ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 CONTROLLED TRANSMUCOSAL RELEASE OF DMT IN COMBINATION WITH A MONOAMINE OXIDASE INHIBITOR CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No.63/550,446, filed February 6, 2024, the contents 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
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 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 subjects with life-threatening cancer: a randomized double- blind trial, Journal of Psychopharmacology 30(12), 1181-1197 (2016)). [0007] DMT is also understood to hold therapeutic value as a psychedelic, with efficacy trials ongoing to assess the effect of DMT or DMT fumarate administered intravenously to subjects with major depressive disorder (“MDD”). However, although the intrinsic properties of DMT
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 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 an extended period of time following administration, which is not achieved with a single dose of DMT via injection or inhalation. [0008] DMT is a natural occurring molecule and is not active upon peroral administration as DMT converts to inactive metabolites in the gastrointestinal tract (GI) and liver before sufficient penetration of the brain to elicit any therapeutic relevant effect. Peroral administration of DMT alone is rendered neuro-chemically inactive by monoamine oxidase (MOA) during first-pass metabolism. Thus, other routes for the administration of DMT have been designed to avoid or mitigate this fate. These predominantly require intravenous (IV) or intramuscular (IM) administration, inhalation (smoking or sublimation) or insufflation (nasal sprays, snuffs), and use of transdermal, sublingual, or buccal absorption. Other routes have been attempted with little reported success (see “Administration of N,N dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT”, Steven A. Barker, Psychopharmacology (2022) 239:1749–1763). Routes of administration such as transmucosal e.g., buccal/sublingual/gingival/mucosal (on the oral mucosa), on the tongue, nasal, vaginal, or rectal application have looked to improve DMT bioavailability by circumventing GI and hepatic first pass metabolism. (see Metabolism GAP Analysis of DMT Literature, Gina Patel, Mpharm, PhD, President and CEO, Patel Kwan Consultancy, 25 Aug, 2020). [0009] Therefore, a significant need exists for readily administrable medications of DMT to treat neurological diseases, disorders and conditions. Such medications, which maximize efficacy while allowing drug-related side effects to be effectively controlled, are of particular interest, especially if administrable via a convenient self-administered or clinician-administered route.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 SUMMARY OF THE INVENTION [0010] The present disclosure provides compositions or kits for transmucosal administration to a subject comprising: (a) N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof; and (b) a monoamine oxidase inhibitor (MAOI) or a pharmaceutically acceptable salt thereof. [0011] In aspects, the DMT or a pharmaceutically acceptable salt or prodrug thereof is formulated into a film composition. In embodiments, the film composition comprises (a) an active layer comprising DMT or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix and (b) a backing layer. In embodiments, the active layer further comprises the MAOI or a pharmaceutically acceptable salt thereof. In embodiments, the DMT or a pharmaceutically acceptable salt or prodrug thereof and the MAOI or a pharmaceutically acceptable salt thereof are formulated in separate compositions. [0012] In aspects, the present disclosure provides methods of increasing or prolonging exposure of DMT in plasma or brain of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition or kit described herein. [0013] In aspects, the present disclosure provides methods of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition or kit described herein. DETAILED DESCRIPTION [0014] The present disclosure relates to compositions and kits comprising N, N- Dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more monoamine oxidase inhibitors (MAOIs). The present disclosure provides methods of increasing or prolonging exposure of DMT in plasma or brain of a subject in need thereof comprising administering to the subject a therapeutically effective amount of a MAOI in an amount effective to inhibit MAO metabolism of DMT, and a therapeutically effective amount of DMT or a pharmaceutically acceptable salt or prodrug thereof.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 Definitions [0015] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [0016] 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. [0017] The term “subject ” “individual” and “patient” are used interchangeably herein and refers to a human. [0018] The terms “treating,” “treat” and “treatment” as used herein with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder. [0019] 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. [0020] 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,
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 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. [0021] The term “carrier” or “vehicle” as used interchangeably herein encompasses carriers, excipients, adjuvants, and diluents or a combination of any of the foregoing, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body. In addition to the adjuvants, excipients and diluents known to one skilled in the art, the carrier includes nanoparticles of organic and inorganic nature. [0022] 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 subject, is capable of performing the intended result. Compositions and Kits [0023] In aspects, the present disclosure provides compositions or kits comprising N,N- dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the compositions or kits further comprise one or more monoamine oxidase inhibitors (MAOIs) or a pharmaceutically acceptable salt thereof. In embodiments, the DMT and the MAOI are formulated in a single pharmaceutical composition, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the single
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 pharmaceutical composition is formulated for oral administration. In embodiments, the single pharmaceutical composition is formulated for transmucosal administration. In embodiments, the DMT and the MAOI are formulated in separate pharmaceutical compositions, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the separate pharmaceutical compositions are both formulated for oral administration. In embodiments, the separate pharmaceutical compositions are both formulated for transmucosal administration. In embodiments, the present disclosure provides kits comprising a first composition comprising DMT or a pharmaceutically acceptable salt or prodrug thereof and a second composition comprising an MAOI or a pharmaceutically acceptable salt thereof. [0024] In aspects, the present disclosure provides for the incorporation of DMT and/or one or more monoamine oxidase inhibitors (MAOIs) into compositions and dosage forms, including but not limited to fast dissolving tablets, microporous hollow fibers, chewing gum, capsules, tablets, fast or rapid disintegrating tablets, wafers, disks, powder, mucoadhesive gels, ointments, pastes, sponges, emulsions, suspensions, single layer film, bilayer film, multilayer film, a film having an inactive backing layer, mouthwashes, aerosols, sprays, gummies, bi-layer or multi-layer tablets, mucoadhesive tablets, suppositories, and other pharmaceutical delivery vehicles. [0025] In aspects, DMT (e.g., stable amorphous DMT) is incorporated into a polymeric film for transmucosal administration. In embodiments, DMT is incorporated into films (e.g., single layer film, bilayer film or multilayered films) with or without inclusion of a backing layer in their film. In embodiments, an inactive backing layer is added on top of the active film to reduce and/or prevent erosion from the back side of the active layer of the film when applied to the mucosal surface. In embodiments, an MAOI is incorporated in combination with the DMT into the film. In embodiments, an MAOI is incorporated separately into a film and administered by transmucosal delivery prior to administration of a DMT film. In embodiments, the MAOI is released simultaneously with DMT or immediately before releasing of DMT. [0026] In aspects, the compositions or kits of the present disclosure comprise DMT or a pharmaceutically acceptable salt or prodrug thereof and a MAOI or a pharmaceutically acceptable salt thereof in a film. In embodiments, the film is a single layer, a bilayer film or a multilayer film. In embodiments, the film comprises a backing layer. In embodiments, the backing layer is inactive and coupled to an active layer of the film such that the backing layer reduces erosion from a back
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 side of the active layer when applied to a mucosal surface. In embodiments, the MAOI decreases metabolization of the DMT and prolongs exposure time (e.g., Tmax) of DMT. [0027] In aspects, the present disclosure provides compositions or kits for transmucosal administration 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. In embodiments, the compositions or kits of the present disclosure for transmucosal administration further comprise one or more MAOIs. [0028] In embodiments, the composition or kits 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 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 A1, the contents of which are hereby incorporated by reference in their entireties for all purposes. [0029] 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 thereof. [0030] In embodiments, the active layer comprises DMT or a pharmaceutically acceptable salt or prodrug thereof 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%,
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, to about 60 wt%, including all values and ranges therebetween. [0031] In embodiments, the active layer of the present disclosure comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof, for example, about 1 mg, about 5 mg, about 10 mg, about 15 mg, 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 290 mg, about 295 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. [0032] In embodiments, more than one active layers may be layered on another (e.g., to provide multiple DMT and/or MAOI-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 and/or MAOI-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 or prodrug thereof. In embodiments, each active layer of the multiple DMT-containing active layers comprises the same amount of DMT or a pharmaceutically acceptable salt or prodrug thereof or different amount of DMT or a pharmaceutically acceptable salt or prodrug 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 or prodrug thereof and the second active layer comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof, including all values and ranges therebetween.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 [0033] In embodiments, the active layer of the present disclosure comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the active layer comprises about 1 mg to about 15 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the active layer comprises about 20 mg to about 200 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the active layer comprises about 60 mg to about 200 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the active layer comprises about 80 mg to about 200 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the active layer comprises about 120 mg to about 200 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the active layer comprises about 160 mg to about 200 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof, including all values and ranges therebetween. [0034] 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. [0035] 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. [0036] 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, AqualonTM 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
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 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.
[0037] In embodiments, the polymeric carrier matrix stabilizes the DMT in an amorphous form within the mucoadhesive therapeutic composition. [0038] In embodiments, the active layer comprises about 1 wt% to about 99 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%, about 90 wt%, about 95%, or about 99% 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. [0039] 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.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 [0040] 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- -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 -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. [0041] 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 1 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. [0042] In embodiments, the active layer comprises a plasticizer. In embodiments, the active layer comprises about 1 wt% to about 10 wt% of the plasticizer. In embodiments, the plasticizer is a polyethylene glycol (PEG) (e.g., PEG300), propylene glycol, glycerol, triacetin, castor oil, or mixtures thereof. [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, lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, or any combination thereof.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 [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 an anti-foaming agent (e.g., simethicone). [0046] 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. [0047] In embodiments, the active layer composition is as shown in Table 2.
[0048] In embodiments, the active layer composition is as shown in Table 3.
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[0049] In embodiments, the active layer composition is as shown in Table 4.
[0050] In embodiments, the active layer composition is as shown in Table 5.
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[0051] In embodiments, the active layer composition is as shown in Table 6.
[0052] In embodiments, the active layer composition is as shown in Table 7.
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[0053] 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). [0054] In embodiments, the 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. [0055] 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, AqualonTM 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
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 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. [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.
[0058] In embodiments, the backing layer composition is as shown in Table 10.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634
[0059] In embodiments, the 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 and/or a MAOI 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. [0060] In embodiments, an MAOI refers to any compound, whether natural or synthetic, that exhibits the ability to inhibit the enzymatic activity of MAO, including MAO-A and MAO-B. It encompasses all chemical structures, including organic molecules, peptides, proteins, nucleic acids, derivatives, analogs, and combinations thereof, capable of interfering with the catalytic function of monoamine oxidase enzymes, thereby preventing or reducing the metabolism or breakdown of monoamine neurotransmitters. In embodiments, the MAOI comprises reversible, irreversible, competitive, non-competitive, selective, or non-selective inhibitors, as well as any substance that indirectly modulates or regulates monoamine oxidase activity through allosteric, regulatory, or indirect mechanisms. In embodiments, the MAOI is an MAO-A-selective inhibitor. In embodiments, the MAOI is an MAO-B-selective inhibitor. In embodiments, the MAOI is a non- selective inhibitor. [0061] In embodiments, the MAOI is a naturally occurring or commercially available reversible inhibitor of monoamine oxidase (RIMA). In embodiments, the MAOI is isocarboxazid, phenelzine, selegiline, tranylcypromine, moclobemide, rasagiline, pargyline, minaprine, iproniazid, iproniazid, or nialamide. In embodiments, the MAOI is a reversible inhibitor of
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 monoamine oxidase A (RIMA). In embodiments, the RIMA is a natural source RIMA. In embodiments, the natural source RIMA is curcumin, harmaline, or harmine. In embodiments, the RIMA is a commercially available RIMA. In embodiments, the commercially available RIMA is brofaromine, cimoxatone, moclobemide, amiflamine caroxazone, eprobemide, minaprine, metralindole, methylene blue, moclobemide, pirlindole, or toloxatone. [0062] In embodiments, the MAOI is selected from the group consisting of isocarboxazid, pargyline, selegiline, furazolidone, phenelzine, amiflamine, iproniazid, nialamide, tranylcypromine, octamoxin, phenoxypropazine, pivalyl benzhydrazine, iproclozide, iproniazide, bifemelane, prodipine, benmoxin, etryptamine, fenoxypropazine, mebanazine, pheniprazine, safrazine, hypericine, iproniazid phosphate, phenelzine sulphate, tranylcypromine sulphate, methylene blue, moclobemide, brofaromine, befloxatone, toloxatone, clorgyline, CX157, cimoxatone, bazinaprine, harmine, harmaline, sercloremine, esuprone, pirlindole, metralindole, tetrindole, and clorgyline hydrochloride. In embodiments, the MAOI is selected from the group consisting of moclobemide, brofaromine, caroxazone, eprobemide, metralindole, minaprine, pirlindole, harmaline, harmine, rosiridin, amiflamine, befloxatone, cimoxatone, esuprone, sercloremine, tetrindole, 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide (CX157), and 3-(2,2,2-trifluoroethoxy)phenoxathiin-10, 10-dioxide (CX009). In embodiments, the MAOI is selected from the group consisting of moclobemide, metralindole, pirlindole, harmaline, harmine, tetrindole, CX157, and CX009. [0063] In embodiments, the MAOI is a reversible inhibitor of MAO-A. In embodiments, the MAOI is a MAO-A selective inhibitor. In embodiments, the MAOI has a selectivity for MAO- A inhibition over monoamine oxidase B (MAO-B) inhibition of at least about 5-fold, about 10- fold, about 50-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 500- fold, or about 1000-fold. In embodiments, the reversible inhibitor of MAO-A is CX157. [0064] In embodiments, the composition and kit comprises a molar ratio of MAOI to DMT that is about 1:1 or less than 1. For example, the composition and kit comprises a weight ratio of the inhibitor of MAOI to DMT ranging from about 1:1 to about 1:500 (e.g., about 1:2, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:30, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230,
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 about 1:240, about 1:250, about 1:260, about 1:270, about 1:280, about 1:290, about 1:300, about 1:310, about 1:320, about 1:330, about 1:340, about 1:350, about 1:360, about 1:370, about 1:380, about 1:390, about 1:400, about 1:410, about 1:420, about 1:430, about 1:440, about 1:450, about 1:460, about 1:470, about 1:480, about 1:490, or about 1:500, among other ratios within these enumerated ratios). [0065] In embodiments, the compositions and kits are suitable for transmucosal application. In embodiments, the compositions and kits are 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 subject’s skin (i.e., on the side of the film opposite that which is put into contact with the subject’s skin). [0066] In embodiments, the composition or kit is administered by a sublingual, buccal, or otherwise oral transmucosal route of administration. [0067] In embodiments, the administration of the composition or kit to the oral mucosa of a subject in need thereof provide residence time of DMT of about 5 min to about 40 min, for example, about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 35 min, or about 40 min, including any values or ranges therebetween following administration. [0068] In embodiments, the administration of the composition or kit to the oral mucosa of a subject in need thereof provide a Tmax of DMT of about 0.1 h to about 10 h, for example, about 0.1 h, about 0.5 h, about 1.0 h, about 1.5 h, about 2.0 h, about 2.5 h, about 3.0 h, about 3.5 h, about 4.0 h, about 4.5 h, about 5.0 h, about 5.5 h, about 6.0 h, about 6.5 h, about 7.0 h, about 7.5 h, about 8.0 h, about 8.5 h, about 9.0 h, about 9.5 h, or about 10.0 h, including any values or ranges therebetween following administration. [0069] In embodiments, the administration of the composition to the oral mucosa of a subject in need thereof provides a Cmax 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,
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 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. [0070] In embodiments, the administration of the composition to the oral mucosa of a subject in need thereof provides a AUClast 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 for Modulating DMT Metabolism [0071] DMT, as with certain other psychedelics, is not orally active as it is rapidly inactivated by monoamine oxidase (MAO) enzymes during first-pass metabolism (Nichols, Pharmacological Reviews, 2016;68(2):264-355). Monoamine oxidase A (MAO-A) is the main metabolizing enzyme of DMT and the two main circulating metabolites of DMT are DMT-NO and IAA. DMT is metabolized by both MAO and CYP enzymes. CYP oxidation results in primarily the DMT-NO formation, while MAO-A metabolism primarily results in IAA, but not DMT-NO. A scheme illustrating the common oxidation is presented in Scheme 1.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 [0072] In aspects, the present disclosure provides methods of increasing the oral bioavailability, decreasing the (in vitro or in vivo) rate of degradation, or increasing the (in vitro or in vivo) half-life of the DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of an MAOI or a pharmaceutically acceptable salt thereof in an amount effective to inhibit MAO metabolism of DMT, and a therapeutically effective amount of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the present disclosure provides methods of increasing or prolonging exposure of DMT in plasma or brain of a subject in need thereof comprising administering to the subject a therapeutically effective amount of a MAOI in an amount effective to inhibit MAO metabolism of DMT, and a therapeutically effective amount of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered before the DMT. In embodiments, the MAOI is administered at the same time as the DMT. [0073] In embodiments, the methods of the present disclosure comprise increasing exposure of DMT in plasma or brain, as compared to a subject administered the same dose of DMT or a pharmaceutically acceptable salt or prodrug thereof without administration of a MAOI in an amount effective to inhibit MAO metabolism of DMT. In embodiments, the exposure of DMT in plasma or brain is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, including all values and ranges therein. [0074] In embodiments, the methods of the present disclosure comprise prolonging exposure of DMT in plasma or brain, as compared to a subject administered the same dose of DMT or a pharmaceutically acceptable salt or prodrug thereof without administration of a MAOI in an amount effective to inhibit MAO metabolism of DMT. In embodiments, the exposure of DMT in plasma or brain is prolonged by about 0.5 hour, about 0.75 hour, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours, about 10.0 hours, about 10.25 hours, about 10.5 hours, about 10.75 hours, about 11.0 hours, about 11.25 hours, about 11.5 hours, about 11.75 hours, about 12.0 hours, about 12.25 hours, about 12.5 hours, about 12.75 hours, about 13.0 hours, about 13.25 hours, about 13.5 hours, about 13.75 hours, about 14.0 hours, about 14.25 hours, about 14.5 hours, about 14.75 hours, about 15.0 hours, about 15.25 hours, about 15.5 hours, about 15.75 hours, about 16.0 hours, about 16.25 hours, about 16.5 hours, about 16.75 hours, about 17.0 hours, about 17.25 hours, about 17.5 hours, about 17.75 hours, about 18.0 hours 18.25 hours, about 18.5 hours, about 18.75 hours, about 19.0 hours, about 19.25 hours, about 19.5 hours, about 19.75 hours, about 20.0 hours, about 20.25 hours, about 20.5 hours, about 20.75 hours, about 21.0 hours, about 21.25 hours, about 21.5 hours, about 21.75 hours, about 22.0 hours, about 22.25 hours, about 22.5 hours, about 22.75 hours, about 23.0 hours, about 23.25 hours, about 23.5 hours, about 23.75 hours, or about 24.0 hours or more including all values and ranges therein. Methods of Use [0075] In aspects, the present disclosure provide methods of treatment of a disease or disorder, wherein the methods comprise administering a therapeutically effective amount of the composition or kit of the present disclosure to a subject in need thereof. The disease or disorder is neurological disease, disorder, or condition, for example, a neuropsychiatric disorder. [0076] As used 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
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 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. [0077] As used herein, the term “treatment-resistant depression” or “TRD” means a depressive disorder which does not respond satisfactorily to adequate treatment. TRD is a complex phenomenon influenced by variety in depressive subtypes, psychiatric comorbidity, and coexisting medical illnesses. Although TRD episodes are most commonly associated with major depressive disorder (MOD), they are also seen in the depressed phase of bipolar disorder. [0078] In embodiments, the neurological disease or condition is addiction. Examples of addiction which can be treated with DMT or a pharmaceutically acceptable salt or prodrug thereof include substance use disorder such as addiction to nicotine, alcohol, cocaine, opioids, amphetamine, methamphetamine, heroin, morphine, phencyclidine, 3,4-methylenedioxy- methamphetamine, as well as other addictive substances. [0079] In embodiments, the neurological disease or condition is addictive behavior. Examples of addictive behavior which can be treated with DMT or a pharmaceutically acceptable salt or prodrug thereof include addiction to eating, gambling, sex, pornography, videogames, work, exercise, spiritual obsession, self-harm, travel, shopping and substance use disorder (SUD). [0080] In embodiments, the present disclosure provides methods of treating depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, a depressive disorder due to a medical
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 condition, or postpartum depression), comprising administering a therapeutically effective amount of the composition or kit of the present disclosure to a subject in need thereof. Dosing Regimens [0081] In embodiments, about 1 mg to about 400 mg of DMT free base or an equivalent dose of the pharmaceutically acceptable salt or prodrug thereof is administered to a subject in need thereof. In embodiments, the therapeutically effective amount comprises a dose ranging from about 1 mg to about 400 mg DMT free base or an equivalent dose of the pharmaceutically acceptable salt or prodrug thereof. In embodiments, the therapeutically effective amount comprises a dose ranging from about 1 mg to about 400 mg, about 5 mg to about 400 mg, or about 10 mg to about 400 mg, or about 200 mg to about 200 mg, or about 40 mg to about 160 mg, or about 80 mg to about 120 mg DMT free base or an equivalent dose of the pharmaceutically acceptable salt or prodrug thereof. In embodiments, the therapeutically effective amount comprises a dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, 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 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 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, about 400 mg, or more DMT free base or an equivalent dose of the pharmaceutically acceptable salt thereof. [0082] In embodiments, the therapeutically effective amount of an MAOI or a pharmaceutically acceptable salt thereof comprises a dose in an amount effective to inhibit MAO metabolism of DMT. In embodiments, the composition or kit comprises a molar ratio of MAOI to DMT being about 1:1 or less than 1. For example, the composition comprises a molar ratio of MAOI to DMT ranging from about 1:1 to about 1:500 (e.g., about 1:2, about 1:5, about 1:10, about
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:30, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240, about 1:250, about 1:260, about 1:270, about 1:280, about 1:290, about 1:300, about 1:310, about 1:320, about 1:330, about 1:340, about 1:350, about 1:360, about 1:370, about 1:380, about 1:390, about 1:400, about 1:410, about 1:420, about 1:430, about 1:440, about 1:450, about 1:460, about 1:470, about 1:480, about 1:490, or about 1:500, among other ratios within these enumerated ratios). [0083] In embodiments, the therapeutically effective amount of an MAOI or a pharmaceutically acceptable salt thereof comprises a dose ranging from about 0.1 mg to about 400 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, 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 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 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. [0084] In embodiments, the MAOI or a pharmaceutically acceptable salt thereof is administered concomitantly or concurrently with the DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI or a pharmaceutically acceptable salt thereof and the DMT or a pharmaceutically acceptable salt or prodrug thereof are formulated in a single composition and the DMT and MAOI-containing composition is administered to a subject in need thereof. In embodiments, the MAOI or a pharmaceutically acceptable salt thereof and the DMT or a pharmaceutically acceptable salt or prodrug thereof are formulated in separate compositions and the DMT composition and the MAOI composition are administered concomitantly to a subject in need thereof.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 [0085] In embodiments, the MAOI is administered before the first dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered as a single dose before the first dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered within about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours , about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours or about 15 hours of administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered within about 12 hours of administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered 1 to 10 days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days) prior to administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered 5 to 7 days prior to administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered as a single daily dose for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days before the first dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered before each dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered before a dose of DMT or a pharmaceutically acceptable salt or prodrug thereof as needed. [0086] In aspects, a subject in need thereof is administered a composition or kit comprising DMT or a pharmaceutically acceptable salt or prodrug thereof and an MAOI or a pharmaceutically acceptable salt thereof via transmucosal administration multiple times over a set a period of time. In embodiments, the subject is administered the composition or kit once every time period of between about 2 weeks and about 6 months for a set treatment period. In embodiments, the subject is administered the composition or kit once every time period of between about 2 weeks and about 3 months for a set treatment period. In embodiments, the subject is administered the composition or kit once every about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In embodiments, the subject is administered the composition or kit once every month for a set treatment period. In embodiments, the subject is administered the composition or kit once every 4 weeks for a set treatment period. In embodiments, the subject is administered the composition or
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 kit once every 2 months for a set treatment period. In embodiments, the subject is administered the composition or kit once every 3 months for a set treatment period. Combination Therapy [0087] In embodiments, the methods described herein comprise administering DMT or a pharmaceutically acceptable salt or prodrug thereof as the sole active agent in combination with an MAOI or a pharmaceutically acceptable salt thereof to increase or prolong exposure of DMT in plasma or brain of a subject in need thereof. In embodiments, the methods described herein for treating a neurological disease or condition comprise administering DMT or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional active agents. [0088] In aspects, one or more additional agents comprise therapeutic agents appropriate for the disease or disorder that is being treated, as is known in the art. In embodiments, DMT or a pharmaceutically acceptable salt or prodrug thereof may be administered to the subject in combination with one or more anti-depressant or antianxiety drugs, such as SSRls, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or serotonin norepinephrine reuptake inhibitors (SNRls). [0089] In embodiments, the disclosure provides methods of reducing anxiety in a subject undergoing treatment with DMT or a pharmaceutically acceptable salt or prodrug thereof, the method comprising administering to the subject: i) DMT or a pharmaceutically acceptable salt or prodrug thereof and ii) one or more benzodiazepines. [0090] In embodiments, the one or more benzodiazepines are administered to the subject at or around the same time as DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the one or more benzodiazepines are administered to the subject prior to administration of DMT or a pharmaceutically acceptable salt thereof, such as about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes before administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the one or more benzodiazepines are administered to the subject after DMT or a pharmaceutically acceptable salt or prodrug thereof, such as about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after administration of the psilocybin or precursor or derivative thereof. [0091] In embodiments, the benzodiazepine is selected from adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam, flunitrazolam, flurazepam, flutazolam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, meclonazepam, medazepam, metizolam, mexazolam, midazolam, nifoxipam, nimetazepam, nitemazepam, nitrazepam, nitrazolam, nordiazepam, norflurazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, rilmazafone, temazepam, tetrazepam, or triazolam. [0092] In embodiments, a subject is administered DMT or a pharmaceutically acceptable salt thereof as described herein along with one or more 5-HT2A specific antagonists and/or inverse agonists. In embodiments, the subject is administered DMT or a pharmaceutically acceptable salt thereof and the one or more 5-HT2A specific antagonists and/or inverse agonists at the same time. In embodiments, the subject is administered one or more 5-HT2A specific antagonists and/or inverse agonists prior to DMT or a pharmaceutically acceptable salt or prodrug thereof administration, such as, but not limited to about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes before DMT or a pharmaceutically acceptable salt or prodrug thereof administration. In embodiments, the subject is administered one or more 5-HT2A specific antagonists and/or inverse agonists after DMT or a pharmaceutically acceptable salt thereof administration, such as, but not limited to about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after DMT or a pharmaceutically acceptable salt or prodrug thereof administration. [0093] Suitable 5-HT2A antagonists include but are not limited to, trazodone, mirtazapine, metergoline, ketanserin, ritanserin, nefazodone, clozapine, olanzapine, quetiapine, risperidone,
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 asenapine, MDL-100907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro- pyrimido-azepine, 9-aminomethyl-9, 10-dihydroanthracene (AMOA), haloperidol, chlorpromazine, hydroxyzine (atarax), 5-MeO-NBpBrT, niaprazine, altanserin, aripiprazole, etoperidone, setoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rauwolscine, phenoxybenzamine, pruvanserin, deramciclane, nelotanserin, lubazodone, mepiprazole, xylamidine, R-(+)-alpha-(2,3-dimethoxyphenyl)-1 -[2-(4-fluorophenethyl)]-4-piperidinemethanol (M100907), mianserin, AT 1015, DV 7028, eplivanserin, 4F 4PP, fanaserin, alpha-phenyl-1 -(2- phenylethyl)-4-piperidinemethanol (MDL 11 ,939), melperone, mesulergine, paliperidone, 1-[2- (3,4-Dihydro-1 /-/-2-benzopyran-1-yl)ethyl]-4-( 4-fluorophenyl)piperazine dihydrochloride (PNU 9641 SE), (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3- pyrrolidinol(R-96544), sarpogrelate, spiperone, ziprasidone, zotepine, and 7-[[4-[2-( 4- fluorophenyl)ethyl]-1- piperazi nyl]carbonyl]-1-i ndole-3-carbonitri le (EM D 281014). [0094] Suitable 5-HT2A reverse agonists include but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and volinaserin. [0095] In embodiments, the disclosure provides a method of reducing the negative side effects associated with a traumatic psychedelic experience in a subject undergoing treatment with DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the method comprises administering to the subject: i) DMT or a pharmaceutically acceptable salt or prodrug thereof, and ii) one or more 5-HT 2A specific antagonists and/or inverse agonists. In embodiments, the method comprises administering to the subject: i) DMT or a pharmaceutically acceptable salt or prodrug thereof, and ii) one or more cannabinoids or cannabinoid derivatives. [0096] In embodiments, the cannabinoid is selected from THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); or CBT (cannabicitran). In particular embodiments, the cannabinoid is CBD (cannabidiol).
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 [0097] Dosage regimens may be adjusted to provide the optimum desired response. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy. [0098] In aspects, when treating a neuropsychiatric disease or disorder, such as depression (e.g. TRD), anxiety or an addiction, compositions or kits of the present disclosure are administered in conjunction with psychotherapy, talk therapy, cognitive behavioral therapy, exposure therapy, biofeedback therapy (e.g. EEG-assisted therapy and virtual reality assisted therapy), systematic desensitization, mindfulness, dialectical behavior therapy, interpersonal therapy, eye movement desensitization and reprocessing, social rhythm therapy, acceptance and commitment therapy, family-focused therapy, psychodynamic therapy, light therapy, computer therapy (including digital cognitive behavioral therapy), cognitive remediation, exercise, or other types of therapy such as transcranial magnetic stimulation (TMS). In embodiments, compositions or kits of the present disclosure are administered to treat depression in conjunction with digital cognitive behavioral therapy, for example, using the digital program DEPREXIS®. In embodiments, compositions or kits of the present disclosure are administered (for example, to treat depression or anxiety) in conjunction with therapy using a transdiagnostic approach (cf. J Consult Clin Psychol. 2020 Mar; 88(3): 179-195). NUMBERED EMBODIMENTS OF THE DISCLOSURE [0099] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments. 1. A composition or kit for transmucosal administration to a subject comprising: (a) N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof; and (b) a monoamine oxidase inhibitor (MAOI) or a pharmaceutically acceptable salt thereof. 2. The composition or kit of embodiment 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is formulated into a film composition. 3. The composition or kit of embodiment 2, wherein the MAOI or a pharmaceutically acceptable salt thereof is formulated in the film composition in combination with the DMT or a pharmaceutically acceptable salt or prodrug thereof.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 The composition or kit of embodiment 2, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof and the MAOI or a pharmaceutically acceptable salt thereof are formulated in separate compositions. The composition or kit of embodiment 2, wherein the film composition is a single layer film. The composition or kit of embodiment 2, wherein the film composition is a bilayer film or a multilayer film. The composition or kit of embodiment 2, wherein the film composition comprises a backing layer. The composition or kit of embodiment 2, wherein the film composition comprises (a) an active layer comprising DMT or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix and (b) a backing layer. The composition or kit of embodiment 8, wherein the active layer further comprises the MAOI or a pharmaceutically acceptable salt thereof. The composition or kit of any one of the preceding embodiments, 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. The composition or kit of any one of the preceding embodiments, 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. The composition or kit of embodiment 1, wherein the DMT salt is DMT succinate. The composition or kit of any one of the preceding embodiments, wherein the active layer comprises about 1 wt% to about 60 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof. The composition or kit of any one of the preceding embodiments, 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.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 The composition or kit of embodiment 14, wherein the composition comprises about 1 mg, 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. The composition or kit of embodiment 1, wherein the polymeric carrier matrix comprises a mucoadhesive polymer. The composition or kit of embodiment 8, 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. The composition or kit of embodiment 8, wherein the polymeric carrier matrix stabilizes the DMT an amorphous form within the transmucosal composition. The composition or kit of embodiment 8, wherein the active layer comprises about 30 wt% to about 95 wt% of the polymeric carrier matrix. The composition or kit of embodiment 8, wherein the active layer comprises a buffering agent. The composition or kit of embodiment 20, 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. The composition or kit of embodiment 8, wherein the active layer comprises a permeation enhancer. The composition or kit of embodiment 22, wherein the permeation enhancer comprises d- -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.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 The composition or kit of embodiment 8, wherein the active layer comprises a stability enhancer or an antioxidant. The composition or kit of embodiment 24, wherein the stability enhancer or the antioxidant comprises -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. The composition or kit of embodiment 8, wherein the active layer comprises a sweetening agent and/or a flavoring agent. The composition or kit of embodiment 26, wherein the sweetening agent comprises advantame, sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or any combination thereof. The composition or kit of embodiment 26, wherein the flavoring agent comprises lime flavor, lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, or any combination thereof. The composition or kit of embodiment 8, 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. The composition or kit of embodiment 8, 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. The composition or kit of embodiment 8, wherein the backing layer comprises a polymeric matrix. The composition or kit of embodiment 31, wherein the polymeric matrix comprises carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyethylene glycol, and copovidone. The composition or kit of embodiment 8, wherein the backing layer comprises titanium dioxide.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 The composition or kit of embodiment 8, wherein the backing layer comprises sodium hydroxide. The composition or kit of any one of the preceding embodiments, wherein the composition or kit is suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application. The composition or kit of any one of the preceding embodiments, wherein the molar ratio of MAOI to DMT is about 1:1 to about 1:500. The composition or kit of any one of the preceding embodiments, wherein the MAOI decreases metabolization of DMT and prolongs a DMT Tmax. The composition or kit of any one of the preceding embodiments, wherein the MAOI is reversible. The composition or kit of any one of the preceding embodiments, wherein the MAOI is isocarboxazid, phenelzine, selegiline, tranylcypromine, moclobemide, rasagiline, pargyline, minaprine, iproniazid, iproniazid, or nialamide. The composition or kit of any one of the preceding embodiments, wherein the MAOI is a reversible inhibitor of monoamine oxidase A (RIMA). The composition or kit of embodiment 40, wherein the RIMA is a natural source RIMA. The composition or kit of embodiment 41, wherein the natural source RIMA is curcumin, harmaline, or harmine. The composition or kit of embodiment 41, wherein the RIMA is a commercially available RIMA. The composition or kit of embodiment 43, wherein the commercially available RIMA is brofaromine, cimoxatone, moclobemide, amiflamine caroxazone, eprobemide, minaprine, metralindole, methylene blue, moclobemide, pirlindole, or toloxatone. A method of increasing or prolonging exposure of DMT in plasma or brain of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition or kit of embodiments 1-44.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 46. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition or kit of embodiments 1-44. 47. The method of embodiment 45 or 46, wherein the MAOI or a pharmaceutically acceptable salt thereof is administered before the DMT or a pharmaceutically acceptable salt or prodrug thereof. 48. The method of embodiment 45 or 46, wherein the MAOI or a pharmaceutically acceptable salt thereof is administered at the same time as the DMT or a pharmaceutically acceptable salt or prodrug thereof. 49. The method of embodiment 47, wherein the MAOI or a pharmaceutically acceptable salt thereof is administered between about 15 minutes to about 75 minutes before the administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof. 50. The method of embodiment 46, wherein the neurological disorder is treatment resistant depression. EXAMPLES [0100] 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. [0101] A clinical study was conducted to administer DMT at various doses via IV infusion, buccal or sublingual routes to healthy human volunteers. DMT was formulated in a buccal film for transmucosal administration via the buccal or sublingual route. Table 11 and Table 12 present pharmacokinetic data from the clinical study.
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634
[0102] The pharmacokinetic data from the clinical study in healthy volunteers illustrates that MAO-A remains as the main and dominating metabolizing enzyme when DMT is administered by a controlled transmucosal release via the buccal and sublingual route. IAA was found to be the major metabolite. In addition, it was found that the overall exposure of DMT was significantly reduced when DMT was administered via the transmucosal route when compared to similar doses via the intravenous route (see Table 13, Part 1/Cohorts 1&2 versus Part 2/Cohorts 2&3). [0103] The Cmax of the primary MAO-A metabolite IAA was found to be about the same for both IV infusion and the transmucosal route (i.e., buccal and sublingual) (see Table 13, Part 1/Cohorts 1&2 versus Part 2/Cohorts 2&3). However, the overall exposure of IAA was larger for
ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 the transmucosal route than the IV infusion route. 0.02-0.04% DMT was detected through the transmucosal route, whereas 0.2-0.8% DMT was detected through IV infusion. [0104] The pharmacokinetic data in Table 13 and Table 14 shows a 63% increase in AUC Geomean and 41% increase in Cmax Geomean when a backing film was applied to the buccal film (see Table 14, P2C5 to P3C1). Similarly, when increasing the dose from 80 to 160 mg while using a backing film, a further 54% increase in AUC Geomean and 73% increase in Cmax Geomean were found (see Table 14, P3C1 to P3C3). The backing film contained an inactive backing layer which was added on top of the active film to reduce and/or prevent erosion from the back side of the active layer of the film when the film was applied to the mucosal surface. [0105] Monoamine oxidase inhibitors (MAOIs) decrease the metabolization of the DMT and prolong the effect time of DMT. Co-administration of one or more MAOIs with DMT concomitantly or sequentially to circumvent monoamine oxidase metabolism in transmucosal delivery achieves desired bioavailability of DMT suitable for treatment of neurological diseases, disorders and conditions.