WO2025054397A1 - Parenteral formulations for n,n-dimethyltryptamine (dmt) and dmt analogs, methods of making, and methods of use thereof - Google Patents

Abstract

Pharmaceutical compositions including stable N-N-dimethyltryptamine (DMT) in solution with pharmaceutically acceptable properties suitable for parenteral administration.

Description

PARENTERAL FORMULATIONS FOR N,N-DIMETHYL TRYPTAMINE (DMT) AND DMT ANALOGS, METHODS OF MAKING, AND METHODS OF USE THEREOF

Cross-Reference To Related Applications

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/581,398, filed September 8, 2023, which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

[0002] Lysergic acid diethylamide (“LSD”), psilocybin and DMT are serotonergic agents often referred to as “classical hallucinogens” or "psychedelics," and have the ability to induce qualitatively altered states of consciousness, such as euphoria, trance, transcendence of time and space, spiritual experiences, or dissolution of self-boundaries, while other effects such as sedation, narcosis, or excessive stimulation are only minimal. Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, with the indoleamine class being divided into two subsets, ergolines and tryptamines.

[0003] Naturally occurring psychedelics, such as the DMT, which is contained in the South American shrub Psychotria viridis, psilocybin, which is contained in over 200 mushroom species, or mescaline, which is contained in the Peyote cactus of the American Southwest and Northern Mexico, have been used for centuries by indigenous cultures in ritualistic or sociocultural contexts, and in the context of religious sacraments. While an unspecific “healing” potential had been ascribed to the use of naturally occurring psychedelics in those settings, more scientific investigations into their potential therapeutic application for defined diseases had not been pursued until after the discovery of the synthetic ergoline lysergic acid diethylamide (“LSD”) in 1943.

[0004] With emerging knowledge about the serotonin system and its role in brain function, researchers began to specify the molecular activity of psychedelic drugs. However, how that activity translated into the observed therapeutic effects in mental disorders was less clear. Two main concepts were proposed: The first concept was coined “psycholytic therapy” and it emphasized the ability of psychedelics given at low doses to facilitate the loosening of psychological defensive mechanisms, which in combination with psychotherapy allows a deep introspective insight and the revival of traumata and their subsequent catharsis. The basic mechanism considered in the psycholytic approach was therefore the activation and deepening of the concomitant psychotherapeutic process, and it required multiple drug and therapy sessions. The second concept was coined as "psychedelic therapy" and it emphasized the ability of psychedelics given at relatively high single doses to induce so called “peak psychedelic experiences.” Peak experiences are predominantly characterized by the loss of judgment to time and space and the dissolution of ego boundaries, which often culminates in the experience of a blissful state and feelings of being a whole and harmonious existence in the cosmic unity. The basic mechanism considered in the psychedelic approach was therefore to produce a unique, overwhelming experience with an intuitive perception of psychological integration and harmony and subsequent self-improvements and enhanced joy in living and a sense of inner peace.

[0005] Although scientific research around the use of psychedelics for the treatment of mental disorders blossomed in the 1960s, there was also a rapidly growing recreational use of these substances, and soon psychedelics were depicted in the media as highly dangerous drugs of abuse. A perceived danger to the social order led to the passage of the United States Controlled Substances Act of 1970, under which LSD and other psychedelics were placed into the most restrictive category Schedule 1, which contains drugs deemed to have no medical use and a high potential for abuse. Very little progress was made regarding possible therapeutic uses of psychedelic drugs for the next 30 years.

[0006] Recently, interest in the field of psychedelic therapy has resurged, and classical psychedelics have shown preclinical and clinical promise in treating psychiatric disorders (Carhart-Harris and Goodwin, The Therapeutic Potential of Psychedelic Drugs: Past, Present and Future, Neuropsychopharmacology; 42, 2105-2113 (2017)). In particular, psilocybin has demonstrated significant improvement in a range of depression and anxiety rating scales in randomized double-blind studies (Griffiths et al., Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial, Journal of Psychopharmacology 30(12), 1181-1197 (2016)).

[0007] DMT is also understood to hold therapeutic value as a psychedelic, with efficacy trials ongoing to assess the effect of DMT or DMT fumarate administered intravenously to subjects with major depressive disorder (“MDD”). However, although the intrinsic properties of DMT make it an attractive possible medication, especially for neurological diseases and conditions, current therapeutic compositions and modes of administration complicate treatment and may not provide optimal therapeutic results. For example, when smoked or delivered intravenously, DMT has a very fast onset of action and a short duration of effect, which presents a challenge to determine a suitable administration regimen with appropriate dosage and frequency of administration of DMT to provide effective therapy for neurological diseases and conditions. This is especially true for neurological diseases and conditions which would benefit from the presence of therapeutic blood levels of DMT over a more extended period of time following administration.

[0008] U.S. Pat. No. 11,406,619, entitled “Injectable Formulations”, describes injectable DMT compositions having pH values of from about 3.5 to about 6.5 and osmolalities of about 250 to about 350 mOsm / kg. These compositions have a concentration of DMT of about 2.5 mg/mL. Such concentrations are suitable for intravenous (IV) ministration where administration can occur over a significant period of time, but unsuitable for other administration routes such as intramuscular (IM) or subcutaneous (SC).

[0009] Therefore, a significant need exists for readily administrable medications of DMT to treat neurological diseases and conditions. Such medications, which maximize efficacy while enabling drug side effects to be effectively controlled, are of particular interest, especially if administrable via a convenient route, including self-administration.

SUMMARY OF THE INVENTION

[0010] In aspects, the present disclosure provides pharmaceutical compositions for parenteral administration. In embodiments, the composition suitable for parenteral administration comprises an active agent, the active agent being DMT or a DMT analog or a pharmaceutically acceptable salt or prodrug thereof in a liquid form or powder constituted in a liquid vehicle. In embodiments, the pharmaceutical composition provides a therapeutically effective blood level of DMT for between about 2 minutes and about 75 minutes when administered to a human. In embodiments, the composition is provided in a liquid composition with the active agent in a solubilized form. [0011] In aspects, the present disclosure provides methods for administering a psychedelic composition comprising: administering a dose of the composition comprising DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof in the range of about 20 to about 40 mg to a human patient over a time period ranging from about 20 to about 120 minutes.

[0012] In aspects, the composition is suitable for parenteral administration, wherein parenteral includes intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal and intrathecal administration.

[0013] In aspects, the composition comprises a tonicity adjusting agent, buffering agent, a chelating agent, and an antioxidant / stability enhancer.

[0014] In aspects, the active agent is a DMT Succinate. Alternatively, the active agent may be a DMT free base.

[0015] In aspects, the composition comprises about 0.5 mg/mL to about 3080 mg/mL DMT or a pharmaceutically acceptable salt thereof; about 0% to about 10% by weight of a tonicity adjusting agent; and about 0% to about 5% by weight of a chelating agent. In embodiments, the composition comprises about 0.0 to about 15.0% by weight of the buffering agent. In embodiments, the composition comprises about 0.0 to about 5.0% by weight of the antioxidant. In embodiments, the composition comprises about 0.0 to about 5.0% by weight of the preservative.

[0016] In aspects, the pH of the composition is between 2-11, or 4-8. In embodiments, the osmolality of the composition ranges from 370 mOsm/kg to about 900 mOSm/kg, or about 400 mOsm/kg to about 650 mOsm/kg.

[0017] In aspects, the composition remains stable after aging at about 2-about 8°C or about 25°C and about 60% relative humidity for about 6 months, and/or after aging at about 40°C and about 75% relative humidity for about 6 months.

[0018] In aspects, the present disclosure provides methods of treating a neurological disease or condition comprising administering to a subject in need thereof any of the above compositions. BRIEF DESCRIPTION OF THE FIGURES

[0019] FIG. 1 is a table of the change in DMT concentration in human serum over time following the administration of a pharmaceutical composition of this disclosure including 50 mg of DMT fumarate.

[0020] FIG. 2 shows the plasma concentration of DMT in rats following a single subcutaneous dose of 5 mg/kg or 10 mg/kg DMT succinate.

[0021] FIG. 3 is a table showing Impurity / Degradation Products of DMT Succinate Solution in Buffers VIR 1-7.

[0022] FIG. 4 is a table showing Impurity / Degradation Products of DMT Succinate Solution in Buffers VIR 8-11 and DMT succinate.

[0023] FIG. 5 shows the pH / solubility profile for DMT succinate.

[0024] FIG. 6 is a table evaluating solutions at ambient storage and at 50 °C. Stability samples were analyzed for appearance, pH, assay and impurity / degradation.

[0025] FIG. 7 shows bulk pre-filtration DMT succinate solution, left to right batch 006/VIR/21, 007/VIR/21, batch 008/VIR/21. Top Image against a black background and lower image against a white background.

[0026] FIG. 8 is a table evaluating solutions at 2-8 °C, ambient conditions, and 50 °C. Stability samples were analyzed for appearance, pH, assay and impurity / degradation.

[0027] FIG. 9 is a table summarizing the Stability testing for storage at 2-8°C over time.

[0028] FIG. 10 is a table summarizing the Stability testing for storage at 25°C/60%RH over time.

[0029] FIG. 11 is a table summarizing the Stability testing for storage at 40°C/75%RH over time.

[0030] FIG. 12A is a table illustrating raw data measurements of systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), temperature, heart rate and respiratory rate ofV4001- 006 and V4001-009. [0031] FIG. 12B is a table illustrating raw data measurements of systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), temperature, heart rate and respiratory rate of V4001- 012 and V4001-013.

[0032] FIG. 13A is a table illustrating raw data measurements of systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), temperature, heart rate and respiratory rate ofV4001- 023 and V4001-040.

[0033] FIG. 13B is a table illustrating raw data measurements of systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), temperature, heart rate and respiratory rate of V4001- 043 and V4001-044.

[0034] FIG. 14 is a table illustrating subjective intensity rating scale (SIRS) value over time for subjects of Cohort 1 and Cohort 2.

[0035] FIG. 15A is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 006 of Cohort 1.

[0036] FIG. 15B is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 009 of Cohort 1.

[0037] FIG. 15C is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 012 of Cohort 1.

[0038] FIG. 15D is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 013 of Cohort 1.

[0039] FIG. 16A is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 023 of Cohort 2.

[0040] FIG. 16B is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 040 of Cohort 2. [0041] FIG. 16C is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 043 of Cohort 2.

[0042] FIG. 16D is a graph illustrating systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), and subjective intensity rating scale (SIRS) value over time for subject V4001- 044 of Cohort 2.

DETAILED DESCRIPTION

[0043] The present disclosure provides parenteral compositions of N, N- Dimethyltryptamine (DMT) including any pharmaceutically acceptable form of DMT, including, but not limited to, salts, esters, polymorphs / solid state form, prodrugs. Parenteral composition refer as composition intended to be administered as injection, infusion or implantation.

Compositions of present invention relate to injectable administration by means of intravenous (IV), intramuscular (IM), or subcutaneous (SC) injection.

[0044] In embodiments, the present disclosure provides parenteral DMT succinate compositions, and more particularly DMT succinate containing parenteral compositions. In embodiments, the drug is formulated as a liquid (solution, suspension, emulsion etc.) or it is lyophilized.

[0045] In aspects, the present disclosure provides a pharmaceutical composition comprising DMT or a pharmaceutically acceptable salt thereof, wherein following administration to a subject, the DMT human blood plasma Tmax is between from about 1 minute to about 60 minutes, or about 1.5 minutes to about 45 minutes, or about 1.7 minutes to about 35 minutes, or about 2 minutes to about 30 minutes, or about 2 minutes to about 20 minutes (e.g., about 5 minutes to about 15 minutes, especially about 5, 6, 7, 8, 9 or 10 minutes). Preferably, after T_max is achieved, the concentration of DMT is maintained at about 50% or more, preferably 80% or more, of Cmax for between about 10 minutes to about 30 minutes (e.g., about 10, about 15, about 20, about 25, about 30 minutes).

DEFINITIONS

[0046] As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise: [0047] The term “about” when immediately preceding a numerical value means a range (e g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5.

[0048] The term “subject, ” “individual” and “patient” are used interchangeably herein, and refers to a human.

[0049] The terms “treating,” “treat” and “treatment” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

[0050] The term “parenteral” includes all injectable routes of administration, such as for example subcutaneous (SC/SQ), intraperitoneal (IP), intravenous (IV), intradermal (ID), intrathecal and intramuscular (IM).

[0051] The term “pharmaceutically acceptable” as used herein, refers to refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0052] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. Salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, tri ethyl amine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethyl ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine di cyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0053] The term “carrier” or “vehicle” as used interchangeably herein encompasses carriers, excipients, adjuvants, and diluents or a combination of any of the foregoing, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body. In addition to the adjuvants, excipients and diluents known to one skilled in the art, the carrier includes nanoparticles of organic and inorganic nature.

[0054] The term “effective amount” or “therapeutically effective amount” as used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to a patient, is capable of performing the intended result.

[0055] The term “neurological disease or condition” as used herein, means a disease or condition selected from: a neuropsychiatric disorder, such as depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder), catatonic depression, a depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder, anxiety, anxiety disorder, social anxiety disorder, general anxiety disorder (GAD), avolition disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder, body dysmorphic disorder, abnormalities of mood or emotion, including the above conditions, dysthymia, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, traumatic stress disorders, phobic disorders, and personality disorders with abnormal mood, such as borderline personality disorder, schizoid and schizotypal disorders and suicide ideation, or rumination/unproductive repetitive thoughts negatively impacting one's behavior/mood/ability to focus, obsessive compulsive disorder, addiction (including substance use disorder such as addiction to nicotine, alcohol, cocaine, opioids, amphetamine, methamphetamine, heroin, morphine, phencyclidine, 3, 4-m ethylenedi oxy-methamphetamine, as well as other addictive substances), addictive behavior (including eating, gambling, sex, pornography, videogames, work, exercise, spiritual obsession, self-harm, travel and shopping addiction), eating disorder (including anorexia nervosa, bulimia nervosa and binge eating disorder), and pain (including pain associated with migraine or headache or chronic pain).

[0056] As used herein, the term “onset” means the time to achieve maximum blood plasma concentration following administration (i.e. Tmax) and may also be described as "onset of action". A "rapid onset" in the context of the present disclosure means that the drug achieves Cmax within about 20 minutes (e.g. within about 2-10 minutes). However, onset following administration of a composition according to the present disclosure is less rapid, and consequently less "harsh" to the patient, than if DMT is administered by IV injection.

[0057] As used herein, the term “offset” means the time between the last time the concentration of DMT is at Cmax ± 10% and the first time the plasma concentration of DMT reduces to a threshold level below which the drug no longer has any meaningful therapeutic effect (e.g., about 250 nmol/L or 47.07 ng/ml). A "rapid offset" in the context of the present disclosure means less than about 10 minutes. However, although rapid, the offset is still sufficiently long for the drug to exert a reasonable duration of psychedelic effects.

FORMULATIONS AND METHODS OF USE

[0058] Development of poorly water-soluble drugs into parenteral compositions is a challenging task. Successful drug delivery vehicle must be capable of maintaining the drug in its dissolved state over an extended storage period.

[0059] DMT as base exhibited poor aqueous solubility (<1 mg/mL), hence selection of vehicle is critical for achieving solubilization of DMT. Various techniques can be utilized to achieve complete solubilization of drug, including but not limited to microemulsion, nano- emulsion, polymeric nanoparticles, polymeric micelles, nanostructured lipid carriers, liposomes, transformers etc.

[0060] Being a weekly basic compound, DMT exhibited pH dependent aqueous solubility. Solubility of DMT can be increased by adding acids including but not limited to citric acid, tartaric acid, maleic acid, succinic acid etc.

[0061] Alternatively, pharmaceutically acceptable forms of DMT, including, but not limited to, salts, esters, polymorphs / solid state form, prodrugs is required to achieve desired solubility of DMT in an injection vehicle.

[0062] In the present disclosure, a salt of DMT is utilized to form parenteral composition, including, but not limited to, succinate salt of DMT, referred to as DMT succinate hereon. Succinate salt of DMT exhibited acceptable aqueous solubility to formulate DMT succinate as parenteral composition, including, but not limited to, IV, IM and SC injectable solution compositions.

[0063] In embodiments, pharmaceutical compositions comprising DMT or a pharmaceutically acceptable salt thereof suitable for parenteral administration are provided in unit dosage forms (e.g., in single-dose ampoules), pre-fdled syringe or in vials containing several doses and in which a suitable preservative is added. In embodiments, the composition is conveniently in the form of a solution, a suspension, or an emulsion, or it is presented as a dry powder to be reconstituted with water or another suitable vehicle before use. In embodiment, apart from DMT or a pharmaceutically acceptable salt thereof, the composition comprises suitable parenterally acceptable carriers and/or excipients. In embodiments, the composition comprises suspending, solubilizing, stabilizing, pH adjusting agents, and/or dispersing agents.

[0064] In embodiments, pharmaceutical compositions of the present disclosure comprise one or more excipients, diluents / vehicles, solvents, co-solvents, desensitizing agents, emulsifiers, solubilizers, suspension agents, viscosity modifiers, ionic tonicity agents, buffers, carriers, surfactants, cryoprotectants, lyoprotectants, antioxidant, chelating agent, inert gases, complexing agents, preservatives or mixtures thereof.

[0065] Depending on the delivery device employed, delivery between about 25% and about 100% of the drug product, i.e., DMT is achieved. It is to be understood however, that due to the nature of drug delivery devices, one of ordinary skill in the art will appreciate that not all of the drug can be delivered as it is the function of the delivery device employed. Thus, for clarity, it is to be understood that about 25% to about 100% of the drug product delivered is dependent on the selected drug delivery method and/or device. Therefore, 100% of the drug product delivered may not be all of the drug product, but it will be all of the drug product a selected device is capable of delivering.

[0066] In embodiments, for parenteral administration, aqueous suspensions, solutions and sterile injectable solutions are used, optionally containing pharmaceutically acceptable excipients, which include dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. In embodiments, suspensions of DMT or a pharmaceutically acceptable salt thereof is prepared as appropriate oily injection suspensions or emulsions. Suitable lipophilic solvents or vehicles include, but is not limited to, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. In embodiments,, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In embodiments, DMT or a pharmaceutically acceptable salt thereof is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In embodiments, the solution or suspension is administered parenterally to the subject by injection using well-known devices and techniques. Any appropriate syringe can conveniently be used, including an autoinjector which can allow self-administration. In embodiments, the composition is suitable for IV/SC/IM administration. In embodiments, the composition has sufficient active concentration for SC or IM administration, wherein an entire dose is delivered in a syringe. In embodiments, the composition is administered IV after dilution with saline.

[0067] The dosage amount of DMT or a pharmaceutically acceptable salt thereof administered to a patient, as defined herein, with a neurological disease or condition, is typically from about 0.1 mg/kg to about 1 mg/kg. A typical human dose (for an adult weighing 50-80kg) would equate to a dose of about 5 mg to about 80 mg. In embodiments, the dose is about 10 mg to about 60 mg, such as about 20-about 60 mg, about 30-about 60 mg, about 40-about 60 mg, or any specific amount there between, including about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, and about 60 mg. In this disclosure, when ranges are set forth, such as "about 20-about 60 mg," the disclosure contemplates all discrete values within that range, some of which are specifically mentioned, but all of which are not, simply for the purpose of brevity.

[0068] In embodiments, the composition comprises about 0.1 mg/mL to about 10000 mg/mL, about 1 mg/mL to about 5000 mg/mL, about 10 mg/mL to about 1000 mg/mL DMT or a pharmaceutically acceptable salt, including any values or ranges therebetween. In embodiments, the composition comprises about 0.5 mg/mL to about 3080 mg/mL DMT or a pharmaceutically acceptable salt. In embodiments, the pharmaceutical composition comprises about 2.51 mg/mL to about 5650 mg/mL DMT or a pharmaceutically acceptable salt.

[0069] In embodiments, the composition of the present disclosure comprises a buffering agent; and a chelating agent. In embodiments, the pharmaceutical composition of the present disclosure comprise a tonicity adjusting agent, buffering agent, a chelating agent, and an antioxidant / stability enhancer. In embodiments, the pharmaceutical composition comprise a preservative.

[0070] In embodiments, the tonicity adjusting agent is a salt such as di-sodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride, potassium chloride etc., mannitol, glycerin, glucose, dextrose or a mixture thereof. In embodiments, the buffering agent is an acid such as citric acid, tartaric acid, maleic acid, acetic acid, etc., a base such as sodium citrate, sodium tartrate, sodium maleate, sodium acetate etc. or a mixture thereof. In embodiments, the chelating agent is ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), n-hydroxy ethylenedi aminetetraacetic acid (HEDTA), Diethylenetriamene pentaacetate (DTP A) or a mixture thereof. In embodiments, the antioxidant / stability enhancer is a-tocopherol, tocopherol acetate, L-Glutahione, L-cysteine, acetyl cysteine, ascorbic acid, uric acid, ascorbyl palmitate, propyl gallate, butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), Tocobiol or a mixture thereof. In embodiments, the preservative is benzyl alcohol, chlorobutanol, m-cresol, methyl paraben, propyl paraben, phenol. Phenoxyethanol, thiomersal, sodium benzoate or a mixture thereof.

[0071] In aspects, the composition comprises about 0.5 mg/mL to about 3080 mg/mL DMT or a pharmaceutically acceptable salt thereof; about 0% to about 10% by weight of a tonicity adjusting agent; and about 0% to about 5% by weight of a chelating agent. In embodiments, the pharmaceutical composition comprises about 2.51 mg/mL to about 5650 mg/mL DMT Succinate. In embodiments, the pharmaceutical composition comprises about 0.01 to about 1.0% by weight of the tonicity agent. In embodiments, the composition comprises about 0.01 to about 1 .0% by weight of the chelating agent. In embodiments, the composition comprises about 0.0 to about 15.0% by weight of the buffering agent. In embodiments, the composition comprises about 0.0 to about 5.0% by weight of the antioxidant. In embodiments, the composition comprises about 0.0 to about 5.0% by weight of the preservative.

[0072] In embodiments, the composition has a pH of from about 4 to about 8. In embodiments, the composition has a pH of from about 6.5 to about 7.5. In embodiments, the composition has a pH of about 4, about 5, about 6, about 7, or about 8.

[0073] In embodiments, the composition has an osmolality ranging from about 370 mOsm/kg to about 900 mOSm/kg. In embodiments, the composition has an osmolality ranging from about 400 mOsm/kg to about 650 mOsm/kg. In embodiments, the composition has an osmolality of about 370 mOSm/kg, about 380 mOSm/kg, about 390 mOSm/kg, about 400 mOSm/kg, about 410 mOSm/kg, about 420 mOSm/kg, about 430 mOSm/kg, about 440 mOSm/kg, about 450 mOSm/kg, about 460 mOSm/kg, about 470 mOSm/kg, about 480 mOSm/kg, about 490 mOSm/kg, about 500 mOSm/kg, about 510 mOSm/kg, about 520 mOSm/kg, about 530 mOSm/kg, about 540 mOSm/kg, about 550 mOSm/kg, about 560 mOSm/kg, about 570 mOSm/kg, about 580 mOSm/kg, about 590 mOSm/kg, about 600 mOSm/kg, about 610 mOSm/kg, about 620 mOSm/kg, about 630 mOSm/kg, about 640 mOSm/kg, about 650 mOSm/kg, about 660 mOSm/kg, about 670 mOSm/kg, about 680 mOSm/kg, about 690 mOSm/kg, about 700 mOSm/kg, about 710 mOSm/kg, about 720 mOSm/kg, about 730 mOSm/kg, about 740 mOSm/kg, about 750 mOSm/kg, about 760 mOSm/kg, about 770 mOSm/kg, about 780 mOSm/kg, about 790 mOSm/kg, about 800 mOSm/kg, about 810 mOSm/kg, about 820 mOSm/kg, about 830 mOSm/kg, about 840 mOSm/kg, about 850 mOSm/kg, about 860 mOSm/kg, about 870 mOSm/kg, about 880 mOSm/kg, about 890 mOSm/kg, or about 900 mOSm/kg.

[0074] In embodiments, the composition remains stable after aging at about 2 °C to about 8°C and about 60% relative humidity for about 6 months. In embodiments, the composition remains stable after aging at about 25°C and about 60% relative humidity for about 6 months. In embodiments, the composition remains stable after aging at about 40°C and about 75% relative humidity for about 6 months.

[0075] In embodiments, DMT or a pharmaceutically acceptable salt thereof is administered to a patient in one or more doses over a 24-hour period, e.g., 1, 2, 3, 4 or 5 doses. However, the total dose administered to the subject should not exceed about 100 mg over a 24- hour period.

[0076] In embodiments, the DMT or DMT analog composition has a concentration that is sufficiently high to enable administration by injection from a syringe, for example, in the case of intramuscular (IM) or subcutaneous (SC) route.

[0077] In embodiments, the DMT or DMT analog composition is administered over a period of time between about 5 minutes and about 120 minutes. In embodiments, the composition is administered between about 10 minutes and about 30 minutes. In embodiments, the composition is administered between about 20 minutes and about 25 minutes. In embodiments, the composition is administered between about 30 minutes and about 60 minutes. In embodiments, the composition is administered between about 40 minutes and about 50 minutes.

[0078] In embodiments, the DMT or DMT analog composition is administered at a rate between about 0.2 mg/min and about 2 mg/min. In embodiments, the composition is administered at a rate between about 0.5 mg/min and about 0.8 mg/min. In embodiments, the composition is administered at a rate of about 0.67 mg/min. In embodiments, the composition is administered at a rate between about 1 .1 mg/min and about 1.5 mg/min. In embodiments, the composition is administered at a rate of about 1.3 mg/min. [0079] In embodiments, the DMT or DMT analog composition is administered over a period of time by an IV infusion. In embodiments, the composition is administered over a period of time by a subcutaneous pump.

[0080] In embodiments, the DMT or DMT analog composition is combined with an enzyme to promote the absorption of the DMT or DMT analog by the body when injected intramuscularly or subcutaneously. In embodiments, the enzyme increases the absorption of the DMT or DMT analog composition to reduce tissue damage by the DMT or DMT analog. In embodiments, the enzyme is formulated with the DMT or DMT analog to be administered as a single injection. In embodiments, the enzyme is administered in sequence with the DMT or DMT analog as separate injections. In embodiments, the enzyme is administered before the DMT or DMT analog. In embodiments, the enzyme is administered after the DMT or DMT analog. In embodiments, the enzyme is hyaluronidase.

[0081] In embodiments, a subject is administered to the composition multiple times over a set a period of time. In embodiments, the subject is administered the composition once every time period of between about 2 weeks and about 6 months for a set treatment period. In embodiments, the subject is administered the composition once every time period of between about 2 weeks and about 3 months for a set treatment period. In embodiments, the subject is administered the composition once every month for a set treatment period. In embodiments, the subject is administered the composition once every about 6 weeks for a set treatment period. In embodiments, the subject is administered the composition once every about 2 months for a set treatment period. In embodiments, the subject is administered the composition once every about 3 months for a set treatment period.

[0082] In embodiments, the administration of the composition provides a Tmax of DMT of from about 1 minute to about 60 minutes, or from about 1.5 minutes to about 45 minutes, or from about 1.7 minutes to about 35 minutes, or from about 2 minutes to about 30 minutes, or from about 2 minutes to about 20 minutes (e.g., from about 5 minutes to about 15 minutes, especially about 5, 6, 7, 8, 9 or 10 minutes), including any values or ranges therebetween following administration of the composition. In embodiments, after Tmax is achieved, the concentration of DMT is maintained at about 50% or more, or 80% or more of Cmax for between about 10 minutes to about 30 minutes (e g., about 10, about 15, about 20, about 25, about 30 minutes).

[0083] In embodiments, the administration of the composition provides a Cmax of DMT of from about 10 ng/mL to about 100 ng/mL, following administration of the composition. In embodiments, the administration of the composition provides a Cmax of DMT of less than about 25 ng/mL. In embodiments, the administration of the composition provides a Cmax of DMT of between about 20 ng/mL and about 25 ng/mL. In embodiments, the administration of the composition provides a Cmax of DMT of about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, or about 100 ng/mL, including any values or ranges therebetween.

[0084] In embodiments, the administration of the composition provides a change in systolic blood pressure less than about 100 mm Hg, about 90 mm Hg, about 80 mm Hg, about 70 mm Hg, about 60 mm Hg, about 50 mm Hg, about 40 mm Hg, about 30 mm Hg, about 20 mm Hg, or about 10 mm Hg, including any values or ranges therebetween, following administration of the composition. In embodiments, the administration of the composition provides a change in systolic blood pressure less than about 50 mm Hg. In embodiments, the administration of the composition provides a change in systolic blood pressure less than about 40 mm Hg.

[0085] In embodiments, the administration of the composition provides a change in diastolic blood pressure less than about 100 mm Hg, about 90 mm Hg, about 80 mm Hg, about 70 mm Hg, about 60 mm Hg, about 50 mm Hg, about 40 mm Hg, about 30 mm Hg, about 20 mm Hg, or about 10 mm Hg, including any values or ranges therebetween, following administration of the composition. In embodiments, the administration of the composition provides a change in diastolic blood pressure less than about 30 mm Hg. In embodiments, the administration of the composition provides a change in diastolic blood pressure less than about 20 mm Hg.

[0086] In aspects, the present disclosure provides methods of treating a neurological disease or condition is, for example, a neuropsychiatric disorder. [0087] Examples of neuropsychiatric disorders which can be treated with DMT or a pharmaceutically acceptable salt thereof include depression (e g. TRD), anxiety, bipolar disorder, post-traumatic stress disorder, abnormalities of mood or emotion, including the above conditions, dysthymia, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, traumatic stress disorders, phobic disorders, eating disorders and personality disorders with abnormal mood, such as borderline personality disorder, schizoid and schizotypal disorders and suicide ideation, or rumination/unproductive repetitive thoughts negatively impacting one's behavior/mood/ability to focus.

[0088] In embodiments, the neurological disease or condition is addiction.

[0089] Examples of addiction which can be treated with DMT or a pharmaceutically acceptable salt thereof include substance use disorder such as addiction to nicotine, alcohol, cocaine, opioids, amphetamine, methamphetamine, heroin, morphine, phencyclidine, 3,4- methylenedioxy-methamphetamine, as well as other addictive substances.

[0090] In embodiments, the neurological disease or condition is an addictive behavior.

[0091] Examples of addictive behaviors which can be treated with DMT or a pharmaceutically acceptable salt thereof include addiction to eating, gambling, sex, pornography, videogames, work, exercise, spiritual obsession, self-harm, travel, shopping and substance use disorder (SUD).

[0092] In embodiments, the present disclosure provides a method of treating depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, a depressive disorder due to a medical condition, or postpartum depression), comprising administering parenterally to a subject an effective amount of DMT or a pharmaceutically acceptable salt thereof.

Combination Therapy

[0093] The methods described herein include administering DMT or a pharmaceutically acceptable salt thereof as the sole active ingredient. However, also encompassed within the scope of the present disclosure are methods for treating a neurological disease or condition that comprise administering DMT or a pharmaceutically acceptable salt thereof in combination with one or more additional agents. [0094] In aspects, these additional agents are therapeutic agents appropriate for the disease or disorder that is being treated, as is known in the art. In embodiments, DMT or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more anti-depressant or antianxiety drugs, such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or serotonin norepinephrine reuptake inhibitors (SNRIs).

[0095] In embodiments, the disclosure provides a method of reducing anxiety in a subject undergoing treatment with DMT or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject: i) DMT or a pharmaceutically acceptable salt thereof and ii) one or more benzodiazepines.

[0096] In embodiments, the one or more benzodiazepines are administered to the subject at or around the same time as DMT or a pharmaceutically acceptable salt thereof. In embodiments, the one or more benzodiazepines are administered to the subject prior to administration of DMT or a pharmaceutically acceptable salt thereof, such as about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes before administration of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the one or more benzodiazepines are administered to the subject after DMT or a pharmaceutically acceptable salt thereof, such as about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after administration of DMT or a pharmaceutically acceptable salt thereof.

[0097] In embodiments, the benzodiazepine is selected from adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam, flunitrazolam, flurazepam, flutazolam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, meclonazepam, medazepam, metizolam, mexazolam, midazolam, nifoxipam, nimetazepam, nitemazepam, nitrazepam, nitrazolam, nordiazepam, norflurazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, rilmazafone, temazepam, tetrazepam, or triazolam.

[0098] In embodiments, a patient is administered DMT or a pharmaceutically acceptable salt thereof as described herein along with one or more 5-HT 2A specific antagonists and/or inverse agonists. In embodiments, the patient is administered DMT or a pharmaceutically acceptable salt thereof and the one or more 5-HT 2A specific antagonists and/or inverse agonists at the same time. In embodiments, the patient is administered one or more 5-HT 2A specific antagonists and/or inverse agonists prior to DMT or a pharmaceutically acceptable salt thereof administration, such as, but not limited to about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes before DMT or a pharmaceutically acceptable salt thereof administration. In embodiments, the patient is administered one or more 5-HT2A specific antagonists and/or inverse agonists after DMT or a pharmaceutically acceptable salt thereof administration, such as, but not limited to about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after DMT or a pharmaceutically acceptable salt thereof administration.

[0099] Suitable 5-HT 2A antagonists include but are not limited to, trazodone, mirtazapine, metergoline, ketanserin, ritanserin, nefazodone, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl- tetrahydro- pyrimido-azepine, 9-aminomethyl-9, 10-dihydroanthracene (AMO A), haloperidol, chlorpromazine, hydroxyzine (atarax), 5-MeO-NBpBrT, niaprazine, altanserin, aripiprazole, etoperidone, setoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rauwol seine, phenoxybenzamine, pruvanserin, deramciclane, nelotanserin, lubazodone, mepiprazole, xylamidine, R-(+)-alpha-(2,3-dimethoxyphenyl)-l -[2-(4-fluorophenethyl)]-4- piperidinemethanol (Ml 00907), mianserin, AT 1015, DV 7028, eplivanserin, 4F 4PP, fanaserin, alpha-phenyl- 1 -(2- phenylethyl)-4-piperidinem ethanol (MDL 1 1 ,939), melperone, mesulergine, paliperidone, l-[2- (3,4-Dihydro-l /-/-2-benzopyran-l-yl)ethyl]-4-( 4- fluorophenyl)piperazine dihydrochloride (PNU 9641 SE), (2R,4R)-5-[2-[2-[2-(3- methoxyphenyl)ethyl]phenoxy]ethyl]-l-methyl-3-pyrrolidinol(R-96544), sarpogrelate, spiperone, ziprasidone, zotepine, and 7-[[4-[2-( 4-fluorophenyl)ethyl]-l- piperazi nyl ] carbonyl ]- 1-i ndole-3-carbonitri le (EM D 281014).

[0100] Suitable 5-HT 2A reverse agonists include but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and volinaserin.

[0101] In embodiments, the disclosure provides a method of reducing the negative side effects associated with a traumatic psychedelic experience in a patient undergoing treatment with DMT or a pharmaceutically acceptable salt thereof. In aspects, the method comprises administering to the patient: i) DMT or a pharmaceutically acceptable salt thereof, and ii) one or more 5-HT 2A specific antagonists and/or inverse agonists. In aspects, the method comprises administering to the patient: i) DMT or a pharmaceutically acceptable salt thereof, and ii) one or more cannabinoids or cannabinoid derivatives.

[0102] In embodiments, the cannabinoid is selected from THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); or CBT (cannabicitran). In particular embodiments, the cannabinoid is CBD (cannabidiol).

[0103] Dosage regimens can be adjusted to provide the optimum desired response. Treatment dosages can be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.

[0104] In embodiments of the present disclosure, when treating a neuropsychiatric disease or disorder, such as depression (e.g. TRD), anxiety or an addiction, compositions of the present disclosure are administered in conjunction with psychotherapy, talk therapy, cognitive behavioral therapy, exposure therapy, biofeedback therapy (e.g. EEG-assisted therapy and virtual reality assisted therapy), systematic desensitization, mindfulness, dialectical behavior therapy, interpersonal therapy, eye movement desensitization and reprocessing, social rhythm therapy, acceptance and commitment therapy, family-focused therapy, psychodynamic therapy, light therapy, computer therapy (including digital cognitive behavioral therapy), cognitive remediation, exercise, or other types of therapy such as transcranial magnetic stimulation (TMS). In embodiments, compositions of the present disclosure are administered to treat depression in conjunction with digital cognitive behavioral therapy, for example, using the digital program DEPREXIS®. In embodiments, compositions of the present disclosure are administered (for example, to treat depression or anxiety) in conjunction with therapy using a transdiagnostic approach (cf. J Consult Clin Psychol. 2020 Mar; 88(3): 179-195).

NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0105] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments.

1. A method for administering a psychedelic composition comprising: administering a dose of the composition comprising DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof in the range of about 20 to about40 mg to a human patient over a time period ranging from about 20 to about 120 minutes.

2. The method of embodiment 1, wherein the composition further comprises: a buffering agent; and a chelating agent; wherein the composition has a pH of about 2-11 and an osmolality from about 370 mOsm/kg to about 900 mOSm/kg.

3. The method of embodiment 1, wherein the DMT salt is DMT succinate.

4. The method of embodiment 1, wherein the composition comprises about 0.5 mg/mL to about 3080 mg/mL DMT or a pharmaceutically acceptable salt.

5. The method of embodiment 1, wherein the composition comprises about 2.51 mg/mL to about 5650 mg/mL DMT or a pharmaceutically acceptable salt.

6. The method of embodiment 2, wherein the composition comprises an amount of buffering agent up to about 15.0% by weight. The method of embodiment 2, wherein the buffering agent is citric acid, tartaric acid, maleic acid, acetic acid, sodium citrate, sodium tartrate, sodium maleate, sodium acetate, or a mixture thereof. The method of embodiment 2, wherein the composition comprises up to about 5% by weight of a chelating agent. The method of embodiment 8, wherein the composition comprises about 0.01 to about 1.0% by weight of the chelating agent. The method of embodiment 2, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), n-hydroxy ethylenediaminetetraacetic acid (HEDTA), diethylenetriamine pentaacetate (DTP A), or a mixture thereof. The method of embodiment 2, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA). The method of embodiment 1, wherein the composition further comprises a tonicity adjusting agent. The method of embodiment 12, wherein the composition comprises up to about 10% by weight of the tonicity adjusting agent. The method of embodiment 12, wherein the tonicity agent is a salt including di-sodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride, potassium chloride, mannitol, glycerin, glucose, dextrose, or a mixture thereof. The method of embodiment 1, wherein the composition further comprises an antioxidant. The method of embodiment 15, wherein the composition comprises up to about 5.0% by weight of the antioxidant. The method of embodiment 1, wherein the composition further comprises a preservative. The method of embodiment 17, wherein the composition comprises up to about 5.0% by weight of the preservative. The method of embodiment 1, wherein the composition has an osmolality of from about 400 mOsm/kg to about 650 mOsm/kg. The method of embodiment 1, wherein the composition has a pH of from about 4 to about 8. The method of embodiment 19, wherein the composition has a pH of from about 6.5 to about 7.5. The method of embodiment 1, wherein the composition remains stable after aging at about 2°C - about 8°C for about 6 months. The method of embodiment 1, wherein the composition remains stable after aging at about 25°C at about 60% relative humidity for about 6 months. The method of embodiment 1, wherein the composition remains stable after aging at about 40°C and about 75% relative humidity for about 6 months. The method of embodiment 1, wherein the administration comprises intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal, or intrathecal administration. The method of embodiment 1, wherein 30 mg of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered. The method of embodiment 26, wherein the administration provides a Cmax of less than about 25 ng/mL. The method of embodiment 26, wherein the administration provides a Cmax of between about 20 ng/mL and about 25 ng/mL. The method of embodiment 1, wherein the composition is administered over a period between about 30 minutes and about 60 minutes. The method of embodiment 1, wherein the composition is administered over a period of about 23 minutes. The method of embodiment 30, wherein the composition is administered over a period between about 30 minutes and about 50 minutes. The method of embodiment 31, wherein the composition is administered over a period of about 45 minutes. The method of embodiment 1, wherein the composition is parenterally administered by an IV infusion. The method of embodiment 1, wherein the composition is parenterally administered intramuscularly. The method of embodiment 1, wherein the composition is parenterally administered subcutaneously. The method of embodiment 1, wherein the composition is parenterally administered by a subcutaneous pump. 37. The method of embodiment 1, wherein the administration provides a Tmax of DMT of between about 20 minutes and about 60 minutes when administered to a human.

38. The method of embodiment 1, wherein the administration provides a Tmax of between about 30 and about 60 minutes.

39. The method of embodiment 38, wherein the administration provides a Tmax of between about 40 and about 60 minutes.

40. The method of embodiment 1, wherein the administration provides a change in systolic blood pressure less than 50 mm Hg.

41. The method of embodiment 1, wherein the administration provides a change in systolic blood pressure less than 40 mm Hg.

42. The method of embodiment 1, wherein the administration provides a change in diastolic blood pressure less than 30 mm Hg.

43. The method of embodiment 42, wherein the administration provides a change in diastolic blood pressure less than 20 mm Hg.

44. The method of embodiment 1, wherein the subject is administered the composition on a reoccurring period, wherein the reoccurring period is between 2 weeks and 3 months.

45. The method of embodiment 17, wherein the preservative comprises benzyl alcohol, chlorobutanol, m-cresol, methyl paraben, propyl paraben, phenol, phenoxyethanol, thiomersal, sodium benzoate, or a mixture thereof.

EXAMPLES

[0106] The following examples are provided to further illustrate the embodiments of the present disclosure but are not intended to limit the scope of the embodiments. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

Example 1

[0107] Desired theoretical drug release profdes for DMT are shown in FIG. 1. The compositions capable of providing DMT release in accordance with these profiles are in development.

Example 2

[0108] DMT plasma concentrations were measured on day 1 following a single subcutaneous (SC) injection of 5 and 10 mg/kg DMT succinate to rats (males and females combined) as indicated in Table 1 below:

The results are shown in FIG. 2.

Example 3

DMT Succinate Solubility [0109] DMT Succinate Solubility in Aqueous and Organic Solvents is shown in Table 2 below.

[0110] In this study, solubility of DMT succinate is evaluated in different buffer system to achieve therapeutically effective dose in reasonable volume less than 5 mb, or less than 2 mb. Solubility of DMT succinate was carried out in different buffer as presented in Table 3.

[0U1] To evaluate the solubility of DMT succinate at various pHs, excess quantity of DMT succinate is added to the suitable buffer as presented in Table 3 and mixed well. Following to that pH of the mixture was checked and adjusted using either IM HC1 or 5 M NaOH to the target pH (Table 3). The mixture was stirred overnight under ambient conditions and on the next day, mixture was filtered through 0.22 pm filter and solution were evaluated for soluble fraction suing HPLC.

[0112] Further, impurity / degradation level of DMT succinate in above buffer was evaluated utilizing HPLC method as presented in FIGS. 3-4. Solution stability of DMT succinate was evaluated in a different pH buffer. The lowest number of total related substances was noted in buffered systems from approximately pH 5.5to pH 7.5 as shown in FIG. 5.

[0113] DMT succinate was found to exhibit pH dependent solubility. Solubility of DMT succinate increased with increased pH. Preferably, higher solubility of DMT succinate was observed in between pH 5.5 to 8.0, more preferably highest solubility of DMT succinate was observed in between pH 6.0-7.0 which is closely related to the physiological pH. Formulating DMT succinate parenteral solution around pH 2.0 to 11.0 more specifically around pH 4.0-7.0 will be preferred for safety and tolerability. Formulating DMT succinate parenteral solution with osmolality ranging from about 370 mOsm/kg to about 900 mOsm/kg will be preferred for safety and tolerability. Similar ranges of pH and Osmolality were targeted in the present invention.

Example 4

[0114] In an exemplary embodiment, the parenteral composition of DMT succinate is as shown in Table 4 below:

[0115] Required quantity of either of the buffering agent dissolved in 70 % of the water for injection. pH of the buffer is adjusted using either 1 M HC1 or 5 M NaOH as presented in above table. DMT succinate was then added to the above solution and stirred till it dissolved. The volume of composition was then made up with the WFI. The resulting solution is filtered through 0.22 pm filter and evaluated for pH and tonicity as presented in below table 5.

[0116] The stability of prepared compositions was evaluated at ambient storage and at 50 °C. Stability samples were analyzed for appearance, pH, assay and impurity / degradation level utilizing HPLC method. Prepared compositions did not exhibit significant change in appearance, pH, assay and impurity / degradation level and demonstrated acceptable stability ambient storage conditions and at 50°C for up to 4 weeks. The stability results are shown in FIG. 6.

Example 5

[0117] Further the DMT is formulated as a finished injectable dosage form with suitable pH ranging from pH 4 to pH 9, more preferably pH 5.5-7.5 with addition of stabilizing agents as shown in Table 6 below.

[0118] Required quantity of Di-Sodium Hydrogen Phosphate Heptahydrate and Sodium Dihydrogen Phosphate Monohydrate dissolved in about 60 % of the water for injection. EDTA disodium dihydrate was then added to the above solution and stirred till it dissolved. DMT succinate was then added to the above solution and stirred till it dissolved. pH of the buffer is adjusted to either 5.5 or 6 using either 1 M HC1 or 5 M NaOH. The volume of composition was then made up with the WFI. FIG. 7 shows bulk pre-filtered DMT succinate solutions, left to right Batch 006/VIR/21, 007/VIR/21, batch 008/VIR/21. The top image uses a black background and lower image uses a white background. [0119] The resulting solution is filtered through 0.22 gm filter and evaluated for pH and tonicity as presented in below Table 7.

[0120] The final solution was filled in clear Type I glass vials overlaid with nitrogen before being stoppered with rubber injection stoppers and crimp sealed. The stability of sealed vials were evaluated under inverted position at 2-8 °C, ambient conditions, and 50 °C for up to 4 weeks. Stability samples were analyzed for appearance, pH, sub visible particulate, assay and impurity / degradation level utilizing HPLC method. Prepared compositions did not exhibit significant change in appearance, pH, sub visible particulate, assay and impurity / degradation level and demonstrated acceptable stability ambient storage conditions and at 50°C for up to 4 weeks. The stability samples were analyzed for pH, sub visible particulates and impurity / degradation level utilizing HPLC method. The stability results can be seen in FIG. 8.

Example 6

[0121] The finished injectable dosage form is prepared with suitable pH ranging from pH 4 to pH 9, or pH 5.5-7.5 containing EDTA (Stabilizer) as shown in Table 8.

[0122] Required quantity of Di-Sodium Hydrogen Phosphate Heptahydrate and Sodium Dihydrogen Phosphate Monohydrate dissolved in about 60 % of the water for injection. EDTA disodium dihydrate was then added to the above solution and stirred till it dissolved. DMT succinate was then added to the above solution and stirred till it dissolved. pH of the buffer is adjusted to either 5.5 or 6 using either 1 M HC1 or 5 M NaOH. The volume of composition was then made up with the WFI. The resulting solution is filtered through 0.22 pm filter and evaluated for stability at 2-8 °C, 25 °C /60% RH and at 40°C /75% RH. The stability results are shown in FIG. 9, FIG. 10, and FIG. 11.

[0123] Based on the solubility assessment, DMT salt form demonstrated high solubility across the studied pH (4.5 to 8.0). At target pH of 5.5-8.0, or 6.0-7.0, composition with and without stabilizer demonstrated acceptable osmolality and stability in solution at all studied conditions for 3 months. However, the composition containing stabilizer i.e., EDTA appeared more stable under the conditions tested. The DMT compositions can be prepared at any concentration ranging from about Img/mL to about 60mg/mL of DMT free base for parenteral administration including IV, IM or SC. Further the composition can be diluted to further lower concentrations prior administration using diluents or isotonic solutions but not limited to WFI, normal saline, sodium chloride solution, dextrose solution, ringer’s solution etc.

Example 7

[0124] In an exemplary embodiment, the parenteral composition of DMT free base is a composition as shown in Table 9 below.

[0125] Required quantity of either of the buffering agents are dissolved in 70 % of the water for injection. DMT is then added to the above solution and stirred till it dissolved. pH of the solution is then adjusted to about 6 using either 1 M HC1 or 5 M NaOH. The volume of composition was then made up with the WFI. The resulting solution is fdtered through 0.22 pm filter.

Example 8

[0126] In an exemplary embodiment, the results of a 30 mg parental composition of DMT Succinate administration to four subjects via IV infusion over the span of 23 minutes, Cohort 1, are shown in Table 10. The infusion rate of 30 mg over 23-minutes resulted in an infusion rate of 1 .3 mg/min. A total of 1 1 samples were taken for subject V4001 -006 while a total of 14 samples were taken for V4001-009, V4001-012, and V4001-013.

[0127] In an exemplary embodiment, the results of a 30 mg parental composition of DMT Succinate administration to four subjects via IV infusion over the span of 45-minutes, Cohort 2, are shown in Table 11. The infusion rate of 30 mg over 45-minutes resulted in an infusion rate of 0.67 mg/min. A total of 15 samples were taken for subjects V4001-023, V4001- 040, V4001-043, and V4001-044.

[0128] In the 45-minute infusion, subject 44 (V4001-044) presented anomalous results which put the subject in view as an outlier. In comparison of the 45-minute infusion data (excluding subject 44) to the 35-minute infusion, the Cmax of the longer infusion is lower while maintaining a comparable AUC. The lesser Cmax of the 45-minute group retained effective psychedelic effects while reducing adverse physiological effects. For example, the blood pressure of the 45-minute group experienced lower blood pressure than the 23-minute group.

[0129] Infusion times for trials and the rate of administration in Table 10 and Table 11 were calculated by modeling data taken from “Strassman, R J, and C R Qualls. “Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects.” Archives of general psychiatry vol. 51,2 (1994): 85-97.” and “Timmermann, Christopher et al. “Neural correlates of the DMT experience assessed with multivariate EEG.” Scientific reports vol. 9,1 16324. 19 Nov. 2019.”

[0130] Biometric measurements of each subject in Cohort 1 are shown in FIG. 12A and FIG. 12B. These measurements include systolic blood pressure (SYSBP), diastolic blood pressure (DIABP), temperature, heart rate and respiratory rate. Biometric measurements of each subject in Cohort 2 are shown in FIG. 13A and FIG. 13B. [0131] The maximum difference between the lowest measurement and the highest measurement for systolic blood pressure, diastolic blood pressure, and heart rate were calculated for each subject in Cohort 1 and Cohort 2. Table 12 presents the changes in these biometric measurements for Cohort 1, the 23-minute infusion group.

[0132] Table 13 presents the changes in these biometric measurements for Cohort 2, the 45-minute infusion group.

[0133] As previously discussed, Subject 44 is treated as an outlier, therefore mean and standard deviation measurements are presented excluding Subject 044.

[0134] The comparison of Table 13 to Table 12 indicates that there is a significant decrease in change of blood pressure, both systolic and diastolic, when infusing the 30 mg DMT composition over 45-minutes as compared to 23 -minutes. The change in blood pressure is reduced by more than half. This reduces the physiological stress of administration and may reduce the likelihood of various complications associated with high blood pressure. [0135] A Subjective Intensity Rating Scale (SIRS) was used to determine and measure the psychological effects of administration on each subject to determine the intensity of the effect. SIRS ratings (0-10 ratings, 0 = not intense, 10 = very intense) were measured over 65 minutes for a total of 14 measurements. These measurements are presented in FIG. 14. The measurements equal to or greater than 8, 9, and 10 for Cohort 1 and Cohort 2 are presented in Table 14 and Table 15, respectively, to evaluate the intensity of the psychedelic effects of each cohort.

[0136] In the comparison of the SIRS data of the 23-minute infusion to the 45-minute infusion, it is seen that the 45-minute infusion, on average, exhibited a longer and more intense experience than the 23-minute infusion. By increasing the time of infusion, the desired psychedelic effect was maintained, if not increased, while reducing the spike in blood pressure due to administration of the DMT compound. This result is unexpected as one would reasonably expect that the intensity and effect of the drug to be measurably reduced when administering the same dose at a lower rate. The reduction in the administration rate increases the overall safety of patients being administered DMT by reducing the spike in blood pressure.

[0137] FIGS. 15A-15D show plots of systolic blood pressure (SYSB), diastolic blood pressure (DIABP), and SIRS measurements versus time for the subjects of Cohort 1. FIGS. 16A- 16D show plots of systolic blood pressure (SYSB), diastolic blood pressure (DIABP), and SIRS measurements versus time for the subjects of Cohort 2. The trend of smaller blood pressure spikes and a larger SIRS curve can be seen in Cohort 2 when compared to Cohort 1.

Example 9

[0138] In an exemplary embodiment, the toxicity of the test article, N, N- dimethyltryptamine (DMT) succinate, when administered as a single subcutaneous injection to CD® [Crl:CD®(SD)] rats, was evaluated in addition to the reversibility of the findings following a 14-day recovery period. The study design is seen in Table 16. Dosing compositions were administered to main study animals once on Day 1 during the study via subcutaneous (SC) bolus injection. The dose levels were 0 (vehicle), 5, 25, or 100 mg/kg, and administered at a dose volume of 5 mL/kg. Dosing compositions were administered between the skin and underlying layers of tissue in the scapular region on the back of each animal. The injection site was marked as necessary. Individual doses were based on the most recent body weights.

[0139] The identification of the test material, DMT succinate, used in this study is identified in Table 17. The vehicle used for administration is identified in Table 18.

[0140] Test article-related microscopic findings noted at the terminal euthanasia are summarized in Table 19.

[0141] Minimal to mild injection site findings included inflammation (mixed cell; dermal, striated muscle, and/or subcutaneous), myofiber degeneration/necrosis, and/or hemorrhage. Inflammatory infiltrates were composed of low numbers of macrophages, neutrophils, mast cells, lymphocytes and/or plasma cells. Mild inflammation was characterized by increased inflammatory cells with prominent neutrophils when compared to minimal inflammation. At 5 mg/kg (females only), mild (4/10) mixed cell inflammation of the subcutaneous tissue was observed. Additionally, one of the four animals had inflammation in the dermis and skeletal muscle. Increased severity as compared to the control and involvement of dermis and skeletal muscle suggests a TA-related response. In males and females dosed at 25 mg/kg, there was mixed cell inflammation within the subcutaneous tissue that variably extended into the epidermis, dermis, and underlying skeletal muscle.

[0142] Degeneration/necrosis of the skeletal muscle, hemorrhage in the subcutis and foreign material were only observed in Group 3 animals at terminal necropsy. Degeneration/necrosis of the skeletal muscle fibers adjacent to the injection site (mostly panniculus camosus (pc) muscle and rarely skeletal muscle underlying pc) was observed in some male (8/10) and female (4/10) animals. These findings were characterized by hyper eosinophilic/fragmented cytoplasm with loss of striation, eosinophilic globule formation, and infiltration of inflammatory cells (macrophages, neutrophils, lymphocytes, and plasma cells). Hemorrhage in the subcutis was observed in males (2/10) and one female (1/10) in Group 3 and was characterized by extravasation of red blood cells. Additionally, two Group 3 female animals had foreign material, admixed with inflammatory cells, at the injection site. All remaining microscopic findings observed were considered incidental, of the nature commonly observed in this strain and age of rat, and/or were of similar incidence and severity in control and treated animals and, therefore, were considered unrelated to administration of DMT succinate.

[0143] Microscopic findings noted at the terminal euthanasia were also observed at the end of the recovery period (Day 15) and are summarized in Table 20.

[0144] At recovery necropsy some male and female animals from Group 2 and 3 had minimal to mild mixed inflammatory cell infiltration at the injection site similar to those observed in the terminal animals. In Group 2 (5 mg/kg dose) recovery animals, 4/5 males and 1/5 female had minimal mixed cell inflammation of the subcutaneous tissue at the injection site. Mixed cell inflammation at the injection site in recovery Group 3 (25 mg/kg dose) mainly involved the subcutaneous tissue (males 5/5; females 3/5) with lesser involvement of the dermis (males 1/5; females 0/5). Skeletal muscle degeneration was observed in one female animal from Group 3. Following the 14-day recovery period, decreased severity of inflammation of the subcutis and lesser involvement of the surrounding tissue (dermis) suggest that females at 5 mg/kg demonstrate partial recovery of test article related findings. The localization of inflammatory infiltrates to the subcutaneous tissue, lesser involvement of surrounding tissues (dermis), decreased incidence of myofiber degeneration and decreased severity suggest partial resolution of test article related findings in males and females at the 25 mg/kg dose at the end of the 14-day recovery period compared to terminal euthanasia Day 2.

[0145] Single dose subcutaneous injection of N, N-dimethyltryptamine (DMT) succinate was associated with mortality or moribundity at 100 mg/kg within two hours of administration. The clinical signs observed were decreased activity, low carriage, splayed limbs, eyes partially closed, salivation, open mouth breathing, increased respiratory effort, hyperreactivity, vocalization, decreased food enrichment appetite, hunched posture, discharge from both nostrils, repetitive behavior, and intermittent convulsions. Due to poor clinical condition across the group, all the surviving animals that received 100 mg/kg were euthanized on Day 1.

[0146] All animals up to and including 25 mg/kg survived to scheduled necropsy. Single dose subcutaneous injection of N, N-dimethyltryptamine (DMT) succinate, to male and female Sprague Dawley rats was systemically tolerated at 25 mg/kg with no systemic adverse findings. Therefore, under the conditions of this study a dose of 25 mg/kg is considered the systemic No- Ob served-Adverse-Effect-Level (NOAEL) in both sexes on. Based on the lack of injection site findings, the local No-Observed-Adverse-Effect-Level (NOAEL) was 5 mg/kg (1 mg/mL).

Example 10

[0147] In an exemplary embodiment, toxicity and maximum tolerated dose (MTD) of DMT succinate, when administered once via subcutaneous injection to CD® [Crl: CD®(SD)] rats, was determined. The potential reversibility of the findings during a 22-day recovery period was additionally evaluated. [0148] The dose levels were selected based on information gathered in the MTD study presented in Example 9 wherein mortality was observed at 100 mg/kg. The next lower dose of the study, 25 mg/kg (5 mg/mL), was well tolerated systemically; however, injection site reactions were observed at this concentration. This study was intended to evaluate doses at or above 15 mg/kg but below 50 mg/kg using the succinate salt form to determine the local and systemic MTD. An additional vehicle was evaluated to determine the impact on the local MTD. Only males were used in the study to reduce animal numbers in line with the 3 R’s. This design can be justified as there were no significant differences in clinical signs between sexes in earlier studies (Example 9) so using one sex would be considered representative and fulfills the purpose of the study. The experimental design of this study is presented in Table 21.

[0149] The identification of the test material, DMT succinate, used in this study is the same as that of Example 9 which is identified in Table 17. The vehicles used for administration are identified in Table 22 and 23.

[0150] The composition of Vehicle 2 consists of 0.36 mg/mL Sodium Phosphate Dibasic Heptahydrate, 1.18 mg/mL Sodium Phosphate Monobasic Monohydrate, 0.5 mg/mL Edetate Disodium in sterile water for injection.

[0151] The test article was injected between the skin and underlying layers of tissue in the scapular region on the back of each animal. The injection site was marked as necessary. Individual doses were based on the most recent body weights. The dose was administered by bolus injection. [0152] Test article-related microscopic findings in subcutaneous injection sites noted on Day 2 are summarized in Table 24.

[0153] At the injection sites, dose-dependent ulceration (minimal to marked), myofiber degeneration/necrosis (minimal to marked) of the cutaneous trunci and deep skeletal muscle mild to moderate mixed subcutaneous inflammation, and minimal to mild subcutaneous hemorrhage. Muscle degeneration/necrosis was characterized by myofibers with hypereosinophilia and loss of cross striations and/or infiltration of inflammatory cells, and mixed subcutaneous inflammation consisted of neutrophils and mononuclear cells with edema. [0154] Test article-related microscopic findings noted in the subcutaneous injection sites at the terminal phase partially reversed by the end of the recovery period (Day 23); displayed in Table 25.

[0155] The injection sites of rats at all dose levels had test article-related, dose-dependent microscopic findings (minimal to marked ulceration, minimal to marked muscle degeneration/necrosis, mild to moderate mixed subcutaneous inflammation, and minimal to mild subcutaneous hemorrhage) that generally occurred at a similar incidence and severity with both vehicles. Following recovery, the injection site findings were partially reversed. Minimal ulceration persisted in only one rat at 40 mg/kg (8 mg/mL) with vehicle 1 (Group 3), while muscle degeneration/necrosis and hemorrhage were not observed. Residual effects included minimal myofiber regeneration and minimal to mild subcutaneous mononuclear cell infiltrates at all dose levels, and mild to marked epidermal crusts with minimal to moderate epidermal hyperplasia at 40 mg/kg (8 mg/mL) with both vehicles (Groups 3 and 5). Therefore, 40 mg/kg in both vehicles was considered as systemically tolerated with no adverse findings. Hence, a dose of 40 mg/kg is considered the systemic No-Observed-Adverse-Effect- Level (NOAEL).

[0156] There were no deaths, unscheduled euthanasia, or macroscopic observations in main study or recovery rats. The injection sites of rats at all dose levels had test article-related, dose-dependent microscopic findings that generally occurred at a similar incidence and severity with both vehicles.

Example 11

[0157] In an exemplary embodiment, the toxicity of DMT Succinate when administered via a subcutaneous (SC) and intramuscular (IM) injections site was evaluated, and comparable dose site responses were compared. Male and female Sprague Dawley (Crl:CD[SD]) were dosed once and observed for a minimum of 24 hours to assess the reversibility or persistence of any dose site findings. Dosing compositions were administered between the skin and underlying layers of tissue in the scapular region on the back of each animal. The study design is shown in Table 26.

[0158] Group 1 was administered vehicle control only, via IM route. Groups 2 and 3 were administered test article, DMT Succinate, via IM route. Group 4 was administered test article, via SC route. Groups 1, 2 and 3 animals were dosed at a volume of 0.8 mL/kg (maximum volume of 0.2 mL). Group 4 animals were dosed at a dose volume of 0.8 mL/kg.

[0159] The test article of this study was DMT Succinate. The vehicle control article was 0.9% Sodium Chloride for Injection. Formulations were prepared on the day of dosing whereby the provided test article solution was further diluted to the target concentration. The test article, DMT Succinate, was provided pre-formulated at 40 mg/mL in the following composition: disodium hydrogen phosphate heptahydrate 0.375 mg/mL, sodium dihydrogen phosphate monohydrate 1.187 mg/mL, ehtylenedinitrilotetraacetic acid di-sodium salt 0.500 mg/mL, water for injection Q.S. to 1 mL, sodium hydroxide or hydrochloric acid (35%) Q.S. for pH 6.0. Further dilution to the target dose concentrations for administration was done with vehicle control article 0.9% sodium chloride for injection.

[0160] The incidence and severity of test article related macroscopic findings from the intramuscular (IM) injections and subcutaneous injections (SC/SQ) are shown in Table 27.

[0161] The incidence and severity of test article related microscopic findings from the intramuscular (IM) injections are shown in Table 28.

[0162] At the intramuscular injection site, degeneration/necrosis of the adjacent skeletal muscle was seen at minimal to moderate severity in both sexes administered 6.4 mg/kg/day. A mixed inflammatory cell infiltrate, often seen closely associated with degenerative/necrotic skeletal muscle, was observed at minimal severity in males administered 3.2 mg/kg/day, and at moderate severity in females at the same dose level. This change was also seen at slight to moderate severity in males administered 6.4 mg/kg/day, and at minimal to moderate severity in females at the same dose level. Hemorrhage within the subcutis was seen in females only. This change was observed at slight severity in females administered 3.2 mg/kg/day and at minimal to slight severity in females administered 6.4 mg/kg/day. In a single female administered

6.4 mg/kg/day, slight hemorrhage within the subcutis correlated with a macroscopic observation of discoloration of the injection site.

[0163] The incidence and severity of test article related microscopic findings from the subcutaneous (SC/SQ) injections are shown in Table 29.

[0164] At the subcutaneous injection site, degeneration/necrosis of the adjacent skeletal muscle was seen at slight to moderate severity in both sexes administered 6.4 mg/kg/day. A mixed inflammatory cell infiltrate, often seen closely associated with degenerative/necrotic skeletal muscle, was observed at slight severity in both sexes administered 6.4 mg/kg/day and at moderate severity in males only at the same dose level. Hemorrhage within the subcutis was seen at minimal to slight severity in two females only when administered 6.4 mg/kg/day. In these females, the hemorrhage seen microscopically correlated with macroscopic observations of discoloration of the injection site.

[0165] No deaths occurred. DMT Succinate-related changes were observed at the intramuscular and subcutaneous injection sites in both sexes at 6.4 mg/kg. All microscopic changes were considered to be non-adverse. Under the conditions of this study, the IM dose resulted in a slightly lower incidence and severity of macroscopic and microscopic findings at the dose site, when compared with the SC dose at the same concentration.

[0166] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application herein is not, and should not, be taken as acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

[0167] Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein, including all U.S. and foreign patents and patent applications, are specifically and entirely hereby incorporated herein by reference. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the invention indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for administering a psychedelic composition comprising: administering a dose of the composition comprising DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof in the range of about 20 to about40 mg to a human patient over a time period ranging from about 20 to about 120 minutes.

2. The method of claim 1, wherein the composition further comprises: a buffering agent; and a chelating agent; wherein the composition has a pH of about 2-11 and an osmolality from about 370 mOsm/kg to about 900 mOSm/kg.

3. The method of claim 1, wherein the DMT salt is DMT succinate.

4. The method of claim 1, wherein the composition comprises about 0.5 mg/mL to about 3080 mg/mL DMT or a pharmaceutically acceptable salt.

5. The method of claim 1 , wherein the composition comprises about 2.51 mg/mL to about 5650 mg/mL DMT or a pharmaceutically acceptable salt.

6. The method of claim 2, wherein the composition comprises an amount of buffering agent up to about 15.0% by weight.

7. The method of claim 2, wherein the buffering agent is citric acid, tartaric acid, maleic acid, acetic acid, sodium citrate, sodium tartrate, sodium maleate, sodium acetate, or a mixture thereof.

8. The method of claim 2, wherein the composition comprises up to about 5% by weight of a chelating agent.

9. The method of claim 8, wherein the composition comprises about 0.01 to about 1 .0% by weight of the chelating agent.

10. The method of claim 2, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), n-hydroxy ethylenediaminetetraacetic acid (HEDTA), diethylenetriamine pentaacetate (DTP A), or a mixture thereof.

11. The method of claim 2, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA).

12. The method of claim 1, wherein the composition further comprises a tonicity adjusting agent.

13. The method of claim 12, wherein the composition comprises up to about 10% by weight of the tonicity adjusting agent.

14. The method of claim 12, wherein the tonicity adjusting agent is a salt including disodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride, potassium chloride, mannitol, glycerin, glucose, dextrose, or a mixture thereof.

15. The method of claim 1, wherein the composition further comprises an antioxidant.

16. The method of claim 15, wherein the composition comprises up to about 5.0% by weight of the antioxidant.

17. The method of claim 1, wherein the composition further comprises a preservative.

18. The method of claim 17, wherein the composition comprises up to about 5.0% by weight of the preservative.

19. The method of claim 1, wherein the composition has an osmolality of from about 400 mOsm/kg to about 650 mOsm/kg.

20. The method of claim 1, wherein the composition has a pH of from about 4 to about 8.

21. The method of claim 19, wherein the composition has a pH of from about 6.5 to about 7.5.

22. The method of claim 1, wherein the composition remains stable after aging at about 2 °C - about 8°C for about 6 months.

23. The method of claim 1, wherein the composition remains stable after aging at about 25°C at about 60% relative humidity for about 6 months.

24. The method of claim 1, wherein the composition remains stable after aging at about 40°C and about 75% relative humidity for about 6 months.

25. The method of claim 1, wherein the administration comprises intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal, or intrathecal administration.

26. The method of claim 1, wherein 30 mg of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered.

27. The method of claim 26, wherein the administration provides a Cmax of less than about 25 ng/mL.

28. The method of claim 26, wherein the administration provides a Cmax of between about 20 ng/mL and about 25 ng/mL.

29. The method of claim 1, wherein the composition is administered over a period between about 30 minutes and about 60 minutes.

30. The method of claim 1, wherein the composition is administered over a period of about 23 minutes.

31. The method of claim 30, wherein the composition is administered over a period between about 30 minutes and about 50 minutes.

32. The method of claim 31, wherein the composition is administered over a period of about 45 minutes.

33. The method of claim 1, wherein the composition is parenterally administered by an IV infusion.

34. The method of claim 1, wherein the composition is parenterally administered intramuscularly.

35. The method of claim 1, wherein the composition is parenterally administered subcutaneously.

36. The method of claim 1, wherein the composition is parenterally administered by a subcutaneous pump.

37. The method of claim 1, wherein the administration provides a Tmax of DMT of between about 20 minutes and about 60 minutes when administered to a human.

38. The method of claim 1 , wherein the administration provides a Tmax of between about 30 and about 60 minutes.

39. The method of claim 38, wherein the administration provides a Tmax of between about 40 and about 60 minutes.

40. The method of claim 1, wherein the administration provides a change in systolic blood pressure less than about 50 mm Hg.

41. The method of claim 1, wherein the administration provides a change in systolic blood pressure less than about 40 mm Hg.

42. The method of claim 1, wherein the administration provides a change in diastolic blood pressure less than about 30 mm Hg.

43. The method of claim 42, wherein the administration provides a change in diastolic blood pressure less than about 20 mm Hg.

44. The method of claim 1, wherein the subject is administered the composition on a reoccurring period, wherein the reoccurring period is between 2 weeks and 3 months.

45. The method of claim 17, wherein the preservative comprises benzyl alcohol, chlorobutanol, m-cresol, methyl paraben, propyl paraben, phenol, phenoxyethanol, thiomersal, sodium benzoate, or a mixture thereof.