WO2025024637A1

WO2025024637A1 - Compositions for limiting sympathomimetic effects of psychedelic therapeutics

Info

Publication number: WO2025024637A1
Application number: PCT/US2024/039503
Authority: WO
Inventors: Glenn Short; Srinivas Rao
Original assignee: Atai Therapeutics Inc
Current assignee: Atai Therapeutics Inc
Priority date: 2023-07-25
Filing date: 2024-07-25
Publication date: 2025-01-30
Anticipated expiration: 2026-01-25

Abstract

Pharmaceutical compositions including N-N-dimethyltryptamine (DMT) acceptable salt or prodrug thereof in combination with an antihypertensive agent to reduce sympathomimetic effects associated with the administration of DMT.

Description

COMPOSITIONS FOR LIMITING SYMPATHOMIMETIC EFFECTS OF

PSYCHEDELIC THERAPEUTICS

Cross-Reference To Related Applications

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/515,389, filed July 25, 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] While psychedelics can induce acute antidepressant, anxiolytic, cognitive improvement, and antiaddiction therapeutic benefits, psychedelics also drive acute sympathomimetic and other adverse side effects (Schlag et al. Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. J Psychopharmacol. 2022 Mar;36(3):258-272.). These side effects may in part be a consequence of the stimulation of the adrenergic nervous system by the psychedelics themselves causing hypertension, tachycardia, hyperthermia, mydriasis, and sometimes agitation or aggressiveness (Nichols DE. Psychedelics. Pharmacol Rev. 2016 Apr;68(2):264-355). For LSD dosed in healthy subjects, the cardiovascular impact in particular is acute and mirrors the overall pharmacokinetic profile where the greatest increases in hypertension and tachycardia are associated near the Cmax (Holze et al. Distinct acute effects of LSD, MDMA, and D- amphetamine in healthy subjects. Neuropsychopharmacology. 2020 Feb;45(3):462-471). Similar cardiovascular side effect profiles have been observed with other psychedelic therapeutics therefore limiting their use in patients with comorbidities such as hypertension, stroke and cardiovascular disease.

[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. This is especially needed for patients with higher cardiovascular risk profiles or preexisting conditions.

SUMMARY

[0010] In aspects, the present disclosure provides compositions for administration comprising DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof in combination with an antihypertensive agent in an amount sufficient to reduce sympathomimetic effects associated with the administration of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof. In embodiments, the antihypertensive agent comprises a beta-blocker or nitrate.

[0011] In aspects, the antihypertensive agent comprises a beta-blocker with a half-life substantially similar to that of DMT. In embodiments, the beta-blocker is esmolol. In embodiments, the dose of esmolol in combination with DMT is between about 0.01 mg/kg/min and about 0.05 mg/kg/min of esmolol. In embodiments, the dose of esmolol in combination with DMT is between about 0.015 mg/kg/min and about 0.04 mg/kg/min of esmolol. In embodiments, the dose of esmolol in combination with DMT is between about 0.02 mg/kg/min and about 0.03 mg/kg/min of esmolol.

[0012] In aspects, the composition comprises short-acting beta-blockers. In embodiments, the short-acting beta-blocker is landiolol. In embodiments, the composition comprises short-acting calcium channel blockers. In embodiments, the short-acting calcium channel blocker is clevidipine.

[0013] In aspects, the antihypertensive agent comprises a nitrate. In one aspect, the nitrate is nitroglycerin. In embodiments, the nitrate is administered at a rate of about 1 pg/kg/min to about 15 pg/kg/min.

[0014] In aspects, the composition is suitable for parenteral application, wherein parenteral includes intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal, and intrathecal application. The composition suitable for parenteral administration being in a liquid form or powder constituted in a liquid vehicle. The composition may be provided in a liquid formulation with the active agent in a solubilized form.

[0015] In aspects, the composition is administered by a sublingual, buccal, or otherwise oral transmucosal route of administration.

[0016] In aspects, the composition comprises a DMT Succinate. In embodiments, the composition comprises a DMT free base.

[0017] In aspects, the disclosure provides methods of treating a neurological disease or condition comprising administering to a subject in need thereof any of the above compositions. In embodiments, the neurological condition is a neuropsychiatric disorder, premenstrual dysphoric disorder, or seasonal affective disorder, anxiety, anxiety disorder, social anxiety disorder, general anxiety disorder (GAD), treatment-resistant depression (TRD), avolition disorder, bipolar disorder, post-traumatic stress disorder, body dysmorphic disorder, abnormalities of mood or emotion, dysthymia, schizoaffective disorder, schizophrenia a, panic disorder, traumatic stress disorders, phobic disorders, and personality disorders with abnormal mood, addiction, addictive behavior, eating disorder, or pain. In embodiments, the composition is administered by a subcutaneous (SC) or an intramuscular (IM) route.

[0018] In aspects, the method comprises administering the composition over a period between about 5 minutes and about 120 minutes, between about 10 minutes and about 30 minutes, and between about 30 minutes and about 50 minutes. In embodiments, the method comprises administering the composition at a rate between about 0.2 mg/min and about 2.0 mg/min, between about 0.5 mg/min and about 0.8 mg/min, and between about 1.1 mg/min and about 1.5 mg/min of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0019] FIG. 1 illustrates an interrelationship between blood pressure and DMT exposure in a single healthy subject.

DETAILED DESCRIPTION

[0020] The present disclosure provides a formulation of N, N-Dimethyltryptamine (DMT), or a DMT analog, including any pharmaceutically acceptable form of DMT, including, but not limited to, salts, esters, polymorphs / solid state form, and prodrugs in combination with an antihypertensive agent. In embodiments, the antihypertensive agent comprises a beta-blocker or nitrate.

[0021] Parenteral formulation refers to a formulation intended to be administered as injection, infusion or implantation. Formulation composition of present disclosure relates to injectable administration by means of intravenous (IV), intramuscular (IM), or subcutaneous (SC) injection.

[0022] An antihypertensive agent refers to drugs and compositions that are used to treat hypertension. Antihypertensive agents seek to prevent complications that may arise due to high blood pressure such as heart failure, stroke, kidney failure, and myocardial infarction. Some examples of antihypertensive agents include, but are not limited to, beta-blockers, nitrates, calcium channel blockers, ACE inhibitors, and angiotensin II receptor blockers (ARBs). [0023] Preferably, the present disclosure provides parenteral DMT succinate formulations, and more particularly to DMT succinate containing parenteral formulations. The drug may be formulated as a liquid (solution, suspension, emulsion etc.) or it may be lyophilized.

[0024] The parenteral route is widely used to administer different types of drugs given its high bioavailability and rapid onset of action. Parenteral administration of fluids, drugs, and nutrition is very common in hospitals. Biopharmaceuticals, such as vaccines, heparin, insulin, growth hormone, hematopoietic growth factors, interferons, monoclonal antibodies, etc., are generally incompatible with oral delivery. Consequently, they must be administered parenterally, by means of intravenous (IV), intramuscular (IM), or subcutaneous (SC) injection.

[0025] From a pharmacokinetic point of view, parenteral routes can be considered near-ideal ways of administration due to the high bioavailability and rapid onset of action usually obtained. In the case of IV administration, the entire dose reaches the systemic circulation, and an immediate physiological response can be achieved, however selfadministration is not possible for IV injections, and it needs intervention of healthcare professionals. On the contrary IM and SC administrations involve an absorption process from the injection site, which leads to a delayed response, since drug molecules must diffuse in the interstitial space in order to reach the capillaries (i.e., to be absorbed), but it offers flexibility of self-administration. The present disclosure s provides formulations of DMT for parenteral administration and more preferably IV, IM and SC administration.

DEFINITIONS

[0026] As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise:

[0027] 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. [0028] The terms “administer,” “administering” or “administration” as used herein refer to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising the compound or pharmaceutically acceptable salt of the compound to a patient.

[0029] The term “subject” “individual” and “patient” are used interchangeably herein, and refers to a human.

[0030] The terms “treating” 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.

[0031] 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).

[0032] The term “pharmaceutically acceptable” as used herein, 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.

[0033] 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, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, 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..

[0034] 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.

[0035] 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.

[0036] 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), treatmentresistant depression (TRD), 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).

[0037] 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.

[0038] 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

[0039] Development of poorly water-soluble drugs into parenteral formulations is a challenging task. A successful drug delivery vehicle must be capable of maintaining the drug in its dissolved state over an extended storage period.

[0040] 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, nanoemulsion, polymeric nanoparticles, polymeric micelles, nanostructured lipid carriers, liposomes, transformers etc.

[0041] 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. [0042] Alternatively, pharmaceutically acceptable forms of DMT, including, but not limited to, salts, esters, polymorphs / solid state form, or prodrugs are required to achieve desired solubility of DMT in an injection vehicle.

[0043] In present disclosure, a salt of DMT is utilized to form parenteral formulation. Preferably, 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 formulation, preferably, but not limited to, IV, IM and SC injectable solution formulation.

[0044] Pharmaceutical compositions comprising DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof, is formulated with antihypertensive agents to limit sympathomimetic effects of the DMT. In embodiments, the antihypertensive agents comprises beta-blockers, short-acting beta-blockers, short-acting calcium channel blockers, nitrates, or any combination thereof.

[0045] In embodiments, the antihypertensive agent comprises a beta-blocker. In embodiments, the beta-blocker is esmolol. In embodiments, the antihypertensive agent comprises a short-acting beta blocker. In embodiments, the short-acting beta blocker is landiolol. In embodiments, the antihypertensive agent comprises a beta-blocker and a shortacting beta blocker. In embodiments, the antihypertensive agent comprises esmolol and landiolol. In embodiments, the antihypertensive agent comprises a short-acting calcium channel blocker. In embodiments, the short-acting calcium channel blocker is clevidipine. In embodiments, the antihypertensive agent comprises a beta-blocker and a short-acting calcium channel blocker. In embodiments, the antihypertensive agent comprises esmolol and clevidipine. In embodiments, the antihypertensive agent comprises a beta-blocker, a shortacting beta blocker and a short-acting calcium channel blocker. In embodiments, the antihypertensive agent comprises esmolol, landiolol, and clevidipine. In embodiments, the antihypertensive agent comprises a nitrate. In one embodiment, the nitrate is nitroglycerin. In another embodiment, the nitrate is isosorbide dinitrate.

[0046] In embodiments, the antihypertensive agent (e.g., a beta-blocker) has a halflife substantially similar to that of DMT. In embodiments, the antihypertensive agent has a half-life at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% of that of DMT. In embodiments, the antihypertensive agent has a half-life between about 8 minutes and about 12 minutes (e.g., about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, or about 12 minutes) when administered intravenously. In embodiments, the beta-blocker has a half-life between about 8 minutes and about 12 minutes (e.g., about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, or about 12 minutes) when administered intravenously.

[0047] In embodiments, the DMT active agent (i.e., DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof) and the antihypertensive agent are formulated in two distinct formulations that are administered simultaneously at two distinct parenteral sites. In embodiments, the DMT active agent and the antihypertensive agent are formulated together as a combination and administered at one parenteral site. In embodiments, the combination of the DMT active agent and the antihypertensive agent is administered across various routes of administration including intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, oral thin films, sublingual sprays, intranasal sprays, transdermal patches, sublingual ODTs, and oral ODTs. In embodiments, the combination drug is a single composition of the DMT active agent and the antihypertensive agent. In embodiments, the combination drug is a staged dosing product wherein the antihypertensive agent is given before the DMT active agent depending on the antihypertensive agent overall half-life. In such embodiments, the antihypertensive agent can be considered prophylactic.

[0048] Pharmaceutical compositions comprising DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof suitable for parenteral administration may be provided in unit dosage forms (e.g., in single-dose ampoules), pre-filled syringe or in vials containing several doses and in which a suitable preservative may be added. The composition may conveniently be in the form of a solution, a suspension, or an emulsion, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. Apart from DMT or a pharmaceutically acceptable salt thereof, the composition may include suitable parenterally acceptable carriers and/or excipients. Furthermore, the composition may include suspending, solubilizing, stabilizing, pH adjusting agents, and/or dispersing agents.

[0049] 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.

[0050] Depending on the delivery device employed, delivery between about 25% and about 100% of the drug product, e.g., 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.

[0051] For parenteral administration, aqueous suspensions, solutions and sterile injectable solutions may be used, optionally containing pharmaceutically acceptable excipients, which may include dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. In addition, suspensions of DMT or a pharmaceutically acceptable salt thereof may be prepared as appropriate oily injection suspensions or emulsions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, DMT or a pharmaceutically acceptable salt thereof may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The solution or suspension may be administered parenterally to the subject by injection using well-known devices and techniques. Any appropriate syringe may conveniently be used, including an autoinjector which may allow self-administration.

[0052] The dosage amount of DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof administered to a patient, as defined herein, with a neurological disease or condition, is typically from about 0.1 mg/kg to about 2 mg/kg of DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. A typical human dose (for an adult weighing 50-80kg) would equate to a dose of about 5 mg to about 160 mg DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. In one embodiment, the dose is about 10 mg to about 160 mg DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof, such as about 20- about 160 mg, about 30- about 160 mg, about 40- about 160 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, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. In this disclosure, when ranges are set forth, such as “about 20-about 160 mg” the inventor 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.

[0053] In embodiments, DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof of between 10 mg and 160 mg DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof (e.g., 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, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg) is paired with the antihypertensive agent of between about 0.10 mg and about 10 mg (e.g., about 0.1 mg, about 0.2 ,mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg). [0054] In embodiments, DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof may be 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.

[0055] In any one of the abovementioned aspects the neurological disease or condition may be, for example, a neuropsychiatric disorder.

[0056] Examples of neuropsychiatric disorders which may be treated with the composition described herein 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. In embodiments, the neurological disease or condition is treatment-resistant depression (TRD).

[0057] In any one of the abovementioned aspects the neurological disease or condition may be, for example, addiction.

[0058] Examples of addiction which may be treated with the composition described herein, 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.

[0059] In any one of the abovementioned aspects the neurological disease or condition may be, for example, addictive behavior.

[0060] Examples of addictive behavior which may be treated with the composition described herein, include addiction to eating, gambling, sex, pornography, videogames, work, exercise, spiritual obsession, self-harm, travel, shopping and substance use disorder (SUD).

[0061] 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 the compositions described herein. [0062] In one aspect of the disclosure, the DMT, DMT analog, or pharmaceutically acceptable salt or prodrug thereof 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.

[0063] In embodiments, the DMT, DMT analog, or pharmaceutically acceptable salt or prodrug thereof composition is administered over a period of time between about 5 minutes and about 120 minutes. In another embodiment, the composition is administered between about 10 minutes and about 30 minutes. In another embodiment, the composition is administered between about 20 minutes and about 25 minutes. In another embodiment, the composition is administered between about 30 minutes and about 60 minutes. In another embodiment, the composition is administered between about 40 minutes and about 50 minutes.

[0064] In one embodiment, the DMT, DMT analog, or pharmaceutically acceptable salt or prodrug thereof composition is administered at a rate between about 0.2 mg/min and about 2 mg/min. In another embodiment, the composition is administered at a rate between about 0.5 mg/min and about 0.8 mg/min. In another embodiment, the composition is administered at a rate of about 0.67 mg/min. In another embodiment, the composition is administered at a rate between about 1.1 mg/min and about 1.5 mg/min. In another embodiment, the composition is administered at a rate of about 1.3 mg/min.

[0065] In embodiments, the dose of a beta-blocker in combination with an DMT active agent (z.e., DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof) is between about 0.01 mg/kg/min and about 0.05 mg/kg/min of the beta-blocker. In embodiments, the dose of the beta-blocker in combination with an DMT active agent is between about 0.015 mg/kg/min and about 0.04 mg/kg/min of the beta-blocker. In embodiments, the dose of beta-blocker in combination with an DMT active agent is between about 0.02 mg/kg/min and about 0.03 mg/kg/min of beta-blocker.

[0066] In embodiments, the nitrate component is administered by IV or subcutaneous infusion between about 0.002 mg/min and about 0.2 mg/min. In embodiments, the nitrate component is administered by IV or subcutaneous infusion between about 0.05 pg/min and about 50 pg/min. In embodiments, the infusion of the nitrate is 30 minutes for a 30-minute infusion of an DMT active agent at about 1.3 mg/min of DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. In embodiments, the nitrate is infused between about 2 gg/min and about 25 gg/min. In one embodiment, between about 60 gg and about 750 gg nitrate is infused over 30 minutes for a about 60 kg individual. In embodiments, the nitrate is infused at a rate of about 1 gg/kg/min to about 15 gg/kg/min.

[0067] In embodiments, the DMT, DMT analog, or pharmaceutically acceptable salt or prodrug thereof 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.

[0068] In embodiments, a subject is administered 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.

Combination Therapy

[0069] 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.

[0070] 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 may be administered to the subject in combination with one or more anti-depressant or antianxiety drugs, such as SSRls, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOls), or serotonin norepinephrine reuptake inhibitors (SNRls).

[0071] 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.

[0072] 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, a DMT analog, or a pharmaceutically acceptable salt or prodrug 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 the DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug 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 the DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof.

[0073] 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.

[0074] In embodiments, a patient is administered DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof, as described herein along with one or more 5-HT2A specific antagonists and/or inverse agonists. In embodiments, the patient is administered DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof and the one or more 5-HT2A specific antagonists and/or inverse agonists at the same time. In embodiments, the patient is administered one or more 5-HT2A specific antagonists and/or inverse agonists prior to DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug 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, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof administration. In embodiments, the patient is administered one or more 5- HT2A specific antagonists and/or inverse agonists after DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug 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, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof administration.

[0075] Suitable 5-HT2A 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 (AMOA), haloperidol, chlorpromazine, hydroxyzine (atarax), 5-MeO-NBpBrT, niaprazine, altanserin, aripiprazole, etoperidone, setoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rauwolscine, 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 1-1-2- 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]- 1- piperazi nyl] carbonyl] -1-i ndole-3 -carb oni tri le (EM D 281014).

[0076] Suitable 5-HT2A reverse agonists include but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and volinaserin.

[0077] 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 one aspect the method comprising 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, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof, and ii) one or more cannabinoids or cannabinoid derivatives.

[0078] 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 embodiments, the cannabinoid is CBD (cannabidiol).

[0079] Dosage regimens may be adjusted to provide the optimum desired response. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.

[0080] In a further aspect 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 may be 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 one embodiment, compositions of the present disclosure may be administered to treat depression in conjunction with digital cognitive behavioral therapy, for example, using the digital program DEPREXIS®. In one embodiment, compositions of the present disclosure may be 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

[0081] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments. A composition for administration to a subject comprising;

N,N-dimethyltryptamine (DMT), a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof; and an antihypertensive agent in an amount sufficient to reduce sympathomimetic effects associated with the administration of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof. The composition of embodiment 1, wherein the composition comprises DMT succinate. The composition of embodiment 1, wherein the composition is for oral administration. The composition of embodiment 1, wherein the composition is for parenteral administration. The composition of embodiment 4, wherein the composition is for subcutaneous or intravenous injection. The composition of embodiment 4, wherein the composition is for subcutaneous or intravenous infusion. The composition of embodiment 1, wherein the antihypertensive agent comprises a beta-blocker. The composition of embodiment 7, wherein the beta-blocker has a half-life substantially similar to that of DMT. The composition of embodiment 8, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously. The composition of embodiment 7, wherein the beta-blocker is esmolol. The composition of embodiment 7, further comprising a short-acting beta-blocker. The composition of embodiment 11, wherein the short-acting beta-blocker is landiolol. The composition of embodiment 7, further comprising a short-acting calcium channel blocker. The composition of embodiment 13, wherein the short-acting calcium channel blocker is clevidipine. The composition of embodiment 1, wherein the antihypertensive agent comprises a nitrate. The composition of embodiment 15, wherein the nitrate is nitroglycerin. The composition of embodiment 15, wherein the composition comprises between about 0.01 mg and about 0.02 mg of nitrate per about 1 mg of the DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. The composition of embodiment 15, wherein the composition comprises between about 0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. The composition of embodiment 15, wherein the composition is a rapidly dissolving oral tablet or film comprising a combination of between about 0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. A method of administering to a subject a composition comprising;

DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof; and an antihypertensive agent in an amount sufficient to reduce sympathomimetic effects associated with the administration of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof. The method of embodiment 20, wherein the composition comprises DMT succinate. The method of embodiment 20, wherein the composition is administered orally. The method of embodiment 20, wherein the composition is administered parenterally. The method of embodiment 23, wherein the composition is administered by subcutaneous or intravenous injection. The method of embodiment 23, wherein the composition is administered by subcutaneous or intravenous infusion. The method of embodiment 20, wherein the antihypertensive agent comprises a betablocker. The method of embodiment 26, wherein the composition is administered over a time period between about 20 minutes and about 60 minutes. The method of embodiment 26, wherein the beta-blocker has a half-life substantially similar to that of the DMT. The method of embodiment 27, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously. The method of embodiment 26, wherein the beta-blocker is esmolol. The method of embodiment 30, wherein the esmolol is administered at a rate between about 0.01 mg/kg/min and about 0.05 mg/kg/min of esmolol. The method of embodiment 30, wherein the esmolol is administered at a rate between aboutl.O mg/min and about 1.5 mg/min of esmolol. The method of embodiment 32, wherein the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered at a rate between about 0.2 mg/min and about 2.0 mg/min of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. The method of embodiment 33, wherein the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered at a rate between about 0.5 mg/min and about 0.8 mg/min of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. The method of embodiment 33, wherein the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered at a rate between about 1.1 mg/min and about 1.5 mg/min of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. The method of embodiment 26, wherein the composition further comprises a shortacting beta-blocker. The method of embodiment 36, wherein the short-acting beta-blocker is landiolol. The method of embodiment 26, wherein the composition further comprises a shortacting calcium channel blocker. The method of embodiment 38, wherein the short acting calcium channel blocker is clevidipine. The method of embodiment 20, wherein the antihypertensive agent comprises a nitrate. The method of embodiment 40, wherein the nitrate is nitroglycerin. The method of embodiment 40, wherein the nitrate is administered at a rate between about 2 pg/min and about 25 pg/min. The method of embodiment 40, wherein the composition comprises between about 0.01 mg and about 0.02 mg of nitrate per about 1 mg of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. The method of embodiment 40, wherein the composition comprises between about

0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof. The method of embodiment 40, wherein the composition is a rapidly dissolving oral tablet or film comprising a combination of between about 0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof, the method comprising the step of: administering the tablet or film every 5 minutes for a total of 15 minutes. A method of parenterally administering a first composition and a second composition to a patient in need thereof, the method comprising parenterally administering the first composition and the second composition at two distinct intravenous sites, wherein the first composition comprises:

DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof; and the second composition comprises: an antihypertensive agent in an amount sufficient to reduce sympathomimetic effects associated with the administration of the first composition. The method of embodiment 46, wherein the first composition and second composition are administered simultaneously. The method of embodiment 47, wherein the antihypertensive agent comprises a betablocker. The method of embodiment 48, wherein the beta-blocker has a half-life substantially similar to that of the DMT. The method of embodiment 49, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously. The method of embodiment 50, wherein the beta-blocker is esmolol. The method of embodiment 48, wherein the second composition further comprises a short-acting beta-blocker. The method of embodiment 52, wherein the short-acting beta-blocker is landiolol. The method of embodiment 48, wherein the second composition further comprises a short-acting calcium channel blocker. The method of embodiment 54, wherein the short-acting calcium channel blocker is clevidipine. The method of embodiment 47, wherein the antihypertensive agent comprises a nitrate. The method of embodiment 56, wherein the nitrate is nitroglycerin. The method of embodiment 46, wherein the composition is administered over a time period between 20 minutes and 60 minutes. The method of embodiment 46, wherein the method comprises: (a) administering the second composition before administering the first composition; and

(b) administering the first composition and the second composition simultaneously.

60. The method of embodiment 59, wherein the antihypertensive agent comprises a betablocker.

61. The method of embodiment 60, wherein the beta-blocker has a half-life substantially similar to that of DMT.

62. The method of embodiment 61, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously.

63. The method of embodiment 62, wherein the beta-blocker is esmolol.

64. The method of embodiment 60, wherein the second composition further comprises a short-acting beta-blocker.

65. The method of embodiment 64, wherein the short-acting beta-blocker is landiolol.

66. The method of embodiment 60, wherein the second composition further comprises a short-acting calcium channel blocker.

67. The method of embodiment 66, wherein the short acting calcium channel blocker is clevidipine.

68. The method of embodiment 59, wherein the second composition is administered at a first rate in step (a) and administered at a second rate in step (b).

EXAMPLES

[0082] 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

[0083] DMT administered by intravenous infusion was found to promote a significant increase in blood pressure and heart rate that correlated with increasing DMT exposure. FIG.

1 demonstrates this interrelationship between DMT exposure and blood pressure in a single healthy subject. The intravenous infusion of DMT was administered at a rate of 1.3 mg/min for 23 min. The pharmacokinetic profile of plasma DMT was compared to blood pressure and a measure of acute subjective drug effects (SIRS-Spoken Intensity Rating Scale, l(min) to 10 (max) scale). The DMT infusion led to a rapid exposure and a Cmax of 15.7 ng/mL of DMT which corresponded to a maximal SIRS score of 10 eight minutes after the start of infusion. Maximal subjective change and exposure correlated with increases in both systolic and diastolic blood pressure. An increase of about +40 mmHg systolic and about +20 mmHg was associated with maximal DMT exposure (Cmax). Three additional subjects tested under the same infusion conditions displayed similar changes in exposure, SIRS, and hypertensive effects.

[0084] To limit the cardiovascular impact of rapidly administered psychedelics by various routes of administration, beta-blockers or nitrates are used in combination with psychedelics to limit the cardiovascular sympathomimetic effects associated with therapeutic psychedelic administration. While many beta-blockers exist, beta-blockers that have pharmacokinetic parameters, such as half-life, similar to that of the psychedelic are preferred to avoid prolonged hypotension after primary drug exposure.

[0085] As an example, the DMT infusion paradigm outlined in FIG. 1 yielded a mean DMT half-life of about 10 minutes across the four subjects tested. This half-life aligns with the betablocker esmolol which has a half-life of 9 min when administered intravenously (Oliver et al. Beta-blockers: Historical Perspective and Mechanisms of Action. Rev Esp Cardiol (Engl Ed). 2019 Oct;72(10):853-862). Moreover, beyond its short half-life, esmolol is of low lipophilicity which decreases its ability to cross the blood brain barrier which ensures that its pharmacological effects are limited to the peripheral pi -receptor targets.

[0086] In embodiments, esmolol and DMT are two distinct formulations that are administered simultaneously at two distinct parenteral sites. In embodiments, esmolol and DMT are formulated together as a combination and administered at one parenteral site. [0087] In embodiments, esmolol and DMT combinations are administered across various routes of administration including intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, oral thin films, sublingual sprays, intranasal sprays, transdermal patches, sublingual ODTs, and oral ODTs.

[0088] Esmolol is administered in combination with DMT to prevent the hypertension induced by the psychedelic. In one embodiment, the preferred dose range of about 1 mg/min to about 1.5 mg/min of esmolol is administered over 30 minutes contemplating a 30 min infusion of DMT at 1.3 mg/min of DMT. For the esmolol dose, this would equate to about 0.025 mg/kg/min for a 60 kg individual for 30 minutes. Varying administration routes, times, formulations, and dosages may require varying doses of esmolol to properly prevent or reduce the hypertensive effects of DMT.

[0089] In embodiments, the dose of esmolol in combination with DMT is between about 0.01 mg/kg/min and about 0.05 mg/kg/min of esmolol. In embodiments, the dose of esmolol in combination with DMT is between about 0.015 mg/kg/min and about 0.04 mg/kg/min of esmolol. In one embodiment, the dose of esmolol in combination with DMT is between about 0.02 mg/kg/min and about 0.03 mg/kg/min of esmolol.

[0090] Additional combinations of beta-blockers, such as esmolol, and DMT further comprise short beta-blockers. In embodiments, the short-beta blocker is landiolol. In one embodiment, the combination comprises DMT, esmolol, and landiolol. In embodiments, short-acting calcium channel blockers are included in the combination. In embodiments, the short-acting calcium channel blocker is clevidipine. In embodiments, the combination comprises DMT, esmolol, and clevidipine. In embodiments, the combination comprises DMT, esmolol, landiolol, and clevidipine.

[0091] In embodiments, the combination drug is a single composition of the psychedelic and the antihypertensive. In embodiments, the combination drug is a staged dosing product wherein the antihypertensive agent is given before the psychedelic depending on the antihypertensive agent overall half-life. In embodiments, the antihypertensive agent can be considered prophylactic.

[0092] In embodiments, esmolol is administered before the DMT formulation. In embodiments, esmolol is administered simultaneously with the DMT formulation. In embodiments, esmolol is administered at a first rate prior to administration of DMT and then simultaneously administered with the DMT at a second rate. In embodiments, esmolol is administered at a rate between about 0.25 mg/kg/min and about 0.5 mg/kg/min for a minute followed by about 0.01 mg/kg/min to about 0.1 mg/kg/min of esmolol while DMT is being administered. (Prescribing information for Brevibloc (Esmolol Hydrochloride): www.baxterpi.com/pi-pdf/Brevibloc_PI.pdf)

Example 2

[0093] The Example 1 method of administering an antihypertensive agent with a psychedelic to control hypertension can also be extended to nitrates. Nitrates, as a drug class, promote rapid vasodilation by providing a donating nitric oxide, an endothelium-derived relaxing factor (EDRF) which in turn increases intracellular cGMP and cGMP-dependent protein kinase I (cGK-I) (Daiber et al. Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress. Antioxid Redox Signal. 2015 Oct 10;23(l l):899-942.). This protein kinase inhibits inositol- 1,4,5-triphosphatedependedent calcium release lowering intracellular calcium levels and causing an inhibition of myosin light chain kinase. This net inhibition causes a release of the myosin head from the actin filament in the vasculature tissue to result in a rapid vasorelaxation.

[0094] Nitrates can be leveraged in a combination context not only to counteract the sympathomimetic effects of psychedelics, but also to improve absorption and potentially limit localized toxicity that is caused upon certain routes of administration. For example, DMT can cause localized inflammation that leads to underlying local necrosis of nearby tissue. A localized inflammatory response associated with necrosis was observed in rodents when a formulation of DMT was administered by either a subcutaneous or intramuscular injection. Upon coadministration of a nitrate and a psychedelic, the nitrate will lead to a localized increase of blood flow allowing a more rapid absorption from the subcutaneous or intramuscular compartment and a decrease in the local dwell-time to limit exposure and minimize the inflammatory process. In this manner, the psychedelic and nitrate combination product can help limit hypertension, but also improve overall local tolerability.

[0095] In embodiments, the combination drug comprises a nitrate component formulated with DMT as a combination to be administered at one parenteral site.

[0096] In embodiments, the DMT formulation and nitrate formulation are distinct from one another and are administered simultaneously at two distinct parenteral sites. [0097] In embodiments, nitrate and DMT combinations are administered across various routes of administration including intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, oral thin films, sublingual sprays, intranasal sprays, transdermal patches, sublingual ODTs (oral disintegrating tablets), and oral ODTs.

[0098] In embodiments, the nitrate component paired with the psychedelic is any nitrate. In embodiments, the nitrate component is any nitrate that can be formulated as a subcutaneous injection, subcutaneous infusion, or intramuscular injection. In embodiments, the nitrate is nitroglycerin (trinitrate: 1,2,3-propanetriol). In embodiments, nitrates known to be administered in the same manner as the method of administration of the psychedelic are used as the nitrate component. In embodiments, the psychedelic is administered orally and an immediate release orally bioavailable nitrate is used as the nitrate component.

[0099] In embodiments, the nitrate component is administered by IV or subcutaneous infusion between about 0.002 mg/min and about 0.2 mg/min. In embodiments, the nitrate component is administered by IV or subcutaneous infusion between about 0.05 pg/min and about 50 pg/min. In one embodiment, the infusion of the nitrate is 30 minutes for a 30-minute infusion of DMT at about 1.3 mg/min of DMT. In embodiments, the nitrate is infused between about 2 pg/min and about 25 pg/min. In one embodiment, between about 60 pg and about 750 pg nitrate is infused over 30 minutes for a 60 kg individual. In embodiments, the nitrate is infused at a rate of about 1 pg/kg/min to about 15 pg/kg/min. In one embodiment, the nitrate infused is nitroglycerin.

[0100] In embodiments, the drug combination of DMT and the nitrate component is injected subcutaneously. In embodiments, between about 10 mg and about 160 mg of DMT is paired with between about 0.10 mg and about 1.5 mg of the nitrate component. In one embodiment, the nitrate component is nitroglycerin.

[0101] In embodiments, the drug combination of DMT and the nitrate component is injected intramuscularly. In embodiments, between about 10 mg and about 160 mg of DMT is paired with between about 0.10 mg and about 1.5 mg of the nitrate component. In one embodiment, the nitrate component is nitroglycerin.

[0102] In embodiments, the drug combination of DMT and the nitrate component is administered by a sublingual, buccal, or otherwise oral transmucosal route of administration. In one embodiment, the between about 10 mg and about 160 mg of DMT (e.g., about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg) is paired with between 0.1 mg and 1.0 mg of sublingual nitroglycerin. In embodiments, the drug combination is administered by rapidly dissolving/disintegrating tablets or oral thin films containing a combination of between 0.1 mg and 1.0 mg of nitroglycerin and between about 10 mg and about 160mg of DMT (e.g., about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg or about 150 mg). In embodiments, the tablets or oral films are administered every about 5 minutes for a total of about 15 minutes.

[0103] 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.

[0104] Other embodiments and uses of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure 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 disclosure indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A composition for administration to a subject comprising;

N,N-dimethyltryptamine (DMT), a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof; and an antihypertensive agent in an amount sufficient to reduce sympathomimetic effects associated with the administration of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof.

2. The composition of claim 1, wherein the composition comprises DMT succinate.

3. The composition of claim 1, wherein the composition is for oral administration.

4. The composition of claim 1, wherein the composition is for parenteral administration.

5. The composition of claim 4, wherein the composition is for subcutaneous or intravenous injection.

6. The composition of claim 4, wherein the composition is for subcutaneous or intravenous infusion.

7. The composition of claim 1, wherein the antihypertensive agent comprises a betablocker.

8. The composition of claim 7, wherein the beta-blocker has a half-life substantially similar to that of DMT.

9. The composition of claim 8, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously.

10. The composition of claim 7, wherein the beta-blocker is esmolol.

11. The composition of claim 7, further comprising a short-acting beta-blocker.

12. The composition of claim 11, wherein the short-acting beta-blocker is landiolol.

13. The composition of claim 7, further comprising a short-acting calcium channel blocker.

14. The composition of claim 13, wherein the short-acting calcium channel blocker is clevidipine.

15. The composition of claim 1, wherein the antihypertensive agent comprises a nitrate.

16. The composition of claim 15, wherein the nitrate is nitroglycerin.

17. The composition of claim 15, wherein the composition comprises between about 0.01 mg and about 0.02 mg of nitrate per about 1 mg of the DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

18. The composition of claim 15, wherein the composition comprises between about 0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

19. The composition of claim 15, wherein the composition is a rapidly dissolving oral tablet or film comprising a combination of between about 0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

20. A method of administering to a subject a composition comprising;

DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof; and an antihypertensive agent in an amount sufficient to reduce sympathomimetic effects associated with the administration of the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof.

21. The method of claim 20, wherein the composition comprises DMT succinate.

22. The method of claim 20, wherein the composition is administered orally.

23. The method of claim 20, wherein the composition is administered parenterally.

24. The method of claim 23, wherein the composition is administered by subcutaneous or intravenous injection.

25. The method of claim 23, wherein the composition is administered by subcutaneous or intravenous infusion.

26. The method of claim 20, wherein the antihypertensive agent comprises a beta-blocker.

27. The method of claim 26, wherein the composition is administered over a time period between about 20 minutes and about 60 minutes.

28. The method of claim 26, wherein the beta-blocker has a half-life substantially similar to that of the DMT.

29. The method of claim 27, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously.

30. The method of claim 26, wherein the beta-blocker is esmolol.

31. The method of claim 30, wherein the esmolol is administered at a rate between about 0.01 mg/kg/min and about 0.05 mg/kg/min of esmolol.

32. The method of claim 30, wherein the esmolol is administered at a rate between aboutl.O mg/min and about 1.5 mg/min of esmolol.

33. The method of claim 32, wherein the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered at a rate between about 0.2 mg/min and about 2.0 mg/min of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

34. The method of claim 33, wherein the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered at a rate between about 0.5 mg/min and about 0.8 mg/min of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

35. The method of claim 33, wherein the DMT, the DMT analog, or the pharmaceutically acceptable salt or prodrug thereof is administered at a rate between about 1.1 mg/min and about 1.5 mg/min of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

36. The method of claim 26, wherein the composition further comprises a short-acting beta-blocker.

37. The method of claim 36, wherein the short-acting beta-blocker is landiolol.

38. The method of claim 26, wherein the composition further comprises a short-acting calcium channel blocker.

39. The method of claim 38, wherein the short-acting calcium channel blocker is clevidipine.

40. The method of claim 20, wherein the antihypertensive agent comprises a nitrate.

41. The method of claim 40, wherein the nitrate is nitroglycerin.

42. The method of claim 40, wherein the nitrate is administered at a rate between about 2 pg/min and about 25 pg/min.

43. The method of claim 40, wherein the composition comprises between about 0.01 mg and about 0.02 mg of nitrate per about 1 mg of the DMT, or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

44. The method of claim 40, wherein the composition comprises between about 0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof.

45. The method of claim 40, wherein the composition is a rapidly dissolving oral tablet or film comprising a combination of between about 0.1 mg and about 1.0 mg of nitrate and between about 10 mg and about 160 mg of the DMT or an equivalent amount of the DMT analog, the pharmaceutically acceptable salt or prodrug thereof, the method comprising the step of: administering the tablet or film every 5 minutes for a total of 15 minutes.

46. A method of parenterally administering a first composition and a second composition to a patient in need thereof, the method comprising parenterally administering the first composition and the second composition at two distinct intravenous sites, wherein the first composition comprises:

DMT, a DMT analog, or a pharmaceutically acceptable salt or prodrug thereof; and the second composition comprises: an antihypertensive agent in an amount sufficient to reduce sympathomimetic effects associated with the administration of the first composition.

47. The method of claim 46, wherein the first composition and second composition are administered simultaneously.

48. The method of claim 47, wherein the antihypertensive agent comprises a beta-blocker.

49. The method of claim 48, wherein the beta-blocker has a half-life substantially similar to that of the DMT.

50. The method of claim 49, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously.

51. The method of claim 50, wherein the beta-blocker is esmolol.

52. The method of claim 48, wherein the second composition further comprises a shortacting beta-blocker.

53. The method of claim 52, wherein the short-acting beta-blocker is landiolol.

54. The method of claim 48, wherein the second composition further comprises a shortacting calcium channel blocker.

55. The method of claim 54, wherein the short-acting calcium channel blocker is clevidipine.

56. The method of claim 47, wherein the antihypertensive agent comprises a nitrate.

57. The method of claim 56, wherein the nitrate is nitroglycerin.

58. The method of claim 46, wherein the composition is administered over a time period between 20 minutes and 60 minutes.

59. The method of claim 46, wherein the method comprises:

(a) administering the second composition before administering the first composition; and

60. The method of claim 59, wherein the antihypertensive agent comprises a beta-blocker.

61. The method of claim 60, wherein the beta-blocker has a half-life substantially similar to that of DMT.

62. The method of claim 61, wherein the beta-blocker has a half-life between about 8 minutes and about 12 minutes when administered intravenously.

63. The method of claim 62, wherein the beta-blocker is esmolol.

64. The method of claim 60, wherein the second composition further comprises a shortacting beta-blocker.

65. The method of claim 64, wherein the short-acting beta-blocker is landiolol.

66. The method of claim 60, wherein the second composition further comprises a shortacting calcium channel blocker.

67. The method of claim 66, wherein the short acting calcium channel blocker is clevidipine.

68. The method of claim 59, wherein the second composition is administered at a first rate in step (a) and administered at a second rate in step (b).