WO2025076151A1

WO2025076151A1 - N-n-dimethyltryptamine (dmt) and dmt analog oral transmucosal film compositions, methods of making, and methods of use thereof

Info

Publication number: WO2025076151A1
Application number: PCT/US2024/049678
Authority: WO
Inventors: Nadine Paiement; Rubo ZHENG; Majed Fawaz; Vaibhav Saxena; Hai MIAO
Original assignee: Atai Therapeutics Inc
Current assignee: Atai Therapeutics Inc
Priority date: 2023-10-02
Filing date: 2024-10-02
Publication date: 2025-04-10
Anticipated expiration: 2026-04-02

Abstract

The disclosure provides transmucosal bilayer film for delivering N,N-dimethyltryptamine (DMT) comprising an active layer comprising DMT or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix and a backing layer.

Description

N-N-DIMETHYLTRYPTAMINE (DMT) AND DMT ANALOG ORAL TRANSMUCOSAL FILM COMPOSITIONS, METHODS OF MAKING, AND METHODS OF USE THEREOF

Cross-Reference To Related Applications

[0001] This application claims the benefit of and priority to U.S. Provisional Application

No. 63/587,292, filed October 2, 2023; and U.S. Provisional Application No. 63/653,981, filed May 30, 2024, the contents of each of which are hereby incorporated by reference in their entirety for all purposes.

BACKGROUND OF THE INVENTION

[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 doubleblind 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 than can be achieved with a single dose of DMT via injection or inhalation.

[0008] Therefore, a significant need exists for readily administrable medications of DMT to treat neurological diseases and conditions. Such medications, which maximize efficacy while enabling drug side effects to be effectively controlled, are of particular interest, especially if administrable via a convenient route, including self-administration.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 shows the study design for Part A of Phase 1 study.

[0010] FIGs. 2A-2B show the Cmax (FIG. 2A) and AUCiast (FIG. 2B) box plots for subjects administered DMT IV dose or a DMT buccal thin film (BTF) of the present disclosure.

[0011] FIG. 3 shows DMT plasma concentration over time for subjects administered

DMT IV dose group or a DMT BTF of the present disclosure.

[0012] FIG. 4 shows Subjective Intensity Rating Scale (SIRS) over time for subjects administered DMT IV dose group or a DMT BTF of the present disclosure.

[0013] FIG. 5 shows the study design for Phase 2 study.

[0014] FIG. 6 shows an in vitro comparison of DMT permeation through pig mucosa for

40 mg and 80 mg DMT films of the present disclosure.

[0015] FIG. 7 shows the XRPD diffractogram for a composition of the present disclosure comprising a 80 mg DMT film and the backing layer. SUMMARY

[0016] In aspects, the present disclosure provides transmucosal compositions comprising:

(a) an active layer comprising N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix, and

(b) a backing layer, wherein the composition comprises about 0.5 wt% to about 60 wt% of DMT or a pharmaceutically acceptable salt or prodrug.

[0017] In embodiments, the administration of a composition of the present disclosure to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.3 h to about 2 h and a DMT Cmax of about 5 ng/mL to about 80 ng/mL following administration. In embodiments, the administration of a composition of the present disclosure to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.3 h to about 2 h and a DMT AUCi_ast of about 3 ng h/mL to about 70 ng h/mL following administration.

[0018] In aspects, the present disclosure provides mucoadhesive composition comprising:

(a) about 0.5 wt % to about 60 wt % of N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix, and

(b) about 15 wt% to about 90 wt% of the polymeric carrier matrix, wherein the polymeric carrier matrix comprises hydroxypropyl cellulose (HPC), copovidone, and carboxymethyl cellulose, and the polymeric carrier matrix stabilizes the DMT in an amorphous form within the mucoadhesive composition.

DETAILED DESCRIPTION

[0019] The present disclosure provides transmucosal compositions comprising an active layer comprising DMT or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix and a backing layer to enhance transmucosal delivery of the DMT. In embodiments, the active layer of the present disclosure stabilizes DMT in amorphous form at high loading (e.g., greater than 27 wt%, including from 28 wt% to about 60 wt%) and provides DMT release in a suitable dosage form, for example, a transmucosal dosage form. In embodiments, the backing layer of the present disclosure is layered on an active layer to provide a multilayer (e.g., bilayer) film in order to reduce or prevent erosion of DMT from the back side of the film when applied to the mucosal surface. In embodiments, more than one active layer may be layered on another (e.g., to provide multiple DMT-containing layers, such as a bilayer of active layer) optionally in combination with a backing layer (e.g., to provide a composition having multiple DMT-containing active layers with a backing layer).

Definitions

[0020] As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise:

[0021] 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.

[0022] The term “subject ” and “patient” are used interchangeably herein and refers to a human.

[0023] The terms “treating,” “treat” and “treatment” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

[0024] 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).

[0025] The term “pharmaceutically acceptable” as used herein, refers to refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0026] 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 dicyclohexylamine 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.

[0027] 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.

Compositions

[0028] In aspects, the present disclosure provides transmucosal compositions for delivering N,N-dimethyltryptamine (DMT) comprising (a) an active layer comprising DMT or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix, and (b) a backing layer, wherein the composition comprises about 0.5 wt% to about 60 wt% of DMT or a pharmaceutically acceptable salt or prodrug. Active layer

[0029] In embodiments, the transmucosal composition of the present disclosure comprises an active layer comprising about 0.5 wt % to about 60 wt % of N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix and about 15 wt% to about 90 wt% of the polymeric carrier matrix. In embodiments, the DMT in the composition is in an amorphous form as characterized by a powder x-ray diffractogram free of any discernable peaks that are attributable to crystalline DMT. In some embodiments, the DMT in the composition is amorphous as characterized by a differential scanning calorimetry (DSC) thermogram lacking a sharp melting endotherm of crystalline DMT and/or lacking an indication of phase change. In embodiments, the indication of phase change is glass transition temperature. DMT and DMT analog compositions, methods of making and methods of use thereof are described in PCT Pub. No. WO2024119075 and US Pat. App. Pub. No. 2023-0136824 Al, the contents of which are hereby incorporated by reference in their entireties for all purposes.

[0030] In embodiments, the active layer comprises about 0.5 wt% to about 60 wt%, including about 0.5 wt% to about 5 wt%, about 5 wt% to about 10 wt%, about 10 wt% to about 20 wt%, about 20 wt% to about 30 wt%, or about 30 wt% to about 60 wt% (including all values and ranges therebetween) of DMT or a pharmaceutically acceptable salt or prodrug.

[0031] In embodiments, the active layer comprises DMT or a pharmaceutically acceptable salt or prodrug of greater than about 27 wt%, including from about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, to about 60 wt%, including all values and ranges therebetween.

[0032] In embodiments, the active layer of the present disclosure comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt thereof, for example, about 1 mg, about 5 mg, about 10 mg, about 15, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 mg of DMT or a pharmaceutically acceptable salt thereof, including all values and ranges therebetween.

[0033] In embodiments, more than one active layers may be layered on another (e.g., to provide multiple DMT-containing layers, such as a bilayer of active layer), optionally in combination with a backing layer (e.g., to provide a composition having multiple DMT-containing active layers with a backing layer). In embodiments, the composition comprises 1, 2, 3, or more active layers. In embodiments, each active layer of the multiple DMT-containing active layers comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt thereof. In embodiments, each active layer of the multiple DMT-containing active layers comprises the same amount of DMT or a pharmaceutically acceptable salt thereof or different amount of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the composition of the present disclosure comprises a first active layer and a second active layer, wherein the first active layer comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt thereof and the second active layer comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt thereof, including all values and ranges therebetween.

[0034] In embodiments, the active layer of the present disclosure comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the active layer comprises about 1 mg to about 15 mg of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the active layer comprises about 20 mg to about 200 mg of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the active layer comprises about 60 mg to about 200 mg of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the active layer comprises about 80 mg to about 200 mg of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the active layer comprises about 120 mg to about 200 mg of DMT or a pharmaceutically acceptable salt thereof. In embodiments, the active layer comprises about 160 mg to about 200 mg of DMT or a pharmaceutically acceptable salt thereof, including all values and ranges therebetween.

[0035] In embodiments, the active layer of the present disclosure is a mucoadhesive film. In embodiments, the active layer has a thickness of about 0.01 mm to about 1.5mm. In embodiments, the active layer has a thickness of about 0.5 mm to about 1.5mm. In embodiments, the active layer has a surface of about 2 cm² to about 10 cm², for example, about 2 cm², about 4 cm², about 6 cm², about 8 cm², or about 10 cm². In embodiments, the active layer comprises about 1 mg/cm² to about 15 mg/cm² amorphous DMT, for example, about 1 mg/cm², about 5 mg/cm², about 10 mg/cm², or about 15 mg/cm², including all values and ranges therebetween. In embodiments, the active layer comprises about 2 mg/cm² to about 10 mg/cm² amorphous DMT.

[0036] In aspects, the active layer of the present disclosure comprises a polymeric carrier matrix that is suitable for transmucosal delivery. In embodiments, the polymeric carrier matrix comprise a mucoadhesive polymer.

[0037] In embodiments, the polymeric carrier matrix comprises a cellulose derivative, a polyacrylic acid, a polyacrylate, a polyethylene oxide, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), copovidone, hydroxypropylmethyl cellulose, polyvinyl alcohol, propylene glycol alginate ester, tragacanth, alginate, a gum, a soluble starch, gelatin, lectin, pectin, chitosan, or any combination thereof. Exemplary CMC includes, but is not limited to, Aquaion™ 7LF sodium CMC of 90.5 KDa having a solution viscosity (mPa s) of 25-50 cps in a 2 wt% aqueous solution (Ashland Global Holdings Inc.). Exemplary copovidone includes, but is not limited to, Plasdone™ S-630 copovidone of 43 KDa having a solution viscosity (mPa s) of 25-31 cps in a 2 wt% aqueous solution (Ashland Global Holdings Inc.). In embodiments, the polymeric carrier matrix comprises HPC. In embodiments, the polymeric carrier matrix comprises HPC-L, HPC-GXF, and HPC-SSL. Exemplary HPC-L, HPC-GXF, and HPC-SSL are shown in Table 1.

[0038] In embodiments, the polymeric carrier matrix stabilizes the DMT in an amorphous form within the mucoadhesive therapeutic composition.

[0039] In embodiments, the active layer comprises about 15 wt% to about 90 wt%, including from about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, or about 90 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises about 15 wt% to about 90 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises 15 wt% to about 50 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises 30 wt% to about 50 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises about 33 wt% to about 40 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises about 35 wt% to about 36.5 wt% of the polymeric carrier matrix.

[0040] In embodiments, the active layer comprises a buffering agent. In embodiments, the active layer comprises about 0.1 wt% to about 10 wt% of the buffering agent. In embodiments, the buffering agent comprises one or more of citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate, or any combination thereof. In embodiments, the active layer comprises a buffering agent, and/or a saliva stimulating agent. In embodiments, the buffering agent is used with a pH adjusting agent, such as sodium hydroxide. In embodiments, the saliva stimulating agent comprises one or more of citric acid, malic acid, lactic acid, ascorbic acid, tartaric acid, or any combination thereof.

[0041] In embodiments, the active layer comprises a permeation enhancer. In embodiments, the active layer comprises about 1 wt% to about 10 wt%, about 1 wt% to about 5 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer. In embodiments, the permeation enhancer comprises d-a-tocopheryl polyethylene glycol succinate (“Vitamin E TPGS”), a bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or any combination thereof. In embodiments, the permeation enhancer comprise Vitamin E TPGS. In embodiments, the composition comprises other stability enhancers including antioxidants or chelators. In embodiments, the stability enhancer comprises one or more of a-tocopherol, tocopherol acetate, L-Glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol, Ethylenediaminetetraacetic acid (EDTA), or any combination thereof.

[0042] In embodiments, the active layer comprises an antioxidant. In embodiments, , the active layer comprises about 0.5 wt% to about 3 wt% of the antioxidant. In embodiments, the permeation enhancer comprises both permeation enhancing and antioxidant properties. For example, vitamin E may include both permeation enhancing and antioxidant characteristics. In embodiments, the active layer comprises about 2 wt% to about 10 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer and the antioxidant.

[0043] In embodiments, the active layer comprises a sweetening agent and/or a flavoring agent. In embodiments, the sweetening agent comprises one or more of Advantame, sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or any combination thereof. In embodiments, the flavoring agent comprises one or more of lime flavor, evospray natural lime flavor, lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, arome type suppresseur amertume or any combination thereof.

[0044] In embodiments, the active layer comprises a coloring agent. In embodiments, the coloring agent comprises one or more of D&C or FD&C red, yellow, green, blue, iron oxide red, iron oxide yellow, titanium dioxide, or any combination thereof.

[0045] In embodiments, the active layer comprises a hydrophilic adjuvant/additive or matrix solubilizing agent. In embodiments, the hydrophilic adjuvant and/or additive comprises cellulose derivative, starch derivative, cross linked povidone, cross linked cellulose, cross linked starch or alginate, sucrose, maltose, sugar alcohol or mixtures thereof.

[0046] In embodiments, the active layer composition is as shown in Table 2.

[0047] In embodiments, the active layer composition is as shown in Table 3.

[0048] In embodiments, the active layer composition is as shown in Table 4.

[0049] In embodiments, the active layer composition is as shown in Table 5.

[0050] In embodiments, the active layer composition is as shown in Table 6.

[0051] In embodiments, the active layer of the present disclosure has a pH of about 7.5 to about 9, including about 8 to about 9, about 8.5 to about 9, or about 8.6. The pH can be measured by a method known to one skilled in the art, such as a standardized method according to United States Pharmacopeial Convention (USP) (e.g., a pH meter or pH electrode).

Backing layer

[0052] In embodiments, the transmucosal composition comprises a backing layer and an active layer (e.g., a DMT mucoadhesive film) as described herein. In embodiments, the backing layer forms the back side (i.e., the non-adhesive side) of the transmucosal composition of the present disclosure. In embodiments, the backing layer is adjacent to the DMT mucoadhesive film. In embodiments, the backing layer is adapted to reduce or prevent DMT from being transported across the backing layer while the mucoadhesive therapeutic product is being administered. In embodiments, the backing layer is substantially impermeable to diffusion of DMT to the back side of the transmucosal bilayer film. In embodiments, the backing layer serves as a protective barrier to prevent, substantially prevent or reduce the amount of saliva contacting the DMT active agent and/or erosion of the back side of transmucosal bilayer film.

[0053] In embodiments, the backing layer comprises a polymeric matrix and a pigment. In embodiments, the backing layer comprises carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyethylene glycol (PEG), copovidone (a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate), or any combination thereof. Exemplary CMC includes, but is not limited to, Aquaion™ 7LF PH sodium CMC of 90.5 KDa having a solution viscosity (mPa s) of 25-50 cps in a 2 wt% aqueous solution (Ashland Global Holdings Inc.). Exemplary copovidone includes, but is not limited to, Plasdone™ S-630 copovidone of 43 KDa having a solution viscosity (mPa • s) of 25-31 cps in a 2 wt% aqueous solution (Ashland Global Holdings Inc.). Plasdone™ S-630 copovidone is a 60:40 linear random copolymer of N-vinyl-2- pyrrolidone and vinyl acetate. Exemplary PEG includes, but is not limited to, PEG300 of 300 Da having a solution viscosity (mPa s) of 5.4-6.2 cps in a 2 wt% aqueous solution. Exemplary HPC is as shown in Table 1.

[0054] In embodiments, the backing layer comprises a plasticizer. In embodiments, the plasticizer is a polyethylene glycol (PEG), propylene glycol, glycerol, triacetin, castor oil, or mixtures thereof.

[0055] In embodiments, the backing layer composition is as shown in Table 7.

[0056] In embodiments, the backing layer composition is as shown in Table 8.

[0057] In embodiments, the backing layer composition is as shown in Table 9.

Transmucosal Composition

[0058] In embodiments, the transmucosal composition of the present disclosure comprises an active layer of about 70 wt% to about 90 wt%, including from about 70 wt%, about 75 wt%, about 80 wt%, or about 85 wt%, to about 90 wt% of the composition. In embodiments, the transmucosal bilayer film composition of the present disclosure comprises a backing layer of about 10 wt% to about 30 wt%, including from about 10 wt%, about 15 wt%, about 20 wt%, or about 25 wt%, to about 30 wt% of the composition. In embodiments, the transmucosal composition of the present disclosure comprises an active layer comprising DMT or a pharmaceutically acceptable salt thereof and a backing layer at a ratio by weight of from about 2: 1 to about 5:1, for example, about 2:1, about 3: 1, about 4: 1, or about 5: 1, including all values and ranges therebetween. In embodiments, the transmucosal composition is in the form of a transmucosal film.

[0059] In embodiments, the transmucosal film composition is as shown in the table below:

[0060] In embodiments, the transmucosal film composition is as shown in the table below.

[0061] In embodiments, the composition is suitable for transmucosal application. In embodiments, the composition is suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application. In embodiments, the film is placed in the oral cavity with the backing layer facing away from the patient’s skin (i.e., on the side of the film opposite that which is put into contact with the patient’s skin).

[0062] In embodiments, the administration of the composition to the oral mucosa of a patient in need thereof provide residence time of DMT of about 5 min to about 20 min, for example, about 5 min, about 10 min, about 15 min, about 20 min, including any values or ranges therebetween following administration.

[0063] In embodiments, the administration of the composition to the oral mucosa of a patient in need thereof provide a T_max of DMT of about 0.1 h to about 4 h (such as about 0.3 h to about 2 h), for example, about 0.1 h, about 0.2 h, about 0.3 h, about 0.4 h, about 0.5 h, about 0.6 h, about 0.7 h, about 0.8 h, about 0.9 h, about 1.0 h, about 1.2 h, about 1.4 h, about 1.6 h, about 1.8 h, about 2.0 h, about 2.2 h, about 2.4 h, about 2.6 h, about 2.8 h, about 3.0 h, about 3.2 h, about 3.4 h, about 3.6 h, about 3.8 h, or about 4.0 h, including any values or ranges therebetween following administration.

[0064] In embodiments, the administration of the composition to the oral mucosa of a patient in need thereof provide a T_max of DMT of about 10 min to about 240 min, for example, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 65 min, about 70 min, about 75 min, about 80 min, about 85 min, about 90 min, about 95 min, about 100 min, about 105 min, about 110 min, about 115 min, about 120 min, about 125 min, about 130 min, about 135 min, about 140 min, about 145 min, about 150 min, about 155 min, about 160 min, about 165 min, about 170 min, about 175 min, about 180 min, about 185 min, about 190 min, about 195 min, about 200 min, about 205 min, about 210 min, about 215 min, about 220 min, about 225 min, about 230 min, about 235 min, or about 240 min, including any values or ranges therebetween following administration.

[0065] In embodiments, the administration of the composition to the oral mucosa of a patient in need thereof provides a C_max of DMT of about 1 ng/mL to about 200 ng/mL, for example, about 1 ng/mL, about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/mL, about 125 ng/mL, about 130 ng/mL, about 135 ng/mL, about 140 ng/mL, about 145 ng/mL, about 150 ng/mL, about 155 ng/mL, about 160 ng/mL, about 165 ng/mL, about 170 ng/mL, about 175 ng/mL, about 180 ng/mL, about 185 ng/mL, about 190 ng/mL, about 195 ng/mL, or about 200 ng/mL, including any values or ranges therebetween following administration.

[0066] In embodiments, the administration of the composition to the oral mucosa of a patient in need thereof provides a AUCiast of DMT of about 1 ng h/mL to about 100 ng h/mL, for example, about 1 ng h/mL, about 2 ng h/mL, about 3 ng h/mL, about 4 ng h/mL, about 5 ng h/mL, about 10 ng h/mL, about 15 ng h/mL, about 20 ng h/mL, about 25 ng h/mL, about 30 ng h/mL, about 35 ng h/mL, about 40 ng h/mL, about 45 ng h/mL, about 50 ng h/mL, about 55 ng h/mL, 60 ng h/mL, about 65 ng h/mL, about 70 ng h/mL, about 75 ng h/mL, about 80 ng h/mL, about 85 ng h/mL, about 90 ng h/mL, about 95 ng h/mL, or about 100 ng h/mL, including any values or ranges therebetween following administration.

Methods of Use

[1] In aspects, the present disclosure provide methods of treatment of a disease or disorder, wherein the method comprises administering a therapeutically effective amount of the composition of the present disclosure to a patient in need thereof. The disease or disorder is neurological disease, disorder, or condition, for example, a neuropsychiatric disorder. [2] As referred to herein, a “neurological disease, disorder, or condition” refers to a disease, disorder, or condition comprising: a neuropsychiatric disorder, such as depressive disorder or depression (including severe depression such as treatment-resistant depression (TRD), major depressive disorder (MDD) and persistent depressive disorder), alexithymia, catatonic depression, a depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, anxiety, anxiety disorder, social anxiety disorder (SAD), general anxiety disorder (GAD), avolition disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder (PTSD), 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, suicide ideation, rumination/unproductive repetitive thoughts negatively impacting one’s behavior, mood, and/or ability to focus, obsessive- compulsive disorder, addiction (including substance use disorders, such as addiction to nicotine, alcohol, cocaine, opioids, amphetamine, methamphetamine, heroin, morphine, phencyclidine, 3,4- methylenedioxy-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, etc.), eating disorders (including anorexia nervosa, bulimia nervosa and binge eating disorder), pain (including pain associated with migraine or headache or chronic pain), prolonged grief disorder, paranoid personality disorder, Autoimmune OCD (adult), behavioral symptoms/anxiety in Fragile X (adult), or Xenomelia.

NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0067] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments. . A transmucosal composition comprising:

(b) a backing layer, wherein the composition comprises about 0.5 wt% to about 60 wt% of DMT or a pharmaceutically acceptable salt or prodrug. 2. The composition of embodiment 1, wherein the composition comprises about 70 wt% to about 90 wt% of the active layer.

3. The composition of embodiment 1, wherein the composition comprises about 10 wt% to about 30 wt% of the backing layer.

4. The composition of embodiment 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as characterized by a powder x-ray diffractogram free of any discernable peaks.

5. The composition of embodiment 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as determined by a differential scanning calorimetry (DSC) thermogram lacking a sharp melting endotherm of crystalline DMT and/or lacking an indication of phase change.

6. The composition of any one of embodiments 1-5, wherein the DMT is a DMT free base.

7. The composition of any one of embodiments 1-6, wherein the active layer comprises about 1 wt% to about 60 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

8. The composition of embodiment 7, wherein the active layer comprises about 30 wt% to about 50 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

9. The composition of embodiment 7, wherein the active layer comprises about 32 wt% to about 46 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

10. The composition of embodiment 7, wherein the active layer comprises about 35 wt% to about 36.5 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof. 1 11. The composition of embodiment 7, wherein the composition comprises about 1 mg to about 200 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

12. The composition of embodiment 11, wherein the composition comprises about 1 mg to about 5 mg, about 5 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 40 mg, about 40 mg to 60 mg, or about 60 mg to 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

13. The composition of embodiment 11 , wherein the composition comprises about 5 mg, about 15 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

14. The composition of embodiment 1, wherein the polymeric carrier matrix comprise a mucoadhesive polymer.

15. The composition of any one of embodiments 1-14, wherein the polymeric carrier matrix comprises a cellulose derivative, a polyacrylic acid, a polyacrylate, a polyethylene oxide, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose, polyvinyl alcohol, propylene glycol alginate ester, tragacanth, alginate, a gum, a soluble starch, gelatin, lectin, pectin, chitosan, or any combination thereof.

16. The composition of embodiment 15, wherein the polymeric carrier matrix comprises HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution, HPC of about 370 KDa having a solution viscosity (mPa s) of about 150 to about 400 cps in a 2 wt% aqueous solution, and HPC of about 40 KDa having a solution viscosity (mPa • s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution.

17. The composition of embodiment 1, wherein the polymeric carrier matrix stabilizes the DMT agent in an amorphous form within the transmucosal composition. 18. The composition of any one of embodiments 1-17, wherein the active layer comprises about 30 wt% to about 90 wt% of the polymeric carrier matrix.

19. The composition of any one of embodiments 1-17, wherein the active layer comprises about 33 wt% to about 40 wt% of the polymeric carrier matrix.

20. The composition of any one of embodiments 1-17, wherein the active layer comprises about 35 wt% to about 36.5 wt% of the polymeric carrier matrix.

21. The composition of any one of embodiments 1-20, wherein the active layer comprises a buffering agent.

22. The composition of embodiment 21, wherein the buffering agent comprises citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate, or any combination thereof.

23. The composition of embodiment 21 or 22, wherein the active layer comprises about 0.1 wt% to about 10 wt% of the buffering agent.

24. The composition of any one of embodiments 1-23, wherein the active layer comprises a permeation enhancer.

25. The composition of embodiment 24, wherein the permeation enhancer comprise d-a- tocopheryl polyethylene glycol succinate (Vitamin E TPGS), a bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or any combination thereof.

26. The composition of embodiment 25, wherein the permeation enhancer comprise Vitamin E TPGS. 27. The composition of any one of embodiments 24-26, wherein the active layer comprises about 1 wt% to 5 wt% of the permeation enhancer.

28. The composition of any one of embodiments 1-27, wherein the active layer comprises a stability enhancer or an antioxidant.

29. The composition of embodiment 28, wherein the stability enhancer or the antioxidant comprises a-tocopherol, tocopherol acetate, L-Glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol, Ethylenediaminetetraacetic acid (EDTA), or any combination thereof.

30. The composition of embodiment 28 or 29, wherein the active layer comprises about 0.5 wt% to about 3 wt% of the stability enhancer or the antioxidant.

31. The composition of any of embodiments 24-30, wherein the active layer comprises about 2 wt% to about 10 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer, and the stability enhancer or the antioxidant.

32. The composition of any of the preceding embodiments, wherein the active layer comprises a sweetening agent and/or a flavoring agent.

33. The composition of embodiment 32, wherein the sweetening agent comprises advantame, sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or any combination thereof.

34. The composition of embodiment 33, wherein the sweetening agent comprises advantame.

35. The composition of any one of embodiments 32-34, wherein the flavoring agent comprises lime flavor, evospray natural lime flavor lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, arome type suppresseur amertume or any combination thereof. 36. The composition of any of the preceding embodiments, wherein the active layer comprises a coloring agent selected from D&C or FD&C red, yellow, green, blue, iron oxide red, iron oxide yellow, titanium dioxide, and any combination thereof.

37. The composition of any of the preceding embodiments, wherein the active layer comprises

(a) about 32 wt% to about 40 wt% of DMT;

(b) about 25 wt% to about 40 wt% of polymeric carrier matrix;

(c) about 5 wt% to about 15 wt% of D-Maltitol;

(d) about 2 wt% to about 10 wt% of citric acid;

(e) about 1 wt% to about 5 wt% of vitamin E TPGS; and

(f) about 0.5 wt% to about 3 wt% of L-Glutathione.

38. The composition of any of the preceding embodiments, wherein the active layer comprises

(a) about 35.85 wt% of DMT;

(b) about 23.10 wt% of HPC of about 40 KDa having a solution viscosity (mPa • s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution;

(c) about 11.15 wt% of Maltitol;

(d) about 5.69 wt% of HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution L;

(e) about 5.03 wt% of citric acid;

(f) about 3.58 wt% of vitamin E TPGS;

(g) about 3.41 wt% of sodium carboxymethylcellulose;

(h) about 3.11 wt% of Arome Type Suppresseur amertume;

(i) about 2.61 wt% of Copovidone;

(j) about 2.11 wt% of L-Glutathione;

(k) about 1.59 wt% of Evospray natural Lime flavor;

(l) about 1.50 wt% of Sucralose;

(m)about 1.14 wt% of HPC of about 370 KDa having a solution viscosity (mPa s) of about 150 to about 400 cps in a 2 wt% aqueous solution;

(n) about 0.12 wt% of Advantame; and (o) about 0.01 wt% of FD&C Yellow No. 06 powder.

39. The composition of any of the preceding embodiments, wherein the active layer has a pH of about 7.5 to about 9.

40. The composition of any of the preceding embodiments, wherein the active layer has a pH of about 8 to about 9.

41. The composition of any of the preceding embodiments, wherein the active layer has a pH of about 8.5 to about 9.

42. The composition of any of the preceding embodiments, wherein the active layer has a pH of about 8.6.

43. The composition of any of the preceding embodiments, wherein the active layer has a thickness of about 0.01 mm to about 1.5mm.

44. The composition of any of the preceding embodiments, wherein the active layer has a thickness of about 0.5 mm to about 1.5mm.

45. The composition of embodiment 43 or 44, wherein the active layer comprises about 2 mg/cm² to about 10 mg/cm² amorphous DMT or a pharmaceutically acceptable salt or prodrug thereof .

46. The composition of any of the preceding embodiments, wherein the backing layer reduces or prevents DMT from being transported across the backing layer while DMT or a pharmaceutically acceptable salt or prodrug thereof is being administered.

47. The composition of any of the preceding embodiments, wherein the backing layer comprises a polymeric carrier matrix. 48. The composition of embodiment 47, wherein the polymeric carrier matrix comprises carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyethylene glycol, and copovidone.

49. The composition of any of the preceding embodiments, wherein the backing layer comprise a pigment.

50. The composition of any of the preceding embodiments, wherein the backing layer comprise titanium dioxide.

51. The composition of any of the preceding embodiments, wherein the backing layer comprise sodium hydroxide.

52. The composition of any of the preceding embodiments, wherein the backing layer comprise methyl alcohol and water.

53. The composition of any of the preceding embodiments, wherein the backing layer comprise

(a) about 65 wt% to about 85 wt% of Hydroxypropyl Cellulose;

(b) about 5 wt% to about 10 wt% of Copovidone;

(c) about 5 wt% to about 10 wt% of Sodium Carboxymethylcellulose;

(d) about 10 wt% to about 20 wt% of Polyethylene Glycol;

(e) about 1 wt% to about 3 wt% of Titanium dioxide; and

(f) about 0.5 wt% to about 2 wt% of Sodium Hydroxide NF solution 50% (w/w).

54. The composition of any of the preceding embodiments, the composition comprising: an active layer comprising:

(a) about 20 wt% to about 60 wt% of N, N-Dimethyltryptamine (DMT);

(b) about 1 wt% to about 5 wt% of Citric acid, anhydrous;

(c) about 1 wt% to about 5 wt% of Glutathione, reduced;

(d) about 0.01 wt% to about 0.1 wt%of Advantame;

(e) about 1 wt% to about 3 wt% of Sucralose; (f) about 0.01 wt% to about 0.1 wt% of FD&C Yellow 6 powder;

(g) about 1 wt% to about 3 wt% of Arome Type Suppresseur Amertume;

(h) about 1 wt% to about 3 wt% of Evospray Natural Lime Flavor;

(i) about 5 wt% to about 15 wt% of Maltitol;

(j) about 0.05 wt% to about 0.5 wt% of HPC of about 370 KDa having a solution viscosity (mPa s) of about 150 to about 400 cps in a 2 wt% aqueous solution;

(k) about 1 wt% to about 5 wt% of Vitamin E TPGS;

(l) about 10 wt% to about 25 wt% of HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution;

(m)about 1 wt% to about 5 wt% of Copovidone;

(n) about 10 wt% to about 25 wt% of HPC of about 40 KDa having a solution viscosity (mPa s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution; and

(o) about 1 wt% to about 10 wt% of Sodium Carboxymethylcellulose; and a backing layer comprising:

(a) about 1 wt% to about 5 wt% of Copovidone;

(b) about 10 wt% to about 25 wt% of HPC of about 40 KDa having a solution viscosity (mPa s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution;

(c) about 1 wt% to about 10 wt% of Sodium Carboxymethylcellulose;

(d) about 1 wt% to about 5 wt% of Polyethylene Glycol;

(e) about 0.1 wt% to about 0.5 wt% of Titanium Dioxide; and

(f) about 0.05 wt% to about 0.5 wt% of Sodium Hydroxide solution 50% (WAV).

55. The composition of any of the preceding embodiments, wherein the composition is suitable for transmucosal application.

56. The composition of embodiment 55, wherein the composition is suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application.

57. The composition of any of the preceding embodiments, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.3 h to about 2 h and a DMT C_max of about 5 ng/mL to about 80 ng/mL following administration. 58. The composition of any of the preceding embodiments, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.3 h to about 2 h and a DMT AUCiast of about 3 ng h/mL to about 70 ng h/mL following administration.

59. The composition of any of embodiment 57 or 58, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.5 h to about 1.5 h following administration.

60. The composition of embodiment 57 or 58, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.6 h to about 0.8 h following administration.

61. The composition of embodiment 58, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of DMT of about 5 ng/mL to about 80 ng/mL following administration.

62. The composition of embodiment 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 5 ng/mL to about 10 ng/mL following administration.

63. The composition of embodiment 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 10 ng/mL to about 30 ng/mL following administration.

64. The composition of embodiment 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 20 ng/mL to about 50 ng/mL following administration. 65. The composition of embodiment 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 25 ng/mL to about 80 ng/mL following administration.

66. The composition of embodiment 57, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCiastof about 3 ng h/mL to about 70 ng h/mL following administration.

67. The composition of embodiment 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCiast of about 3 ng h/mL to about 9 ng h/mL following administration.

68. The composition of embodiment 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCiast of about 8 ng h/mL to about 30 ng h/mL following administration.

69. The composition of embodiment 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCiast of about 15 ng • h/mL to about 50 ng h/mL following administration.

70. The composition of embodiment 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCiast of about 25 ng h/mL to about 70 ng h/mL following administration.

71. A mucoadhesive composition comprising:

(a) about 1 wt % to about 60 wt % of N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix, and

(b) about 15 wt% to about 90 wt% of the polymeric carrier matrix, wherein the polymeric carrier matrix comprises hydroxypropyl cellulose (HPC), copovidone, and carboxymethyl cellulose, and the polymeric carrier matrix stabilizes the DMT in an amorphous form within the mucoadhesive composition. 72. The composition of embodiment 71, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as characterized by a powder x-ray diffractogram free of any discernable peaks.

73. The composition of embodiment 71, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as characterized by a differential scanning calorimetry (DSC) thermogram lacking a sharp melting endotherm of crystalline DMT and/or lacking an indication of phase change.

74. The composition of any one of embodiments 71-73, wherein DMT is a DMT free base.

75. The composition of any one of embodiments 71-74, wherein the composition comprises about 30 wt% to about 50 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

76. The composition of embodiment 75, wherein the composition comprises about 32 wt% to about 46 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

77. The composition of embodiment 75, wherein the composition comprises about 35 wt% to about 36.5 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

78. The composition of embodiment 75, wherein the composition comprises about 1 mg to about 200 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

79. The composition of embodiment 75, wherein the composition comprises about 1 mg to about 5 mg, about 5 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 40 mg, about 40 mg to 60 mg, or about 60 mg to 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof. 80. The composition of embodiment 75, wherein the composition comprises about 5 mg, about 15 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

81. The composition of embodiment 71, wherein the polymeric carrier matrix comprises HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution, HPC of about 370 KDa having a solution viscosity (mPa s) of about 150 to about 400 cps in a 2 wt% aqueous solution, and HPC of about 40 KDa having a solution viscosity (mPa • s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution.

82. The composition of any one of embodiments 71-81, wherein the composition comprises about 30 wt% to about 50 wt% of the polymeric carrier matrix.

83. The composition of embodiment 82, wherein the composition comprises about 33 wt% to about 40 wt% of the polymeric carrier matrix.

84. The composition of embodiment 82, wherein the composition comprises about 35 wt% to about 36.5 wt% of the polymeric carrier matrix.

85. The composition of any one of embodiments 71-84, wherein the composition comprises a buffering agent.

86. The composition of embodiment 85, wherein the buffering agent comprises citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate, or any combination thereof.

87. The composition of embodiment 85 or 86, wherein the composition comprises about 0.1 wt% to about 10 wt% of the buffering agent.

88. The composition of any one of embodiments 71-87, wherein the composition comprises a permeation enhancer. 89. The composition of embodiment 88, wherein the permeation enhancer comprise Vitamin E TPGS, a bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L- menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or any combination thereof.

90. The composition of embodiment 89, wherein the permeation enhancer comprise Vitamin E TPGS.

91. The composition of any one of embodiments 88-90, wherein the composition comprises about 1 wt% to 5 wt% of the permeation enhancer.

92. The composition of any one of embodiments 71-91, wherein the composition comprises a stability enhancer or an antioxidant.

93. The composition of embodiment 92, wherein the stability enhancer or the antioxidant comprises a-tocopherol, tocopherol acetate, L-Glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol, Ethylenediaminetetraacetic acid (EDTA), or any combination thereof.

94. The composition of embodiment 93 or 93, wherein the composition comprises about 0.5 wt% to about 3 wt% of the stability enhancer or the antioxidant.

95. The composition of any of embodiments 88-94, wherein the composition comprises about 2 wt% to about 10 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer, and the stability enhancer or the antioxidant.

96. The composition of any one of embodiments 71-95, wherein the composition comprises a sweetening agent and/or a flavoring agent. 97. The composition of embodiment 96, wherein the sweetening agent comprises advantame, sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or any combination thereof.

98. The composition of embodiment 97, wherein the sweetening agent comprises advantame.

99. The composition of any one of embodiments 96-98, wherein the flavoring agent comprises lime flavor, evospray natural lime flavor lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, arome type suppresseur amertume or any combination thereof.

100. The composition of any one of embodiments 71-99, wherein the composition comprises comprising a coloring agent selected from D&C or FD&C red, yellow, green, blue, iron oxide red, iron oxide yellow, titanium dioxide, and any combination thereof.

101. The composition of any of embodiments 71-100, wherein the active layer comprises

(a) about 32 wt% to about 40 wt% of DMT;

(b) about 25 wt% to about 40 wt% of polymeric carrier matrix;

(c) about 5 wt% to about 15 wt% of a sweetening agent;

(d) about 2 wt% to about 10 wt% of a buffering agent;

(e) about 1 wt% to about 5 wt% of a permeation enhancer; and

(f) about 0.5 wt% to about 3 wt% of a stability enhancer or antioxidant.

102. The composition of any one of embodiments 71-101, wherein the composition comprises

(a) about 32 wt% to about 40 wt% of DMT;

(b) about 25 wt% to about 40 wt% of polymeric carrier matrix;

(c) about 5 wt% to about 15 wt% of D-Maltitol;

(d) about 2 wt% to about 10 wt% of citric acid;

(e) about 1 wt% to about 5 wt% of vitamin E TPGS; and

(f) about 0.5 wt% to about 3 wt% of L-Glutathione.

103. The composition of any one of embodiments 71-102, wherein the composition comprises (a) about 35.9 wt% of DMT;

(b) about 23.1 wt% of HPC of about 40 KDa having a solution viscosity (mPa s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution;

(c) about 11.2 wt% of Maltitol;

(d) about 5.7 wt% of HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution;

(e) about 5.0 wt% of citric acid;

(f) about 3.6 wt% of vitamin E TPGS;

(g) about 3.4 wt% of sodium carboxymethylcellulose;

(h) about 3.1 wt% of Arome Type Suppresseur amertume;

(i) about 2.6 wt% of Copovidone;

(j) about 2.1 wt% of L-Glutathione;

(k) about 1.6 wt% of Evospray natural Lime flavor;

(l) about 1.5 wt% of Sucralose;

(m)about 1.1 wt% of HPC of about 370 KDa having a solution viscosity (mPa s) of about 150 to about 400 cps in a 2 wt% aqueous solution;

(n) about 0.1 wt% of Advantame; and

(o) about 0.01 wt% of FD&C Yellow No. 06 powder.

104. The composition of any one of embodiments 71-103, wherein the composition has a pH of about 7.5 to about 9.

105. The composition of any one of embodiments 71-104, wherein the composition has a pH of about 8 to about 9.

106. The composition of any one of embodiments 71-105, wherein the composition has a pH of about 8.5 to about 9.

107. The composition of any one of embodiments 71-106, wherein the composition has a pH of about 8.6. 108. The composition of any one of embodiments 71-107, wherein the composition has a thickness of about 0.01 mm to about 1.5mm.

109. The composition of any one of embodiments 71-108, wherein the composition has a thickness of about 0.5 mm to about 1.5mm.

110. The composition of embodiment 108 or 109, wherein the comprises about 2 mg/cm² to about 10 mg/cm² amorphous DMT or a pharmaceutically acceptable salt or prodrug thereof.

111. The composition of any of any one of embodiments 71-110, wherein the composition is suitable for transmucosal application.

112. The composition of embodiment 111, wherein the composition is suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application.

EXAMPLES

[0068] The following examples are provided to further illustrate the embodiments of the present disclosure but are not intended to limit the scope of the claims. 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. Phase 1 study of DMT oral transmucosal film (OTF)

[0069] A Phase 1 study of DMT oral transmucosal film (OTF) was completed. The study provided a supportive PK/PD profile for an OTF formulation of DMT. The study was designed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the DMT film applied to the sublingual and buccal surfaces compared to intravenous (IV) DMT. The study enrolled a total of 74 healthy participants across three parts. The third part of the study evaluated the DMT film administered and dosed as follows: sublingual 80mg (n=8), buccal 80mg with backing layer (n=10), and buccal 160mg with backing layer (n=8).

[0070] The DMT film composition was well-tolerated with a favorable safety profile, and dose-dependent increases in exposure were observed. The preliminary PK parameters for the DMT film containing 80 mg DMT without backing layer and with backing layer are shown in

Table 10

Table 10. Summary of plasma pharmacokinetic parameter results

[0071] The administration of the DMT films of the present disclosure provided subjective effects in most participants across doses. It was observed that participants that received 160 mg of the DMT film with a backing layer via buccal administration experienced the most robust and consistent increases in exposure and subjective effects compared to the other OTF cohorts, with results comparable to those seen in the IV cohort of DMT.

Example 2. Phase lb study of DMT oral transmucosal film (OTF)

[0072] A Phase lb, single-center, open- label, two-part study of DMT administered via intravenously administration (DMT -IV), via buccal administration using the oral thin film (OTF) strips (DMT-BU), and via subcutaneous administration (DMT-SC) in healthy volunteers. The primary objective was to assess the plasma pharmacokinetics (PK) and urine PK characteristics of DMT and 2 DMT predominant metabolites (N,N-dimethyltryptamine-N-oxide [DMT-NO] and indole-3 -acetic acid [IAA]) when administered as an IV infusion, BU via an OTF and via SC injection/infusion. [0073] Part A had two cohorts of 8 participants per cohort. Both cohorts in Part A received a total of 4 administrations of DMT, with a 28-day washout between administrations. Following an up to 28-day screening period, all participants in Part A received a single 30 mg IV infusion of DMT-IV administered over 57-minutes (Treatment Period 1), followed by 3 doses of DMT-BU (Treatment Period 2), and a safety follow-up visit 14 days after the last dose of Investigational medicinal product (IMP). The two cohorts in Part A received a starting dose of 160 mg of DMT-BU. Both cohorts then received a second dose of DMT-BU at either 60 mg or 120 mg and a third dose of DMT-BU at 120 mg or 20 mg, with each cohort receiving a different dose of DMT-BU. The study design for Part A is presented in FIG. 1.

[0074] The treatment with repeated doses of DMT OTF was safe and tolerated by study participants. There were no serious adverse events (SAEs) or severe adverse events (AEs). Optimized DMT OTF demonstrated good tolerability with all adverse events classified as either mild or moderate, and most resolving on the day of dosing.

[0075] Serial blood samples were collected for the determination of concentrations of

DMT and its predominant metabolites (DMT-NO and IAA). PK sampling timepoints are provided in Table 11.

[0076] The plasma PK parameters measured in this study are provided in Table 12.

[0077] The PK results were conducted using an NCA with nominal times collapsing across cohort. The preliminary PK parameters for DMT, DMT-NO and IAA are shown in Table 13 and the C_max and AUCiast box plots for DMT by dose group are shown in FIGs. 2A and 2B.

[0078] In the buccal dose groups, systemic exposure to DMT, DMT-NO and IAA increased with increasing dose of DMT-BU. DMT C_max and AUCiast increased with increasing dose in an approximately dose-proportional manner. The C_max and AUCi_ast of DMT from the 57- min IV slow infusion was most closely matched by the C_max and AUCiast of the 120 mg dose of DMT-BU. In all dose groups, IAA represented the majority of circulating drug -related material with mean MRAUC values for IAA/DMT ranging from 399 to -1507 (Table 12). In contrast, DMT-NO plasma concentrations were far lower than IAA in all cohorts. Mean MRAUC values for DMT NO/DMT in the BTF dose groups ranging from 0.6 - 1.5. Very little DMT-NO is produced in the IV infusion cohort.

[0079] The DMT plasma concentration over time for all cohorts is shown in FIG. 3.

DMT OTF rapidly reached peak plasma concentration (T_max) within 30-45 minute.

[0080] The pharmacodynamics (PD) parameters measured in this study are provided in

Table 14

[0081] SIRS over time for all cohorts is shown in FIG. 4. DMT OTF groups show dosedependent effects, with robust patientive effects seen at the 120 mg and 160 mg doses. 13/14 participants in the 120 mg cohort achieved SIRS scores greater than 7. Perceptual effects generally fully resolved within 90-120 minutes. This result indicates that DMT OTF has the potential to offer a predictable dosing model administered around a 2-hour in-clinic treatment paradigm.

Example 3 Examples and characterization of transmucosal formulations

[0082] Table 15 provides compositions for an exemplary dual layer buccal film and the amounts for an 80 mg DMT strength.

[0083] Table 16 provides formulation composition of the backing layer of the dual layer buccal film.

[0084] Table 17 provides the composition of the film (without backing layer ) that was used in the phase 1 trial, along with the dual layer film with (1) active layer containing the DMT and (2) backing layer without DMT.

[0085] Table 18 provides an exemplary composition per strength of the transmucosal film.

[0086] Table 19 provides an exemplary composition per strength of the transmucosal film.

[0087] Table 20 shows clinical batch impurities of the DMT film used in Phase 1

(Example 1) and Phase lb (Example 2) studies.

[0088] The Phase 1 active layer had a pH of 7.60. The Phase lb active layer pH was modified to 8.60. The modified pH for the Phase lb DMT buccal film was determined through testing DMT solubility in aqueous solutions at various pH, followed by in vitro permeation testing on fresh mucosa layers from porcine cheeks. FIG. 6 shows phase 1 and phase lb DMT film permeation. The study was done using in vitro permeation (diffusion) testing on fresh mucosa layers from porcine cheeks. FIG. 6 shows that 80 mg Plb DMT film demonstrates about 200% increase in % DMT release as compared to 40 mg Pl DMT film. The results indicates that the current formulation with optimized pH along with permeation enhancer Vitamin E TPGS is superior to the previously used Phase 1 active layer formulation.

[0089] FIG. 7 illustrates the amorphous state of the DMT film and that of the backing layer. The backing layer includes TiCh and PEG, which are not present in the active layer. FIG. X shows the XRPD diffractogram for the 80 mg DMT film and the backing layer. The backing layer includes three discernable peaks at 2-theta values of approximately 25, 38, and 48.

[0090] Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein, including all U.S. and foreign patents and patent applications, are specifically and entirely hereby incorporated herein by reference. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the invention indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A transmucosal composition comprising:

2. The composition of claim 1, wherein the composition comprises about 70 wt% to about 90 wt% of the active layer comprises.

3. The composition of claim 1, wherein the composition comprises about 10 wt% to about 30 wt% of the backing layer.

4. The composition of claim 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as characterized by a powder x-ray diffractogram free of any discernable peaks.

5. The composition of claim 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as determined by a differential scanning calorimetry (DSC) thermogram lacking a sharp melting endotherm of crystalline DMT and/or lacking an indication of phase change.

6. The composition of any one of claims 1-5, wherein the DMT is a DMT free base.

7. The composition of any one of claims 1-6, wherein the active layer comprises about 1 wt% to about 60 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

8. The composition of claim 7, wherein the active layer comprises about 30 wt% to about 50 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

9. The composition of claim 7, wherein the active layer comprises about 32 wt% to about 46 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

10. The composition of claim 7, wherein the active layer comprises about 35 wt% to about 36.5 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

11. The composition of claim 7, wherein the composition comprises about 1 mg to about 200 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

12. The composition of claim 11, wherein the composition comprises about 1 mg to about 5 mg, about 5 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 40 mg, about 40 mg to 60 mg, or about 60 mg to 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

13. The composition of claim 11, wherein the composition comprises about 5 mg, about 15 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

14. The composition of claim 1, wherein the polymeric carrier matrix comprises a mucoadhesive polymer.

15. The composition of any one of claims 1-14, wherein the polymeric carrier matrix comprises a cellulose derivative, a polyacrylic acid, a polyacrylate, a polyethylene oxide, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose, polyvinyl alcohol, propylene glycol alginate ester, tragacanth, alginate, a gum, a soluble starch, gelatin, lectin, pectin, chitosan, or any combination thereof.

16. The composition of claim 15, wherein the polymeric carrier matrix comprises HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution, HPC of about 370 KDa having a solution viscosity (mPa s) of about 150 to about 400 cps in a 2 wt% aqueous solution, and HPC of about 40 KDa having a solution viscosity (mPa s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution.

17. The composition of claim 1 , wherein the polymeric carrier matrix stabilizes the DMT an amorphous form within the transmucosal composition.

18. The composition of any one of claims 1-17, wherein the active layer comprises about 30 wt% to about 90 wt% of the polymeric carrier matrix.

19. The composition of any one of claims 1-17, wherein the active layer comprises about 33 wt% to about 40 wt% of the polymeric carrier matrix.

20. The composition of any one of claims 1-17, wherein the active layer comprises about 35 wt% to about 36.5 wt% of the polymeric carrier matrix.

21. The composition of any one of claims 1-20, wherein the active layer comprises a buffering agent.

22. The composition of claim 21, wherein the buffering agent comprises citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate, or any combination thereof.

23. The composition of claim 21 or 22, wherein the active layer comprises about 0.1 wt% to about 10 wt% of the buffering agent.

24. The composition of any one of claims 1-23, wherein the active layer comprises a permeation enhancer.

25. The composition of claim 24, wherein the permeation enhancer comprise d-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS), a bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or any combination thereof.

26. The composition of claim 25, wherein the permeation enhancer comprise Vitamin E TPGS.

27. The composition of any one of claims 24-26, wherein the active layer comprises about 1 wt% to 5 wt% of the permeation enhancer.

28. The composition of any one of claims 1-27, wherein the active layer comprises a stability enhancer or an antioxidant.

29. The composition of claim 28, wherein the stability enhancer or the antioxidant comprises a-tocopherol, tocopherol acetate, L-Glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol, Ethylenediaminetetraacetic acid (EDTA), or any combination thereof.

30. The composition of claim 28 or 29, wherein the active layer comprises about 0.5 wt% to about 3 wt% of the stability enhancer or the antioxidant.

31. The composition of any of claims 24-30, wherein the active layer comprises about 2 wt% to about 10 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer, and the stability enhancer or the antioxidant.

32. The composition of any of the preceding claims, wherein the active layer comprises a sweetening agent and/or a flavoring agent.

33. The composition of claim 32, wherein the sweetening agent comprises advantame, sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or any combination thereof.

34. The composition of claim 33, wherein the sweetening agent comprises advantame.

35. The composition of any one of claims 32-34, wherein the flavoring agent comprises lime flavor, evospray natural lime flavor lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, arome type suppresseur amertume or any combination thereof.

36. The composition of any of the preceding claims, wherein the active layer comprises a coloring agent selected from D&C or FD&C red, yellow, green, blue, iron oxide red, iron oxide yellow, titanium dioxide, and any combination thereof.

37. The composition of any of the preceding claims, wherein the active layer comprises

(a) about 32 wt% to about 40 wt% of DMT;

(b) about 25 wt% to about 40 wt% of polymeric carrier matrix;

(c) about 5 wt% to about 15 wt% of a sweetening agent;

(d) about 2 wt% to about 10 wt% of a buffering agent;

(e) about 1 wt% to about 5 wt% of a permeation enhancer; and

(f) about 0.5 wt% to about 3 wt% of a stability enhancer or antioxidant.

38. The composition of any of the preceding claims, wherein the active layer comprises

(a) about 32 wt% to about 40 wt% of DMT;

(b) about 25 wt% to about 40 wt% of polymeric carrier matrix;

(c) about 5 wt% to about 15 wt% of D-Maltitol;

(d) about 2 wt% to about 10 wt% of citric acid;

(e) about 1 wt% to about 5 wt% of vitamin E TPGS; and

(f) about 0.5 wt% to about 3 wt% of L-Glutathione.

39. The composition of any of the preceding claims, wherein the active layer comprises

(a) about 35.9 wt% of DMT;

(c) about 11.2 wt% of Maltitol; (d) about 5.7 wt% of HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution;

(e) about 5.0 wt% of citric acid;

(f) about 3.6 wt% of vitamin E TPGS;

(g) about 3.4 wt% of sodium carboxymethylcellulose;

(h) about 3.1 wt% of Arome Type Suppresseur amertume;

(i) about 2.6 wt% of Copovidone;

(j) about 2.1 wt% of L-Glutathione;

(k) about 1.6 wt% of Evospray natural Lime flavor;

(l) about 1.5 wt% of Sucralose;

(n) about 0.1 wt% of Advantame; and

(o) about 0.01 wt% of FD&C Yellow No. 06 powder.

40. The composition of any of the preceding claims, wherein the active layer has a pH of about

7.5 to about 9.

41. The composition of any of the preceding claims, wherein the active layer has a pH of about 8 to about 9.

42. The composition of any of the preceding claims, wherein the active layer has a pH of about

8.5 to about 9.

43. The composition of any of the preceding claims, wherein the active layer has a pH of about 8.6.

44. The composition of any of the preceding claims, wherein the active layer has a thickness of about 0.01 mm to about 1.5mm.

45. The composition of any of the preceding claims, wherein the active layer has a thickness of about 0.5 mm to about 1.5mm.

46. The composition of claim 43 or 44, wherein the active layer comprises about 2 mg/cm² to about 10 mg/cm² amorphous DMT or a pharmaceutically acceptable salt or prodrug thereof .

47. The composition of any of the preceding claims, wherein the backing layer reduces or prevents DMT from being transported across the backing layer while DMT or a pharmaceutically acceptable salt or prodrug thereof is being administered.

48. The composition of any of the preceding claims, wherein the backing layer comprises a polymeric matrix.

49. The composition of claim 47, wherein the polymeric matrix comprises carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyethylene glycol, and copovidone.

50. The composition of any of the preceding claims, wherein the backing layer comprises a pigment.

51. The composition of any of the preceding claims, wherein the backing layer comprises titanium dioxide.

52. The composition of any of the preceding claims, wherein the backing layer comprises sodium hydroxide.

53. The composition of any of the preceding claims, wherein the backing layer comprises

(a) about 65 wt% to about 85 wt% of Hydroxypropyl Cellulose;

(b) about 5 wt% to about 10 wt% of Copovidone;

(c) about 5 wt% to about 10 wt% of Sodium Carboxymethylcellulose;

(d) about 10 wt% to about 20 wt% of Polyethylene Glycol; (e) about 1 wt% to about 3 wt% of Titanium dioxide; and

(f) about 0.5 wt% to about 2 wt% of Sodium Hydroxide NF solution 50% (w/w).

54. The composition of any of the preceding claims, the composition comprising: an active layer comprising

(a) about 20 wt% to about 60 wt% of N, N-Dimethyltryptamine (DMT);

(b) about 1 wt% to about 5 wt% of Citric acid, anhydrous;

(c) about 1 wt% to about 5 wt% of Glutathione, reduced;

(d) about 0.01 wt% to about 0.1 wt%of Advantame;

(e) about 1 wt% to about 3 wt% of Sucralose;

(f) about 0.01 wt% to about 0.1 wt% of FD&C Yellow 6 powder;

(g) about 1 wt% to about 3 wt% of Arome Type Suppresseur Amertume;

(h) about 1 wt% to about 3 wt% of Evospray Natural Lime Flavor;

(i) about 5 wt% to about 15 wt% of Maltitol;

(k) about 1 wt% to about 5 wt% of Vitamin E TPGS;

(m)about 1 wt% to about 5 wt% of Copovidone;

(a) about 1 wt% to about 5 wt% of Copovidone;

(c) about 1 wt% to about 10 wt% of Sodium Carboxymethylcellulose;

(d) about 1 wt% to about 5 wt% of Polyethylene Glycol;

(e) about 0.1 wt% to about 0.5 wt% of Titanium Dioxide; and

(f) about 0.05 wt% to about 0.5 wt% of Sodium Hydroxide solution 50% (WAV).

55. The composition of any of the preceding claims, wherein the composition is suitable for transmucosal application.

56. The composition of claim 55, wherein the composition is suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application.

57. The composition of any of the preceding claims, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.3 h to about 2 h and a DMT C_max of about 5 ng/mL to about 80 ng/mL following administration.

58. The composition of any of the preceding claims, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.3 h to about 2 h and a DMT AUCi_ast of about 3 ng h/mL to about 70 ng h/mL following administration.

59. The composition of any of claim 57 or 58, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.5 h to about 1.5 h following administration.

60. The composition of claim 57 or 58, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT T_max of about 0.6 h to about 0.8 h following administration.

61. The composition of claim 58, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of DMT of about 5 ng/mL to about 80 ng/mL following administration.

62. The composition of claim 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 5 ng/mL to about 10 ng/mL following administration.

63. The composition of claim 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 10 ng/mL to about 30 ng/mL following administration.

64. The composition of claim 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 20 ng/mL to about 50 ng/mL following administration.

65. The composition of claim 61, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT C_max of about 25 ng/mL to about 80 ng/mL following administration.

66. The composition of claim 57, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCi_ast of about 3 ng h/mL to about 70 ng h/mL following administration.

67. The composition of claim 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCi_ast of about 3 ng • h/mL to about 9 ng • h/mL following administration.

68. The composition of claim 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCiast of about 8 ng h/mL to about 30 ng h/mL following administration.

69. The composition of claim 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCi_ast of about 15 ng h/mL to about 50 ng h/mL following administration.

70. The composition of claim 66, wherein the administration of the composition to the oral mucosa of a patient in need thereof provides a DMT AUCiast of about 25 ng h/mL to about 70 ng h/mL following administration.

71. A mucoadhesive composition comprising:

72. The composition of claim 71, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as characterized by a powder x-ray diffractogram free of any discernable peaks.

73. The composition of claim 71, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as characterized by a differential scanning calorimetry (DSC) thermogram lacking a sharp melting endotherm of crystalline DMT and/or lacking an indication of phase change.

74. The composition of any one of claims 71-73, wherein DMT is a DMT free base.

75. The composition of any one of claims 71-74, wherein the composition comprises about 30 wt% to about 50 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

76. The composition of claim 75, wherein the composition comprises about 32 wt% to about 46 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

77. The composition of claim 75, wherein the composition comprises about 35 wt% to about 36.5 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.

78. The composition of claim 75, wherein the composition comprises about 1 mg to about 200 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

79. The composition of claim 75, wherein the composition comprises about 1 mg to about 5 mg, about 5 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 40 mg, about 40 mg to 60 mg, or about 60 mg to 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

80. The composition of claim 75, wherein the composition comprises about 5 mg, about 15 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.

81. The composition of claim 71, wherein the polymeric carrier matrix comprises HPC of about 140 KDa having a solution viscosity (mPa s) of about 6 to about 10 cps in a 2 wt% aqueous solution, HPC of about 370 KDa having a solution viscosity (mPa s) of about 150 to about 400 cps in a 2 wt% aqueous solution, and HPC of about 40 KDa having a solution viscosity (mPa s) of about 2 to about 2.9 cps in a 2 wt% aqueous solution.

82. The composition of any one of claims 71-81, wherein the composition comprises about 30 wt% to about 50 wt% of the polymeric carrier matrix.

83. The composition of claim 82, wherein the composition comprises about 33 wt% to about 40 wt% of the polymeric carrier matrix.

84. The composition of claim 82, wherein the composition comprises about 35 wt% to about 36.5 wt% of the polymeric carrier matrix.

85. The composition of any one of claims 71-84, wherein the composition comprises a buffering agent.

86. The composition of claim 85, wherein the buffering agent comprises citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate, or any combination thereof.

87. The composition of claim 85 or 86, wherein the composition comprises about 0.1 wt% to about 10 wt% of the buffering agent.

88. The composition of any one of claims 71-87, wherein the composition comprises a permeation enhancer.

89. The composition of claim 88, wherein the permeation enhancer comprise Vitamin E TPGS, a bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or any combination thereof.

90. The composition of claim 89, wherein the permeation enhancer comprise Vitamin E TPGS.

91. The composition of any one of claims 88-90, wherein the composition comprises about 1 wt% to 5 wt% of the permeation enhancer.

92. The composition of any one of claims 71 -91 , wherein the composition comprises a stability enhancer or an antioxidant.

93. The composition of claim 92, wherein the stability enhancer or the antioxidant comprises a-tocopherol, tocopherol acetate, L-Glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol, Ethylenediaminetetraacetic acid (EDTA), or any combination thereof.

94. The composition of claim 93 or 93, wherein the composition comprises about 0.5 wt% to about 3 wt% of the stability enhancer or the antioxidant.

95. The composition of any of claims 88-94, wherein the composition comprises about 2 wt% to about 10 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer, and the stability enhancer or the antioxidant.

96. The composition of any one of claims 71-95, wherein the composition comprises a sweetening agent and/or a flavoring agent.

97. The composition of claim 96, wherein the sweetening agent comprises advantame, sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or any combination thereof.

98. The composition of claim 97, wherein the sweetening agent comprises advantame.

99. The composition of any one of claims 96-98, wherein the flavoring agent comprises lime flavor, evospray natural lime flavor lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, arome type suppresseur amertume or any combination thereof.

100. The composition of any one of claims 71-99, wherein the composition comprises comprising a coloring agent selected from D&C or FD&C red, yellow, green, blue, iron oxide red, iron oxide yellow, titanium dioxide, and any combination thereof.

101. The composition of any of the preceding claims, wherein the active layer comprises

(a) about 32 wt% to about 40 wt% of DMT;

(b) about 25 wt% to about 40 wt% of polymeric carrier matrix;

(c) about 5 wt% to about 15 wt% of a sweetening agent;

(d) about 2 wt% to about 10 wt% of a buffering agent;

(e) about 1 wt% to about 5 wt% of a permeation enhancer; and

(f) about 0.5 wt% to about 3 wt% of a stability enhancer or antioxidant

102. The composition of any one of claims 71-101, wherein the composition comprises:

(a) about 32 wt% to about 40 wt% of DMT;

(b) about 25 wt% to about 40 wt% of polymeric carrier matrix;

(c) about 5 wt% to about 15 wt% of D-Maltitol;

(d) about 2 wt% to about 10 wt% of citric acid; (e) about 1 wt% to about 5 wt% of vitamin E TPGS; and

(f) about 0.5 wt% to about 3 wt% of L-Glutathione.

103. The composition of any one of claims 71-102, wherein the composition comprises

(a) about 35.9 wt% of DMT;

(c) about 11.2 wt% of Maltitol;

(e) about 5.0 wt% of citric acid;

(f) about 3.6 wt% of vitamin E TPGS;

(g) about 3.4 wt% of sodium carboxymethylcellulose;

(h) about 3.1 wt% of Arome Type Suppresseur amertume;

(i) about 2.6 wt% of Copovidone;

(j) about 2.1 wt% of L-Glutathione;

(k) about 1.6 wt% of Evospray natural Lime flavor;

(l) about 1.5 wt% of Sucralose;

(n) about 0.1 wt% of Advantame; and

(o) about 0.01 wt% of FD&C Yellow No. 06 powder.

104. The composition of any one of claims 71-103, wherein the composition has a pH of about

7.5 to about 9.

105. The composition of any one of claims 71-104, wherein the composition has a pH of about 8 to about 9.

106. The composition of any one of claims 71-105, wherein the composition has a pH of about

8.5 to about 9.

107. The composition of any one of claims 71-106, wherein the composition has a pH of about 8.6.

108. The composition of any one of claims 71-107, wherein the composition has a thickness of about 0.01 mm to about 1.5mm.

109. The composition of any one of claims 71-108, wherein the composition has a thickness of about 0.5 mm to about 1.5mm.

110. The composition of claim 108 or 109, wherein the comprises about 2 mg/cm² to about 10 mg/cm² amorphous DMT or a pharmaceutically acceptable salt or prodrug thereof.

111. The composition of any of any one of claims 71-110, wherein the composition is suitable for transmucosal application.

112. The composition of claim 111, wherein the composition is suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application.