Methods of administering parenteral formulations containing psychedelic agents

Abstract

The present invention relates to dosage regimens, methods of treatment, delivery devices, or parenteral formulations for use in treating psychiatric or neurological disorders in a patient. In particular, the present invention relates to the administration of psychedelic agents.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to a dosing regimen, method of treatment, delivery device, or parenteral formulation for use in treating a psychiatric or neurological disorder in a patient. In particular, the present invention relates to the administration of psychedelic agents. BACKGROUND OF THE INVENTION

[0002] Classical psychedelics have shown promise preclinically and clinically in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, psilocybin (also known as psilocybin) has shown significant improvements in various depression and anxiety rating scales in randomized, double-blind trials (Griffiths et al. Journal of Psychopharmacology, 30(12), 1181-1197 (2016)). The efficacy of psilocybin has been shown 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), 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 rooted in psychologically destructive thought processing patterns (anorexia nervosa: NCT# NCT04052568).

[0003] N,N-dimethyltryptamine (DMT) has also been proposed to have therapeutic value as a short-acting psychedelic. A review of studies on DMT biosynthesis and metabolism in the brain and peripheral tissues, as well as methods and results for DMT detection in body fluids and the brain, is published by SA Barker in Front. Neurosci., 12, 536, 1-17 (2018). Barker et al. suggest that "further characterization of DMT's cellular distribution, receptors, and general biochemistry could lead to more effective pharmaceutical agents and new targets for intervention." D. Nutt et al. (Cell. 2020 Apr 2;181(1):24-28. doi: 10.1016 / j.cell.2020.03.020) suggest the potential therapeutic role of DMT, stating, "However, theoretically, a short-term trip, such as that administered intravenously, could 'shake up' or 'reset' abnormal patterns of brain activity, potentially resulting in some therapeutic effect." Both Barker et al. and Nutt et al. conclude that further research is needed into the role and function of DMT.

[0004] Sanches et al. and Palhano-Fontes et al. reported that a single oral dose of ayahuasca, a natural psychedelic-containing plant, was associated with improvement in depressive symptoms in patients with recurrent major depressive disorder (MDD) or treatment-resistant depression (TRD) (Sanches RF, de Lima Osorio F, dos Santos RG, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A SPECT study. J Clin Psychopharmacol 2016;36(1):77-81 and Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med 2019;49(4):655-663). N,N-dimethyltryptamine (DMT) is the primary psychedelic compound found in ayahuasca.

[0005] Good et al. discuss the results of a phase 1 study examining the pharmacokinetics of N,N-dimethyltryptamine fumarate in healthy subjects (Meghan Good, Tiffanie Benway, Zelah Joel, et al., Authorea. May 12, 2022; DOI: 10.22541 / au.165237523.39763980 / v1). This study did not include patients with psychiatric or neurological disorders. This report has not been peer-reviewed.

[0006] D'Souza et al. reported "An exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and patients with major depressive disorder" (D'Souza, S.A. Syed, L.T. Lynn, H. Safi-Aghdam, N.V. Cozzi, and M. Ranganathan, Neuropsychopharmacology (2022) 47:1854-1862). Seven patients with major depressive disorder received two doses of DMT hemifumarate (0.1 mg / kg, followed by 0.3 mg / kg) at least 48 hours apart. Subjects received DMT via intravenous push, or bolus, injection over 30-60 seconds.

[0007] WO2022195489 discusses a method of using psychedelics, which involves an initial bolus injection followed by a lower maintenance dose, and WO2022031566 discusses the intravenous administration of DMT.

[0008] Timmermann et al. discuss the results of a clinical trial examining the effects of intravenous DMT in healthy individuals ( Translational Psychiatry (2023) 13:172, published online May 23, 2023).

[0009] Cybin has completed the first phase of a Phase 1 / 2a clinical trial evaluating its deuterated psilocybin compound (CYB003) in healthy participants with and without major depressive disorder (ClinicalTrials.gov Identifier: NCT05385783). In February 2023, Cybin announced that after a single oral dose of CYB003, the psychedelic effects were felt within approximately 15 minutes, with a mean duration of peak effects of approximately 2 hours. This data is based on an interim analysis of CYB003 in healthy volunteers (https: / / cybin.com / cyb003 / ).

[0010] In May 2023, Cybin announced that it was evaluating intravenous administration of its deuterated dimethyltryptamine compound (CYB004) in healthy volunteers. Part C of the Phase 1 CYB004-E trial is a crossover study design evaluating an IV bolus plus infusion regimen of CYB004 in up to two cohorts.

[0011] As interest in the potential uses of psychedelics, such as psilocybin and DMT, in psychiatry grows, so does the need for methods to administer these drugs in a safe and tolerable manner. Summary of the Invention

[0012] In a first aspect, the present invention provides a dosing regimen for administering a psychedelic agent to a patient for the treatment of a psychiatric or neurological disorder, the dosing regimen comprising parenterally administering the psychedelic agent over an administration period of about 5 to about 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides the patient with a delayed-onset breakthrough psychedelic experience.

[0013] In a second aspect, the present invention provides a method for treating a psychiatric or neurological disorder in a patient, the method comprising parenterally administering to the patient a psychedelic agent over an administration period of about 5 to 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0014] In a third aspect, the present invention provides a delivery device for use in treating a psychiatric or neurological disorder in a patient, wherein the delivery device is configured to deliver a parenterally administered psychedelic agent over an administration period of about 5 to about 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogues thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0015] In a fourth aspect, the present invention provides a parenteral formulation for use in treating a psychiatric or neurological disorder in a patient, comprising parenteral administration of a psychedelic agent over an administration period of about 5 to about 15 minutes, wherein said psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein said parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0016] In a fifth aspect, the present invention provides a parenteral formulation comprising a psychedelic agent for use in treating a psychiatric or neurological disorder in a patient, comprising parenteral administration of a psychedelic agent over an administration period of about 5 to about 15 minutes, wherein said psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein said parenteral administration provides the patient with a delayed breakthrough psychedelic experience. [Brief explanation of the drawings]

[0017] [Figure 1]Figure 1 shows the percentage of subjects who achieved a 50% or greater reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores compared to baseline assessments at weeks 1 and 2 after DMT fumarate or placebo administration. [Figure 2] Figure 2 shows the percentage of subjects with a MADRS score ≦10 at weeks 1 and 2 after administration of DMT fumarate or placebo. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition Throughout this specification, one or more aspects of the present invention may be combined with one or more features described herein to define separate embodiments of the present invention.

[0019] In the detailed description, reference will be made to a number of terms, which shall be understood to have the meanings set forth below unless the context clearly indicates to the contrary.

[0020] The nomenclature used herein for the psychedelic agents used in the present invention is that commonly used in the art. The compounds described herein may also be referred to by nomenclature in accordance with the International Union of Pure and Applied Chemistry (IUPAC) rules for chemical compounds, specifically the "IUPAC Compendium of Chemical Terminology (Gold Book)" (see AD Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). For the avoidance of doubt, in the event that the rules of the IUPAC organization conflict with a definition set forth herein, the definition set forth herein shall prevail.

[0021] N,N-Dimethyltryptamine is also known by the IUPAC name: 2-(1H-indol-3-yl)-N,N-dimethylethanamine. 5-Methoxy-N,N-dimethyltryptamine is also known by the IUPAC name: 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine. 4-Acetoxy-N,N-dimethyltryptamine is also known by the IUPAC name: [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl]acetate. Psilocybin is also known by the IUPAC name: [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate. Psilocin is also known by the IUPAC name: 3-[2-(dimethylamino)ethyl]-1H-indol-4-ol.

[0022] As used herein, the term "deuterated analog" of a psychedelic agent refers to one or more hydrogen atoms in the structure of the psychedelic agent replaced with deuterium atoms, where a deuterium atom is a hydrogen atom to which a neutron has been added. Deuterium substitution may be at one or more of the α- and β-positions, on a methyl group, on the indole ring, and in certain compounds, on a substituent on the indole ring, e.g., the methoxy group of 5-methoxy-N,N-dimethyltryptamine. In some embodiments, deuteration may be at the methyl group, the α-position, and optionally the β-position.

[0023] When a compound described herein is designated or described as a deuterated analog, the compound is enriched with deuterium by an amount dependent on the proportion of deuterium available in the reagent from which the compound is derived. For example, the d6-dimethylamino moiety of a compound of Formula I can be represented by -NR 2 R 3When is -N(CD3)2, it is derived from dimethyl-d7-amine or dimethyl-d6-amine (commonly available as the HCl salt), which are available from commercial chemical suppliers with deuterium purities ranging from 98% to 99%. The resulting purity of deuterium in the resulting d6-dimethylamino substituent is 98% to 99%. This means that, as will be appreciated by those skilled in the art, not all compounds of Formula I (for example) will contain d6-dimethylamino substituents, and some may contain d0-d5 dimethylamino, but the average purity of deuterium will be about 98% to 99%.

[0024] In some embodiments, the psychedelic agent is substituted at the 5-position with methoxy, or at the 4-position with acetoxy or hydroxy, or with monohydrogen phosphate. The term "acetoxy" (often abbreviated as OAc) defines a monovalent group derived from acetic acid by removing a hydrogen atom from the OH moiety. The term "methoxy" (often abbreviated as OMe) defines a monovalent group derived from methanol by removing a hydrogen atom from the OH moiety. The term "hydroxy" (often abbreviated as OH) defines a monovalent group derived from water by removing a hydrogen atom from the HO moiety. The term "monohydrogen phosphate" defines a divalent group of formula HPO4 derived from phosphoric acid by removing protons from two of the three OH moieties, thus having the formula -OP(O)(OH)O - means a substituent of the formula:

[0025] When the 4-position of a dimethyltryptamine compound is substituted with a hydroxyl group, the psychedelic agent is referred to herein as psilocin. When the 4-position of a dimethyltryptamine compound is substituted with a monohydrogen phosphate, this reflects the fact that psilocybin (also known as [3-(2-dimethylaminoethyl)-1H-indol-4-yl]dihydrogen phosphate) in water generally has a monohydrogen phosphate at the 4-position, which is generally understood to be the predominant form due to the estimated pKa values ​​of the two terminal phosphate oxygen atoms of 1.3 and 6.5. Furthermore, it is understood that the monohydrogen phosphate-containing form of psilocybin exists as a zwitterion (i.e., an inner salt) in which the nitrogen atom of the dimethylamino moiety is protonated. Therefore, this form, and psilocybin, are considered salts of dimethyltryptamine compounds substituted with a monohydrogen phosphate at the 4-position.

[0026] For the avoidance of doubt, the 4- and 5-positions, and the α- and β-positions in psychedelics refer to the positions labeled in the structures below (substituents not shown). [ka]

[0027] As used herein, a dose or total dose of a psychedelic agent refers to the dose or total dose as the free base equivalent of the agent.

[0028] As used herein, the terms "parenteral administration" or "parenterally administering" refer to the administration of a dose of a psychedelic agent by any route other than oral, in one or more separate doses over an administration period. Parenteral administration is essentially continuous over an administration period of 5 to 15 minutes. For the avoidance of doubt, "parenteral administration" excludes an initial bolus administration of a psychedelic agent (a single dose of agent administered at a rapid rate, typically over 30 to 60 seconds, which single dose provides an early-onset breakthrough psychedelic experience).

[0029] Fast onset refers to a breakthrough psychedelic experience that peaks within two minutes of initiating psychedelic administration. As used herein, the term "slow onset breakthrough psychedelic experience" refers to a breakthrough psychedelic experience that peaks more than two minutes after initiating psychedelic administration.

[0030] As used herein, a reference to the singular form of a noun includes the plural form of that noun (and vice versa), unless the context requires otherwise.

[0031] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to mean the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of other elements, integers or steps, or other groups of elements, integers or steps. The term "comprising" includes within its scope the terms "consisting only of" or "consisting essentially only of."

[0032] The term "consisting only of" or variations thereof will be understood to mean including the stated elements, integers or steps, or groups of elements, integers or steps, and to the exclusion of other elements, integers or steps, or other groups of elements, integers or steps.

[0033] The term "consisting essentially of" or variations thereof is understood to mean including the recited elements, integers or steps, or group of elements, group of integers or group of steps, and that additional components may be present, but only so long as they do not materially affect the essential characteristics of the embodiment of the invention.

[0034] As used herein, the term "about," when modifying a numerical value or value, refers to a value within ±5% of the specified value. For the avoidance of doubt, when a numerical value or value is specified in the present specification without the term "about," the numerical value or value should be understood according to standard numerical rounding practices according to the number of decimal places. For example, an integer such as 6 is understood to include values ​​equal to or greater than 5.5 and less than 6.5. Similarly, a numerical value specified to one decimal place, such as 5.3, is understood to include values ​​equal to or greater than 5.25 and less than 5.35.

[0035] Where a range of values ​​is provided, the range is inclusive of the endpoints, e.g., the range 20 to 28, or 20-28, includes the values ​​20, 21, 22, 23, 24, 25, 26, 27, and 28, and the range 5 to 15, or 5-15, includes the values ​​5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15.

[0036] As used herein, the term "patient" preferably refers to a mammal. Typically, the mammal is a human, but may also refer to domestic mammals. This term does not include laboratory mammals.

[0037] As used herein, the term "in combination with psychotherapy" refers to the treatment of a psychiatric disorder by psychological means that is augmented by a dosing regimen, treatment method, delivery device, or parenteral formulation for use in the present invention.

[0038] The term "treatment" refers to the therapeutic treatment of a patient to slow or stop the rate of progression of a disorder (disease), or to improve or cure the disorder. Also included is prophylactic treatment of patients with a diagnosed psychiatric or neurological disorder. Such prophylactic treatment, also known as secondary prevention, aims to reduce the effects of the disorder and / or prevent the progression of the disorder through treatment according to the present invention.

[0039] As used herein, "neurological disorder (neurological disease)" refers to a disorder that may be associated with dysfunction in the brain or nervous system and may result in physical and / or psychological symptoms. As used herein, the term "mental disorder (mental illness)" is characterized by a clinically significant impairment in an individual's cognition, emotional regulation, or behavior, and is associated with current distress (e.g., painful symptoms) or disability (i.e., impairment in one or more important areas of functioning), or a significantly increased risk of suffering from death, pain, disability, or significant loss of freedom.

[0040] The diagnostic criteria for the psychiatric or neurological disorders referred to herein are set out in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

[0041] As used herein, the term "psychedelic assisted psychotherapy" is defined as any psychotherapeutic practice provided in conjunction with a dose of a psychedelic therapeutic formulation (e.g., including any dose defined herein). The term "psychedelic assisted psychotherapy" includes assisted therapies that provide patient preparation, psychological support, and therapeutic integration before, during, and after the administration of psychedelics.

[0042] As used herein, the term "obsessive-compulsive disorder (OCD)" is defined by the presence of either obsessions or compulsions (usually both). The symptoms can cause significant functional impairment and / or distress. Obsessions are defined as unwanted, intrusive thoughts, images, or urges that repeatedly invade a person's mind. Compulsions are repetitive behaviors or mental acts that a person feels compelled to perform. OCD typically manifests as one or more obsessions that lead to compulsions. For example, an obsession with germs may lead to a compulsion to clean, or an obsession with food may lead to a compulsion to overeat, undereat, or vomit after eating (i.e., a food obsession may manifest as an eating disorder). Compulsions can be overt and observable, such as checking to see if the door is locked, or covert and unobservable, such as repeating a particular phrase in one's mind.

[0043] As used herein, the term "eating disorder" is defined as a severe and persistent disturbance in eating behavior and associated distressing thoughts and feelings. "Eating disorders" includes anorexia nervosa and bulimia nervosa, binge eating disorder, avoidant restrictive food intake disorder, other specific eating behavior disorders and eating disorders, pica, and rumination disorder.

[0044] Eating disorders often co-occur with anxiety disorders and obsessive-compulsive disorders. Neziroglu and Sandler distinguish between OCD and eating disorders: "Patients with eating disorders are primarily concerned about their physical appearance and, as a result, alter their eating patterns in an effort to lose weight. Patients with OCD may restrict their eating for reasons entirely different from body image concerns" (https: / / iocdf.org / expert-opinions / expert-opinion-eating-disorders-and-ocd / ).

[0045] The term "eating disorders" includes anorexia nervosa, bulimia, and binge eating disorder (BED). Symptoms of anorexia nervosa include eating too little or exercising too much in order to lose as much weight as possible. Symptoms of bulimia include eating a lot of food in a very short period of time (i.e., binge eating) and then making oneself sick, using laxatives, eating too little, or exercising too much to prevent weight gain. Symptoms of BED include regularly eating large amounts of food until one is uncomfortably full and feeling upset or guilty as a result.

[0046] As used herein, the term "depressive disorder" includes major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and end-stage depression.

[0047] As used herein, the term "major depressive disorder" (also referred to as MDD, major depression, or clinical depression) is defined as the presence of five or more of the following symptoms most of the day, nearly every day, for a period of two weeks or more (also referred to herein as a "major depressive episode"): Depressed mood, such as feeling sad, empty, or tearful (in children and teenagers, depressed mood can appear as constant irritability); ·Significantly decreased interest in or pleasure from all or most activities; · Significant weight loss, weight gain, or decreased or increased appetite when not dieting (in children, failure to gain weight as expected); Insomnia or increased need to sleep; · Restlessness or slowness of movement observable by others; Fatigue or loss of energy; · Feelings of worthlessness or excessive or inappropriate guilt; · Poor decision-making or difficulty thinking or concentrating; Recurrent thoughts of death or suicide, or suicide attempts At least one of the symptoms must be either depressed mood or loss of interest or pleasure.

[0048] Persistent depressive disorder, also known as dysthymia, is defined as a condition in which an individual exhibits two characteristics: A: Depressed mood most of the time, almost every day, for at least 2 years. Children and adolescents may have an irritable mood that has lasted for at least 1 year. B: When you are depressed, you experience at least two of the following symptoms: Overeating or loss of appetite -Excessive sleepiness or sleep disorders. · Fatigue, loss of energy. Low self-esteem · Poor concentration or decision-making ability

[0049] As used herein, the term "treatment-resistant major depressive disorder" refers to MDD that does not respond adequately to standard treatments.

[0050] As used herein, "bipolar disorder," also known as manic depression, refers to a disorder characterized by abnormal changes in mood, energy, activity level, and ability to carry out daily tasks.

[0051] There are two subcategories of bipolar disorder, both of which involve distinct changes in mood, energy, and activity levels. These moods range from periods of very upbeat, elated, and energetic behavior (known as manic episodes and further defined below) to periods of very sad, down, or hopeless moods (known as depressive episodes). Less severe manic states are called hypomanic episodes.

[0052] Bipolar I disorder: Defined by a manic episode lasting at least 7 days or by manic symptoms severe enough to require immediate hospital treatment. Depressive episodes usually occur as well, usually lasting at least 2 weeks. Mixed depressive episodes (in which both depressive and manic symptoms are present) are also possible.

[0053] Bipolar II disorder: Defined by a pattern of depressive and hypomanic episodes, but without the full-blown manic episodes described above.

[0054] As used herein, "bipolar depression" is defined as an individual experiencing depressive symptoms who has previously experienced or is experiencing concurrent manic episodes but who does not meet the clinical criteria for bipolar disorder.

[0055] As used herein, the term "anxiety disorders" includes generalized anxiety disorder, phobias, panic disorders, social anxiety disorders, and post-traumatic stress disorder.

[0056] As used in this document, "generalized anxiety disorder" (GAD) refers to a chronic disorder characterized by long-lasting anxiety that is not focused on any particular object or situation. People with GAD experience persistent, nonspecific fear and worry and become excessively concerned with everyday things. 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 disturbance.

[0057] A "phobia" is defined as a persistent fear of an object or situation, which the sufferer goes to great lengths to avoid (usually out of proportion to the actual risk). If the feared object or situation cannot be completely avoided, the sufferer endures it with significant distress and causes significant impairment in social or occupational functioning.

[0058] A patient suffering from "panic disorder" is defined as one who experiences one or more brief attacks of intense fear and anxiety (also called panic attacks), often characterized by trembling, shaking, confusion, dizziness, nausea, and / or difficulty breathing. A panic attack is defined as a sudden feeling of fear or discomfort that peaks in less than 10 minutes.

[0059] "Social anxiety disorder" is defined as an intense fear and avoidance of negative public opinion, public embarrassment, humiliation, or social interactions. Social anxiety often manifests with specific physical symptoms, including blushing, sweating, and difficulty speaking.

[0060] Post-traumatic stress disorder (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, natural disasters, rape, hostage situations, child abuse, bullying, or serious accidents. Common symptoms include hypervigilance, flashbacks, avoidance behaviors, anxiety, anger, and depression.

[0061] As used herein, the term "postpartum depression" (PPD) refers to a form of depression experienced by either parent of a newborn. Symptoms typically begin within four weeks of birth and often include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleep or eating patterns.

[0062] As used herein, the term "substance abuse" means a patterned use of a drug in which the user takes the substance in amounts or in ways that are harmful to themselves or others.

[0063] As used herein, the term "gambling disorder" refers to persistent and recurrent problematic gambling behavior that results in clinically significant impairment or distress. This disorder is similar to substance abuse.

[0064] As used herein, the term "avolition disorder" refers to a disorder whose symptoms include a decreased motivation to initiate and carry out voluntary purposeful activity.

[0065] As used herein, the term "psychedelic experience" refers to a period during which a patient experiences one or more intense reactions or emotions, altered states of perception, visual and other sensory hallucinations, spiritual experiences, ego dissolution, and dissociation. Ego dissolution refers to a state in which the boundaries between the individual and the outside world disappear (dissolve). Dissociation refers to a state in which different parts of the brain experience a sense of disconnection, such as a split between mind and body.

[0066] The Mystical Experience Questionnaire (MEQ), specifically designed to address hallucinogen-induced experiences, allows researchers to understand the typically elusive subjective experiences associated with psychedelics. The MEQ consists of 30 questions, and participants are asked to answer each question according to their feelings, thoughts, and experiences during the session. Each item is rated on a scale of 0 to 5 (from 0 = not at all to 5 = highest (more than at any time in my life)). The minimum score is 0 and the maximum score is 150, with higher scores indicating greater mystical experience. The MEQ total score is calculated by averaging the responses to all items. In some embodiments, a "psychedelic experience" is an experience that has a percentage score of at least 40% on the Mystical Experience Questionnaire (MEQ), e.g., 40% or more, 45% or more, 50% or more, 55% or more, or 60% or more points on the MEQ.

[0067] "Breakthrough psychedelic experience" means an intense and immersive psychedelic experience in which nearly all connection with the real world is lost. In some embodiments, a breakthrough psychedelic experience is an experience with a percentage score of 45% or greater, 50% or greater, 55% or greater, or 60% or greater on the MEQ.

[0068] Detailed Description The dosing regimens, treatment methods, delivery devices, or parenteral formulations for use with the present invention provide a slower onset regimen (e.g., compared to bolus administration, such as an IV bolus), which may improve patient therapeutic benefit by delaying the onset of the peak experience and may improve tolerability. Additionally, the psychedelic experience is slightly prolonged, which may improve therapeutic potential. The dosing regimens, treatment methods, delivery devices, or parenteral formulations for use with the present invention provide an additional safety measure by allowing the physician the opportunity to stop the infusion upon patient request or if required by clinical observation.

[0069] Therefore, a first aspect of the present invention provides the following as embodiment 1. A dosing regimen for administering a psychedelic agent to a patient for the treatment of a psychiatric or neurological disorder, comprising parenterally administering the psychedelic agent over an administration period of about 5 to about 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, wherein said parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0070] A second aspect of the present invention provides, as embodiment 2, a method for treating a psychiatric or neurological disorder in a patient, the method comprising parenterally administering to the patient a psychedelic agent over an administration period of about 5 to about 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, wherein said parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0071] A third aspect of the present invention provides, as embodiment 3, a delivery device for use in treating a psychiatric or neurological disorder in a patient, the delivery device configured to deliver a parenteral dose of a psychedelic agent over an administration period of about 5 to about 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogues thereof, and pharmaceutically acceptable salts thereof, and wherein said parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0072] A fourth aspect of the present invention provides, as embodiment 4, a parenteral formulation for use in treating a psychiatric or neurological disorder in a patient, comprising parenteral administration of a psychedelic agent over an administration period of about 5 to about 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogues thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0073] A fifth aspect of the present invention provides, as embodiment 5, a parenteral formulation comprising a psychedelic agent for use in treating a psychiatric or neurological disorder in a patient, comprising parenteral administration of the psychedelic agent over an administration period of about 5 to about 15 minutes, wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogues thereof, and pharmaceutically acceptable salts thereof, and wherein said parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

[0074] As embodiment 6, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the parenteral administration is selected from the group consisting of intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, and transdermal administration, and inhalation.

[0075] As embodiment 7, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the administration is by intravenous infusion, preferably wherein the intravenous administration is performed using a syringe pump.

[0076] As an embodiment 8, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the parenteral administration is by two-phase intravenous infusion.

[0077] As embodiment 9, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any one of embodiments 1 to 7, wherein the parenteral administration is by single-phase intravenous infusion.

[0078] In embodiment 10, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the administration period is from about 8 minutes to about 12 minutes.

[0079] In embodiment 11, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the administration period is about 9 to about 11 minutes, or about 10 minutes.

[0080] As embodiment 12, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, comprising parenteral administration of a total dose of a psychedelic agent selected from the group consisting of: · about 20 to about 70 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 15 to about 30 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 5 to about 15 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 10 to about 30 mg of 5-methoxy-N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; · about 1 to about 5 mg of psilocybin, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 3 to about 15 mg of 4-acetoxy-N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; and About 1 to about 5 mg, or about 3 to about 25 mg, of psilocin, a deuterated analog, or a pharmaceutically acceptable salt thereof.

[0081] As embodiment 13, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, comprising parenteral administration of a total dose of about 20 to about 29 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof.

[0082] As embodiment 14, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, comprising parenteral administration of a total dose of about 20 to about 23 mg, or about 26 to about 29 mg, of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof.

[0083] As embodiment 15, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to embodiment 8, wherein the administration is by biphasic intravenous infusion, the psychedelic agent is N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 20 to about 23 mg.

[0084] As embodiment 16, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to embodiment 9, wherein the administration is by monophasic intravenous infusion, the psychedelic agent is N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 26 to about 29 mg.

[0085] As embodiment 17, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to embodiment 9, wherein the administration is by monophasic intravenous infusion, the psychedelic agent is N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 7 to about 10 mg, or about 10 to about 20 mg.

[0086] As embodiment 18, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to embodiment 9, wherein the administration is by intramuscular administration, the psychedelic agent is N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 20 to about 70 mg.

[0087] As embodiment 19, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any of embodiments 1-12, comprising parenteral administration of a total dose of about 1.5 to about 3 mg of psilocybin, a deuterated analogue, or a pharmaceutically acceptable salt thereof; or a total dose of about 1.5 to about 3 mg of psilocin, a deuterated analogue, or a pharmaceutically acceptable salt thereof.

[0088] As embodiment 20, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the psychedelic agent is a compound of Formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Ra is selected from H, D, —OH, —OAc, and —PO3OH, and Rb is H or D; or Ra is H or D and Rb is selected from H, D and -Ome; R 2 and R 3 are each independently C(H z ) selected from 3; and Each H x , H y and H z is independently selected from protium and deuterium.

[0089] In embodiment 21, the present invention provides a dosing regimen, a method of treatment, a delivery device, or a parenteral formulation for use according to embodiment 20, wherein R 2 and R 3 are each independently selected from C(H)3 and C(D)3.

[0090] In embodiment 22, the present invention provides a dosing regimen, a method of treatment, a delivery device, or a parenteral formulation for use according to embodiment 20, wherein R 2 and R 3 are both C(H)3 or R 2 and R 3 are both C(D)3.

[0091] As embodiment 23, the present invention provides a dosing regimen, a method of treatment, a delivery device, or a parenteral formulation for use according to any of embodiments 20-21, wherein each H x is H or each H x is D or one Hx is H, and one H x is D.

[0092] As embodiment 24, the present invention provides a dosing regimen, a method of treatment, a delivery device, or a parenteral formulation for use according to any one of embodiments 20 to 23, wherein each H y is H or each H y is D or one H y is H, and one H y is D.

[0093] In embodiment 25, the present invention provides a dosing regimen, a method of treatment, a delivery device, or a parenteral formulation for use according to any one of embodiments 20 to 24, wherein each H x , H y and H z is deuterium.

[0094] As embodiment 26, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the psychedelic agent is selected from the group consisting of the following compounds, or pharmaceutically acceptable salts thereof (wherein Ra and Rb are as defined in embodiment 20): [ka]

[0095] In embodiment 27, the present invention provides a dosing regimen, a method of treatment, a delivery device, or a parenteral formulation for use according to any one of embodiments 20 to 26, wherein Ra is H.

[0096] In embodiment 28, the present invention provides a dosing regimen, a method of treatment, a delivery device, or a parenteral formulation for use of any one of embodiments 20 to 27, wherein Rb is H.

[0097] As embodiment 29, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the parenteral formulation comprises intravenous infusion via one or two syringe pumps.

[0098] In embodiment 30, the present invention provides an administration regimen, a treatment method, a delivery device, or a parenteral formulation for use according to any preceding embodiment, wherein the psychiatric or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, and (v) anorexia (avoidant disorder). Often, the disorder is selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, obsessive-compulsive disorder, and eating disorders (such as compulsive eating disorder). Preferably, the psychiatric or neurological disorder is selected from the group consisting of depressive disorder and anxiety disorder.

[0099] As embodiment 31, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the psychiatric or neurological disorder is a depressive disorder.

[0100] As embodiment 32, the invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the psychiatric or neurological disorder is major depressive disorder.

[0101] As embodiment 33, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the duration of the psychedelic experience is 3 hours or less, or 2 hours or less, or 1 hour or less.

[0102] As embodiment 34, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein the duration of the psychedelic experience is as follows: about 15 minutes to about 30 minutes, or about 30 minutes to about 90 minutes, when the psychedelic agent is N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; or about 15 minutes to about 45 minutes, or about 45 minutes to about 180 minutes, when the psychedelic agent is selected from psilocybin, 4-acetoxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, psilocin, deuterated analogs thereof, or pharmaceutically acceptable salts thereof; or about 20 minutes to about 30 minutes, wherein the psychedelic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; or about 60 minutes to about 90 minutes, wherein the psychedelic agent is a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

[0103] As embodiment 35, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to embodiment 33 or 34, wherein the duration of the experience is assessed by a primary care physician, psychiatrist, or therapist.

[0104] As embodiment 36, the present invention provides a dosage regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, further comprising: a. Preparation phase: includes preparing the patient for the psychedelic experience; b. administering: comprising a dosing regimen or method of treatment according to any preceding embodiment; and c. Integration phase: involves a psychiatrist- or therapist-led interview or discussion with the patient focused on the psychedelic experience.

[0105] As embodiment 37, the present invention provides a dosing regimen, method of treatment, delivery device, or parenteral formulation for use according to any preceding embodiment, wherein treating a psychiatric or neurological disorder in a patient comprises psychedelic-assisted psychotherapy.

[0106] Psychedelic agents for use in the dosing regimens, methods of treatment, delivery devices, or parenteral formulations for use in the present invention can be prepared according to the synthetic processes described in WO2021 / 089873, US20210395201, WO2022 / 117359, US11242318, US11724985, and US20220202775, the disclosures of which are incorporated herein by reference in their entireties.

[0107] The dosage of a psychedelic agent for use in the first, second, third, and fourth aspects of the present invention may preferably be in the form of a pharmaceutically acceptable salt, wherein the salt comprises an acid and the free base of the psychedelic agent, the psychedelic agent being selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, and deuterated analogs thereof. An example of a salt comprising an acid and a dimethyltryptamine compound is N,N-dimethyltryptamine fumarate, the fumarate salt of N,N-dimethyltryptamine. P.H. Stahl and C.G. Wermuth provide an overview of pharmaceutical salts and the acids contained therein in "Handbook of Pharmaceutical Salts: Properties, Selection and Use," Weinheim / Zurich: Wiley-VCH / VHCA, 2002. The acids listed in this review are suitable for inclusion in pharmaceutical salt formulations.

[0108] For clarity, when the phrase "a psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof" is used, this is meant to include 1) any one of the listed compounds, 2) a pharmaceutically acceptable salt of any one of the listed compounds, 3) a deuterated analog of any one of the listed compounds, and 4) a pharmaceutically acceptable salt of any one of the deuterated analogs of any one of the listed compounds. For example, as a non-limiting example, "psychedelic agent" includes N,N-dimethyltryptamine, a pharmaceutically acceptable salt of N,N-dimethyltryptamine, a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt of a deuterated analog of N,N-dimethyltryptamine. The same applies to the other listed compounds.

[0109] Preferred psychedelic agents for use in any embodiment of the present invention are selected from the following: 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-Prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine; α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; 5-Methoxy-N,N-dimethyltryptamine; 5-Methoxy-α-prothio,α-deutero-N,N-dimethyltryptamine; 5-Methoxy-α,α-dideutero-N,N-dimethyltryptamine; 5-Methoxy-α,α,β,β-tetradeutero-N,N-dimethyltryptamine; 5-Methoxy-N,N-di(trideuteromethyl)tryptamine; 5-Methoxy-α-prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine; 5-Methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 5-Methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; psilocybin; α-protio,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,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-syloin; 4-hydroxy-N,N-di(trideuteromethyl)tryptamine; 4-Hydroxy-α-prothio,α-deutero-N,N-di(trideuteromethyl)tryptamine; 4-Hydroxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine; 4-hydroxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and and pharmaceutically acceptable salts thereof.

[0110] The salt may comprise 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 (camphoric acid), camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactosyl esters, methyl ... Lactaric acid, gentisic acid (gentisic acid), glucoheptonic acid, glucuronic 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 acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid.

[0111] Preferably, the pharmaceutically acceptable salt is selected from fumarate, tartrate, citrate and hydrochloride salts. More preferably, the pharmaceutically acceptable salt of the psychedelic agent is a fumarate salt.

[0112] Parenteral administration routes include intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, transdermal, and inhalation administration. Any parenteral route capable of administration over a period of about 5 to about 15 minutes is suitable for use in the present invention. Preferred routes of parenteral administration according to any aspect of the present invention are selected from intravenous, intramuscular, subcutaneous, 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. One skilled in the art will understand that the delivery device for use in the present invention will be selected depending on the route of administration of the psychedelic agent.

[0113] When the parenteral administration route is intravenous, the delivery device may include an infusion bag or a syringe, and preferably may further include a syringe pump. When two syringe pumps are used to perform intravenous infusion, the syringe pumps may be connected to a single cannula via a three-way tap. When the parenteral administration route is intramuscular, the delivery device may include a syringe. When the parenteral administration route is intranasal, the delivery device may include a pump-activated spray means. When the parenteral administration route is transmucosal, the delivery device may include an oromucosal film. When the parenteral administration route is transdermal, the delivery device may include a transdermal patch. When the administration route is inhalation, the delivery device may include a metered-dose inhaler, vaporizer, or nebulizer.

[0114] Dosage forms suitable for parenteral administration have a pH of about 3 to about 9 and, for liquid formulations, an osmolality of about 250 to about 600 mOsm / kg. I. Usach et al. reported that pH values ​​above 9 are associated with tissue necrosis (cell death within tissue) (Adv. Ther., 36, 2986-2996 (2019)), while pH values ​​below 3 have been reported to cause pain and phlebitis (inflammation of the veins). Osmolality above 600 mOsm / kg has also been reported to cause pain. Usach et al. also recommended that parenteral formulations be formulated as isotonic solutions (osmolality of about 300 mOsm / kg), with an upper limit of 600 mOsm / kg suggested to minimize pain.

[0115] Osmotic pressure is formally defined as the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water, and is given by the following formula:

number

[0116] As used herein, when a first solution is defined as being isotonic with a second solution, the solutions have the same osmotic pressure. For example, when a formulation is defined as being isotonic with human blood serum, the formulation has the same osmotic pressure as human blood serum. Human blood serum typically has an osmotic pressure of about 275 to about 300 mOsm / kg (L. Hooper et al., BMJ Open, 2015; 5(10): e008846).

[0117] Suitable formulations for injection according to the present invention are described in WO2022 / 043227 and US11406619. Formulations suitable for inhaled administration according to the present invention are described in WO2022 / 117640. Formulations suitable for transdermal administration are described in US20210346347 and US17 / 866,477. Other suitable formulations according to the present invention are described in co-pending patent application US17 / 574,424. The disclosures of each of these patent applications are incorporated herein by reference in their entirety.

[0118] In some embodiments, a parenteral formulation for use in the present invention comprises a salt of a psychedelic agent, a base agent, water, and optionally a buffer separate from the salt, wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg / ml or more as the free base, and an osmolality of about 250 to about 350 mOsm / Kg; and wherein the formulation contains a dose of an optionally substituted dimethyltryptamine compound in a volume of 5 ml or less.

[0119] The base agent adjusts the pH of the formulation to the required pH range, for example, pH 5 to pH 6. The pH of formulations containing an optionally substituted dimethyltryptamine salt, water, and a buffer is often low, for example, below pH 5, and therefore may require pH adjustment with a base agent. Those skilled in the art can evaluate a suitable base agent for adjusting the pH of the solution without risking decomposition of the optionally substituted dimethyltryptamine salt. The base agent may be sodium hydroxide or potassium hydroxide.

[0120] Parenteral formulations optionally contain a buffer, but this buffer is distinct from the salt; i.e., the buffer is not simply a counterion of the psychedelic agent. For example, if the salt is N,N-dimethyltryptamine fumarate (i.e., the fumarate salt of N,N-dimethyltryptamine), a buffer in excess of the buffering effect provided by the fumarate salt may be required. The term "buffer" is well known in the art and refers to a chemical substance contained in a formulation that resists changes in pH due to the addition of an acid or base to the formulation. In a formulation, a buffer includes a weak acid and its conjugate base. Suitable buffers include acids with pKa values ​​within ±1 of the desired pH of the formulation. For example, if the desired pH of the formulation is about 5.0, suitable buffers include weak acids with pKa values ​​of about 4.0 to about 6.0. If the acid in the buffer has more than one pKa value (i.e., each molecule of the acid can donate more than one proton), at least one of the pKa values ​​must be within the desired pH range for the buffer to be suitable.

[0121] The weak acid and conjugate base of a buffer are in equilibrium with each other. According to Le Châtelier's principle (adding a constraint to a system at equilibrium (e.g., a change in the concentration of a reactant) shifts the equilibrium in a way that counteracts the effect of the constraint), adding an acid or base to a formulation shifts the position of equilibrium in favor of the conjugate base or weak acid, respectively. As a result, the concentration of free protons in the formulation (i.e., pH) remains relatively unchanged.

[0122] Suitable buffer systems include acetate with acetic acid (pKa=4.75); citrate with citric acid (pKa=3.13, 4.76, 6.40); and phosphate with phosphoric acid (pKa=2.14, 7.20, 12.37); or mixtures thereof. pKa values ​​quoted herein are those reported in water at 25°C. Typically, buffers contain only one of the above pairs, i.e., one acid and its conjugate base.

[0123] In some embodiments, the buffer comprises acetate and acetic acid; citrate and citric acid; or phosphate and phosphoric acid. Sometimes, the buffer comprises acetate and acetic acid; or citrate and citric acid. In some embodiments, the buffer comprises acetate and acetic acid, often sodium acetate and acetic acid, or potassium acetate and acetic acid.

[0124] The concentration of the buffer in the formulation is typically sufficient to resist significant pH change of the formulation when the formulation is stored for two weeks (i.e., the pH typically fluctuates by less than about 0.1 pH units). One skilled in the art can assess and achieve an appropriate buffer concentration. In many cases, the buffer concentration is about 15 mM to about 75 mM, e.g., about 20 mM to about 30 mM. In some embodiments, the buffer concentration is about 25 mM.

[0125] Sometimes, the concentration of the psychedelic agent and any buffer in the formulation results in the desired osmolality. Alternatively, the desired osmolality can be achieved by including one or more tonicity agents in the formulation. Thus, in some embodiments, the formulation further comprises a tonicity agent. As used herein, a tonicity agent is defined as a chemical substance that, when contained within a formulation, increases the osmolality of the formulation. As noted above, osmolality is the number of osmotically active particles (solute particles) in 1 kg of solution. Therefore, chemical substances that act as solutes when incorporated into a formulation are included within the definition of a tonicity agent.

[0126] In some embodiments, the formulation includes a tonicity agent. The concentration of the tonicity agent depends on the concentration of other components in the formulation, such as the psychedelic agent and buffer. For example, if the formulation without the tonicity agent has an osmolality of about 60 mOsm / Kg, a tonicity of at least about 190 mOsm / Kg would be provided by the tonicity agent (e.g., 95 mM sodium chloride). M.F. Powell, T. Nguyen, and L. Baloian provide a review of excipients suitable for parenteral administration (administration via a route other than the mouth or digestive tract) (PDA J. Pharm. Sci. Technol., 52, 238-311 (1998)). All of the soluble intravenously administrable excipients listed in this review contribute to the osmolality of the formulation and can therefore be considered tonicity agents.

[0127] When used in accordance with the present invention, suitable excipients for use in administering psychedelics may be selected from the group consisting of: 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.

[0128] Some excipients may act as cosolvents. Solvents or cosolvents suitable for use in the formulations of the present invention may be selected from ethanol, polyethylene glycol, propylene glycol, and mixtures thereof. In some embodiments, the formulation includes a cosolvent. In some embodiments, the formulation does not include a cosolvent. In particular, when the salt of the optionally substituted dimethyltryptamine compound is a fumarate salt, such as N,N-dimethyltryptamine fumarate or α,α-dideutero-N,N-dimethyltryptamine fumarate, the formulation does not include a cosolvent.

[0129] The dosing regimens, methods of treatment, delivery devices, or parenteral formulations for use in the present invention may offer many advantages, such as a slower onset regimen (compared to bolus administration), which may improve tolerability and may improve therapeutic benefit in patients by delaying the onset of peak experience.

[0130] Tolerability can be assessed after cessation of a subjective psychedelic experience by asking the patient, "Do you wish you hadn't had that experience?" A "Yes" response indicates poor tolerance, a "No" response indicates good tolerance.

[0131] In a study by D'Souza et al. (DCD'Souza, SASyed, LTFlynn, H. Safi-Aghdam, NV Cozzi and M. Ranganathan, Neuropsychopharmacology (2022) 47:1854-1862), all three healthy volunteer participants reported tolerability scores above 70 (on a scale of 0 to 100) after receiving 0.3 mg / kg of DMT, indicating good tolerability. In contrast, of six MDD patients receiving 0.3 mg / kg, three reported tolerability scores below 50, indicating poor tolerability (see Figure S1).

[0132] These results indicate that the patient group exhibited lower tolerability than the healthy volunteer group, which may be due to the patient population being composed of individuals with psychiatric or neurological disorders. Garcia-Romeu and Richards (International Review of Psychiatry, Vol. 30, 2018, Issue 4, pp. 291-316) discuss the use of serotonergic hallucinogens in clinical interventions, stating that "issues such as recent suicidality, drug or alcohol use disorders, dissociative disorders, and past traumatic histories may be exacerbated by high doses of psychedelics or increase the risk of adverse events, and should be considered depending on the treatment target." They further state that "psychodynamic autobiographical experiences are dominated by emotional recollections and reflections on significant past or present life events and relationships." These experiences can take many forms, but often include resurfacing of past transgressions for which the patient may still feel guilt or grief, grief for deceased loved ones or lost relationships, anger or forgiveness for unresolved trauma, and insight into how one has been and related throughout life. These types of experiences can occur even at low doses in a supportive environment. Psychodynamic autobiographical experiences can also occur during moderate or high doses of psychedelic therapy. Because patients with psychiatric disorders such as depressive disorders are more likely than healthy volunteers to exhibit the psychodynamic-autobiographical experiences discussed by Garcia-Romeu and Richards, therapists and psychiatrists experienced in the field of psychedelic-assisted psychotherapy expect that patients will have more difficult (challenging) psychedelic experiences and be less likely to report them as tolerable compared to healthy volunteers. Patients' subjective experiences can be assessed using the Challenging Experience Questionnaire (CEQ). The CEQ is a questionnaire designed to measure the difficult psychological experiences associated with psychedelic experiences.

[0133] The onset and cessation of the psychedelic experience can be assessed by a primary care physician, psychiatrist, or therapist. As used herein, "duration of the psychedelic experience" refers to the time from the start of continuous parenteral administration to the cessation of the psychedelic experience. The duration of the psychedelic experience may vary from patient to patient. As used herein, the term "duration" encompasses the average duration of the psychedelic experience.

[0134] Therapeutic benefit and effectiveness can be assessed using rating scales. For patients with depressive disorders such as MDD or TRD, the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAMD-17), or Beck's Depression Inventory (BDI-II) can be used. Rating scales are used before psychedelic administration to provide a baseline assessment and again after psychedelic administration.

[0135] In some embodiments, the psychedelic agent may be administered intramuscularly.

[0136] In some embodiments, the psychedelic agent may be administered as a biphasic IV infusion (intravenous infusion) over about 6 to about 11 minutes via an intravenous cannula. In some embodiments, the psychedelic agent may be administered as a biphasic IV infusion via an intravenous cannula, where each phase comprises about a 5 minute infusion. In some embodiments, the psychedelic agent may be administered as a monophasic IV infusion over about 6 to about 11 minutes, preferably about 10 minutes, via an intravenous cannula. When a biphasic IV infusion is used, preferably, syringe pumps are connected to a single cannula via a three-way tap: once the infusion with the first pump is completed, the three-way tap is adjusted to the on position, allowing the infusion from the second pump to continue.

[0137] The term "monophasic" IV infusion refers to IV infusion administration via one syringe pump, where the administration of the psychedelic agent is from one syringe pump. The term "biphasic" IV infusion refers to IV infusion administration via two syringe pumps, where the first phase involves the administration of the psychedelic agent from the first syringe pump, followed by the second phase involving the administration of the psychedelic agent from the second syringe pump. A biphasic IV infusion is essentially continuous, with no substantial interruption in the infusion to change administration from the first syringe pump to the second syringe pump. [Example]

[0138] A double-blind, randomized, placebo-controlled trial of intravenous DMT fumarate was conducted in patients with major depressive disorder (MDD) (ClinicalTrials.gov Identifier: NCT04673383, Part B). The protocol included the following steps: Day 1 of the exam -MADRS evaluation by an independent assessor Day 1 of the exam Placebo or DMT fumarate administered by continuous intravenous infusion with an administration period of approximately 10 minutes. -Tolerance assessment after cessation of psychedelic experience Test day 8 (± 1 day), test day 15 (± 1 day) -MADRS evaluation Day 15 of the exam -DMT fumarate is administered by intravenous continuous infusion over an administration period of approximately 10 minutes. - Tolerance assessment after cessation of psychedelic experience. Study day 22 (± 1 day), study day 29 (± 2 days), study day 45 (± 2 days), study day 105 (± 2 days). -MADRS evaluation

[0139] Administration of the study drug, DMT fumarate, in Part B of NCT04673383 was in accordance with the present invention. Group A received one dose of the active agent (DMT fumarate) on Day 1 and was assessed using the MADRS on Days 8 and 15. Group P received placebo on Day 1 and was assessed on Days 8 and 15, which comprised the blinded phase of the study. Group P then received one dose of the active agent during the open label phase of the study on Day 15 and was assessed on Days 22 and 29. Data for this group after administration of the active agent are designated PA.

[0140] All patient participants in this study answered "No" to the question "Do you wish you hadn't had that experience?" after receiving a single dose of DMT fumarate, indicating that this psychedelic is well tolerated. In Part A of the same study, healthy adults received a single, ascending dose of DMT fumarate. All healthy volunteers answered "No" to the same question at the highest dose tested. This study indicates that administration of DMT fumarate according to the dosing regimen is well tolerated by healthy volunteers and patients alike.

[0141] Participant experiences were assessed using the Challenging Experience Questionnaire (CEQ). In Part A of the study, the active group reported a mean CEQ score of 0.172, compared with a mean of 0.052 for the placebo group. In Part B of the study, the PA group reported a mean CEQ score of 0.350 and the A group reported a mean CEQ score of 0.360, compared with a mean CEQ score of 0.120 for the P group (placebo).

[0142] These data indicate that the patient cohort in Part B perceived the experience as significantly more challenging compared to the healthy participant cohort in Part A, with mean CEQ scores of 0.350 and 0.360 (compared to 0.172). Despite the more challenging experience reported by patients, it is surprising that the dosing regimen of the present invention was equally well tolerated by both healthy volunteers and patients. Furthermore, as of the filing date of this patent application, no drug-related serious adverse events have been reported.

[0143] On the other hand, in the data reported by D'Souza, as mentioned above, DMT administered as an intravenous push (bolus) was not well tolerated by the patient group. Overall tolerability was rated on a scale of 0 to 100 (0 = not tolerated, 100 = well tolerated). Three patients who received a 0.3 mg / kg dose, which was supposedly selected to reliably induce a psychedelic experience, reported tolerability scores below 50, indicating that this dosing regimen was poorly tolerated (Figure S1). Furthermore, after administration of the 0.3 mg / kg dose, the mean score in response to the question, "How likely are you to use this drug again?" was listed as 22.44 on a 0 to 100 scale, also indicating poor tolerability (Table S5). It should be noted that this sample included three healthy volunteers and six patients.

[0144] D'Souza et al. reported that the mean change in HAMD-17 score between baseline (n=7) and 1 day after the final dose (n=6) for both the 0.1 mg / kg and 0.3 mg / kg doses was -4.5 (Table S6), an improvement approximating a -3.9 improvement on the MADRS scale.

[0145] Blinded data from all patients in Part B of NCT04673383 showed that the mean improvement in MADRS score at Day 8 was -7.5 points, a mean reduction from baseline of -18.4%. A clinically meaningful change from baseline in MADRS score is considered a reduction of -6 to -9 points. These data are averaged across both patients receiving placebo and patients receiving DMT fumarate, demonstrating that efficacy was achieved following administration of DMT fumarate according to the present invention.

[0146] Open-label data at 7 and 14 days post-dose (study days 8, 15, 22, and 29) are shown in Table 1. As described above, Group A received one dose of the active agent (DMT fumarate) on day 1 and was evaluated on days 8 and 15. Group P received a placebo on day 1 and was evaluated on days 8 and 15. Group P then received one dose of the active agent on day 15 and was evaluated on days 22 and 29, and these data were expressed as PA.

[0147] [Table 1]

[0148] These data demonstrate a clear improvement in mean symptom scores for subjects receiving one dose of active agent (Groups A and PA) compared to subjects receiving placebo only (Group P), with a statistically significant difference in mean change from baseline between Groups A and P at Day 8 of -10.8 points (p=0.002) and a statistically significant difference at Day 15 of -7.4 points (p=0.02).

[0149] Data showing the percentage of subjects in groups A and P who achieved a 50% or greater reduction from BL and the percentage of subjects in groups A and P who achieved a MADRS score of 10 or less are shown in Figures 1 and 2, respectively.

[0150] Analysis of patient-reported depression scores confirmed the MADRS assessments by independent clinical assessors. Improvements in depression scores from baseline, as measured by the Beck Depression Inventory (BDI), were observed at all study time points in patients receiving at least one dose of active agent. This included a statistically significant improvement in depressive symptoms compared to placebo at 2 weeks post-dose (p=0.002). The BDI efficacy results were consistent with the MADRS, further supporting the rapid and sustained therapeutic profile of DMT fumarate for the treatment of MDD when administered according to the present invention.

[0151] Scales assessing patient anxiety and well-being, areas often adversely affected by depression, were also analyzed throughout the study. After administration of one dose of DMT fumarate in accordance with the present invention along with supportive care, patients demonstrated rapid and sustained improvement in anxiety symptoms as measured by the STAI-T (State-Trait Anxiety Inventory-Trait) scale. Two weeks after administration, a statistically significant improvement in anxiety symptoms was observed compared to placebo (p=0.03). At 12 weeks after open-label administration (PA group), a mean change from baseline (CFB) of -14.2 was observed in the patient group.

[0152] Furthermore, rapid and sustained improvements in well-being, as measured by the Warwick-Edinburgh Mental Well-being Scale (WEMWBS), were observed after administration of at least one dose of DMT fumarate in accordance with the present invention, along with supportive care. Results two weeks after blinded administration of DMT fumarate or placebo showed a mean CFB of 10.1 in the active group compared to 0.9 in the placebo group.

[0153] Statistical analysis was performed on the MADRS open-label data (PA group). Statistically significant differences were observed in the mean MADRS total scores at all open-label study time points (p<0.05). This analysis further supports the finding that a single dose of DMT fumarate administered in accordance with the present invention is sufficient to elicit a rapid and sustained antidepressant effect.

[0154] [Table 2] [Example]

[0155] The safety and tolerability of a single intravenous dose of a deuterated analog of DMT is being investigated in healthy subjects in ongoing clinical trials. The deuterated analog of DMT is being administered in accordance with the present invention. Tolerance is assessed by asking the question "Do you wish you hadn't had that experience?" after the psychedelic experience.

[0156] In accordance with the present invention, a cohort of six psychedelically exposed healthy subjects was administered a deuterated analog (9 mg dose). Preliminary data were compared with pharmacokinetic data from Cohort 1 (9 mg DMT fumarate), Part A of NCT04673383. Both studies used equivalent pharmaceutical formulations.

[0157] A significant increase in half-life (4.7-fold) and Intensity Rating Visual Analogue Scale (IRVAS) scores (1.5-fold) was observed after administration of 9 mg of the deuterated analog compared with 9 mg of DMT. The IRVAS is a rating scale that measures the intensity of the psychedelic experience. Furthermore, the perceived duration of the psychedelic experience was approximately 25 minutes with DMT, whereas it ranged from 37 to 57 minutes with the deuterated analog. The duration and intensity of the psychedelic experience were significantly greater with the deuterated analog, but no difference was observed in tolerability of the psychedelic experience compared with DMT.

[0158] These data indicate that deuterated analogs of DMT are equally well tolerated by the patient population.

Claims

1. 1. A parenteral formulation comprising a psychedelic agent for use in treating a psychiatric or neurological disorder in a patient, comprising: parenteral administration of a psychedelic agent for an administration period of about 5 minutes to about 15 minutes; wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof; The parenteral administration provides the patient with a delayed breakthrough psychedelic experience. Parenteral formulations.

2. 2. The parenteral formulation for use according to claim 1, wherein the parenteral administration is selected from the group consisting of intravenous administration, intramuscular administration, subcutaneous administration, nasal administration, transmucosal administration, sublingual administration, rectal administration, and transdermal administration, and inhalation.

3. 3. A parenteral formulation for use according to claim 1 or claim 2, wherein the administration is by intravenous infusion, preferably the intravenous administration is performed using a syringe pump.

4. The parenteral formulation for use according to any one of claims 1 to 3, wherein the administration period is from about 8 minutes to about 12 minutes.

5. The parenteral formulation for use according to any one of claims 1 to 4, wherein the administration period is from about 9 minutes to about 11 minutes, or about 10 minutes.

6. - about 20 to about 70 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; - about 15 to about 30 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; - about 5 to about 15 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 10 to about 30 mg of 5-methoxy-N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof - about 1 to about 5 mg of psilocybin, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 3 to about 15 mg of 4-acetoxy-N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; and About 1 to about 5 mg, or about 3 to about 25 mg, of psilocin, a deuterated analog, or a pharmaceutically acceptable salt thereof 6. A parenteral formulation for use according to any one of claims 1 to 5, comprising parenteral administration of a total dose of a psychedelic agent selected from the group consisting of:

7. 7. The parenteral formulation for use according to any one of claims 1 to 6, comprising parenteral administration of a total dose of about 20 to about 29 mg of N,N-dimethyltryptamine, a deuterated analogue, or a pharmaceutically acceptable salt thereof.

8. 8. The parenteral formulation for use according to any one of claims 1 to 7, comprising parenteral administration of a total dose of about 20 to about 23 mg, or about 26 to about 29 mg of N,N-dimethyltryptamine, a deuterated analogue, or a pharmaceutically acceptable salt thereof.

9. 7. The parenteral formulation for use according to any one of claims 1 to 6, comprising parenteral administration of a total dose of about 7 to about 9 mg, or about 10 to about 20 mg of N,N-dimethyltryptamine, a deuterated analogue, or a pharmaceutically acceptable salt thereof.

10. 7. The parenteral formulation for use according to any one of claims 1 to 6, comprising parenteral administration of a total dose of about 1.5 to about 3 mg of psilocybin, a deuterated analogue, or a pharmaceutically acceptable salt thereof, or a total dose of about 1.5 to about 3 mg of psilocin, a deuterated analogue, or a pharmaceutically acceptable salt thereof.

11. 11. The parenteral formulation for use according to any one of claims 1 to 10, wherein the psychedelic agent is a compound of formula I or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, Ra is H, D, -OH, -OAc and -PO 3 OH, and Rb is H or D; or Ra is H or D, and Rb is selected from H, D and -Ome; R 2 and R 3 are each independently C(H z ) 3 selected from; and Each H x , H y and H z are independently selected from protium and deuterium).

12. R 2 and R 3 are independently C(H) 3 and C(D) 3 12. The parenteral formulation for use according to claim 11, selected from:

13. R 2 and R 3 Both are C(H) 3 or R 2 and R 3 Both are C(D) 3 or R 2 is C(H) 3 and R 3 is C(D) 3 That is, A parenteral formulation for use according to claim 11.

14. Each H x is H, or Each H x is D, or One H x is H, and one H x is D, A parenteral formulation for use according to any one of claims 11 to 13.

15. Each H y is H, or Each H y is D, or One H y is H, and one H y is D, A parenteral formulation for use according to any one of claims 11 to 14.

16. Each H x , H y and H z 16. The parenteral formulation for use according to any one of claims 11, 12, 13 and 15, wherein is deuterium.

17. 17. The parenteral formulation for use according to any one of claims 1 to 16, wherein the psychedelic agent is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof, wherein Ra and Rb are as defined in claim 11: 【Chemistry 2】

18. The parenteral formulation for use according to any one of claims 11 to 17, wherein Ra is H.

19. The parenteral formulation for use according to any one of claims 11 to 18, wherein Rb is H.

20. 20. The parenteral formulation for use according to any one of claims 1 to 19, wherein parenteral administration comprises intravenous infusion by one or two syringe pumps.

21. 21. The parenteral formulation for use according to any one of claims 1 to 20, wherein the psychiatric or neurological disorder is selected from the group consisting of: (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, (v) anorexia disorder, or selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, obsessive-compulsive disorder, and eating disorders (e.g., compulsive eating disorder).

22. The parenteral formulation for use according to any one of claims 1 to 21, wherein the psychiatric or neurological disorder is selected from the group consisting of depressive disorders and anxiety disorders.

23. 23. The parenteral formulation for use according to any one of claims 1 to 22, wherein the duration of the psychedelic experience is: about 15 minutes to about 30 minutes, or about 30 minutes to about 90 minutes, when the psychedelic agent is N,N-dimethyltryptamine, a deuterated analogue, or a pharmaceutically acceptable salt thereof; or about 15 minutes to about 45 minutes, or about 45 minutes to about 180 minutes, when the psychedelic agent is selected from psilocybin, 4-acetoxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, psilocin, deuterated analogs thereof, or pharmaceutically acceptable salts thereof; or - about 20 minutes to about 30 minutes when the psychedelic agent is N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; or - about 60 minutes to about 90 minutes when the psychedelic agent is a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

24. the psychedelic agent is N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the duration of the psychedelic experience is about 20 to about 30 minutes; or the psychedelic agent is a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the duration of the psychedelic experience is about 30 to about 60 minutes; A parenteral formulation for use according to any one of claims 1 to 23.

25. 25. A parenteral formulation for use according to any one of claims 1 to 24, wherein the treatment of a psychiatric or neurological disorder comprises psychedelic-assisted psychotherapy.

26. 1. A method of treating a psychiatric or neurological disorder in a patient, comprising: parenterally administering a psychedelic agent to a patient over an administration period of about 5 minutes to about 15 minutes; wherein the psychedelic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, psilocin, deuterated analogs thereof, and pharmaceutically acceptable salts thereof; and A method wherein the parenteral administration provides the patient with a delayed breakthrough psychedelic experience.

27. 27. The method of claim 26, wherein the parenteral administration is selected from the group consisting of intravenous administration, intramuscular administration, subcutaneous administration, intranasal administration, transmucosal administration, sublingual administration, rectal administration, and transdermal administration, and inhalation.

28. 28. A method of treatment according to claim 26 or claim 27, wherein the administration is by intravenous infusion, preferably the intravenous administration is performed using a syringe pump.

29. The method of any one of claims 26 to 28, wherein the administration period is from about 8 minutes to about 12 minutes.

30. 30. The method of any one of claims 26 to 29, wherein the administration period is about 9 minutes to about 11 minutes, or about 10 minutes.

31. - about 20 to about 70 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; - about 15 to about 30 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; - about 5 to about 15 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 10 to about 30 mg of 5-methoxy-N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; - about 1 to about 5 mg of psilocybin, a deuterated analog, or a pharmaceutically acceptable salt thereof; about 3 to about 15 mg of 4-acetoxy-N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof; and About 1 to about 5 mg, or about 3 to about 25 mg, of psilocin, a deuterated analog, or a pharmaceutically acceptable salt thereof 31. A method of treatment according to any one of claims 26 to 30, comprising parenteral administration of a total dose of a psychedelic agent selected from the group consisting of:

32. 32. The method of any one of claims 26-31, comprising parenteral administration of a total dose of about 20 to about 29 mg of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof.

33. 33. The method of any one of claims 26 to 32, comprising parenteral administration of a total dose of about 20 to about 23 mg, or about 26 to about 29 mg, of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof.

34. 34. The method of any one of claims 26 to 33, comprising parenteral administration of a total dose of about 7 to about 9 mg, or about 10 to about 20 mg, of N,N-dimethyltryptamine, a deuterated analog, or a pharmaceutically acceptable salt thereof.

35. 35. The method of any one of claims 26-34, comprising parenteral administration of a total dose of about 1.5 to about 3 mg of psilocybin, a deuterated analog, or a pharmaceutically acceptable salt thereof, or a total dose of about 1.5 to about 3 mg of psilocin, a deuterated analog, or a pharmaceutically acceptable salt thereof.

36. 36. The method of treatment of any one of claims 26 to 35, wherein the psychedelic agent is a compound of formula I or a pharmaceutically acceptable salt thereof: 【Chemistry 3】 (In the formula, Ra is H, D, -OH, -OAc and -PO 3 OH, and Rb is H or D; or Ra is H or D, and Rb is selected from H, D, and -OMe; R 2 and R 3 are each independently C(H z ) 3 selected from; and Each H x , H y and H z are independently selected from protium and deuterium).

37. R 2 and R 3 are each independently C(H) 3 and C(D) 3 37. The method of claim 36, wherein the therapeutic agent is selected from the group consisting of:

38. R 2 and R 3 Both are C(H) 3 or R 2 and R 3 Both are C(D) 3 or R 2 is C(H) 3 and R 3 is C(D) 3 is 37. The method of treatment according to claim 36.

39. Each H x is H, or Each H x is D, or One H x is H, and one H x is D, The method of treatment according to any one of claims 36 to 38.

40. Each H y is H, or Each H y is D, or One H y is H, and one H y is D, The method of treatment according to any one of claims 36 to 39.

41. Each H x , H y and H z 41. The method of any one of claims 36, 37, 38 and 40, wherein is deuterium.

42. 42. The method of treatment of any one of claims 26 to 41, wherein the psychedelic agent is selected from the group consisting of the following compounds, or pharmaceutically acceptable salts thereof, wherein Ra and Rb are as defined in claim 36: 【Chemistry 4】

43. The method of any one of claims 36 to 42, wherein Ra is H.

44. The method of any one of claims 36 to 43, wherein Rb is H.

45. 45. The method of any one of claims 26 to 44, wherein parenteral administration comprises intravenous infusion by one or two syringe pumps.

46. 46. ​​The method of any one of claims 26 to 45, wherein the psychiatric or neurological disorder is selected from the group consisting of: (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, (v) anorexia disorder, or selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, obsessive-compulsive disorder, and eating disorders (e.g., compulsive eating disorder).

47. 47. The method of any one of claims 26 to 46, wherein the psychiatric or neurological disorder is selected from the group consisting of depressive disorders and anxiety disorders.

48. The method of treatment according to any one of claims 26 to 47, wherein the duration of the psychedelic experience is about 15 minutes to about 30 minutes, or about 30 minutes to about 90 minutes, when the psychedelic agent is N,N-dimethyltryptamine, a deuterated analogue, or a pharmaceutically acceptable salt thereof; or about 15 minutes to about 45 minutes, or about 45 minutes to about 180 minutes, when the psychedelic agent is selected from psilocybin, 4-acetoxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, psilocin, deuterated analogs thereof, or pharmaceutically acceptable salts thereof; or - about 20 minutes to about 30 minutes when the psychedelic agent is N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; or - about 60 minutes to about 90 minutes when the psychedelic agent is a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

49. the psychedelic agent is N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the duration of the psychedelic experience is about 20 to about 30 minutes; or the psychedelic agent is a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the duration of the psychedelic experience is about 60 to about 90 minutes; The method of treatment according to any one of claims 26 to 48.

50. 50. The method of any one of claims 26 to 49, wherein the treatment of a psychiatric or neurological disorder comprises psychedelic-assisted psychotherapy.

Images