Novel N,N-Dimethyltryptamine Compositions and Methods

Abstract

A composition comprising N,N-dimethyltryptamine (DMT), or a pharma- ceutically acceptable salt thereof, capable of providing therapeutically effective blood levels of DMT for about 20 to about 60 minutes when administered to a human. A method of treating a neurological disease or condition comprising buccal, sublingual, subcutaneous, or intranasal administration to a subject in need thereof of an effective amount of DMT, or a pharma- ceutically acceptable salt thereof, capable of providing therapeutically effective blood levels of DMT for about 20 to about 60 minutes when administered to a human.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 179,679, filed April 26, 2021, the entire contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates to novel N,N-dimethyltryptamine (DMT) compositions and methods for treating neurological diseases and conditions. In particular, the present disclosure provides improved pharmaceutical compositions comprising N,N-dimethyltryptamine or a pharma- ceutically acceptable salt thereof for the treatment of neurological diseases and conditions. [Background technology]

[0003] Lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine are serotonergic drugs often referred to as "classic hallucinogens" or "psychedelics" that have the ability to induce qualitatively altered states of consciousness such as euphoria, ecstasy, transcendence of time and space, spiritual experiences, or the collapse of personal boundaries, while only minimally producing other effects such as sedation, narcosis, or hyperstimulation. Chemically, serotonergic hallucinogens are either phenylalkylamines or indolamines, and the indolamine class is divided into two subsets, the ergolines and the tryptamines.

[0004] Naturally occurring hallucinogens such as N,N-dimethyltryptamine from the South American shrub Psychotria viridis, psilocybin from over 200 mushroom species, or mescaline from the peyote cactus of southwestern South America and northern Mexico have been used for hundreds of years by indigenous cultures in ritual or sociocultural contexts and in religious ritual situations. The potential for nonspecific "cures" has been ascribed to the use of naturally occurring hallucinogens in those settings, but more scientific investigations of their potential therapeutic applications for defined disorders were not pursued until the discovery of the synthetic ergoline lysergic acid diethylamide (LSD) in 1943.

[0005] With the advent of knowledge about the serotonin system and its role in brain function, researchers began to identify the molecular activity of hallucinogens. However, it was less clear how that activity translated into the therapeutic effects observed in psychiatric disorders. Two main concepts were proposed. The first concept, called "psychotherapy", emphasized the ability of hallucinogens given in low doses to promote the loosening of psychological defense mechanisms, which, in combination with psychotherapy, allows for deep inward insight and recovery from trauma and its subsequent cathartic effects. Thus, the basic mechanism considered in psychotherapy was the activation and deepening of the concomitant psychotherapeutic process, which also required multiple drugs and therapy sessions. The second concept, called "psychedelic therapy", emphasized the ability of hallucinogens given in a relatively high single dose to induce the so-called "peak hallucinogenic experience". Peak experiences are primarily characterized by the loss of judgments over time and space, as well as the collapse of ego boundaries, which often culminates in the experience of the most blissful state and sensation of being a whole and harmonious being in the unity of the universe. Thus, the basic mechanism believed in psychedelic therapy was to produce a unique and overwhelming experience of psychological integration and harmony and subsequent intuitive perception of self-improvement, as well as enhanced pleasure in life and a sense of inner peace.

[0006] Scientific research surrounding the use of hallucinogens to treat psychiatric disorders flourished in the 1960s, but recreational use of these substances rapidly increased, and hallucinogens were soon presented in the media as highly dangerous drugs of abuse. The perceived danger to social order led to the passage of the U.S. Controlled Substances Act in 1970, under which LSD and other hallucinogens were classified as Schedule 1, the most restrictive category, which is considered to contain drugs that have no medical use and a high potential for abuse. Over the next three decades, little progress has been made regarding the possible therapeutic use of hallucinogens.

[0007] Recently, there has been a resurgence of interest in the field of psychedelic therapy, and classical psychedelics have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, The Therapeutic Potential of Psychedelic Drugs: Past, Present and Future, Neuropsychopharmacology;42,2105-2113(2017)). Specifically, psilocybin demonstrated significant improvements in a wide range of depression and anxiety rating scales in a randomized double-blind study (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)).

[0008] N,N-Dimethyltryptamine (hereinafter, DMT) is also understood to hold therapeutic value as a hallucinogen, and efficacy trials are underway to evaluate the effects of intravenously administered DMT or DMT fumarate in subjects with major depressive disorder (MDD). However, while the unique properties of DMT make it an attractive potential drug treatment, particularly for neurological diseases and conditions, current therapeutic compositions and administration methods may complicate treatment and not provide optimal therapeutic outcomes. 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 in determining a suitable administration regimen with an appropriate dose and frequency of administration of DMT to provide an effective therapy for neurological diseases and conditions. This is especially true for neurological diseases and conditions that would benefit from the presence of therapeutic blood levels of DMT for a longer period of time after administration than can be achieved with a single dose of DMT via injection or inhalation.

[0009] Thus, there is a significant need for easily administrable drug treatments of DMTs to treat neurological diseases and conditions. Such drug treatments that maximize efficacy while effectively controlling drug side effects are particularly interesting, especially when they can be administered via convenient routes, including self-administration. The present disclosure solves this need by providing a novel composition comprising DMTs or pharma- ceutically acceptable salts thereof, which has a rapid onset of action when administered by intranasal, buccal, sublingual, or subcutaneous injection, but also extends the duration of effective action of DMTs compared to DMTs administered by intravenous injection or inhalation. Summary of the Invention

[0010] In one aspect, the disclosure provides a pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof, wherein after administration to a subject, the human plasma Tmax of DMT is 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, specifically about 5, 6, 7, 8, 9 minutes, or 10 minutes). Preferably, after Tmax is achieved, the concentration of DMT is maintained at about 50% or more, preferably 80% or more, of Cmax for about 10 minutes to about 30 minutes (e.g., about 10, about 15, about 20, about 25, about 30 minutes).

[0011] In one embodiment, a pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof is administered bucally, sublingually, subcutaneously, or intranasally.

[0012] In one aspect, the disclosure provides a pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof, wherein after buccal, sublingual, subcutaneous, or intranasal administration to a subject, the blood level of DMT is maintained at a therapeutically effective blood level, preferably at a concentration of about 250 nmol / L (or equivalent to 47.07 ng / mL of the free base at 188.27 g / mol) or greater, for at least about 10 minutes (e.g., about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 minutes), and is thereafter reduced to about 10% or less of Cmax, preferably within about 20 minutes (e.g., about 10, about 15, or about 20 minutes).

[0013] In one aspect, the disclosure provides a pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof, wherein after buccal, sublingual, subcutaneous, or intranasal administration to a subject, the human plasma T1 / 2 is about 5 minutes to about 20 minutes, e.g., about 10 minutes to about 20 minutes.

[0014] In one aspect, the disclosure provides a pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof, wherein about 100% of the drug is released from the composition within about 15 minutes to about 50 minutes, e.g., about 20 minutes to about 30 minutes, following buccal, sublingual, subcutaneous, or intranasal administration to a subject at a dose of about 5 mg to 80 mg (e.g., about 50 mg).

[0015] In one embodiment of any of the foregoing aspects, the agent is delivered transmucosally.

[0016] In one embodiment of any of the foregoing aspects, the pharmaceutical composition is administered intranasally. In certain embodiments, the agent is absorbed across the nasal mucosa.

[0017] In one embodiment of any of the foregoing aspects, the pharmaceutical composition is administered bucally. In certain embodiments, the agent is absorbed across the buccal mucosa.

[0018] In one embodiment of any of the foregoing aspects, the pharmaceutical composition is administered sublingually. In certain embodiments, the agent is absorbed across the sublingual mucosa.

[0019] In one embodiment of any of the foregoing aspects, the pharmaceutical composition is administered subcutaneously. In certain embodiments, the pharmaceutical composition is administered by subcutaneous injection.

[0020] In one aspect, the present disclosure provides a method for treating a neurological disease or condition, comprising transmucosally administering to a subject an effective amount of DMT or a pharma- ceutically acceptable salt thereof. In one embodiment of this aspect, the agent is absorbed across the buccal mucosa. In one embodiment of this aspect, the agent is absorbed across the sublingual mucosa. In one embodiment of this aspect, the agent is absorbed across the nasal mucosa.

[0021] In one aspect, the present disclosure provides a method for treating a neurological disease or condition, comprising subcutaneously administering to a subject an effective amount of DMT or a pharma- ceutically acceptable salt thereof. In one embodiment of this aspect, the agent is administered by subcutaneous injection. [Brief description of the drawings]

[0022] Various objects and advantages of the present disclosure as well as a more complete understanding will become apparent and will be more readily appreciated by reference to the following detailed description and claims, taken in conjunction with the accompanying drawings.

[0023] [Figure 1] FIG. 1 is a table of the change in DMT concentration in human serum over time following administration of a pharmaceutical composition of the present disclosure containing 50 milligrams ("mg") of the fumarate salt of DMT. [Diagram 2] 2 is a table of the % release of DMT over time in serum following administration of three different formulations of the present disclosure that include DMT fumarate. Formulations 1, 2, and / or 3 may be selected, for example, from a buccal film for subcutaneous administration and parenteral injection. [Figure 3a] FIG. 3a shows the mean and standard deviation of three replicate measurements of DMT permeation through porcine buccal mucosa as measured with Franz diffusion cells. [Figure 3b] FIG. 3b shows DMT permeability data through porcine buccal mucosa measured with Franz diffusion cells for each of the three replicates. [Figure 4] FIG. 4 shows the plasma concentration of DMT in rats following a single subcutaneous administration of 5 mg / kg or 10 mg / kg of DMT succinate. [Diagram 5] FIG. 5 shows the components of a Franz diffusion cell. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Drugs can be absorbed through mucosal surfaces, such as in the nasal cavity and oral cavity. Drug delivery through mucosal surfaces can be efficient because they lack the stratum corneum of the epidermis, which is the main barrier to absorption across the skin. Mucosal surfaces also typically have a rich blood supply, which can rapidly transport drugs systemically while avoiding significant degradation by first-pass hepatic metabolism.

[0025] There are three absorption pathways for drugs sprayed onto the olfactory mucosa, including by olfactory neurons, by supporting cells and the surrounding capillary bed, and into the cerebrospinal fluid. Absorption by olfactory neurons and into the cerebrospinal fluid has the potential for direct effects on the brain while minimizing systemic concentrations. Absorption of drugs through the nasal mucosa tends to be rapid.

[0026] Similar to intranasal administration, oral transmucosal absorption is generally rapid due to the rich vascular supply of the mucosa and the lack of a stratum corneum in the epidermis. Such drug delivery typically provides a rapid rise in blood concentration and also avoids the enterohepatic circulation and immediate destruction by gastric acid or the partial first-pass effect of the intestinal wall and hepatic metabolism.

[0027] The present disclosure is based, in one embodiment, on the discovery of certain compositions of DMT or pharma- ceutically acceptable salts thereof, which provide rapid onset of the drug following administration to a subject in need thereof, particularly when the drug is administered transmucosally by nasal, buccal, or sublingual routes, but also when given subcutaneously. The rapid onset is, in certain embodiments of the present disclosure, followed by a period of effective DMT exposure that can exceed the period of effective exposure achievable when the same drug is administered intravenously.

[0028] The compositions of the present disclosure, in another embodiment, can achieve long-term exposure of DMT at therapeutically effective levels, followed by rapid elimination. Thus, for example, therapeutically effective blood levels of DMT may be maintained for up to about 15 minutes to about 60 minutes after administration, after which time there is a rapid decline in DMT blood levels. For example, a decline in DMT blood levels over a period of about 20 minutes or less may result in blood containing DMT at a Cmax level of about 10% or less. In one embodiment, 100% of DMT is released within about 60 minutes after administration.

[0029] The unique PK profile exhibited by the compositions of the present disclosure translates into particular advantages in treating neurological diseases or conditions, which are superior to compositions of DMT or a pharma- ceutically acceptable salt thereof that exhibit (1) harsh onset effects (e.g., caused by very rapid onset), (2) shorter duration of therapeutic exposure of the DMT, and / or (3) slower elimination.

[0030] Therefore, the present disclosure relates to a new pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof, and its use, particularly for the treatment of neurological diseases or conditions. In particular, the present disclosure provides, in one aspect, a pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof, which exhibits rapid onset, long-term therapeutic exposure of DMT, and rapid clearance after transmucosal (e.g., buccal, sublingual, or intranasal) administration to a subject. The present disclosure also provides, in a second aspect, a pharmaceutical composition comprising DMT or a pharma- ceutically acceptable salt thereof, which exhibits rapid onset, long-term therapeutic exposure of DMT, and rapid clearance after subcutaneous administration to a subject.

[0031] [Definition] As used herein, unless expressly stated otherwise, the following terms are defined with the following meanings:

[0032] The term "about" when used before a numerical designation, e.g., pH, temperature, amount, or concentration, denotes an approximation that may vary by up to (+) or (-) 5%.

[0033] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a pharma- ceutically acceptable carrier" may include a plurality of pharma- ceutically acceptable carriers, including mixtures thereof.

[0034] The term "and / or" is intended to mean either or both of the two components of the invention.

[0035] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human.

[0036] As used herein, the term "device" refers to an equipment or system capable of delivering a drug to a patient in need thereof.

[0037] The terms "in need of treatment" and "in need of" when referring to treatment are used interchangeably and refer to the judgment that the patient would benefit from treatment administered by a caring person (e.g., a doctor, nurse, nurse practitioner, etc.).

[0038] The terms "treat" and "treatment" herein refer to therapeutic treatment, including prophylactic or preventative measures, where the purpose is to prevent or slow down (reduce) undesirable physiological changes associated with a disease or condition. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slow down the progression of a disease or condition, improvement or alleviation of a disease or condition, and remission (partial or total) of a disease or condition. "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. Those in need of treatment include those already with a disease or condition, as well as those prone to have a disease or condition, or those in whom a disease or condition is to be prevented. "Treatment", when referring to depression, can also include reducing at least one sign or symptom of depression. Examples of signs or symptoms of depression include depressed mood, decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or slowing, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to concentrate or indecisiveness, or suicidal thoughts or behaviors.

[0039] The terms "nasal delivery", "intranasal delivery", "nasal administration" or "intranasal administration" refer to the route of administration, where a pharmaceutical dosage form is taken into or through the nose (e.g., nasal cavity). Similarly, "nasal delivery device" or "intranasal delivery device" is intended to mean a device that administers a drug into the nasal cavity. Non-limiting examples of intranasal administration include the introduction of a solution or suspension in the form of a nasal spray or nasal drops (direct drops), or the intranasal application of a gel, emulsion, or ointment.

[0040] The term "buccal delivery" or "buccal administration" refers to a route of administration whereby a pharmaceutical dosage form is applied between the patient's cheek and gums (ie, the buccal cavity).

[0041] The term "sublingual delivery" refers to a route of administration whereby a pharmaceutical dosage form is applied under the patient's tongue.

[0042] The term "subcutaneous delivery" refers to a route of administration in which a pharmaceutical dosage form is injected into the tissue layer between the skin and muscle with a short needle.

[0043] As used herein, the term "pharmaceutical acceptable" refers to a component of a pharmaceutical composition that is compatible with the other ingredients of the formulation and not unduly harmful to the recipient thereof.

[0044] As used herein with respect to "DMT or a pharma- ceutically acceptable salt thereof," the term "pharmaceutically acceptable salt" refers to a pharma- ceutically acceptable acid addition salt. Typically, an acidic agent may be used to prepare a salt, particularly a pharma- ceutical acceptable salt, of DMT. Examples of suitable acidic agents include fumaric acid, hydrochloric acid, tartaric acid, citric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, lactic acid, tartaric acid, and gluconic acid. Often, the form of DMT salt used in the pharmaceutical composition of the present disclosure or in another method according to various aspects of the present disclosure, and embodiments thereof, is a pharma- ceutical acceptable salt of the fumarate, hydrochloride, tartrate, or citrate, e.g., the fumarate.

[0045] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered, and includes, but is not limited to, such liquids and powders that are hydrophilic substances, hydrophobic substances, and substances with both hydrophilic and hydrophobic properties, such as emulsifying agents.

[0046] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an active agent that elicits in a tissue, system, or individual the biological or medicinal response desired by a researcher, medical practitioner, or individual.

[0047] As used herein, the term neurological disease or condition refers to a psychoneurotic disorder, (such as depression (including severe depression such as treatment-resistant depression, major depressive disorder, and persistent depressive disorder), catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder), anxiety, anxiety disorder, social anxiety disorder, generalized anxiety disorder (GAD), anorexia disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder, body dysmorphic disorder, mood or affect abnormalities including the above conditions, dysthymia, schizoaffective disorder, schizophrenia, and other psychotic disorders, panic disorder, post-traumatic stress disorder, phobic disorder, and personality disorders with abnormal moods (such as borderline personality disorder, schizotypal disorder, schizophrenic disorder, schizophrenic disorder, schizophrenia, and other psychotic disorders). "means a disease or condition selected from obsessive-compulsive disorder, addiction (including substance use disorders such as addiction to nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamines, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances), addictive behaviors (including eating, gambling, sex, pornography, video games, work, exercise, spiritual obsessions, self-harm, travel, and shopping addictions), eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), and pain (including pain associated with migraines or headaches, or chronic pain) in which suicidal ideation or rumination / repetitive, unproductive thoughts adversely affect a person's behavior / mood / ability to concentrate."

[0048] As used herein, the term "treatment-resistant depression" or "TRD" refers to a depressive disorder that does not respond satisfactorily to appropriate treatment. TRD is a complex phenomenon influenced by variability in depression subtypes, psychiatric comorbidities, and coexisting disorders. Although TRD symptom manifestations are most commonly associated with major depressive disorder (MDD), they are also found in the depressive phase of bipolar disorder.

[0049] As used herein, the term "onset" refers to the time to achieve maximum plasma concentration (i.e., Tmax) following administration, and may also be described as "onset of action." "Rapid onset" in the context of the present disclosure means that the agent achieves Cmax within about 20 minutes (e.g., within about 2-10 minutes). However, the onset following administration of a composition according to the present disclosure is less rapid than when the DMT is administered by intravenous injection, and is consequently less "harsh" to the patient.

[0050] As used herein, the term "disappearance" refers to the time between the last time the concentration of DMT is at Cmax±10% and the first time the plasma concentration of DMT decreases to a threshold level (e.g., about 250 nmol / L or 47.07 ng / mL) below which the drug no longer has any meaningful therapeutic effect. "Rapid disappearance" in the context of this disclosure means less than about 10 minutes. However, although rapid, the disappearance is still long enough for the drug to exert a reasonable duration of hallucinogenic effects.

[0051] Pharmaceutical Compositions and Delivery Pharmaceutical compositions containing DMT or its pharma- ceutical acceptable salt suitable for intranasal administration include compositions in which active ingredient is present in liquid carrier.In various embodiments, the composition may be in the form of an aqueous or non-aqueous solution, suspension, liposomal dispersion, emulsion, microemulsion, or sol-gel.The carrier may contain additives such as solubilizers (e.g., propylene glycol), surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, mucoadhesives, and / or preservatives such as parabens.Methods well known in the art for making intranasal formulations may be found, for example, in Remington, 2000.In addition, methods for formulating compounds for intranasal administration are well known, including prolonging the presence of the active agent in the nasal cavity, combining with agents to increase solubility, and increasing bioavailability.

[0052] Pharmaceutical compositions containing DMT or a pharma- ceutical acceptable salt thereof suitable for buccal and sublingual administration include fast dissolving tablets, wafers, films, strips or patches, orodispersible tablets, oral gels, medicated lollipops, sprays, drops, and other formulations that are retained on the buccal or sublingual mucosal surfaces.

[0053] Pharmaceutical compositions containing DMT or a pharma- ceutically acceptable salt thereof suitable for subcutaneous administration may be provided in unit dosage form (e.g., in single-dose ampoules) or in vials containing several doses and to which suitable preservatives may be added (see below). The compositions may conveniently be in the form of a solution, suspension, or emulsion, or may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. Apart from DMT or a pharma- ceutically acceptable salt thereof, the compositions may include suitable parenterally acceptable carriers and / or excipients. Moreover, the compositions may include suspending agents, solubilizing agents, stabilizing agents, pH adjusting agents, and / or dispersing agents.

[0054] The pharmaceutical composition of the present disclosure may include one or more excipients, diluents, binders, lubricants, glidants, disintegrants, desensitizers, emulsifiers, mucoadhesives, solubilizers, suspending agents, viscosity adjusters, ionic tonicity agents, buffers, carriers, surfactants, or mixtures thereof.The pharmaceutical composition of the present disclosure may also include components such as permeation enhancers, bioadhesive polymers, and means for providing controlled release, such as sustained release of active ingredients.The composition may also include one or more pharma- ceutically acceptable flavoring agents or other taste-masking agents.

[0055] The in vivo release rate and in vivo clearance of DMT can be influenced by means well known in the art.For example, the incorporation of active material into or on microparticle preparations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, or into liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.It is also understood herein that the compound is modified by covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, cyclodextrin, cucurbituril, polyvinylpyrrolidone, or polyproline.The modified compound may exhibit a substantially longer half-life in blood after administration than the corresponding unmodified compound.

[0056] Depending on the delivery device employed, delivery of about 25% to about 100% of the drug product, i.e., DMT, is achieved. However, those skilled in the art will understand that not all drugs can be delivered due to the nature of the drug delivery device, as this is a function of the delivery device employed. Therefore, for clarity, it will be understood that about 25% to about 100% of the drug product delivered will depend on the drug delivery method and / or device selected. Thus, 100% of the drug product delivered may not be all of the drug product, but all of the drug product that the selected device has the ability to deliver.

[0057] [Intranasal composition] Relative to oral dosage forms such as tablets or capsules, intranasal delivery offers rapid absorption, faster onset of therapeutic action, and avoidance of first-pass metabolism in the intestinal wall or liver. For patients who have difficulty swallowing tablets, capsules, or other solids, or who have intestinal failure, the intranasal delivery route may be preferred.

[0058] The composition of the present disclosure for nasal administration comprises DMT or its pharma- ceutically acceptable salt, and can also optionally comprise other components, including, but not limited to, carriers and excipients, such as absorption enhancers, which promote the nasal absorption of the active ingredient after nasal administration, and agents that improve the brain penetration of the drug after nasal administration.Other optional excipients include diluents, binders, lubricants, glidants, disintegrants, desensitizing agents, emulsifiers, mucoadhesives, solubilizers, suspending agents, viscosity adjusters, ionic tonicity agents, buffers, carriers, flavoring agents, and mixtures thereof.In one embodiment, the particle size of the active ingredient is about 60 micrometers or less, which can help ensure the uniformity of any mixture of the particles with other ingredients or provide proper dispersion in liquid vehicles.

[0059] The amount of drug absorbed depends on many factors.These factors include drug concentration, drug delivery vehicle, mucosal contact time, venous drainage of mucosal tissue, the degree to which drug is ionized at the pH of absorption site, the size of drug molecule, and its relative lipid solubility.Those skilled in the art can easily prepare suitable intranasal composition that delivers suitable amount of active drug by taking these factors into account.

[0060] The transport of active ingredients across normal mucosal surfaces (such as nasal or buccal mucosa) can be enhanced by optionally combining with absorption enhancers. Examples of these absorption enhancers include, but are not limited to, cationic polymers, surface active agents, chelating agents, mucolytic agents, cyclodextrins, polymeric hydrogels, combinations thereof, and any other similar absorption enhancers known to those skilled in the art. Representative absorption enhancer excipients include phospholipids such as phosphatidylglycerol or phosphatidylcholine, lysophosphatidyl derivatives such as lysophosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidylglycerol, lysophosphatidylserine, or lysophosphatidic acid, polyols such as glycerol or propylene glycol, glycerides, amino acids, and their fatty acid esters such as their esters, and cyclodextrins. Gelling excipients or viscosity-increasing excipients can also be used.

[0061] Transport of active ingredients across intact mucosal surfaces can also be enhanced by increasing the time that the formulation adheres to the mucosal surface. Mucoadhesive / bioadhesive polymers, such as polymers that form hydrogels, exhibit mucoadhesion and controlled drug release properties and can include the compositions described herein intranasally or bucally. Representative bioadhesive or hydrogel-forming polymers capable of binding to the nasal mucosa are well known to those skilled in the art and include one or more poloxomers such as polycarbophil, polylysine, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose, pectin, carbopol 934P, polyethylene oxide 600K, pluronic F127 and / or pluronic F-68, polyisobutylene (PIB), polyisoprene (PIP), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), xanthan gum, guar gum, and locust bean gum. Other nasal delivery compositions are chitosan-based and are also suitable for increasing the residence time of active ingredients on mucosal surfaces, thereby increasing their bioavailability. Thiolated polymeric excipients that form covalent bonds with cysteine-rich subdomains of the mucus membrane can also provide mucoadhesion that extends the contact time between the active ingredient and the membrane.

[0062] The intranasal composition may also include one or more preservatives. Representative preservatives include quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride, benzododecinium chloride, cetylpyridium chloride, cetrimide, domiphen bromide, etc., alcohols such as benzyl alcohol, chlorobutanol, o-cresol, phenylethyl alcohol, organic acids or their salts such as benzoic acid, sodium benzoate, potassium sorbate, parabens, or complexing agents such as EDTA.

[0063] Carriers and excipients include ion-exchange microspheres carrying suitable anionic groups such as carboxylic acid residues, carboxymethyl groups, sulfopropyl groups, and methylsulfonate groups. Ion-exchange resins such as cation exchangers can also be used. Chitosan, which is partially deacetylated chitin, or poly-N-acetyl-D-glucosamine, or its pharma- ceutically acceptable salts, such as hydrochloride, lactate, glutamate, maleate, acetate, formate, propionate, malate, malonate, adipate, or succinate. Other components suitable for use as non-ion-exchange microspheres include starch, gelatin, collagen, and albumin.

[0064] The composition may also include a suitable acid selected from the group consisting of hydrochloric acid, lactic acid, glutamic acid, maleic acid, acetic acid, formic acid, propionic acid, malic acid, malonic acid, adipic acid, and succinic acid.Other components, such as diluents, are cellulose, microcrystalline cellulose, hydroxypropyl cellulose, starch, hydroxypropyl methylcellulose, and the like.Excipients that adjust the tonicity of the composition may be added, such as sodium chloride, glucose, dextrose, mannitol, sorbitol, lactose, and the like.Acidic or basic buffers may also be added to the intranasal composition to control pH.

[0065] In addition to using absorption enhancers to increase the transport of active agents through mucosa and bioadhesive materials to extend the contact time of active agents along mucosa, administration of active agents can be controlled by using controlled release formulations. There are numerous particulate drug delivery vehicles known to those skilled in the art that can contain active ingredients and deliver them in a controlled manner. Examples include particulate polymeric drug delivery vehicles, such as particles formed from biodegradable polymers and non-polymeric components. These particulate drug delivery vehicles can be in the form of powders, microparticles, nanoparticles, microcapsules, liposomes, and the like. Typically, when an active agent is in particulate form without added components, its release rate depends on the release of the active agent itself. Typically, the absorption rate is enhanced by presenting the agent in a micronized form, with particles less than 20 micrometers in diameter. In contrast, when an active agent is in particulate form as a blend of active agent and polymer, the release of the active agent is at least partially controlled by the removal of the polymer, typically by dissolution, biodegradation, or diffusion from the polymer matrix.

[0066] [Intranasal delivery] Intranasal delivery devices are known in the art.Therefore, any device suitable for delivery of medicaments to nasal mucosa may be used.Non-limiting examples of devices useful for administering liquid compositions include steam devices (e.g. steam inhalers), droppers (e.g. catheters, single-dose droppers, multiple-dose droppers, and unit dose pipettes), mechanical spray pump devices (e.g. squeeze bottles, multiple-dose metered-dose spray pumps, and single / double-dose spray pumps), bidirectional spray pumps (e.g. breath-actuated nasal delivery devices), gas-driven spray systems / atomizers (e.g. single-dose or multiple-dose HFA or nitrogen propellant-driven metered-dose inhalers, including conventional and circumferential velocity inhalers), and motorized nebulizers / atomizers (e.g. pulsed membrane nebulizers, vibratory mechanical nebulizers, and handheld mechanical nebulizers). Non-limiting examples of devices useful for administration of powder compositions (e.g., lyophilized or otherwise dried pooled compositions) include mechanical powder sprayers (e.g., manually actuated capsule-based powder spray devices and manually actuated powder spray devices, manually actuated gel delivery devices), breath actuated inhalers (e.g., single or multi-dose nasal inhalers and capsule-based single or multi-dose nasal inhalers), and insufflation devices (e.g., breath actuated nasal delivery devices).

[0067] The use of a metered dose spray for intranasal delivery can also be accomplished by including the active ingredient in a solution or dispersion in a suitable vehicle that can be administered as a spray. Representative devices of this type are disclosed in the following patents, patent applications, and publications: WO 03 / 026559, WO 02 / 011800, WO 00 / 51672, WO 02 / 068029, WO 02 / 068030, WO 02 / 068031, WO 02 / 068032, WO 03 / 000310, WO 03 / 020350, WO 03 / 082393, WO 03 / 084591, WO 03 / 090812, WO 00 / 41755, and in the pharmaceutical literature (see Bell, A. Intranasal Delivery Devices, in Drug Delivery Devices Fundamentals and Applications, TyIe P. (ed), Dekker, New York, 1988), Remington's Pharmaceutical Sciences, Mack Publishing Co., 1975. all of which are incorporated herein by reference.

[0068] In addition to the above, the compound can also be administered intranasally in the form of irrigation and douche, as known in the art. Nasal douche involves periodically drenching the nasal cavity with a solution containing a drug. Nasal douche is typically used by filling a douche with a solution containing a drug, inserting the nozzle from the douche into one nostril, having the subject open their mouth and breathe, and allowing the solution to flow into one nostril, rinse around the septum, and drain out of the other nostril.

[0069] Means of delivering drugs to the upper portions of the nasal cavity, such as the cribriform cavity, are of particular interest herein. Also of interest is delivery of drugs along the trigeminal nerve pathway.

[0070] Buccal and Sublingual Compositions and Delivery For oral dosage forms such as tablets or capsules, oral transmucosal delivery, like intranasal delivery, offers rapid absorption, faster onset of therapeutic action, and avoidance of first-pass metabolism in the liver or intestinal wall. For patients who have difficulty swallowing tablets, capsules, or other solids, or who have intestinal failure, buccal or sublingual delivery routes are preferred.

[0071] The composition for buccal or sublingual administration comprises DMT or a pharma- ceutically acceptable salt thereof, and at least one excipient to form a solid dosage form. The solid dosage form decomposes in the oral cavity or under the tongue with minimal liquid exposure and body temperature, and ideally adheres to the body tissue of the oral cavity or tissue under the tongue via direct adhesion to the tissue, or in the case of buccal administration, via entrapment of the dosage form between the gums and the inner cheek. The solid dosage form decomposes or melts at body temperature with or without the aid of fluids, saliva, mechanical erosion, or a combination thereof. Alternatively, the dosage form can be sprayed in the oral cavity or under the tongue in the form of a solution spray or dry powder. In general, the composition can be an adhesive that is directed to the body tissue inside the oral cavity of the patient, or under the tongue.

[0072] The dosage form can be, but is not limited to, a tablet, a bioadhesive patch or film, a sponge, a lozenge, a hard candy, a wafer, a lollipop, a spray, a gum, a pill, a pellet, a sphere, combinations thereof, and other forms known to one of skill in the art.

[0073] Buccal or sublingual films represent a particularly convenient vehicle for administering the pharmaceutical composition of the present disclosure. Examples of films include, in one aspect, compositions comprising DMT or a pharma- ceutically acceptable salt thereof in a mucoadhesive polymer. Suitable mucoadhesive polymers include one or more polymers selected from cellulose derivatives, polyacrylic acid, polyacrylates, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, tragacanth, alginates, gums (including karaya gum, guar gum, xanthan gum), soluble starch, gelatin, lectin, pectin, and chitosan. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from hydrophilic polymers, polysaccharides and their derivatives, and hydrogels. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from polyacrylic acid, polyacrylates, celluloses, such as carboxycelluloses (e.g., sodium carboxymethylcellulose), hydroxyalkylcelluloses (e.g., hydroxypropylcellulose, hydroxyethylcellulose, and hydroxyethylethylcellulose), polyvinylpyrrolidone, and polyvinyl alcohol. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from carbopol (polyacrylic acid), carboxymethylcellulose, carboxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and gums. In some embodiments, the mucoadhesive polymer is water-swellable. Typically, the mucoadhesive polymer is present in an amount of about 15% to about 60% by weight of the film composition.

[0074] The film composition may further comprise a permeation enhancer and / or an antioxidant. For example, in some embodiments, the film composition comprises a permeation enhancer, including one or more permeation enhancers selected from, for example, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, and surfactants. In some embodiments, the permeation enhancer is present in an amount of about 5% to about 30% by weight of the film composition. In some embodiments, the film composition comprises an antioxidant, for example, tocopherol acetate, α-tocopherol, L-glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butyl hydroxytoluene (BHT), butyl hydroxyanisole (BHA), tocobiol, and ethylenediaminetetraacetic acid (EDTA).

[0075] In some embodiments, the film composition can form a bilayer or multilayer film composition. Typically, such bilayer or multilayer films can provide a biphasic release profile, which can be advantageous in certain circumstances. In some embodiments, the fast-release film layer comprises a water-soluble polymer. In some embodiments, the water-soluble polymer in the fast-release film comprises one or more polymers selected from hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), povidone, copovidone, polyvinyl alcohol (PVA), low molecular weight polyethylene oxide, and starch-based polymers. In some embodiments, the fast-release film can also optionally comprise a permeation enhancer, including one or more permeation enhancers selected from, for example, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, and surfactants. In some embodiments, the fast-release film can also optionally comprise an antioxidant, such as tocopherol acetate.

[0076] There are numerous compositions and delivery vehicles suitable for buccal or sublingual delivery of active ingredients. In addition to DMT or a pharma- ceutically acceptable salt thereof, other components of the dosage form include inorganic salts such as starch, mannitol, xylitol, saccharin, sucralose, l-menthol, citric acid, l-glutathione, kaolin, calcium sulfate, sodium chloride, and the like, powdered cellulose derivatives, dibasic and tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, hydroxypropyl methylcellulose, anionic excipients, cationic excipients, zwitterionic excipients (such excipients are incorporated herein by reference). Examples of suitable excipients include, but are not limited to, polymeric hydrogels, powdered microsphere mucoadhesive compositions, thiolated polymeric excipients, polycationic materials, chitosan, crosslinked starch, fats, carbohydrates, polyols, buffers, phosphate buffer, acetate buffer, methocel, sodium chloride, water, lactic acid, benzalkonium chloride, demineralized water, cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydrogenated vegetable oils, flavorings, phospholipids, xylitol, cocoa, combinations thereof, and other similar excipients known to those skilled in the art. A plasticizer may also be present. Exemplary plasticizers include polyethylene glycol, propylene glycol, castor oil, vegetable oil, and the like.

[0077] A binder may also be present. Suitable binders include materials such as cellulose, including but not limited to cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose and hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, polyethylene glycol, starch, natural gums (such as acacia, alginates, guar, and acacia), and synthetic gums and waxes.

[0078] Subcutaneous Composition and Delivery For subcutaneous administration, aqueous suspensions, isotonic saline solutions, and sterile injection solutions may be used, optionally containing pharma- ceutically acceptable excipients, such as propylene glycol or butylene glycol, and / or humectants. In addition, suspensions of DMT or its pharma- ceutically acceptable salts may be prepared as oily injection suspensions, if appropriate. 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 carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions. Alternatively, DMT or its pharma-ceutically acceptable salts may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use. Solutions or suspensions may be administered subcutaneously to subjects by injection, using well-known devices and techniques. Any suitable syringe may be conveniently used, including an auto-injector, which may allow self-administration. dosage

[0079] The dose of DMT or a pharma- ceutically acceptable salt thereof administered to a patient having a neurological disease or condition, as defined herein, is typically about 0.1 mg / kg to about 1 mg / kg. A typical human dose (for an adult weighing 50-80 kg) would equate to a dose of about 5 mg to about 80 mg. In one embodiment, the dose is about 10 mg to about 60 mg, such as about 20-60 mg, about 30-60 mg, about 40-60 mg, or any particular amount therebetween, including 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, In the present disclosure, when a range is recited, such as "about 20 to 60 mg," the inventors contemplate all individual values ​​within the range, although some may be specifically recited, but not all may be recited merely for purposes of brevity.

[0080] In certain embodiments, the DMT or a pharma- ceutically acceptable salt thereof may be administered to a patient in one or more doses, for example, 1, 2, 3, 4, or 5 doses, over a 24-hour period, but the total dose administered to a subject should not exceed about 100 mg over a 24-hour period.

[0081] [use] In one aspect, the disclosure provides a pharmaceutical composition, as further described herein, for use in the treatment of a neurological disease or condition.

[0082] In one aspect, the disclosure provides a method of treating a neurological disease or condition comprising transmucosally administering to a subject an effective amount of a DMT or a pharma- ceutically acceptable salt thereof.

[0083] In one aspect, the disclosure provides a method of treating a neurological disease or condition comprising intranasally administering to a subject an effective amount of DMT or a pharma- ceutically acceptable salt thereof.

[0084] In one aspect, the disclosure provides a method of treating a neurological disease or condition comprising buccal administration to a subject of an effective amount of DMT, or a pharma- ceutically acceptable salt thereof.

[0085] In one aspect, the disclosure provides a method of treating a neurological disease or condition comprising sublingually administering to a subject an effective amount of DMT or a pharma- ceutically acceptable salt thereof.

[0086] In one aspect, the disclosure provides a method of treating a neurological disease or condition comprising subcutaneously administering to a subject an effective amount of a DMT or a pharma- ceutically acceptable salt thereof.

[0087] In any one of the above aspects, the neurological disease or condition may be, for example, a neuropsychiatric disorder.

[0088] Examples of neuropsychiatric disorders that may be treated with DMT or a pharma- ceutically acceptable salt thereof include depression (e.g., TRD), anxiety, bipolar disorder, post-traumatic stress disorder, mood or emotional disorders including those listed above, dysthymia, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, post-traumatic stress disorder, phobic disorders, eating disorders and personality disorders accompanied by mood disorders (such as borderline personality disorder, schizophrenia and schizotypal disorder and suicidal ideation), or rumination / repetitive, unproductive thoughts that adversely affect a person's behavior / mood / ability to concentrate.

[0089] In any one of the above aspects, the neurological disease or condition may be, for example, an addiction.

[0090] Examples of addictions that may be treated with DMT or a pharma- ceutically acceptable salt thereof include substance use disorders such as addiction to nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamines, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances.

[0091] In any one of the above aspects, the neurological disease or condition can be, for example, an addictive behavior.

[0092] Examples of addictive behaviors that may be treated with DMT or its pharma- ceutically acceptable salts include addictions to eating, gambling, sex, pornography, video games, work, exercise, spiritual obsessions, self-harm, traveling, shopping, and substance use disorders (SUDs).

[0093] In certain embodiments, the disclosure provides a method of treating depression (including treatment-resistant depression, major depressive disorder, and severe depression such as persistent depressive disorder, catatonic depression, depressive disorder due to a medical condition, or postpartum depression) comprising administering to a subject an effective amount of DMT or a pharma- ceutically acceptable salt thereof transmucosally (e.g., buccally, sublingually, or intranasally).

[0094] In certain embodiments, the disclosure provides a method of treating depression (including treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, depressive disorder due to a medical condition, or severe depression such as postpartum depression) comprising subcutaneously administering to a subject an effective amount of DMT or a pharma- ceutically acceptable salt thereof.

[0095] [Combination therapy] The methods described herein include administering DMT or a pharma- ceutically acceptable salt thereof as the sole active ingredient. However, methods for treating neurological diseases or conditions that include administering DMT or a pharma- ceutically acceptable salt thereof in combination with one or more additional agents are also included within the scope of the present disclosure.

[0096] In one aspect, these additional agents are suitable therapeutic agents for the disease or disorder being treated, as known in the art. In some embodiments, DMT or a pharma- ceutically acceptable salt thereof may be administered to a subject in combination with one or more antidepressants or anxiolytics, such as SSRIs, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or serotonin norepinephrine reuptake inhibitors (SNRIs).

[0097] In some embodiments, the disclosure provides a method of reducing anxiety in a subject undergoing treatment with DMT or a pharma- ceutically acceptable salt thereof, the method comprising administering to the subject i) DMT or a pharma- ceutically acceptable salt thereof, and ii) one or more benzodiazepines.

[0098] In some embodiments, one or more benzodiazepines are administered to a subject at the same time or about the same time as DMT or a pharma- ceutically acceptable salt thereof. In some embodiments, one or more benzodiazepines are administered to a subject before administration of DMT or a pharma- ceutically acceptable salt thereof, for example, 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 psilocybin or its precursor or derivative. In some embodiments, one or more benzodiazepines are administered to a subject after DMT or a pharma- ceutically 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 psilocybin or its precursor or derivative.

[0099] In some embodiments, the benzodiazepine is 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, fluralprazolam, flubromazepam, flubromazolam, fluclotizolam, Selected from the group consisting of 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, and triazolam.

[0100] In certain embodiments, the patient is at least one 2A The patient is administered a DMT or a pharma- ceutically acceptable salt thereof as described herein together with a specific antagonist and / or inverse agonist. In some embodiments, the patient is administered a DMT or a pharma- ceutically acceptable salt thereof together with one or more 5-HT 2A In another embodiment, the patient is administered one or more 5-HT specific antagonists and / or inverse agonists. 2A The specific antagonist and / or inverse agonist is administered 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 prior to administration of the DMT or a pharma- ceutically acceptable salt thereof. In some embodiments, the patient is administered one or more 5-HT 2AThe specific antagonist and / or inverse agonist is administered after administration of the DMT or a pharma- ceutically acceptable salt thereof, 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 administration of the DMT or a pharma- ceutically acceptable salt thereof.

[0101] Preferred 5-HT 2AAntagonists include trazodone, mirtazapine, metergoline, ketanserin, ritanserin, nefazodone, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines, 9-aminomethyl-9,10-dihydroanthracene (AMDA), haloperidol, chlorpromazine, hydroxyzine (Atarax), and 5-MeO-NBp. BrT, niaprazine, altanserin, aripiprazole, etoperidone, setoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rauwolscine, phenoxybenzamine, pulvanserin, deramciclane, nerotanserin, rubazodone, mepiprazole, xylamidine, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinemethanol (M100907), mianserin, AT 1015, DV 7028, eplivanserin, 4F 4PP, fanaserin, alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol (MDL 1 1,939), melperone, mesulergine, paliperidone, 1-[2-(3,4-dihydro-1 / - / -2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine dihydrochloride (PNU 96415E), (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol (R-96544), sarpogrelate, spiperone, ziprasidone, zotepine, and 7-[[4-[2-(4-fluorophenyl)ethyl]-1-piperazinyl]carbonyl]-1-indole-3-carbonitrile (EMD 281014).

[0102] Preferred 5-HT 2A Inverse agonists include, but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and vorinaserin.

[0103] In some embodiments, the present disclosure provides a method for reducing the negative side effects associated with traumatic hallucinatory experiences in patients undergoing treatment with DMT or a pharma- ceutically acceptable salt thereof. In one aspect, the method comprises administering to a patient: i) DMT or a pharma- ceutically acceptable salt thereof; and ii) one or more 5-HT 2A In another embodiment, the method comprises administering to the patient i) DMT or a pharma- ceutically acceptable salt thereof, and ii) one or more cannabinoids or cannabinoid derivatives.

[0104] In some embodiments, the cannabinoid is selected from the group consisting of 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), and CBT (cannabicitran). In certain embodiments, the cannabinoid is CBD (cannabidiol).

[0105] 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.

[0106] In a further aspect of the present disclosure, when treating a neuropsychiatric disease or disorder, such as depression (e.g., TRD), anxiety, or addiction, the compositions of the present disclosure may be administered in conjunction with other types of therapy, such as 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 commitment therapy, family-focused therapy, psychodynamic therapy, light therapy, computer therapy (including digital cognitive behavioral therapy), cognitive remediation, exercise, or transcranial magnetic stimulation (TMS). In one embodiment, the 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, the compositions of the present disclosure may be administered in conjunction with a therapy using a transdiagnostic approach (e.g., to treat depression or anxiety) (see J Consult Clin Psychol. 2020 Mar;88(3):179-195).

[0107] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, mention of any references, articles, publications, patents, patent publications, and patent applications herein is not, and should not be, taken as an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country throughout the world.

[0108] Example 1: Buccal administration of DMT through porcine mucosa

[0109] [Table 1]

[0110] [method] The permeability of the DMT buccal films was assessed using Franz diffusion cells (see FIG. 5). A buccal film of a specific size was placed in the donor compartment. A pH 7 M phosphate buffer was added into the receptor chamber. Both compartments were separated by porcine buccal mucosa. The temperature of the receptor medium was maintained at 37 ± 1°C throughout the entire study by a circulating water bath and was continuously stirred. · 0.5 mL samples were withdrawn at predetermined time intervals over a 4-hour period and replaced with an equal volume of medium. Drug concentrations in the withdrawn samples were analyzed by HPLC.

[0111] [Results](See Figures 3a and 3b). The permeability of DMT from buccal films was evaluated on both sides of porcine buccal mucosa in 0.01 M phosphate buffer solution at pH 7. · To present the percent cumulative amount of DMT permeated through the buccal mucosa at different time points. Based on the DMT permeability profile, a linear increase in the permeability of DMT was observed. Cumulative DMT permeation was found to be approximately 20% from the finalized buccal film formulation over a 4-hour period.

[0112] Example 2: Study of subcutaneously administered DMT succinate [Table 2]

[0113] [Table 3] The results are also shown in FIG.

Claims

1. A composition comprising N,N-dimethyltryptamine (DMT) or a pharma- ceutically acceptable salt thereof, which, when administered to a human, has the ability to provide a therapeutically effective blood level of DMT (e.g., a concentration of about 250 nmol / L or greater) for about 20 to about 60 minutes.

2. 10. The composition of claim 1, which exhibits therapeutically effective levels of DMT for about 20 to about 45 minutes.

3. 10. The composition of claim 1, which exhibits therapeutically effective levels of DMT for about 30 to about 45 minutes.

4. 10. The composition of claim 1, which exhibits therapeutically effective levels of DMT for about 45 minutes.

5. The composition according to any one of claims 1 to 4, wherein Tmax is 60 minutes or less.

6. The composition according to any one of claims 1 to 4, wherein Tmax is from 5 to 60 minutes.

7. The composition according to any one of claims 1 to 4, wherein the Tmax is from 8 to 24 minutes.

8. The composition according to any one of claims 1 to 4, wherein Tmax is from 10 to 20 minutes.

9. 5. The composition of any one of claims 1 to 4, wherein after Tmax is achieved, the concentration of DMT is maintained at about 50% or greater of Cmax for about 5 minutes to about 60 minutes.

10. 5. The composition of any one of claims 1 to 4, wherein after Tmax is achieved, the concentration of DMT is maintained at about 80% or greater of Cmax for about 5 minutes to about 45 minutes.

11. 11. The composition of claim 10, wherein the concentration of DMT is maintained at or above about 80% of Cmax for about 10 minutes to about 30 minutes.

12. The composition of any one of claims 1 to 4, wherein the concentration of DMT is reduced to about 10% of Cmax or less within about 20 minutes.

13. The composition of any one of claims 1 to 4, having the ability to maintain blood levels of DMT at a concentration of at least about 250 nmol / L for at least about 20 minutes.

14. The composition of any one of claims 1 to 4, having the ability to maintain blood levels of DMT at a concentration of at least about 250 nmol / L for about 20 minutes to about 45 minutes.

15. The composition of any one of claims 1 to 4, in a form suitable for buccal, sublingual, subcutaneous, or intranasal administration.

16. 16. The composition of claim 15, having the ability to release 100% of the DMT from the composition within about 20 minutes after administration to a subject.

17. 16. The composition of claim 15, having the ability to release 100% of said DMT from said composition within about 20 minutes to about 30 minutes after administration to a subject.

18. The composition of claim 15, suitable for intranasal administration.

19. The composition of claim 15, suitable for buccal administration.

20. 16. The composition of claim 15, suitable for sublingual administration.

21. 16. The composition of claim 15, suitable for subcutaneous administration.

22. 5. The composition of any one of claims 1 to 4, comprising about 0.1 mg / kg to about 1 mg / kg of the free base equivalent of DMT or a pharma- ceutically acceptable salt thereof.

23. 20. The composition of claim 19, wherein the composition is in the form of a fast dissolving tablet, wafer, film, strip, or patch, or a dispersible tablet, oral gel, medicated lollipop, spray, or drop.

24. 24. The composition of claim 23 in the form of a film.

25. The composition of any one of claims 1 to 4, wherein the active agent is DMT.

26. The composition of claim 25, wherein the composition is suitable for buccal administration.

27. The composition of any one of claims 1 to 4, wherein the active agent is the succinate salt of DMT.

28. 28. The composition of claim 27, wherein the composition is suitable for subcutaneous administration.

29. The composition of any one of claims 1 to 4 in combination with one or more additional therapeutic agents.

30. 30. The composition of claim 29, wherein the one or more additional therapeutic agents comprises an antidepressant or an anti-anxiety agent.

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