Methods of administering parenteral formulations comprising magical agent

Abstract

The present invention relates to dosing regimens, methods of treatment, delivery devices or parenteral formulations for the treatment of psychiatric or neurological disorders in a patient. In particular, the present invention relates to the administration of a fantastic agent.

Description

Field of the Invention

[0001] The present invention relates to dosing regimens, treatment methods, delivery devices or parenteral preparations for treating psychiatric or neurological disorders in a patient. In particular, the present invention relates to the administration of hallucinogens. Background of the Invention

[0003] Classic hallucinogens have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, psilocybin has been shown to produce significant improvements in a range of depression and anxiety rating scales in randomized double-blind studies (Griffiths et al., Journal of Psychopharmacology, 30(12), 1181-1197 (2016)). The efficacy of psilocybin has been shown in depression (R.L. Carhart-Harris et al., Psychopharmacology, 2018, 235, 399-408), end-of-life anxiety (R.R. Griffiths et al., J. Psychopharmacol., 2016, 30, 12, 1181-1197) and addiction (M.W. Johnson, A. Garcia-Romeu and R.R. Griffiths, Am. J. Drug Alcohol Abuse, 2017, 43, 1, 55-60), and it is currently being investigated for several other mental health disorders resulting from psychologically damaging thought processing patterns (Anorexia Nervosa: NCT#NCT04052568).

[0004] N,N-Dimethyltryptamine (DMT) has also been proposed to have therapeutic value as a short-acting hallucinogenic agent. S.A. Barker provided a review of the research on the biosynthesis and metabolism of DMT in the brain and peripheral tissues, as well as the methods and results for the detection of DMT in body fluids and the brain, in Front. Neurosci., 12, 536, 1-17 (2018). Barker et al. proposed that "further characterization of DMT cell distribution, receptors, and general biochemistry could lead to new targets for more effective drug substances and interventions". D. Nutt et al. (Cell. April 2, 2020; 181(1):24-28. doi:10.1016 / j.cell.2020.03.020) proposed the possible therapeutic effects of DMT: "It is theoretically possible that, however, a short trip, such as i.v. DMT, could'reorganize' and'reset' abnormal patterns of brain activity and thus could have some therapeutic benefits". Both Barker et al. and Nutt et al. concluded that further research on the effects and functions of DMT is needed.

[0005] Sanches et al. and Palhano-Fontes et al. reported that in a study of patients with recurrent major depressive disorder (MDD) or treatment-resistant depression (TRD), a single oral dose of ayahuasca (a plant brew containing natural hallucinogens) was associated with improvement in depressive symptoms (Sanches RF, de Lima Osorio F, dos Santos RG et al., Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A SPECT study. J Clin Psychopharmacol 2016;36(1):77-81 and Palhano-Fontes F, Barreto D, Onias H et al., Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med 2019;49(4):655-663). N,N-Dimethyltryptamine (DMT) is the main hallucinogenic compound contained in ayahuasca.

[0006] Good et al. discussed the results of a Phase 1 study investigating the pharmacokinetics of N,N-dimethyltryptamine fumarate in healthy subjects (Meghan Good, Tiffanie Benway, Zelah Joel et al., Authorea. May 12, 2022; DOI: 10.22541 / au.165237523.39763980 / v1). The study did not include patients with psychiatric or neurological disorders. The report has not been peer-reviewed.

[0007] D'Souza et al. reported an "Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder" (D.C. D'Souza, S.A. Syed, L.T. Flynn, H. Safi-Aghdam, NV Cozzi and M. RanganathaN, Neuropsychopharmacology (2022) 47:1854-1862). Seven patients with major depressive disorder received two doses of DMT hemifumarate (0.1 mg / kg, followed by 0.3 mg / kg), at least 48 hours apart. DMT was administered to the participants by intravenous bolus injection over 30 - 60 seconds.

[0008] WO2022195489 discusses methods of using hallucinogens, where a first bolus injection is administered, followed by a lower maintenance dose. WO2022031566 discusses the intravenous administration of DMT.

[0009] Timmermann et al. discussed the results of a clinical trial investigating the effects of intravenous DMT in healthy participants (Translational Psychiatry (2023) 13:172, published online on May 23, 2023).

[0010] Cybin Inc. has completed the Phase 1 portion of a Phase 1 / 2a clinical trial evaluating a deuterated psilocybin compound (CYB003) in healthy participants with and without major depressive disorder (ClinicalTrials.gov Identifier: NCT05385783). In February 2023, Cybin Inc. announced that after a single oral dose of CYB003, hallucinogenic effects were observed within approximately 15 minutes, and the mean duration of peak effects lasted approximately 2 hours, based on a mid-stage analysis of CYB003 in healthy volunteers (https: / / cybin.com / cyb003 / ).

[0011] In May 2023, Cybin Inc. announced that the company was evaluating the intravenous administration of a deuterated dimethyltryptamine compound (CYB004) in healthy volunteers. Part C of the Phase 1 CYB004-E trial is a crossover study design that will evaluate an IV bolus + infusion regimen of CYB004 in up to two cohorts.

[0012] With the growing interest in the potential uses of hallucinogens such as psilocybin and DMT in psychiatry, there is an increasing need for methods to administer these agents in a safe and tolerable manner. Summary of the Invention

[0013] As a first aspect, the present invention provides a dosing regimen for administering a hallucinogen to a patient for the treatment of a psychiatric or neurological disorder, comprising parenterally administering a dose of the hallucinogen over a dosing period of about 5 to about 15 minutes, wherein the hallucinogen is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, its deuterated analogs, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

[0014] As a second aspect, the present invention provides a method for treating a psychiatric or neurological disorder in a patient, comprising parenterally administering a dose of a hallucinogen to the patient over a dosing period of about 5 to 15 minutes, wherein the hallucinogen is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, its deuterated analogs, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

[0015] As a third aspect, the present invention provides a delivery device for treating a psychiatric or neurological disorder in a patient, wherein the delivery device is configured to deliver a parenteral dose of a hallucinogen over a dosing period of about 5 to about 15 minutes, wherein the hallucinogen is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, its deuterated analogs, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

[0016] As a fourth aspect, the present invention provides a parenteral formulation for treating a psychiatric or neurological disorder in a patient, comprising parenterally administering a dose of a hallucinogenic agent for a dosing period of about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, its deuterated analogs, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

[0017] As a fifth aspect, the present invention provides a parenteral formulation comprising a hallucinogenic agent for treating a psychiatric or neurological disorder in a patient, comprising parenterally administering a dose of a hallucinogenic agent for a dosing period of about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, its deuterated analogs, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows the percentage of subjects with a ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 1 and week 2 after administration of DMT fumarate or placebo, compared to baseline assessment.

[0019] Figure 2 shows the percentage of subjects with MADRS scores ≤10 at week 1 and week 2 after administration of DMT fumarate or placebo.

[0020] DEFINITIONS

[0021] Throughout this specification, one or more aspects of the invention may be combined with one or more features described in this specification to define different embodiments of the invention.

[0022] In the detailed description, a number of terms are used, which, unless the context clearly dictates otherwise, are to be understood as having the meanings provided below.

[0023] The nomenclature used herein for the hallucinogenic agents of the present invention is the same as that commonly used in the art. The compounds described herein may also be named according to the rules of the International Union of Pure and Applied Chemistry (IUPAC) for chemical compounds, in particular the "IUPAC Compendium of Chemical Terminology (Gold Book)" (see A.D. Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). To avoid doubt, if the rules of the IUPAC organization conflict with the definitions provided herein, the definitions herein shall prevail.

[0024] The IUPAC name of N,N-dimethyltryptamine is also known as 2-(1H-indol-3-yl)-N,N-dimethylethanamine.

[0025] The IUPAC name of 5-methoxy-N,N-dimethyltryptamine is also known as 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine.

[0026] The IUPAC name of 4-acetoxy-N,N-dimethyltryptamine is also known as [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] acetate.

[0027] The IUPAC name of psilocybin is also known as [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate.

[0028] The IUPAC name of dimethyl-4-hydroxytryptamine is also known as 3-[2-(dimethylamino)ethyl]-1H-indol-4-ol.

[0029] As used herein, the term "deuterated analogue" of a hallucinogen means that one or more hydrogen atoms in the structure of the hallucinogen are replaced by deuterium atoms, where a deuterium atom is a hydrogen atom with an extra neutron. The deuterium substitution can occur at one or more of the alpha and beta positions, on methyl groups, and on the indole ring, as well as on substituents of the indole ring in certain compounds, such as the methoxy group of 5-methoxy-N,N-dimethyltryptamine. In some embodiments, the deuteration can occur on methyl groups and at the alpha position and optionally the beta position.

[0030] If a compound described herein is indicated as or described as a deuterated analogue, the amount of deuterium enrichment of the compound involved depends on the percentage of deuterium available in the reagent from which the compound is derived. For example, the d6-dimethylamino moiety of a compound of formula I, where -NR 2 R 3 is -N(CD3)2, can be derived from dimethyl-d7-amine or dimethyl-d6-amine (usually provided as the HCl salt), which is available from chemical suppliers with a deuterium purity range of 98% to 99%. Thus, the deuterium purity in the resulting d6-dimethylamino substituent is between 98% and 99%. This means that, as will be understood by those skilled in the art, not all compounds of formula I, for example, will contain a d6-dimethylamino substituent - some may contain a d0-d5 dimethylamino, but the average deuterium purity is approximately 98% to 99%.

[0031] In some embodiments, the hallucinogen is substituted at the 5-position with a methoxy group, or at the 4-position with an acetoxy group or a hydroxy group, or with a monohydrogen phosphate group. The term "acetoxy" (usually abbreviated as OAc) defines a monovalent group derived from acetic acid by removing a hydrogen atom from the OH moiety. The term "methoxy" (usually abbreviated as OMe) defines a monovalent group derived from methanol by removing a hydrogen atom from the OH moiety. The term "hydroxy" (usually abbreviated as OH) defines a monovalent group derived from water by removing a hydrogen atom from the H2O moiety. The term monohydrogen phosphate group defines a divalent group of the formula HPO4, derived from phosphoric acid by removing protons from two of the three OH moieties, and thus represented by the formula -OP(O)(OH)O - as a substituent.

[0032] When the dimethyltryptamine compound is substituted at the 4-position with a hydroxy group, the hallucinogen is referred to herein as dimethyl-4-hydroxytryptamine. When the dimethyltryptamine compound is substituted at the 4-position with a monohydrogen phosphate group, this reflects that psilocybin (also known as [3-(2-dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate) typically has a monohydrogen phosphate group at the 4-position in water, which is generally understood to be the predominant form since the pKa values of the two terminal phosphate oxygen atoms are estimated to be 1.3 and 6.5. It is further understood that psilocybin in the monohydrogen phosphate form exists as a zwitterion (i.e., an inner salt), where the nitrogen atom of the dimethylamino moiety is protonated. Thus, this form, and psilocybin should be regarded as salts of dimethyltryptamine compounds substituted at the 4-position with a monohydrogen phosphate group.

[0033] For the avoidance of doubt, the 4- and 5-positions, and the α- and β-positions of the hallucinogen refer to the positions labeled in the following structure (substitutions not shown).

[0034]

[0035] The dose or total dose of the hallucinogen referred to herein is the dose or total dose of the free base equivalent of the agent.

[0036] The term "parenteral administeration / parenterally administering" as used herein means administering a dose of the hallucinogen, either singly or in multiple doses, by any route other than oral, over the duration of the dosing period. Parenteral administration is substantially continuous over a dosing period of 5 to 15 minutes. For the avoidance of doubt, "parenteral administration" does not include an initial bolus administration of the hallucinogen, i.e., administering a single dose of the agent at a rapid rate, typically within 30 to 60 seconds, which provides a rapid-onset breakthrough hallucinogenic experience.

[0037] "Rapid onset" means a breakthrough hallucinogenic experience that peaks within two minutes after the start of administration of the hallucinogenic agent. The term "slow onset breakthrough hallucinogenic experience" as used herein means a breakthrough hallucinogenic experience that peaks two minutes or more after the start of administration of the hallucinogenic agent.

[0038] Unless the context otherwise indicates, the singular of a noun mentioned herein includes the plural of the noun and vice versa.

[0039] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of the 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 "comprise" includes within its scope the term "consist of" or "consist essentially of".

[0040] The term "consist of" or variations thereof shall be understood to imply the inclusion of the 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.

[0041] The term "consist essentially of" or variations thereof shall be understood to imply the inclusion of the stated element, integer or step, or group of elements, integers or steps, and additional components that may be present, but only those that do not materially affect the essential characteristics of the embodiments of the invention.

[0042] The term "about" as used herein, when qualifying a number or value, is used to refer to a value that lies within ±5% of the specified value. To avoid doubt, if a number or value is specified herein and there is no term "about", the number or value shall be understood according to the standard rules of rounding of numbers according to the number of decimal places. For example, an integer such as 6 is understood to encompass values ≥5.5 and <6.5. Similarly, a number specified to one decimal place, such as 5.3, is understood to encompass values ≥5.25 and <5.35.

[0043] If a range of values is provided, the range includes the endpoint values. For example, the range 20 to 28, or 20 - 28 will include the values 20, 21, 22, 23, 24, 25, 26, 27 and 28; the range 5 to 15, or 5 - 15 will include the values 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.

[0044] The term "patient" as used herein preferably refers to a mammal. Typically, the mammal is a human, but may also refer to a domesticated mammal. The term does not include laboratory mammals.

[0045] As used herein, the term "in combination with psychotherapy" refers to the treatment of psychiatric disorders by psychological means, which is enhanced by a dosing regimen, treatment method, delivery device, or parenteral formulation for use in the present invention.

[0046] The term "treatment" defines the therapeutic treatment of a patient to reduce or halt the rate of progression of a disorder, or to improve or cure the disorder. It also includes prophylactic treatment of patients diagnosed with a psychiatric or neurological disorder. Such prophylactic treatment, also known as secondary prevention, is intended to reduce the impact of the disorder and / or impede the development of the disorder by treatment according to the present invention.

[0047] As used herein, "neurological disorder" refers to a disorder that can be associated with a dysfunction of the brain or nervous system and can cause physical and / or psychological symptoms. The term "psychiatric disorder" as used herein is characterized by a clinically significant disturbance in an individual's cognition, emotional regulation, or behavior, and is associated with current distress (e.g., distressing symptoms) or disability (i.e., impairment in one or more important areas of functioning), or with a significantly increased risk of death, distress, disability, or severe loss of freedom.

[0048] The diagnostic criteria for psychiatric or neurological disorders mentioned herein are provided in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5).

[0049] As used herein, the term "psychedelic-assisted psychotherapy" is defined as any psychotherapeutic practice provided in combination with a therapeutic dose of a psychedelic preparation, including, for example, any dose as defined in the present invention. The term "psychedelic-assisted psychotherapy" includes supportive therapy that provides preparation, psychological support, and therapeutic integration to the patient before, during, and after the administration of the psychedelic.

[0050] As used herein, the term "obsessive-compulsive disorder" (OCD) is defined as the presence of obsessions or compulsions, although typically both are present. The symptoms can cause significant functional impairment and / or distress. Obsessions are defined as unwanted, intrusive thoughts, images, or impulses that repeatedly enter a person's mind. Compulsions are repetitive behaviors or mental acts that a person feels driven to perform. Typically, OCD presents as one or more obsessions that drive the adoption of compulsions. For example, an obsession with germs can drive the compulsion to clean, or an obsession with food can drive the compulsions of binge eating, eating too little, or vomiting after eating (i.e., an obsession with food can manifest as an eating disorder). Compulsions can be overt and observable to others, such as checking whether a door is locked, or covert mental acts that cannot be observed, such as repeating a phrase in one's mind.

[0051] As used herein, the term "eating disorder" is defined as severe and persistent eating behavior disturbances, as well as associated distressing thoughts and emotions. The term "eating disorder" includes anorexia nervosa and bulimia nervosa, binge eating disorder, avoidant restrictive food intake disorder, other specified feeding and eating disorders, pica, and rumination disorder.

[0052] Eating disorders often co-occur with anxiety disorders and obsessive-compulsive disorder. Neziroglu and Sandler distinguished OCD from eating disorders: "Patients with eating disorders are mainly driven by concerns about appearance and thus change their eating patterns to lose weight accordingly. OCD patients may restrict their eating for reasons quite distinct from concerns about body image" (https: / / iocdf.org / expert-opinions / expert-opinion-eating-disorders-and-ocd / ).

[0053] The term "eating disorder" includes anorexia nervosa, bulimia nervosa, and binge eating disorder (BED). Symptoms of anorexia nervosa include eating too little and / or exercising too much to maintain the lowest possible weight. Symptoms of bulimia nervosa include eating large amounts of food in a very short period of time (i.e., binge eating), then deliberately vomiting, using laxatives, eating too little and / or exercising too much to prevent weight gain. Symptoms of BED include frequently eating large portions of food until uncomfortably full and thus feeling upset or guilty.

[0054] As used herein, the term "depressive disorder" includes major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in end-stage patients.

[0055] As used herein, the term "major depressive disorder" (MDD, also known as major depression or clinical depression) is defined as the presence of five or more of the following symptoms most of the day, nearly every day, for a period of two weeks or longer (also referred to herein as a "major depressive episode"):

[0056] ● Depressed mood, such as feeling sad, empty, or tearful (in children and adolescents, depressed mood may present as persistent irritability);

[0057] ● Markedly diminished interest or pleasure in all, or almost all, activities;

[0058] ● Significant weight loss when not dieting, weight gain, or decrease or increase in appetite (in children, failure to gain weight as expected);

[0059] ● Insomnia or increased desire to sleep;

[0060] ● Restlessness or psychomotor retardation that can be observed by others;

[0061] ● Fatigue or loss of energy;

[0062] ● Feelings of worthlessness, or excessive or inappropriate guilt;

[0063] ● Difficulty making decisions, or difficulty thinking or concentrating;

[0064] ● Recurrent thoughts of death or suicide, or suicide attempts.

[0065] At least one of the symptoms must be either a depressed mood or a loss of interest or pleasure.

[0066] Persistent depressive disorder, also known as dysthymia, is defined as the patient presenting with the following two characteristics:

[0067] A. Depressed mood for most of the day, nearly every day, for at least two years. In children and adolescents, it can be an irritable mood, and the time frame is at least one year.

[0068] B. When depressed, the person experiences at least two of the following symptoms:

[0069] ● Overeating or loss of appetite;

[0070] ● Excessive sleep or difficulty falling asleep;

[0071] ● Fatigue, lack of energy;

[0072] ● Low self-esteem;

[0073] ● Difficulty concentrating or making decisions.

[0074] The term "treatment-resistant major depressive disorder" as used herein describes MDD that fails to achieve an adequate response to standard care therapies.

[0075] "Bipolar disorder" as used herein, also known as manic-depressive illness, is a disorder that causes abnormal changes in mood, energy, activity levels, and the ability to perform daily tasks.

[0076] There are two well-defined subclasses of bipolar disorder; both involve distinct changes in mood, energy, and activity levels. These moods range from periods of extreme "highs," elation, and energetic behavior (referred to as manic episodes, defined further below) to periods of profound sadness, "lows," or hopelessness (referred to as depressive episodes). Less severe manic periods are called hypomanic episodes.

[0077] Bipolar I disorder - is defined as a manic episode that lasts at least 7 days, or manic symptoms that are severe enough for the person to require immediate hospital care. Usually, depressive episodes also occur, typically lasting at least 2 weeks. Depressive episodes with mixed features (having both depressive and manic symptoms) are also possible.

[0078] Bipolar II disorder - defined as a pattern of depressive and hypomanic episodes, but not the full manic episodes described above.

[0079] As used herein, "bipolar depression" is defined as an individual who experiences depressive symptoms accompanied by past or concurrent manic symptom episodes, but does not meet the clinical criteria for bipolar disorder.

[0080] The term "anxiety disorder" as used herein includes generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

[0081] As used herein, "generalized anxiety disorder" (GAD) refers to a chronic disorder characterized by long-term anxiety that does not focus on any one object or situation. Those with GAD experience non-specific, persistent fear and worry and become overly concerned with daily matters. GAD is characterized by long-term excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbance.

[0082] "Phobia" is defined as a persistent fear of an object or situation that the affected person will go to great lengths to avoid, typically out of proportion to the actual danger posed. If the feared object or situation cannot be completely avoided, the affected person will experience significant distress and severe interference in social or occupational activities.

[0083] A patient with "panic disorder" is defined as an individual who experiences one or more brief episodes of intense panic and fear (also known as panic attacks), typically marked by shaking, trembling, confusion, dizziness, nausea, and / or difficulty breathing. A panic attack is defined as a sudden onset of fear or discomfort that peaks in less than 10 minutes.

[0084] "Social anxiety disorder" is defined as a strong fear of and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety typically presents as specific physical symptoms, including blushing, sweating, and difficulty speaking.

[0085] "Post-traumatic stress disorder" (PTSD) is an anxiety disorder caused by a traumatic experience. Post-traumatic stress can be caused by extreme situations such as combat, natural disasters, rape, hostage-taking, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidance behavior, anxiety, anger, and depression.

[0086] The term "postpartum depression" (PPD, also known as perinatal depression) as used herein is a form of depression experienced by either parent of a newborn. Typically, symptoms appear within 4 weeks of the baby's birth and usually include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleep or eating patterns.

[0087] As used herein, the term "substance abuse" means a patterned use of a drug in which the user consumes the substance in amounts or by methods that are harmful to themselves or others.

[0088] As used herein, the term "gambling disorder" means persistent and recurrent problematic gambling behavior leading to clinically significant impairment or distress. This disorder has similarities to substance abuse.

[0089] As used herein, the term "avolition disorder" refers to a disorder that includes as a symptom a decrease in motivation to initiate and engage in self-directed, purposeful activities.

[0090] As used herein, the term "hallucinogenic experience" refers to a period during which a patient experiences one or more intense reactions or changes in emotional, perceptual states, visual or other sensory hallucinations, spiritual experiences, ego dissolution, and dissociation. Ego dissolution describes a state in which the boundaries between the individual and the external world dissolve. Dissociation describes a state in which the individual experiences a sense that different parts of the brain are not connected (such as mind-body separation).

[0091] The Mystical Experience Questionnaire (MEQ) was designed to address experiences specifically caused by hallucinogens and to allow researchers to understand the apparently incomprehensible subjective experiences associated with hallucinogens. The MEQ consists of 30 questions; participants are asked to answer each question based on their feelings, thoughts, and experiences at the moment of the session, and each item is scored on a scale of 0 - 5 (0 - none / not at all to 5 - extremely intense, more than at any other time in life). The minimum score is 0 and the maximum score is 150, with higher scores indicating a higher degree of mystical experience. The total MEQ score is calculated by taking the average response of all items. In some embodiments, a "hallucinogenic experience" is an experience that has a percentage score of at least 40% on the Mystical Experience Questionnaire (MEQ), such as more than 40%, more than 45%, more than 50%, more than 55%, or more than 60% of the MEQ score.

[0092] A "breakthrough hallucinogenic experience" means an intense and immersive hallucinogenic experience in which almost all connection to the real world is lost. In some embodiments, a breakthrough hallucinogenic experience is an experience that has a percentage score of more than 45%, more than 50%, more than 55%, or more than 60% on the MEQ. Detailed Description

[0093] The dosing regimens, treatment methods, delivery devices, or parenteral formulations for use in the present invention provide a slower onset regimen (compared to bolus administration, such as an IV bolus), which can improve the therapeutic benefit to the patient by slowing the onset of the peak experience and can improve tolerance. Additionally, the hallucinogenic experience will be slightly prolonged, which can improve the therapeutic potential. The dosing regimens, treatment methods, delivery devices, or parenteral formulations for use in the present invention provide an additional safety measure by giving the physician the opportunity to stop the infusion at the patient's request or if clinical observation requires it.

[0094] Accordingly, as Embodiment 1, a first aspect of the present invention provides a dosing regimen for administering a hallucinogenic agent to a patient for treating a psychiatric or neurological disorder, comprising parenterally administering a dose of a hallucinogenic agent over a dosing period of about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow onset breakthrough hallucinogenic experience in the patient.

[0095] As Embodiment 2, a second aspect of the present invention provides a method for treating a psychiatric or neurological disorder in a patient, comprising parenterally administering a dose of a hallucinogenic agent to the patient over a dosing period of about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow onset breakthrough hallucinogenic experience in the patient.

[0096] As Embodiment 3, a third aspect of the present invention provides a delivery device for treating a psychiatric or neurological disorder in a patient, wherein the delivery device is configured to deliver a parenteral dose of a hallucinogenic agent over a dosing period of about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow onset breakthrough hallucinogenic experience in the patient.

[0097] As embodiment 4, a fourth aspect of the present invention provides a parenteral formulation for treating a psychiatric or neurological disorder in a patient, comprising parenterally administering a dose of a hallucinogenic agent for a dosing period of about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

[0098] As embodiment 5, a fifth aspect of the present invention provides a parenteral formulation comprising a hallucinogenic agent for treating a psychiatric or neurological disorder in a patient, comprising parenterally administering a dose of a hallucinogenic agent for a dosing period of about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, deuterated analogs thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

[0099] As embodiment 6, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for the use according to any one of the preceding embodiments, wherein the parenteral administration is selected from the group consisting of intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, and transdermal administration and inhalation.

[0100] As embodiment 7, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for the use according to any one of the preceding embodiments, wherein the administration is by intravenous infusion, preferably, wherein the intravenous administration is performed using an infusion pump.

[0101] As embodiment 8, according to any one of the preceding embodiments, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for the use, wherein the parenteral administration is by two-stage intravenous infusion.

[0102] As embodiment 9, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for the use according to any one of embodiments 1 to 7, wherein the parenteral administration is by single-stage intravenous infusion.

[0103] As embodiment 10, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for the use according to any one of the preceding embodiments, wherein the dosing period is about 8 to about 12 minutes.

[0104] As embodiment 11, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for said use according to any one of the foregoing embodiments, wherein the dosing period is about 9 to about 11 minutes, or about 10 minutes.

[0105] As embodiment 12, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for said use according to any one of the foregoing embodiments, comprising parenterally administering a total dose of a hallucinogenic agent selected from the group consisting of:

[0106] - about 20 to about 70 mg of N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof;

[0107] - about 15 to about 30 mg of N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof;

[0108] - about 5 to about 15 mg of N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof;

[0109] - about 10 to about 30 mg of 5-methoxy-N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof;

[0110] - about 1 to about 5 mg of psilocybin, its deuterated analog, or a pharmaceutically acceptable salt thereof;

[0111] - about 3 to about 15 mg of 4-acetoxy-N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof; and

[0112] - about 1 to about 5 mg, or about 3 to about 25 mg of dimethyl-4-hydroxytryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof.

[0113] As embodiment 13, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for said use according to any one of the foregoing embodiments, comprising parenterally administering a total dose of about 20 to about 29 mg of N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof.

[0114] As embodiment 14, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral formulation for said use according to any one of the foregoing embodiments, comprising parenterally administering a total dose of about 20 to about 23 mg, or a total dose of about 26 to about 29 mg of N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof.

[0115] As embodiment 15, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to embodiment 8, wherein the administration is by two-stage intravenous infusion, the hallucinogenic agent is N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 20 to about 23 mg.

[0116] As embodiment 16, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to embodiment 9, wherein the administration is by single-stage intravenous infusion, the hallucinogenic agent is N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 26 to about 29 mg.

[0117] As embodiment 17, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to embodiment 9, wherein the administration is by single-stage intravenous infusion, the hallucinogenic agent is N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 7 to about 10 mg, or about 10 to about 20 mg.

[0118] As embodiment 18, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to embodiment 9, wherein the administration is by intramuscular administration, the hallucinogenic agent is N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, and the total dose is about 20 to about 70 mg.

[0119] As embodiment 19, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to any one of embodiments 1 to 12, comprising parenteral administration of psilocybin, its deuterated analog, or a pharmaceutically acceptable salt thereof in a total dose of about 1.5 to about 3 mg; or dimethyl-4-hydroxytryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof in a total dose of about 1.5 to about 3 mg.

[0120] As embodiment 20, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to any one of the foregoing embodiments, wherein the hallucinogenic agent is a compound of formula I, or a pharmaceutically acceptable salt thereof:

[0121]

[0122] Ra is selected from H, D, -OH, -OAc, and -PO3OH, and Rb is H or D; or

[0123] Ra is H or D, and Rb is selected from H, D, and -OMe;

[0124] R 2 and R 3 are each independently selected from C(H z )3; and

[0125] each H x , H y and H z is independently selected from protium and deuterium.

[0126] As embodiment 21, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for said use according to embodiment 20, wherein R 2 and R 3 are each independently selected from C(H)3 and C(D)3.

[0127] As embodiment 22, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for said use according to embodiment 20, wherein R 2 and R 3 are both C(H)3, or R 2 and R 3 are both C(D)3.

[0128] As embodiment 23, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for said use according to any one of embodiments 20 to 21, wherein each H x is H, or each H x is D, one H x is H and one H x is D.

[0129] As embodiment 24, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for said use according to any one of embodiments 20 to 23, wherein each H y is H, or each H y is D, or one H y is H and one H y is D.

[0130] As embodiment 25, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for said use according to any one of embodiments 20 to 24, wherein each H x , H y and H z is deuterium.

[0131] As embodiment 26, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for said use according to any one of the foregoing embodiments, wherein the hallucinogen is selected from the group consisting of:

[0132]

[0133] or a pharmaceutically acceptable salt thereof; wherein Ra and Rb are as defined in embodiment 20.

[0134] As embodiment 27, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for the said use according to any one of embodiments 20 to 26, wherein Ra is H.

[0135] As embodiment 28, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for the said use according to any one of embodiments 20 to 27, wherein Rb is H.

[0136] As embodiment 29, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for the said use according to any one of the foregoing embodiments, wherein the parenteral administration comprises intravenous infusion through one or two infusion pumps.

[0137] As embodiment 30, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for the said use according to any one of the foregoing embodiments, wherein the psychiatric or neurological disorder is selected from the group consisting of: (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, and (v) abulia disorder. Generally, the disorder is selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, obsessive-compulsive disorder and eating disorders, such as compulsive eating disorder. Preferably, the psychiatric or neurological disorder is selected from the group consisting of depressive disorder and anxiety disorder.

[0138] As embodiment 31, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for the said use according to any one of the foregoing embodiments, wherein the psychiatric or neurological disorder is a depressive disorder.

[0139] As embodiment 32, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for the said use according to any one of the foregoing embodiments, wherein the psychiatric or neurological disorder is major depressive disorder.

[0140] As embodiment 33, the present invention provides a dosing regimen, treatment method, delivery device or parenteral preparation for the said use according to any one of the foregoing embodiments, wherein the duration of the hallucinogenic experience is less than 3 hours, or less than 2 hours, or less than 1 hour.

[0141] As embodiment 34, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to any of the foregoing embodiments, wherein the duration of the hallucinogenic experience is:

[0142] - When the hallucinogenic agent is N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, from about 15 to about 30 minutes, or from about 30 to about 90 minutes; or

[0143] - When the hallucinogenic agent is selected from psilocybin, 4-acetoxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, dimethyl-4-hydroxytryptamine, their deuterated analogs, or a pharmaceutically acceptable salt thereof, from about 15 minutes to about 45 minutes, or from about 45 minutes to about 180 minutes; or

[0144] - From about 20 to about 30 minutes, wherein the hallucinogenic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; or

[0145] - From about 60 to about 90 minutes, wherein the hallucinogenic agent is a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

[0146] As embodiment 35, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to embodiment 33 or 34, wherein the duration of the experience is evaluated by the attending clinician, psychiatrist, or therapist.

[0147] As embodiment 36, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to any of the foregoing embodiments, further comprising:

[0148] a. A preparation phase, including preparing the patient for the hallucinogenic experience;

[0149] b. An administration phase, including the dosing regimen or treatment method according to any of the foregoing embodiments; and

[0150] c. An integration phase, including an interview or discussion led by a psychiatrist or therapist with the patient focusing on the hallucinogenic experience.

[0151] As embodiment 37, the present invention provides a dosing regimen, treatment method, delivery device, or parenteral preparation for said use according to any of the foregoing embodiments, wherein the treatment of the patient's psychiatric or neurological disorder includes hallucinogen-assisted psychotherapy.

[0152] The hallucinogens for the uses, dosing regimens, treatment methods, delivery devices, or parenteral formulations of the present invention can be prepared according to the synthetic methods described in WO2021 / 089873, US20210395201, WO2022 / 117359, US11242318, US11724985, and US20220202775, the disclosures of which are incorporated herein by reference in their entirety.

[0153] The doses of the hallucinogens for the first, second, third, and fourth aspects of the present invention can preferably be in the form of pharmaceutically acceptable salts, wherein the salts comprise an acid and the free base of a hallucinogen selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, and their deuterated analogs. An example of a salt comprising an acid and a dimethyltryptamine compound is N,N-dimethyltryptamine fumarate, which is the fumarate salt of N,N-dimethyltryptamine. P.H. Stahl and C.G. Wermuth provide an overview of pharmaceutical salts and the acids they contain in Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. The acids described in this review are suitable acids for inclusion in the formulation salts.

[0154] For great clarity, when using the phrase "the hallucinogen is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, its deuterated analogs, and its pharmaceutically acceptable salts", this is meant to include: 1) any one of the listed compounds, 2) the pharmaceutically acceptable salts of any one of the listed compounds, 3) the deuterated analogs of any one of the listed compounds, and 4) the pharmaceutically acceptable salts of any one of the deuterated analogs of any one of the listed compounds. For example, as a non-limiting instance, the "hallucinogen" will include N,N-dimethyltryptamine, the pharmaceutically acceptable salts of N,N-dimethyltryptamine, the deuterated analogs of N,N-dimethyltryptamine, or the pharmaceutically acceptable salts of the deuterated analogs of N,N-dimethyltryptamine. The same applies to the other listed compounds.

[0155] Preferred hallucinogens for any one of the embodiments of the present invention are selected from:

[0156] N,N-dimethyltryptamine;

[0157] α-protio, α-deuterated-N,N-dimethyltryptamine;

[0158] α,α-Dideuterio-N,N-dimethyltryptamine;

[0159] α,α,β,β-Tetradeuterio-N,N-dimethyltryptamine;

[0160] N,N-Bis(trideuteriomethyl)tryptamine;

[0161] α-H,α-deuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0162] α,α-Dideuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0163] α,α,β,β-Tetradeuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0164] 5-Methoxy-N,N-dimethyltryptamine;

[0165] 5-Methoxy-α-H,α-deuterio-N,N-dimethyltryptamine;

[0166] 5-Methoxy-α,α-dideuterio-N,N-dimethyltryptamine;

[0167] 5-Methoxy-α,α,β,β-tetradeuterio-N,N-dimethyltryptamine;

[0168] 5-Methoxy-N,N-bis(trideuteriomethyl)tryptamine;

[0169] 5-Methoxy-α-H,α-deuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0170] 5-Methoxy-α,α-dideuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0171] 5-Methoxy-α,α,β,β-tetradeuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0172] Psilocybin;

[0173] α-H,α-deuterio-psilocybin;

[0174] α,α-Dideuterio-psilocybin;

[0175] α,α,β,β-Tetradeuterio-psilocybin;

[0176] 4-(Dihydrogen phosphate)-N,N-bis(trideuteriomethyl)tryptamine;

[0177] 4-(Dihydrogen phosphate)-α-H,α-deuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0178] 4-(Dihydrogen phosphate)-α,α-dideuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0179] 4-(Dihydrogen phosphate)-α,α,β,β-tetradeuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0180] Dimethyl-4-hydroxytryptamine;

[0181] α-H,α-D-dimethyl-4-hydroxytryptamine;

[0182] α,α-Dideuterio-dimethyl-4-hydroxytryptamine;

[0183] α,α,β,β-Tetradeuterio-dimethyl-4-hydroxytryptamine;

[0184] 4-Hydroxy-N,N-bis(trideuteriomethyl)tryptamine;

[0185] 4-Hydroxy-α-H,α-D-N,N-bis(trideuteriomethyl)tryptamine;

[0186] 4-Hydroxy-α,α-dideuterio-N,N-bis(trideuteriomethyl)tryptamine;

[0187] 4-Hydroxy-α,α,β,β-tetradeuterio-N,N-bis(trideuteriomethyl)tryptamine; and

[0188] Pharmaceutically acceptable salts thereof.

[0189] The salts may include acids selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, gluconic acid, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid, glucoheptonic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid.

[0190] Preferably, the pharmaceutically acceptable salts are selected from fumarate, tartrate, citrate, and hydrochloride.

[0191] More preferably, the pharmaceutically acceptable salt of the hallucinogen is fumarate.

[0192] Parenteral routes of administration include intravenous, intramuscular, subcutaneous, intranasal, transmucosal, sublingual, rectal, and transdermal administration and inhalation. Any parenteral route that can administer within about 5 to about 15 minutes is suitable for the present invention. According to any aspect of the present invention, the preferred parenteral route of administration is selected from intravenous infusion, intramuscular infusion, subcutaneous infusion, intranasal, transmucosal, and transdermal administration and inhalation. Intravenous infusion is a particularly preferred route of administration. Intramuscular administration is a particularly preferred route of administration. Those skilled in the art will appreciate that the delivery device for the present invention is selected according to the route of administration of the dosage hallucinogen.

[0193] When the parenteral route of administration is intravenous, the delivery device may include an infusion bag or syringe, and may preferably further include an infusion pump. If two infusion pumps are used for intravenous infusion, the infusion pumps may be connected to a single cannula through a three-way tap. When the parenteral route of administration is intramuscular, the delivery device may include a syringe. When the parenteral route is intranasal, the delivery device may include a pump-action spray means. When the parenteral route is transmucosal, the delivery device may include an oral mucosal patch. When the parenteral route is transdermal, the delivery device may include a transdermal patch. When the route of administration is inhalation, the delivery device may include a metered-dose inhaler, or an evaporator or nebulizer.

[0194] Dosage forms suitable for parenteral administration have a pH of about 3 to 9, and for liquid preparations, an osmolarity of about 250 to about 600 mOsm / Kg. I. Usach et al. reported in Adv. Ther., 36, 2986 - 2996 (2019) that pH values greater than 9 are associated with tissue necrosis (cell death within tissue), while values reported to be below 3 cause pain and phlebitis (inflammation of the vein). Osmolarity values greater than 600 mOsm / Kg have also been reported to cause pain. Usach et al. also suggested that parenteral preparations should be formulated as isotonic solutions (an osmolarity of about 300 mOsm / Kg), with an upper limit of 600 mOsm / Kg recommended to minimize pain.

[0195] Osmolarity is formally defined as the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water, as shown in the formula:

[0196]

[0197] Where p is the partial vapor pressure of water in the solution and p* is the partial vapor pressure of pure water. In short, osmolarity is the number of osmotically active particles (number of solute particles) in 1 kg of solution. Thus, osmolarity is only a function of the number of particles and is independent of particle molecular weight, size, shape, or charge (see the review by D.K. Faria et al., M.E. Mendes and N.M. Sumita, J. Bras. Patol. Med. Lab., 53, 1, 38 - 45 (2017) regarding the measurement of serum osmolarity). For example, 1 mole of a non-dissociating substance (e.g., DMT as the free base) dissolved in 1 kg of water has an osmolarity of 1 Osm / kg (1000 mOsm / kg), while 1 mole of a substance that dissociates into two different species in solution (e.g., DMT fumarate) dissolved in 1 kg of water has an osmolarity of 2 Osm / kg (2000 mOsm / kg).

[0198] If a first solution is defined herein as being isotonic with a second solution, the solutions have the same osmolarity. For example, if a formulation is defined as being isotonic with human serum, the formulation has the same osmolarity as human serum. Typically, human serum has an osmolarity of about 275 to about 300 mOsm / Kg (L. Hooper et al., BMJ Open, 2015; 5(10):e008846).

[0199] WO2022 / 043227 and US11406619 describe suitable formulations for injection according to the present invention. WO2022 / 117640 describes suitable formulations for administration by inhalation according to the present invention. US20210346347 and 17 / 866,477 describe suitable formulations for transdermal administration. Other suitable formulations according to the present invention are described in the co-pending patent application US17 / 574,424. The disclosure of each of these patent applications is incorporated herein by reference in its entirety.

[0200] In some embodiments, the parenteral formulation for the present invention comprises a salt of a hallucinogenic agent, a base agent, water, and optionally a buffer (the buffer is separate from the salt), wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg / ml or more as the free base, an osmolarity of about 250 to about 350 mOsm / Kg; and wherein the formulation comprises a dose of an optionally substituted dimethyltryptamine compound in a volume of 5 ml or less.

[0201] The base agent adjusts the pH of the formulation to the desired pH range, for example, from pH 5 to pH 6. Typically, the pH of a formulation comprising an optionally substituted dimethyltryptamine salt, water, and a buffer is lower, for example, below pH 5, and thus it may be necessary to adjust the pH with a base agent. A person skilled in the art can evaluate a suitable base agent to adjust the pH of the solution without the risk of degradation of the optionally substituted dimethyltryptamine salt. The base agent can be sodium hydroxide or potassium hydroxide.

[0202] The parenteral formulation optionally contains a buffer, which is separate from the salt, i.e., the buffer is not merely the counterion of the hallucinogenic agent. For example, if the salt is N,N-dimethyltryptamine fumarate (i.e., the fumarate salt of N,N-dimethyltryptamine), in addition to the buffering effect provided by the fumarate, a certain amount of buffer may be required. The term "buffer" is well known in the art and refers to a chemical that, when included in a formulation, resists changes in pH when an acid or base is added to the formulation. In a formulation, the buffer contains a weak acid and its conjugate base. Suitable buffers contain an acid with a pKa value falling within ±1 of the desired pH of the formulation. For example, if the desired pH of the formulation is about 5.0, suitable buffers contain a weak acid with a pKa value from about 4.0 to about 6.0. If the acid of the buffer has more than one pKa value (i.e., each molecule of the acid can donate more than one proton), for the buffer to be suitable, at least one pKa value falls within the desired pH range.

[0203] The weak acid and conjugate base of the buffer are in balance with each other. According to Le Chatelier's principle (if a constraint is imposed on a system in equilibrium, such as changing the concentration of a reactant, the equilibrium will shift so as to counteract the effect of the constraint), adding an acid or base to the formulation causes the equilibrium position to shift in favor of the conjugate base or weak acid, respectively. Thus, the concentration of free protons (and hence the pH) in the formulation remains relatively constant.

[0204] Suitable buffer systems include acetate and acetic acid (pKa = 4.75); citrate and citric acid (pKa = 3.13, 4.76, and 6.40); phosphate and phosphoric acid (pKa = 2.14, 7.20, and 12.37); or mixtures thereof. The pKa values cited herein are the pKa values reported in water at 25 °C. Typically, the buffer contains only one of the pairs listed above, i.e., an acid and its conjugate base.

[0205] In some embodiments, the buffer contains acetate and acetic acid; citrate and citric acid; or phosphate and phosphoric acid. Sometimes, the buffer contains acetate and acetic acid; or citrate and citric acid. In some embodiments, the buffer contains acetate and acetic acid, typically sodium acetate and acetic acid, or potassium acetate and acetic acid.

[0206] The concentration of the buffer in the formulation is typically sufficient to resist significant pH changes in the formulation within two weeks of storage of the formulation (i.e., the pH typically fluctuates by less than about 0.1 pH units), and one skilled in the art can evaluate and achieve an appropriate buffer concentration. Generally, the concentration of the buffer is from about 15 mM to about 75 mM, such as from about 20 mM to about 30 mM. In some embodiments, the concentration of the buffer is about 25 mM.

[0207] Sometimes, the concentrations of the hallucinogen and optional buffer in the formulation result in a desired osmolarity. Alternatively, the desired osmolarity can be achieved by including one or more tonicity agents in the formulation. Thus, in some embodiments, the formulation further includes a tonicity agent. As used herein, a tonicity agent is defined as a chemical that, when included in the formulation, increases the osmolarity of the formulation. As described above, osmolarity is the number of osmotically active particles (number of solute particles) in 1 kg of solution. Thus, when a chemical is added to the formulation to act as a solute, that chemical is within the definition of a tonicity agent.

[0208] In some embodiments, the formulation includes a tonicity agent. The concentration of the tonicity agent depends on the other components in the formulation, such as the concentrations of the hallucinogen and buffer. For example, if a formulation without a tonicity agent has an osmolarity of about 60 mOsm / kg, the tonicity agent will provide at least about 190 mOsm / kg (e.g., 95 mM sodium chloride). M.F. Powell, T. Nguyen, and L. Baloian provided a review of excipients suitable for parenteral administration (administration other than through the oral or digestive tract) in PDA J. Pharm. Sci. Technol., 52, 238 - 311 (1998). All soluble excipients listed in this review article that can be administered by the intravenous route, when added to the formulation, contribute to the osmolarity and can thus be considered tonicity agents.

[0209] When used in accordance with the present invention, suitable excipients for the hallucinogen dosage can be selected from the group consisting of ethanol, citric acid, trisodium citrate, benzalkonium chloride, microcrystalline cellulose, sodium carboxymethylcellulose, chlorobutanol, disodium edetate, glycerin, hydrochloric acid, methylparaben, polyethylene glycol, propylene glycol, propylparaben, sodium saccharin, sodium bicarbonate, sodium bisulfate, sodium bisulfite, sodium chloride, sodium hydroxide, sodium metabisulfite, sodium phosphate, sodium citrate, sulfuric acid, trisodium citrate, tromethamine, and mixtures thereof.

[0210] Some excipients can act as co-solvents. Suitable solvents or co-solvents for the formulations of the present invention can be selected from ethanol, polyethylene glycol, propylene glycol, and mixtures thereof. In some embodiments, the formulation comprises a co-solvent. In some embodiments, the formulation does not comprise a co-solvent. In particular, when the salt of the optionally substituted dimethyltryptamine compound is fumarate, such as N,N-dimethyltryptamine fumarate or α,α-dideuterio-N,N-dimethyltryptamine fumarate, the formulation does not comprise a co-solvent.

[0211] The dosing regimens, methods of treatment, delivery devices, or parenteral formulations for the uses of the present invention can provide many advantages, such as a slower onset regimen (compared to bolus administration), which can improve tolerability and can improve the therapeutic benefit to the patient by slowing the onset of the peak experience.

[0212] After cessation of the subjective hallucinogenic experience, tolerability can be assessed by asking the patient the question "Do you wish you had not had that experience?" A response of "yes" is considered to indicate poor tolerability, while a response of "no" is considered to indicate good tolerability.

[0213] In the study by D'Souza et al. (D.C. D'Souza, S.A. Syed, L.T. Flynn, H. Safi-Aghdam, N.V. Cozzi, and M. Ranganathan, Neuropsychopharmacology (2022) 47:1854-1862), after a 0.3 mg / kg dose of DMT, all three healthy volunteer participants reported tolerability scores greater than 70 (on a 0-100 scale), indicating a good level of tolerability. In contrast, among 6 patients with MDD who received a 0.3 mg / kg dose, 3 reported tolerability scores less than 50, indicating poor tolerability (see Figure S1).

[0214] These results suggest that the tolerance of the patient group is lower than that of the healthy volunteer group, which may be due to the fact that the patient group consists of patients with psychiatric or neurological disorders. Garcia-Romeu and Richards (International review of Psychiatry, Vol. 30, 2018, No. 4, pp. 291-316) discussed the use of serotonergic hallucinogens in clinical interventions and stated that "depending on the treatment goal, issues such as recent suicidal tendencies, substance or alcohol use disorders, dissociative disorders, and a history of trauma should be taken into account, as these issues can be exacerbated by high-dose hallucinogen administration or increase the risk of adverse events." They further stated that: Psychodynamic-autobiographical experiences are dominated by emotional recollection and reflection on significant life events and relationships in the past or present. This can take many forms, but often involves the recurrence of past mistakes for which the patient may harbor persistent guilt or sadness, grief over a deceased loved one or a lost relationship, anger or forgiveness for unresolved trauma, and insights into the way a person has lived and interacted throughout their life. These types of experiences can occur at lower doses in a supportive environment,... Psychodynamic-autobiographical experiences can also occur during hallucinogen treatment at moderate or high doses." Since patients with psychiatric disorders (such as depressive disorders) are more likely to have the psychodynamic-autobiographical experiences discussed by Garcia-Romeu and Richards than healthy volunteers, therapists and psychiatrists experienced in the field of hallucinogen-assisted psychotherapy expect patients to be more likely to experience more challenging hallucinogenic experiences than healthy volunteers and less likely to report that the experience is tolerable. The subjective experience of the patient can be evaluated using the Challenging Experience Questionnaire (CEQ), which is designed to measure challenging psychological experiences associated with hallucinogenic experiences.

[0215] The onset and cessation of the hallucinogenic experience can be evaluated by the attending clinician, psychiatrist, or therapist. As used herein, the "duration of the hallucinogenic experience" refers to the time from the start of continuous parenteral administration until the cessation of the hallucinogenic experience. The duration of the hallucinogenic experience can vary from patient to patient. The term "duration" as used herein encompasses the average duration of the hallucinogenic experience.

[0216] Rating scales can be used to evaluate therapeutic benefit or efficacy. For patients with depressive disorders such as MDD or TRD, the Montgomery-Åsberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD-17), or the Beck Depression Inventory (BDI-II) can be used. The rating scale is used before the administration of the hallucinogen to provide a baseline assessment and again after the administration of the hallucinogen.

[0217] In some embodiments, the hallucinogen can be administered by intramuscular injection.

[0218] In some embodiments, the hallucinogen can be administered as a two-stage IV infusion via an intravenous cannula over about 6 to about 11 minutes. In some embodiments, the hallucinogen can be administered as a two-stage IV infusion via an intravenous cannula, where each stage comprises an infusion of about 5 minutes. In some embodiments, the hallucinogen can be administered as a single-stage IV infusion via an intravenous cannula over about 6 to about 11 min, preferably about 10 minutes. If a two-stage IV infusion is used, the infusion pump is appropriately connected to a single cannula via a three-way tap: once the infusion from the first pump is complete, the three-way tap is adjusted to the open position to allow continued infusion from the second pump.

[0219] The term "single-stage" IV infusion refers to the administration of an IV infusion via one infusion pump, administering the hallucinogen from a single infusion pump. The term "two-stage" IV infusion refers to the administration of an IV infusion via two infusion pumps, where the first stage comprises administering the hallucinogen from the first infusion pump and then the second stage comprises administering the hallucinogen from the second infusion pump. The two-stage IV infusion is substantially continuous, with a non-material interruption in the infusion to switch from the first infusion pump to the second infusion pump for administration.

[0220] Example 1

[0221] A double-blind, randomized, placebo-controlled study of intravenous administration of DMT fumarate in patients with major depressive disorder (MDD) (ClinicalTrials.gov identifier: NCT04673383, Part B) was conducted. The protocol included the following steps:

[0222] Study Day 1 -

[0223] - Evaluated by the independent assessor MADRS

[0224] Study Day 1

[0225] - Administer placebo or a dose of DMT fumarate via continuous intravenous infusion for a dosing period of about 10 minutes.

[0226] - Tolerance assessment after the hallucinogenic experience ceases.

[0227] Study Day 8 (±1 day), Study Day 15 (±1 day)

[0228] - MADRS assessment

[0229] Study Day 15

[0230] - Administer a dose of DMT fumarate via continuous intravenous infusion for a dosing period of about 10 minutes.

[0231] - Tolerance assessment after the hallucinogenic experience ceases.

[0232] On the 22nd (±1 day), 29th (±2 days), 45th (±2 days), and 105th (±2 days) of the study

[0233] -MADRS assessment

[0234] The investigational drug DMT fumarate (NCT04673383, Part B) was administered according to the present invention. Group A received a dose of the active drug (DMT fumarate) on Day 1 and was evaluated using MADRS on Days 8 and 15. Group P received a placebo on Day 1 and was also evaluated on Days 8 and 15. This constituted the blinded phase of the study. Group P then received a dose of the active drug during the open-label phase of the study on Day 15 and was evaluated on Days 22 and 29. Data from this group after administration of the active drug dose are denoted as PA.

[0235] All patient participants in this study, after receiving a dose of DMT fumarate, answered "no" to the question "Do you wish you had not had that experience?", indicating good tolerance to the hallucinogen. In Part A of the same study, healthy adults received a single escalating dose of DMT fumarate. All healthy volunteers answered "no" to the same question at the highest dose tested. The study shows that both healthy volunteers and patients tolerated DMT fumarate administered according to the dosing regimen equally well.

[0236] The participants' experiences were evaluated using the Challenging Experience Questionnaire (CEQ). In Part A of the study, the mean CEQ score of the active drug group was recorded as 0.172 compared to a mean of 0.052 in the placebo group. In Part B of the study, the mean CEQ score of the PA group was reported as 0.350 and the mean CEQ score of Group A was reported as 0.360 compared to a mean CEQ score of 0.120 in Group P (placebo).

[0237] These data show that the patient cohort in Part B found the experience significantly more challenging compared to the healthy participant cohort in Part A, with mean CEQ scores of 0.350 and 0.360 compared to 0.172. Surprisingly, despite patients reporting a more challenging experience, both healthy volunteers and patients tolerated the dosing regimen of the present invention equally well.

[0238] In addition, no drug-related serious adverse events were reported as of the date of filing this patent application.

[0239] In contrast, as discussed above, the data reported by D'Souza indicate that the patient group had poor tolerance to DMT administered as an intravenous push / bolus. Overall tolerance was evaluated on a scale of 0 to 100, where 0 = intolerant and 100 = well-tolerated. Three patients who received a dose of 0.3 mg / kg (which was stated to be selected to reliably induce a hallucinogenic experience) reported tolerance scores below 50, indicating poor tolerance to this dosing regimen (Figure S1). Additionally, after administration of the 0.3 mg / kg dose, the average score when answering the question "How likely are you to use this drug?" was described as 22.44 (on a scale of 0 to 100), again indicating low tolerance (Table S5). It should be noted that this sample included 3 healthy volunteers and 6 patients.

[0240] D'Souza et al. reported that the mean change in HAMD-17 scores between baseline (7 subjects) and 1 day after the last administration of both the 0.1 mg / kg and 0.3 mg / kg doses (6 subjects) was -4.5 (Table S6). This improvement was similar to the improvement of -3.9 on the MADRS scale.

[0241] Blinded data for all patients in part B of study NCT04673383 showed that the mean improvement in MADRS scores on day 8 was -7.5, and the mean percent reduction from baseline was -18.4%. A clinically significant change in MADRS scores from baseline was considered to range from a reduction of -6 to -9 points. Since these data are the average of both patients receiving placebo and patients receiving DMT fumarate, they indicate that this efficacy is achieved after administration of DMT fumarate according to the present invention.

[0242] Table 1 shows non-blinded data from time points 7 days and 14 days after dosing (study days 8, 15, 22, and 29). As described above, group A received a dose of the active drug (DMT fumarate) on day 1 and was evaluated on days 8 and 15. Group P received placebo on day 1 and was also evaluated on days 8 and 15. Group P then received a dose of the active drug on day 15 and was evaluated on days 22 and 29, and these data are represented as PA.

[0243] Table 1

[0244]

[0245]

[0246] BL = Baseline assessment

[0247] These data confirm that there was a significant mean improvement in symptoms in subjects who received a single dose of the active drug (Groups A and PA) compared to subjects who received only placebo (Group P); there was a statistically significant difference in the mean change from baseline between Group A and Group P of -10.8 points on Day 8 (p = 0.002); and a statistically significant difference of -7.4 points on Day 15 (p = 0.02).

[0248] Figure 1 and Figure 2 respectively show data confirming the percentage of subjects in Groups A and P with a ≥50% reduction from BL and the percentage of subjects in Groups A and P with a MADRS score ≤10.

[0249] Analysis of the patient-reported depression scores confirmed the MADRS assessment by independent clinical assessors. Improvement from baseline in the depression scores of patients who received at least one dose of the active drug was observed at all study time points, as measured by the Beck Depression Inventory (“BDI”). This included a statistically significant improvement in depressive symptoms two weeks after dosing compared to placebo (p = 0.002). The efficacy results of the BDI were consistent with the MADRS, providing additional support for the rapid and sustained treatment properties of DMT fumarate when administered according to the present invention for the treatment of MDD.

[0250] Measures assessing the anxiety and well-being of the patients were also analyzed throughout the study, aspects that are often negatively affected by depression. After administration of a single dose of DMT fumarate according to the present invention and supportive therapy, the patients demonstrated a rapid and sustained improvement in anxiety symptoms, as measured by the State-Trait Anxiety Inventory-Trait (“STAI-T”) scale. A statistically significant improvement in anxiety symptoms was observed two weeks after dosing compared to placebo (p = 0.03). At 12 weeks after open-label dosing (Group PA), the mean change from baseline (“CFB”) for the patient group was confirmed to be -14.2.

[0251] Furthermore, after administration of at least one dose of DMT fumarate according to the present invention and supportive therapy, a rapid and sustained improvement in well-being was observed, as measured by the Warwick-Edinburgh Mental Well-being Scale (“WEMWBS”). Results two weeks after the blinded dose of DMT fumarate or placebo showed a mean CFB of 10.1 for the active drug group compared to 0.9 for the placebo group.

[0252] Statistical analysis was performed on the MADRS open-label data (Group PA). A statistically significant difference in the mean total MADRS score was observed at all open-label study time points (p < 0.05). This analysis provides further support that a single dose of DMT fumarate administered according to the present invention is sufficient to induce a rapid and sustained antidepressant effect.

[0253]

[0254] Example 2

[0255] In an ongoing clinical trial, the safety and tolerability of a single intravenous dose of a deuterated analogue of DMT are being studied in healthy participants. The deuterated analogue of DMT is administered according to the present invention. After the hallucinogenic experience, tolerability is evaluated by the question "Do you wish you had not had that experience?".

[0256] A cohort of 6 healthy participants with a hallucinogenic experience is administered a 9 mg dose of the deuterated analogue according to the present invention. The preliminary data are compared with the pharmacokinetic data from Part A, Cohort 1 (9 mg DMT fumarate) of NCT04673383. Similar drug formulations are used in both trials.

[0257] When compared to the administration of 9 mg DMT, a 4.7-fold significant increase in half-life and a 1.5-fold significant increase in the Intensity Rating Visual Analogue Scale (IRVAS) score were observed after the administration of 9 mg of the deuterated analogue. IRVAS is a rating scale for measuring the intensity of the hallucinogenic experience. Additionally, the perceived duration of the hallucinogenic experience of the deuterated analogue was in the range of 37 - 57 minutes compared to approximately 25 minutes for DMT. When compared to DMT, although the duration and intensity of the hallucinogenic experience of the deuterated analogue were shown to be significantly higher, no difference in tolerance to the hallucinogenic experience was observed.

[0258] These data indicate that the patient group will be equally well-tolerated to the deuterated analogue of DMT.

Claims

1. A parenteral preparation containing a hallucinogenic agent for treating psychiatric or neurological disorders in a patient, comprising parenterally administering a dose of said hallucinogenic agent for a dosing period of about 5 to about 15 minutes, wherein said hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, its deuterated analogs, and pharmaceutically acceptable salts thereof, wherein said parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

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

3. The parenteral preparation for said use according to claim 1 or claim 2, wherein said administration is by intravenous infusion, preferably, wherein said intravenous administration is carried out using an infusion pump.

4. The parenteral preparation for said use according to any one of the preceding claims, wherein said dosing period is about 8 to about 12 minutes.

5. The parenteral preparation for said use according to any one of the preceding claims, wherein said dosing period is about 9 to about 11 minutes, or about 10 minutes.

6. The parenteral preparation for said use according to any one of the preceding claims, comprising parenterally administering a total dose of a hallucinogenic agent selected from the group consisting of: - about 20 to about 70 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof; - about 15 to about 30 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof; - about 5 to about 15 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof; - about 10 to about 30 mg of 5-methoxy-N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof; - about 1 to about 5 mg of psilocybin, its deuterated analogs, or pharmaceutically acceptable salts thereof; - about 3 to about 15 mg of 4-acetoxy-N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof; and - about 1 to about 5 mg, or about 3 to about 25 mg of dimethyl-4-hydroxytryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof.

7. The parenteral preparation for said use according to any one of the preceding claims, comprising parenterally administering a total dose of about 20 to about 29 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof.

8. The parenteral preparation for said use according to any one of the preceding claims, comprising parenterally administering a total dose of about 20 to about 23 mg, or about 26 to about 29 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof.

9. A parenteral preparation for said use according to any one of claims 1 to 6, comprising a total dose of about 7 to about 9 mg, or about 10 to about 20 mg of N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, administered parenterally.

10. A parenteral preparation for said use according to any one of claims 1 to 6, comprising a total dose of about 1.5 to about 3 mg of psilocybin, its deuterated analog, or a pharmaceutically acceptable salt thereof; or a total dose of about 1.5 to about 3 mg of dimethyl-4-hydroxytryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, administered parenterally.

11. A parenteral preparation for said use according to any one of the preceding claims, wherein the hallucinogenic agent is a compound of formula I, or a pharmaceutically acceptable salt thereof: Ra is selected from H, D, -OH, -OAc and -PO3OH, and Rb is H or D; or Ra is H or D, and Rb is selected from H, D and -OMe; R 2 and R 3 are each independently selected from C(H z )3; and Each H x 、H y and H z is independently selected from protium and deuterium.

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

13. The parenteral preparation for the use according to claim 11, wherein R 2 and R 3 are both C(H)3, or R 2 and R 3 are both C(D)3, or R 2 is C(H)3 and R 3 is C(D)3.

14. A parenteral preparation for said use according to any one of claims 11 to 13, wherein each H x is H, or each H x is D, one H x is H and one H x is D.

15. A parenteral preparation for said use according to any one of claims 11 to 14, wherein each H y is H, or each H y is D, or one H y is H and one H y is D.

16. A parenteral preparation for said use according to any one of claims 11, 12, 13 and 15, wherein each H x , H y and H z is deuterium.

17. A parenteral preparation for said use according to any one of the preceding claims, wherein the hallucinogenic agent is selected from the group consisting of: or a pharmaceutically acceptable salt thereof; wherein Ra and Rb are as defined in claim 11.

18. A parenteral preparation for said use according to any one of claims 11 to 17, wherein Ra is H.

19. A parenteral preparation for said use according to any one of claims 11 to 18, wherein Rb is H.

20. A parenteral preparation for said use according to any one of the preceding claims, wherein the parenteral administration comprises intravenous infusion via one or two infusion pumps.

21. A parenteral preparation for said use according to any one of the preceding claims, wherein the psychiatric or neurological disorder is selected from the group consisting of: (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance use and gambling disorder, and (v) anhedonia disorder, or is selected from the group consisting of: major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, obsessive-compulsive disorder, and eating disorders, such as compulsive eating disorder.

22. A parenteral preparation for said use according to any one of the preceding claims, wherein the psychiatric or neurological disorder is selected from the group consisting of depressive disorder and anxiety disorder.

23. A parenteral preparation for said use according to any one of the preceding claims, wherein the duration of the hallucinogenic experience: - when the hallucinogenic agent is N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, is about 15 to about 30 minutes, or about 30 to about 90 minutes; or - when the hallucinogenic agent is selected from psilocybin, 4-acetoxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, dimethyl-4-hydroxytryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, is about 15 minutes to about 45 minutes, or about 45 minutes to about 180 minutes; or - is about 20 to about 30 minutes, wherein the hallucinogenic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; or - is from about 60 to about 90 minutes, wherein the hallucinogenic agent is a deuterated analogue of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

24. The parenteral preparation for the use according to any one of the preceding claims, wherein the hallucinogenic agent is N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the duration of the hallucinogenic experience is from about 20 to about 30 minutes; or the hallucinogenic agent is a deuterated analogue of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the duration of the hallucinogenic experience is from about 30 to about 60 minutes.

25. The parenteral preparation for the use according to any one of the preceding claims, wherein the treatment of the psychiatric or neurological disorder comprises hallucinogenic agent-assisted psychotherapy.

26. A method for treating a psychiatric or neurological disorder in a patient, the method comprising parenterally administering to the patient a dose of a hallucinogenic agent for a dosing period of from about 5 to about 15 minutes, wherein the hallucinogenic agent is selected from N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, psilocybin, dimethyl-4-hydroxytryptamine, deuterated analogues thereof, and pharmaceutically acceptable salts thereof, and wherein the parenteral administration provides a slow-onset breakthrough hallucinogenic experience in the patient.

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

28. The method for treatment according to claim 26 or claim 27, wherein the administration is by intravenous infusion, preferably wherein the intravenous administration is performed using an infusion pump.

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

30. The method for treatment according to any one of claims 26 to 29, wherein the dosing period is from about 9 to about 11 minutes, or about 10 minutes.

31. The method for treatment according to any one of claims 26 to 30, the method comprising parenterally administering a total dose of a hallucinogenic agent selected from the group consisting of: - about 20 to about 70 mg of N,N-dimethyltryptamine, a deuterated analogue thereof, or a pharmaceutically acceptable salt thereof; - about 15 to about 30 mg of N,N-dimethyltryptamine, a deuterated analogue thereof, or a pharmaceutically acceptable salt thereof; - about 5 to about 15 mg of N,N-dimethyltryptamine, a deuterated analogue thereof, or a pharmaceutically acceptable salt thereof; - about 10 to about 30 mg of 5-methoxy-N,N-dimethyltryptamine, a deuterated analogue thereof, or a pharmaceutically acceptable salt thereof; - about 1 to about 5 mg of psilocybin, a deuterated analogue thereof, or a pharmaceutically acceptable salt thereof; - about 3 to about 15 mg of 4-acetoxy-N,N-dimethyltryptamine, a deuterated analogue thereof, or a pharmaceutically acceptable salt thereof; and - about 1 to about 5 mg, or about 3 to about 25 mg of dimethyl-4-hydroxytryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof.

32. The method for treatment according to any one of claims 26 to 31, the method comprising parenterally administering a total dose of about 20 to about 29 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof.

33. The method for treatment according to any one of claims 26 to 32, the method comprising parenterally administering a total dose of about 20 to about 23 mg, or about 26 to about 29 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof.

34. The method for treatment according to any one of claims 26 to 33, the method comprising parenterally administering a total dose of about 7 to about 9 mg, or about 10 to about 20 mg of N,N-dimethyltryptamine, its deuterated analogs, or pharmaceutically acceptable salts thereof.

35. The method for treatment according to any one of claims 26 to 34, the method comprising parenterally administering a total dose of about 1.5 to about 3 mg of psilocybin, its deuterated analogs or pharmaceutically acceptable salts thereof; or a total dose of about 1.5 to about 3 mg of dimethyl-4-hydroxytryptamine, its deuterated analogs or pharmaceutically acceptable salts thereof.

36. The method for treatment according to any one of claims 26 to 35, wherein the hallucinogen is a compound of formula I, or a pharmaceutically acceptable salt thereof: Ra is selected from H, D, -OH, -OAc and -PO3OH, and Rb is H or D; or Ra is H or D, and Rb is selected from H, D and -OMe; R 2 and R 3 each independently selected from C(H z )3; and Each H x 、H y and H z is independently selected from protium and deuterium.

37. The method for treatment according to claim 36, wherein R 2 and R 3 are each independently selected from C(H)3 and C(D)3.

38. The method for treatment according to claim 36, wherein R 2 and R 3 are both C(H)3, or R 2 and R 3 are both C(D)3, or R 2 is C(H)3 and R 3 is C(D)3.

39. A method for treatment according to any one of claims 36 to 38, wherein each H x is H, or each H x is D, one H x is H and one H x is D.

40. A method for treatment according to any one of claims 36 to 39, wherein each H y is H, or each H y is D, or one H y is H and one H y is D.

41. A method for treatment according to any one of claims 36, 37, 38 and 40, wherein each H x , H y and H z is deuterium.

42. The method for treatment according to any one of claims 26 to 41, wherein the hallucinogen is selected from the group consisting of: or a pharmaceutically acceptable salt thereof; wherein Ra and Rb are as defined in claim 36.

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

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

45. The method for treatment according to any one of claims 26 to 44, wherein the parenteral administration comprises intravenous infusion through one or two infusion pumps.

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

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

48. A method for treatment according to any one of claims 26 to 47, wherein, The duration of the hallucinogenic experience: - When the hallucinogenic agent is N,N-dimethyltryptamine, its deuterated analog, or a pharmaceutically acceptable salt thereof, it is about 15 to about 30 minutes, or about 30 to about 90 minutes; or - When the hallucinogenic agent is selected from psilocybin, 4-acetoxy-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, dimethyl-4-hydroxytryptamine, their deuterated analogs, or pharmaceutically acceptable salts thereof, it is about 15 minutes to about 45 minutes, or about 45 minutes to about 180 minutes; or - It is about 20 to about 30 minutes, wherein the hallucinogenic agent is N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof; or - It is about 60 to about 90 minutes, wherein the hallucinogenic agent is a deuterated analog of N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

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

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

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