New N,N-dimethyltryptamine salts and crystalline salt forms.

Abstract

The present disclosure provides N,N-dimethyltryptamine salts and crystalline salt forms, their preparation, pharmaceutical compositions comprising said salts and crystalline salt forms, and their use in the treatment of neurological diseases and conditions.

Description

[Technical field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 192,938, filed May 25, 2021, the entire contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates to new N,N-dimethyltryptamine salts and crystalline salt forms, their preparation and uses. The new salts and salt forms may be incorporated into pharmaceutical compositions for treating neurological diseases and conditions. [Background technology]

[0003] N,N-Dimethyltryptamine (hereinafter "DMT") has therapeutic value as a hallucinogen, and its unique properties make it an attractive potential drug treatment, especially for neurological diseases and conditions. However, DMT free base, isolated as clear or white crystals, has a low melting point of 44.6 °C to 46.8 °C and extremely low solubility in water. In solution, DMT free base has a rapid decomposition rate and should be stored at minus 20 °C, protected from air and light (Brito-da-Costa et al, Pharmaceuticals 2020, 13, 334). Salts of DMT have been prepared with improved solubility, including the fumarate and hydrochloride hemihydrates. However, there remains a need for new DMT salt forms that exhibit superior physicochemical properties to DMT free base, especially to facilitate improved formulation (e.g., solubility, stability) and performance (e.g., bioavailability). The present disclosure addresses this need by providing novel DMT salt forms with improved melting point (higher), aqueous solubility (higher), and / or hygroscopicity (lower) properties compared to DMT free base. Summary of the Invention

[0004] New salts and crystalline salt forms of DMT are described herein. Specifically, the salt forms DMT fumarate Form A, DMT succinate Form A, DMT malate Form A, DMT oxalate Form A, and DMT sulfate Form A are described herein. Also described herein are DMT succinate, DMT malate, DMT sulfate, and DMT phosphate.

[0005] According to one embodiment, the present disclosure provides DMT fumarate Form A.

[0006] According to one aspect, the present disclosure provides DMT succinate Form A.

[0007] According to one aspect, the present disclosure provides DMT malate Form A.

[0008] According to one aspect, the present disclosure provides DMT oxalate Form A.

[0009] According to one aspect, the present disclosure provides DMT sulfate Form A.

[0010] According to one aspect, the present disclosure provides a DMT succinate salt.

[0011] According to one aspect, the present disclosure provides a DMT malate salt.

[0012] According to one aspect, the present disclosure provides a DMT sulfate salt.

[0013] According to one aspect, the present disclosure provides a DMT phosphate salt. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) for DMT fumarate Form A, including the observed peaks. [Diagram 2] FIG. 2 shows the XRPD for DMT succinate Form A, including the observed peaks. [Diagram 3]FIG. 3 shows the XRPD for DMT malate Form A, including the observed peaks. [Figure 4] FIG. 4 shows the XRPD for DMT sulfate Form A, including the observed peaks. [Diagram 5] FIG. 5 shows the XRPD for DMT oxalate Form A, including the observed peaks. [Figure 6] FIG. 6 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for DMT sulfate Form A. [Figure 7] FIG. 7 shows the TGA and DSC thermograms for DMT oxalate Form A. [Figure 8] FIG. 8 shows the TGA and DSC thermograms for DMT fumarate Form A. [Figure 9] FIG. 9 shows the TGA and DSC thermograms for DMT malate Form A. [Figure 10] FIG. 10 shows the TGA and DSC thermograms for DMT succinate Form A. [Figure 11] FIG. 11 shows the dynamic vapor sorption (DVS) isotherm for DMT fumarate form A. [Figure 12] FIG. 12 shows the DVS isotherm for DMT malate form A. [Figure 13] FIG. 13 shows the DVS isotherm for DMT succinate form A. [Figure 14] FIG. 14 shows a variable temperature XRPD analysis for DMT succinate Form A. [Figure 15] FIG. 15 shows the DSC isotherm for DMT succinate Form A prepared using ethanol as the solvent. [Figure 16] FIG. 16 shows the XRPD for DMT succinate Form A prepared using ethanol or acetone as the solvent. [Figure 17] FIG. 17 shows the X-ray diffraction for DMT succinate Form A prepared on either the milligram scale (XRPD data) or gram scale (single crystal X-ray diffraction, SCXRD). [Figure 18] FIG. 18 shows the DVS isotherm for DMT succinate Form A from the scale-up batch. [Figure 19] FIG. 19 shows the TGA and DSC thermograms for DMT succinate Form A from a scale-up batch. [Figure 20] FIG. 20 shows the DSC isotherm of a physical mixture of DMT succinate Form A and succinic acid at an overall composition of 0.34 mole fraction of DMT. [Figure 21] FIG. 21 shows a hot stage micrograph of DMT succinate Form A prepared from acetone (small scale) confirming melting at 142° C. [Figure 22] FIG. 22 shows a hot stage micrograph of DMT succinate Form A prepared from ethanol (large scale). [Diagram 23] FIG. 23 shows the XRPD for DMT phosphate. [Figure 24] FIG. 24 shows the melting points of five salt forms of DMT compared to the DMT free base. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In one aspect, the present disclosure is directed to succinate, malate, sulfate, or phosphate salts of DMT.

[0016] In one aspect, the present disclosure is directed to DMT succinate.

[0017] Also included in the disclosure are any solvates, such as hydrates, complexes, and polymorphs, of the salts of DMT described herein.

[0018] Salts of DMT may exist in crystalline or non-crystalline forms, or as mixtures thereof. For salts of DMT that are in crystalline form, those skilled in the art will understand that pharma- ceutically acceptable solvates may be formed, in which solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents, such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or may include water as the solvent that is incorporated into the crystal lattice. Solvates in which water is the solvent that is incorporated into the crystal lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions that contain variable amounts of water. As those skilled in the art will appreciate, the amount of water may depend on conditions, such as humidity. For example, a decrease in humidity may result in a decrease in the amount of water, and an increase in humidity may result in an increase in the amount of water. Such variations in the amount of water are within the scope of the present invention.

[0019] In one aspect, the present disclosure is directed to DMT fumarate crystalline Form A.

[0020] In one embodiment, the present disclosure is directed to DMT fumarate crystalline form A, characterized as providing an XRPD pattern including peaks (°2θ) at about 10.78, about 15.38, about 15.73, about 15.97, about 16.93, about 18.33, about 19.61, about 19.75, about 20.49, about 23.55, about 23.91, and / or about 24.94.

[0021] In another embodiment, the present disclosure is directed to DMT fumarate crystalline Form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 6.

[0022] In another embodiment, the present disclosure is directed to DMT fumarate crystalline Form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 5.

[0023] In a further embodiment, the present disclosure is directed to DMT fumarate crystalline Form A, characterized by providing an XRPD pattern substantially in accordance with FIG.

[0024] In one embodiment, the present disclosure is directed to DMT fumarate Form A, characterized by exhibiting a TGA thermogram substantially in accordance with FIG.

[0025] In one embodiment, the present disclosure is directed to DMT fumarate crystalline Form A, characterized by exhibiting a DSC thermogram substantially in accordance with FIG.

[0026] In one embodiment, the present disclosure is directed to DMT fumarate crystalline Form A, characterized by exhibiting a DVS isotherm substantially in accordance with FIG.

[0027] In one embodiment, the present disclosure is directed to DMT fumarate crystalline form A, characterized by having a melting point of about 151.8° C. when measured under ambient conditions.

[0028] In one aspect, the present disclosure is directed to DMT succinate crystalline Form A.

[0029] In one embodiment, the present disclosure is directed to DMT succinate crystalline form A, characterized as providing an XRPD pattern including peaks (°2θ) at about 9.75, about 14.27, about 16.90, about 19.58, about 20.58, about 23.08, about 23.39, about 24.83, about 26.79, and / or about 27.60.

[0030] In another embodiment, the present disclosure is directed to a DMT succinate crystalline Form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 8.

[0031] In another embodiment, the present disclosure is directed to a DMT succinate crystalline form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 7.

[0032] In a further embodiment, the present disclosure is directed to DMT succinate crystalline Form A, characterized by providing an XRPD pattern substantially in accordance with FIG. 2.

[0033] In one embodiment, the present disclosure is directed to DMT succinate crystalline Form A, characterized by exhibiting a TGA thermogram substantially in accordance with FIG.

[0034] In one embodiment, the present disclosure is directed to DMT succinate crystalline Form A, characterized by exhibiting a DSC thermogram substantially in accordance with FIG.

[0035] In one embodiment, the present disclosure is directed to a DMT succinate crystalline form A characterized by exhibiting a DVS isotherm substantially in accordance with FIG.

[0036] In a further embodiment, the present disclosure is directed to a DMT succinate crystalline form A, characterized by providing a variable temperature XRPD pattern substantially in accordance with FIG.

[0037] In another embodiment, the present disclosure is directed to a DMT succinate crystalline form A, characterized by exhibiting a DSC isotherm substantially in accordance with FIG.

[0038] In a further embodiment, the present disclosure is directed to DMT succinate crystalline form A, characterized by providing an XRPD pattern substantially in accordance with FIG.

[0039] In a further embodiment, the present disclosure is directed to DMT succinate crystalline Form A, characterized by providing an XRPD pattern substantially in accordance with FIG.

[0040] In a further embodiment, the present disclosure is directed to DMT succinate crystalline form A, characterized by providing an SCXRD pattern substantially in accordance with FIG.

[0041] In another embodiment, the present disclosure is directed to a DMT succinate crystalline form A, characterized by exhibiting a DVS isotherm substantially in accordance with FIG.

[0042] In one embodiment, the present disclosure is directed to DMT succinate crystalline Form A, characterized by exhibiting a TGA thermogram substantially in accordance with FIG. 19.

[0043] In one embodiment, the present disclosure is directed to DMT succinate crystalline Form A, characterized by exhibiting a DSC thermogram substantially in accordance with FIG.

[0044] In one embodiment, the present disclosure is directed to DMT succinate crystalline form A, characterized by having a melting point of about 141.9° C. when measured under ambient conditions.

[0045] In one aspect, the present disclosure is directed to DMT malate crystalline form A.

[0046] In one embodiment, the present disclosure is directed to DMT malate crystalline form A, characterized as providing an XRPD pattern including peaks (°2θ) at about 9.92, about 13.96, about 16.55, about 19.71, about 20.16, about 22.07, about 22.23, about 22.79, about 23.82, about 25.06, and / or about 29.87.

[0047] In another embodiment, the present disclosure is directed to DMT malate crystalline Form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 10.

[0048] In another embodiment, the present disclosure is directed to DMT malate crystalline Form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 9.

[0049] In a further embodiment, the present disclosure is directed to DMT malate crystalline form A, characterized by providing an XRPD pattern substantially in accordance with FIG.

[0050] In one embodiment, the present disclosure is directed to DMT malate crystalline Form A, characterized by exhibiting a TGA thermogram substantially in accordance with FIG.

[0051] In one embodiment, the present disclosure is directed to DMT malate crystalline Form A, characterized by exhibiting a DSC thermogram substantially in accordance with FIG.

[0052] In one embodiment, the present disclosure is directed to DMT malate crystalline Form A, characterized by exhibiting a DVS isotherm substantially in accordance with FIG.

[0053] In one embodiment, the present disclosure is directed to DMT malate crystalline form A, characterized by having a melting point of about 109.1° C. when measured under ambient conditions.

[0054] In one aspect, the present disclosure is directed to DMT sulfate salt crystalline form A.

[0055] In one embodiment, the present disclosure is directed to DMT sulfate crystalline form A, characterized as providing an XRPD pattern including peaks (°2θ) at about 11.05, about 15.32, about 15.89, about 16.24, about 19.71, about 19.88, about 22.22, about 23.54, about 23.92, about 24.40, about 25.03, and / or about 25.47.

[0056] In another embodiment, the present disclosure is directed to DMT sulfate crystalline Form A, characterized by providing an XRPD pattern including peaks (°2θ) substantially as presented in Table 12.

[0057] In another embodiment, the present disclosure is directed to DMT sulfate crystalline Form A, characterized by providing an XRPD pattern including peaks (°2θ) substantially as presented in Table 11.

[0058] In a further embodiment, the present disclosure is directed to DMT sulfate salt crystalline Form A, characterized by providing an XRPD pattern substantially in accordance with FIG.

[0059] In one embodiment, the present disclosure is directed to DMT sulfate crystalline Form A, characterized by exhibiting a TGA thermogram substantially in accordance with FIG.

[0060] In one embodiment, the present disclosure is directed to DMT sulfate crystalline Form A, characterized by exhibiting a DSC thermogram substantially in accordance with FIG.

[0061] In one embodiment, the present disclosure is directed to DMT sulfate crystalline form A, characterized by having a melting point of about 105.2° C. when measured under ambient conditions.

[0062] In one aspect, the present disclosure is directed to DMT oxalate crystalline Form A.

[0063] In one embodiment, the present disclosure is directed to DMT oxalate crystalline Form A, characterized as providing an XRPD pattern including peaks (°2θ) at about 5.86, about 14.63, about 17.60, about 19.26, about 20.32, about 22.07, about 22.03, about 23.57, about 24.34, about 25.78, and / or about 27.51.

[0064] In another embodiment, the present disclosure is directed to DMT oxalate crystalline Form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 14.

[0065] In another embodiment, the present disclosure is directed to DMT oxalate crystalline Form A, characterized by providing an XRPD pattern comprising peaks (°2θ) substantially as presented in Table 13.

[0066] In a further embodiment, the present disclosure is directed to DMT oxalate crystalline Form A, characterized by providing an XRPD pattern substantially in accordance with FIG. In one embodiment, the present disclosure is directed to DMT oxalate crystalline Form A, characterized by exhibiting a TGA thermogram substantially in accordance with FIG.

[0067] In one embodiment, the present disclosure is directed to DMT oxalate crystalline Form A, characterized by exhibiting a DSC thermogram substantially in accordance with FIG.

[0068] In one embodiment, the present disclosure is directed to DMT oxalate crystalline Form A, characterized by having a melting point of about 135.2° C. when measured under ambient conditions.

[0069] When it is stated herein that there is a peak in an XRPD pattern at a given value, this typically means that the peak is within ±0.2 of the quoted value.

[0070] The present disclosure encompasses salt forms of DMT and salts of DMT when isolated in pure form or mixed with other materials, such as other salt forms or solvates of DMT.

[0071] Thus, in one embodiment of the present disclosure, there is provided an isolated or pure form of DMT succinate crystalline form A. "Isolated form" or "pure form" refers to a sample in which DMT succinate crystalline form A is present in an amount of >75%, specifically >90%, more specifically >95%, and even more specifically >99%, relative to other materials that may be present in the sample.

[0072] Terms and Definitions As used herein, the symbols and conventions used in these processes, tables, figures, and examples are consistent with those used in modern academic scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. In particular, the following abbreviations may be used in the examples and throughout this specification: - DMT: N,N-Dimethyltryptamine - XRPD: X-ray powder diffraction - TGA: Thermogravimetric analysis - DSC: Differential Scanning Calorimetry - DVS: Dynamic Vapor Sorption - SCXRD: Single crystal X-ray diffraction - RH: Relative humidity - RT: room temperature - EtOH: Ethanol - Sorp: Sorption - Desorp: Detach - ACN: Acetonitrile - DMF: Dimethylformamide - EtOAc: ethyl acetate - HFIPA: Hexafluoro-2-propanol - IPA: Isopropyl alcohol - MeOH: Methanol - NMP: N-methyl-2-pyrrolidone - TFE: 2,2,2-trifluoroethanol - PTFE: Polytetrafluoroethylene - VD: Vapor diffusion - VS: Steam stressing - FE: Fast evaporation - CC: Crash Cooling

[0073] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered, and includes, but is not limited to, such liquids and powders that are hydrophilic substances, hydrophobic substances, and substances with both hydrophilic and hydrophobic properties, such as emulsifying agents.

[0074] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an active agent that elicits in a tissue, system, or individual the biological or medicinal response desired by a researcher, medical practitioner, or individual.

[0075] As used herein, the term neurological disease or condition refers to a psychoneurotic disorder, (such as depression (including severe depression such as treatment-resistant depression, major depressive disorder, and persistent depressive disorder), catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder), anxiety, anxiety disorder, social anxiety disorder, generalized anxiety disorder (GAD), anorexia disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder, body dysmorphic disorder, mood or affect abnormalities including the above conditions, dysthymia, schizoaffective disorder, schizophrenia, and other psychotic disorders, panic disorder, post-traumatic stress disorder, phobic disorder, and personality disorders with abnormal moods (such as borderline personality disorder, schizotypal disorder, schizophrenic disorder, schizophrenic disorder, schizophrenia, and other psychotic disorders). "means a disease or condition selected from obsessive-compulsive disorder, addiction (including substance use disorders such as addiction to nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamines, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances), addictive behaviors (including eating, gambling, sex, pornography, video games, work, exercise, spiritual obsessions, self-harm, travel, and shopping addictions), eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), and pain (including pain associated with migraines or headaches, or chronic pain) in which suicidal ideation or rumination / repetitive, unproductive thoughts adversely affect a person's behavior / mood / ability to concentrate."

[0076] As used herein, the term "treatment-resistant depression" or "TRD" refers to a depressive disorder that does not respond satisfactorily to appropriate treatment. TRD is a complex phenomenon influenced by variability in depression subtypes, psychiatric comorbidities, and coexisting disorders. Although TRD symptom manifestations are most commonly associated with major depressive disorder (MDD), they are also found in the depressive phase of bipolar disorder.

[0077] The term "about," when used before a numerical designation, e.g., pH, temperature, amount, or concentration, denotes an approximation that may vary by up to (+) or (-) 5%, unless otherwise specifically defined herein.

[0078] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a pharma- ceutically acceptable carrier" may include a plurality of pharma- ceutically acceptable carriers, including mixtures thereof.

[0079] The term "and / or" is intended to mean either or both of the two components of the invention.

[0080] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human.

[0081] As used herein, the term "device" refers to an equipment or system capable of delivering a drug to a patient in need thereof.

[0082] The terms "in need of treatment" and "in need of" when referring to treatment are used interchangeably and refer to the judgment that the patient would benefit from treatment administered by a caring person (e.g., a doctor, nurse, nurse practitioner, etc.).

[0083] The terms "treat" and "treatment" herein refer to therapeutic treatment, including prophylactic or preventative measures, where the purpose is to prevent or slow down (reduce) undesirable physiological changes associated with a disease or condition. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slow down the progression of a disease or condition, improvement or alleviation of a disease or condition, and remission (partial or total) of a disease or condition. "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. Those in need of treatment include those already with a disease or condition, as well as those prone to have a disease or condition, or those in whom a disease or condition is to be prevented. "Treatment", when referring to depression, can also include reducing at least one sign or symptom of depression. Examples of signs or symptoms of depression include depressed mood, decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or slowing, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to concentrate or indecisiveness, or suicidal thoughts or behaviors.

[0084] The terms "nasal delivery", "intranasal delivery", "nasal administration" or "intranasal administration" refer to the route of administration, where a pharmaceutical dosage form is taken into or through the nose (e.g., nasal cavity). Similarly, "nasal delivery device" or "intranasal delivery device" is intended to mean a device that administers a drug into the nasal cavity. Non-limiting examples of intranasal administration include the introduction of a solution or suspension in the form of a nasal spray or nasal drops (direct drops), or the intranasal application of a gel, emulsion, or ointment.

[0085] The term "buccal delivery" or "buccal administration" refers to a route of administration whereby a pharmaceutical dosage form is applied between the patient's cheek and gums (ie, the buccal cavity).

[0086] The term "sublingual delivery" refers to a route of administration whereby a pharmaceutical dosage form is applied under the patient's tongue. Preparation of Salts and Salt Forms

[0087] The present disclosure is also directed to processes for preparing salts and salt forms of DMT.

[0088] In a further aspect, the disclosure provides a process for preparing a salt or crystalline salt form A of DMT, the method comprising contacting DMT free base with a suitable acid, such as fumaric acid, succinic acid, L-(-)malic acid, sulfuric acid, oxalic acid, or phosphoric acid, in the presence of a suitable solvent, such as acetone or ethanol, to form a slurry, preferably stirred for 1-5 days or more, and collecting the formed solid by filtration, such as by using a Swinnex® positive pressure filter assembly using a 0.2-μm nylon filter. The process may conveniently be carried out at between about −20° C. and about room temperature.

[0089] The present disclosure further provides for recrystallizing the DMT salt of Form A from a suitable solvent including ACN, DMF, EtOAc, HFIPA, IPA, MeOH, NMP, and TFE at temperatures between -20°C and 50°C.

[0090] DMT free base may be prepared according to known procedures or purchased from a commercial supplier.

[0091] Pharmaceutical Compositions and Delivery In one aspect, the disclosure provides a pharmaceutical composition comprising a DMT salt selected from DMT succinate, DMT malate, DMT sulfate, and DMT phosphate (e.g., DMT succinate), together with one or more carriers and / or excipients.

[0092] In one aspect, the disclosure provides a pharmaceutical composition comprising a DMT salt form selected from DMT fumarate Form A, DMT succinate Form A, DMT malate Form A, DMT oxalate Form A, and DMT sulfate Form A (e.g., DMT succinate Form A), together with one or more carriers and / or excipients.

[0093] Pharmaceutical compositions containing DMT salts and salt forms (e.g., DMT succinate crystal form A) may be compressed into solid dosage units such as tablets, or processed into capsules or suppositories. With pharma-ceutical suitable liquids, the compounds can also be prepared in the form of solutions, suspensions, emulsions, or as sprays. To make dosage units, including tablets, the use of conventional additives such as fillers, colorants, polymeric binders, and the like is contemplated. In general, any pharma-ceutical acceptable additives can be used. Suitable fillers with which pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose, and derivatives thereof, and the like, or mixtures thereof used in suitable amounts.

[0094] For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injection solutions, including DMT salts and salt forms (e.g., DMT succinate crystalline form A), may be used, containing pharma- ceutically acceptable dispersing and / or wetting agents, such as propylene glycol or butylene glycol.

[0095] The disclosure also provides a pharmaceutical composition as described herein in combination with suitable packaging material for the composition, the packaging material including instructions for use of the pharmaceutical composition.

[0096] Pharmaceutical compositions containing DMT salts and salt forms (e.g., DMT succinate crystalline form A) suitable for intranasal administration include compositions in which the active ingredient is present in a liquid carrier. In various embodiments, the composition may be in the form of an aqueous or non-aqueous solution, a suspension, a liposomal dispersion, an emulsion, a microemulsion, or a sol-gel. The carrier may contain additives such as solubilizers (e.g., propylene glycol), surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, mucoadhesives, and / or preservatives such as parabens. Methods well known in the art for making intranasal formulations may be found, for example, in Remington, 2000. In addition, methods for formulating compounds for intranasal administration are well known, including prolonging the presence of the active agent in the nasal cavity, combining with agents to increase solubility, and increasing bioavailability.

[0097] Pharmaceutical compositions containing DMT salts and salt forms (e.g., DMT succinate crystalline Form A) suitable for buccal and sublingual administration include fast dissolving tablets, wafers, films, strips or patches, orodispersible tablets, oral gels, medicated lollipops, sprays, drops, and other formulations that are retained on the surface of the buccal or sublingual mucosa.

[0098] Pharmaceutical compositions containing DMT salts and salt forms suitable for subcutaneous administration (e.g., DMT succinate crystalline form A) may be provided in unit dosage form (e.g., in single-dose ampoules) or in vials containing several doses and to which suitable preservatives may be added (see below). The compositions may conveniently be in the form of a solution, suspension, or emulsion, or may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. Apart from the DMT salt or salt form (e.g., DMT succinate crystalline form A), the compositions may include suitable parenterally acceptable carriers and / or excipients. Moreover, the compositions may include suspending agents, solubilizing agents, stabilizing agents, pH adjusting agents, and / or dispersing agents.

[0099] The pharmaceutical composition of the present disclosure may include one or more excipients, diluents, binders, lubricants, glidants, disintegrants, desensitizers, emulsifiers, mucoadhesives, solubilizers, suspending agents, viscosity adjusters, ionic tonicity agents, buffers, carriers, surfactants, or mixtures thereof.The pharmaceutical composition of the present disclosure may also include components such as permeation enhancers, bioadhesive polymers, and means for providing controlled release, such as sustained release of active ingredients.The composition may also include one or more pharma- ceutically acceptable flavoring agents or other taste-masking agents.

[0100] The in vivo release rate and in vivo clearance of DMT can be influenced by means well known in the art.For example, by incorporating into or onto microparticle preparations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, or by incorporating active materials into liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.It is also understood herein that compounds are modified by covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, cyclodextrin, cucurbituril, polyvinylpyrrolidone, or polyproline.Modified compounds may exhibit substantially longer half-life in blood after administration than the corresponding unmodified compounds.

[0101] Depending on the delivery device employed, delivery of about 25% to about 100% of the drug product, i.e., DMT, may be achieved. However, as one skilled in the art will appreciate, it is understood that due to the nature of the drug delivery device, not all of the drug is necessarily delivered, since the amount delivered depends on the efficiency of the delivery device employed. Therefore, for clarity, it is understood that about 25% to about 100% of the drug product delivered depends on the drug delivery method and / or device selected. Thus, 100% of the drug product delivered may not be all of the drug product, but all of the drug product that the selected device has the ability to deliver.

[0102] Intranasal composition Relative to oral dosage forms such as tablets or capsules, intranasal delivery offers rapid absorption, faster onset of therapeutic action, and avoidance of first-pass metabolism in the intestinal wall or liver. For patients who have difficulty swallowing tablets, capsules, or other solids, or who have intestinal failure, the intranasal delivery route may be preferred.

[0103] The composition of the present disclosure for nasal administration comprises DMT salt or salt form (e.g., DMT succinate crystalline form A), and can also optionally comprise other ingredients, including, but not limited to, carriers and excipients such as absorption enhancers that promote nasal absorption of the active ingredient after nasal administration, and agents that improve brain penetration of the drug after nasal administration. Other optional excipients include diluents, binders, lubricants, glidants, disintegrants, desensitizing agents, emulsifiers, mucoadhesives, solubilizers, suspending agents, viscosity adjusters, ionic tonicity agents, buffers, carriers, flavoring agents, and mixtures thereof. In one embodiment, the particle size of the active ingredient is about 60 micrometers or less, which can help ensure uniformity of any mixture of the particles with other ingredients or provide proper dispersion in a liquid vehicle.

[0104] The amount of drug absorbed depends on many factors.These factors include drug concentration, drug delivery vehicle, mucosal contact time, venous drainage of mucosal tissue, the degree to which drug is ionized at the pH of absorption site, the size of drug molecule, and its relative lipid solubility.Those skilled in the art can easily prepare suitable intranasal composition that delivers suitable amount of active drug by taking these factors into account.

[0105] The transport of active ingredients across normal mucosal surfaces (such as nasal or buccal mucosa) can be enhanced by optionally combining with absorption enhancers. Examples of these absorption enhancers include, but are not limited to, cationic polymers, surface active agents, chelating agents, mucolytic agents, cyclodextrins, polymeric hydrogels, combinations thereof, and any other similar absorption enhancers known to those skilled in the art. Representative absorption enhancer excipients include phospholipids such as phosphatidylglycerol or phosphatidylcholine, lysophosphatidyl derivatives such as lysophosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidylglycerol, lysophosphatidylserine, or lysophosphatidic acid, polyols such as glycerol or propylene glycol, glycerides, amino acids, and their fatty acid esters such as their esters, and cyclodextrins. Gelling excipients or viscosity-increasing excipients can also be used.

[0106] Transport of active ingredients across intact mucosal surfaces can also be enhanced by increasing the time that the formulation adheres to the mucosal surface. Mucoadhesive / bioadhesive polymers, such as hydrogel-forming polymers, exhibit mucoadhesion and controlled drug release properties and can include the compositions described herein intranasally or bucally. Representative bioadhesive or hydrogel-forming polymers capable of binding to the nasal mucosa are well known to those skilled in the art and include one or more poloxomers, such as polycarbophil, polylysine, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose, pectin, carbopol 934P, polyethylene oxide 600K, pluronic F127 and / or pluronic F-68, polyisobutylene (PIB), polyisoprene (PIP), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), xanthan gum, guar gum, and locust bean gum. Other nasal delivery compositions are chitosan-based and are also suitable for increasing the residence time of the active ingredient on the mucosal surface, thereby increasing its bioavailability. Thiolated polymeric excipients that form covalent bonds with cysteine-rich subdomains of the mucus membrane can also provide mucoadhesion that extends the contact time between the active ingredient and the membrane.

[0107] The intranasal composition may also include one or more preservatives. Representative preservatives include quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride, benzododecinium chloride, cetylpyridium chloride, cetrimide, domiphen bromide, etc., alcohols such as benzyl alcohol, chlorobutanol, o-cresol, phenylethyl alcohol, organic acids or their salts such as benzoic acid, sodium benzoate, potassium sorbate, parabens, or complexing agents such as EDTA.

[0108] Carriers and excipients include ion-exchange microspheres carrying suitable anionic groups such as carboxylic acid residues, carboxymethyl groups, sulfopropyl groups, and methylsulfonate groups. Ion-exchange resins such as cation exchangers can also be used. Chitosan, which is partially deacetylated chitin, or poly-N-acetyl-D-glucosamine, or its pharma- ceutically acceptable salts, such as hydrochloride, lactate, glutamate, maleate, acetate, formate, propionate, malate, malonate, adipate, or succinate. Other components suitable for use as non-ion-exchange microspheres include starch, gelatin, collagen, and albumin.

[0109] The composition may also contain other ingredients such as cellulose, microcrystalline cellulose, hydroxypropyl cellulose, starch, hydroxypropyl methylcellulose, and the like. Excipients that adjust the tonicity of the composition may be added, such as sodium chloride, glucose, dextrose, mannitol, sorbitol, lactose, and the like. Acidic or basic buffers may also be added to intranasal compositions to control pH.

[0110] In addition to the use of absorption enhancers to increase the transport of active agents through mucosa and bioadhesive materials to extend the contact time of active agents along mucosa, the administration of active agents can be controlled by using controlled release formulations. There are numerous particulate drug delivery vehicles known to those skilled in the art that can contain active ingredients and deliver them in a controlled manner. Examples include particulate polymeric drug delivery vehicles, such as particles formed from biodegradable polymers and non-polymeric components. These particulate drug delivery vehicles can be in the form of powders, microparticles, nanoparticles, microcapsules, liposomes, and the like. Typically, when an active agent is in particulate form without added components, its release rate depends on the release of the active agent itself. Typically, the absorption rate is enhanced by presenting the agent in a micronized form, with particles less than 20 micrometers in diameter. In contrast, when an active agent is in particulate form as a blend of active agent and polymer, the release of the active agent is at least partially controlled by the removal of the polymer, typically by dissolution, biodegradation, or diffusion from the polymer matrix.

[0111] intranasal delivery Intranasal delivery devices are known in the art.Therefore, any device suitable for delivery of medicaments to nasal mucosa may be used.Non-limiting examples of devices useful for administering liquid compositions include steam devices (e.g. steam inhalers), droppers (e.g. catheters, single-dose droppers, multiple-dose droppers, and unit dose pipettes), mechanical spray pump devices (e.g. squeeze bottles, multiple-dose metered-dose spray pumps, and single / double-dose spray pumps), bidirectional spray pumps (e.g. breath-actuated nasal delivery devices), gas-driven spray systems / atomizers (e.g. single-dose or multiple-dose HFA or nitrogen propellant-driven metered-dose inhalers, including conventional and circumferential velocity inhalers), and motorized nebulizers / atomizers (e.g. pulsed membrane nebulizers, vibratory mechanical nebulizers, and handheld mechanical nebulizers). Non-limiting examples of devices useful for administration of powder compositions (e.g., lyophilized or otherwise dried pooled compositions) include mechanical powder sprayers (e.g., manually actuated capsule-based powder spray devices and manually actuated powder spray devices, manually actuated gel delivery devices), breath actuated inhalers (e.g., single or multi-dose nasal inhalers and capsule-based single or multi-dose nasal inhalers), and insufflation devices (e.g., breath actuated nasal delivery devices).

[0112] The use of a metered dose spray for intranasal delivery can also be accomplished by including the active ingredient in a solution or dispersion in a suitable vehicle that can be administered as a spray. Representative devices of this type are disclosed in the following patents, patent applications, and publications: Nos. WO 03 / 026559, WO 02 / 011800, WO 00 / 51672, WO 02 / 068029, WO 02 / 068030, WO 02 / 068031, WO 02 / 068032, WO 03 / 000310, WO 03 / 020350, WO 03 / 082393, WO 03 / 084591, WO 03 / 090812, WO 00 / 41755, and in the pharmaceutical literature (see Bell, A. Intranasal Delivery Devices, in Drug Delivery Devices Fundamentals and Applications, TyIe P. (ed), Dekker, New York, 1988), Remington's Pharmaceutical Sciences, Mack Publishing Co., 1975, all of which are incorporated herein by reference.

[0113] In addition to the above, the salts / salt forms can also be administered intranasally in the form of irrigation and douche, as known in the art. Nasal irrigation involves periodically drenching the nasal passages with a solution containing the drug. Nasal douche is typically used by filling a douche with a solution containing the drug, inserting the nozzle from the douche into one nostril, having the subject open their mouth and breathe, and allowing the solution to flow into one nostril, rinse around the septum, and drain out the other nostril.

[0114] Means of delivering drugs to the upper portions of the nasal cavity, such as the cribriform cavity, are of particular interest herein. Also of interest is delivery of drugs along the trigeminal nerve pathway.

[0115] Buccal and Sublingual Compositions and Delivery For oral dosage forms such as tablets or capsules, oral transmucosal delivery, like intranasal delivery, offers rapid absorption, faster onset of therapeutic action, and avoidance of first-pass metabolism in the liver or intestinal wall. For patients who have difficulty swallowing tablets, capsules, or other solids, or who have intestinal failure, buccal or sublingual delivery routes are preferred.

[0116] Compositions for buccal or sublingual administration include a DMT salt or salt form (e.g., DMT succinate crystalline form A) and at least one excipient to form a solid dosage form. The solid dosage form decomposes in the oral cavity or under the tongue with minimal liquid exposure and body temperature, and ideally adheres to the body tissue of the oral cavity or tissue under the tongue via direct adhesion to the tissue, or in the case of buccal administration, via entrapment of the dosage form between the gums and the inner cheek. The solid dosage form decomposes or melts at body temperature with or without the aid of fluid, saliva, mechanical erosion, or a combination thereof. Alternatively, the dosage form can be sprayed in the oral cavity or under the tongue in the form of a solution spray or dry powder. In general, the composition can be an adhesive that is directed to the body tissue inside the oral cavity of the patient, or under the tongue.

[0117] The dosage form can be, but is not limited to, a tablet, a bioadhesive patch or film, a sponge, a lozenge, a hard candy, a wafer, a lollipop, a spray, a gum, a pill, a pellet, a sphere, combinations thereof, and other forms known to one of skill in the art.

[0118] Buccal or sublingual films represent a particularly convenient vehicle for administering the pharmaceutical composition of the present disclosure. Examples of films include, in one aspect, compositions comprising DMT salt or salt form (e.g., DMT succinate crystalline form A) in mucoadhesive polymers. Suitable mucoadhesive polymers include one or more polymers selected from cellulose derivatives, polyacrylic acid, polyacrylates, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, tragacanth, alginates, gums (including karaya gum, guar gum, xanthan gum), soluble starch, gelatin, lectin, pectin, and chitosan. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from hydrophilic polymers, polysaccharides and their derivatives, and hydrogels. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from polyacrylic acid, polyacrylate, cellulose, such as carboxycellulose (e.g., sodium carboxymethylcellulose), hydroxyalkylcellulose (e.g., hydroxypropylcellulose, hydroxyethylcellulose, and hydroxyethylethylcellulose), polyvinylpyrrolidone, and polyvinyl alcohol. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from carbopol (polyacrylic acid), carboxymethylcellulose, carboxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and gums. In some embodiments, the mucoadhesive polymer is water-swellable. Typically, the mucoadhesive polymer is present in an amount of about 15% to about 60% by weight of the film composition.

[0119] The film composition may further comprise a permeation enhancer and / or an antioxidant. For example, in some embodiments, the film composition comprises a permeation enhancer, including, for example, one or more permeation enhancers selected from dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, and surfactants. In some embodiments, the permeation enhancer is present in an amount of about 5% to about 30% by weight of the film composition. In some embodiments, the film composition comprises an antioxidant, for example, tocopherol acetate.

[0120] In some embodiments, the film composition can form a bilayer or multilayer film composition. Typically, such bilayer or multilayer films can provide a biphasic release profile, which can be advantageous in certain circumstances. In some embodiments, the fast-release film layer comprises a water-soluble polymer. In some embodiments, the water-soluble polymer in the fast-release film comprises one or more polymers selected from hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), povidone, polyvinyl alcohol (PVA), low molecular weight polyethylene oxide (PEO, such as Poly Ox N10, supplied by Dow Chemical), and starch-based polymers (Lycoat, manufactured by Roquette). In some embodiments, the fast-release film can also optionally comprise a permeation enhancer, including one or more permeation enhancers selected from, for example, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, and surfactants. In some embodiments, the immediate release film can also optionally include an antioxidant, such as tocopherol acetate.

[0121] There are numerous compositions and delivery vehicles suitable for buccal or sublingual delivery of active ingredients. In addition to DMT or a pharma- ceutically acceptable salt thereof, other components of the dosage form include starch, mannitol, kaolin, inorganic salts such as calcium sulfate, sodium chloride, powdered cellulose derivatives, dibasic and tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, hydroxypropyl methylcellulose, anionic excipients, cationic excipients, zwitterionic excipients, see U.S. Pat. No. 6,436,950, which is incorporated herein by reference, for a description of such excipients. However, these include, but are not limited to, polymeric hydrogels, powdered microsphere mucoadhesive compositions, thiolated polymeric excipients, polycationic materials, chitosan, crosslinked starch, fats, carbohydrates, polyols, buffers, phosphate buffer, acetate buffer, methocel, sodium chloride, water, lactic acid, benzalkonium chloride, demineralized water, cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydrogenated vegetable oils, flavorings, phospholipids, xylitol, cocoa, combinations thereof, and other similar excipients known to those of skill in the art.

[0122] Permeation enhancers can also be present. Representative permeation enhancers include, but are not limited to, 23-lauryl ether, aprontinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid, lysophosphatidylcholine, menthol, sodium methoxysalicylate, methyl oleate, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbatc, sodium EDTA, sodium glycocholate, sodium glycodeoxyocholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides, short and medium chain mono-, di-, and triglycerides, as well as other polyol esters, and various alkyl glycosides.

[0123] A binder may also be present. Suitable binders include materials such as cellulose, including but not limited to cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose and hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, polyethylene glycol, starch, natural gums (such as acacia, alginates, guar, and acacia), and synthetic gums and waxes.

[0124] Subcutaneous Compositions and Delivery For subcutaneous administration, aqueous suspensions, isotonic saline solutions, and sterile injection solutions may be used, optionally containing pharma- ceutically acceptable excipients, such as propylene glycol or butylene glycol, and / or humectants. In addition, suspensions of DMT salts or salt forms (e.g., DMT succinate crystalline form A) may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the salts / salt forms, to allow for the preparation of highly concentrated solutions. Alternatively, DMT salts or salt forms (e.g., DMT succinate crystalline form A) may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use. The solution or suspension may be administered subcutaneously to a subject by injection, using well-known devices and techniques. Any suitable syringe may be conveniently used, including an auto-injector, which may allow for self-administration.

[0125] dosage The dose of a DMT salt or salt form (e.g., DMT succinate crystal form A) administered to a patient having a neurological disease or condition, as defined herein, is typically about 0.1 mg / kg to about 1 mg / kg. A typical human dose (for an adult weighing 50-80 kg) would equate to a dose of about 5 mg to about 80 mg. In one embodiment, the dose is about 10 mg to about 60 mg, such as about 20-60 mg, about 30-60 mg, about 40-60 mg, or any specific amount therebetween, including 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, In the present disclosure, when a range is recited, such as "about 20 to 60 mg," the inventors contemplate all individual values ​​within the range, although some may be specifically recited, but not all may be recited merely for purposes of brevity.

[0126] In certain embodiments, the DMT salt or salt form (e.g., DMT succinate crystalline form A) may be administered to the patient in one or more doses over a 24 hour period, for example, 1, 2, 3, 4, or 5 doses. However, the total dose administered to the subject should not exceed about 100 mg over a 24 hour period.

[0127] use In one aspect, the present disclosure provides a DMT salt (e.g., DMT succinate) selected from DMT succinate, DMT malate, DMT sulfate, and DMT phosphate, for use in the treatment of a neurological disease or condition.

[0128] In one aspect, the present disclosure provides a DMT salt form selected from DMT fumarate Form A, DMT succinate Form A, DMT malate Form A, DMT oxalate Form A, and DMT sulfate Form A (e.g., DMT succinate Form A), for use in the treatment of a neurological disease or condition.

[0129] In one aspect, the disclosure provides a method of treating a neurological disease or condition, comprising administering to a subject an effective amount of a DMT salt (e.g., DMT succinate) selected from DMT succinate, DMT malate, DMT sulfate, and DMT phosphate.

[0130] In one aspect, the disclosure provides a method of treating a neurological disease or condition comprising administering to a subject an effective amount of a DMT salt form (e.g., DMT succinate Form A) selected from DMT fumarate Form A, DMT succinate Form A, DMT malate Form A, DMT oxalate Form A, and DMT sulfate Form A.

[0131] To administer the DMT salt or salt form of the present disclosure (e.g., DMT succinate crystal form A), any suitable method generally available for administering DMT fumarate may be used. Advantageously, the DMT salt or salt form (e.g., DMT succinate crystal form A) may be administered orally, parenterally, transmucosally, intranasally, bucally, or sublingually. In one embodiment, the DMT salt or salt form (e.g., DMT succinate crystal form A) may be administered parenterally, for example, by intravenous or intramuscular injection.

[0132] In any one of the above aspects, the neurological disease or condition may be, for example, a neuropsychiatric disorder.

[0133] Examples of neuropsychiatric disorders that may be treated with DMT salts or salt forms (e.g., DMT succinate crystal form A) include depression (e.g., TRD), anxiety, bipolar disorder, post-traumatic stress disorder, mood or emotional disorders including those conditions listed above, dysthymia, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, post-traumatic stress disorder, phobic disorders, eating disorders and personality disorders accompanied by mood disorders (such as borderline personality disorder, schizophrenia and schizotypal disorder and suicidal ideation), or rumination / repetitive, unproductive thoughts that adversely affect a person's behavior / mood / ability to concentrate.

[0134] In any one of the above aspects, the neurological disease or condition may be, for example, an addiction.

[0135] Examples of addictions that may be treated with DMT salts or salt forms (e.g., DMT succinate crystalline Form A) include substance use disorders such as addiction to nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamine, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances.

[0136] In any one of the above aspects, the neurological disease or condition can be, for example, an addictive behavior.

[0137] Examples of addictive behaviors that may be treated with DMT salts or salt forms (e.g., DMT succinate crystalline Form A) include addictions to eating, gambling, sex, pornography, video games, work, exercise, spiritual obsessions, self-harm, traveling, and shopping.

[0138] In certain embodiments, the present disclosure provides a method for treating depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, depressive disorder due to a medical condition, or postpartum depression) comprising administering to a subject an effective amount of a DMT salt (e.g., DMT succinate) selected from DMT succinate, DMT malate, DMT sulfate, and DMT phosphate. In one embodiment, the DMT salt may be administered transmucosally (e.g., bucally, sublingually, or intranasally).

[0139] In certain embodiments, the present disclosure provides a method of treating depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, depressive disorder due to a medical condition, or postpartum depression) comprising administering to a subject an effective amount of a DMT salt form (e.g., DMT succinate Form A) selected from DMT fumarate Form A, DMT succinate Form A, DMT malate Form A, DMT oxalate Form A, and DMT sulfate Form A. In one embodiment, the DMT salt form may be administered transmucosally (e.g., bucally, sublingually, or intranasally).

[0140] In certain embodiments, the present disclosure provides a method of treating depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, depressive disorder due to a medical condition, or postpartum depression) comprising subcutaneously administering to a subject an effective amount of a DMT salt (e.g., DMT succinate) selected from DMT succinate, DMT malate, DMT sulfate, and DMT phosphate.

[0141] In certain embodiments, the present disclosure provides a method of treating depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, depressive disorder due to a medical condition, or postpartum depression) comprising subcutaneously administering to a subject an effective amount of a DMT salt form (e.g., DMT succinate Form A) selected from DMT fumarate Form A, DMT succinate Form A, DMT malate Form A, DMT oxalate Form A, and DMT sulfate Form A.

[0142] Combination therapy The methods described herein include administering a DMT salt or salt form (e.g., DMT succinate crystalline form A) as the sole active ingredient. However, methods for treating neurological diseases or conditions that include administering a DMT salt or salt form (e.g., DMT succinate crystalline form A) in combination with one or more additional agents are also included within the scope of the present disclosure.

[0143] In one aspect, these additional agents are suitable therapeutic agents for the disease or disorder being treated, as known in the art. In some embodiments, the DMT salt or salt form (e.g., DMT succinate crystal form A) may be administered to a subject in combination with one or more antidepressants or anti-anxiety agents, such as SSRIs, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or serotonin norepinephrine reuptake inhibitors (SNRIs).

[0144] In some embodiments, the present disclosure provides a method of reducing anxiety in a subject undergoing treatment with a DMT salt or salt form (e.g., DMT succinate crystal form A), the method comprising administering to the subject i) a DMT salt or salt form (e.g., DMT succinate crystal form A) and ii) one or more benzodiazepines.

[0145] In some embodiments, one or more benzodiazepines are administered to a subject simultaneously or about simultaneously with a DMT salt or salt form (e.g., DMT succinate crystal form A). In some embodiments, one or more benzodiazepines are administered to a subject prior to administration of a DMT salt or salt form (e.g., DMT succinate crystal form A), 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 prior to administration of psilocybin or a precursor or derivative thereof. In some embodiments, the one or more benzodiazepines are administered to the subject after the DMT salt or salt form (e.g., DMT succinate crystalline Form A), such as about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after administration of psilocybin, or a precursor or derivative thereof.

[0146] In some embodiments, the benzodiazepine is adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, fluralprazolam, flubromazepam, flubromazolam, fluclotizolam, Selected from the group consisting of flunitrazepam, flunitrazolam, flurazepam, flutazolam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, meclonazepam, medazepam, metizolam, mexazolam, midazolam, nifoxipam, nimetazepam, nitemazepam, nitrazepam, nitrazolam, nordiazepam, norflurazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, rilmazafone, temazepam, tetrazepam, and triazolam.

[0147] In certain embodiments, the patient is at least one 2A The patient is administered a DMT salt or salt form as described herein (e.g., DMT succinate crystalline form A) together with a specific antagonist and / or inverse agonist. In some embodiments, the patient is administered a DMT salt or salt form (e.g., DMT succinate crystalline form A) and one or more 5-HT 2A In another embodiment, the patient is administered one or more 5-HT specific antagonists and / or inverse agonists. 2A The specific antagonist and / or inverse agonist is administered prior to administration of the DMT salt or salt form (e.g., DMT succinate crystal form A), 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 prior to administration of the DMT salt or salt form (e.g., DMT succinate crystal form A). In some embodiments, the patient is administered one or more 5-HT 2A The specific antagonist and / or inverse agonist is administered after administration of the DMT salt or salt form (e.g., DMT succinate crystal form A), such as, but not limited to, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after administration of the DMT salt or salt form (e.g., DMT succinate crystal form A).

[0148] Preferred 5-HT 2AAntagonists include trazodone, mirtazapine, metergoline, ketanserin, ritanserin, nefazodone, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines, 9-aminomethyl-9,10-dihydroanthracene (AMDA), haloperidol, chlorpromazine, hydroxyzine (Atarax), and 5-MeO-NBp. BrT, niaprazine, altanserin, aripiprazole, etoperidone, setoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rauwolscine, phenoxybenzamine, pulvanserin, deramciclane, nerotanserin, rubazodone, mepiprazole, xylamidine, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinemethanol (M100907), mianserin, AT 1015, DV 7028, eplivanserin, 4F 4PP, fanaserin, alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol (MDL 1 1,939), melperone, mesulergine, paliperidone, 1-[2-(3,4-dihydro-1 / - / -2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine dihydrochloride (PNU 96415E), (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol (R-96544), sarpogrelate, spiperone, ziprasidone, zotepine, and 7-[[4-[2-(4-fluorophenyl)ethyl]-1-piperazinyl]carbonyl]-1-indole-3-carbonitrile (EMD 281014).

[0149] Preferred 5-HT 2A Inverse agonists include, but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and vorinaserin.

[0150] In some embodiments, the present disclosure provides a method for reducing negative side effects associated with traumatic hallucinatory experiences in a patient undergoing treatment with a DMT salt or salt form (e.g., DMT succinate crystalline form A). In one aspect, the method comprises: i) administering a DMT salt or salt form (e.g., DMT succinate crystalline form A) to a patient; and ii) administering one or more 5-HT 2A In another embodiment, the method comprises administering to the patient i) a DMT salt or salt form (e.g., DMT succinate crystalline Form A) and ii) one or more cannabinoids or cannabinoid derivatives.

[0151] In some embodiments, the cannabinoid is selected from the group consisting of THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran). In certain embodiments, the cannabinoid is CBD (cannabidiol).

[0152] 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.

[0153] In a further aspect of the present disclosure, when treating a neuropsychiatric disease or disorder, such as depression (e.g., TRD), anxiety, or addiction, the composition of the present disclosure may be administered in conjunction with psychotherapy. This may include talk therapy, cognitive behavioral therapy, simulated exposure therapy, biofeedback therapy (e.g., EEG-assisted therapy and virtual reality-assisted therapy), systematic desensitization, mindfulness, dialectical behavior therapy, interpersonal therapy, eye movement desensitization and reprocessing, social rhythm therapy, acceptance commitment therapy, family-focused therapy, psychodynamic therapy, light therapy, computer therapy (including digital cognitive behavioral therapy), cognitive remediation, exercise, or other types of therapy such as transcranial magnetic stimulation (TMS). In one embodiment, DMT salt or salt form (e.g., DMT succinate crystal form A) may be administered to treat depression in conjunction with digital cognitive behavioral therapy, for example, using the digital program DEPREXIS®. In one embodiment, a DMT salt or salt form (e.g., DMT succinate crystal form A) may be administered in conjunction with a therapy (e.g., to treat depression or anxiety) using a transdiagnostic approach (see J Consult Clin Psychol. 2020 Mar;88(3):179-195).

[0154] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, mention of any references, articles, publications, patents, patent publications, and patent applications herein is not, and should not be taken as, an admission or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country throughout the world.

[0155] In the examples below, product samples were analyzed according to the following methodology. XRPD: XRPD patterns were collected using a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer using an incident beam of Cu radiation generated using a long fine focus source. An elliptical graded multilayer mirror was used to focus the Cu Kα X-rays through the specimen and onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and anti-scatter knife edges were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize spread and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.5.5. Data acquisition parameters are listed within the images of each pattern displayed herein. Variable Temperature XRPD: XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Kα radiation generated using a long fine focus source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Data were collected and analyzed using Data Collector software v.2.2b. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST certified position. Sample specimens were packed into nickel-coated copper wells. Anti-scatter slits (SS) were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v. 2.2b. Data acquisition parameters for each pattern are displayed herein, including the divergence slit (DS) and the incident beam anti-scatter slit (SS). An Anton Paar Temperature and Humidity Chamber (THC) was used to collect in situ XRPD patterns as a function of temperature. The temperature of the specimen was varied using a Peltier thermoelectric device located directly below the specimen holder and monitored using a platinum-100 resistive sensor located within the specimen holder. The thermoelectric device was powered and controlled by an Anton Paar TCU50 interfaced with the data collector. TGA: TGA was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy adjustments were performed using indium, tin, and zinc, then verified with indium. The balance was verified with calcium oxalate. The sample was placed in an open aluminum pan. The pan was then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. Samples were analyzed from 25° C. to 350° C. at 10° C. / min. DSC: DSC was performed using a Mettler-Toledo DSC3+ Differential Scanning Calorimeter. Taurag adjustments are performed with indium, tin, and zinc. Temperature and enthalpy are adjusted with octane, phenyl salicylate, indium, tin, and zinc. The adjustments are then verified with octane, phenyl salicylate, indium, tin, and zinc. Samples were placed into hermetically sealed aluminum DSC pans, the weight accurately recorded, the lid pierced, and the sample inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The lid of the pan was pierced prior to sample analysis. Samples were analyzed from -30°C to 250°C at 10°C / min. Cyclic DSC: The sample cell was equilibrated at -30.0°C and then heated under nitrogen to 135°C at a rate of 10.0°C / min. The sample cell was then allowed to cool and equilibrate at 25.0°C. It was heated again to 250.0°C at a rate of 10.0°C / min. DVS: Automated Vapor Sorption (VS) data were collected on a Surface Measurement System DVS specific instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected over the range 5%-95% RH in 10% RH increments under a nitrogen purge. The equilibration criteria used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples. EXAMPLES

[0156] A. Fumarate Form A A slurry containing 49.4 mg of fumaric acid and 79.2 mg of DMT in 1 mL of acetone was stirred at room temperature for 1 day. The solids were collected using a Swinnex® positive pressure filter assembly using a 0.2-μm nylon filter.

[0157] B. Succinate Form A The salts were prepared from either acetone or ethanol and were successfully recrystallized from a variety of solvents and solvent mixtures including ACN, DMF, EtOAc, HFIPA, IPA, MeOH, NMP, and TFE. 1) Preparation of succinate salt Form A in acetone: A slurry containing 65.1 mg succinic acid and 98.8 mg DMT in 1 mL acetone was stirred at room temperature for 1 day. The solids were collected using a Swinnex® positive pressure filter assembly using a 0.2-μm nylon filter. 2) Preparation of succinate salt form A in ethanol: A slurry containing 57.3 mg succinic acid and 86.4 mg DMT in 0.5 mL ethanol was stirred at room temperature for 2 days. The solids were collected using a Swinnex® positive pressure filter assembly using a 0.2-μm nylon filter.

[0158] C. Malate Form A A slurry containing 63.6 mg of L-(-)-malic acid and 81.0 mg of DMT in 0.5 mL of ethanol was stirred at room temperature for 2 days. The solids were collected using a Swinnex® positive pressure filter assembly using a 0.2-μm nylon filter.

[0159] D. Sulfate Form A A slurry containing 28.5 μL of 95-98% concentrated sulfuric acid and 95.8 mg of DMT in 0.5 mL of ethanol was stirred for 5 days at −20° C. The solids were collected using a Swinnex® positive pressure filter assembly using a 0.2-μm PTFE filter.

[0160] E. Oxalate Form A A slurry containing 49.5 mg of oxalic acid and 99.4 mg of DMT in 1 mL of acetone was stirred at room temperature for 9 days. A single crystal was picked before collecting the remaining solids with a Swinnex® positive pressure filter assembly using a 0.2-μm nylon filter.

[0161] F. Phosphate A slurry containing 27.0 μL of 85% concentrated phosphoric acid and 76.1 mg of DMT in 0.5 mL of ethanol was stirred at room temperature for 2 days. The solids were collected using a Swinnex® positive pressure filter assembly using a 0.2-μm nylon filter.

[0162] The above processes A to E are summarized in Table 1. [Table 1-1] [Table 1-2]

[0163] G. Recrystallization of DMT succinate in various solvents The methods are summarized in Table 2. [Table 2-1] [Table 2-2]

[0164] H. Scale-up preparation of DMT succinate form A A slurry containing 1.3014 g succinic acid and 2.0447 g DMT in 10 mL ethanol was stirred at room temperature for 4 days. The solid was isolated by water suction vacuum filtration and dried under vacuum at room temperature for 1 day. The yield was 95.4% of theoretical.

[0165] The above process H is summarized in Table 3. [Table 3]

[0166] I. Preparation of DMT succinate form A single crystals A saturated solution of DMT succinate Form A was prepared from succinic acid (1.3014 g) and DMT (2.0447 g) in methanol (10 mL) at room temperature. The solution was filtered into a clean 1-dram vial using a 0.2 μm nylon syringe filter. The 1-dram vial was placed inside an uncapped 20-mL vial containing 2 mL of diethyl ether. The 20-mL vial was capped and left at room temperature for 1 day. A single crystal was evident within 1 day. A single crystal was picked and the structure was successfully solved (FIG. 17).

[0167] A comparison of the properties of the six new DMT salt forms prepared according to the above procedure is shown in Table 4 below. [Table 4-1] [Table 4-2]

[0168] X-ray powder diffraction (XRPD) peak positions have been determined for five XRPD patterns of DMT salt forms. Observed and prominent or representative peaks are included below and in the figures, but characteristic peaks are not included.

[0169] J.DMT Fumarate Form A One pattern was analyzed and preferred orientation and particle statistical effects were not evaluated. The observed peaks are shown in Figure 1 and Table 5 below, and prominent peaks are listed in Table 6 below. The XRPD pattern of DMT fumarate Form A was successfully indexed by a single unit cell, providing strong evidence that the pattern represents a single crystalline phase. This form has a triclinic unit cell that likely contains two fumarate anions and two DMT cations. As a result, the estimated formula unit volume of 404 Å3 calculated from the indexing results would be consistent with the anhydrate form. [Table 5-1] [Table 5-2] [Table 6]

[0170] K. DMT succinate form A One pattern was analyzed and preferred orientation and particle statistical effects were assessed through comparison to the XRPD pattern calculated from the single crystal structure and determined to be negligible. The observed peaks are shown in Figure 2 and Table 7 below, and representative peaks are listed in Table 8 below. The crystal system is orthorhombic and the space group is P212121. The lattice parameters and calculated volume are a = 8.50595(7) Å, b = 10.69563(10) Å, c = 16.96938(14) Å, α = 90°, β = 90°, γ = 90°, V = 1543.82(2) Å3. [Table 7-1] [Table 7-2] [Table 7-3] [Table 8]

[0171] L. DMT Malate Form A One pattern was analyzed and preferred orientation and particle statistical effects were not evaluated. The observed peaks are shown in Figure 3 and Table 9 below, and prominent peaks are listed in Table 10 below. Note that the state of preferred orientation in this sample is not known, and therefore none of the peaks are known to be representative or characteristic of this material. The crystal system is orthorhombic and the space group is P212121. Lattice parameters and calculated volume are a=8.50595(7) Å, b=10.69563(10) Å, c=16.96938(14) Å, α=90°, β=90°, γ=90°, V=1543.82(2) Å3. [Table 9-1] [Table 9-2] [Table 10]

[0172] M.DMT sulfate form A One pattern was analyzed, and preferred orientation and particle statistical effects were not evaluated. The observed peaks are shown in Figure 4 and Table 11 below, and prominent peaks are listed in Table 12 below. Note that the state of preferred orientation in this sample is not known, and therefore none of the peaks are known to be representative or characteristic of this material. The XRPD pattern of DMT sulfate Form A is successfully indexed by a single unit cell, providing strong evidence that the pattern represents a single crystalline phase. This form has a pristine orthorhombic unit cell that likely contains four sulfate anions and four DMT cations. As a result, the estimated formula unit volume of 354 Å3 calculated from the indexing results would be consistent with the anhydrate form. [Table 11-1] [Table 11-2] [Table 11-3] [Table 12-1] [Table 12-2]

[0173] N. DMT oxalate form A One pattern was analyzed, and preferred orientation and particle statistics effects were evaluated through comparison to the XRPD pattern calculated from the single crystal structure. The influence of preferred orientation was noted in the experimental XRPD pattern, and only prominent peaks consistent between both patterns are listed as representative. The observed peaks are shown in FIG. 5 and Table 13 below, and representative peaks are listed in Table 14. The crystal system is monoclinic and the space group is P21 / c. The lattice parameters and calculated volume are a=15.01660(18)Å, b=8.37069(10)Å, c=11.03060(13)Å, α=90°, β=91.9039(11)°, γ=90°, V=1385.77(3)Å3. [Table 13-1] [Table 13-2] [Table 14]

[0174] Thermal analysis of five DMT salt forms was determined and the results are presented in Figures 6-10. Water sorption isotherms of three DMT salt forms were determined and the results are presented in Figures 11-13. A DVS for DMT oxalate Form A was not obtained because the salt exhibited two endotherms in the DSC indicating two physical forms. A DVS for DMT sulfate Form A was not obtained because the salt deliquesced after 1 day at RT at 90% RH.

[0175] Further analysis of DMT succinate Form A prepared according to the method described above was performed. The results are presented in Figures 14-22. Hence, DMT succinate Form A was further analyzed by variable temperature XRPD to see if morphological changes could be observed. The sample was held at 25°C, 105°C, and 133°C during heating and X-ray patterns were obtained. The sample was then held at 105°C during cooling. X-ray patterns were obtained during cooling at 105°C and 25°C. No morphological changes were observed at any time during the experiment (Figure 14). The succinate was also prepared on a larger laboratory (gram) scale and further characterized (DVS in Figure 18, DSC / TGA in Figure 19). An endotherm with an onset near 142°C is attributed to the melting of DMT succinate Form A (Figures 21 and 22). The remaining events, such as the minor endotherm and endothermic shoulder near 102°C sometimes observed before the melting of the salt, are due to the eutectic formed in the physical mixture of succinic acid and DMT succinate form A. The peak onset of the eutectic melt is always observed at one temperature, while the temperature at which the peak maximum for the broad endotherm is observed depends on the overall mixture composition. A physical mixture of succinic acid and DMT succinate form A at an overall composition of 0.34 mole fraction of DMT was analyzed by DSC to confirm the above observed events (Figure 20). The composition of 0.34 mole fraction of DMT was arbitrarily selected as the best approximation of the eutectic composition. As expected, the resulting DSC thermogram shows a sharp and well-defined endotherm for the eutectic melt with an onset at 102°C. The well-defined shape of the endotherm suggests that the overall composition of the mixture is not far from the true eutectic composition. The small endothermic shoulder immediately to the right of the eutectic melt represents the completion of melting of any of the remaining components at the liquidus boundary.

[0176] A representative XRPD pattern for the DMT phosphate material prepared as described above is presented in FIG.

[0177] A chart demonstrating the elevated melting points of the five DMT salt forms of the present disclosure compared to that of the DMT free base is presented in FIG.

[0178] The aqueous solubilities of DMT fumarate Form A, DMT succinate Form A, and DMT malate Form A were determined to be 20-100 mg / mL, and the results are shown in Table 15 below. [Table 15]

[0179] The hygroscopicity of DMT fumarate Form A, DMT succinate Form A, and DMT malate Form A was also determined and the results are shown in Table 16 below. [Table 16]

[0180] DMT succinate Form A was found to be the least hygroscopic of the three salt forms tested. Other favorable features of DMT succinate Form A are its high melting point, high crystallinity, and retention of physical form after absorbing water and upon heating and cooling.

Claims

1. A crystalline N,N-dimethyltryptamine (DMT) salt, wherein the crystalline DMT salt is (a) DMT succinate crystal form A, or (b) DMT fumarate crystal form A, or (c) DMT malate crystal form A, or (d) DMT sulfate crystal form A, or (e) DMT oxalate crystal form A.

2. (i) (a) having peaks (°2θ) at about 9.75 ± 0.2, about 14.27 ± 0.2, about 16.90 ± 0.2, about 19.58 ± 0.2, about 20.58 ± 0.2, about 23.08 ± 0.2, about 23.39 ± 0.2, about 24.83 ± 0.2, about 26.79 ± 0.2, and / or about 27.60 ± 0.2, or (b) having peaks (°2θ) substantially as presented in Table 8, or (c) having peaks (°2θ) substantially as presented in Table 7, or (d) providing an XRPD pattern substantially in accordance with FIG. 2, or (ii) (a) a TGA thermogram substantially in accordance with FIG. 10, or (b) a DSC thermogram substantially in accordance with FIG. 10, or (c) a DVS isotherm substantially in accordance with FIG. 13, The DMT succinate crystal form A according to Claim 1.

3. (i) providing a variable temperature XRPD pattern substantially in accordance with FIG. 14, or (ii) showing a DSC isotherm substantially in accordance with FIG. 15, or (iii) providing an XRPD pattern substantially in accordance with FIG. 16, or (iv) providing an XRPD pattern substantially in accordance with FIG. 17, or (v) providing a single crystal X-ray diffraction (SCXRD) pattern substantially in accordance with FIG. 17, or (vi) showing a DVS isotherm substantially in accordance with FIG. 18, The DMT succinate crystal form A according to Claim 1.

4. (i) showing a TGA thermogram substantially in accordance with FIG. 19, or (ii) showing a DSC thermogram substantially in accordance with FIG. 19, or (iii) having a melting point of about 141.9 °C when measured under ambient conditions, and optionally (a) an XRPD pattern as described in any one of subparts (i)(a) to (i)(d) of Claim 2, subpart (i) of Claim 3, subpart (iii) of Claim 3, and subpart (iv) of Claim 3, or (b) an SCXRD pattern as described in subpart (v) of Claim 3, The DMT succinate crystal form A according to Claim 1.

5. (i) (a) having peaks (°2θ) at about 10.78 ± 0.2, about 15.38 ± 0.2, about 15.73 ± 0.2, about 15.97 ± 0.2, about 16.93 ± 0.2, about 18.33 ± 0.2, about 19.61 ± 0.2, about 19.75 ± 0.2, about 20.49 ± 0.2, about 23.55 ± 0.2, about 23.91 ± 0.2 and / or about 24.94 ± 0.2, or (b) containing peaks (°2θ) substantially as presented in Table 6, or (c) containing peaks (°2θ) substantially as presented in Table 5, or (d) providing an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1, or (ii) (a) a thermogravimetric analysis (TGA) thermograph substantially in accordance with FIG. 8, or (b) a differential scanning calorimetry (DSC) thermograph substantially in accordance with FIG. 8, or (c) showing a dynamic vapor sorption (DVS) isotherm substantially in accordance with FIG. 11, or (iii) having a melting point of about 151.8 °C when measured under ambient conditions and optionally having an XRPD pattern as described in any one of parts (i)(a) to (i)(d) of claim 2, The DMT fumarate crystal form A according to claim 1. [

6. ] (i) (a) having peaks (°2θ) at about 9.92 ± 0.2, about 13.96 ± 0.2, about 16.55 ± 0.2, about 19.71 ± 0.2, about 20.16 ± 0.2, about 22.07 ± 0.2, about 22.23 ± 0.2, about 22.79 ± 0.2, about 23.82 ± 0.2, about 25.06 ± 0.2 and / or about 29.87 ± 0.2, or (b) containing peaks (°2θ) substantially as presented in Table 10, or (c) containing peaks (°2θ) substantially as presented in Table 9, or (d) providing an XRPD pattern substantially in accordance with FIG. 3, or (ii) (a) a TGA thermograph substantially in accordance with FIG. 9, or (b) a DSC thermograph substantially in accordance with FIG. 9, or (c) showing a DVS isotherm substantially in accordance with FIG. 12, or (iii) having a melting point of about 109.1 °C when measured under ambient conditions and optionally having an XRPD pattern as described in any one of parts (i)(a) to (i)(d) of claim 2, The DMT malate crystal form A according to claim 1. [

7. ] (i) (a) having peaks (°2θ) at approximately 11.05 ± 0.2, approximately 15.32 ± 0.2, approximately 15.89 ± 0.2, approximately 16.24 ± 0.2, approximately 19.71 ± 0.2, approximately 19.88 ± 0.2, approximately 22.22 ± 0.2, approximately 23.54 ± 0.2, approximately 23.92 ± 0.2, approximately 24.40 ± 0.2, approximately 25.03 ± 0.2 and / or approximately 25.47 ± 0.2, or (b) containing peaks (°2θ) substantially as presented in Table 12, or (c) containing peaks (°2θ) substantially as presented in Table 11, or (d) providing an XRPD pattern substantially in accordance with FIG. 4, or (ii) (a) a TGA thermogram substantially in accordance with FIG. 6, or (b) a DSC thermogram substantially in accordance with FIG. 6, or (iii) having a melting point of approximately 105.2 °C when measured under ambient conditions and optionally having an XRPD pattern as described in any one of parts (i)(a) to (i)(d) of claim 2, The DMT sulfate crystal form A according to claim 1.

8. (i) (a) having peaks (°2θ) at approximately 5.86 ± 0.2, approximately 14.63 ± 0.2, approximately 17.60 ± 0.2, approximately 19.26 ± 0.2, approximately 20.32 ± 0.2, approximately 22.03 ± 0.2, approximately 23.57 ± 0.2, approximately 24.34 ± 0.2, approximately 25.78 ± 0.2 and / or approximately 27.51 ± 0.2, or (b) containing peaks (°2θ) substantially as presented in Table 14, or (c) containing peaks (°2θ) substantially as presented in Table 13, or (d) providing an XRPD pattern substantially in accordance with FIG. 5, or (ii) (a) a TGA thermogram substantially in accordance with FIG. 7, or (b) a DSC thermogram substantially in accordance with FIG. 7, or (iii) having a melting point of approximately 135.2 °C when measured under ambient conditions and optionally having an XRPD pattern as described in any one of parts (i)(a) to (i)(d) of claim 2, The DMT oxalate crystal form A according to claim 1.

9. A pharmaceutical composition comprising the DMT crystal salt form according to any one of claims 1 to 3.

10. A composition comprising a solution of the DMT succinate form A according to any one of claims 2 to 3 in an amount effective for parenteral administration and water.

11. The DMT crystal salt form according to claim 1 for use in the treatment of a neurological disorder or condition.

12. A composition for use in the treatment of a neurological disorder or condition, comprising (i) the DMT succinate form A according to claim 2, and (ii) water, wherein the composition is administered by parenteral injection.

13. The neurological disorder or condition is (i) Psychoneurotic disorder, premenstrual dysphoric disorder, seasonal affective disorder, anxiety, anxiety disorder, social anxiety disorder, generalized anxiety disorder (GAD), anhedonia disorder, bipolar disorder, post-traumatic stress disorder, body dysmorphic disorder, mood or emotional abnormalities, mood swings, schizoaffective disorder, schizophrenia, panic disorder, traumatic stress disorder, phobic disorder, personality disorders with abnormal moods (borderline personality disorder, schizoid disorder, and schizotypal disorder), and suicidal ideation, or obsessive-compulsive disorder, addictions (including substance use disorders such as nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamine, heroin, morphine, fencicline, 3,4-methylenedioxy-methamphetamine, as well as addictions to other addictive substances), addictive behaviors (including addictions to eating, gambling, sex, porn, video games, work, exercise, spiritual obsessions, self-harm, travel, and shopping), eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), or pain (including pain associated with migraine or headache, or chronic pain), or (ii) Psychoneurotic disorder, or (iii) Depression, the DMT crystalline salt for use according to claim 11 or the composition for use according to claim 12.

14. The DMT salt or the DMT salt form thereof is co-administered with one or more additional therapeutic agents, preferably (i) The one or more additional therapeutic agents are antidepressants or anxiolytics, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and / or serotonin-norepinephrine reuptake inhibitors (SNRIs), and / or (ii) The additional one or more agents are administered as one or more separate compositions, the DMT crystalline salt form for use according to claim 11.

15. The DMT salt or the DMT salt form thereof is co-administered with one or more additional therapeutic agents, preferably (i) the one or more further therapeutic agents are antidepressants or anxiolytics, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and / or serotonin-norepinephrine reuptake inhibitors (SNRIs), and / or (ii) the further one or more agents are administered as one or more separate compositions, a composition for use according to claim 12.

16. A DMT salt form according to any one of claims 1 to 3 for use in the treatment of a neuropsychiatric disorder or disorder or addiction, together with psychotherapy, talk therapy, cognitive behavioral therapy, placebo experience therapy, biofeedback therapy, systematic desensitization, mindfulness, dialectical behavior therapy, interpersonal therapy, desensitization and reprocessing by eye movement, social rhythm therapy, acceptance and commitment therapy, family focused therapy, psychodynamic therapy, light therapy, computer therapy (including digital cognitive behavioral therapy), cognitive improvement, exercise or TMS, optionally wherein the therapy is digitally managed via an online program or the like.

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