Pharmaceutical compositions comprising deuterated n,n-dimethyltryptamine

Abstract

Pharmaceutical compositions comprising deuterated N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, uses thereof, and methods of treatment using the compositions. These compositions comprise an effective dose of deuterated N,N- dimethyltryptamine to elicit a psychedelic experience, and have potential uses in the treatment of psychiatric or neurological disorders, and in psychedelic-assisted psychotherapy.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING DEUTERATED N.N-DIMETHYLTRYPTAMINE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to pharmaceutical compositions, uses thereof, and methods of treatment using the compositions. The pharmaceutical compositions comprise deuterated N,N- dimethyltryptamine, or a pharmaceutically acceptable salt thereof. These compositions comprise an effective dose of deuterated / V, / V-dimethyltryptamine to elicit a psychedelic experience and have potential uses in the treatment of psychiatric or neurological disorders, and in psychedelic-assisted psychotherapy.

[0004] BACKGROUND OF THE INVENTION

[0005] Classical psychedelics have shown preclinical and clinical promise in treating psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, psilocybin has demonstrated significant improvement in a range of depression and anxiety rating scales in randomised double-blind studies (Griffiths et al. Journal of Psychopharmacology, 30(12), 1181-1197 (2016)).

[0006] N,N-dimethyltryptamine (DMT) is also understood to hold therapeutic value as a short-acting psychedelic. A review of research into the biosynthesis and metabolism of DMT in the brain and peripheral tissues, methods and results for DMT detection in body fluids and the brain is provided by S. A. Barker in Front. Neurosci., 12, 536, 1-17 (2018). Barker et al. suggest that ‘Further characterization of DMT cellular distribution, receptors and general biochemistry may lead to new targets for more effective pharmaceutical substances and interventions.’

[0007] Small Pharma Ltd has conducted a double-blind, randomised, placebo-controlled study of intravenous doses of DMT Fumarate (SPL026) in healthy subjects (Phase 1) and in patients with major depressive disorder (Phase Ila) (clinicaltrials.gov identifier NCT04673383). Pharmacokinetics of DMT fumarate in humans were determined and reported in Good et al., Eur J Drug Metab Pharmacokinet. 2023 May;48(3):311-327, while the safety, tolerability, pharmacodynamic and wellbeing effects of DMT fumarate in healthy subjects were reported by James et al., Front Psychiatry. 2024 Jan 11:14:1305796. In January 2023, Small Pharma reported that the Phase Ila study met the primary endpoint demonstrating a statistically significant and clinically relevant reduction in depressive symptoms two-weeks following a dose of SPL026 with supportive therapy, compared to placebo, demonstrating a -7.4 point difference in MADRS (p=0.02). Analysis of key secondary endpoints demonstrated a rapid onset of antidepressant effect one-week post-dose, with a statistically significant difference in MADRS score between the active and placebo groups of -10.8 (p=0.002).

[0008] Small Pharma Ltd has conducted a Phase I study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous and intramuscular dosing of a deuterated DMT Fumarate (SPL028) in healthy participants (EudraCT Number: 2022-002618- 17). In January 2024, Small Pharma reported that intravenous (IV) and intramuscular (IM) dosing of SPL028 demonstrated a favorable safety and tolerability profile. No serious adverse events were observed, and the majority of adverse events were mild to moderate and selflimiting.

[0009] Cybin IRL Ltd has conducted a Phase 1 clinical study to evaluate the safety, PK, and PD of escalating doses of DMT and a deuterated DMT (CYB004) in healthy participants. In January 2024, Cybin reported that CYB004 was well-tolerated with no serious adverse events, and the majority of adverse events were mild to moderate and self-limiting.

[0010] SUMMARY OF THE INVENTION

[0011] The present invention addresses the problem of providing pharmaceutical formulations of deuterated DMT which both elicit a psychedelic experience and are well tolerated, and which are therefore suitable for the treatment of a psychiatric or neurological disorder. The inventors have surprisingly found that this problem is addressed when deuterated DMT is administered via intramuscular injection to achieve a maximum plasma concentration (Cmax) from about 15 to about 75 ng / mL, and / or an area under the curve (AUC) from about 1200 to about 3100 hr.ng / mL.

[0012] Accordingly, as a first aspect, the invention provides a pharmaceutical composition comprising deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered as an intramuscular injection and wherein the administration provides: (i) a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL; or

[0013] (ii) an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL; or

[0014] (iii) a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL and an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL.

[0015] As a second aspect, the invention provides an aqueous intramuscular pharmaceutical composition comprising a dose of deuterated / V, / V-dimethyltryptamine, wherein the deuterated N,N-dimethyltryptamine comprises two or more compounds selected from the group consisting of: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;

[0016] N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof; and wherein the dose of the deuterated / V, / V-dimethyltryptamine is greater than 15 mg and less than 30 mg (as the free base).

[0017] As a third aspect, the invention provides a method of treating a psychiatric or neurological condition in a human, the method comprising intramuscular administration to the human of a dose of deuterated / V, / V-dimethyltryptamine or a pharmaceutically acceptable salt thereof, wherein the administration provides:

[0018] (i) a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL; or

[0019] (ii) an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL; or (iii) a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL and an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL.

[0020] As a fourth aspect, the invention provides a method of treating a psychiatric or neurological condition in a human, the method comprising intramuscular administration into the deltoid, or gluteal muscle of the human of a dose of deuterated / V, / V-dimethyltryptamine or a pharmaceutically acceptable salt thereof, which is greater than 15 mg and less than 30 mg (as the free base).

[0021] As a fifth aspect, the invention provides a pharmaceutical composition for use in the treatment of a psychiatric or neurological condition in a human, wherein the pharmaceutical composition is as defined in the first or the second aspect

[0022] DEFINITIONS

[0023] Throughout this specification, one or more aspects of the invention may be combined with one or more features described in the specification to define distinct embodiments of the invention.

[0024] In the detailed description, reference is made to a number of terms, which are to be understood to have the meanings provided below, unless a context expressly indicates to the contrary.

[0025] References herein to a singular of a noun encompass the plural of the noun, and vice-versa, unless the context implies otherwise.

[0026] Throughout this specification the word ‘comprise’, or variations such as ‘comprises’ or ‘comprising’, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The term ‘comprising’ includes within its ambit the term ‘consisting’ or ‘consisting essentially of’. The term ’consisting’ or variants thereof is to be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step or group of elements, integers or steps.

[0027] The term ‘consisting essentially of’ or variants thereof is to be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, and that further components may be present, but only those not materially affecting the essential characteristics of the embodiment of the invention.

[0028] The term ‘about’ herein, when qualifying a number or value, is used to refer to values that lie within ± 5% of the value specified. For the avoidance of doubt, where a number or value is specified herein in the absence of the term ‘about’, the number or value should be understood according to standard numeric rounding conventions according to the number of decimal places. For example, a whole number, such as 15, is understood to encompass values > 14.5 and < 15.5.

[0029] Where a range of values is provided, the range includes the end point values. For example, the range 15 to 30, or from 15 to 30, would include the values 15, 16, 17, 18, 29, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30; the range 20 to 28, or from 20 to 28, would include the values 20, 21 , 22, 23, 24, 25, 26, 27 and 28.

[0030] As used herein, the term ‘AllCo-t’ or ‘AUC’ refers to the area under the concentration versus time curve from time 0 to the last quantifiable data point.

[0031] As used herein, the term “Cmax” refers to the maximum observed plasma concentration measured after dosing of the deuterated DMT.

[0032] As used herein, the term ‘as the free base’ refers to the dose equivalent to the dose of the free base of the deuterated DMT. For example, a dose of greater than 15 mg and less than 30 mg (as the free base) of a pharmaceutically acceptable salt of the deuterated DMT is understood to refer to the dose of the salt equivalent to greater than 15 mg and less than 30 mg of the free base.

[0033] As used herein, the term ‘patient’ refers to a human. As used herein, the term ‘in combination with support therapy’ refers to the use of a support therapy providing preparation, psychological support and therapeutic integration to patients around and during administration of the deuterated DMT.

[0034] As used herein, the term ‘psychedelic assisted psychotherapy’, or ‘in combination with psychotherapy’ is defined as any psychotherapeutic practice that is provided alongside a dose of the deuterated DMT, including for example any dose as defined in the present invention. The term ‘psychedelic assisted psychotherapy’ includes support therapy as defined herein above.

[0035] The term ‘treatment’ defines the therapeutic treatment of a patient, in order to reduce or halt the rate of progression of a disorder, or to ameliorate or cure the disorder. Prophylactic treatment of a patient having a diagnosed psychiatric disorder is also included. Such prophylactic treatment, also referred to as secondary prevention, aims to reduce the impact of the disorder and / or to hinder development of the disorder and / or to prevent relapse through treatment in accordance with the invention.

[0036] As used herein, the term ‘psychiatric disorder’ is characterised by a clinically significant disturbance in an individual's cognition, emotional regulation, or behaviour, and that is associated with present distress (e.g., a painful symptom) or disability (i.e. , impairment in one or more important areas of functioning) or with a significantly increased risk of suffering death, pain, disability, or an important loss of freedom. Diagnostic criteria for psychiatric disorders referred to herein are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5).

[0037] As used herein the term ‘obsessive-compulsive disorder’ (OCD) is defined by the presence of either obsessions or compulsions, but commonly both. The symptoms can cause significant functional impairment and / or distress. An obsession is defined as an unwanted intrusive thought, image or urge that repeatedly enters the person's mind. Compulsions are repetitive behaviours or mental acts that the person feels driven to perform. Typically, OCD manifests as one or more obsessions, which drive adoption of a compulsion. For example, an obsession with germs may drive a compulsion to clean, or an obsession with food may drive a compulsion to overeat, eat too little or throw up after eating (i.e., an obsession with food may manifest itself as an eating disorder). A compulsion can either be overt and observable by others, such as checking that a door is locked, or a covert mental act that cannot be observed, such as repeating a certain phrase in one's mind. The Yale-Brown Obsessive Compulsive Scale (Y- BOCS) rating scale may be used to assess OCD.

[0038] As used herein, the term ‘eating disorder’ is defined by severe and persistent disturbance in eating behaviours and associated distressing thoughts and emotions. The term ‘eating disorder’ includes, but is not limited to, anorexia nervosa and bulimia nervosa, binge eating disorder, avoidant restrictive food intake disorder, other specified feeding and eating disorder, pica and rumination disorder.

[0039] Eating disorders often co-occur with anxiety disorders and obsessive compulsive disorder. Neziroglu and Sandler differentiate between OCD and an eating disorder: ‘Whereas patients with eating disorders are primarily driven by concerns of physical appearance, and consequently alter their eating patterns in order to lose weight accordingly. OCD patients may be restricting their eating for reasons very different than body image concerns’ (https: / / iocdf.org / expert-opinions / expert-opinion-eating-disorders-and-ocd / ).

[0040] The term “eating disorder” includes anorexia nervosa, bulimia and binge eating disorder (BED). The symptoms of anorexia nervosa include eating too little and / or exercising too much in order to keep weight as low as possible. The symptoms of bulimia include eating a lot of food in a very short amount of time (i.e., binging) and then being deliberately sick, using laxatives, eating too little and / or exercising too much to prevent weight gain. The symptoms of BED include regularly eating large portions of food until uncomfortably full, and consequently feeling upset or guilty.

[0041] As used herein, the term ‘depressive disorder’ includes, but is not limited to, major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, depression in terminally ill patients, and treatment resistant depression.

[0042] As used herein, the term ‘major depressive disorder’ (MDD, also referred to as major depression or clinical depression) is defined as the presence of five or more of the following symptoms over a period of two-weeks or more (also referred to herein as a ‘major depressive episode’), most of the day, nearly every day: • depressed mood, such as feeling sad, empty or tearful (in children and teens, depressed mood can appear as constant irritability);

[0043] • significantly reduced interest or feeling no pleasure in all or most activities;

[0044] • significant weight loss when not dieting, weight gain, or decrease or increase in appetite (in children, failure to gain weight as expected);

[0045] • insomnia or increased desire to sleep;

[0046] • either restlessness or slowed behaviour that can be observed by others;

[0047] • fatigue or loss of energy;

[0048] • feelings of worthlessness, or excessive or inappropriate guilt;

[0049] • trouble making decisions, or trouble thinking or concentrating;

[0050] • recurrent thoughts of death or suicide, or a suicide attempt.

[0051] At least one of the symptoms must be either a depressed mood or a loss of interest or pleasure.

[0052] Persistent depressive disorder, also known as dysthymia, is defined as a patient exhibiting the following two features:

[0053] A. Has depressed mood for most of the time almost every day for at least two years. Children and adolescents may have irritable mood, and the time frame is at least one year.

[0054] B. While depressed, a person experiences at least two of the following symptoms:

[0055] • Either overeating or lack of appetite.

[0056] • Sleeping too much or having difficulty sleeping.

[0057] • Fatigue, lack of energy.

[0058] • Poor self-esteem.

[0059] • Difficulty with concentration or decision-making.

[0060] As used herein, the term ‘treatment resistant major depressive disorder’ describes MDD that fails to achieve an adequate response to treatment with standard of care therapy.

[0061] As used herein, ‘bipolar disorder’, also known as manic-depressive illness, is a disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks.

[0062] There are two defined sub-categories of bipolar disorder; both of them involve clear changes in mood, energy, and activity levels. These moods range from periods of extremely ‘up,’ elated, and energised behaviour (known as manic episodes, and defined further below) to very sad, ‘down,’ or hopeless periods (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.

[0063] Bipolar I Disorder — defined by manic episodes that last at least 7 days, or by manic symptoms that are so severe that the person needs immediate hospital care. Usually, depressive episodes occur as well, typically lasting at least 2 weeks. Episodes of depression with mixed features (having depression and manic symptoms at the same time) are also possible.

[0064] Bipolar II Disorder — defined by a pattern of depressive episodes and hypomanic episodes, but not the full-blown manic episodes described above.

[0065] As used herein ‘bipolar depression’ is defined as an individual who is experiencing depressive symptoms with a previous or coexisting episode of manic symptoms, but does not fit the clinical criteria for bipolar disorder.

[0066] Depressive disorders are typically assessed using a rating scale selected from Clinical Global Impression scale (CGI); the Montgomery-Asberg Depression Rating Scale (MADRS); Hamilton Depression Rating Scale (HAMD-17); the Beck Depression Inventory-ll; the Beck Anxiety Inventory (BAI); suicidality rating scales such as the Beck Scale for Suicidal Ideation (BSS), Columbia-Suicide Severity Rating Scale (C-SSRS), the suicidal thoughts item of the MADRS for suicidal ideation, the Clinical Global Impression of Severity of Suicidality - Revised (CGI-SS-R) scale, or the Columbia-Suicide Severity Rating Scale (C-SSRS); and combinations of these scales. Depressive disorders may also be assessed using patient reported outcomes selected from the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF); the EQ-5D-5L descriptive system and EQ VAS; the Patient Global Impression of Severity scale (PGI-S); and combinations of these outcome assessments.

[0067] Depressive disorders are preferably assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), the Beck Depression Inventory-ll, the Beck Scale for Suicidal Ideation (BSS), the Montgomery-Asberg Depression Rating Scale (MADRS), and / or the 17-item Hamilton Depression Rating Scale (HAMD-17), and combinations of these scales. As used herein, the term ‘anxiety disorder’ includes, but is not limited to, generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder. Anxiety disorders are typically assessed using a rating scale selected from the Beck Anxiety Inventory (BAI), Hamilton Anxiety Scale (HAM-A), State-Trait Anxiety Inventory (STAI or STAI- T), Generalised Anxiety Disorder Assessment (GAD-7), and combinations of these scales. Anxiety disorders may also be assessed using patient reported outcomes, as described above.

[0068] ‘Generalised anxiety disorder’ (GAD) as used herein means a chronic disorder characterised by long-lasting anxiety that is not focused on any one object or situation. Those suffering from GAD experience non-specific persistent fear and worry, and become overly concerned with everyday matters. GAD is characterised by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbance.

[0069] ‘Phobia’ is defined as a persistent fear of an object or situation the affected person will go to great lengths to avoid, typically disproportional to the actual danger posed. If the feared object or situation cannot be avoided entirely, the affected person will endure it with marked distress and significant interference in social or occupational activities.

[0070] A patient suffering from a ‘panic disorder’ is defined as one who experiences one or more brief attack (also referred to as a panic attack) of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, and / or difficulty breathing. A panic attack is defined as a fear or discomfort that abruptly arises and peaks in less than ten minutes.

[0071] ‘Social anxiety disorder’ is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests specific physical symptoms, including blushing, sweating, and difficulty speaking.

[0072] ‘Post-traumatic stress disorder’ (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, natural disaster, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidant behaviours, anxiety, anger and depression. The Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS) may be used to assess PTSD symptoms.

[0073] As used herein, the term ‘post-partum depression’ (PPD, also known as postnatal depression) is a form of depression experienced by either parent of a newborn baby. Symptoms typically develop within 4 weeks of delivery of the baby and often include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleeping or eating patterns.

[0074] As used herein, the term ‘substance abuse’ means a patterned use of a drug in which the user consumes the substance in amounts or with methods that are harmful to themselves or others. ‘Substance abuse’ includes alcohol use disorder and opioid use disorder. Alcohol use disorder (AUD) is a condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. Opioid use disorder (OUD) is a condition characterized by the chronic use of opioids that causes clinically significant distress or impairment. Symptoms of this disease include an overpowering desire to use opioids, increased opioid tolerance, and withdrawal syndrome when opioids are discontinued.

[0075] As used herein, the term ‘gambling disorder’ means persistent and recurrent problematic gambling behaviour leading to clinically significant impairment or distress. The disorder has similarities with substance abuse.

[0076] As used herein, the term ‘an avolition disorder’ refers to a disorder that includes as a symptom the decrease in motivation to initiate and perform self-directed purposeful activities.

[0077] As used herein, the term ‘a psychedelic experience’ refers to a period in which the patient experiences one or more intense reactions or emotions, altered state of perception, visual or other sensory hallucinations, spiritual experience, ego dissolution and dissociation. Ego dissolution describes a state in which the boundary between an individual and the outside world dissolves. Dissociation describes a state in which an individual experiences a sensation that different parts of the brain are not connected, such as a disconnect between mind and body.

[0078] The psychedelic experience may be assessed by a number of psychometric scales, including the Mystical Experience Questionnaire (MEQ), Ego Dissolution Inventory (EDI), Emotional Breakthrough Inventory (EBI), Challenging Experience Questionnaire (CEQ), and visual analogue scale (VAS) scales, and combinations thereof.

[0079] The Mystical Experience Questionnaire (MEQ) was designed to measure experiences occasioned specifically by hallucinogens and allows researchers to understand the characteristically incomprehensible subjective experiences associated with psychedelics. The MEQ consists of 30 questions; participants are asked to answer each question according to one's feelings, thoughts, and experiences at the time of the session, each item being rated on a 0-5 scale (0-None / not at all to 5-Extreme, more than any other time in my life). The minimum score is 0 and the maximum score is 150 with higher scores indicating a greater degree of mystical experience. The MEQ total score is computed by taking the average response to all items and converting it to a percentage. A MEQ percentage score in the range from 40% to 100% is considered indicative of a psychedelic experience. In some embodiments, IM administration of deuterated DMT in accordance with the claimed provides a percentage score of at least 40% on the Mystical Experience Questionnaire (MEQ), for example 40% or more, 45% or more, 50% or more, 55% or more, or 60% or more points on the MEQ, or a range of 40- 100%, 45-100%, 50-100% or 60-100%.

[0080] The Ego-Dissolution Inventory (EDI) is an 8-item self-reported scale designed to measure egodissolution.

[0081] The Emotional Breakthrough Inventory (EBI) is a 6-item scale used to measure emotional breakthrough, reported to be an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Maximum possible score of 100 corresponds to higher emotional breakthrough ratings.

[0082] The Challenging Experience Questionnaire (CEQ) is a 26-item scale that measures the acute adverse psychological reactions to classic hallucinogens ("bad trips" or "challenging experiences"). Seven Challenging Experience Questionnaire factors (grief, fear, death, insanity, isolation, physical distress, and paranoia) provide a phenomenological profile of challenging aspects of experiences with psychedelics. The maximum possible score for each question is 5 and the total score (maximum 130) is typically converted to a percentage score. A percentage score of 70% or higher on the Challenging Experience Questionnaire (CEQ) is considered indicative of a poorly tolerated experience. In some embodiments, IM administration of deuterated DMT in accordance with the claimed provides a CEQ less than 70%, or a range from 1 to 69%.

[0083] The VAS intensity rating scale (IRVAS) measures the subjective intensity of the psychedelic experience. Subjects are asked to rate the intensity of their experience on a scale of 0 to 100. A score of 40% to 100% is considered indicative of a psychedelic experience. In some embodiments, IM administration of deuterated DMT in accordance with the claimed provides a percentage score of at least 40% on the IRVAS, for example 40% or more, 45% or more, 50% or more, 55% or more, or 60% or more points on the IRVAS, or a range of 40-100%, 45-100%, 50-100% or 60-100%.

[0084] The nomenclature used herein for the deuterated / V, / V-dimethyltryptamine compounds for use in the invention is as commonly used in the field. The compounds described herein may also be referred to by nomenclature in accordance with the rules of the International Union of Pure and Applied Chemistry (IUPAC) for chemical compounds, specifically the ‘IUPAC Compendium of Chemical Terminology (Gold Book)’ (see A. D. Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). For the avoidance of doubt, if a rule of the IUPAC organisation is contrary to a definition provided herein, the definition herein is to prevail.

[0085] The compound / V, / V-dimethyltryptamine (DMT) is also known by the IUPAC name 2-(1 / 7-indol-3- yl)- / V, / V-dimethylethanamine, with CAS Registry Number 61-50-7.

[0086] The compound a,a-dideutero- / V, / V-dimethyltryptamine (DMT-d2) is also known as [2-(1 H-indol- 3-yl)(1 ,1-D-2)ethyl]dimethylamine, or 2-(1 H-indol-3-yl)- / V, / V-dimethylethan-1-amine-1, 1-d2.

[0087] The compound a,a-dideutero- / V, / V-di(trideuteromethyl)tryptamine (DMT-d8) is also known as [2- (1 H-indol-3-yl)(1 ,1-D-2)ethyl]di(trideuteromethyl)amine, or 2-(1 / 7-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1 ,1-d2.

[0088] The compound a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine (DMT-d10) is also known as [2-(1 H-indol-3-yl)(1 ,1 ,2,2-D-4)ethyl]di(trideuteromethyl)amine, or 2-(1 / 7-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1 , 1 ,2,2-d4. As used herein the term ‘deuterated / V, / V-dimethyltryptamine’ means that one or more hydrogen atom(s) in the structure of the DMT molecule is replaced with a deuterium atom, wherein a deuterium atom is a hydrogen atom with an additional neutron. Substitution with deuterium may be at one or more of the a and p positions, and / or on one or both of the methyl groups represented by R2and R3in the formulae below, and / or at any one of positions 2 and 4-7 on the indole ring. In some embodiments, deuteration may be at the a positions, the a positions, and the positions, the methyl groups represented by R2and R3in the formulae below, the methyl groups represented by R2and R3in the formulae below and the a positions, the methyl groups represented by R2and R3in the formulae below and the a positions, and the p positions.

[0089] The ‘deuterated / V, / V-dimethyltryptamine’ compounds described herein are enriched with deuterium by an amount that is dependent on the percentage of deuterium available in the reagents from which the compounds are derived. For example, the d6-dimethylamino portions of compounds of formula I, wherein -NR2R3 is -N(CDa)2, may be derived from dimethyl-d7- amine, or dimethyl-d6-amine (commonly available as HCI salts), which are available from chemical vendors in purities of deuterium that range from 98% to 99%. The purity of deuterium in the resultant d6-dimethylamino substituents is consequently between 98% and 99%. This means, as the skilled person will understand, that not all compounds of formula I (for example) will comprise d6-dimethylamino substituents - some may comprise d0-d5-dimethylamino, but the average purity of deuterium is about 98% to 99%. It will be understood that the term ‘deuterated compounds’ includes isotopic mixtures of these compounds, for example an isotopic mixture of d1 and d2- deuterated / V, / V-dimethyltryptamine, d7 and d8- deuterated N,N- dimethyltryptamine, or d9 and d10- deuterated / V, / V-dimethyltryptamine. Preferably, the ‘deuterated / V, / V-dimethyltryptamine’ compounds described herein have an isotopic purity of 85% or greater, 90% or greater, or 92% or greater. Such isotopic mixtures are described in published patent applications WO2022 / 117359, WO2020 / 245133 and WO 2021 / 234608, the disclosures of which are hereby incorporated by reference in their entireties.

[0090] For the avoidance of doubt, positions of the DMT molecule refer to the positions labelled in the structure below, wherein R2and R3are individually -CH3, or -CD3, or as defined in any one of the embodiments below.

[0091]

[0092] As used herein, the term ‘in conjunction with’, ‘adjuvant treatment’, ‘adjunctive treatment’ or ‘combined treatment’ as used herein refers to treatment with the deuterated N,N- dimethyltryptamine or composition of any aspect of the invention, administered to a patient receiving treatment with a second active agent. Typically, the second active agent is an antidepressant agent or anti-anxiety agent. Preferably, the second active agent is a monoamine antidepressant agent. Preferably, the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention is administered to a patient who has received an adequate course of one or more antidepressant agents, and is continuing to receive treatment with a monoamine antidepressant agent, i.e., the patient receives ongoing treatment with the monoamine antidepressant agent before and during treatment with the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention. An adequate course of a monoamine antidepressant agent will vary according to the specific antidepressant agent, but will typically be a course of treatment over a period of 4 weeks or more, preferably a period of 6 weeks or more. For example, the patient may take a once (or twice or more) a day dose of a monoamine antidepressant agent over a period of 4 weeks or more, preferably a period of 6 weeks or more. Typically, the patient has not experienced a clinically meaningful improvement in symptoms following administration of an adequate course of treatment with the monoamine antidepressant agent. The term ‘in conjunction with’ as used herein does not require simultaneous administration with the monoamine antidepressant agent and the deuterated N,N- dimethyltryptamine or composition of any aspect of the invention. For the avoidance of doubt, the monoamine antidepressant agent and the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention may be administered and / or prescribed by different healthcare practitioners, such as different physicians. Typically, the monoamine antidepressant agent and the deuterated N,N-dimethyltryptamine or composition are administered separately, and may be administered sequentially. Optionally, the monoamine antidepressant agent and the deuterated N,N-dimethyltryptamine or composition may be administered simultaneously.

[0093] References herein to a ‘monoamine antidepressant agent’ refer to a non-psychedelic agent characterised by a mode of action which addresses one or more imbalance of neurotransmitters selected from serotonin, norepinephrine and dopamine. As a proviso, the monoamine antidepressant agent is preferably not a monoamine oxidase-inhibitor class antidepressant. At certain dosage levels, monoamine oxidase-inhibitor antidepressants may interfere with and extend the duration of the short-duration psychedelic.

[0094] Preferred monoamine antidepressant agents for use in the present invention are serotonin reuptake inhibitors, such as selective serotonin reuptake inhibitors (SSRIs) and serotoninnorepinephrine reuptake inhibitors (SNRIs).

[0095] Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of monoamine antidepressant agents which inhibit the reuptake of serotonin and norepinephrine, and which are used to treat a number of disorders including depressive disorders, anxiety disorders and obsessive- compulsive disorder (OCD). SNRIs approved by the Food and Drug Administration (FDA) in the US include desvenlafaxine, duloxetine, levomilnacipran, milnacipram, and venlafaxine.

[0096] Selective serotonin reuptake inhibitors (SSRIs) are a class of monoamine antidepressant agents which selectively inhibit the reuptake of serotonin and are used to treat a number of disorders including depressive disorders, anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). In the United Kingdom, SSRIs are recommended as the first line treatment for depressive disorders. Fluoxetine is approved by the FDA in the US and by the EMA in Europe for the treatment of bulimia nervosa. Approved SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine.

[0097] FIGURES

[0098] Figure 1: Mean Concentrations of DMT and DMT-d2 following IV and IM administration to Sprague Dawley rats. Figure 2: Mean Concentrations of DMT and DMT-d8 following IV and IM administration to Sprague Dawley rats.

[0099] Figure 3: Mean Concentrations of DMT and DMT-d10 following IV and IM administration to Sprague Dawley rats.

[0100] Figure 4: Mean Concentrations (±Standard Deviation) of DMT and DMT-d10 in Male Beagle Dogs after A) IV Bolus (0.1 + 0.1 mg / kg), B) IM (0.1 + 0.1 mg / kg),

[0101] DETAILED DESCRIPTION

[0102] The invention relates to the intramuscular (IM) administration of deuterated DMT to a human. The pharmacokinetics produced by such IM administration are determined by a number of factors, including not only the dose of the deuterated DMT, but also the injection site (muscle), the individual’s muscle volume and density, concentration of the deuterated DMT in solution, volume for injection, and the rate of administration. For therapeutic use, the administration must achieve sufficient exposure, while also being well tolerated.

[0103] The inventors have surprisingly found that when a maximum plasma concentration (Cmax) from about 15 ng / mL to about 75 ng / mL and / or an area under the curve (AUC) from about 1200 hr.ng / mL to about 3100 hr.ng / mL is achieved, the requirements for both sufficient exposure and good tolerability are met. Hence, when a deuterated DMT, or a pharmaceutically acceptable salt thereof, is administered as an IM injection to achieve a maximum plasma concentration (Cmax) from about 15 ng / mL to about 75 ng / mL and / or an area under the curve (AUC) from about 1200 hr.ng / mL to about 3100 hr.ng / mL is achieved, the requirements for both sufficient exposure and good tolerability are met. This can be achieved with a dose of deuterated DMT, or a pharmaceutically acceptable salt thereof, of greater than 15 mg and less than 30 mg (of free base).

[0104] The invention therefore provides pharmaceutical compositions, method of treatment, and pharmaceutical compositions for use, as defined in the first, second, third, fourth and fifth aspects. Various embodiments of the first, second, third, fourth and fifth aspects are described below. In some embodiments, the pharmaceutical compositions, method of treatment, and pharmaceutical compositions for use, as defined in the first, second, third, fourth and fifth aspects of the invention provide a maximum plasma concentration (Cmax) from about 18 ng / mL to about 70 ng / mL. In some embodiments, the pharmaceutical compositions, method of treatment, and pharmaceutical compositions for use, as defined in the first, second, third, fourth and fifth aspects of the invention provide a maximum plasma concentration (Cmax) from about 20 ng / mL to about 65 ng / mL.

[0105] In some embodiments, the pharmaceutical compositions, method of treatment, and pharmaceutical compositions for use, as defined in the first, second, third, fourth and fifth aspects of the invention provide an area under the curve (AUC) from about 1200 hr. ng / mL to about 3000 hr. ng / mL.

[0106] In some embodiments, deuterated compounds for use in the present invention are compounds of formula I, or a pharmaceutically acceptable salt thereof: wherein: n is 0, 1 , 2, 3, 4 or 5;

[0107] R1is D;

[0108] R2and R3are each independently selected from -CH3 and -CD3; each Hx and Hy is independently selected from H and D, wherein R2is -CD3 when each Hx and Hy is H.

[0109] In preferred embodiments, n is 0.

[0110] In preferred embodiments, both Hy are D. In preferred embodiments, both Hx are D.

[0111] In preferred embodiments, both Hx are H.

[0112] In preferred embodiments, both R2and R3are -CD3

[0113] Specific deuterated / V, / V-dimethyltryptamine compounds suitable for use in the first to fifth aspects of the present invention include: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;

[0114] N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0115] Preferably the deuterated / V, / V-dimethyltryptamine compounds for use in the first to fifth aspects of the present invention have isotopic purity of about 85% or greater, for example from about 85% to about 99% isotopic purity. More preferably, the deuterated / V, / V-dimethyltryptamine compounds have isotopic purity of about 90% or greater, for example from about 90% to about 99% isotopic purity.

[0116] Preferred deuterated / V, / V-dimethyltryptamine compounds suitable for use in the first to fifth aspects of the present invention are: a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof. In some preferred embodiments of the first to fifth aspects, a,a-dideutero-N,N- dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero- N,N-di(trideuteromethyl)tryptamine, or a pharmaceutically acceptable salt thereof, has an isotopic purity of about 90% or greater, for example from about 90% to about 99% isotopic purity.

[0117] In some preferred embodiments of the first to fifth aspects, a,a-dideutero-N,N- dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero- N,N-di(trideuteromethyl)tryptamine, or a pharmaceutically acceptable salt thereof, has an isotopic purity of about 92% or greater, for example from about 92% to about 99% isotopic purity.

[0118] In some preferred embodiments of the first to fifth aspects, a,a-dideutero-N,N- dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a pharmaceutically acceptable salt thereof, has an isotopic purity of about 95% or greater, for example from about 95% to about 99% isotopic purity.

[0119] In some preferred embodiments of the first to fifth aspects, a,a-dideutero-N,N- dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a pharmaceutically acceptable salt thereof, has an isotopic purity of about 97% or greater, for example from about 97% to about 99% isotopic purity.

[0120] Preferred deuterated / V, / V-dimethyltryptamine compounds suitable for use in the second aspect of the present invention are: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof. Preferably the deuterated / V, / V-dimethyltryptamine for use in the second aspect of the present invention comprises:

[0121] (i) a-protio, a-deutero-N,N-dimethyltryptamine and a,a-dideutero-N,N- dimethyltryptamine;

[0122] (ii) a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine and a,a-dideutero-N,N- di(trideuteromethyl)tryptamine;

[0123] (iii) a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine and a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine or a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine;

[0124] (iv) a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine, a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine and a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine and pharmaceutically acceptable salts thereof.

[0125] In some embodiments of the first to fifth aspects, the deuterated / V, / V-dimethyltryptamine is in the form of a pharmaceutically acceptable salt. Preferably, the deuterated N,N- dimethyltryptamine is in the form of the fumarate salt. It is to be understood that, unless otherwise specified, the deuterated / V, / V-dimethyltryptamine includes pharmaceutically acceptable salts of the deuterated / V, / V-dimethyltryptamine, even if the term “pharmaceutically acceptable salt” is not explicitly specified.

[0126] In some embodiments of the first, third, and fifth aspects, the dose of the deuterated N,N- dimethyltryptamine is from 15 mg to 30 mg (as free base). In some embodiments of the first to fifth aspects, the dose of the deuterated / V, / V-dimethyltryptamine is greater than 15 mg and less than 30 mg (as free base). Preferably, the dose of the deuterated / V, / V-dimethyltryptamine is from about 17 mg to about 27 mg (as free base). Preferably, the dose of the deuterated N,N- dimethyltryptamine is from about 18 mg to about 25 mg (as free base). Preferably, the dose of the deuterated / V, / V-dimethyltryptamine is from about 19 to about 23 mg (as free base). Most preferably, the dose of the deuterated / V, / V-dimethyltryptamine is about 20 mg (as free base).

[0127] In some embodiments, the site of IM injection in any one of the first to third, and fifth aspects is the vastus lateralis, deltoid, or gluteal muscle. Preferably, the site of IM injection is the deltoid or the gluteal muscle. Most preferably, the site of IM injection in any one of the first to fifth aspects is the ventrogluteal muscle. In some embodiments, the volume for injection for use in any one of the first to fifth aspects is about 3 ml or less, or from about 0.2 to about 3 ml. Preferably, the volume for injection is about 2 ml or less, or from about 0.2 to 2.5 ml, or from about 0.5 to about 2.5 ml.

[0128] In some embodiments for use in any one of the first to fifth aspects, the deuterated N,N- dimethyltryptamine is in aqueous solution having a concentration from about 15 to about 40 mg / mL. Preferably, the concentration is from about 20 to about 30 mg / ml. More preferably, the concentration is from about 22 to about 28 mg / mL. Most preferably, the concentration is about 25 mg / mL.

[0129] In some embodiments for use in any one of the first to fifth aspects, the rate of administration is about 1 mL / 10 s. In some embodiments, the rate of administration is greater than 1 mL / 10 s, such as from about 1 mL / 10 s to about 1 mL / s.

[0130] In some embodiments for use in any one of the third, fourth and fifth aspects, the psychiatric or neurological condition is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and gambling disorders, and (v) an avolition disorder. Preferably, the psychiatric or neurological condition is selected from the group consisting of (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a substance abuse disorder. Preferably, the psychiatric or neurological condition is selected from the group consisting of (ii) major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients; (iii) generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder; and (iv) alcohol use disorder and opioid use disorder. More preferably, the psychiatric or neurological condition is selected from the group consisting of major depressive disorder, generalized anxiety disorder, alcohol use disorder and opioid use disorder.

[0131] In some embodiments for use in in any one of the third, fourth and fifth aspects, the method of treating, or pharmaceutical composition for use, is in combination with psychotherapy.

[0132] In some embodiments for use in in any one of the third, fourth and fifth aspects, the method of treating, or pharmaceutical composition for use, is in combination with support therapy. Synthesis

[0133] Deuterated / V, / V-dimethyltryptamine compounds suitable for use in the present invention may be prepared by the synthetic methods described in WO 2020 / 245133, WO 2021 / 089873, WO 2022 / 117359 and WO 2021 / 234608, the disclosures of which are hereby incorporated by reference in their entireties.

[0134] Pharmaceutical Compositions

[0135] Pharmaceutical compositions comprising deuterated / V, / V-dimethyltryptamine compounds suitable for use in the present invention include those described in WO 2022 / 043227, WO 2023 / 135237 and PCT / EP2022 / 055324 (published as WO2023 / 089132), the disclosures of which are hereby incorporated by reference in their entireties.

[0136] The aqueous compositions for use in the first to fifth aspects of the invention comprise the deuterated / V, / V-dimethyltryptamine and water or saline.

[0137] In some embodiments, the compositions for use in the first, second, and fifth aspects of the invention comprise a base agent, which adjusts the pH of the formulation to the required pH range, for example from about pH 4 to about pH 7, preferably from about pH 5 to about pH 6. The pH of an aqueous formulation including the deuterated / V, / V-dimethyltryptamine is often low, e.g., less than pH 5, and so a pH adjustment with a base agent may be required. The skilled person is able to assess suitable base agents to adjust the pH of the solution without risk of degradation of the deuterated / V, / V-dimethyltryptamine. The base agent may be sodium hydroxide or potassium hydroxide.

[0138] In some embodiments, the for use in the first, second, and fifth aspects of the invention do not comprise a base agent.

[0139] In some embodiments, the compositions for use in the first, second, and fifth aspects of the invention comprise a buffer. The term ‘buffer’ is well known in the art and refers to a chemical which, on inclusion within a formulation, resists a change in pH on addition of acid or base to the formulation. Any pharmaceutically acceptable buffer agent may be used in the formulations of the invention, including phosphoric acid, citric acid, acetic acid, phosphate salt, citrate salt, and acetate salt, and combinations thereof. Preferably, the buffer comprises sodium phosphate, sodium citrate, or sodium acetate. The concentration of buffer within the formulation is typically sufficient to resist significant pH change of the formulation on storage of the formulation for two weeks (i.e., the pH typically fluctuates less than about 0.1 pH unit), while also ensuring that the osmolality of the formulation lies within the desired range of from about 250 to about 350 mOsm / Kg. The skilled person is able to assess suitable buffer concentrations to achieve this. Often, the concentration of buffer is from about 15 mM to about 75 mM, such as about 20 mM to about 30 mM. In some embodiments, the concentration of the buffer is about 25 mM.

[0140] In some embodiments, the compositions for use in the first, second, and fifth aspects of the invention comprise a pH adjuster. The pH adjuster may be a suitable acid, such as an acid selected from acetic acid, aspartic acid, benzene sulphonic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, methane sulphonic acid, propionic acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid, maleic acid, and sulphuric acid, or mixtures thereof. Preferably, the pH adjuster is selected from acetic acid, aspartic acid, benzene sulphonic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, methane sulphonic acid, tartaric acid, fumaric acid, maleic acid, and sulphuric acid, or mixtures thereof. Preferably, the formulations of the invention comprise a pH adjuster which is hydrochloric acid.

[0141] In some embodiments, the compositions for use in the first, second, and fifth aspects of the invention comprise a base agent and a buffer.

[0142] In some embodiments, the compositions for use in the first, second, and fifth aspects of the invention comprise a buffer and do not comprise a base agent.

[0143] In some embodiments, the compositions for use in the first, second, and fifth aspects of the invention comprise a tonicity agent. A tonicity agent is defined herein as a chemical that, on inclusion within a formulation, increases the osmolality of the formulation. Osmolality is the number of osmotically active particles (the number of solute particles) in 1 kg of a solution. Thus, a chemical that acts as a solute when incorporated into the formulation lies within the definition of a tonicity agent.

[0144] If the formulation further comprises a tonicity agent, the concentration of tonicity agent depends on the concentration of other components within the formulation, such as the optionally substituted dimethyltryptamine and buffer. For example, where the formulation without tonicity agent has an osmolality of about 60 mOsm / kg, at least about 190 mOsm / kg would be provided by a tonicity agent (e.g., 95 mM of sodium chloride). M. F. Powell, T. Nguyen and L. Baloian provide a review of excipients suitable for parenteral administration (administration other than by the mouth or alimentary canal) in PDA J. Pharm. Sci. Technol., 52, 238-311 (1998). All soluble excipients listed in this review article that can be given by the intramuscular route will, when added to the formulation, contribute to the osmolality and thus can be considered tonicity agents.

[0145] A suitable tonicity agent is any one or a combination selected from the group consisting of dextrose, sodium chloride; phosphoric acid; a phosphate salt such as sodium phosphate or potassium phosphate; acetic acid; ethanol; citric acid; a citrate salt such as sodium citrate or potassium citrate; arginine; edetic acid; an edetate salt such as sodium edetate or calcium edetate; propylene glycol; sodium bicarbonate; sodium hydroxide; and hydrochloric acid.

[0146] Some of the tonicity agents listed above also may be used to buffer the formulation (e.g., acetate salt, acetic acid, citrate salt, citric acid, phosphate salt, phosphoric acid). For the avoidance of doubt, where one of the tonicity agents listed above is used as the buffer, it is not also the defined tonicity agent, i.e., where the formulation further comprises a tonicity agent, the tonicity agent is different from the buffer. Typically, the tonicity agent is sodium chloride or dextrose.

[0147] In some embodiments, the compositions for use in the first, second, and fifth aspects of the invention comprise one or more pharmaceutically acceptable excipients. Suitable excipients for use in the formulations of the invention may be selected from the group consisting of ethanol, citric acid, trisodium citrate, benzalkonium chloride, microcrystalline cellulose, carboxymethylcellulose sodium, chlorobutanol, edetate disodium, glycerin, hydrochloric acid, methylparaben, polyethylene glycol, propylene glycol, propylparaben, saccharin sodium, sodium bicarbonate, sodium bisulphate, sodium bisulphite, sodium chloride, sodium hydroxide, sodium metabisulphite, sodium phosphate, sodium citrate, sulphuric acid, trisodium citrate, tromethamine, and mixtures thereof.

[0148] Such excipients include anti-oxidants and antimicrobial preservatives. For an overview of pharmaceutical excipients and their properties, including those with anti-oxidant and antimicrobial properties, see P. J. Sheskey, W G Cook and C G Cable, Handbook of Pharmaceutical Excipients, Eighth Edition, Pharmaceutical Press, London 2017.

[0149] It will be understood that some excipients may have more than one function. For example, citric acid may be utilised as a buffer, or as an anti-oxidant. A pH adjuster, for example hydrochloric acid, may also function as a tonicity agent.

[0150] An example composition for use in the first to fifth aspects of the invention, as described in PCT / EP2022 / 055324 (published as WO2023 / 089132), is detailed in the following table. q.s. means a sufficient quantity

[0151] Adjunctive treatment

[0152] A phase 1 clinical trial conducted by Small Pharma Ltd evaluated the safety and tolerability of a single intravenous (IV) administration (infusion over 10 minutes) of DMT with therapy in major depressive disorder (MDD) participants who were taking a selective serotonin reuptake inhibitor (SSRI) at the time of the study that was ineffective in fully relieving their depression (Test Cohort), compared to a single IV administration of DMT with therapy in MDD participants who were not taking any pharmacological treatment for their depression at the time of the study (Control Cohort) (clinicatrials.gov id NCT05553691). It was reported that in the Test Cohort a decrease in depressive and anxiety symptoms was observed at each consecutive visit, i.e. , clinical symptoms scores were lower at Day 29 assessments compared to Day 15 assessments and (MADRS and STAI-T only) Day 8 assessments, suggesting a prolonged effect on depressive symptoms over time when DMT was added to existing SSRI treatment. WO 2024 / 200710, the disclosure of which is hereby incorporated by reference in its entirety, discloses the administration of a short-duration psychedelic agent such as N,N- dimethyltryptamine and deuterated N,N- dimethyltryptamine in combination with a monoamine antidepressant agent, for example a selective serotonin reuptake inhibitor (SSRI).

[0153] In some embodiments, the pharmaceutical composition of any of the first, second or fifth aspects of the invention, or the deuterated DMT of the method of treating of the third or fourth aspects, may be administrated as an adjunctive treatment in combination with a monoamine antidepressant agent, preferably a selective serotonin reuptake inhibitor (SSRI) or serotoninnorepinephrine reuptake inhibitor (SNRI).

[0154] Typically the monoamine antidepressant agent is administered daily over the period of a course of treatment, while the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention is administered as one dose or as two doses. Preferably, the administration of the one dose or two doses of the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention occurs only one time in any three-month period, or at most once every three months. In some embodiments, the administration of the one dose or two doses of the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention occurs only one time in any six-month period, or at most once every six months. In some embodiments, the administration of the one dose or two doses of the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention occurs only one time in any nine-month period, or at most once every nine months. In some embodiments, the administration of the one dose or two doses of the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention occurs only one time in any twelve-month period, or at most once every twelve months.

[0155] Adjunctive treatment according to the present invention can be achieved by administering a monoamine antidepressant agent and a deuterated N,N-dimethyltryptamine or composition of any aspect of the invention, simultaneously, sequentially, or separately. The monoamine antidepressant agent and the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention are preferably formulated and administered separately. The monoamine antidepressant agent and the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention are often prescribed and / or administered by different healthcare practitioners (such as physicians). The invention also provides for administering the two in a single formulation. Other combinations may also be encompassed by adjunctive therapy. For example, two agents can be formulated together and administered in conjunction with a separate formulation containing a further dose of one of the agents, or a third agent. While the two or more agents in the combination treatment can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other, for example where the monoamine antidepressant is administered as a controlled release dosage form. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in an adjunctive treatment be present within the patient’s body at the same time, that is, the administration regimes of the monoamine antidepressant and the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention provide detectable plasma levels at the same time, this need not be so. Adjunctive treatment can also include two or more administrations of one or more of the agents used in the combination. The two agents may be administered according to different dosing schedules, and by different healthcare practitioners. For example, the monoamine antidepressant agent may be delivered on a daily schedule, with separate administration of one dose or two doses of the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention in any three-month period, or six-month, or nine- month, or twelve-month period. For example, the monoamine antidepressant agent may be delivered on a daily schedule, with separate administration of a single dose of the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention at most once every three months, or at most once every six months, or at most once every nine months, or at most once every twelve months. The two agents of the present invention may be administered sequentially in any combination one or more times. Preferably, the adjunctive treatment according to the present invention is achieved by administration regimes of the antidepressant agent and the deuterated N,N-dimethyltryptamine or composition of any aspect of the invention which provide simultaneous detectable plasma levels of the two agents at the same time.

[0156] The invention is further illustrated by the following numbered embodiments.

[0157] In accordance with the first aspect, the invention provides the following embodiments:

[0158] E1.1 A pharmaceutical composition comprising deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered as an intramuscular injection and wherein the administration provides: a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL; or

[0159] (ii) an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL; or

[0160] (iii) a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL and an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL.

[0161] E1.2 A pharmaceutical composition according to embodiment E1.1 , wherein the deuterated N,N-dimethyltryptamine is a compound of formula I, or a pharmaceutically acceptable salt thereof: Formula I wherein: n is 0, 1 , 2, 3, 4 or 5;

[0162] R1is D;

[0163] R2and R3are each independently selected from -CH3 and -CD3; each Hx and Hy is independently selected from H and D, wherein R2is -CD3 when each Hx and Hy is H.

[0164] E1.3 A pharmaceutical composition according to embodiment E1.2, wherein n is 0.

[0165] E1.4 A pharmaceutical composition according to embodiment E1.2 or E1.3, wherein both Hy are D. E1.5 A pharmaceutical composition according to embodiment E1.2, E1.3 or E1.4, wherein both Hx are D.

[0166] E1.6 A pharmaceutical composition according to embodiment E1.2, E1.3 or E1.4 , wherein both Hx are H.

[0167] E1.7 A pharmaceutical composition according to embodiment E1.2, E1.3, E1.4, E1.5 or E1.6, wherein both R2and R3are -CD3.

[0168] E1.8 A pharmaceutical composition according to any one of embodiments E1.1 , E1.2, E1.3, E1.4, E1.5, E1.6 and E1.7, wherein the deuterated N,N-dimethyltryptamine is selected from: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;

[0169] N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0170] E1.9 A pharmaceutical composition according to any one of embodiments E1.1 E1.2, E1.3, E1.4, E1.5, E1.6, E1.7, and E1.8, wherein the deuterated N,N-dimethyltryptamine is selected from: a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0171] E1.10 A pharmaceutical composition according to any one of embodiments E1.1 to E1.9, wherein the deuterated N,N-dimethyltryptamine is in the form of a pharmaceutically acceptable salt. E1.11 A pharmaceutical composition according to any one of embodiments E1.1 to E1.10, wherein the deuterated N,N-dimethyltryptamine is in the form of the fumarate salt.

[0172] E1.12 A pharmaceutical composition according to any one of embodiments E1.1 to E1.11 , wherein the administration provides a maximum plasma concentration (Cmax) from about 18 ng / mL to about 70 ng / mL.

[0173] E1.13 A pharmaceutical composition according to any one of embodiments E1.1 to E1.12, wherein the administration provides a maximum plasma concentration (Cmax) from about 20 ng / mL to about 65 ng / mL.

[0174] E1.14 A pharmaceutical composition according to any one of embodiments E1.1 to E1.13, wherein the administration provides an area under the curve (AUC) from about 1200 hr.ng / mL to about 3000 hr.ng / mL.

[0175] E1.15 A pharmaceutical composition according to any one of embodiments E1.1 to E1.14, comprising a dose from 15 mg to 30 mg (as free base) of the deuterated N,N- dimethyltryptamine or pharmaceutically acceptable salt thereof, or a dose of greater than 15 mg to less than 30 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0176] E1.16 A pharmaceutical composition according to any one of embodiments E1.1 to E1.15, comprising a dose from about 17 mg to about 27 mg (as free base) of the deuterated N,N- dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0177] E1.17 A pharmaceutical composition according to any one of embodiments E1.1 to E1.16, comprising a dose from about 18 mg to about 25 mg (as free base) of the deuterated N,N- dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0178] E1.18 A pharmaceutical composition according to any one of embodiments E1.1 to E1.17, comprising a dose from about 19 mg to about 23 mg (as free base) of the deuterated N,N- dimethyltryptamine or pharmaceutically acceptable salt thereof. E1.19 A pharmaceutical composition according to any one of embodiments E1.1 to E1.18, comprising a dose of about 20 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0179] E1.20 A pharmaceutical composition according to any one of embodiments E1.1 to E1.19, wherein the intramuscular injection is administered into the vastus lateralis, deltoid, or gluteal muscle.

[0180] E1.21 A pharmaceutical composition according to any one of embodiments E1.1 to E1.19, wherein the intramuscular injection is administered into the deltoid or gluteal muscle.

[0181] E1.22 A pharmaceutical composition according to any one of embodiments E1.1 to E1.21 , wherein the volume for injection is from about 0.2 to about 3 mL.

[0182] E1.23 A pharmaceutical composition according to any one of embodiments E1.1 to E1.22, wherein the volume for injection is from about 0.2 to about 2.5 mL.

[0183] E1.24 A pharmaceutical composition according to any one of embodiments E1.1 to E1.23, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 15 to about 40 mg / mL.

[0184] E1.25 A pharmaceutical composition according to any one of embodiments E1.1 to E1.24, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 20 to about 30 mg / mL.

[0185] E1.26 A pharmaceutical composition according to any one of embodiments E1.1 to E1.25, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 22 to about 28 mg / mL.

[0186] E1.27 A pharmaceutical composition according to any one of embodiments E1.1 to E1.26, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 25 mg / mL.

[0187] E1.28 A pharmaceutical composition according to any one of embodiments E1.1 to E1.27, wherein the rate of administration is from about 1 mL / 10 s to about 1 mL / s. In accordance with the second aspect, the invention provides the following embodiments:

[0188] E2.1 An aqueous intramuscular injectable pharmaceutical composition comprising a dose of deuterated / V, / V-dimethyltryptamine, wherein the deuterated N,N-dimethyltryptamine comprises two or more compounds selected from the group consisting of: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;

[0189] N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof; and wherein the dose of the deuterated / V, / V-dimethyltryptamine is greater than 15 mg and less than 30 mg (as the free base).

[0190] E2.2 A pharmaceutical composition according to embodiment E2.1 , wherein the deuterated / V, / V-dimethyltryptamine comprises two or more compounds selected from the group consisting of: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0191] E2.3 A pharmaceutical composition according to embodiment E2.1 or E2.2, wherein the deuterated / V, / V-dimethyltryptamine comprises: (i) a-protio, a-deutero-N,N-dimethyltryptamine and a,a-dideutero-N,N- dimethyltryptamine;

[0192] (ii) a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine and a,a-dideutero-N,N- di(trideuteromethyl)tryptamine;

[0193] (iii) a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine and a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine or a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine; or

[0194] (iv) a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine, a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine and a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine and pharmaceutically acceptable salts thereof.

[0195] E2.4 A pharmaceutical composition according to embodiment E2.1, E2.2 or E2.3, wherein the deuterated / V, / V-dimethyltryptamine comprises a,a-dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N- di(trideuteromethyl)tryptamine, or a pharmaceutically acceptable salt thereof, wherein the a,a-dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N- di(trideuteromethyl)tryptamine has an isotopic purity of about 85% or greater.

[0196] E2.5 A pharmaceutical composition according to embodiment E2.4, wherein the a,a- dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N- di(trideuteromethyl)tryptamine has an isotopic purity of about 90% or greater.

[0197] E2.6 A pharmaceutical composition according to embodiment E2.4, wherein the a,a- dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N- di(trideuteromethyl)tryptamine has an isotopic purity of about 92% or greater.

[0198] E2.7 A pharmaceutical composition according to embodiment E2.4, wherein the a,a,p,p- tetradeutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 92% or greater. E2.8 A pharmaceutical composition according to embodiment E2.4, wherein the a,a- dideutero-N,N-dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 95% or greater.

[0199] E2.9 A pharmaceutical composition according to embodiment E2.4, wherein the a,a- dideutero-N,N-dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 97% or greater.

[0200] E2.10 A pharmaceutical composition according to any one of embodiments E2.1 to E2.9, wherein the deuterated N,N-dimethyltryptamine is in the form of a pharmaceutically acceptable salt.

[0201] E2.11 A pharmaceutical composition according to any one of embodiments E2.1 to E2.10, wherein the deuterated N,N-dimethyltryptamine is in the form of the fumarate salt.

[0202] E2.12 A pharmaceutical composition according to any one of embodiments E2.1 to E2.11 , comprising a dose from about 17 mg to about 27 mg (as free base) of the deuterated N,N- dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0203] E2.13 A pharmaceutical composition according to any one of embodiments E2.1 to E2.12, comprising a dose from about 18 mg to about 25 mg (as free base) of the deuterated N,N- dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0204] E2.14 A pharmaceutical composition according to any one of embodiments E2.1 to E2.13, comprising a dose from about 19 mg to about 23 mg (as free base) of the deuterated N,N- dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0205] E2.15 A pharmaceutical composition according to any one of embodiments E2.1 to E2.14, comprising a dose of about 20 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0206] E2.16 A pharmaceutical composition according to any one of embodiments E2.1 to E2.15, wherein the volume for injection is from about 0.2 to about 3 mL. E2.17 A pharmaceutical composition according to any one of embodiments E2.1 to E2.16, wherein the volume for injection is from about 0.2 to about 2.5 mL.

[0207] E2.18 A pharmaceutical composition according to any one of embodiments E2.1 to E2.17, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 15 to about 40 mg / mL (as the free base).

[0208] E2.19 A pharmaceutical composition according to any one of embodiments E2.1 to E2.18, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 20 to about 30 mg / mL (as the free base).

[0209] E2.20 A pharmaceutical composition according to any one of embodiments E2.1 to E2.19, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 22 to about 28 mg / mL (as the free base).

[0210] E2.21 A pharmaceutical composition according to any one of embodiments E2.1 to E1.20, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 25 mg / mL.

[0211] In accordance with the third aspect, the invention provides the following embodiments:

[0212] E3.1 A method of treating a psychiatric or neurological condition in a human, the method comprising intramuscular administration to the human of a dose of deuterated N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof, wherein the administration provides:

[0213] (i) a maximum plasma concentration (Cmax) of deuterated / V, / V-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL; or

[0214] (ii) an area under the curve (AUC) of deuterated / V, / V-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL; or

[0215] (iii) a maximum plasma concentration (Cmax) of deuterated / V, / V-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL and an area under the curve (AUC) of deuterated / V, / V-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL. E3.2 A method of treating according to E3.1, wherein the deuterated N,N-dimethyltryptamine is a compound of formula I, or a pharmaceutically acceptable salt thereof: Formula I wherein: n is 0, 1 , 2, 3, 4 or 5;

[0216] R1is D;

[0217] R2and R3are each independently selected from -CH3 and -CD3; each Hx and Hy is independently selected from H and D, wherein R2is -CD3 when each Hx and Hy is H.

[0218] E3.3 A method of treating according to E3.2, wherein n is 0.

[0219] E3.4 A method of treating according to E3.2 or E3.3, wherein both Hy are D.

[0220] E3.5 A method of treating according to E3.2, E3.3 or E3.4, wherein both Hx are D.

[0221] E3.6 A method of treating according to E3.2, E3.3 or E3.4, wherein both Hx are H.

[0222] E3.7 A method of treating according to E3.2, E3.3, E3.4, E3.5 or E3.6, wherein both R2and

[0223] R3are -CD3.

[0224] E3.8 A method of treating according to E3.1, E3.2, E3.3, E3.4, E3.5, E3.6 or E3.7, wherein the deuterated N,N-dimethyltryptamine is selected from: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine; N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0225] E3.9 A method of treating according to any one of embodiments E3.1 to E3.8, wherein the deuterated N,N-dimethyltryptamine is selected from: a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0226] E3.10 A method of treating according to any one of embodiments E3.1 to E3.9, wherein the deuterated N,N-dimethyltryptamine is in the form of a pharmaceutically acceptable salt.

[0227] E3.11 A method of treating according to any one of embodiments E3.1 to E3.10, wherein the deuterated N,N-dimethyltryptamine is in the form of the fumarate salt.

[0228] E3.12 A method of treating according to any one of embodiments E3.1 to E3.11 , wherein the administration provides a maximum plasma concentration (Cmax) f deuterated N,N- dimethyltryptamine about 18 ng / mL to about 70 ng / mL.

[0229] E3.13 A method of treating according to any one of embodiments E3.1 to E3.12, wherein the administration provides a maximum plasma concentration (Cmax) of deuterated N,N- dimethyltryptamine from about 20 ng / mL to about 65 ng / mL.

[0230] E3.14 A method of treating according to any one of embodiments E3.1 to E3.13, wherein the administration provides an area under the curve (AUC) of deuterated / V, / V-dimethyltryptamine from about 1200 hr.ng / mL to about 3000 hr.ng / mL. E3.15 A method of treating according to any one of embodiments E3.1 to E3.14, comprising a dose from 15 mg to 30 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0231] E3.16 A method of treating according to any one of embodiments E3.1 to E3.15, comprising a dose from about 17 mg to about 27 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0232] E3.17 A method of treating according to any one of embodiments E3.1 to E3.16, comprising a dose from about 18 mg to about 25 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0233] E3.18 A method of treating according to any one of embodiments E3.1 to E3.17, comprising a dose from about 19 mg to about 23 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0234] E3.19 A method of treating according to any one of embodiments E3.1 to E3.18, comprising a dose of about 20 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0235] E3.20 A method of treating according to any one of embodiments E3.1 to E3.19, wherein the intramuscular injection is administered into the vastus lateralis, deltoid, or gluteal muscle.

[0236] E3.21 A method of treating according to any one of embodiments E3.1 to E3.19, wherein the intramuscular injection is administered into the deltoid or gluteal muscle.

[0237] E3.22 A method of treating according to any one of embodiments E3.1 to E3.21, wherein the volume for injection is from about 0.2 to about 3 mL.

[0238] E3.23 A method of treating according to any one of embodiments E3.1 to E3.22, wherein the volume for injection is from about 0.2 to about 2.5 mL.

[0239] E3.24 A method of treating according to any one of embodiments E3.1 to E3.23, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 15 to about 40 mg / mL. E3.25 A method of treating according to any one of embodiments E3.1 to E3.24, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 20 to about 30 mg / mL.

[0240] E3.26 A method of treating according to any one of embodiments E3.1 to E3.25, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 22 to about 28 mg / mL.

[0241] E3.27 A method of treating according to any one of embodiments E3.1 to E1.26, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 25 mg / mL.

[0242] E3.28 A method of treating according to any one of embodiments E3.1 to E3.27, wherein the rate of administration is from about 1 mL / 10 s to about 1 mL / s.

[0243] E3.29 A method of treating according to any one of embodiments E3.1 to E3.28, wherein the psychiatric or neurological condition is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and gambling disorders, and (v) an avolition disorder.

[0244] E3.30 A method of treating according to any one of embodiments E3.1 to E3.29, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a substance abuse disorder.

[0245] E3.31 A method of treating according to any one of embodiments E3.1 to E3.30, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients; (iii) generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder; and (iv) alcohol use disorder and opioid use disorder.

[0246] E3.32 A method of treating according to any one of embodiments E3.1 to E3.31, wherein the psychiatric or neurological condition is selected from the group consisting of major depressive disorder, generalised anxiety disorder, alcohol use disorder and opioid use disorder. E3.33 A method of treating according to any one of embodiments E3.1 to E3.32, in combination with support therapy.

[0247] E3.34 A method of treating according to any one of embodiments E3.1 to E3.33, comprising a method of adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, obsessive compulsive disorder, and an eating disorder.

[0248] E3.35 A method of treating according to embodiment E3.34, wherein the monoamine antidepressant agent is selected from a selective serotonin reuptake inhibitor and a serotoninnorepinephrine reuptake inhibitor.

[0249] E3.36 A method of treating according to embodiment E3.34, wherein the monoamine antidepressant agent is selected from at least one of desvenlafaxine, duloxetine, levomilnacipran, milnacipram, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and the pharmaceutically acceptable salts thereof.

[0250] In accordance with the fourth aspect, the invention provides the following embodiments:

[0251] E4.1 A method of treating a psychiatric or neurological condition in a human, the method comprising intramuscular administration into the deltoid, or gluteal muscle of the human of a dose of deuterated / V, / V-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, which is greater than 15 mg and less than 30 mg (as the free base).

[0252] E4.2 A method of treating according to embodiment E4.1, wherein the deuterated N,N- dimethyltryptamine comprises two or more compounds selected from the group consisting of: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;

[0253] N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0254] E4.3 A method of treating according to embodiment E4.1, wherein the deuterated N,N- dimethyltryptamine comprises two or more compounds selected from the group consisting of: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.

[0255] E4.4 A method of treating according to embodiment E4.1, wherein the deuterated N,N- dimethyltryptamine comprises:

[0256] (i) a-protio, a-deutero-N,N-dimethyltryptamine and a,a-dideutero-N,N- dimethyltryptamine;

[0257] (ii) a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine and a,a-dideutero-N,N- di(trideuteromethyl)tryptamine;

[0258] (iii) a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine and a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine or a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine; or

[0259] (iv) a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine, a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine and a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine and pharmaceutically acceptable salts thereof.

[0260] E4.5 A method of treating according to embodiment E4.1, wherein the deuterated N,N- dimethyltryptamine comprises a,a-dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N- di(trideuteromethyl)tryptamine, or a pharmaceutically acceptable salt thereof, and wherein the a,a-dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N- di(trideuteromethyl)tryptamine has an isotopic purity of about 85% or greater.

[0261] E4.6 A method of treating according to embodiment E4.5, wherein the a,a-dideutero-N,N- dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero- N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 90% or greater.

[0262] E4.7 A method of treating according to embodiment E4.5, wherein the wherein the a,a- dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,P,P- tetradeutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 92% or greater.

[0263] E4.8 A method of treating according to embodiment E4.5, wherein the a,a,p,p-tetradeutero- N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 92% or greater.

[0264] E4.9 A method of treating according to embodiment E4.5, wherein the a,a-dideutero-N,N- dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 95% or greater.

[0265] E4.10 A method of treating according to embodiment E4.5, wherein the a,a-dideutero-N,N- dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 97% or greater.

[0266] E4.11 A method of treating according to any one of embodiments E4.1 to E4.10, wherein the deuterated N,N-dimethyltryptamine is in the form of a pharmaceutically acceptable salt.

[0267] E4.12 A method of treating according to any one of embodiments E4.1 to E4.11, wherein the deuterated N,N-dimethyltryptamine is in the form of the fumarate salt.

[0268] E4.13 A method of treating according to any one of embodiments E4.1 to E4.12, comprising a dose from about 17 mg to about 27 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof. E4.14 A method of treating according to any one of embodiments E4.1 to E4.13, comprising a dose from about 18 mg to about 25 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0269] E4.15 A method of treating according to any one of embodiments E4.1 to E4.14, comprising a dose from about 19 mg to about 23 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0270] E4.16 A method of treating according to any one of embodiments E4.1 to E4.15, comprising a dose of about 20 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.

[0271] E4.17 A method of treating according to any one of embodiments E4.1 to E4.16, wherein the volume for injection is from about 0.2 to about 3 mL.

[0272] E4.18 A method of treating according to any one of embodiments E4.1 to E4.17, wherein the volume for injection is from about 0.2 to about 2.5 mL.

[0273] E4.19 A method of treating according to any one of embodiments E4.1 to E4.18, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 15 to about 40 mg / mL (as the free base).

[0274] E4.20 A method of treating according to any one of embodiments E4.1 to E4.19, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 20 to about 30 mg / mL (as the free base).

[0275] E4.21 A method of treating according to any one of embodiments E4.1 to E4.20, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 22 to about 28 mg / mL (as the free base).

[0276] E4.22 A method of treating according to any one of embodiments E4.1 to E4.21, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 25 mg / mL. E4.23 A method of treating according to embodiment E4.1 or E4.22, wherein the psychiatric or neurological condition is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and gambling disorders, and (v) an avolition disorder.

[0277] E4.24 A method of treating according to any one of embodiments E4.1 to E4.23, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a substance abuse disorder.

[0278] E4.25 A method of treating according to any one of embodiments E4.1 to E4.24, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients; (iii) generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder; and (iv) alcohol use disorder and opioid use disorder.

[0279] E4.26 A method of treating according to any one of embodiments E4.1 to E4.25, wherein the psychiatric or neurological condition is selected from the group consisting of major depressive disorder, generalised anxiety disorder, alcohol use disorder and opioid use disorder.

[0280] E4.27 A method of treating according to any one of embodiments E4.1 to E4.26, in combination with support therapy.

[0281] E4.28 A method of treating according to any one of embodiments E4.1 to E4.26, comprising a method of adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, obsessive compulsive disorder, and an eating disorder.

[0282] E4.29 A method of treating according to embodiment E4.28, wherein the monoamine antidepressant agent is selected from a selective serotonin reuptake inhibitor and a serotoninnorepinephrine reuptake inhibitor. E4.30 A method of treating according to embodiment E4.29, wherein the monoamine antidepressant agent is selected from at least one of desvenlafaxine, duloxetine, levomilnacipran, milnacipram, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and the pharmaceutically acceptable salts thereof.

[0283] In accordance with the fifth aspect, the invention provides the following embodiments:

[0284] E5.1 A pharmaceutical composition as defined in any one of embodiments E1.1 to E1.29 for use in the treatment of a psychiatric or neurological condition in a human,

[0285] E5.2 A pharmaceutical composition according to embodiment E5.1, wherein the psychiatric or neurological condition is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and gambling disorders, and (v) an avolition disorder.

[0286] E5.3 A pharmaceutical composition according to embodiment E5.1 or E5.2, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a substance abuse disorder.

[0287] E5.4 A pharmaceutical composition according to embodiment E5.1, E5.2 or E5.3, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients; (iii) generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder; and (iv) alcohol use disorder and opioid use disorder.

[0288] E5.5 A pharmaceutical composition according to any one of embodiments E5.1 to E5.4, wherein the psychiatric or neurological condition is selected from the group consisting of major depressive disorder, generalised anxiety disorder, alcohol use disorder and opioid use disorder.

[0289] E5.6 A pharmaceutical composition for use according to any one of embodiments E5.1 to E5.5, in combination with support therapy. E5.7 A pharmaceutical composition for use according to any one of embodiments E5.1 to E5.6, wherein the use comprises a method of adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, obsessive compulsive disorder, and an eating disorder.

[0290] E5.8 A pharmaceutical composition for use according to embodiment E5.7, wherein the monoamine antidepressant agent is selected from a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor.

[0291] E5.9 A pharmaceutical composition for use according to embodiment E5.7, wherein the monoamine antidepressant agent is selected from at least one of desvenlafaxine, duloxetine, levomilnacipran, milnacipram, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and the pharmaceutically acceptable salts thereof.

[0292] E5.10 A pharmaceutical composition as defined in any one of embodiments E2.1 to E2.21 for use in the treatment of a psychiatric or neurological condition in a human,

[0293] E5.11 A pharmaceutical composition according to embodiment E5.10, wherein the psychiatric or neurological condition is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and gambling disorders, and (v) an avolition disorder.

[0294] E5.12 A pharmaceutical composition according to embodiment E5.10 or E5.11, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a substance abuse disorder.

[0295] E5.13 A pharmaceutical composition according to embodiment E5.10, E5.11 or E5.12, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients; (iii) generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder; and (iv) alcohol use disorder and opioid use disorder. E5.14 A pharmaceutical composition according to any one of embodiments E5.10 to E5.13, wherein the psychiatric or neurological condition is selected from the group consisting of major depressive disorder, generalised anxiety disorder, alcohol use disorder and opioid use disorder.

[0296] E5.15 A pharmaceutical composition for use according to any one of embodiments E5.10 to E5.14, in combination with support therapy.

[0297] E5.16 A pharmaceutical composition for use according to any one of embodiments E5.10 to E5.15, wherein the use comprises a method of adjunctive treatment of a psychiatric disorder in a patient receiving treatment with a monoamine antidepressant agent, preferably wherein the psychiatric disorder is selected from at least one of a depressive disorder, an anxiety disorder, obsessive compulsive disorder, and an eating disorder.

[0298] E5.17 A pharmaceutical composition for use according to embodiment E5.16, wherein the monoamine antidepressant agent is selected from a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor.

[0299] E5.18 A pharmaceutical composition for use according to embodiment E5.16, wherein the monoamine antidepressant agent is selected from at least one of desvenlafaxine, duloxetine, levomilnacipran, milnacipram, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, and vortioxetine, and the pharmaceutically acceptable salts thereof.

[0300] EXPERIMENTAL

[0301] EXAMPLE 1

[0302] The inventors have conducted a Phase 1 clinical trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous and intramuscular dosing of deuterated DMT fumarate (SPL028) in healthy participants (EudraCT Number: 2022-002618- 17). The objective of this study was to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of escalating doses of SPL028 in healthy participants. This was a two- part study, consisting of Part 1 (IV vs IM cross-over dosing in 16 psychedelic-experienced healthy participants) and Part 2 (single IM doses of SPL028 in 22 healthy participants with little- to-no psychedelic experience).

[0303] The drug product SPL028 comprises [2-(1H-indol-3-yl)(1,1-D-2)ethyl]dimethylamine (DMT-d2), formulated as a fumarate salt at a 1:1 ratio.

[0304] Part 1

[0305] In Part 1, participants took part in two Treatment Periods. For each participant in Part 1, the study consisted of:

[0306] ■ Screening Visit (Day -42 to Day -2): Informed consent, Screening and eligibility assessments and enrolment of eligible participants. A preparation session also occurred.

[0307] ■ Inpatient Period (Day -1 to Day 2 of each Treatment Period): o Day -1: A Preparation session and baseline safety and PD assessments. o Day 1: § Prior to dosing, safety assessments and a preparation session occurred. § On Day 1 of Treatment Period 1, participants were administered a single dose of SPL028 or matched placebo administered as a continuous 10-minute IV infusion via a cannula. § On Day 1 of Treatment Period 2, participants were administered a single dose of SPL028 or matched placebo via an IM injection. Two participants were randomised to receive placebo within each dosing session; however, no participant was administered placebo in both Treatment Periods. PK blood sampling were performed. § Upon completion of the dose session, when the psychedelic event was judged to be over, acute subjective PD assessments, an integration session, and an assessment of tolerability and safety assessments were performed. PK blood sampling was also performed predose and postdose. o Day 2: Prior to discharge, an Integration session was performed, as well as safety assessments. ■ Safety / End-of-Study Follow-up Video Call (Day 15 [±2 days] of each Treatment Period): An Integration session, PD and safety assessments were performed.

[0308] Participants had a washout period of 3 to 6 weeks between Treatment Period 1 and Treatment Period 2.

[0309] Part 2

[0310] For each participant in Part 2, the study consisted of:

[0311] ■ Screening Visit (Day -42 to Day -2): Informed consent, Screening and eligibility assessments and enrolment of eligible participants. A preparation session also occurred.

[0312] ■ Inpatient Period (Day -1 to Day 2): o Day -1 : A Preparation session and baseline safety and PD assessments. o Day 1 : § Prior to dosing, safety assessments and a preparation session occurred. § Participants were administered SPL028 as an IM injection. PK blood sampling was performed. § Upon completion of the dose session, when the psychedelic event was judged to be over, acute subjective PD assessments, an integration session, an assessment of tolerability and safety assessments were performed. PK blood sampling was performed predose and postdose. o Day 2: Prior to discharge, an integration session was performed, as well as safety assessments.

[0313] ■ End-of-Study Follow-up Video Call (Day 15 [±2 days]): An Integration session, PD and safety assessments were performed.

[0314] In Part 1 , the SPL028 or matched placebo was administered as a continuous 10-minute IV infusion via a cannula on Day 1 of Treatment Period 1. On Day 1 of Treatment Period 2, the SPL028 or matched placebo was administered via an IM injection directly into the ventrogluteal muscle.

[0315] In Part 2, the SPL028 or matched placebo was administered via an IM injection to participants on Day 1 directly into the ventrogluteal muscle. The SPL028 drug product for IM administration was formulated as a sterile solution for injection in a 5 mL clear glass vial, the formulation comprising 25 mg / mL (as free base) deuterated DMT in a 5 mL aqueous solution at pH 6. The IM placebo was based on the active IM formulation excluding the deuterated DMT and was provided as a sterile solution for injection in a 5 mL clear glass vial at pH 6.

[0316] Pharmacokinetic blood sampling was conducted within 4 hours predose and within the following time windows postdose: 2 (±0.5 min), 5 (±0.5 min), 10 (±0.5 min), 15 (±0.5 min), 20 (±0.5 min), 30 (±0.5 min), 45 (±0.5 min), 60 (±5min), 90 (±5min), 120 (±5min), 175 (±5min), 240 (±5min), 300 (±5min) and 475 (±5min) minutes from IM injection.

[0317] Pharmacodynamics were assessed by the use of psychometric scales and questionnaires. Participants self-completed the following psychometric scales after dosing on Day 1: MEQ, EDI, EBI, CEQ, and IRVAS. The IRVAS was completed after the integration session by both the participant and the therapist or psychiatrist.

[0318] Tolerability was assessed using the CEQ scale. A score of 70% or greater on this scale indicates a less tolerable experience.

[0319] Results

[0320] The data show that a Cmax from about 15 to about 75 ng / mL, and / or an AUC from about 1200 to about 3100 hr.ng / mL typically provided a MEQ30 total score and / or an IRVAS score within the desired range of 40-100%, indicating sufficient exposure for therapeutic use. Two participants who had Cmax of 80 or higher and / or an AUC of 3200 or higher, above the claimed range, had a CEQ of 70% or higher, indicating that these participants did not tolerate the experience well. Possible treatment-related adverse events (AEs)

[0321] *value given is the cumulative total of the highest severity event reported per participant. For example, for the IV 17mg cohort, 4 participants recorded events. For 3 of these participants, the highest severity AE recorded was moderate, while for 1 participant the highest severity AE recorded was severe. A total of 16 AEs were recorded by the 4 participants.

[0322] These data indicate that IM administration was associated with fewer possible treatment related adverse events as well as less severe adverse events when compared with IV administration.

[0323] IM, 30mg cohort

[0324] *individual events

[0325] It can be seen from these data that two participants in the 30mg cohort with a Cmax of 100 ng / mL or higher, reported a total of 8 adverse events, 6 mild and 2 moderate. In contrast, only 1 participant with a Cmax of less than 80 ng / mL reported any adverse events, 1 mild event. 8 out of 9 adverse events were reported by participants with a Cmax above the claimed range. These data indicate improved tolerability of the active pharmaceutical ingredient for participants with a Cmax within the claimed range of about 15 to about 75 ng / mL. IM administration of deuterated DMT providing a Cmax and / or AUC within the claimed ranges was associated with fewer and less severe possible treatment related adverse events and good tolerability of the deuterated DMT. The inventors have surprisingly found that when a Cmax from about 15 to about 75 ng / mL and / or an AUC from about 1200 to about 3100 hr.ng / mL is achieved by IM administration of deuterated DMT, participants had both sufficient exposure for therapeutic use and good tolerability of the psychedelic experience, as well as good tolerability of the deuterated DMT.

[0326] EXAMPLE 2

[0327] A study was carried out in rats to compare the pharmacokinetics of two deuterated DMT compounds administered by intravascular and by intramuscular injection.

[0328] 4 male Sprague Dawley rats were co-dosed with a,a-dideutero- / V, / V-dimethyltryptamine (DMT- d2) and DMT, a,a-dideutero- / V, / V-di(trideuteromethyl)tryptamine (DMT-d8) and DMT and a,a,p,p-tetradeutero- / V, / V-di(trideuteromethyl)tryptamine (DMT-d10) and DMT following a wash- out period (> 1 week) via the IV administration route at 0.5 mg / kg per compound.

[0329] *data dose adjusted to 0.5 mg / kg

[0330] It has previously been reported that deuterated DMT exhibits an extension in half-life when compared with DMT (WO2022 / 117359, WO2020 / 245133 and WO 2021 / 234608). Following IV dosing of DMT-d2, DMT-d8 and DMT-d10, a small increase in AUG exposure was observed relative to DMT. The increase in exposure was comparable between the deuterated DMT compounds.

[0331] A separate group of 4 male Sprague Dawley rats were co-dosed with a,a-dideutero- / V, / \ / - dimethyltryptamine (DMT-d2) and DMT, a,a-dideutero- / V, / V-di(trideuteromethyl)tryptamine (DMT-d8) and DMT, and a,a,p,p-tetradeutero- / V, / V-di(trideuteromethyl)tryptamine (DMT-d10) and DMT following a wash-out period (> 1 week) via the IM administration route at 5 mg / kg I compound.

[0332] An extension in half life was also observed following IM administration with DMT-d2, DMT-d8 and DMT-d10. A significant increase in exposure (Cmax and AUC), as well as a delayed Tmax and longer half-life, was observed relative to DMT. The relative changes in PK parameters were similar between the deuterated DMT compounds.

[0333] These data, as presented in Figures 1 to 3, show that three different deuterated compounds exhibit similar pharmacokinetics following IM administration of deuterated DMT compared with the undeuterated compound. IM administration of the deuterated DMT compounds provided not only a surprising increase in exposure when compared with DMT, but also when compared with the corresponding increase in IV exposure following IV administration.

[0334] These data indicate that the results observed from the clinical study described in Example 1 would also be applicable to other deuterated DMT molecules, including DMT-d8 and DMT-d10.

[0335] EXAMPLE 3

[0336] A study was conducted to investigate the pharmacokinetics of DMT-d10 (fumarate salt) when administered to dogs by intravascular and by intramuscular injection.

[0337] In each Phase, equal concentrations of DMT and DMT-d10 (fumarate salt) were administered to three, non-naive, male Beagle dogs aged ca 2-5 years and weighing 10-15 kg at dosing.

[0338] Phase 1 (intravenous (IV) bolus). Appropriate volumes of dose were calculated per each animal based on real animal body weights and a target dose volume of 1 mL / kg. Animals were dosed via IV bolus injection into the cephalic vein over ca 30-60 seconds.

[0339] Phase 2 (intramuscular (IM) injection). Following a 7-day washout, appropriate volumes of dose were calculated per each animal based on real animal body weights and a target dose volume of 0.25 mL / kg. Animals were dosed via IM injection into the left hind limb.

[0340] The Phase 1 dose was formulated at a concentration of 0.2 mg / mL (free base) (0.1 mg / mL per test item as free base) as a solution in 0.9% saline, pH 5.5-6.0 The doses for Phases 2 and 3 were formulated at a concentration of 0.8 mg / mL (free base) (0.4 mg / mL per test item as a free base) as solutions in 0.9% saline, pH 5.5-6. The Dose Level for Phase 1 and Phase 2 was 0.2 mg / kg (0.1 mg / kg per test item).

[0341] Results aDMT and DMT-d10 were co-dosed, each at 0.1 mg / kg (free base) in 0.9% saline vehiclebParameters are mean (± SD)cmedian

[0342] NA: Not applicable

[0343] While deuteration effects were significant and seen across both routes of administration, deuteration effects were unexpectedly profound following intramuscular (IM) administration. For example, deuteration of DMT resulted in a 450% increase in Cmax and a 1450% increase in exposure (AUCiast) following IM administration, compared to native DMT administered intramuscularly. When compared across both administration routes, the deuteration effects on exposure (AUCiast) following IM administration was surprisingly found to be more than 12-fold greater than those observed following IV injections. Likewise, the deuteration effects on maximum plasma concentration (Cmax) following IM administration was also unique — 75-fold greater than observed following IV injections. These data, as presented in Figure 4, confirm that IM administration of deuterated DMT provides a surprising increase in exposure.

Claims

CLAIMS1 An aqueous intramuscular injectable pharmaceutical composition comprising a dose of deuterated / V, / V-dimethyltryptamine, wherein the deuterated / V, / V-dimethyltryptamine comprises two or more compounds selected from the group consisting of: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof; and wherein the dose of the deuterated / V, / V-dimethyltryptamine is greater than 15 mg and less than 30 mg (as the free base).2 A pharmaceutical composition according to claim 1 , wherein the deuterated N,N- dimethyltryptamine comprises two or more compounds selected from the group consisting of: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,p,p-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,-trideutero-N,N-di(trideuteromethyl)tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.3 A pharmaceutical composition according to claim 1 or 2, wherein the deuterated N,N- dimethyltryptamine comprises:(i) a-protio, a-deutero-N,N-dimethyltryptamine and a,a-dideutero-N,N- dimethyltryptamine;(ii) a-protio, a-deutero-N,N-di(trideuteromethyl)tryptamine and a,a-dideutero-N,N- di(trideuteromethyl)tryptamine;(iii) a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine and a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine or a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine; or(iv) a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine, a,p,p-trideutero-N,N- di(trideuteromethyl)tryptamine and a,a,p,-trideutero-N,N- di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.4 A pharmaceutical composition according to any one of claims 1 to 3, wherein the deuterated / V, / V-dimethyltryptamine comprises a,a-dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N- di(trideuteromethyl)tryptamine, or a pharmaceutically acceptable salt thereof, wherein the a,a-dideutero-N,N-dimethyltryptamine, a,a-dideutero-N,N- di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 85% or greater.5 A pharmaceutical composition according to claim 4, wherein the a,a-dideutero-N,N- dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero- N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 90% or greater.6 A pharmaceutical composition according to claim 4, wherein the a,a-dideutero-N,N- dimethyltryptamine, a,a-dideutero-N,N-di(trideuteromethyl)tryptamine, or a,a,p,p-tetradeutero- N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 92% or greater.7 A pharmaceutical composition according to claim 4, wherein the a,a,p,p-tetradeutero- N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 92% or greater.8 A pharmaceutical composition according to claim 4, wherein the a,a-dideutero-N,N- dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 95% or greater.9 A pharmaceutical composition according to claim 4, wherein the a,a-dideutero-N,N- dimethyltryptamine or a,a-dideutero-N,N-di(trideuteromethyl)tryptamine has an isotopic purity of about 97% or greater.10 A pharmaceutical composition according to any one of claims 1 to 9, wherein the deuterated N,N-dimethyltryptamine is in the form of a pharmaceutically acceptable salt.11 A pharmaceutical composition according to any one of claims 1 to 10, wherein the deuterated N,N-dimethyltryptamine is in the form of the fumarate salt.12 A pharmaceutical composition according to any one of claims 1 to 11, comprising a dose from about 17 mg to about 27 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.13 A pharmaceutical composition according to any one of claims 1 to 12, comprising a dose from about 18 mg to about 25 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.14 A pharmaceutical composition according to any one of claims 1 to 13, comprising a dose from about 19 mg to about 23 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.15 A pharmaceutical composition according to any one of claims 1 to 14, comprising a dose of about 20 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.16 A pharmaceutical composition according to any one of claims 1 to 15, wherein the volume for injection is from about 0.2 to about 3 ml.17 A pharmaceutical composition according to any one of claims 1 to 16, wherein the volume for injection is from about 0.2 to about 2.5 ml.18 A pharmaceutical composition according to any one of claims 1 to 17, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 15 to about 40 mg / mL (as the free base).19 A pharmaceutical composition according to any one of claims 1 to 18, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 20 to about 30 mg / mL (as the free base).20 A pharmaceutical composition according to any one of claims 1 to 19, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 22 to about 28 mg / mL (as the free base).21 A pharmaceutical composition according to any one of claims 1 to 20, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 25 mg / mL.22 A pharmaceutical composition comprising deuterated N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered as an intramuscular injection and wherein the administration provides:(i) a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL; or(ii) an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL; or(iii) a maximum plasma concentration (Cmax) of deuterated N,N-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL and an area under the curve (AUC) of deuterated N,N-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL.23 A pharmaceutical composition according to claim 22, wherein the deuterated N,N- dimethyltryptamine is a compound of formula I, or a pharmaceutically acceptable salt thereof:Formula I wherein: n is 0, 1 , 2, 3, 4 or 5;R1is D;R2and R3are each independently selected from -CH3 and -CD3; each Hx and Hy is independently selected from H and D, wherein R2is -CD3 when each Hx and Hy is H.24 A pharmaceutical composition according to claim 23, wherein n is 0.25 A pharmaceutical composition according to claim 23 or 24, wherein both Hy are D.26 A pharmaceutical composition according to any one of claims 23 to 25, wherein both Hx are D.27 A pharmaceutical composition according to any one of claims 23 to 25, wherein both Hx are H.28 A pharmaceutical composition according to any one of claims 23 to 27, wherein both R2and R3are -CD3.29 A pharmaceutical composition according to any one of claims 22 to 28, wherein the deuterated N,N-dimethyltryptamine is selected from: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.30 A pharmaceutical composition according to any one of claims 22 to 29, wherein the deuterated N,N-dimethyltryptamine is selected from: a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.31 A pharmaceutical composition according to any one of claims 22 to 30, wherein the deuterated N,N-dimethyltryptamine is in the form of a pharmaceutically acceptable salt.32 A pharmaceutical composition according to any one of claims 22 to 31 , wherein the deuterated N,N-dimethyltryptamine is in the form of the fumarate salt.33 A pharmaceutical composition according to any one of claims 22 to 32, wherein the administration provides a maximum plasma concentration (Cmax) from about 18 ng / mL to about 70 ng / mL.34 A pharmaceutical composition according to any one of claims 22 to 33, wherein the administration provides a maximum plasma concentration (Cmax) from about 20 ng / mL to about 65 ng / mL.35 A pharmaceutical composition according to any one of claims 22 to 34, wherein the administration provides an area under the curve (AUC) from about 1200 hr.ng / mL to about 3000 hr.ng / mL.36 A pharmaceutical composition according to any one of claims 22 to 35, comprising a dose from 15 mg to 30 mg (as free base) of the deuterated N,N-dimethyltryptamine orpharmaceutically acceptable salt thereof, or a dose of greater than 15 mg to less than 30 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.37 A pharmaceutical composition according to any one of claims 22 to 36, comprising a dose from about 17 mg to about 27 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.38 A pharmaceutical composition according to any one of claims 22 to 37, comprising a dose from about 18 mg to about 25 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.39 A pharmaceutical composition according to any one of claims 22 to 38, comprising a dose from about 19 mg to about 23 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.40 A pharmaceutical composition according to any one of claims 22 to 39, comprising a dose of about 20 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.41 A pharmaceutical composition according to any one of claims 22 to 40, wherein the intramuscular injection is administered into the vastus lateralis, deltoid, or gluteal muscle.42 A pharmaceutical composition according to any one of claims 22 to 41 , wherein the intramuscular injection is administered into the deltoid or gluteal muscle.43 A pharmaceutical composition according to any one of claims 22 to 42, wherein the volume for injection is from about 0.2 to about 3 ml.44 A pharmaceutical composition according to anyone of claims 22 to 43, wherein the volume for injection is from about 0.2 to about 2.5 ml.45 A pharmaceutical composition according to any one of claims 22 to 44, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 15 to about 40 mg / mL46 A pharmaceutical composition according to any one of claims 22 to 45, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 20 to about 30 mg / mL.47 A pharmaceutical composition according to any one of claims 22 to 46, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 22 to about 28 mg / mL.48 A pharmaceutical composition according to any one of claims 22 to 47, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 25 mg / mL.49 A pharmaceutical composition according to any one of claims 22 to 48, wherein the rate of administration is from about 1 mL / 10 s to about 1 mL / s.50 A method of treating a psychiatric or neurological condition in a human, the method comprising intramuscular administration to the human of a dose of deuterated N,N- dimethyltryptamine or a pharmaceutically acceptable salt thereof, wherein the administration provides:(i) a maximum plasma concentration (Cmax) of deuterated / V, / V-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL; or(ii) an area under the curve (AUC) of deuterated / V, / V-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL; or(iii) a maximum plasma concentration (Cmax) of deuterated / V, / V-dimethyltryptamine from about 15 ng / mL to about 75 ng / mL and an area under the curve (AUC) of deuterated / V, / V-dimethyltryptamine from about 1200 hr.ng / mL to about 3100 hr.ng / mL.51 A method of treating according to claim 50, wherein the deuterated N,N- dimethyltryptamine is a compound of formula I, or a pharmaceutically acceptable salt thereof:Formula I wherein: n is 0, 1 , 2, 3, 4 or 5;R1is D;R2and R3are each independently selected from -CH3 and -CD3; each Hx and Hy is independently selected from H and D, wherein R2is -CD3 when each Hx and Hy is H.52 A method of treating according to claim 51 , wherein n is 0.53 A method of treating according to claim 51 or 52, wherein both Hy are D.54 A method of treating according to any one of claims 51 to 53, wherein both Hx are D.55 A method of treating according to any one of claims 51 to 53, wherein both Hx are H.56 A method of treating according to any one of claims 51 to 55, wherein both R2and R3are -CD3.57 A method of treating according to any one of claims 50 to 56, wherein the deuterated N,N-dimethyltryptamine is selected from: a-protio, a-deutero-N,N-dimethyltryptamine; a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine;N,N-di(trideuteromethyl)tryptamine; a-protio, a-deutero-N,N- di(trideuteromethyl)tryptamine;a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.58 A method of treating according to any one of claims 50 to 57, wherein the deuterated N,N-dimethyltryptamine is selected from: a,a-dideutero-N,N-dimethyltryptamine; a,a,p,p-tetradeutero-N,N-dimethyltryptamine; a, a-dideutero-N,N-di(trideuteromethyl) tryptamine; a,a,p,p-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and pharmaceutically acceptable salts thereof.59 A method of treating according to any one of claims 50 to 58, wherein the deuterated N,N-dimethyltryptamine is in the form of a pharmaceutically acceptable salt.60 A method of treating according to any one of claims 50 to 59, wherein the deuterated N,N-dimethyltryptamine is in the form of the fumarate salt.61 A method of treating according to any one of claims 50 to 60, wherein the administration provides a maximum plasma concentration (Cmax) from about 18 ng / mL to about 70 ng / mL.62 A method of treating according to any one of claims 50 to 61 , wherein the administration provides a maximum plasma concentration (Cmax) from about 20 ng / mL to about 65 ng / mL.63 A method of treating according to any one of claims 50 to 62, wherein the administration provides an area under the curve (AUC) from about 1200 hr. ng / mL to about 3000 hr. ng / mL.64 A method of treating according to any one of claims 50 to 63, comprising a dose from 15 mg to 30 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.65 A method of treating according to any one of claims 50 to 64, comprising a dose from about 17 mg to about 27 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.66 A method of treating according to any one of claims 50 to 65, comprising a dose from about 18 mg to about 25 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.67 A method of treating according to any one of claims 50 to 66, comprising a dose from about 19 mg to about 23 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.68 A method of treating according to any one of claims 50 to 67, comprising a dose of about 20 mg (as free base) of the deuterated N,N-dimethyltryptamine or pharmaceutically acceptable salt thereof.69 A method of treating according to any one of claims 50 to 68, wherein the intramuscular injection is administered into the vastus lateralis, deltoid, or gluteal muscle.70 A method of treating according to any one of claims 50 to 69, wherein the intramuscular injection is administered into the deltoid or gluteal muscle.71 A method of treating according to any one of claims 50 to 70, wherein the volume for injection is from about 0.2 to about 3 ml.72 A method of treating according to any one of claims 50 to 71 , wherein the volume for injection is from about 0.2 to about 2.5 ml.73 A method of treating according to any one of claims 50 to 72, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 15 to about 40 mg / mL.74 A method of treating according to any one of claims 50 to 73, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 20 to about 30 mg / mL.75 A method of treating according to any one of claims 50 to 74, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 22 to about 28 mg / mL.76 A method of treating according to any one of claims 50 to 75, wherein the concentration of the deuterated / V, / V-dimethyltryptamine is about 25 mg / mL.77 A method of treating according to any one of claims 50 to 76, wherein the rate of administration is from about 1 mL / 10 s to about 1 mL / s.78 A method of treating according to any one of claims 50 to 77, wherein the psychiatric or neurological condition is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and gambling disorders, and (v) an avolition disorder.79 A method of treating according to any one of claims 50 to 78, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a substance abuse disorder.80 A method of treating according to any one of claims 50 to 79, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients; (iii) generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder; and (iv) alcohol use disorder and opioid use disorder.81 A method of treating according to any one of claims 50 to 80, wherein the psychiatric or neurological condition is selected from the group consisting of major depressive disorder, generalised anxiety disorder, alcohol use disorder and opioid use disorder.82 A method of treating according to any one of claims 50 to 80, in combination with support therapy.83 A method of treating a psychiatric or neurological condition in a human, the method comprising intramuscular administration into the deltoid, or gluteal muscle of the human of a dose of deuterated / V, / V-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, which is greater than 15 mg and less than 30 mg (as the free base).84 A method of treating according to claim 83, comprising administration of the aqueous intramuscular pharmaceutical composition according to any one of claims 29 to 49.85 A method of treating according to claim 83 or 84, wherein the psychiatric or neurological condition is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and gambling disorders, and (v) an avolition disorder.86 A method of treating according to any one of claims 83 to 85, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a substance abuse disorder.87 A method of treating according to any one of claims 83 to 86, wherein the psychiatric or neurological condition is selected from the group consisting of (ii) major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients; (iii) generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder; and (iv) alcohol use disorder and opioid use disorder.88 A method of treating according to any one of claims 83 to 87, wherein the psychiatric or neurological condition is selected from the group consisting of major depressive disorder, generalised anxiety disorder, alcohol use disorder and opioid use disorder.89 A method of treating according to any one of claims 83 to 88, in combination with support therapy.

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