Crystalline forms of N,N-dimethyltryptamine and methods of use thereof

Abstract

The present disclosure provides crystalline forms of N,N-dimethyltryptamine (N,N-DMT). [Formula 1] JPEG2025538044000016.jpg86159 Also provided herein are methods of using crystalline forms of N,N-DMT and compositions comprising them, for example, in the treatment of psychiatric diseases and / or disorders.

Description

[Background technology]

[0001] N,N-Dimethyltryptamine (N,N-DMT) has therapeutic value as a hallucinogen and possesses unique properties that make it an attractive potential drug treatment, particularly for neurological diseases and conditions. The crystalline form of an active pharmaceutical ingredient provides the best means for controlling important physiochemical qualities such as stability, solubility, bioavailability, particle size, bulk density, flow properties, polymorph content, and other properties. Two crystalline forms of N,N-DMT have previously been identified and designated "Form I" (Bergin et al. Acta Crystallogr., Sect. B24, 882 (1968) and Gaujac et al. Talanta 106, 394 (2013)) and "Form II" (Falkenberg et al. Acta Crystallogr., Sect. B28, 3075 (1972)). There remains a need in the art to develop additional crystalline forms of N,N-DMT. Summary of the Invention

[0002] The present disclosure relates to crystalline forms of N,N-dimethyltryptamine. [ka]

[0003] In embodiments, the present disclosure provides Form IV of N,N-dimethyltryptamine.

[0004] In embodiments, Form IV is characterized by peaks in an X-ray powder diffraction (XRPD) pattern at 13.6±0.2, 20.8±0.2, and 17.8±0.2 degrees 2θ. In embodiments, Form IV is further characterized by at least one XRPD peak selected from 13.9±0.2, 14.0±0.2, 15.4±0.2, 18.6±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, or 26.7±0.2 degrees 2θ.

[0005] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 17.8±0.2, and 20.8±0.2, and at least one XRPD peak selected from 13.9±0.2, 14.0±0.2, 15.4±0.2, 18.6±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, or 26.7±0.2 degrees 2θ.

[0006] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 13.9±0.2, 14.0±0.2, 15.4±0.2, 17.8±0.2, 18.6±0.2, 20.8±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, and 26.7±0.2 degrees 2θ.

[0007] In embodiments, Form IV is 7.7±0.2, 10.4±0.2, 11.9±0.2, 13.0±0.2, 13.6±0.2, 13.9±0.2, 14.0±0.2, 15.2±0.2, 15.4±0.2, 16.2±0.2, 16.9±0.2, 17.5±0.2, 17.8±0.2, 18.1±0.2, 18.6±0.2, 19.3±0.2, 19.8±0.2, 20.8±0.2, 21.1±0.2, 21.6±0.2, 22.4±0.2, 22.7±0.2, 23.6±0.2, 23.8±0.2, 24.5±0.2, 24.8±0.2 The XRPD patterns are characterized by peaks at 0.2, 25.2 ± 0.2, 26.1 ± 0.2, 26.7 ± 0.2, 26.9 ± 0.2, 27.5 ± 0.2, 28.0 ± 0.2, 28.2 ± 0.2, 28.6 ± 0.2, 28.8 ± 0.2, 29.3 ± 0.2, 29.5 ± 0.2, 29.6 ± 0.2, 30.2 ± 0.2, 30.4 ± 0.2, 30.6 ± 0.2, 30.9 ± 0.2, 31.1 ± 0.2, 31.6 ± 0.2, 31.9 ± 0.2, 32.8 ± 0.2, 33.2 ± 0.2, 33.7 ± 0.2, 34.5 ± 0.2, and 35.3 ± 0.2 °2θ.

[0008] In embodiments, Form IV is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0009] In embodiments, Form IV exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at 69±5° C. In embodiments, Form IV exhibits a DSC thermogram comprising an endothermic peak at 70±5° C.

[0010] In embodiments, Form IV exhibits substantially no weight loss at temperatures below 225±5° C. as measured by thermogravimetric (TGA) analysis.

[0011] In embodiments, Form IV exhibits a melting point of 69±5°C.

[0012] In embodiments, the present disclosure provides Form III of N,N-dimethyltryptamine.

[0013] In embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2 and 15.2±0.2, hi embodiments, Form III is further characterized by at least one XRPD peak selected from 19.2±0.2 degrees 2θ, 19.6±0.2, or 23.0±0.2 degrees 2θ.

[0014] In embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 19.2±0.2, 19.6±0.2, and 22.9±0.2 degrees 2θ.

[0015] In embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 16.8±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.4±0.2, 20.7±0.2, 21.5±0.2, 22.4±0.2, 22.9±0.2, 23.1±0.2, 26.3±0.2, 27.1±0.2, 27.8±0.2, 28.5±0.2, 30.7±0.2, and 31.56±0.2 degrees 2θ.

[0016] In embodiments, Form III is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0017] In embodiments, Form III exhibits a DSC thermogram comprising an endothermic peak with an onset at 67±5° C. In embodiments, Form III exhibits a DSC thermogram comprising an endothermic peak at 68±5° C.

[0018] In embodiments, Form III exhibits substantially no weight loss at temperatures below 200±5° C. as measured by TGA analysis.

[0019] In embodiments, Form III exhibits a melting point of 39±5°C.

[0020] In embodiments, the present disclosure provides a pharmaceutical composition comprising Form IV of N,N-dimethyltryptamine. In embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral dosage form comprising Form IV of N,N-dimethyltryptamine.

[0021] In embodiments, the present disclosure provides a pharmaceutical composition comprising Form III of N,N-dimethyltryptamine. In embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In embodiments, the present disclosure provides an oral dosage form comprising Form III of N,N-dimethyltryptamine.

[0022] The present disclosure provides a method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of N,N-dimethyltryptamine Form IV, N,N-dimethyltryptamine Form III, pharmaceutical composition, or oral dosage form described herein.

[0023] The present disclosure provides a method for treating post-traumatic stress disorder (PTSD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of N,N-dimethyltryptamine Form IV, N,N-dimethyltryptamine Form III, pharmaceutical composition, or oral dosage form described herein. In some embodiments, the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

[0024] The present disclosure provides a method of treating an anxiety disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of N,N-dimethyltryptamine Form IV, N,N-dimethyltryptamine Form III, a pharmaceutical composition, or an oral dosage form. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 shows the XRPD diffractogram of a sample of Form I of N,N-DMT. [Figure 2] FIG. 2 shows the XRPD diffractogram of a sample of Form III of N,N-DMT. [Figure 3] FIG. 3 shows the XRPD diffractogram of a sample of Form IV of N,N-DMT. [Figure 4] Figure 4 shows the atomic displacement ellipsoid diagram of Form I of N,N-DMT. [Figure 5] FIG. 5 shows the atomic displacement ellipsoid diagram of Form IV of N,N-DMT. [Figure 6] FIG. 6 shows the XRPD diffractograms of a sample of Form I of N,N-DMT before (top plot) and after (bottom plot) dynamic vapor sorption (DVS). [Figure 7] FIG. 7 shows the DCS thermogram of a sample of Form I of N,N-DMT. [Figure 8] FIG. 8 shows the DCS thermogram of a sample of Form I of N,N-DMT. [Figure 9]FIG. 9 shows the DSC thermogram (top) and TGA thermogram (bottom) of a sample of Form I of N,N-DMT collected at a heating rate of 10° C. / min. [Figure 10] FIG. 10 shows a DSC thermogram of a sample of Form I of N,N-DMT collected at a heating rate of 2° C. / min. [Figure 11] FIG. 11 shows the DSC thermogram (top) and TGA thermogram (bottom) collected at a heating rate of 10° C. / min of a sample of N,N-DMT Form III. [Figure 12] FIG. 12 shows a DSC thermogram of a sample of N,N-DMT Form III collected at a heating rate of 2° C. / min. [Figure 13] FIG. 13 shows the DSC thermogram (top) and TGA thermogram (bottom) collected at a heating rate of 10° C. / min of a sample of N,N-DMT Form IV. [Figure 14] FIG. 14 shows the DSC thermogram (top) and TGA thermogram (bottom) collected at a heating rate of 10° C. / min of a sample of N,N-DMT Form IV. [Figure 15] FIG. 15 shows a DSC thermogram collected at a heating rate of 2° C. / min of a sample of N,N-DMT Form IV. [Figure 16] FIG. 16 shows a polarized light micrograph of a sample of Form I of N,N-DMT. [Figure 17] FIG. 17 shows a polarized light micrograph of a sample of Form IV of N,N-DMT. [Figure 18] FIG. 18 shows an in situ cycling DSC thermogram of amorphous N,N-DMT starting from a sample of Form IV. [Figure 19] FIG. 19 shows the 1H NMR spectrum of N,N-DMT. DETAILED DESCRIPTION OF THE INVENTION

[0026] All publications, patents, and patent applications, including any drawings and appendices therein, are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0027] definition Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to facilitate explanation of the subject matter of the present disclosure.

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

[0029] The term "preventing" as used herein with respect to a patient or subject refers to preventing the onset of a disease if it has not yet occurred, preventing the disease or disorder from occurring in a subject or patient who is susceptible to the disorder or disease but has not yet been diagnosed with the disorder or disease, and / or preventing further onset of the disease / disorder if already present.

[0030] As used herein with respect to analytical spectra such as XRPD patterns, the term "substantially similar" means that the spectrum is similar to a reference spectrum in both peak positions and their relative intensities, allowing for appropriate variability in the art. For example, two spectra may be "substantially similar" if they share sufficient defining characteristics to distinguish them from spectra obtained for different solid forms. In embodiments, spectra or characterization data that are substantially similar to those of a reference crystalline form are understood by those skilled in the art to correspond to the same crystalline form as the particular reference. When analyzing whether spectra or characterization data are substantially similar, those skilled in the art will understand that specific characterization data points may vary to a reasonable extent while still describing a given solid form, for example, due to experimental error and routine sample-to-sample analysis.

[0031] The term "treating," as used herein with respect to a patient or subject, refers to improving at least one symptom of a disorder in the patient or subject. In some embodiments, treating can be improving or at least partially reversing the disorder or one or more symptoms of the disorder.

[0032] The term "therapeutically effective" as applied to a dose or amount refers to an amount of a compound or pharmaceutical preparation that is sufficient to result in a desired clinical benefit following administration to a patient or subject in need thereof.

[0033] All XRPD peaks and patterns are given in degrees 2θ using Cu Kα1 radiation at a wavelength of 1.5406 Å. The value of degrees 2θ allows for an appropriate margin of error. For example, "approximately 17.48±0.2" degrees 2θ indicates a range of approximately 17.46 to 17.50 degrees 2θ. Those skilled in the art will recognize that, depending on sample preparation techniques, calibration techniques applied to the instrument, human performance variations, etc., an appropriate margin of error for XRPD may be ±0.2, including any value less than ±0.2, such as ±0.1, ±0.05, or less.

[0034] TGA thermograms and DSC thermograms of a given crystalline form of the same compound will vary within a range of error. Single-peak values ​​expressed in degrees Celsius allow for an appropriate margin of error. Typically, the margin of error is expressed as "±." For example, a single-peak characteristic value of approximately "120±5" indicates a range of approximately 115-125. Those skilled in the art will recognize that, depending on sample preparation techniques, calibration techniques applied to the instrument, human performance variability, etc., an appropriate margin of error for a single-peak characteristic value may be ±5, including any value less than ±5, such as ±4, ±3.5, ±3, ±2.5, ±2.0, ±1.5, ±1.0, ±0.5, or less.

[0035] The following description contains information that may be useful in understanding the present invention. No admission is made that any information provided herein is prior art or relevant to the invention claimed in this application, or that any specifically or implicitly referenced publication is prior art.

[0036] Crystalline forms of N,N-dimethyltryptamine (N,N-DMT) In one aspect, the present disclosure provides a crystalline form of N,N-DMT. In embodiments, the crystalline form of N,N-DMT is Form III. In embodiments, the crystalline form of N,N-DMT is Form IV. In embodiments, the crystalline form of N,N-DMT is a mixture of Form III and Form IV.

[0037] In some embodiments, the crystalline form of N,N-DMT comprises a mixture of one or more forms of N,N-DMT (e.g., Form III or IV). In some embodiments, the crystalline form of N,N-DMT comprises a substantially pure form of one form of N,N-DMT. In some embodiments, the substantially pure form is Form III. In some embodiments, the substantially pure form is Form IV.

[0038] In embodiments, the crystalline form of N,N-DMT comprises greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of a form of N,N-DMT (e.g., Form III and / or Form IV).

[0039] In embodiments, the crystalline form of N,N-DMT comprises greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a form of N,N-DMT. In some embodiments, the crystalline form of N,N-DMT comprises greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a form of N,N-DMT (e.g., Form III and / or Form IV).

[0040] I. Form III In embodiments, the crystalline form of N,N-DMT is Form III.

[0041] In embodiments, Form III is characterized by peaks in the XRPD pattern at 7.6±0.2 and 15.2±0.2, hi embodiments, the variance around either of these peaks is ±0.1 degrees 2θ.

[0042] In some embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2 and 15.2±0.2, and at least one peak in an XRPD pattern selected from 19.2±0.2 degrees 2θ, 19.6±0.2, or 23.0±0.2 degrees 2θ. In some embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0043] In embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 19.2±0.2, and 19.6±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0044] In embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 19.2±0.2, and 23.0±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0045] In embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 19.2±0.2, 19.6±0.2, and 22.9±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0046] In embodiments, Form III is characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 16.8±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.4±0.2, 20.7±0.2, 21.5±0.2, 22.4±0.2, 22.9±0.2, 23.1±0.2, 26.3±0.2, 27.1±0.2, 27.8±0.2, 28.5±0.2, 30.7±0.2, and 31.56±0.2 degrees 2θ.

[0047] In embodiments, Form III is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0048] In embodiments, Form III is characterized by an XRPD pattern comprising the peaks shown in Table 4.

[0049] In embodiments, Form III is characterized by an XRPD pattern comprising the peaks shown in Table 5.

[0050] In embodiments, Form III exhibits a DSC thermogram comprising an endothermic peak with an onset at 67±5° C. In embodiments, Form III exhibits a DSC thermogram comprising an endothermic peak at 68±5° C.

[0051] In embodiments, Form III exhibits substantially no weight loss at temperatures below 200±5° C. as measured by TGA analysis.

[0052] In embodiments, Form III exhibits a melting point of 39±5°C.

[0053] II. Form IV In embodiments, the crystalline form of N,N-DMT is Form IV.

[0054] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 20.8±0.2, and 17.8±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0055] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 20.8±0.2, and 17.8±0.2 degrees 2θ, and at least one peak in an XRPD pattern selected from 13.9±0.2, 14.0±0.2, 15.4±0.2, 18.6±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, or 26.7±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0056] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 13.9±0.2, 17.8±0.2, and 20.8±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0057] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 15.4±0.2, 17.8±0.2, and 20.8±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0058] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 17.8±0.2, 18.6±0.2, and 20.8±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0059] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 17.8±0.2, 20.8±0.2, and 23.6±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0060] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 17.8±0.2, 20.8±0.2, and 24.5±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0061] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 17.8±0.2, 20.8±0.2, and 26.0±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0062] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 17.8±0.2, 20.8±0.2, and 26.7±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0063] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 20.8±0.2, and 17.8±0.2, and at least one XRPD peak selected from 13.9±0.2, 14.0±0.2, 15.4±0.2, 18.6±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, or 26.7±0.2 °2θ. In embodiments, the variance around any of these peaks is ±0.1 °2θ.

[0064] In embodiments, Form IV is characterized by peaks in an XRPD pattern at 13.6±0.2, 13.9±0.2, 14.0±0.2, 15.4±0.2, 17.8±0.2, 18.6±0.2, 20.8±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, and 26.7±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0065] In embodiments, Form IV is 7.7±0.2, 10.4±0.2, 11.9±0.2, 13.0±0.2, 13.6±0.2, 13.9±0.2, 14.0±0.2, 15.2±0.2, 15.4±0.2, 16.2±0.2, 16.9±0.2, 17.5±0.2, 17.8±0.2, 18.0±0.2, 18.6±0.2, 19.3±0.2, 19.8±0.2, 20.8±0.2, 21.1±0.2, 21.6±0.2, 22.4±0.2, 22.7±0.2, 23.6±0.2, 23.8±0.2, 24.5±0.2, 24.8±0.2 The XRPD patterns are characterized by peaks at 0.2, 25.2 ± 0.2, 26.1 ± 0.2, 26.7 ± 0.2, 26.9 ± 0.2, 27.5 ± 0.2, 28.0 ± 0.2, 28.2 ± 0.2, 28.6 ± 0.2, 28.8 ± 0.2, 29.3 ± 0.2, 29.5 ± 0.2, 29.6 ± 0.2, 30.2 ± 0.2, 30.4 ± 0.2, 30.6 ± 0.2, 30.9 ± 0.2, 31.1 ± 0.2, 31.6 ± 0.2, 31.9 ± 0.2, 32.8 ± 0.2, 33.2 ± 0.2, 33.7 ± 0.2, 34.5 ± 0.2, and 35.3 ± 0.2 °2θ. In embodiments, the variance at any of these peaks is ±0.1 degrees 2θ.

[0066] In embodiments, Form IV is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0067] In embodiments, Form IV is characterized by an XRPD pattern comprising the peaks shown in Table 6.

[0068] In embodiments, Form IV is characterized by an XRPD pattern comprising the peaks shown in Table 7.

[0069] In embodiments, Form IV exhibits a DSC thermogram comprising an endothermic peak with an onset at 69±5° C. In embodiments, Form IV exhibits a DSC thermogram comprising an endothermic peak at 70±5° C.

[0070] In embodiments, Form IV exhibits substantially no weight loss at temperatures below 225±5° C. as measured by TGA analysis.

[0071] In embodiments, Form IV exhibits a melting point of 69±5°C.

[0072] Pharmaceutical Composition In one aspect, the present disclosure provides a composition comprising at least one crystalline form of N,N-DMT described herein (e.g., Form III and / or Form IV) and one or more excipients. In several embodiments, the composition is a pharmaceutical composition comprising a crystalline form of N,N-DMT and one or more pharmaceutically acceptable excipients.

[0073] In embodiments, the pharmaceutical composition comprises Form III of N,N-DMT.

[0074] In embodiments, the pharmaceutical composition comprises Form IV of N,N-DMT.

[0075] In embodiments, the composition comprises a pharmaceutically acceptable carrier. In embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable excipient, binder, and / or diluent. In embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents, and sterile aqueous or organic solutions. In embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, saline, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 th Edition (Lippincott Williams & Wilkins, 2005).

[0076] In several embodiments, one or more crystalline forms of N,N-DMT of the present disclosure (e.g., Form III and / or Form IV) are formulated for administration by various means, including oral, parenteral, inhalation spray, topical, or rectal, in a formulation containing a pharmaceutically acceptable carrier, adjuvant, vehicle, or mixture thereof. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intraarterial injections using various infusion techniques. Intraarterial and intravenous injections as used herein include administration through a catheter.

[0077] In embodiments, the present disclosure provides an oral dosage form comprising the composition described herein.

[0078] In some embodiments, the oral dosage form is a solid dosage form such as a tablet, capsule, pill, powder, or granule. Types of oral tablets include compressed, chewable lozenges and tablets, which may be enteric-coated, sugar-coated, or film-coated. Capsules can be hard or soft gelatin capsules, while granules and powders can be provided in non-effervescent or effervescent form, along with other ingredients known to those skilled in the art.

[0079] Treatment method In one aspect, the present disclosure provides a method of treating or preventing a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof.

[0080] In some embodiments, the neurological disorder is a mood disorder. In some embodiments, the mood disorder is clinical depression, postpartum depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, dual depression, depressive personality disorder, recurrent brief depression, major depressive disorder, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic condition, treatment-resistant depression, treatment-refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect to subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), or women's health disorders or conditions. In some embodiments, the mood disorder is depression. In some embodiments, the mood disorder is treatment-resistant depression or major depressive disorder. In embodiments, the mood disorder is major depressive disorder, hi embodiments, the mood disorder is treatment-resistant depression.

[0081] In some embodiments, the present disclosure provides a method of treating or preventing PTSD, a mood disorder, a generalized anxiety disorder, an addictive disorder, and / or substance dependence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof.

[0082] In embodiments, the present disclosure provides a method of treating or preventing PTSD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof.

[0083] In some embodiments, the present disclosure provides a method for treating or preventing a behavioral or mood disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a crystalline form of N,N-DMT (e.g., Form III and / or Form IV) disclosed herein or a pharmaceutical composition thereof to the subject. In some embodiments, the behavioral or mood disorder comprises anxiety, such as social anxiety in autistic subjects (e.g., adults with autism) and anxiety associated with a life-threatening illness. In some embodiments, the behavioral or mood disorder comprises stress (relief of which is measured, for example, by an effect on amygdala response). In some embodiments, the anxiety disorder is panic disorder, obsessive-compulsive disorder, and / or generalized anxiety disorder. In some embodiments, the subject suffers from a lack of motivation, attention, memory recall accuracy, response speed, perseveration, and / or cognitive engagement. Further examples include depression (e.g., MDD or TRD), attention disorders, disorders of executive function and / or cognitive engagement, obsessive-compulsive disorder, bipolar disorder, panic disorder, phobias, schizophrenia, psychopathy, antisocial personality disorder, and / or neurocognitive disorders.

[0084] In embodiments, the present disclosure provides a method for treating or preventing an addictive disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof to the subject. In embodiments, the addictive disorder is alcohol abuse, drug abuse, smoking, obesity, or a combination thereof. In embodiments, the disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, etc.) or an auditory disorder.

[0085] In embodiments, the present disclosure provides a method of treating or preventing an impulse control disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof to the subject. In embodiments, the impulse control disorder is attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome, autism, or a combination thereof.

[0086] In embodiments, the present disclosure provides a method of treating or preventing obsessive-compulsive disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof to the subject. In embodiments, the obsessive-compulsive disorder is obsessive-compulsive disorder (OCD), gambling, aberrant sexual behavior, or a combination thereof.

[0087] In embodiments, the present disclosure provides a method of treating or preventing a personality disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof to the subject. In embodiments, the personality disorder is conduct disorder, antisocial personality, aggressive behavior toward the subject, or a combination thereof.

[0088] In embodiments, the present disclosure provides a method of treating or preventing PTSD, social anxiety disorder (e.g., social anxiety disorder in autism spectrum disorder), autism spectrum disorder, binge eating disorder, alcohol use disorder, treatment-resistant depression, major depressive disorder, generalized anxiety disorder, schizophrenia, borderline personality disorder, opioid use disorder, narcissistic personality disorder, avoidant personality disorder, tinnitus, anorexia nervosa, substance use disorder, chronic pain, tobacco addiction, bulimia nervosa, antisocial personality disorder, ADHD, traumatic brain injury, body dysmorphic disorder, hypoactive sexual desire disorder, migraine, agoraphobia, narcolepsy, obsessive-compulsive disorder, and / or fibromyalgia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of N,N-DMT disclosed herein (e.g., Form III and / or Form IV) or a pharmaceutical composition thereof. [Example]

[0089] The following examples detail the preparation and isolation of crystalline forms of N,N-DMT (e.g., Form III and Form IV). This work demonstrates that Form III of N,N-DMT is metastable to date across all temperatures, and Form IV is the most thermodynamically stable polymorph of N,N-DMT, with the highest known melting point.

[0090] I. Screening Experiments Screening experiments were conducted to identify stable and polymorphic forms of N,N-DMT. These experiments included exploring various solvent systems, temperatures, crystallization conditions, and starting materials. Crystallization techniques employed included slurrying, evaporation, pH rotation, vapor diffusion, antisolvent precipitation, vapor stressing, and heating. Each of these techniques is described in further detail below.

[0091] Slurrying: A suspension was prepared by adding enough solid to a given solvent under the conditions stated so that undissolved solid was present. The mixture was then agitated (typically by stirring or shaking) in a sealed vial at a given temperature for an extended period of time.

[0092] Evaporation: For fast evaporation, solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. Unless otherwise noted, each solution was evaporated from an open vial at ambient conditions. For slow evaporation, solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. Each solution was evaporated from a covered vial (e.g., loosely capped or covered with perforated aluminum foil) at ambient conditions.

[0093] pH rotation experiments were performed by combining N,N-DMT solid with water while stirring at ambient temperature, resulting in a solution with undissolved solids. An aliquot of strong acid (e.g., 0.1 N HCl) was added while stirring, resulting in a clear solution. An aliquot of strong base (e.g., 0.1 N NaOH) was added while stirring, resulting in a white suspended solid. In some cases, needles, blades, and aggregates were observed. The crystals were crushed and analyzed.

[0094] Vapor diffusion: Concentrated solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. The filtered solutions were dispensed into small vials, which were then placed into a larger vial containing an antisolvent. The caps of the small vials were removed and the larger vial was capped to allow vapor diffusion to occur.

[0095] Anti-solvent precipitation: Solutions were prepared in various solvents and aliquots of various anti-solvents were dispensed with stirring until precipitation occurred. The mixtures were stirred under specified conditions.

[0096] Steam Stressing: A small vial containing a given material was placed inside a larger vial containing the solvent. The small vial was left uncapped, and the larger vial was capped, allowing steam stressing to occur at the temperature stated.

[0097] Heating: was performed either by DSC (used for examination of thermograms and / or recovery of heated solids for XRPD) or by heating on a hot plate / hot bench.

[0098] Three anhydrous / nonsolvated polymorphs were observed: Forms I, III, and IV (Form II, reported in the literature, was not observed in this screening). A comparison of the properties of the three polymorphic forms of N,N-DMT is shown in Table 1. [Table 1]

[0099] Figure 19 shows the H NMR of N,N-DMT. The H NMR spectrum of each N,N-DMT sample disclosed herein was substantially the same as that shown in Figure 19.

[0100] II. X-ray powder diffraction (XRPD) experiments XRPD analysis was carried out in transmission and reflection geometry.

[0101] XRPD in Transmission Geometry: XRPD patterns were collected on a PANalytical X'Pert PRO MPD or PANalytical Empyrean Diffractometer using an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptical graduated multilayer mirror was used to focus the Cu Kα X-rays through the specimen 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 matched the NIST-certified position. Sample specimens were sandwiched between 3 μm-thick films and analyzed in transmission geometry. A beam stop, a short anti-scatter extension, and an anti-scatter knife edge 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 specimen and Data Collector software v.5.5. The data acquisition parameters for each pattern are displayed above the images in the data section of this report. In all images, the instrument is labeled X'Pert PRO MPD, regardless of the instrument used.

[0102] XRPD in reflection geometry

[0103] XRPD patterns were collected on 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. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si 111 peak matched the NIST-certified position. Sample preparations were prepared as thin, circular layers centered on a silicon zero-background substrate. 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.5.5. Data acquisition parameters for each pattern, including the divergence slit (DS) and incident beam SS, are displayed above the images in the data section of this report.

[0104] The XRPD peak positions for N,N-DMT Forms I, III, and IV were determined and are listed below.

[0105] Form I

[0106] The XRPD pattern of Form I is shown in Figure 1. Preferred orientation and particle statistics effects were assessed through comparison with the XRPD pattern calculated from the single crystal structure and determined to be negligible.

[0107] The observed diffraction peaks are shown in Figure 1 and listed in Table 2, with representative peaks tabulated in Table 3. [Table 2] [Table 3]

[0108] Form III

[0109] The preferred orientation and particle statistics effects were evaluated by comparing XRPD patterns obtained from diffractometers with different geometries and found to be significant. The observed diffraction peaks are shown in Figure 2 and listed in Table 4, with prominent diffraction peaks tabulated in Table 5. Note that because the state of preferred orientation in this sample is not known, none of the peaks are known to be representative or characteristic of this material. [Table 4] [Table 5]

[0110] Form IV

[0111] Preferred orientation and particle statistical effects were assessed through comparison with the XRPD pattern calculated from the single crystal structure and determined to be negligible. The observed peaks are shown in Figure 3 and listed in Table 6, with representative peaks tabulated in Table 7. [Table 6] JPEG2025538044000009.jpg32159 [Table 7]

[0112] III. Single crystal XRD experiments Single crystal structures were obtained for Forms I and IV as described below.

[0113] Sample preparation for single crystal XRD:

[0114] Form I: N,N-DMT solid (83.7 mg) was combined with water (2 mL) with stirring at ambient temperature to give a solution with undissolved solids. Aliquots of 0.1 N HCl totaling 10.5 mL were added with stirring to give a clear solution. Aliquots of 0.1 N NaOH totaling 11.5 mL were added with stirring to give a white suspended solid. Needles, blades, and aggregates were observed. The crystals were crushed and analyzed.

[0115] Form IV: N,N-DMT solid (102.01 mg) was combined with heptane (1 mL) with stirring at about 40° C. to give a solution with undissolved solid present. The slurry was left stirring at about 40° C. for 12 days, after which thick birefringent needles were observed. The crystals were crushed and analyzed.

[0116] Single crystal XRD data collection:

[0117] Form I: Approximate dimensions: 0.18 x 0.11 x 0.06 mm 3 A colorless block with the α-axis was mounted in a random orientation on a polymer loop. Preliminary testing and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (Cu Kαλ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector.

[0118] The cell constant and orientation matrix for data collection were obtained by least-squares fitting using set angles of 2590 reflections in the range 4.4940° < θ < 75.3650°. The space group was determined to be P21 / c (International Table Number 14) by the program CRYSALISPRO

[13] . Data were collected at room temperature up to a maximum diffraction angle (2θ) of 151.432°.

[0119] Form IV: Approximate dimensions 0.17 x 0.15 x 0.06 mm 3A colorless block with the α-axis was mounted in a random orientation on a polymer loop. Preliminary testing and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (Cu Kαλ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector.

[0120] The cell constant and orientation matrix for data collection were obtained by least-squares fitting using set angles of 5465 reflections in the range 3.8290° < θ < 74.9960°. The space group was determined to be P21 / n (International Table Number 14) by the program CRYSALISPRO

[13] . Data were collected at room temperature up to a maximum diffraction angle (2θ) of 151.584°.

[0121] The single crystal data obtained from Forms I and IV are listed in Table 8 below. [Table 8]

[0122] Atomic displacement ellipsoid diagrams for Form I and Form IV N,N-DMT are shown in Figures 4 and 5, respectively.

[0123] IV. Thermal behavior experiment Differential scanning calorimetry (DSC):

[0124] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Taurag adjustments are performed using indium, tin, and zinc. Temperature and enthalpy adjustments are made using octane, phenyl salicylate, indium, tin, and zinc. The adjustments are then verified using octane, phenyl salicylate, indium, tin, and zinc. The sample was placed into a hermetically sealed aluminum DSC pan, the weight was accurately recorded, and the sample was inserted into the DSC cell. A pre-weighed aluminum pan configured as the sample pan was placed into the reference side of the cell. The pan lid was pierced prior to sample analysis. Unless otherwise noted, samples were analyzed from -25°C to 250°C at 10°C / min.

[0125] Thermogravimetry and Differential Scanning Calorimetry (TGA or TGA / DSC)

[0126] TGA or TGA / DSC analyses were performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy adjustments were performed using indium, tin, zinc, and phenyl salicylate, then verified with indium. The balance was verified with calcium oxalate. Samples were placed in aluminum pans. The pans were sealed, the lids were pierced, and the pans were then inserted into the TG furnace. A pre-weighed aluminum pan configured as a 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. Thermogravimetric analyses typically undergo an equilibration period at the beginning of each analysis, which is indicated by a bracket on the thermogram in Figure Section (V). The starting temperature for the relevant weight loss calculations is selected beyond this region (typically above 35°C) for accuracy.

[0127] Form I:

[0128] DVS cycling studies on Form I of N,N-DMT showed a morphology change when dried at 60°C (as the final step in drying the API during manufacturing) (Figure 6). To further study this behavior, a solid-state cycling DSC thermogram of Form I was collected (Figure 7). Figure 7 shows a thermogram of a sample that was first melted by heating to 60°C. The molten material was held at 60°C for 20 minutes, then cooled to 45°C and reheated to 250°C. No significant events of the higher-melting form, such as recrystallization or melting, were observed.

[0129] A similar experiment was performed, but the molten material was cooled to -20°C and then reheated to 250°C (Figure 8). In this experiment, an exotherm was observed at approximately 39°C during the final heating step, consistent with crystallization, followed immediately by an endotherm at approximately 45°C (onset), indicative of melting. This melting point is similar to that observed for Form III. DSC experiments indicate that drying the solid after DVS at 60°C resulted in the material melting, followed by recrystallization to the lower-melting Form III upon cooling to ambient temperature.

[0130] DSC and TGA thermograms of Form I were also collected at a standard heating rate of 10°C / min (Figure 9). Additional DSC thermograms were acquired at a slower heating rate (2°C / min) to obtain more precise data (Figure 10).

[0131] A melting endotherm at 58°C (onset) is observed in both thermograms, consistent with the melting point reported in the literature for Form I. The TGA thermograms show only a 1.0% weight loss up to 240°C, which is consistent with anhydrous / unsolvated material. Decomposition, evidenced by a sharp decline in the TGA thermograms, begins above approximately 240°C.

[0132] Form III:

[0133] DSC and TGA thermograms collected at a heating rate of 10°C / min (Figure 11). A melting endotherm is observed by DSC at 39°C (onset). A slight weight loss by TGA up to 201°C is consistent with anhydrous / unsolvated material. Decomposition is observed above approximately 240°C. To obtain more precise data, DSC thermograms were collected at a heating rate of 2°C / min (Figure 12). In Figure 12, when the ramping rate was reduced to 2°C / min, the crystallization (to another form) and melting of Form III are simultaneous due to the lower temperature ramping rate. Based on the melting endotherm with an onset at 66.94°C, it can be concluded that Form III melted and then recrystallized to form IV, which melted at approximately 67°C.

[0134] Solid-state heating experiments were also performed starting with Form III (plus traces of unknown components) (Figure 13). These experiments were designed to observe the melting and recrystallization behavior at various temperatures. The approximate onset melting temperature of Form III (39°C) obtained from DSC characterization was used as a reference for determining form transformation.

[0135] Form III was observed to simultaneously melt and recrystallize to Form IV when held between 35°C and 40°C. However, cooling the molten material to room temperature or -20°C occasionally resulted in recrystallization to Form III. In one experiment, the molten material showed no signs of crystallization when left undisturbed in a freezer for 1 day, so heptane was added and the sample was left stirring in the freezer for 12 days, resulting in crystallization to Form IV.

[0136] Form IV:

[0137] DSC and TGA thermograms were collected at a heating rate of 10°C / min, and an additional DSC thermogram was obtained at 2°C / min (Figures 14 and 15, respectively). Both DSC thermograms show a sharp melting endotherm with an onset of 69°C. The slight weight loss by TGA up to 223°C is consistent with anhydrous / unsolvated material. Decomposition is observed above approximately 240°C.

[0138] Solid-state heating experiments were performed starting with Form IV (Figure 16). For Form III, these experiments were designed to observe the melting and recrystallization behavior at various temperatures, and the approximate onset melting temperature of Form IV (69°C) obtained from DSC characterization was used as a reference for determining form transformation. Form IV showed no change when heated at 50°C for 10 minutes.

[0139] V. Stability Experiments to Determine the Relative Stability of Forms I, III, and IV Slurry experiments were performed to determine the relative stability of Forms I, III, and IV. Screening conditions are tabulated in Tables 9-11. [Table 9] [Table 10] [Table 11]

[0140] In these experiments, saturated solutions containing excess undissolved solids were stirred for extended periods. Under these conditions, the metastable form dissolved at concentrations supersaturated with the stable form, causing the crystallization of the more stable form over time. Slurries were run at room temperature, 40°C, 5°C, and -20°C for approximately two weeks. Solvent systems in which the compound was expected to exhibit limited solubility were employed in an effort to provide suitable conditions for conversion to the more stable form. Note that even with these efforts, a lack of form change does not definitively determine the stable form and may be due to insufficient solubility or time for conversion to the more stable form.

[0141] The observed form transformations suggest that Form IV is the most thermodynamically stable polymorph. Form IV also remained unchanged upon slurrying in various solvent systems. All slurry experiments starting with Form III converted to other forms, indicating metastable properties at all conditions tested. Furthermore, the transformation of Form III to Form I at -20°C and room temperature suggests that Form I is likely more stable than Form III within that temperature range. Furthermore, Form III exhibited a tendency to crystallize in mixtures with minor unknowns or other known forms throughout the screening process, consistent with its metastable nature.

[0142] Since Forms I and IV were identified as the two stable forms, further interchangeable slurries of them into each other were investigated.

[0143] VI. Stability Studies to Determine the Relative Stability of Forms III and IV Interconversion slurries were performed in heptane at room temperature, -20°C, and 40°C, as shown in Table 12. For these slurries, heptane was pre-saturated with N,N-DMT with Form IV solid at the specified temperature, and a portion of the liquid phase was filtered to yield a mixture of Form I and Form IV solids. The pre-saturated liquid phase is utilized to minimize any kinetic dissolution effects, dissolving the less stable (and less soluble) form and precipitating the most stable (and least soluble) form. [Table 12]

[0144] Complete conversion to Form IV was observed in all three slurries, indicating that it is more stable under these conditions.

[0145] VI. Polarized light micrographs of Forms I and IV Polarized light microscopy of selected forms (Forms I and IV) was performed using a Leica DM LP microscope equipped with a SPOT Insight™ color digital camera. Each sample was placed on a glass slide, a cover slip was placed over the sample, and a drop of mineral oil was added to cover the sample by capillary action. Each sample was viewed with crossed polarizers and a primary red compensator. Images were captured using SPOT software (v. 4.5.9). A micron bar was inserted into each image as a particle size reference. Micrographs are shown in Figure 17 (Form I) and Figure 18 (Form IV) and show aggregates and individual particles consisting of blades, flakes, and anhedral particles and drusy particles.

[0146] VIII. Amorphous N,N-DMT Attempts to produce amorphous materials did not result in free-flowing amorphous solids, and heating / melting experiments were performed to determine T g was determined. Observations from heating / melting experiments indicated that the amorphous solid readily crystallized at temperatures ranging from -20 °C to 40 °C. Cycling DSC experiments were performed to investigate potential glass transition temperatures by preparing amorphous solids in situ, starting from Form IV.

[0147] The thermogram is shown in Figure 19. At the start of the experiment, Form IV solid was heated above its melting point (to 80°C) and held for 10 minutes. The molten material was rapidly cooled to -80°C and then reheated to 200°C. The glass transition temperature (T g ) is observed as a step in the green curve at -18 °C. Amorphous materials exhibit a T g N,N-DMT tends to crystallize spontaneously at temperatures above this low T g indicates poor physical stability of amorphous materials, especially at temperatures above -18°C.

[0148] IX. Conclusion The polymorph identified in this study, Form IV, was found to be the most thermodynamically stable form and, as a result, exhibits a higher melting point than the other known polymorphs. In contrast, the known polymorph, Form I, has been found to be less stable (converting to Forms III and IV) under various conditions, making it less suitable as an API.

[0149] Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein, including U.S. and foreign patents and patent applications, are specifically and entirely incorporated herein by reference. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. N,N-Dimethyltryptamine Form IV.

2. 2. Form IV of N,N-dimethyltryptamine according to claim 1, characterized by peaks in an X-ray powder diffraction (XRPD) pattern at 13.6±0.2, 20.8±0.2, and 17.8±0.2 degrees 2θ.

3. 3. Form IV of N,N-dimethyltryptamine of claim 2, further characterized by at least one XRPD peak selected from 13.9±0.2, 14.0±0.2, 15.4±0.2, 18.6±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, or 26.7±0.2 degrees two-theta.

4. 4. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 3, characterized by an XRPD peak at 13.9±0.2 degrees 2θ.

5. 5. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 4, characterized by an XRPD peak at 14.0±0.2 degrees 2θ.

6. 6. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 5, characterized by an XRPD peak at 15.4±0.2 degrees 2θ.

7. 7. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 6, characterized by an XRPD peak at 18.6±0.2 degrees 2θ.

8. 8. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 7, characterized by an XRPD peak at 23.6±0.2 degrees 2θ.

9. 9. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 8, characterized by an XRPD peak at 24.5±0.2 degrees 2θ.

10. 10. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 9, characterized by an XRPD peak at 26.0±0.2 degrees 2θ.

11. 11. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 10, characterized by an XRPD peak at 26.7±0.2 degrees 2θ.

12. 2. Form IV of N,N-dimethyltryptamine of claim 1, characterized by peaks in an XRPD pattern at 13.6±0.2, 17.8±0.2, and 20.8±0.2, and at least one XRPD peak selected from 13.9±0.2, 14.0±0.2, 15.4±0.2, 18.6±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, or 26.7±0.2 °2θ.

13. 2. Form IV of N,N-dimethyltryptamine of claim 1, characterized by peaks in an XRPD pattern at 13.6±0.2, 13.9±0.2, 14.0±0.2, 15.4±0.2, 17.8±0.2, 18.6±0.2, 20.8±0.2, 23.6±0.2, 24.5±0.2, 26.0±0.2, and 26.7±0.2 degrees 2θ.

14. 7.7±0.2, 10.4±0.2, 11.9±0.2, 13.0±0.2, 13.6±0.2, 13.9±0.2, 14.0±0.2, 15.2±0.2, 15.4±0.2, 16.2±0.2, 16.9±0.2, 17.5±0.2, 17.8±0.2, 18.1±0.2, 18.6±0.2, 19.3±0.2, 19.8±0.2, 20.8±0.2, 21.1±0.2, 21.6±0.2, 22.4±0.2, 22.7±0.2, 23.6±0.2, 23.8±0.2, 24.5±0.2, 24.8±0.2, 25.2±0.2, 26.1±0.2, 2. Form IV of N,N-dimethyltryptamine of claim 1, characterized by peaks in an XRPD pattern at 26.7±0.2, 26.9±0.2, 27.5±0.2, 28.0±0.2, 28.2±0.2, 28.6±0.2, 28.8±0.2, 29.3±0.2, 29.5±0.2, 29.6±0.2, 30.2±0.2, 30.4±0.2, 30.6±0.2, 30.9±0.2, 31.1±0.2, 31.6±0.2, 31.9±0.2, 32.8±0.2, 33.2±0.2, 33.7±0.2, 34.5±0.2, and 35.3±0.2 degrees 2θ.

15. 15. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 14, characterized by an XRPD pattern substantially similar to that shown in Figure 3.

16. 16. Form IV of N,N-dimethyltryptamine of any of claims 1 to 15, exhibiting a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at 69±5°C.

17. 17. Form IV of N,N-dimethyltryptamine according to any one of claims 1 to 16, exhibiting a DSC thermogram comprising an endothermic peak at 70±5°C.

18. 18. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 17, which exhibits substantially no weight loss at temperatures below 225±5°C as measured by thermogravimetric (TGA) analysis.

19. 19. Form IV of N,N-dimethyltryptamine according to any of claims 1 to 18, having a melting point of 69±5°C.

20. N,N-dimethyltryptamine Form III.

21. 21. Form III of N,N-dimethyltryptamine according to claim 20, characterized by X-ray powder diffraction (XRPD) pattern peaks at 7.6±0.2 and 15.2±0.

2.

22. 22. Form III of N,N-dimethyltryptamine of claim 21, further characterized by at least one XRPD peak selected from 19.2±0.2 degrees two-theta, 19.6±0.2, or 23.0±0.2 degrees two-theta.

23. 23. Form III of N,N-dimethyltryptamine according to any of claims 20 to 22, characterized by an XRPD peak at 19.6±0.2 degrees 2θ.

24. 24. Form III of N,N-dimethyltryptamine according to any of claims 20 to 23, characterized by an XRPD peak at 23.0±0.2 degrees 2θ.

25. 21. Form III of N,N-dimethyltryptamine of claim 20, characterized by peaks in an XRPD pattern at 7.6±0.2 and 15.2±0.2, and at least one XRPD peak selected from 19.2±0.2 degrees two-theta, 19.6±0.2, or 22.9±0.2 degrees two-theta.

26. 21. Form III of N,N-dimethyltryptamine of claim 20, characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 19.2±0.2, 19.6±0.2, and 22.9±0.2 degrees two-theta.

27. 21. Form III of N,N-dimethyltryptamine of claim 20, characterized by peaks in an XRPD pattern at 7.6±0.2, 15.2±0.2, 16.8±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.4±0.2, 20.7±0.2, 21.5±0.2, 22.4±0.2, 22.9±0.2, 23.1±0.2, 26.3±0.2, 27.1±0.2, 27.8±0.2, 28.5±0.2, 30.7±0.2, and 31.56±0.2 degrees 2θ.

28. 28. Form III of N,N-dimethyltryptamine according to any of claims 20 to 27, characterized by an XRPD pattern substantially similar to that shown in Figure 2.

29. 29. Form III of N,N-dimethyltryptamine according to any of claims 20 to 28, which exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at 39±5°C when heated at a rate of 10°C / min.

30. 30. Form III of N,N-dimethyltryptamine according to any of claims 20 to 29, which exhibits a DSC thermogram comprising an endothermic peak at 44±5°C when heated at a rate of 10°C / min.

31. 31. Form III of N,N-dimethyltryptamine according to any of claims 20 to 30, which exhibits substantially no weight loss at temperatures below 200±5°C as measured by thermogravimetric (TGA) analysis.

32. 32. Form III of N,N-dimethyltryptamine according to any one of claims 20 to 31, having a melting point of 39±5°C.

33. A pharmaceutical composition comprising Form IV of N,N-dimethyltryptamine according to any one of claims 1 to 13.

34. 34. The pharmaceutical composition of claim 33, further comprising a pharmaceutically acceptable excipient.

35. An oral dosage form comprising the pharmaceutical composition of any one of claims 33 to 34.

36. A pharmaceutical composition comprising Form III of N,N-dimethyltryptamine according to any one of claims 14 to 32.

37. 37. The pharmaceutical composition of claim 36, further comprising a pharmaceutically acceptable excipient.

38. An oral dosage form comprising the pharmaceutical composition of any one of claims 36 to 37.

39. 38. A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form IV of N,N-dimethyltryptamine according to any of claims 1-13, Form III of N,N-dimethyltryptamine according to any of claims 14-32, a pharmaceutical composition according to any of claims 33-34 and 36-37, or an oral dosage form according to any of claims 35 and 38.

40. 38. A method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form IV of N,N-dimethyltryptamine according to any of claims 1 to 13, Form III of N,N-dimethyltryptamine according to any of claims 14 to 32, a pharmaceutical composition according to any of claims 33 to 34 and 36 to 37, or an oral dosage form according to any of claims 35 and 38.

41. 41. The method of claim 40, wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

42. 37. A method of treating an anxiety disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form IV of N,N-dimethyltryptamine according to any of claims 1 to 13, Form III of N,N-dimethyltryptamine according to any of claims 14 to 32, a pharmaceutical composition according to any of claims 33 to 34 and 36 to 37, or an oral dosage form according to any of claims 35 and 38.

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