0149] The invention also provides, as embodiment 51, a combination, a combination for use, a method for treatment, a kit, a dosage regimen, an adjuvant treatment method, or a short-duration psychedelic agent for use, according to any of embodiments 42 to 50, wherein the compound is selected from: Petition 870250088636, dated 09 / 30 / 2025, page 55 / 403 44 / 69 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-prothium, 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-prothium, α-deutero-N,N-dimethyltryptamine; 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine; 5-methoxy-α,α,β,β-tetradeutero-N,N-dimethyltryptamine; 5-methoxy-N,N-di(trideuteromethyl)tryptamine; 5-methoxy-α-prothium, α-deutero-N,N-di(trideuteromethyl)tryptamine; 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 5-methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof and mixtures thereof; or the compound is selected from the group consisting of: psilocybin; α-prothio, α-deutero-psilocybin; α,α-dideutero-psilocybin; α,α,β,β-tetradeutero-psilocybin; 4-(dihydrogen phosphate)-N,N-di(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α-protio,α-deutero-N,Ndi(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α,α-dideutero-N,Ndi(trideuteromethyl)tryptamine; 4-(dihydrogen phosphate)-α,α,β,β-tetradeutero-N,Ndi(trideuteromethyl)tryptamine; Petition 870250088636, dated 09 / 30 / 2025, page 56 / 403 45 / 69 psilocin; a-protio,a-deutero-psilocina; α,α-dideutero-psilocin; α,α,β,β-tetradeutero-psilocin; 4-hydroxy-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy - a-prothio,a-deutero- N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-a,a-dideutero-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-α,α,ε,ε-tetradeutero-N,N-di(trideuteromethyl)tryptamine; psilocin-4-glutarate; a-prothio,a-deutero-psilocin-4-glutarate; a,a-dideutero-psilocin-4-glutarate; a,a,e,e-tetradeutero-psilocin-4-glutarate; 4-hydroxy-N,N-di(trideuteromethyl)tryptamine-4-glutarate; 4-Hydroxy-- a-prothio,a-deutero- N,N-di(trideuteromethyl)tryptamine-4glutarate; 4-hydroxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine-4-glutarate; 4-hydroxy-α,α,ε,ε-tetradeutero-N,N-di(trideuteromethyl)tryptamine-4-glutarate; iprocin-4-glutarate; a-prothio,a-deutero-iprocin-4-glutarate; a,a-dideutero-iprocin-4-glutarate; a,a,e,e-tetradeutero-iprocin-4-glutarate; 4-hydroxy-N,N-di(heptadeuteroisopropyl)tryptamine-4-glutarate; 4-Hydroxy-a-prothio,a-deutero-N,N-di(heptadeuteroisopropyl)tryptamine-4glutarate; 4-hydroxy-α,α-dideutero-N,N-di(heptadeuteroisopropyl)tryptamine-4-glutarate; 4-hydroxy-α,α,ε,ε-tetradeutero-N,N-di(heptadeuteroisopropyl)tryptamine-4-glutarate; and pharmaceutically acceptable salts and mixtures thereof. Petition 870250088636, dated 09 / 30 / 2025, page 57 / 403 46 / 69

[0150] The invention also provides, as embodiment 52, a combination for use, a method for treating, kit, dosage regimen, adjunctive treatment method or short-acting psychedelic agent for use, according to any of embodiments 18 to 51, comprising administration to the patient, or instructions for administration to the patient, of (i) oral administration to the patient of a selective serotonin reuptake inhibitor for a period of 4 weeks or more; (ii) parenteral administration to the patient of a short-acting psychedelic agent selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated analogues thereof and pharmaceutically acceptable salts thereof.

[0151] Steps (i) and (ii) of modality 52 can be administered by different health professionals.

[0152] The invention also provides, as embodiment 53, a combination for use, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to embodiment 52, wherein oral administration to the patient of a selective serotonin reuptake inhibitor is made over a period of 6 weeks or more.

[0153] The invention also provides, as embodiment 54, a combination, a combination for use, a method for treating, a kit, a dosage regimen, an adjunctive treatment method, or a short-acting psychedelic agent for use, according to any previous embodiment, for use in the treatment of a psychiatric disorder in a patient, wherein the treatment comprises assisted psychedelic psychotherapy.

[0154] The invention also provides, as embodiment 55, a kit according to claim 54, comprising instructions for psychedelic-assisted psychotherapy.

[0155] The invention further provides, as embodiment 56, a method for treating, dosage regimen, combination for use, dosage regimen, adjuvant treatment method or short-duration psychedelic agent for use, of Petition 870250088636, dated 09 / 30 / 2025, page 58 / 403 47 / 69 in accordance with modality 54, comprising: A. administering to the patient (i) a monoamine antidepressant and (ii) a short-acting psychedelic agent, preferably a parenteral form of a short-acting psychedelic agent selected from 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, iprocin-4-glutarate, deuterated iprocin-4-glutarate and pharmaceutically acceptable salts thereof; and B. a psychotherapy session.

[0156] Steps (i) and (ii) of modality 56 can be administered by different health professionals.

[0157] The invention further provides, as embodiment 57, a method for treatment, dosage regimen, combination for use, adjunctive treatment method or short-acting psychedelic agent for use, according to embodiment 54 or 56, wherein the psychotherapy session comprises: a. Preparation stage, which includes preparing the patient for a psychedelic experience; b. Administration stage, which comprises the administration of the short-acting psychedelic agent as defined in any of the previous modalities; and c. Integration stage, which includes an interview or discussion conducted by a psychiatrist or therapist with the patient, focusing on the psychedelic experience.

[0158] The invention also provides, as embodiment 58, a kit according to embodiment 55, additionally comprising instructions for: a. Preparation stage, which includes preparing the patient for a psychedelic experience; Petition 870250088636, dated 09 / 30 / 2025, page 59 / 403 48 / 69 b. Administration stage, which comprises the administration of the short-acting psychedelic agent as defined in any of the previous modalities; and c. Integration stage, which includes an interview or discussion conducted by a psychiatrist or therapist with the patient, focusing on the psychedelic experience.

[0159] The invention also provides, as embodiment 59, an adjunctive treatment method according to embodiment 5, in which the short-acting psychedelic agent is administered to a patient who has received adequate treatment with a monoamine antidepressant agent.

[0160] The invention also provides, as embodiment 60, an adjunctive treatment method according to embodiment 5 or 59, in which the short-acting psychedelic agent and the monoamine antidepressant agent are administered separately.

[0161] The invention further provides, as embodiment 61, an adjunctive treatment method according to embodiment 5, 59 or 60, wherein (i) the short-acting psychedelic agent is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and pharmaceutically acceptable salts thereof; and (ii) the monoamine antidepressant agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof.

[0162] The invention also provides, as embodiment 62, a short-acting psychedelic agent for use according to embodiment 6, wherein the short-acting psychedelic agent is administered to a patient who has received adequate treatment with a monoamine antidepressant agent.

[0163] The invention also provides, as embodiment 63, an agent Petition 870250088636, dated 09 / 30 / 2025, page 60 / 403 49 / 69 short-acting psychedelic for use according to modality 6 or 62, wherein the short-acting psychedelic agent and the monoamine antidepressant agent are administered separately to a patient.

[0164] The invention also provides, as embodiment 64, a short-acting psychedelic agent for use in accordance with embodiment 6, 62 or 63, wherein (i) the short-acting psychedelic agent is selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and pharmaceutically acceptable salts thereof; and (ii) the monoamine antidepressant agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof.

[0165] The invention also provides, as embodiment 65, a combination comprising: (i) a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof; and (ii) a short-acting psychedelic agent selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and pharmaceutically acceptable salts thereof; for simultaneous, sequential or separate use in the treatment of a psychiatric disorder in a patient, preferably where the psychiatric disorder is selected from among a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder and an eating disorder. Petition 870250088636, dated 09 / 30 / 2025, page 61 / 403 50 / 69

[0166] The invention further provides, as embodiment 66, a combination for use, according to embodiment 65, for separate use in the treatment of a psychiatric disorder in a patient, preferably wherein the psychiatric disorder is selected from among a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder and an eating disorder.

[0167] The invention further provides, as embodiment 67, a combination for use, according to embodiment 65 or 66, wherein the short-acting psychedelic agent is administered to a patient who has received an adequate course of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

[0168] The invention also provides, as embodiment 68, a combination for use, according to embodiments 65 to 67, comprising an SSRI selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof.

[0169] The invention also provides, as the seventh aspect, the use of a short-acting psychedelic agent for the manufacture of a medicament for the adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from among a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, and an eating disorder.

[0170] The invention provides, as the eighth aspect, a parenteral formulation comprising a dose of a short-acting psychedelic agent for use in the treatment of a psychiatric disorder in a patient undergoing treatment with a monoamine antidepressant; wherein the treatment comprises administering, preferably parenterally, to the patient the dose of the short-acting psychedelic agent; preferably wherein the psychiatric disorder is selected from among a depressive disorder, a disorder of Petition 870250088636, dated 09 / 30 / 2025, page 62 / 403 51 / 69 anxiety, obsessive-compulsive disorder, and an eating disorder, preferably selected from among a depressive disorder and an anxiety disorder. The depressive disorder may be selected from major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, terminal depression, and treatment-resistant depression. The anxiety disorder may be selected from generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

[0171] The invention also provides, as a ninth aspect, a delivery device for use in the treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, wherein the delivery device is configured to deliver the administration, preferably parenteral administration, to the patient of a parenteral dose of a short-acting psychedelic agent.

[0172] For the avoidance of doubt, all embodiments and aspects disclosed herein in relation to the first to sixth aspects apply mutatis mutandis to the seventh to ninth aspects of the invention.

[0173] The combination of the monoamine antidepressant agent and the short-acting psychedelic agent, as defined in any aspect or embodiment of the present invention, when administered to a patient, preferably provides simultaneous detectable plasma levels of the monoamine antidepressant agent and the short-acting psychedelic agent.

[0174] Short-acting psychedelic agents for use in combination, combination for use, dosage regimen, treatment method, adjunctive treatment method, short-acting psychedelic agent for use, kit, delivery device or parenteral formulation for use of the invention may be prepared according to the synthetic processes described in documents WO2021 / 089873, US20210395201, WO2022 / 117359 and US20220202775, the disclosures of which are incorporated by reference in their entirety.

[0175] The dose of the short-acting psychedelic agent for use in Petition 870250088636, dated 09 / 30 / 2025, page 63 / 403 52 / 69 combination, combination for use, dosage regimen, treatment method, adjunctive treatment method, short-acting psychedelic agent for use, kit, delivery device or parenteral formulation for use of the invention may preferably be in the form of a pharmaceutically acceptable salt, wherein the salt comprises an acid and the free base of a short-acting psychedelic agent selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, psilocybin, psilocin, psilocin-4-glutarate, iprocin-4-glutarate and deuterated analogues thereof. An example of a salt comprising an acid and dimethyltryptamine compound is N,N-dimethyltryptamine fumarate, which is the fumaric acid salt of N,N-dimethyltryptamine. PPH Stahl and CG Wermuth provide an overview of pharmaceutical salts and the acids they contain in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002.The acids described in this review are suitable for inclusion in the salt formulation.

[0176] The salt may include an acid selected from the group consisting of 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, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, glucuronic acid, acid glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acidmethanesulfonic 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, acid, Petition 870250088636, dated 09 / 30 / 2025, page 64 / 403 53 / 69 succinic acid, sulfuric acid, thiocyanic acid, toluenesulfonic acid and undecylenic acid.

[0177] Preferably, the pharmaceutically acceptable salt is selected from fumarate, tartrate, citrate, succinate, benzoate, and hydrochloride. Preferably, the pharmaceutically acceptable salt is fumarate.

[0178] Preferably, the pharmaceutically acceptable salt of the short-acting psychedelic agent is the fumarate salt.

[0179] Parenteral routes of administration include intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, transdermal, and inhalation administration. Any parenteral routes capable of administration over a period of up to about 15 minutes, preferably over a period of about 5 to about 15 minutes, are suitable for use in the present invention. Preferred routes of parenteral administration, according to any aspect of the present invention, are selected from intravenous infusion, intramuscular infusion, subcutaneous infusion, intranasal, transmucosal, and transdermal administration, and inhalation. Intravenous infusion is a particularly preferred route of administration. Intramuscular administration is a particularly preferred route of administration.

[0180] When the parenteral route of administration is intravenous, the delivery device may comprise an infusion bag or a syringe and may preferably additionally comprise a syringe pump. When two syringe pumps are used to administer the intravenous infusion, the syringe pumps may be joined by means of a 3-way stopcock into a single cannula. When the parenteral route of administration is intramuscular, the delivery device may comprise a syringe. When the parenteral route is intranasal, the delivery device may comprise a pump-action spray medium. When the parenteral route is transmucosal, the delivery device may comprise an oromucosal film. When the parenteral route is transdermal, the delivery device Petition 870250088636, dated 09 / 30 / 2025, page 65 / 403 54 / 69 may include a transdermal patch. When the route of administration is inhalation, the delivery device may include a metered-dose inhaler, a vaporizer, or a nebulizer.

[0181] Suitable dosage forms for parenteral administration have a pH of approximately 3 to 9 and, for liquid formulations, an osmolality of approximately 250 to approximately 600 mOsm / Kg. pH values ​​above 9 are reported by I. Usach et al. in Adv. Ther., 36, 2986-2996 (2019) to be related to tissue necrosis (death of cells within the tissue), while values ​​below 3 are reported as causing pain and phlebitis (inflammation of the veins). Osmolality values ​​above 600 mOsm / Kg are also reported as causing pain. Usach et al. also recommend that parenteral formulations be formulated as isotonic solutions (osmolality of approximately 300 mOsm / Kg), proposing an upper limit of 600 mOsm / Kg to minimize pain.

[0182] Osmolality is formally defined as the quotient between the negative natural logarithm of the rational activity of water and the molar mass of water, as represented by the formula: osmolality = —lnaw18.015'aw P p* where p is the partial vapor pressure of water in the solution and p* is the partial vapor pressure of pure water. In simpler terms, osmolality is the number of osmotically active particles (the number of solute particles) in 1 kg of a solution. Thus, osmolality is a function only of the number of particles and is not related to the molecular weight, size, shape, or charge of the particles (see DK Faria et al., ME Mendes and NM Sumita, J. Bras. Patol. Med. Lab., 53, 1, 38-45 (2017) for a review of serum osmolality measurement). For example, one mole of a non-dissociable substance (e.g., DMT as a free base) dissolved in 1 kg of water has an osmolality of 1 Osm / kg (1000 mOsm / kg), while one mole of a substance that dissociates into two separate species in solution (e.g., DMT as a free base) Petition 870250088636, dated 09 / 30 / 2025, p. 66 / 403 55 / 69 For example, DMT fumarate) dissolved in 1 kg of water has an osmolality of 2 Osm / kg (2,000 mOsm / kg).

[0183] When a first solution is defined in this document as isotonic with a second solution, the solutions have the same osmolality. For example, when a formulation is defined to be isotonic with human blood serum, the formulation has the same osmolality as human blood serum. Human blood serum typically has an osmolality of about 275 to about 300 mOsm / Kg (L. Hooper et al., BMJ Open, 2015; 5(10): e008846).

[0184] Suitable formulations for injection according to the present invention are described in documents WO2022 / 043227 and US11406619. Suitable formulations for inhalation administration according to the invention are described in document WO2022 / 117640. Suitable formulations for transdermal administration are described in documents US 20210346347 and US17 / 866477. Suitable formulations for buccal administration are described in document WO2022 / 232179. Other suitable formulations according to the present invention are described in pending patent application US17 / 574424. The entire disclosures of each of these patent applications are incorporated herein by reference in their entirety.

[0185] In some embodiments, the parenteral formulation for use in the present invention comprises a salt of the short-acting psychedelic agent, a base agent, water and, optionally, a buffer that is separate from the salt, wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg / ml as free base or greater and an osmolality 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.

[0186] The base agent adjusts the pH of the formulation to the required pH range, for example, from pH 5 to pH 6. The pH of a formulation that includes the salt of the short-acting psychedelic agent, water, and a buffer is generally Petition 870250088636, dated 09 / 30 / 2025, page 67 / 403 56 / 69 low, for example, less than pH 5, and therefore pH adjustment with a base agent may be necessary. A qualified person can assess suitable bases to adjust the solution pH without risk of degradation of the short-acting psychedelic agent salt. The base agent can be sodium hydroxide or potassium hydroxide.

[0187] The parenteral formulation optionally comprises a buffer, which is separate from the salt; that is, the buffer is not merely a counter-ion for the short-acting psychedelic agent. For example, when the salt is N,N-dimethyltryptamine fumarate (i.e., the fumaric acid salt of N,N-dimethyltryptamine), an amount of buffer may be required in addition to the buffering effect provided by the fumarate salt. The term buffer is well known in the art and refers to a chemical that, when included in a formulation, resists a change in pH with the addition of acid or base to the formulation. As used in this document, the term buffer refers to the buffer system or the buffering agent. In a formulation, a buffer comprises a weak acid and its conjugate base. A suitable buffer comprises an acid with a pKa value that is within ±1 of the desired pH of the formulation.For example, if the desired pH of the formulation is approximately 5.0, a suitable buffer comprises a weak acid with a pKa value of about 4.0 to about 6.0. If the acid in a buffer has more than one pKa value (that is, each molecule of the acid is capable of donating more than one proton), for the buffer to be suitable, at least one of the pKa values ​​must be within the desired pH range.

[0188] The weak acid and conjugate base of the buffer are in equilibrium with each other. According to Le Chatelier's principle (if a restriction (such as a change in the concentration of a reactant) is applied to a system at equilibrium, the equilibrium will shift so as to counteract the effect of the restriction), the addition of acid or base to the formulation shifts the equilibrium position in favor of the conjugate base or the weak acid, respectively. Consequently, the concentration of free protons in the formulation (and thus the pH) becomes relatively Petition 870250088636, dated 09 / 30 / 2025, page 68 / 403 57 / 69 unchanged.

[0189] Suitable buffer systems include an acetate salt and acetic acid (pKa = 4.75); a citrate salt 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 in this document are those reported at 25 °C in water. Typically, the buffer comprises only one of the pairs listed above, i.e., an acid and its conjugate base.

[0190] In some embodiments, the buffer comprises an acetate salt and acetic acid; a citrate salt and citric acid; or a phosphate salt and phosphoric acid. Sometimes, the buffer comprises an acetate salt and acetic acid; or a citrate salt and citric acid. In some embodiments, the buffer comprises an acetate salt and acetic acid, usually sodium acetate and acetic acid, or potassium acetate and acetic acid.

[0191] The buffer concentration in the formulation is normally sufficient to withstand a significant change in the formulation's pH during storage of the formulation for two weeks (i.e., the pH typically fluctuates less than about 0.1 pH units). In general, the buffer concentration is about 15 mM to about 75 mM, such as about 20 mM to about 30 mM. In some embodiments, the buffer concentration is about 25 mM.

[0192] As used in this document, the term buffering agent refers to a weak acid or a weak base. Any pharmaceutically acceptable buffering agent may be used in the formulations of the invention, including phosphoric acid, citric acid, acetic acid, phosphate salt, citrate salt, and acetate salt. In some embodiments, the buffer comprises sodium phosphate, sodium citrate, or sodium acetate.

[0193] Sometimes, the concentration of the short-acting psychedelic agent and the optional buffer in the formulation gives rise to the desired osmolality. Alternatively, the desired osmolality can be obtained by including one or more tonicity agents in the formulation. Thus, in some modalities, the Petition 870250088636, dated 09 / 30 / 2025, page 69 / 403 58 / 69 formulation additionally comprises a tonicity agent. A tonicity agent is defined herein as a chemical that, when included in a formulation, increases the osmolality of the formulation. As described above, osmolality is the number of osmotically active particles (the number of solute particles) in 1 kg of a solution. Thus, a chemical that acts as a solute when incorporated into the formulation falls within the definition of a tonicity agent.

[0194] In some embodiments, the formulation comprises a tonicity agent. The concentration of the tonicity agent depends on the concentration of other components of the formulation, such as the short-acting psychedelic agent and the buffer. For example, when the formulation without a tonicity agent has an osmolality of about 60 mOsm / kg, at least about 190 mOsm / kg would be provided by a tonicity agent (e.g., 95 mM sodium chloride). MF Powell, T. Nguyen, and L. Baloian provide a review of excipients suitable for parenteral administration (administration other than by mouth or alimentary canal) in PDA J. Pharm. Sci. Technol., 52, 238-311 (1998). All soluble excipients listed in this review article that can be administered intravenously, when added to the formulation, contribute to the osmolality and therefore can be considered tonicity agents.

[0195] Suitable excipients for use in the dose of a short-acting psychedelic agent, when used in accordance with the 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 bisulfate, sodium bisulfite, sodium chloride, sodium hydroxide, sodium metabisulfite, sodium phosphate, sodium citrate, sulfuric acid, trisodium citrate, tromethamine and mixtures thereof.

[0196] Some excipients can act as cosolvents. The solvents or Petition 870250088636, dated 09 / 30 / 2025, page 70 / 403 59 / 69 Suitable cosolvents for use in the formulations of the invention may be selected from ethanol, polyethylene glycol, propylene glycol and mixtures thereof. In some embodiments, the formulation comprises a cosolvent. In some embodiments, the formulation does not comprise a cosolvent. In particular, when the salt of the short-acting psychedelic agent is a fumarate, for example, N,N-dimethyltryptamine fumarate or α,α-dideuteroN,N-dimethyltryptamine fumarate, the formulation does not comprise a cosolvent.

[0197] Therapeutic improvement can be assessed using a rating scale commonly used in the field. For patients with depressive disorder, such as MDD or TRD, the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAMD-17) can be used. The rating scale is used before administration of the short-acting psychedelic agent to provide a baseline assessment, and again after administration of the short-acting psychedelic agent (post-dosage) to assess the therapeutic effect. Preferably, the post-dosage assessment occurs from about 24 hours to about one month after administration of the short-acting psychedelic agent, preferably about one week, about two weeks, about three weeks, and / or about four weeks after administration of the short-acting psychedelic agent. A reduction in symptoms to an essentially asymptomatic level is considered an indication of 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.

[0198] In some embodiments, the short-acting psychedelic agent may be administered as a two-phase IV infusion via a venous cannula over 6-11 minutes. In some embodiments, the short-acting psychedelic agent may be administered as a two-phase IV infusion via a venous cannula, wherein each phase comprises a Petition 870250088636, dated 09 / 30 / 2025, page 71 / 403 60 / 69 5-minute infusion. In some modalities, the short-acting psychedelic agent may be administered as a single-phase IV infusion via a venous cannula over 6-11 minutes, preferably around 10 minutes. When a two-phase IV infusion is used, the syringe pumps are suitably joined by means of a 3-way stopcock on a single cannula: once the infusion has been completed in the first pump, the 3-way stopcock is rotated to allow the infusion to continue from the second pump.

[0199] The term single-phase IV infusion refers to the administration of an IV infusion by a syringe pump, with the administration of the short-acting psychedelic agent from a single syringe pump. The term two-phase IV infusion refers to the administration of an IV infusion by two syringe pumps, with the first phase comprising the administration of the short-acting psychedelic agent by the first syringe pump, followed by the second phase comprising the administration of the short-acting psychedelic agent by the second syringe pump. The two-phase IV infusion is essentially continuous, with a non-material interruption in the infusion to switch administration from the first syringe pump to the second syringe pump.

[0200] In some modalities, the short-acting psychedelic agent may be administered intramuscularly.

[0201] In some embodiments, the kit is a kit for treating a psychiatric disorder in a patient, according to any previous embodiment, and the kit includes a) a container comprising a parenteral dose of a short-acting psychedelic agent 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 package label or leaflet attached to the container, comprising instructions for administration of the parenteral formulation, indicating that administration to a patient is in conjunction with the administration of a Petition 870250088636, dated 09 / 30 / 2025, page 72 / 403 61 / 69 monoamine antidepressant, preferably a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor.

[0202] In some embodiments, the parenteral formulation, combination, combination for use, treatment method, adjunctive treatment method, short-acting psychedelic agent for use, kit, delivery device or dosage regimen according to any previous embodiment are for use in the treatment of a patient who has not responded to an adequate course of treatment with at least one antidepressant agent, preferably at least one monoamine antidepressant or at least two different antidepressant agents.

[0203] The term "non-responder," as used in this document, refers to a lack of clinically significant improvement in symptoms, for example, as measured by one or more of the rating scales described above. Non-response to an appropriate course of treatment with a monoamine antidepressant agent may be determined retrospectively or prospectively. Prospective determination of non-response refers to a determination made by the prescribing therapist or physician after administration of part of a course of treatment. Retrospective determination refers to a determination made by the prescribing physician or therapist after administration of a complete and appropriate course of treatment.

[0204] The present invention is directed to the treatment of a disorder with a combination of agents; a monoamine antidepressant and a short-acting psychedelic agent. A therapeutically effective dose of the two agents refers to an amount of the monoamine antidepressant and the short-acting psychedelic agent that, when administered in combination, elicits a clinically significant response in a patient. The dose of each agent, when administered as a single agent, may not be therapeutically effective. For example, the dose of Petition 870250088636, dated 09 / 30 / 2025, page 73 / 403 62 / 69 monoamine antidepressant agent may be less than a therapeutically effective amount when administered as a single agent, but may be therapeutically effective when administered in combination with the short-acting psychedelic agent according to the present invention. For the avoidance of doubt, the dose of (i) the monoamine antidepressant agent and (ii) the short-acting psychedelic agent, as defined in any prior embodiment, comprises in combination a therapeutically effective dose.

[0205] The combination treatment 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 generally prescribed and / or administered by different healthcare professionals (such as physicians). The invention also provides for the administration of the two in a single formulation. Other combinations may also be encompassed by the combination therapy. For example, two agents may be formulated together and administered in conjunction with a separate formulation containing an additional dose of one of the agents or a third agent. Although the two or more agents of the combination treatment may be administered simultaneously, it is not necessary that they be.For example, the administration of a first agent (or combination of agents) may precede the administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents may be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other, for example, when the monoamine antidepressant is administered as a controlled-release dosage form. In some cases, even longer intervals are possible. Although in many cases it is desirable that the two or more agents be used. Petition 870250088636, dated 09 / 30 / 2025, page 74 / 403 While it's not necessary for both monoamine antidepressant and short-acting psychedelic agents to be present in the patient's body simultaneously—meaning that the administration regimens of the monoamine antidepressant and the short-acting psychedelic agent provide detectable plasma levels at the same time—combination treatment may also include two or more administrations of one or more of the agents used in the combination. The two agents may be administered according to different dosage schedules and by different healthcare professionals. For example, the monoamine antidepressant may be administered on a daily schedule, with separate administration of a single dose of the short-acting psychedelic agent at any three-month, six-month, nine-month, or twelve-month interval.For example, the monoamine antidepressant agent may be administered on a daily schedule, with separate administration of a single dose of the short-acting psychedelic agent at most once every three months, or at most once every six months, or at most once every nine months, or at most once every twelve months. The two agents of the present invention may be administered sequentially in any combination, one or more times. Preferably, the combination treatment according to the present invention is achieved by administration regimens of the antidepressant agent and the short-acting psychedelic agent that provide simultaneous detectable plasma levels of both agents at the same time. EXAMPLES.

[0206] A non-blinded study of a single dose of N,N-dimethyltryptamine fumarate [DMT] is underway in patients currently taking a selective serotonin reuptake inhibitor (SSRI) for their depression, but for whom the SSRI is not fully relieving progression (ClinicalTrials.gov Identifier: NCT05553691). The study comprises two groups: - Test cohort: Patients currently on a stable course of SSRI treatment that has been ineffective in completely relieving depression symptoms (SSRI prescribed outside the study). Petition 870250088636, dated 09 / 30 / 2025, page 75 / 403 64 out of 69 patients received a single dose of DMT fumarate by intravenous infusion; and - Control cohort: Patients who are not currently undergoing any pharmacological treatment for depression (control group). Patients received a single dose of DMT fumarate via intravenous infusion.

[0207] Patients were recruited with moderate-to-severe Major Depressive Disorder (MDD), as defined by a score on the Hamilton Depression Rating Scale (HAM-D) >14. Efficacy was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) to measure any change in patients’ depression symptoms from baseline (Day 0). Additional exploratory endpoints included the Beck Depression Inventory (BDI) to assess patient-reported depression and the State-Trait Anxiety Inventory (STAI-T) to assess patient-reported anxiety.

[0208] DMT fumarate is administered by intravenous infusion on Day 1. MADRS Efficacy

[0209] The results of the MADRS scale are shown in Table 1 below. MADRS Test Cohort Control Cohort Day 0 8 15 29 Day 0 8 15 29 S1001 28 2 4 1 S2001 37 21 18 18 S1003 36 1 9 0 S2002 35 21 21 15 S1004 25 8 0 2 S2003 33 24 26 30 S1005 31 2 0 0 S2004 33 9 7 0 S1006 13 1 1 0 S2005 39 7 8 17 S1007 29 0 0 0 Petition 870250088636, dated 09 / 30 / 2025, page 76 / 403 65 / 69 MADRS Test Cohort Control Cohort Day 0 8 15 29 Day 0 8 15 29 S1008 36 27 27 8 S1009 28 21 15 11 S1010 23 0 0 1 S1011 32 10 8 6 S1012 33 1 3 0 S1013 32 7 5 7 n 12 12 12 12 n 5 5 5 5 Mean 28.8 6.7 6.0 3.0 Mean 35.4 16.4 16.0 16.0 SD 6.4 8.8 8.1 3.9 SD 2.6 7.8 8.3 10.7 % mean change from baseline -78.1 -81.2 -90.2% average change from baseline - 53.1 - 54.2 - 54.8 Response* 100% Response* 80% Remission* 92% Remission* 20% * Response is defined as a > 50% reduction in the MADRS score from baseline; Remission is defined as a MADRS score < 10. Table 1

[0210] It can be observed that treatment with DMT fumarate in combination with an SSRI (test cohort) resulted in a mean % change from baseline (Day 0) of -78.1% on day 8 to -90.2% on day 29 for the test cohort participants (n=12). The response rate was 100% on day 29 for the test cohort. It is surprising that, on day 29, remission Petition 870250088636, dated 09 / 30 / 2025, p. 77 / 403 Complete 66 / 69 remission was observed in 11 participants in this test cohort (92%), while 10 participants showed remission at all other time points. One participant was observed to have a MADRS score of 11 on day 29, missing only the remission criterion of 10.

[0211] In comparison, the control cohort (n=5) showed a mean % change from baseline of -53.1% on day 8 and -54.8% on day 29, with a response rate on day 29 of 80%. One participant in the control cohort showed remission on Day 29 (20%).

[0212] It was surprising to observe such a marked difference in efficacy between the antidepressant effect of DMT treatment in the test cohort compared with the control cohort. These data suggest a potentially enhanced efficacy effect when DMT fumarate is administered in combination with SSRIs. BDI-II

[0213] These data were corroborated by the assessment of the Becks Intake Disorders Index (BDI-II) on day 15 and day 29, as shown in Table 2 below: BDI-II Test Cohort Control Cohort Day 0 15 29 Day 0 15 29 S1001 33 0 0 S2001 42 17 13 S1003 46 5 0 S2002 37 17 16 S1004 25 1 0 S2003 33 22 31 S1005 40 0 ​​0 S2004 27 8 2 S1006 18 0 0 S2005 41 20 12 S1007 28 3 4 S1008 41 29 11 S1009 14 6 7 S1010 21 3 1 S1011 33 5 7 Petition 870250088636, dated 09 / 30 / 2025, page 78 / 403 67 / 69 BDI-II Test Cohort Control Cohort Day 0 15 29 Day 0 15 29 S1012 28 1 2 S1013 33 8 5 n 12 12 12 n 5 5 5 Mean 30.0 5.1 3.1 Mean 36.0 16.8 14.8 SD 6.6 1.9 1.0 SD 7.6 3.7 3.7 % mean change from baseline -84 -88 % mean change from baseline -54 -59 Table 2

[0214] Again, treatment with DMT fumarate resulted in a significant mean % change from baseline (Day 0) of -84% on day 15 to -88% on day 29 for participants in the test cohort (n=12). This compares to a mean % change from baseline of -54% on day 15 to -59% on day 29 for participants in the control cohort (n=5). STAI-T

[0215] The results of the STAI-T scale are shown below. STAI-T Test Cohort Control Cohort Day 0 8 15 29 Day 0 8 15 29 S1001 71 34 33 34 S2001 72 40 46 49 S1003 69 28 25 26 S2002 69 44 39 47 S1004 56 29 22 23 S2003 59 50 52 59 Petition 870250088636, dated 09 / 30 / 2025, p. 79 / 403 68 / 69 STAI-T Test Cohort Control Cohort Day 0 8 15 29 Day 0 8 15 29 S1005 61 38 32 32 S2004 58 38 41 32 S1006 50 47 44 45 S2005 70 60 58 51 S1007 63 40 30 34 S1008 67 66 62 41 S1009 48 49 45 43 S1010 59 34 33 28 S1011 70 40 40 40 S1012 56 26 42 32 S1013 61 46 40 44 n 12 12 12 12 n 5 5 5 5.0 Average 60.9 39.8 37.3 35.2 Average 65.6 46.4 47.2 47.6 SD 7.6 11.2 10.7 7.4 SD 5.9 7.9 7.0 8.8 % average change from baseline - - 33.6 - 37.5 -41.0 % average change from baseline - - 28.9 - 27.6 - 27.2 Table 3

[0216] It can be observed in the data presented in Table 3 that treatment with DMT fumarate resulted in a significant mean % change from baseline (Day 0) of -41.0% on day 29 for participants in the test cohort (n=12). This compares to a mean % change from baseline of -27.2% on day 29 for participants in the control cohort (n=5).

[0217] The data presented above in Tables 1 to 3 show a significant reduction in symptoms of depression and anxiety after treatment. Petition 870250088636, dated 09 / 30 / 2025, page 80 / 403 69 / 69 with DMT fumarate for patients taking a selective serotonin reuptake inhibitor (SSRI) for depression, but for whom the SSRI is not fully relieving the depression. Safety and tolerability

[0218] DMT fumarate administration was well tolerated by all patients in both the test and control cohorts, with no apparent differences between the cohorts. No serious drug-related adverse events were reported. A small number of drug-related adverse events (AEs) were reported (8 in the test cohort and 3 in the control cohort), all considered mild or moderate in severity. Most drug-related AEs resolved during the dosing visit. Petition 870250088636, dated 09 / 30 / 2025, p. 81 / 403

Claims

1 / 18 CLAIMS 1. Combination characterized by comprising: (i) a monoamine antidepressant agent; and (ii) a short-acting psychedelic agent.

2. Combination according to claim 1, wherein the combination is characterized by being synergistic.

3. Combination, according to any of the preceding claims, characterized in that the monoamine antidepressant agent is selected from a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor.

4. Combination, according to any of the preceding claims, characterized in that the short-acting psychedelic agent is selected from 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, iprocin-4-glutarate, deuterated iprocin-4-glutarate, mixtures thereof and pharmaceutically acceptable salts thereof.

5. Combination, according to any of the preceding claims, characterized in that the monoamine antidepressant agent is selected from desvenlafaxine, duloxetine, levomilnacipran, milnacipram, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof.

6. Combination, according to any of the preceding claims, characterized by comprising: (i) an appropriate course of treatment with a monoamine antidepressant agent; and (ii) a single dose of a short-acting psychedelic agent. Petition 870250088636, dated 09 / 30 / 2025, p. 82 / 403 2 / 18 7. Combination, according to claim 6, characterized in that the appropriate course of treatment comprises a treatment period of 4 weeks or more.

8. Combination, according to any of claims 6 and 7, characterized in that said single dose of a short-acting psychedelic agent is to be administered only once in any three-month period.

9. Combination, according to any one of claims 6 to 7, characterized in that a single dose of a short-acting psychedelic agent must be administered at most once every three months.

10. Combination, according to any one of claims 6 to 7, characterized in that a single dose of a short-acting psychedelic agent is to be administered only once in any six-month period.

11. Combination, according to any one of claims 6 to 7, characterized in that a single dose of a short-acting psychedelic agent must be administered at most once every six months.

12. Combination, according to any one of claims 6 to 7, characterized in that a single dose of a short-acting psychedelic agent is to be administered only once in any nine-month period.

13. Combination, according to any one of claims 6 to 7, characterized in that a single dose of a short-acting psychedelic agent must be administered at most once every nine months.

14. Combination, according to any one of claims 6 to 7, characterized in that said single dose of a short-acting psychedelic agent is for administration only once in any twelve-month period.

15. Combination, according to any of claims 6 to 7, characterized in that a single dose of a short-duration psychedelic agent (Petition 870250088636, dated 09 / 30 / 2025, page 83 / 403 3 / 18) must be administered at most once every twelve months.

16. Combination, according to any of the preceding claims, characterized by comprising: (i) an oral dosage form of the monoamine antidepressant agent; and (ii) a parenteral dosage form of the short-acting psychedelic agent.

17. Combination, according to any of the preceding claims, characterized in that it is for use in the treatment of a psychiatric disorder, preferably wherein the psychiatric disorder is selected from among a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a post-traumatic stress disorder, a panic disorder, and an eating disorder.

18. Combination, according to any of the preceding claims, characterized by being 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. Combination, according to any of the preceding claims, characterized by being for use in the treatment of an anxiety disorder selected from among generalized anxiety disorder, phobia, panic disorder, social anxiety disorder and post-traumatic stress disorder.

20. Combination for use in accordance with any of claims 17 to 19, characterized by further comprising the steps of: a. baseline assessment of a patient using a rating scale and / or physician-reported results and / or patient-reported results; and b. post-dosage assessment of the patient following administration of the short-acting psychedelic agent.

21. Combination for use according to claim 20, Petition 870250088636, dated 09 / 30 / 2025, p. 84 / 403 4 / 18 characterized in that the baseline assessment is made by a rating scale selected from the Clinical Global Impression (CGI) scale; the Montgomery-Asberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD17); the Beck Depression Inventory-II; the Beck Anxiety Inventory (BAI); the Hamilton Anxiety Scale (HAM-A); the State-Trait Anxiety Inventory (STAI or STAI-T); the Generalized Anxiety Disorder Assessment (GAD-7); the Clinician-Administered Post-Traumatic Stress Disorder Scale (CAPS); the Yale-Brown Obsessive-Compulsive Scale; The Beck Scale for Suicidal Ideation (BSS); the Columbia Suicide Risk Assessment Scale (C-SSRS); and the suicidal thoughts item of the MADRS for suicidal ideation.The Clinical Global Impression of Suicidality Severity Scale Revised (CGI-SS-R); the Beck Depression Inventory (BDI-II); the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF); the EQ-5D-5L and EQ VAS descriptive systems; the Patient Global Impression of Severity Scale (PGI-S); and combinations thereof.

22. Combination for use, according to claim 20 or 21, characterized in that the post-dose assessment is made by a rating scale selected from the Clinical Global Impression (CGI) scale; the Montgomery-Asberg Depression Rating Scale (MADRS); the Hamilton Depression Rating Scale (HAMD17); the Beck Depression Inventory-II; the Beck Anxiety Inventory (BAI); the Hamilton Anxiety Scale (HAM-A); the State-Trait Anxiety Inventory (STAI or STAI-T); the Generalized Anxiety Disorder Assessment (GAD-7); the Clinician-Administered Post-Traumatic Stress Disorder Scale (CAPS); the Yale-Brown Obsessive-Compulsive Scale; the Beck Scale for Suicidal Ideation (BSS); the Columbia Suicide Risk Assessment Scale (C-SSRS); The MADRS item for suicidal ideation; the Clinical Global Impression of Suicidality Severity Scale - Revised (CGI-SS-R);The Beck Depression Inventory (BDI-II); the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF); the EQ-5D-5L and EQ VAS descriptive systems; the Patient Global Impression of Severity scale (PGI-S); the Clinical Global Improvement scale (CGI-I); the Patient Global Impression of Improvement scale (PGI-I); and combinations thereof.

23. Combination for use, according to any one of claims 17, 18 and 20 to 22, characterized in that the psychiatric disorder is a depressive disorder, and in which the initial and post-dosage assessment is performed using a depression rating scale selected from the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD17), the Beck Depression Inventory-II and combinations thereof.

24. Combination for use, according to any one of claims 13 to 23, characterized by providing a patient with remission of the psychiatric disorder.

25. Combination for use, according to any one of claims 17 to 24, characterized in that remission is assessed at a time of 6 to 10 days after administration of the short-acting psychedelic agent, preferably 6 to 8 days.

26. Combination for use, according to any one of claims 17 to 25, characterized in that the administration of the short-acting psychedelic agent comprises: administering parenterally to the patient a dose of the short-acting psychedelic agent over a dosing period of up to about 15 minutes, preferably from about 5 to about 15 minutes, and wherein the parenteral administration is essentially continuous.

27. Combination for use, according to any one of claims 17 to 26, characterized in that the administration of the short-acting psychedelic agent is a parenteral administration selected from the group consisting of intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal and transdermal administration and inhalation, preferably a parenteral administration selected from the group consisting of intravenous, intramuscular, intranasal, transmucosal and transdermal administration and inhalation.

28. Combination for use, according to claim 27, characterized in that parenteral administration is by intravenous infusion, preferably wherein the intravenous administration is conducted using a syringe pump.

29. Combination for use, according to claim 28, characterized in that parenteral administration is done by a two-phase intravenous infusion.

30. Combination for use, according to claim 28, characterized in that parenteral administration is done by a single-phase intravenous infusion.

31. Combination for use, according to any one of claims 28 to 30, characterized in that the dosing period is about 8 to about 12 minutes.

32. Combination for use, according to claim 31, characterized in that the dosing period is about 9 to about 11 minutes, or about 10 minutes.

33. Combination or blend for use, according to any one of claims 6 to 32, characterized in that the dose of the short-acting psychedelic agent is selected from the group consisting of: - about 20 to about 80 mg of N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - about 20 to about 80 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - about 15 to about 30 mg of deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; - about 10 to about 30 mg of 5-methoxy-N,N-dimethyltryptamine, Petition 870250088636, dated 09 / 30 / 2025, p.87 / 403 7 / 18 a deuterated analogue or a pharmaceutically acceptable salt thereof; and - about 10 to about 30 mg of deuterated 5-methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; or the dose of the short-acting psychedelic agent is selected from the group consisting of: - about 10 to about 30 mg of psilocybin or a pharmaceutically acceptable salt thereof; - about 10 to about 20 mg of deuterated psilocybin or a pharmaceutically acceptable salt thereof; - about 1 to about 20 mg of psilocin or a pharmaceutically acceptable salt thereof; - about 1 to about 20 mg of deuterated psilocin or a pharmaceutically acceptable salt thereof; and - approximately 20 to approximately 50 mg of psilocin-4-glutarate, deuterated psilocin-4-glutarate, iprocin-4-glutarate, deuterated iprocin-4-glutarate, or a pharmaceutically acceptable salt thereof.

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

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

36. Combination for use, according to any of claims 17 to 33, characterized in that 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, and the total dose is about 7 to about 10 mg.

37. Combination for use, according to any one of claims 26 to 33, characterized in that the 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, and the total dose is from about 20 to about 23 mg.

38. Combination for use, according to any one of claims 26 to 33, characterized in that the 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, and the total dose is from about 26 to about 29 mg.

39. Combination for use, according to claim 27, characterized in that administration is by intramuscular injection.

40. Combination for use, according to claim 39, characterized in that the short-acting psychedelic agent is N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the total dose is from about 20 to about 70 mg, preferably from about 50 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 from about 20 to about 60 mg, or from about 15 to about 30 mg.

41. Combination or combination for use, according to any of the preceding claims, characterized in that the short-acting psychedelic agent is a compound of formula I or a pharmaceutically acceptable salt thereof: Ra is selected from H and D; or Ra is selected from -OH, -OPO3H2 and -OC(O)C1-C3alkyleneCO2H; Rb is selected from H, D, -OCH3 and -OCD3; R2 and R3 are each independently selected from C(Hz)3; or R2 and R3 are independently selected from C2(Hz)5 and C3(Hz)7; and each Hx, Hy and Hz is independently selected from protium and deuterium.

42. Combination or combination for use, according to claim 41, characterized in that R2 and R3 are each independently selected from CH3 and CD3.

43. Combination or combination for use, according to claim 42, characterized in that R2 and R3 are both CH3, or R2 and R3 are both CD3, or R2 is CH3 and R3 is CD3.

44. Combination or combination for use, according to any one of claims 41 to 43, characterized in that each Hx is H, or each Hx is D.

45. Combination or combination for use, according to any of claims 41 to 44, characterized in that each Hy is H, or each Hy is D, or one Hy is H and one Hy is D. Petition 870250088636, dated 09 / 30 / 2025, page 90 / 403 10 / 18 46. ​​Combination or blend for use, according to any one of claims 41 to 45, characterized in that each Hx, Hy and Hz is deuterium.

47. Combination or blend for use, according to any of the preceding claims, characterized in that the short-acting psychedelic agent is selected from the group consisting of: either a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; wherein Ra and Rb are as defined in claim 41. Petition 870250088636, dated 09 / 30 / 2025, p. 91 / 403 11 / 18 48. Combination or combination for use, according to any one of claims 41 to 47, characterized in that Ra is H or Ra is D.

49. Combination or combination for use, according to any one of claims 41 to 48, characterized in that Rb is H, or Rb is D.

50. Combination or blend for use, according to any one of claims 41 to 48, characterized in that the short-acting psychedelic agent is selected from the group consisting of: N,N-dimethyltryptamine; α-protio, 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-protio, 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-prothium, α-deutero-N,N-dimethyltryptamine; 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine; 5-methoxy-α,α,β,β-tetradeutero-N,N-dimethyltryptamine; 5-methoxy-N,N-di(trideuteromethyl)tryptamine; 5-methoxy-α-prothium, α-deutero-N,N-di(trideuteromethyl)tryptamine; 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 5-methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine;and / or pharmaceutically acceptable salts thereof; or the compound is selected from the group consisting of: psilocybin; α-protio, α-deutero-psilocybin; α,α-dideutero-psilocybin; α,α,β,β-tetradeutero-psilocybin; 4-(dihydrogen phosphate)-N,N-di(trideuteromethyl)tryptamine; Petition 870250088636, dated 09 / 30 / 2025, page 92 / 403 12 / 18 4-(dihydrogen phosphate)-α-protio, 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(trideuteromethyl)tryptamine; psilocin; α-protio,α-deutero-psilocin; α,α-dideutero-psilocin; α,α,β,β-tetradeutero-psiloin; 4-hydroxy-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-α-protio,α-deutero-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; psilocin-4-glutarate; α-prothio,α-deuteropsilocin-4-glutarate;α,α-dideuteropsilocin-4-glutarate; α,α,β,β-tetradeutero-psilocin-4-glutarate; 4-hydroxy-N,N-di(trideuteromethyl)tryptamine-4-glutarate; 4-hydroxy - α-prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine-4-glutarate; 4-hydroxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine-4-glutarate; 4-hydroxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine-4glutarate; iprocin-4-glutarate; α-prothio,α-deutero-iprocin-4-glutarate; α,α-dideutero-iprocine-4-glutarate; α,α,β,β-tetradeutero-iprocine-4-glutarate; 4-hydroxy-N,N-di(heptadeuteroisopropyl)tryptamine-4-glutarate; 4-hydroxy-α-protio,α-deutero-N,N-di(heptadeuteroisopropyl)tryptamine-4-glutarate; Petition 870250088636, dated 09 / 30 / 2025, page 93 / 403 13 / 18 4-hydroxy-α,α-dideutero-N,N-di(heptadeuteroisopropyl)tryptamine-4-glutarate; 4-hydroxy-α,α,ε,ε-tetradeutero-N,N-di(heptadeuteroisopropyl)tryptamine-4-glutarate; and / or pharmaceutically acceptable salts thereof.

51. Combination for use, according to any one of claims 17 to 46, characterized by comprising: (i) oral administration to the patient of a selective serotonin reuptake inhibitor for a period of 4 weeks or more; and (ii) parenteral administration to the patient of a short-acting psychedelic agent selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, deuterated analogues thereof and pharmaceutically acceptable salts thereof.

52. Combination for use, according to claim 51, characterized in that oral administration to the patient of a selective serotonin reuptake inhibitor occurs over a period of 6 weeks or more.

53. Combination for use, according to any one of claims 17 to 52, characterized in that the treatment of a psychiatric disorder in a patient includes psychedelic-assisted psychotherapy.

54. Combination for use according to claim 53, characterized by comprising: A. the administration to the patient of (i) a monoamine antidepressant agent and (ii) a short-acting psychedelic agent, preferably a parenteral form of a short-acting psychedelic agent selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, psilocin, deuterated psilocin, psilocybin, deuterated psilocybin, psilocin-4 Petition 870250088636, dated 09 / 30 / 2025, p. 94 / 403 14 / 18 glutarate, psilocin-4-glutarate deuterated, iprocin-4-glutarate, iprocin-4-glutarate deuterated and pharmaceutically acceptable salts thereof; and B. a session of psychotherapy.

55. Combination for use, according to claim 53 or 54, characterized by comprising: a. Preparation stage, comprising preparing the patient for a psychedelic experience; b. Administration stage, comprising administering the short-duration psychedelic agent as defined in any of the preceding claims; and c. Integration stage, comprising an interview or discussion conducted by a psychiatrist or therapist with the patient, focusing on the psychedelic experience.

56. Short-acting psychedelic agent for use in the adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant, preferably characterized in that the psychiatric disorder is selected from among a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a post-traumatic stress disorder, a panic disorder, and an eating disorder.

57. Short-acting psychedelic agent for use according to claim 56, wherein the short-acting psychedelic agent is characterized by being administered to a patient who has received an adequate course of a monoamine antidepressant agent.

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

59. Short-acting psychedelic agent for use, according to Petition 870250088636, dated 09 / 30 / 2025, page 95 / 403 15 / 18, any of claims 56 to 58, characterized in that (i) the monoamine antidepressant agent is a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and 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.

60. Short-acting psychedelic agent for use according to any one of claims 56 to 59, wherein the short-acting psychedelic agent is characterized by being a compound of formula I or a pharmaceutically acceptable salt thereof: Formula I Ra is selected from H and D; or Rb is selected from H and D; R2 and R3 are each selected independently from C(Hz)3; and each Hx, Hy and Hz is selected independently from protium and deuterium.

61. Short-acting psychedelic agent for use, according to Petition 870250088636, dated 09 / 30 / 2025, pp. 96 / 403 16 / 18, any of claims 56 to 60, characterized in that R2 and R3 are both CHa or R2 and R3 are both CD3.

62. Short-acting psychedelic agent for use, according to any one of claims 56 to 61, characterized in that each Hy is H or each Hy is D.

63. Short-acting psychedelic agent for use according to any one of claims 56 to 62, characterized in that each Hx, Hy and Hz is deuterium.

64. Short-acting psychedelic agent for use according to any one of claims 56 to 63, wherein the short-acting psychedelic agent is characterized by being selected from the group consisting of: Petition 870250088636, dated 09 / 30 / 2025, page 97 / 403 17 / 18 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; wherein Ra and Rb are as defined in claim 60.

65. Short-acting psychedelic agent for use according to any one of claims 56 to 64, characterized in that Ra is H.

66. Short-acting psychedelic agent for use according to any one of claims 56 to 65, characterized in that Rb is H.

67. Combination characterized by comprising: (i) a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), preferably selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof; and (ii) a short-acting psychedelic agent selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and pharmaceutically acceptable salts thereof; for simultaneous, sequential or separate use in the treatment of a psychiatric disorder in a patient.

68. Combination for use, according to claim 67, for separate use in the treatment of a psychiatric disorder in a patient, characterized in that the psychiatric disorder is selected from Petition 870250088636, dated 09 / 30 / 2025, page 98 / 403 18 / 18 a depressive disorder, an anxiety disorder, an obsessive-compulsive disorder, a post-traumatic stress disorder, a panic disorder and an eating disorder.

69. Combination for use, according to claim 67 or 68, characterized in that the short-acting psychedelic agent is administered to a patient who has received an adequate course of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

70. Combination for use, according to any one of claims 67 to 69, characterized by comprising an SSRI selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine and vortioxetine, and pharmaceutically acceptable salts thereof. Petition 870250088636, dated 09 / 30 / 2025, pp. 99 / 403