Composition of raclosibin and dimethyl-4-hydroxytryptamine and application

Abstract

The present disclosure provides a method of treating or ameliorating a disease or disorder comprising administering to a subject a crystalline form of a composition comprising crystalline forms A, B, and C of dimethyl-4-hydroxytryptamine and raclosibin. The present disclosure also provides methods of stimulating neurogenesis or neurite growth resulting in an increase in neuronal length.

Description

Technical Field

[0001] The present invention relates to crystalline forms of the compounds psilocybin and dimethyl-4-hydroxytryptamine and the use of said compounds in the treatment of mental health disorders and / or other central nervous system conditions and disorders. Background Art

[0002] Various naturally occurring plants and fungi contain hallucinogenic compounds that cause changes in brain function or activity ("neuroactive" compounds) and may also cause an individual to experience hallucinations or similar experiences ("psychedelic" compounds). Psilocybin, one of the most common naturally occurring types of hallucinogens, has been found in more than 180 species of mushrooms worldwide. Psilocybin-containing mushrooms also have other neuroactive and hallucinogenic compounds, the most abundant of which is its major metabolite, dimethyl-4-hydroxytryptamine. In humans, psilocybin is metabolized in the gastrointestinal system, primarily to dimethyl-4-hydroxytryptamine, which is then absorbed and produces the hallucinogenic effects.

[0003] These hallucinogenic effects are dose-dependent and often include changes in visual, auditory, and cognitive experiences. These psilocybin experiences may occur because both psilocybin and dimethyl-4-hydroxytryptamine are structurally similar to the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) and both bind to a variety of 5-HT receptors.

[0004] Compared to psilocybin, 4-HT is chemically unstable and oxidizes rapidly when exposed to air. For this reason, there are few clinical or investigational studies on the effects of 4-HT given alone or compared to psilocybin. Preclinical studies that have been performed suggest that 4-HT has a faster absorption rate and a more rapid onset of action than psilocybin. 4-HT binds to a different range of 5-HT receptors and binds at different concentrations than psilocybin, and therefore has a different range of action.

[0005] Because of the different properties of psilocybin and 4-HT, compounds combining both psilocybin and 4-HT are expected to have unique and beneficial properties compared to either compound alone.

[0006] Psychedelics (such as psilocybin and dimethyl-4-hydroxytryptamine) have been suggested to be potentially useful in treating certain mental health disorders and central nervous system disorders. This is particularly true for disorders that are thought to be resistant to currently available treatments, such as post-traumatic stress disorder (PTSD) and treatment-resistant major depressive disorder, also known as treatment-resistant depression (TRD).

[0007] New treatments are needed for various mental health disorders and central nervous system disorders. One such treatment could be a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, particularly for disorders that are resistant to current treatments. Summary of the invention

[0008] The present disclosure provides several novel compositions and uses thereof, the compositions comprising crystalline forms of dimethylserotonin and psilocybin:

[0009]

[0010] Described herein and identified as crystalline forms A, B, and C. Crystalline form A may be characterized in that the XRPD pattern comprises a significant peak at a 2θ angle of about 10.1°. The XRPD pattern of crystalline form A may additionally comprise a significant peak at a 2θ angle of about 19.16°. The XRPD pattern of crystalline form A may additionally comprise a significant peak at a 2θ angle of about 10.74°, about 25.3°, and about 24.07°. Still further, the XRPD pattern of crystalline form A may additionally comprise a significant peak at a 2θ angle of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. Crystalline form B may be characterized in that the XRPD pattern comprises a significant peak at a 2θ angle of about 18.54°. The XRPD pattern of crystalline form B may additionally comprise a significant peak at a 2θ angle of about 8.54°. The XRPD pattern of crystalline Form B may additionally include significant peaks at 2θ angles of about 22.78°, about 14.27°, and about 21.12°. Still further, the XRPD pattern of crystalline Form B may additionally include significant peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02°. Crystalline Form C may be characterized in that the XRPD pattern includes significant peaks at 2θ angles of about 9.18°. The XRPD pattern of crystalline Form C may additionally include significant peaks at 2θ angles of about 17.95°. The XRPD pattern of crystalline Form C may additionally include significant peaks at 2θ angles of about 10.42°, about 24.22°, and about 18.38°. Still further, the XRPD pattern of crystalline Form C may additionally comprise significant peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°.

[0011] In one embodiment, the present application provides a pharmaceutical composition comprising a crystalline form of dimethyl-4-hydroxytryptamine and psilocybin and a pharmaceutically acceptable excipient. In one embodiment, the crystalline form is crystalline form A, crystalline form B, or crystalline form C. In one embodiment, crystalline form A is characterized in that the XRPD pattern comprises a significant peak at a 2θ angle of about 10.1°; the XRPD pattern also comprises a 2θ angle of about 19.16°; at 2θ angles of about 10.74°, about 25.3°, and about 24.07°; and / or the XRPD pattern also comprises significant peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline form A is about 1:1. In one embodiment, the chemical purity of crystalline form A is about 95% or higher. In some embodiments, crystalline Form A contains no more than about 5 mol% of other solid forms. In some embodiments, the composition of crystalline Form A of dimethyl-4-hydroxytryptamine and psilocybin comprises about 95 mol% crystalline Form A, about 2.5 mol% dimethyl-4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form A is a co-crystal formed between dimethyl-4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form A is a salt formed between dimethyl-4-hydroxytryptamine and psilocybin.

[0012] In one embodiment, crystalline Form B is characterized by an XRPD pattern comprising a significant peak at about 18.54° 2θ; the XRPD pattern also comprises a significant peak at about 8.54° 2θ; the XRPD pattern also comprises significant peaks at about 22.78°, about 14.27°, and about 21.12° 2θ and / or the XRPD pattern also comprises significant peaks at about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02° 2θ. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form B is about 1.3:1. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form B is about 1:1. In one embodiment, the chemical purity of crystalline Form B is about 95% or greater. In some embodiments, crystalline Form B contains no more than about 5 mol% of other solid forms. In some embodiments, the composition of 4-hydroxytryptamine and crystalline Form B of psilocybin comprises about 95 mol% crystalline Form B, about 2.5 mol% 4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form B is a co-crystal formed between 4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form B is a salt formed between 4-hydroxytryptamine and psilocybin.

[0013] In one embodiment, crystalline Form C is characterized by an XRPD pattern comprising a significant peak at about 9.18° 2θ; the XRPD pattern also comprises a significant peak at about 17.95° 2θ; the XRPD pattern also comprises significant peaks at about 10.42°, about 24.22°, and about 18.38° 2θ; and / or the XRPD pattern also comprises significant peaks at about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06° 2θ. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form C is about 1:1. In one embodiment, the chemical purity of crystalline Form C is about 95% or greater. In some embodiments, crystalline Form C contains no more than about 5 mol% of other solid forms. In some embodiments, the composition of 4-hydroxytryptamine and crystalline Form C of psilocybin comprises about 95 mol% crystalline Form C, about 2.5 mol% 4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form C is a co-crystal formed between 4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form C is a salt formed between 4-hydroxytryptamine and psilocybin.

[0014] In one embodiment, the present invention provides a method of treating or ameliorating a disease or disorder by administering to a subject a composition comprising dimethyl-4-hydroxytryptamine and a crystalline form of psilocybin, thereby treating the disease or disorder.

[0015] In one embodiment, the disease or disorder is a mental health disorder or a central nervous system (CNS) disorder. In one embodiment, the mental health disorder is selected from depressive disorders, anxiety disorders, post-traumatic stress disorders, and addiction disorders. In one embodiment, the CNS disorder is selected from chronic pain disorders and cognitive disorders.

[0016] In one embodiment, the present invention provides a method of stimulating neurogenesis or neurite growth, comprising administering to a subject a composition comprising dimethyl-4-hydroxytryptamine and a crystalline form of psilocybin, thereby stimulating neurogenesis or neurite growth. In some embodiments, stimulating neurogenesis or neurite growth results in an increase in neuron length. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 An X-ray powder diffraction (XRPD) pattern of crystalline Form A is shown.

[0018] Figure 2 The XRPD pattern of crystalline Form B is shown.

[0019] Figure 3 The XRPD pattern of crystalline Form C is shown.

[0020] Figure 4 A thermogravimetric mass spectrometry (TGMS) thermogram of crystalline Form A is shown.

[0021] Figure 5 A differential scanning calorimetry (DSC) thermogram of crystalline Form A is shown.

[0022] Figure 6 The TGMS thermogram of crystalline Form B is shown.

[0023] Figure 7 The DSC thermogram of crystalline Form B is shown.

[0024] Figure 8 The TGMS thermogram of crystalline Form C is shown.

[0025] Fig. 9 The DSC thermogram of crystalline Form C is shown.

[0026] Fig.10 Crystalline Form A and psilocybin are shown 1 H-NMR.

[0027] Fig.11 The results showed that the crystalline form A and psilocybin were between 6 ppm and 7.5 ppm. 1 H-NMR.

[0028] Fig.12 Crystalline Form A, Crystalline Form B and Psilocybin are shown. 1 H-NMR.

[0029] Fig.13 The results show that the concentrations of crystalline form A, crystalline form B and psilocybin between 6 ppm and 7.5 ppm 1 H-NMR.

[0030] Fig.14 The dynamic vapor sorption (DVS) isotherm of crystalline Form A is shown.

[0031] Fig.15 The DVS isotherm of crystalline Form B is shown.

[0032] Fig.16 The DVS isotherm of crystalline Form C is shown.

[0033] Fig.17 The HPLC chromatogram of crystalline Form A is shown.

[0034] Fig.18 The HPLC chromatogram of crystalline Form B is shown.

[0035] Fig.19The HPLC chromatogram of crystalline Form C is shown.

[0036] Fig. 20 Shown is the molecular structure and atomic numbering schematic of the dimethyl-4-hydroxytryptamine-psilocybin pair obtained by simulated annealing based on powder diffraction data of crystalline form A.

[0037] Fig.21 Schematic diagram of crystal packing and hydrogen bonding along the direction [1 0 0] in crystals of crystalline form A is shown.

[0038] Fig. 22 A graphical representation of the final cycle of the Rietveld refinement of crystalline Form A is shown.

[0039] Fig.23 showed that h5HT2a-dependent Ca 2+ Compound activity was quantified as Ca release from CHO-K1 cells stably expressing h5HT2a and treated with 0.1 nM-10 μM (left) compound alone or (right) a 1:1 equimolar combination of dimethyl-4-HT and psilocybin. 2+ release.

[0040] Fig.24 h5HT2a-dependent β-arrestin2 recruitment is shown. Compound activity was quantified as β-arrestin2 recruitment from CHO-K1 cells expressing h5HT2a and treated with 0.1 nM–10 μM compound.

[0041] Fig.25 Shows [ 3 H] ketanserin binding, compound affinities were estimated using membranes from CHO-K1 cells stably expressing h5HT2a and incubated with 0.1 nM–10 μM compound for 2 h.

[0042] Fig.26 Physiological changes in C57BL / 6 mice are shown. Compound activity was quantified in C57BL / 6 mice for freezing (10 min) (top), nociception in the tail-flick latency test (15 min) (middle), and body temperature relative to baseline (20 min) (bottom).

[0043] Fig. 27 Shown are head twitch responses in C57BL / 6 mice quantified for simulated rodent hallucinations 0-10 min after compound administration (ip) and the time course of head twitches observed per minute for LSD (top), dimethylserotonin (middle), and psilocybin (bottom) are presented.

[0044] Fig.28Shown are the open field test in C57BL / 6 mice, quantification of OFT compound activity in C57BL / 6 mice for total distance traveled (top, left), speed (middle, left), and time in the center quadrant (bottom, left) 30 minutes after treatment, and a representative movement track of a male C57BL / 6 mouse from Ethovision (right).

[0045] Fig.29 Shown are EPMs of C57BL / 6 mice for which compound activity was quantified in C57BL / 6 mice 30 minutes after treatment for total distance traveled and speed (top, left), EPM time per arm (bottom, left), number of arm entries (bottom, right). Representative locomotion traces from Ethovision male C57BL / 6 mice (top, right).

[0046] Fig.30 Pharmacokinetic quantification of dimethyl-4-hydroxytryptamine in C57BL / 6 mouse plasma is shown. To date, HPLC-MS / MS method validation includes internal standard selection (top left), voltage optimization (top right), mobile phase tissue solvent optimization (top middle), lysis and standard curve creation (bottom middle), and the bottom panel shows an example chromatogram from mouse plasma.

[0047] Fig.31 Shown are EdU+ / NeuN+ / EdU+ data after treatment with psilocybin and / or dimethylserotonin.

[0048] Fig.32 Ki67+ data after treatment with psilocybin and / or dimethyl-4-HT are shown.

[0049] Fig.33 Data for Sox2-positive cells after treatment with psilocybin and / or dimethyl-4-HT are shown.

[0050] Fig.34 Results are shown for neurite outgrowth after treatment with psilocybin and / or dimethyl-4-hydroxytryptamine. DETAILED DESCRIPTION

[0051] The present invention is based on the seminal discovery that psilocybin and dimethyl-4-hydroxytryptamine form crystalline forms, and in particular, that crystalline forms of compositions comprising psilocybin and dimethyl-4-hydroxytryptamine are useful for treating certain mental health disorders and central nervous system disorders and for stimulating neurogenesis.

[0052] Before describing the compositions and methods of the present invention, it should be understood that the present invention is not limited to the specific processes, formulations, compositions or methods described, as these may vary. It should also be understood that the terms used in the specification are only used to describe specific versions or embodiments, and are not intended to limit the scope of the embodiments herein, which will only be limited by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art are generally understood. Although any methods and materials similar or equivalent to the methods and materials described herein can be used in the practice or testing of the embodiments herein, preferred methods, devices and materials are now described. All publications mentioned herein are incorporated herein in their entirety by reference. Nothing herein is interpreted as admitting that the embodiments herein are not entitled to be disclosed earlier than such due to prior inventions.

[0053] It must also be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0054] The transitional term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0055] As used herein, the terms "consists of" or "consisting of" mean that a composition, formulation or method includes only those elements, steps or ingredients specifically recited in a particular claimed embodiment or claim.

[0056] As used herein, the term "consisting essentially of or consists essentially of" means that a composition, formulation, or method includes only the elements, steps, or ingredients specifically listed in a particular claimed embodiment or claim, and may optionally include additional elements, steps, and ingredients that do not materially affect the basic and novel features of the particular embodiment or claim. For example, the only one or more active ingredients in a formulation or method for treating a particular condition (e.g., nutrient depletion) are one or more therapeutic agents specifically listed in a particular embodiment or claim.

[0057] As used herein, two embodiments are "mutually exclusive" when one embodiment is defined as something different from the other.

[0058] When a range of values ​​is disclosed and the notation "from n1 ... to n2" or "between n1 ... to n2" is used, where n1 and n2 are numbers, unless otherwise specified, the notation is intended to include the numbers themselves and the range between them. The range can be an integer or continuous value between and including the endpoint values. For example, the range "from 1°C to 3°C" is intended to include 1°C, 3°C, and each meaningful number between the two to any number (e.g., 1.255°C, 2.1°C, 2.9999°C, etc.).

[0059] As used herein, the term "about" refers to plus or minus 10% of the numerical value of the number with which it is used. Thus, about 50% means within the range of 45% to 55%. For example, "about 100°C" refers to a temperature within the range of 90°C to 110°C. For example, "about 10° of 2θ angle" refers to a 2θ angle within the range of 9° to 11°.

[0060] The term "substantially free" or as used herein, alone or in combination, and used interchangeably with the term "substantially pure", refers to a compound that is free of all other compounds within the limits of detection as measured by any means including nuclear magnetic resonance (NMR), gas chromatography / mass spectrometry (GC / MS), or liquid chromatography / mass spectrometry (LC / MS). In embodiments, substantially free may be less than about 1.0%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01%.

[0061] Crystalline form

[0062] The present disclosure includes embodiments directed to compositions comprising dimethylserotonin and a crystalline form of psilocybin:

[0063]

[0064] In some embodiments, the crystalline form of the composition comprising dimethylserotonin and psilocybin is crystalline Form A.

[0065] In some embodiments, crystalline Form A is characterized in that the XRPD pattern comprises a significant peak at a 2θ angle of about 10.1°. In some embodiments, the XRPD pattern of crystalline Form A may additionally comprise a significant peak at a 2θ angle of about 19.16°. In some embodiments, the XRPD pattern of crystalline Form A may additionally comprise significant peaks at 2θ angles of about 10.74°, about 25.3°, and about 24.07°. In some embodiments, the XRPD pattern of crystalline Form A may additionally comprise significant peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. In some embodiments, crystalline Form A is characterized in that Figure 1 XRPD pattern of.

[0066] In one embodiment, crystalline Form A has Figure 4 A representative TGMS thermogram plotted in TGMS thermogram substantially corresponding to TGMS thermogram. In some embodiments, negligible weight loss is observed. Weight loss (1.3%) was observed for crystalline Form A between 40-200°C by TGMS.

[0067] In one embodiment, crystalline Form A has Figure 5 A substantially corresponding DSC thermogram is plotted in . In certain embodiments, crystalline Form A is characterized in that the DSC plot comprises a sharp endothermic event at a temperature of about 255°C.

[0068] In some embodiments, the ratio of psilocybin in crystalline Form A to dimethyl-4-hydroxytryptamine is about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2. In some embodiments, the ratio of psilocybin in crystalline Form A to dimethyl-4-hydroxytryptamine is about 1:1.

[0069] In some embodiments, the chemical purity of crystalline Form A is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In some embodiments, crystalline Form A is substantially pure.

[0070] In some embodiments, the crystalline Form A contains no more than about 0.01 mol%, about 0.02 mol%, about 0.03 mol%, about 0.04 mol%, about 0.05 mol%, about 0.06 mol%, about 0.07 mol%, about 0.08 mol%, about 0.09 mol%, about 0.1 mol%, about 0.15 mol%, about 0.2 mol%, about 0.25 mol%, about 0.3 mol%, about 0.35 mol%, about 0.4 mol%, about 0.45 mol%, about 0.5 mol%, about 0.55 mol%, about 0.6 mol%, about 0.65 mol%, about 0.75 mol%, about 0.85 mol%, about 0.95 mol%, about 0.10 mol%, about 0.11 mol%, about 0.12 mol%, about 0.13 mol%, about 0.14 mol%, about 0.15 mol%, about 0.16 mol%, about 0.17 mol%, about 0.18 mol%, about 0.19 mol%, about 0.21 mol%, about 0.23 mol%, about 0.24 mol%, about 0.25 mol%, about 0.25 mol%, about 0.26 mol%, about 0.27 mol%, about 0.28 mol%, about 0.29 mol%, about 0.30 mol%, about 0.31 mol%, about 0.31 mol%, about 0.32 mol%, about 0.33 mol%, about 0.35 In some embodiments, the crystalline Form A is substantially free of other solid forms.

[0071] In some embodiments, the composition of crystalline Form A of dimethyl-4-hydroxytryptamine and psilocybin comprises about 99 mol% crystalline Form A, about 0.5 mol% dimethyl-4-hydroxytryptamine, and about 0.5 mol% psilocybin; about 98 mol% crystalline Form A, about 1.0 mol% dimethyl-4-hydroxytryptamine, and about 1.0 mol% psilocybin; about 97 mol% crystalline Form A, about 1.5 mol% dimethyl-4-hydroxytryptamine, and about 1.5 mol% psilocybin; about 96 mol% crystalline Form A, about 2.0 mol% dimethyl-4-hydroxytryptamine, and about 2.0 mol% psilocybin; about 95 mol% crystalline Form A, about 2.5 mol% dimethyl-4-hydroxytryptamine, and about 2.5 mol% psilocybin. serotonin and about 2.5 mol % psilocybin; about 94 mol % crystalline Form A, about 3.0 mol % dimethyl-4-hydroxytryptamine, and about 3.0 mol % psilocybin; about 93 mol % crystalline Form A, about 3.5 mol % dimethyl-4-hydroxytryptamine, and about 3.5 mol % psilocybin; about 92 mol % crystalline Form A, about 4.0 mol % dimethyl-4-hydroxytryptamine, and about 4.0 mol % psilocybin; about 91 mol % crystalline Form A, about 4.5 mol % dimethyl-4-hydroxytryptamine, and about 4.5 mol % psilocybin; or about 90 mol % crystalline Form A, about 5.0 mol % dimethyl-4-hydroxytryptamine, and about 5.0 mol % psilocybin.

[0072] In some embodiments, crystalline Form A is anhydrous.

[0073] In some embodiments, crystalline Form A is a salt formed between dimethylserotonin and psilocybin.

[0074] In some embodiments, crystalline Form A is a co-crystal formed between dimethylserotonin and psilocybin.

[0075] Some embodiments relate to compositions comprising 4-HT and a crystalline form of psilocybin:

[0076]

[0077] Wherein crystalline Form A is characterized by unit cell parameters substantially equal to the following:

[0078] Unit cell size:

[0079]

[0080] α=90 degrees

[0081] β=90 degrees

[0082] γ=90 degrees

[0083] Space group = P212121

[0084] Molecule / asymmetric unit=1.

[0085] In some embodiments, the unit cell parameters are measured at about 296K.

[0086] In some embodiments, crystalline Form A has a hydrogen bonding geometry substantially as listed in Table A.

[0087] Table A

[0088]

[0089] In some embodiments, crystalline Form A has atomic coordinates for non-hydrogen atoms substantially as listed in Table B.

[0090] Table B

[0091]

[0092]

[0093] In some embodiments, crystalline Form A has atomic coordinates for hydrogen atoms substantially as listed in Table C.

[0094] Table C

[0095]

[0096]

[0097] In some embodiments, the crystalline form of the composition comprising dimethylserotonin and psilocybin is crystalline Form B.

[0098] In some embodiments, crystalline Form B is characterized in that the XRPD pattern comprises a significant peak at a 2θ angle of about 18.54°. In some embodiments, crystalline Form B is characterized in that the XRPD pattern of crystalline Form B may additionally comprise a significant peak at a 2θ angle of about 8.54°. In some embodiments, crystalline Form B is characterized in that the XRPD pattern of crystalline Form B may additionally comprise a significant peak at a 2θ angle of about 22.78°, about 14.27°, and about 21.12°. In some embodiments, crystalline Form B is characterized in that the XRPD pattern of crystalline Form B may additionally comprise a significant peak at a 2θ angle of about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02°. In some embodiments, crystalline Form B is characterized in that Figure 2 XRPD pattern of.

[0099] In one embodiment, crystalline Form B has Figure 6 A representative TGMS thermogram plotted in TGMS thermogram substantially corresponding to TGMS thermogram. In some embodiments, negligible weight loss is observed. Weight loss (15.8%) was observed for crystalline Form B by TGMS between 40-200°C.

[0100] In one embodiment, crystalline Form B has Figure 7 A substantially corresponding DSC thermogram is plotted in . In certain embodiments, crystalline Form B is characterized by a DSC plot comprising a broad endothermic event at a temperature of about 168.2°C.

[0101] In some embodiments, the ratio of psilocybin in crystalline Form B to dimethyl-4-hydroxytryptamine is about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2. In some embodiments, the ratio of psilocybin in crystalline Form B to dimethyl-4-hydroxytryptamine is about 1.3:1. In some embodiments, the ratio of psilocybin in crystalline Form B to dimethyl-4-hydroxytryptamine is about 1:1.

[0102] In some embodiments, the chemical purity of crystalline Form B is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In some embodiments, crystalline Form B is substantially pure.

[0103] In some embodiments, the crystalline Form B contains no more than about 0.01 mol%, about 0.02 mol%, about 0.03 mol%, about 0.04 mol%, about 0.05 mol%, about 0.06 mol%, about 0.07 mol%, about 0.08 mol%, about 0.09 mol%, about 0.1 mol%, about 0.15 mol%, about 0.2 mol%, about 0.25 mol%, about 0.3 mol%, about 0.35 mol%, about 0.4 mol%, about 0.45 mol%, about 0.5 mol%, about 0.55 mol%, about 0.6 mol%, about 0.65 mol%, about 0.75 mol%, about 0.85 mol%, about 0.95 mol%, about 0.10 mol%, about 0.11 mol%, about 0.12 mol%, about 0.13 mol%, about 0.14 mol%, about 0.15 mol%, about 0.16 mol%, about 0.17 mol%, about 0.18 mol%, about 0.19 mol%, about 0.20 mol%, about 0.21 mol%, about 0.23 mol%, about 0.24 mol%, about 0.25 mol%, about 0.25 mol%, about 0.26 mol%, about 0.27 mol%, about 0.28 mol%, about 0.29 mol%, about 0.30 mol%, about 0.31 mol%, about 0.31 mol%, about 0.32 mol%, about 0.33 mol%, about 0.35 In some embodiments, the crystalline Form B is substantially free of other solid forms.

[0104] In some embodiments, crystalline Form B is anhydrous.

[0105] In some embodiments, crystalline Form B is a salt formed between dimethylserotonin and psilocybin.

[0106] In some embodiments, crystalline Form B is a co-crystal formed between dimethylserotonin and psilocybin.

[0107] In some embodiments, the crystalline form of the composition comprising dimethylserotonin and psilocybin is crystalline Form C.

[0108] In some embodiments, crystalline Form C is characterized in that the XRPD pattern comprises a significant peak at a 2θ angle of about 9.18°. In some embodiments, crystalline Form C is characterized in that the XRPD pattern of crystalline Form C may additionally comprise a significant peak at a 2θ angle of about 17.95°. In some embodiments, crystalline Form C is characterized in that the XRPD pattern of crystalline Form C may additionally comprise a significant peak at a 2θ angle of about 10.42°, about 24.22°, and about 18.38°. In some embodiments, crystalline Form C is characterized in that the XRPD pattern of crystalline Form C may additionally comprise a significant peak at a 2θ angle of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°. In some embodiments, crystalline Form C is characterized in that Figure 3 XRPD pattern of.

[0109] In one embodiment, crystalline Form C has Figure 8 A representative TGMS thermogram plotted in TGMS thermogram substantially corresponding to TGMS thermogram. In some embodiments, negligible weight loss is observed. Weight loss (13.5%) was observed for crystalline Form C by TGMS between 40-160°C.

[0110] In one embodiment, crystalline Form C has Fig. 9 A substantially corresponding DSC thermogram is plotted in . In certain embodiments, crystalline Form C is characterized by a DSC plot comprising a broad endothermic event at temperatures between about 25-140°C, with a peak at 98.7°C.

[0111] In some embodiments, the ratio of psilocybin in crystalline Form C to dihydroxytryptamine is about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2. In some embodiments, the ratio of psilocybin in crystalline Form C to dihydroxytryptamine is about 1:1.

[0112] In some embodiments, the chemical purity of crystalline Form C is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In some embodiments, crystalline Form C is substantially pure.

[0113] In some embodiments, the crystalline Form C contains no more than about 0.01 mol%, about 0.02 mol%, about 0.03 mol%, about 0.04 mol%, about 0.05 mol%, about 0.06 mol%, about 0.07 mol%, about 0.08 mol%, about 0.09 mol%, about 0.1 mol%, about 0.15 mol%, about 0.2 mol%, about 0.25 mol%, about 0.3 mol%, about 0.35 mol%, about 0.4 mol%, about 0.45 mol%, about 0.5 mol%, about 0.55 mol%, about 0.6 mol%, about 0.65 mol%, about 0.75 mol%, about 0.85 mol%, about 0.95 mol%, about 0.10 mol%, about 0.11 mol%, about 0.12 mol%, about 0.13 mol%, about 0.14 mol%, about 0.15 mol%, about 0.16 mol%, about 0.17 mol%, about 0.18 mol%, about 0.19 mol%, about 0.20 mol%, about 0.21 mol%, about 0.23 mol%, about 0.24 mol%, about 0.25 mol%, about 0.25 mol%, about 0.26 mol%, about 0.27 mol%, about 0.28 mol%, about 0.29 mol%, about 0.30 mol%, about 0.31 mol%, about 0.31 mol%, about 0.32 mol%, about 0.33 mol%, about 0.35 In some embodiments, the crystalline Form C is substantially free of other solid forms.

[0114] In some embodiments, crystalline Form C is anhydrous.

[0115] In some embodiments, crystalline Form C is a salt formed between dimethylserotonin and psilocybin.

[0116] In some embodiments, crystalline Form C is a co-crystal formed between dimethylserotonin and psilocybin.

[0117] Pharmaceutical composition

[0118] In one embodiment, the present application provides a pharmaceutical composition comprising a crystalline form of dimethylserotonin and psilocybin and a pharmaceutically acceptable excipient.

[0119] In one embodiment, the crystalline form is crystalline Form A, crystalline Form B, or Form C. In one embodiment, crystalline Form A is characterized by an XRPD pattern comprising a significant peak at a 2θ angle of about 10.1°; the XRPD pattern also comprises a 2θ angle of about 19.16°; at 2θ angles of about 10.74°, about 25.3°, and about 24.07°; and / or the XRPD pattern also comprises significant peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form A is about 1:1. In one embodiment, the chemical purity of crystalline Form A is about 95% or greater. In some embodiments, the pharmaceutical composition of crystalline Form A contains no more than about 5 mol% of other solid forms. In some embodiments, the pharmaceutical composition of crystalline Form A of dimethyl-4-hydroxytryptamine and psilocybin comprises about 95 mol% crystalline Form A, about 2.5 mol% dimethyl-4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form A is a co-crystal formed between dimethyl-4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form A is a salt formed between dimethyl-4-hydroxytryptamine and psilocybin.

[0120] In one embodiment, crystalline Form A is characterized by unit cell parameters substantially equal to the following:

[0121] Unit cell size:

[0122]

[0123] α=90 degrees

[0124] β=90 degrees

[0125] γ=90 degrees

[0126] Space group = P212121

[0127] Molecule / asymmetric unit=1.

[0128] In one embodiment, the unit cell parameters are measured at about 296 K. In one embodiment, crystalline Form A has a hydrogen bonding geometry substantially as listed in Table A. In one embodiment, crystalline Form A has atomic coordinates for non-hydrogen atoms substantially as listed in Table B. In one embodiment, crystalline Form A has atomic coordinates for hydrogen atoms substantially as listed in Table C. In one embodiment, crystalline Form A is a co-crystal formed between dimethyl-4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form A is a salt formed between dimethyl-4-hydroxytryptamine and psilocybin.

[0129] In one embodiment, crystalline Form B is characterized by an XRPD pattern comprising a significant peak at about 18.54° 2θ; the XRPD pattern also comprises a significant peak at about 8.54° 2θ; the XRPD pattern also comprises significant peaks at about 22.78°, about 14.27°, and about 21.12° 2θ and / or the XRPD pattern also comprises significant peaks at about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02° 2θ. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form B is about 1.3:1. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form B is about 1:1. In one embodiment, the chemical purity of crystalline Form B is about 95% or greater. In some embodiments, the pharmaceutical composition of crystalline Form B contains no more than about 5 mol% of other solid forms. In some embodiments, the pharmaceutical composition of crystalline Form B of dimethyl-4-hydroxytryptamine and psilocybin comprises about 95 mol% crystalline Form B, about 2.5 mol% dimethyl-4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form B is a co-crystal formed between dimethyl-4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form B is a salt formed between dimethyl-4-hydroxytryptamine and psilocybin.

[0130] In one embodiment, crystalline Form C is characterized by an XRPD pattern comprising a significant peak at about 9.18° 2θ; the XRPD pattern also comprises a significant peak at about 17.95° 2θ; the XRPD pattern also comprises significant peaks at about 10.42°, about 24.22°, and about 18.38° 2θ; and / or the XRPD pattern also comprises significant peaks at about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06° 2θ. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form C is about 1:1. In one embodiment, the chemical purity of crystalline Form C is about 95% or greater. In some embodiments, pharmaceutical compositions of crystalline Form C contain no more than about 5 mol% of other solid forms. In some embodiments, the pharmaceutical composition of crystalline Form C of dimethyl-4-hydroxytryptamine and psilocybin comprises about 95 mol% crystalline Form C, about 2.5 mol% dimethyl-4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form C is a co-crystal formed between dimethyl-4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form C is a salt formed between dimethyl-4-hydroxytryptamine and psilocybin.

[0131] As used herein, "pharmaceutical composition" refers to a formulation comprising an active ingredient and an optional pharmaceutically acceptable carrier, diluent or excipient. The term "active ingredient" may refer interchangeably to "effective ingredient," meaning any agent capable of producing the desired effect after administration. Examples of active ingredients include, but are not limited to, compounds, drugs, therapeutic agents, small molecules, and the like. In one embodiment, the active ingredients are crystalline forms of psilocybin and dimethyl-4-hydroxytryptamine, such as crystalline Form A, crystalline Form B, or Form C described herein.

[0132] As used herein, the terms "excipient" and "pharmaceutically acceptable excipient" are generally synonymous and are used interchangeably with the terms "carrier", "pharmaceutically acceptable carrier", "diluent", and "pharmaceutically acceptable diluent". "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof or to the activity of the active ingredients of the formulation. Pharmaceutically acceptable carriers, excipients or stabilizers are well known in the art, for example, Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980). Pharmaceutically acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol or benzyl alcohol, alkyl parabens such as methyl paraben or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol); low molecular weight (less than 100 μg / ml); about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as TWEEN TM 、PLURONICS TMOr polyethylene glycol (PEG). Examples of carriers include, but are not limited to, liposomes, nanoparticles, ointments, micelles, microspheres, microparticles, creams, emulsions, and gels. Examples of excipients include, but are not limited to, antiadhesives such as magnesium stearate, adhesives such as sugars and their derivatives (sucrose, lactose, starch, cellulose, sugar alcohols, etc.), protein-like gelatin, and synthetic polymers, lubricants such as talc and silicon dioxide, and preservatives such as antioxidants, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium sulfate, and parabens. Examples of diluents include, but are not limited to, water, ethanol, saline solutions, glycols, mineral oils, and dimethyl sulfoxide (DMSO).

[0133] In one embodiment, the pharmaceutically acceptable excipient is selected from phosphate buffer; citrate buffer; ascorbic acid; methionine; octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol alcohol; butyl alcohol; benzyl alcohol; methyl paraben; propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol; low molecular weight (less than about 10 residues) polypeptides; serum albumin; gelatin; immunoglobulin; polyvinylpyrrolidone; glycine; glutamine; asparagine; histidine; arginine; lysine; monosaccharides; disaccharides; glucose; mannose; dextrin; EDTA; trehalose, lactose, dextrose, sucrose, sorbitol , mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose, including eutectic solvents, eutectic-based ionic liquids, ionic liquids, sorbitol; sodium; saline; metal surfactants; nonionic surfactants; polyethylene glycol (PEG); magnesium stearate; water; ethanol; saline solution; glycols; mineral oil and dimethyl sulfoxide (DMSO).

[0134] The active compound can be effective within a wide dosage range and can generally be administered in a therapeutically effective amount. However, it should be understood that the amount of compound actually administered is generally determined by a physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0135] Treatment

[0136] In one embodiment, the present invention provides a method of treating or ameliorating a disease or disorder by administering to a subject a composition comprising dimethyl-4-hydroxytryptamine and a crystalline form of psilocybin, thereby treating the disease or disorder.

[0137] In one embodiment, the disease or disorder is selected from a mental health disorder or a central nervous system (CNS) disorder. In one embodiment, the mental health disorder is selected from a depressive disorder, an anxiety disorder, a post-traumatic stress disorder, and an addiction disorder. In one embodiment, the CNS disorder is selected from a chronic pain disorder and a cognitive disorder.

[0138] In one embodiment, the present invention provides a method of stimulating neurogenesis or neurite growth, comprising administering to a subject a composition comprising dimethyl-4-hydroxytryptamine and a crystalline form of psilocybin, thereby stimulating neurogenesis or neurite growth. In some embodiments, stimulating neurogenesis or neurite growth results in an increase in neuron length.

[0139] In some embodiments, stimulation of neurogenesis or neurite outgrowth results in improvement of cognitive impairment or other neurological manifestations associated with a disorder of the central nervous system. In some embodiments, the disorder of the central nervous system is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, Alzheimer's disease, Pick's disease, Parkinson's dementia syndrome, progressive subcortical gliosis, progressive supranuclear palsy, thalamic degeneration syndrome, hereditary aphasia, myoclonic epilepsy, sleep deprivation, depression, stroke, ischemia, brain trauma, psychological and physical trauma, chronic pain caused by any cause, cognitive impairment and cognitive decline.

[0140] In one embodiment, the crystalline form is crystalline form A, crystalline form B, or crystalline form C. In one embodiment, crystalline form A is characterized by an XRPD pattern comprising a significant peak at a 2θ angle of about 10.1°; the XRPD pattern also comprises a 2θ angle of about 19.16°; at 2θ angles of about 10.74°, about 25.3°, and about 24.07°; and / or the XRPD pattern also comprises significant peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline form A is about 1:1. In one embodiment, the chemical purity of crystalline form A is about 95% or greater. In some embodiments, crystalline form A contains no more than about 5 mol% of other solid forms. In some embodiments, the composition of crystalline Form A of dimethyl-4-hydroxytryptamine and psilocybin comprises about 95 mol% crystalline Form A, about 2.5 mol% dimethyl-4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form A is a co-crystal formed between dimethyl-4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form A is a salt formed between dimethyl-4-hydroxytryptamine and psilocybin.

[0141] In one embodiment, crystalline Form A is characterized by unit cell parameters substantially equal to the following:

[0142] Unit cell size:

[0143]

[0144] α=90 degrees

[0145] β=90 degrees

[0146] γ=90 degrees

[0147] Space group = P212121

[0148] Molecule / asymmetric unit=1.

[0149] In one embodiment, the unit cell parameters are measured at about 296 K. In one embodiment, crystalline Form A has a hydrogen bonding geometry substantially as listed in Table A. In one embodiment, crystalline Form A has atomic coordinates for non-hydrogen atoms substantially as listed in Table B. In one embodiment, crystalline Form A has atomic coordinates for hydrogen atoms substantially as listed in Table C. In one embodiment, crystalline Form A is a co-crystal formed between dimethyl-4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form A is a salt formed between dimethyl-4-hydroxytryptamine and psilocybin.

[0150] In one embodiment, crystalline Form B is characterized by an XRPD pattern comprising a significant peak at about 18.54° 2θ; the XRPD pattern also comprises a significant peak at about 8.54° 2θ; the XRPD pattern also comprises significant peaks at about 22.78°, about 14.27°, and about 21.12° 2θ and / or the XRPD pattern also comprises significant peaks at about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02° 2θ. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form B is about 1.3:1. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form B is about 1:1. In one embodiment, the chemical purity of crystalline Form B is about 95% or greater. In some embodiments, crystalline Form B contains no more than about 5 mol% of other solid forms. In some embodiments, the composition of 4-hydroxytryptamine and crystalline Form B of psilocybin comprises about 95 mol% crystalline Form B, about 2.5 mol% 4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form B is a co-crystal formed between 4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form B is a salt formed between 4-hydroxytryptamine and psilocybin.

[0151] In one embodiment, crystalline Form C is characterized by an XRPD pattern comprising a significant peak at about 9.18° 2θ; the XRPD pattern also comprises a significant peak at about 17.95° 2θ; the XRPD pattern also comprises significant peaks at about 10.42°, about 24.22°, and about 18.38° 2θ; and / or the XRPD pattern also comprises significant peaks at about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06° 2θ. In one embodiment, the ratio of psilocybin to dimethyl-4-hydroxytryptamine in crystalline Form C is about 1:1. In one embodiment, the chemical purity of crystalline Form C is about 95% or greater. In some embodiments, crystalline Form C contains no more than about 5 mol% of other solid forms. In some embodiments, the composition of 4-hydroxytryptamine and crystalline Form C of psilocybin comprises about 95 mol% crystalline Form C, about 2.5 mol% 4-hydroxytryptamine, and about 2.5 mol% psilocybin. In one embodiment, crystalline Form C is a co-crystal formed between 4-hydroxytryptamine and psilocybin. In one embodiment, crystalline Form C is a salt formed between 4-hydroxytryptamine and psilocybin.

[0152] As used herein, the terms "treat, treated, treating or treatment" refer to both therapeutic treatment and prophylactic or preventive measures, wherein the purpose is to prevent or slow down (mitigate) an undesirable physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, relief of symptoms; alleviation of the extent of a condition, disorder or disease; stabilization (i.e., not worsening) of a condition, disorder or disease state; delaying the onset of a condition, disorder or disease or slowing its progression; improvement of a condition, disorder or disease state; and relief (whether partial or complete, whether induced or maintained), whether detectable or undetectable, or gain or improvement of a condition, disorder or disease. Treatment includes causing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival without treatment. Treatment may also be preemptive in nature, i.e., it may include preventing a disease. Preventing a disease may involve complete protection from the disease, such as in the case of preventing infection by a pathogen, or may involve preventing disease progression. For example, preventing a disease may not mean completely eliminating any effects associated with the disease at any level, but may mean preventing disease symptoms to a clinically significant or detectable level. Preventing a disease may also mean preventing the disease from progressing to a later stage of the disease and prolonging disease-free survival compared to disease-free survival if not receiving treatment.

[0153] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both: 1) therapeutic treatments or measures that cure, alleviate, lessen the symptoms of, and / or prevent the progression of a diagnosed pathological condition or disorder, and 2) preventive / prophylactic measures. Those in need of treatment may include individuals who already have a particular medical disorder as well as those who may eventually develop the disorder (i.e., those in need of preventive measures).

[0154] The terms "therapeutically effective amount", "effective dose", "therapeutically effective dose", "effective amount", etc. refer to the amount of the test compound that will elicit the biological or medical response of a tissue, system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician. Generally, the response is an improvement in symptoms of the patient, or a desired biological outcome (e.g., improvement in PTSD symptoms). An effective amount can be determined as described herein.

[0155] The term "administration of and / or administering" is understood to mean providing a therapeutically effective amount of a pharmaceutical composition to a subject in need of treatment. The route of administration may be enteral, topical or parenteral. Thus, routes of administration include, but are not limited to, intradermal, subcutaneous, intravenous, intraarterial, intraorbital, intracardiac, intradermal, transdermal, subarachnoid, intraspinal, oral, sublingual, buccal, rectal, nasal administration, and infusion. Suitable unit dosage forms include, but are not limited to, powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injections, implantable sustained-release formulations, lipid complexes, and the like.

[0156] The term "patient" is often synonymous with the term "subject" and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs and rabbits, and companion animals such as dogs, cats, rabbits and horses. Preferably, the patient is a human.

[0157] Mental health disorders or mental illnesses refer to a wide range of disorders, including but not limited to mood disorders, depressive disorders, mood instability disorders, mixed anxiety and depressive disorders, bipolar disorder, anxiety disorders, generalized anxiety disorder, social anxiety disorder, panic disorder, panic attack disorder, schizophrenia, psychosis, schizoaffective disorder, eating disorders, anorexia nervosa, bulimia nervosa, substance abuse disorders, addiction disorders, alcohol abuse or dependence, opioid abuse or dependence, cocaine abuse or dependence, mixed drug abuse or dependence, behavioral addiction, gambling disorder, trauma-related disorders, post-traumatic stress disorder, grief-related disorders, loss-related disorders, end-of-life-related disorders, cancer disorders, attention deficit disorder (ADD), attention deficit and hyperactivity disorder (ADHD), personality disorders and obsessive-compulsive disorder, and any combination of these. A complete list of currently accepted mental health disorders is provided in Diagnostic and Statical Manual, 5th edition (DSM5), the entire contents of which are incorporated herein by reference. Central nervous system (CNS) disorders include, but are not limited to, both psychological and physical trauma from burns, injuries, or any other physical cause, post-amputation, post-brain injury, post-stroke, post-heart attack, post-diabetes, chronic pain disorders, migraines, chronic headaches, chronic back pain, chronic arthritis pain, chronic pain from any cause, cognitive impairment, cognitive decline, Alzheimer's disease, dementia at any stage, dementia from any cause, age-related memory impairment, neuropsychiatric disorders, fetal alcohol spectrum (FAS) disorders, autism spectrum disorders, multiple sclerosis, Parkinson's disease, fragile X, Down syndrome, fatigue, chronic fatigue, insomnia from any cause, and all post-COVID-19 syndromes. Symptoms vary in severity, with some individuals experiencing debilitating illness that precludes normal social functioning, while others suffer intermittent recurring episodes throughout their lives. Although the presentation and diagnostic criteria for mental illness and CNS disorders are in part different, these disorders share significant endophenotypes and comorbidities are often present.

[0158] Specifically, there are phenotypic endophenotypes associated with changes in mood, cognition, and behavior. Interestingly, many of these endophenotypes also extend to neurological conditions. For example, attention deficits have been reported in patients with attention deficit disorder, attention deficit hyperactivity disorder, eating disorders, substance use disorders, schizophrenia, depression, obsessive-compulsive disorder, traumatic brain injury, fragile X, Alzheimer's disease, Parkinson's disease, and frontotemporal dementia.

[0159] Depressive disorders are characterized by low mood, feelings of sadness or hopelessness, increased irritability, sleep disturbances, decreased energy and tiredness, difficulty concentrating, decreased self-esteem or feelings of worthlessness, lack of interest or pleasure in things, slowed movements, thoughts that death and self-harm would be better, and active thoughts and attempts at suicide, and include major depressive disorder, bipolar depression, treatment-resistant depression, and dysthymic disorder.

[0160] Anxiety disorders are characterized by feeling nervous, anxious, shortness of breath, avoiding people or activities, excessive worrying, and physical symptoms including chest pain, palpitations, sweating, nausea, stomach pain, headache, neck pain, poor sleep, difficulty concentrating, sweating, and dizziness, and include generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, phobias, and separation anxiety disorder.

[0161] Post-traumatic stress disorder (PTSD) is characterized by flashbacks, nightmares, involuntary memories, emotional distress or physical reactions to recalling the trauma, avoidance of anything that might trigger such memories, avoidance of activities, social isolation, increased anger or aggression, increased irritability, engagement in risky behaviors, difficulty concentrating, sleep problems, and increased startle response, which can be further described as those with dissociative experiences.

[0162] When an individual repeatedly uses alcohol or drugs, resulting in significant impairment due to problems that negatively affect health, work, school, and family, they are considered to have a substance abuse and addiction disorder, the severity of which depends on the type and frequency of substance use, social and interpersonal problems related to this use, the impact on family, friends, work, school, and relationships, withdrawal symptoms, tolerance, failed attempts to stop, physical and mental health problems caused by this use, and cravings, and include alcohol use disorder, cannabis use disorder, hallucinogen use disorder, inhalant use disorder, opioid use disorder, sedative-hypnotic or anxiolytic use disorder, stimulant use disorder, tobacco use disorder, and unknown substance use disorder, which occur alone or in combination.

[0163] Chronic pain disorders are characterized by pain in one or more areas of the body and include headaches, low back pain, neck pain, arthritic pain, pain in the setting of cancer, neuropathic pain, psychiatric pain, and include conditions such as chronic arthritis, osteoarthritis, chronic fatigue syndrome, endometriosis, fibromyalgia, inflammatory bowel disease, interstitial cystitis, temporomandibular joint dysfunction, vulvodynia, cluster headaches, migraines, herpes zoster, frozen shoulder, complex regional pain syndrome, gout, postoperative pain syndrome, herniated disc, sciatica, and trigeminal neuralgia.

[0164] Cognitive impairment is characterized by poor brain function that worsens memory and other functions, including movement, speech, attention and concentration, problem solving, analytical sleep, tremor, fatigue, dizziness, headache, hallucinations, and confabulation, and includes age-related memory impairment, Alzheimer's disease, Pick's disease, vascular dementia, post-stroke dementia, multi-infarct dementia, Parkinson's disease, frontal lobe dementia, alcohol-induced dementia, and amnesia disorders including Korsakoff syndrome.

[0165] Neurogenesis is an important process in the animal and human brain whereby new nerve cells are continuously generated throughout the life span of the organism. The newly generated cells are able to differentiate into functional cells of the central nervous system and integrate into existing neural circuits in the brain. Stimulating neurogenesis, or neurite outgrowth, can improve cognitive performance associated with various disorders of the central nervous system, such as depression and anxiety.

[0166] In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating post-traumatic stress disorder (PTSD). In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating refractory PTSD. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory PTSD. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form B, is provided for use in treating refractory PTSD. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form C, is provided for use in treating refractory PTSD. In one embodiment, a high purity crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory PTSD. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form B, is provided for use in treating refractory PTSD. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form C, is provided for use in treating refractory PTSD.

[0167] In one embodiment, a method of treating PTSD is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory PTSD is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory PTSD is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form A. In one embodiment, a method of treating refractory PTSD is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form B. In one embodiment, a method of treating refractory PTSD is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form C.

[0168] In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating depression. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating refractory depression. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory depression. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form B, is provided for use in treating refractory depression. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form C, is provided for use in treating refractory depression. In one embodiment, a high purity crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory depression. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form B, is provided for use in treating refractory depression. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form C, is provided for use in treating refractory depression.

[0169] In one embodiment, a method of treating depression is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory depression is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory depression is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form A. In one embodiment, a method of treating refractory depression is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form B. In one embodiment, a method of treating refractory depression is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form C.

[0170] In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating anxiety disorders. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating refractory anxiety disorders. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory anxiety disorders. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form B, is provided for use in treating refractory anxiety disorders. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form C, is provided for use in treating refractory anxiety disorders. In one embodiment, a high purity crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory anxiety disorders. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form B, is provided for use in treating refractory anxiety disorders. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form C, is provided for use in treating refractory anxiety disorders.

[0171] In one embodiment, a method of treating anxiety is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory anxiety is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory anxiety is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form A. In one embodiment, a method of treating refractory anxiety is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form B. In one embodiment, a method of treating refractory anxiety is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of dimethyl-4-hydroxytryptamine, crystalline Form C.

[0172] In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating pain. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof, is provided for use in treating refractory pain. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory pain. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form B, is provided for use in treating refractory pain. In one embodiment, a crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form C, is provided for use in treating refractory pain. In one embodiment, a high purity crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline form A, is provided for use in treating refractory pain. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form B, is provided for use in treating refractory pain. In one embodiment, a highly pure crystalline form of psilocybin and dimethyl-4-hydroxytryptamine, crystalline Form C, is provided for use in treating refractory pain.

[0173] In one embodiment, a method of treating pain is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory pain is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form A, crystalline Form B, crystalline Form C, or a combination thereof. In one embodiment, a method of treating refractory pain is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form A. In one embodiment, a method of treating refractory pain is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form B. In one embodiment, a method of treating refractory pain is provided, comprising administering to a subject in need thereof an effective dose of psilocybin and a crystalline form of 4-hydroxytryptamine, crystalline Form C.

[0174] In some embodiments, the composition is administered by intradermal, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual, buccal, or nasal routes of administration.

[0175] In some embodiments, the method further comprises administering a second pharmaceutically active compound.

[0176] In some embodiments, the second pharmaceutically active compound is one or more of an antianxiety drug, an antidepressant drug, or an analgesic drug.

[0177] In some embodiments, the second pharmaceutically active compound is a psychoactive alkaloid. In some embodiments, the psychoactive compound or alkaloid is psilocybin, dimethyl-4-hydroxytryptamine, monomethylpsilocybin (baeocystin), norbaeocystin, norpsilocin, aeruginascin, toad tryptamine, toad tenidine, 5-MeO-DMT (5-methoxy-NN-dimethyltryptamine), N,N-dimethyltryptamine (DMT), 4-hydroxytryptamine, N,N,N-trimethyl-4-hydroxytryptamine lysine (LSA), ergonovine, ergometrine, muscimol, ibotenic acid, lysergic acid hydroxyethylamide (LSH), lysine, ergonovine, or lysine, or any combination thereof.

[0178] In some embodiments, the second pharmaceutically active compound is administered simultaneously with the composition.

[0179] In some embodiments, the second pharmaceutically active compound is administered sequentially with the composition.

[0180] In some embodiments, the method further comprises administering a guiding therapy.

[0181] In some embodiments, the lead therapy is administered concurrently with the composition.

[0182] In some embodiments, the lead therapy and the composition are administered sequentially.

[0183] In some embodiments, the lead therapy is administered concurrently with the second pharmaceutically active compound.

[0184] In some embodiments, the lead therapy is administered sequentially with the second pharmaceutically active compound.

[0185] The following examples are provided to further illustrate embodiments of the present invention, but are not intended to limit the scope of the present invention. Although they are typical examples that may be used, other procedures, methods or techniques known to those skilled in the art may also be used instead.

[0186] Example

[0187] Example 1

[0188] Salt screening

[0189] Lyophilization / recrystallization: A physical mixture of dimethyl-4-hydroxytryptamine and psilocybin in a 1:1 ratio was prepared in water:acetonitrile (60:40 v / v) + 0.1% formic acid. The solution was divided into 11 vials to achieve a dimethyl-4-hydroxytryptamine content of 30 mg in each vial. The solvent was removed by freeze drying. The amorphous material obtained was then resuspended in 10 solvents and the samples were heated to 50°C and cooled to 5°C, with a constant heating rate of 10°C / h and variable cooling rates of -20°C / h, -10°C / h and -5°C / h from the first to the third cycle. After the temperature profile, the solids were collected in the environment and dried in vacuum and analyzed by XPRD. All solids were then exposed to 40°C / 75% RH (AAC) for 2 days and remeasured by XRPD. The results are shown in Table 1.

[0190] Table 1

[0191]

[0192]

[0193] pc = poor crystallization

[0194] Slurry conversion: A physical mixture of dimethyl-4-hydroxytryptamine and psilocybin in a molar ratio was prepared in an organic solvent mixture to form a suspension. The sample was heated to 50°C and cooled to 5°C, with a constant heating rate of 10°C / h and a variable cooling rate of -20°C / h, -10°C / h and -5°C / h from the first to the third cycle. The sample was then aged at RT for 72 hours. After the aging time, the solid was separated from the liquid phase by centrifugation and dried under ambient conditions and vacuum, and then analyzed by HT-XRPD. All solids were exposed at 40°C / 75% RH (AAC) for 2 days and re-measured by XRPD. The results are shown in Table 2.

[0195] Table 2

[0196]

[0197] pc = poor crystallization

[0198] Example 2

[0199] XRPD analysis

[0200] XRPD patterns were obtained using an Ardena T2 high throughput XRPD apparatus. The plates were mounted on a The gas area detector was measured on a Bruker Total Area Detector Diffraction System (GADDS) and corrected for intensity and geometric variations. The NIST SRM1976 standard (corundum) was used for calibration of measurement accuracy (peak position).

[0201] Data collection was performed at room temperature using monochromatic Cu Kα radiation in the 2θ region between 1.5° and 41.5°, which is the most distinctive part of the XRPD pattern. The diffraction pattern of each hole was collected in two 2θ ranges (1.5°≤2θ≤21.5° for the first frame and 19.5°≤2σ≤41.5° for the second frame), with an exposure time of 90 seconds per frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

[0202] The unit cell parameters and crystal system were obtained using the LSI Index (Coelho, 2003; Coelho & Kern, 2005) indexing program. The space group was selected based on the reflection conditions and crystal density. The unit cell parameters, purity and instrument parameters were refined using the full powder pattern decomposition method.

[0203] For Rietveld calculations, the unit cell parameters, crystal system and atomic positions were obtained from the single crystal file (cif). During the refinement process, the following parameters were refined: unit cell constants, background, instrument geometry, zero drift and absorption.

[0204] Neither atomic positions nor thermal parameters were refined during the entire process. The following fitting criteria were used:

[0205] Yo,m and Yc,m are the observed data and calculated data at data point m, respectively.

[0206] M is the number of data points,

[0207] P is the number of parameters,

[0208] wm is the weight given to data point m, which for counting statistics is given by wm=1 / σ(Yo,m)2, where σ(Yo,m) is the error in Yo,m,

[0209]

[0210] The XRPD of crystalline Form A from Experiment No. TCS2 is Figure 1 The peaks are shown in Table 3.

[0211] Table 3

[0212]

[0213]

[0214] The XRPD pattern of crystalline Form B from Experiment No. TCS24 is Figure 2 The peaks are shown in Table 4.

[0215] Table 4

[0216]

[0217]

[0218] The XRPD pattern of crystalline Form C from Experiment No. TCS26 is Figure 3 The peaks are shown in Table 5.

[0219] Table 5

[0220]

[0221] Example 3

[0222] TGMS and DSC analysis

[0223] The mass loss due to solvent or water loss from the crystal is determined by TGA / DSC. The sample weight is monitored during heating in a TGA / DSC 3+STARe system (Mettler-Toledo GmbH, Switzerland) to obtain a weight-equivalent temperature curve and a heat flow signal. The temperature of the TGA / DSC 3+ is calibrated with indium and aluminum samples. The sample (about 2 mg) is weighed into a 100 μL aluminum crucible and sealed. The seal is pierced with a pinhole and the crucible is heated from 25°C to 300°C in the TGA at a heating rate of 10°C min-1. Purge with dry N2 gas.

[0224] The gases from the TGA samples were analyzed by a mass spectrometer Omnistar GSD 350 (Pfeiffer Vacuum GmbH, Germany). The mass spectrometer was a quadrupole mass spectrometer that analyzed masses in the temperature range of 0-200 amu.

[0225] Thermal events were obtained from DSC thermograms, recorded with a heat flux DSC3+STARe system (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated for temperature and enthalpy using small pieces of indium (mp=156.6°C; δHf=28.45 J / g) and zinc (mp=419.6°C; δHf=107.5 J / g). The sample (about 2 mg) was sealed in a standard 40 μL aluminum pan, pierced with a pinhole, and heated from 25°C to 300°C in the DSC at a heating rate of 10°C / min. During the measurement, the DSC instrument was purged with dry N2 gas at a flow rate of 50 mL / min.

[0226] TGMS analysis of crystalline Form A showed a mass loss of 1.3% between 40 and 200°C due to residual ethanol / water. Thermal decomposition began above 200°C. The DSC trace showed that at 255.0°C (T onset 252.5℃) peak This corresponds to the melting of crystalline form A. The TGMS thermogram of crystalline form A is shown in Figure 4 As shown, the DSC thermogram of crystalline form A is as follows Figure 5 shown.

[0227] Based on the MS signal, TGMS analysis of crystalline Form B showed a mass loss of 15.8% due to TFE and toluene between 40 and 200°C. Thermal decomposition started above 200°C. The DSC trace showed that at 168.2°C (T onset 156.1℃) peak This corresponds to the desolvation of crystalline form B. The TGMS thermogram of crystalline form B is shown in Figure 6As shown, the DSC thermogram of crystalline form B is as follows Figure 7 as shown in .

[0228] Based on the MS signal, TGMS analysis of crystalline Form C showed a mass loss of 13.5% due to water between 40 and 160°C. Thermal decomposition started above 160°C. The DSC trace showed that the mass loss of crystalline Form C was 13.5% due to water between 40 and 160°C. The thermal decomposition started above 160°C. The DSC trace showed that the mass loss of crystalline Form C was 13.5% due to peak 98.7℃, T onset 84.7°C), which corresponds to the dehydration of crystalline form C. The TGMS thermogram of crystalline form C is shown in Figure 8 As shown, the DSC thermogram of crystalline form C is as follows Fig. 9 shown.

[0229] Example 4

[0230] NMR spectroscopy

[0231] D2O 1 H-NMR spectroscopy was used for compound integrity characterization of psilocybin and psilocybin-dimethyl-4-hydroxytryptamine polymorphs (crystalline form A and crystalline form B). Spectra were recorded on a 500 MHz instrument (Bruker BioSpin GmbH) at room temperature using standard pulse sequences. Data were processed using ACD Labs software Spectrus Processor 2016.2.2 (Advanced Chemistry Development Inc. Canada).

[0232] Fig.10 Superposition of crystalline form A and psilocybin 1 H-NMR, and Fig.11 Crystalline Form A and psilocybin were shown between 6 ppm and 7.5 ppm 1 H-NMR. Fig.12 Superposition of crystalline form A, crystalline form B and psilocybin 1 H-NMR, and Fig.13 The superposition of 6ppm to 7.5ppm of crystalline form A, crystalline form B and psilocybin 1 H-NMR.

[0233] Example 5

[0234] DVS Analysis

[0235] Hygroscopic isotherms were collected on a DVS Adventure system from Surface Measurement Systems (London, UK). The sample size was approximately 10 mg of solid material. Complete adsorption and desorption isotherms were recorded at a constant temperature of 25°C by varying the relative humidity from 40-95-0-40% in steps of 10%. The weight balance for each step was set to a dm / dt of 0.002% / min. The samples were then measured by HT-XRPD.

[0236] Crystalline Form A: The total mass difference between 0-95% RH was 3.6%, and the mass absorption at 80% RH was 2.4%, indicating that the material is moderately hygroscopic according to the EP hygroscopicity classification. Analysis of the solid recovered after DVS by XRPD analysis confirmed that PSY1 is physically stable after the adsorption-desorption cycle. The DVS isotherm of Crystalline Form A is shown in Figure 2. Fig.14 Drawn.

[0237] Crystalline Form B: The total mass difference between 0-95% RH was 8.0%, and the mass absorption at 80% RH was 4.3%, indicating that the material is moderately hygroscopic according to the EP hygroscopicity classification. Analysis of the solid recovered after DVS by XRPD analysis confirmed that PSY5 is physically stable after the adsorption-desorption cycle. The DVS isotherm of Crystalline Form B is shown in Fig.15 Drawn.

[0238] Crystalline Form C: The total mass difference between 0-95% RH was 16.4%, and the mass uptake at 80% RH was 1.8%, indicating that the material is slightly hygroscopic according to the EP hygroscopicity classification. Analysis of the solid recovered after DVS by XRPD confirmed that Crystalline Form C is physically stable after adsorption-desorption cycles. The gradual water uptake between 20-95% RH was 5.2%, which corresponds to 1.5 water molecules. The DVS isotherm of Crystalline Form C is shown in Figure 2. Fig.16 Drawn.

[0239] Example 6

[0240] UPLC analysis

[0241] UPLC analysis method

[0242] UPLC System:

[0243] UPLC: Agilent 1290

[0244] Detector 1: UV detector set to 267nm

[0245] Detector 2: MSD XT in positive scan mode

[0246] UPLC conditions:

[0247] Autosampler temperature: RT

[0248] ·Column: ACE Avanor C18-PVP (100x 2.1mm; 1.7μm)

[0249] Column temperature: 40℃

[0250] ·gradient:

[0251] Mobile phase A: 0.7 g ammonium formate in 0.1% formic acid in water

[0252] Mobile phase B: 0.1% formic acid in methanol

[0253] Flow: 0.27mL / min

[0254] Running time: 25 minutes

[0255] ·gradient:

[0256]

[0257]

[0258] Sample preparation:

[0259] Concentration: about 1.0 mg / mL

[0260] Solvent: water: acetonitrile (60:40 v / v) + 0.1% formic acid

[0261] Injection volume: 1μl

[0262] Crystalline Form A: Prepare a reference solution of dimethyl-4-hydroxytryptamine at a concentration of about 1 mg / ml. Prepare a solution of about 2 mg / ml of Crystalline Form A in ACN / water 40 / 60% v / % v + 0.01% formic acid. The stoichiometry (psilocybin: dimethyl-4-hydroxytryptamine) of Crystalline Form A was determined to be 1:1. The HPLC chromatogram is shown in Fig.17 shown.

[0263] Crystalline Form B: A reference solution of psilocybin was prepared at a concentration of approximately 1 mg / ml. A solution of crystalline Form B was prepared at approximately 2 mg / ml in ACN / water 40 / 60% v / % v + 0.01% formic acid. Using equation (1) presented below, the stoichiometry of crystalline Form B (psilocybin: psilocybin) was determined to be 1.3:1. The HPLC chromatogram is shown in Fig.18 shown.

[0264] Crystalline Form C: Prepare a reference solution of dimethyl-4-hydroxytryptamine at a concentration of about 1 mg / ml. Prepare a solution of crystalline Form C at about 2 mg / ml in ACN / water 40 / 60% v / % v + 0.01% formic acid. The stoichiometry (psilocybin: dimethyl-4-hydroxytryptamine) of crystalline Form C was determined to be 1:1. The HPLC chromatogram is shown in Fig.19 shown.

[0265] Example 7

[0266] Crystal structure

[0267] High-resolution X-ray powder diffraction (HR-XRPD): using Cu Kα1 radiation HR-XRPD data of crystalline form A were collected on a D8Advance diffractometer with a germanium monochromator at RT. Diffraction data were collected in a 2θ range of 2.15-41.5°. Detector scanning was performed on a solid-state LynxEye detector using 0.0157° per step at a scan rate of 5 seconds per step. The sample was measured in an 8 mm long glass capillary with an outer diameter of 0.3 mm. Before being transferred to the capillary, the analyzed solid (from Example 1 Experiment No. TCS2) was ground in an agate mortar until all visible crystals disappeared and the material became a fine powder.

[0268] The unit cell parameters and crystal system were obtained using the LSI Index indexing program. The space group was selected based on the reflection conditions and crystal density. The unit cell parameters, purity and instrument parameters were refined using the full powder pattern decomposition method.

[0269] The structure was solved using the simulated annealing technique implemented in TOPAS6. For both components, hydroxytryptamine and psilocybin, Z_Matrix models were created using cif files from the Cambridge Structural Database, with CCDC1238288 for hydroxytryptamine and CCDC2128419 for psilocybin.

[0270] Rietveld refinement was performed using TOPAS6 (Bruker, 2017). All bond distances and angles were fixed, except for the following torsion angles (C6-O5-P4-O2; C16-C15-C13-C14; C25-C24-N23-C22; C26-C25-C24-N23), for which only rotation and translation of the molecule were allowed.

[0271] The following fitting criteria were used:

[0272] Yo,m and Yc,m are the observed and calculated data at data point m, respectively.

[0273] M is the number of data points

[0274] P is the number of parameters

[0275] wm is the weight given to data point m, which for count statistics is given by wm = 1 / σ(Yo,m)2, where σ(Yo,m) is the error in Yo,m

[0276]

[0277] The structure was determined using the simulated annealing method, in which a rigid body was allowed to rotate and translate freely within the unit cell for both molecules. In addition, the torsion angles of the phosphate and the two amine groups were considered as variables. After obtaining a chemically plausible solution, the model was refined using the Rietveld algorithm.

[0278] Based on the reflection conditions, crystalline form A crystallized in an orthorhombic primitive space group, and the result of simulated annealing P212121 space group was finally selected. Table 6 presents the final crystal and refinement data of the selected model.

[0279] Table 6: Solid crystal data and final Rietveld parameters for psilocybin polymorphic form A.

[0280]

[0281] The solution shows that there is a single SS-psilocybin pair in the asymmetric unit and no additional solvent or API molecules. All x, y, z positions of atoms can be found. Fig. 20 The molecular structure of serotonin-psilocybin in crystalline form A is presented. It can be seen that the phosphate group of psilocybin interacts directly with the N amine atom of serotonin. The crystals are held together by an extensive network of intermolecular hydrogen bonds, with each non-protonated O or N atom acting as an acceptor and each NH and OH acting as a donor. Table 7 presents the geometries of all hydrogen bonds found in the analyzed crystals.

[0282] Table 7: Hydrogen bonds found in methyl-4-hydroxytryptamine-psilocybin crystals of crystalline form A

[0283]

[0284] Symmetric transformation: (i)1-x,y-0.5,1.5-z; (ii)x-1,y,z; (iii)-x,0.5+y,0.5-z; (iv)0.5-x,-y,0.5+z; (v)0.5-x,1-y,0.5+z

[0285] The hydrogen-bonded network of crystalline form A forms a layered structure in which alternating layers are built up of dimethyl-4-HT and psilocybin molecules. These layers are parallel to the ab plane, such as Fig.21 The presented.

[0286] Table 8 shows the atomic coordinates and equivalent isotropic displacement parameters of the non-hydrogen atoms of Form A U(eq) is defined as one third of the orthogonalized Uij tensor trajectory.

[0287] Table 8

[0288]

[0289]

[0290] Table 9 shows the hydrogen coordinates and isotropic displacement parameters of Form A. U(eq) is defined as one third of the orthogonalized Uij tensor trajectory.

[0291] Table 9

[0292]

[0293]

[0294] Fig. 22 A graphical representation of the final cycle of the Rietveld refinement is shown, which confirms that the model fits the collected diffraction pattern of crystalline Form A very well.

[0295] Example 8

[0296] Ca 2+ Release test

[0297] AequoScreen CHO-K1 cells stably expressing h5HT2a contain aequorin, which is activated when combined with Ca 2+ When bound, it catalyzes the decomposition of coelenterazine molecules to produce light. The level of light emitted is related to the endoplasmic reticulum Ca 2+ CHO-K1 cells were treated with 0.1 nM-10 μM of each compound for 1 min before recording chemiluminescence. The resulting data were then fitted to a three-parameter nonlinear regression to determine potency (EC 50 ) and efficacy (E max ). The result is Fig.23 Data were fitted to a three-parameter nonlinear regression in GraphPad (v.9). n = 3-29 independent experiments performed in duplicate or triplicate. Data are presented as mean ± SEM. EC 50 and E max Reported in Table 10.

[0298] Table 10

[0299]

[0300] Dimethyl-4-hydroxytryptamine is Ca 2+ A 1:1 equimolar mixture of dimethyl-4-HT and psilocybin produced a Ca release intermediate between that of either compound alone. 2+ Release the response.

[0301] Example 9

[0302] βarrestin2 recruitment assay

[0303] CHO-K1 cells expressed h5HT2a-smBiT and βarrestin2-lgBiT fusion proteins. When h5HT2a and βarrestin2 come into contact with each other, the smBiT and lgBiT peptides complement each other to produce the complete NanoBit luciferase. When completed, the enzyme is able to catalyze the breakdown of the molecule coelenterazine to produce light. The level of light emitted is proportional to the interaction between h5HT2a and βarrestin2. CHO-K1 cells were treated with 0.1nM-10μM of each compound for 2 hours, during which time chemiluminescence was recorded. The area under the curve data for the cumulative chemiluminescence was then fit to a three-parameter nonlinear regression to determine the potency (EC 50 ) and efficacy (E max ). The result is Fig.24 Data were fitted to a three-parameter nonlinear regression in GraphPad (v.9). n = 3-13 independent experiments performed in duplicate or triplicate. Data are presented as mean ± SEM. EC 50 and E max Reported in Table 11.

[0304] Table 11

[0305] Compound pEC50±SEM(EC50 nM) Emax(%)±SEM n LSD 7.8±0.50(16) 100±16 13 5HT 7.6±1.1(28) 81±35 3 Dimethyl-4-hydroxytryptamine 7.7±0.67(22) 89±22 4 Psilocybin No convergence -34±5.9 3 Norpsilocin 8.6±1.7(2.4) 2.9±27 3 Ergotamine 8.1±1.0(7.3) 106±25 3 LSD 7.8±0.50(16) 100±16 13

[0306] Dimethyl-4-HT is an activator of β-arrestin2 recruitment. Psilocybin is not a potent or effective activator of β-arrestin2 recruitment. Dimethyl-4-HT and psilocybin are active in Ca 2+ The potency was greater in the release assay than in the βarrestin2 recruitment assay.

[0307] Example 10

[0308] βarrestin2 recruitment assay

[0309] CHO-K1 cells stably expressing h5HT2a were grown, harvested, and frozen at -80°C. Cells were thawed as needed and pressure cavitation was performed using a Dounce homogenizer to rupture the cell membranes. Cell membranes were then collected by high-speed centrifugation of the cell lysate at 20,000 x g for 30 minutes at 4°C. Homogenization and centrifugation were repeated to enrich the sample for cell membranes containing the receptor. CHO-K1 cell membranes were homogenized with 1 nM [ 3 H] Ketanserin and 0.1 nM-10 μM of each compound were co-incubated for 2 hours. The samples were then pipetted onto filter paper and then rinsed and washed three times by vacuum filtration, dried, and incubated overnight in scintillation fluid. The remaining bound radioactivity was then read on a liquid scintillation counter and normalized to the maximum LSD response (i.e., 0%). The resulting data were then fitted to a three-parameter nonlinear regression to determine the affinity (Ki). The results are shown in Fig.25 Data were fitted to a three-parameter nonlinear regression in GraphPad (v.9). n = 3-6 independent experiments. Data are presented as mean ± SEM. EC 50 and E max Reported in Table 12.

[0310] Table 12

[0311] Compound <![CDATA[pK i ±S.E.M.(K i nM)]]> n LSD 7.4±0.16(36) 6 5HT 7.5±0.17(34) 3 Dimethyl-4-hydroxytryptamine 8.5±0.26(3.4) 6 Psilocybin 6.4±0.34(390) 3 Ergotamine 6.9±0.55(110) 5

[0312] Embodiment 11

[0313] Physiology: rigidity, temperature, and nociception

[0314] C57BL / 6 mice are treated with increasing doses of compound via ip injection as indicated. Testing is as follows: Body temperature is measured as a baseline before the first dose of compound is administered. Freezing - Rod holding test, 10 minutes after compound administration. The mouse is placed with its front paws clamped around a 0.7 cm ring clamp located 4.5 cm above the surface of the testing space. The length of time the ring is held is recorded (seconds). The test is terminated if the mouse turns its head or body, or makes 3 consecutive escape attempts, up to a maximum of 60 seconds. Nociception - 15 minutes after compound administration, the mouse's tail is placed in 52°C water. The latency to remove the tail from the water is recorded, up to a maximum of 20 seconds. Body temperature - Rectal thermometer 20 minutes after administration. Results are in Fig.26 The data were plotted in GraphPad (v.9). n≥6 animals per dose. The data are presented as mean ± SEM.

[0315] 4-HT and psilocybin did not produce catalepsy. No freezing behavior or seizures were expected with any of the drugs or combinations. 4-HT and psilocybin produced dose-dependent hypothermia. Finally, 4-HT significantly reduced pain perception, peaking at 1 mg / kg.

[0316] Example 12

[0317] Rodent Hallucination Models: Head Twitch Response (HTR)

[0318] C57BL / 6 mice were treated with increasing doses of compound via ip injection as indicated. Mice were placed in a transparent cylinder and video recorded for 10 minutes immediately after compound administration. Head twitches were recorded by individuals blinded to the treatment as lateral rhythmic head shaking, distinct from grooming or vertical nodding. Results are shown in Fig. 27 Data were plotted in GraphPad (v.9). n≥3 animals per dose. Data are presented as mean ± SEM.

[0319] As models of hallucinations or dissociation in rodents, dimethyl-4-hydroxytryptamine and psilocybin produce a time-dependent head-twitch response. At several doses tested, the peak effect appears to occur 3-4 minutes after compound administration. In contrast, the peak effect of LSD appears to be around 7 minutes after administration.

[0320] Embodiment 13

[0321] Movement Effects: Open Field Task (OFT)

[0322] As indicated, C57BL / 6 mice were treated with increasing doses of compound via ip injection. 30 minutes after compound administration, mice were placed in an open field. The dimensions of the open field were 1 m x 1 m, and the test lasted for 5 minutes. Total distance traveled, speed, and time spent in the center quadrant of the field were recorded and analyzed using EthoVision XT (Noldus, v.17). The results are shown in Fig.28 Data were plotted in GraphPad (v.9). n≥4 animals per dose. Data are presented as mean ± SEM.

[0323] Both 4-HT and psilocybin produced dose-dependent decreases in locomotion, speed, and time in the center of the open field, with significant effects on locomotion and speed but not time in the center at the highest doses tested (i.e., 7 or 10 mg / kg).

[0324] Embodiment 14

[0325] Cognitive performance and anxiety: elevated plus maze (EPM)

[0326] C57BL / 6 mice were treated with 3 mg / kg of compound via ip injection. Mice were placed in the EPM 30 minutes after compound administration. The dimensions of the EPM were 1 m x 1 m and the test lasted 5 minutes. Total distance traveled, speed, arm entries, and time in each arm were recorded and analyzed using EthoVision XT (Noldus, v.17). The results are shown in Fig.29 Data were plotted in GraphPad (v.9). n = 3-5 animals per treatment. Data are presented as mean ± SEM.

[0327] Based on preliminary evidence requiring additional animals, 3 mg / kg ip dimethyl-4-HT significantly reduced closed arm time (p=0.029, unpaired t-test) but not open arm time (p=0.12, unpaired t-test); arm entries were not significantly different. The data showed a trend toward a decrease in overall locomotion and speed, consistent with the OFT data.

[0328] Embodiment 15

[0329] Pharmacokinetics (PK)

[0330] Dimethyl-4-hydroxytryptamine D-10 was prepared as an internal standard for the quantification of dimethyl-4-hydroxytryptamine in mouse plasma samples ( Fig.30 , top left), compounds were quantified by high performance liquid chromatography tandem mass spectrometry (HPLC-MS / MS) (AB SciEx 4000 ) for voltage ( Fig.30 , top right), organic solvents (80% methanol + 0.1% formic acid, 90% methanol + 0.1% formic acid, 100% methanol + 0.1% formic acid, 90% acetonitrile + 0.1% formic acid or 100% methanol + 0.10% formic acid) ( Fig.30 The injection volume and flow rate were optimized and a standard curve was created ( Fig.30 , top middle right). The organic solvent selected was 100% acetonitrile + 0.1% formic acid ( Fig.30 , middle upper right red line) because it shows the largest signal-to-noise ratio and the narrowest peak; the optimal injection volume and flow rate are 5 μL at 0.2 mL / min. The fragmentation pattern and mass-to-charge ratio (m / z) of dimethyl-4-hydroxytryptamine D-10 were determined ( Fig.30 , lower middle left). A standard curve for the detection of dimethyl-4-hydroxytryptamine in mouse plasma was constructed, with the upper and lower quality controls set at 2.5 ng / mL and 400 ng / mL, respectively ( Fig.30 , middle lower right).

[0331] Example 16

[0332] Neurogenesis and plasticity in healthy brain organoids

[0333] The effects of 16, 50, 160, 500, and 1600 nM psilocybin, dimethyl-4-HT, or a 1:1 molar ratio of psilocybin + dimethyl-4-HT after a single exposure (6 hours followed by washout) were measured in three experiments starting with control brain organoids and validating the results in patient-derived organoids.

[0334] 3-month-old human brain organoids were exposed to EdU pulses 6 hours after the final drug treatment. Newborn neurons were quantified (i.e. EdU+ / NeuN+ / EdU+) to determine the extent of neurogenesis. Ki67+ / Sox2+ co-labeling was used to investigate changes in the progenitor pool. EdU+ / NeuN+ / EdU+ data are shown in Fig.31 , Ki67+ data are shown in Fig.32 , Sox2-positive cell data are shown in Fig.33 .

[0335] Three-month-old organoids were exposed to psilocybin or 4-HT or psilocybin + 4-HT at a 1:1 molar ratio for 6 h and then cut into small pieces and mounted on Matrigel. TM The plates were placed for 2 days. TUJ1 was used to label neurite outgrowth and its length (μm) and number of branches were quantified. The results of neurite outgrowth are shown in Fig.34 middle.

[0336] Treatment with psilocybin + dimethyl-4-HT in a 1:1 molar ratio combination was found to result in an approximately 20% increase in neurogenesis 6 hours after a single administration, with a corresponding decrease in proliferation. The 1:1 molar ratio combination of psilocybin + dimethyl-4-HT was observed to have the greatest neuronal length two days after administration, approximately doubling at the highest dose, greater than psilocybin alone.

[0337] Although the present invention has been described with reference to the above embodiments, it should be understood that modifications and variations are also encompassed within the spirit and scope of the present invention. Therefore, the present invention is limited only by the appended claims.

Claims

1. A crystalline form of a composition comprising dimethylserotonin and psilocybin:

2. The crystalline form of claim 1, wherein the crystalline form is Form A.

3. The crystalline form of claim 2, wherein Form A is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 10.1°.

4. The crystalline form of claim 3, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 19.16°.

5. The crystalline form of claim 4, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 10.74°, about 25.3°, and about 24.07°.

6. The crystalline form of claim 5, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°.

7. The crystalline form of claim 2, wherein Form A is characterized by a DSC trace comprising a sharp endothermic event at a temperature of about 255°C.

8. The crystalline form of any one of claims 2-7, wherein the ratio of psilocybin in Form A to dimethyl-4-hydroxytryptamine is about 1:

1.

9. The crystalline form of any one of claims 2-8, wherein the chemical purity of Form A is about 95% or greater.

10. The crystalline form of any one of claims 2-9, wherein Form A contains no more than about 5 mol% of other solid forms.

11. The crystalline form according to any one of claims 2 to 10, wherein Form A is a salt formed between dimethylserotonin and psilocybin.

12. The crystalline form of claim 1, wherein the crystalline form is Form B.

13. The crystalline form of claim 12, wherein Form B is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 18.54°.

14. The crystalline form of claim 13, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 8.54°.

15. The crystalline form of claim 14, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 22.78°, about 14.27°, and about 21.12°.

16. The crystalline form of claim 15, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02°.

17. The crystalline form of claim 12, wherein Form B is characterized by a DSC trace comprising a broad endothermic event at a temperature of about 168.2°C.

18. The crystalline form of any one of claims 12-17, wherein the ratio of psilocybin in Form B to dimethylserotonin is about 1.3:

1.

19. The crystalline form of any one of claims 12-18, wherein the chemical purity of Form B is about 95% or greater.

20. The crystalline form of any one of claims 12-19, wherein Form B contains no more than about 5 mol% of other solid forms.

21. The crystalline form according to any one of claims 12-20, wherein Form B is a salt formed between dimethylserotonin and psilocybin.

22. The crystalline form of claim 1, wherein the crystalline form is Form C.

23. The crystalline form of claim 22, wherein Form C is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 9.18°.

24. The crystalline form of claim 23, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 17.95°.

25. The crystalline form of claim 24, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 10.42°, about 24.22°, and about 18.38°.

26. The crystalline form of claim 25, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°.

27. The crystalline form of claim 22, wherein Form C is characterized by a DSC trace comprising a broad endothermic event at temperatures between about 25-140°C, with a peak at 98.7°C.

28. The crystalline form of any one of claims 22-27, wherein the ratio of psilocybin in Form C to dimethyl-4-hydroxytryptamine is about 1:

1.

29. The crystalline form of any one of claims 22-28, wherein the chemical purity of Form C is about 95% or greater.

30. The crystalline form of any one of claims 22-29, wherein Form C contains no more than about 5 mol% of other solid forms.

31. The crystalline form of any one of claims 22-30, wherein Form C is a salt formed between dimethylserotonin and psilocybin.

32. A pharmaceutical composition comprising a crystalline form of a composition comprising dimethyl-4-hydroxytryptamine and psilocybin and a pharmaceutically acceptable excipient 33. The pharmaceutical composition of claim 32, wherein the crystalline form is Form A.

34. The pharmaceutical composition of claim 33, wherein Form A is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 10.1°.

35. The pharmaceutical composition of claim 34, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 19.16°.

36. The pharmaceutical composition of claim 35, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 10.74°, about 25.3°, and about 24.07°.

37. The pharmaceutical composition of claim 36, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°.

38. The pharmaceutical composition of any one of claims 33-37, wherein the ratio of psilocybin in Form A to dimethyl-4-hydroxytryptamine is about 1:

1.

39. The pharmaceutical composition of any one of claims 33-38, wherein the chemical purity of Form A is about 95% or greater.

40. The pharmaceutical composition of any one of claims 33-39, wherein Form A is a salt formed between dimethylserotonin and psilocybin.

41. The pharmaceutical composition of claim 32, wherein the crystalline form is Form B.

42. The pharmaceutical composition of claim 41, wherein Form B is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 18.54°.

43. The pharmaceutical composition of claim 42, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 8.54°.

44. The pharmaceutical composition of claim 43, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 22.78°, about 14.27°, and about 21.12°.

45. The pharmaceutical composition of claim 44, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02°.

46. ​​The pharmaceutical composition of any one of claims 41-45, wherein the ratio of psilocybin in Form B to dimethylserotonin is about 1.3:

1.

47. The pharmaceutical composition of any one of claims 41-46, wherein the chemical purity of Form B is about 95% or greater.

48. The pharmaceutical composition of any one of claims 41-47, wherein Form B is a salt formed between dimethylserotonin and psilocybin.

49. The pharmaceutical composition of claim 32, wherein the crystalline form is Form C.

50. The pharmaceutical composition of claim 49, wherein Form C is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 9.18°.

51. The pharmaceutical composition of claim 50, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 17.95°.

52. The pharmaceutical composition of claim 51, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 10.42°, about 24.22°, and about 18.38°.

53. The pharmaceutical composition of claim 52, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°.

54. The pharmaceutical composition of any one of claims 49-53, wherein the ratio of psilocybin in Form C to dimethylserotonin is about 1:

1.

55. The pharmaceutical composition of any one of claims 49-54, wherein the chemical purity of Form C is about 95% or greater.

56. The pharmaceutical composition of any one of claims 49-55, wherein Form C is a salt formed between dimethylserotonin and psilocybin.

57. A composition comprising 4-hydroxytryptamine and a crystalline form of psilocybin: wherein the crystalline form is Form A, Wherein crystalline Form A is characterized by unit cell parameters substantially equal to the following: Unit cell size: α=90 degrees β=90 degrees γ=90 degrees Space group = P212121 Molecule / asymmetric unit=1.

58. The composition of claim 57, wherein the unit cell parameters of crystalline Form A are measured at about 296K.

59. The composition of claim 57, wherein crystalline Form A has a hydrogen bonding geometry substantially as set forth in Table A.

60. The composition of claim 57, wherein crystalline Form A has atomic coordinates for non-hydrogen atoms substantially as listed in Table B.

61. The composition of claim 57, wherein crystalline Form A has atomic coordinates of hydrogen atoms substantially as listed in Table C.

62. A pharmaceutical composition comprising a crystalline form of dimethylserotonin and psilocybin and a pharmaceutically acceptable excipient wherein the crystalline form is crystalline Form A; and Wherein crystalline Form A is characterized by unit cell parameters substantially equal to the following: Unit cell size: α=90 degrees β=90 degrees γ=90 degrees Space group = P212121 Molecule / asymmetric unit=1.

63. The pharmaceutical composition of claim 62, wherein the unit cell parameters of crystalline Form A are measured at about 296K.

64. The pharmaceutical composition of claim 62, wherein crystalline Form A has a hydrogen bonding geometry substantially as set forth in Table A.

65. The pharmaceutical composition of claim 62, wherein crystalline Form A has atomic coordinates of non-hydrogen atoms substantially as listed in Table B.

66. The pharmaceutical composition of claim 62, wherein crystalline Form A has atomic coordinates of hydrogen atoms substantially as listed in Table C.

67. A method of treating or ameliorating a disease or disorder comprising administering to a subject a crystalline form of a composition comprising dimethyl-4-hydroxytryptamine and psilocybin The disease or disorder is thereby treated.

68. The method of claim 67, wherein the disease or disorder is selected from a mental health disorder or a central nervous system (CNS) disorder.

69. The method of claim 68, wherein the mental health disorder is selected from the group consisting of a depressive disorder, an anxiety disorder, post-traumatic stress disorder, and an addiction disorder.

70. The method of claim 69, wherein the mental health disorder is a depressive disorder.

71. The method of claim 69, wherein the mental health disorder is an anxiety disorder.

72. The method of claim 68, wherein the CNS disorder is a chronic pain disorder.

73. A method of stimulating neurogenesis or neurite outgrowth comprising administering to a subject a composition comprising dimethyl-4-hydroxytryptamine and a crystalline form of psilocybin Thereby stimulating neurogenesis.

74. The method of claim 73, wherein stimulating neurogenesis or neurite outgrowth results in an increase in neuronal length.

75. The method of claim 73, wherein stimulating neurogenesis or neurite outgrowth results in an improvement in impaired cognitive performance or other neurological aspects associated with a central nervous system disorder.

76. The method of claim 75, wherein the disorder of the central nervous system is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Alzheimer's disease, Pick's disease, Parkinson's dementia syndrome, progressive subcortical gliosis, progressive supranuclear palsy, thalamic degeneration syndrome, hereditary aphasia, myoclonic epilepsy, sleep deprivation, depression, stroke, ischemia, brain trauma, psychological and physical trauma, chronic pain of any cause, cognitive impairment, and cognitive decline.

77. The method of claims 67-76, wherein the crystalline form is Form A.

78. The method of claim 77, wherein Form A is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 10.1°.

79. The method of claim 78, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 19.16°.

80. The method of claim 79, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 10.74°, about 25.3°, and about 24.07°.

81. The method of claim 80, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°.

82. The method of claim 77, wherein Form A is characterized by a DSC trace comprising a sharp endothermic event at a temperature of about 255°C.

83. The method of any one of claims 77-82, wherein the ratio of psilocybin in Form A to dimethyl-4-hydroxytryptamine is about 1:

1.

84. The method of any one of claims 77-83, wherein the chemical purity of Form A is about 95% or greater.

85. The method of any one of claims 77-84, wherein Form A contains no more than about 5 mol% of other solid forms.

86. The method of any one of claims 77-85, wherein Form A is a salt formed between dimethylserotonin and psilocybin.

87. The method of claims 67-76, wherein the crystalline form is Form B.

88. The method of claim 87, wherein Form B is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 18.54°.

89. The method of claim 88, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 8.54°.

90. The method of claim 89, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 22.78°, about 14.27°, and about 21.12°.

91. The method of claim 90, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02°.

92. The method of claim 87, wherein Form B is characterized by a DSC trace comprising a broad endothermic event at a temperature of about 168.2°C.

93. The method of any one of claims 87, wherein the ratio of psilocybin in Form B to dimethyl-4-hydroxytryptamine is about 1.3:

1.

94. The method of any one of claims 87-92, wherein Form B has a chemical purity of about 95% or greater.

95. The method of any one of claims 87-93, wherein Form B contains no more than about 5 mol% of other solid forms.

96. The method of any one of claims 87-94, wherein Form B is a salt formed between dimethylserotonin and psilocybin.

97. The method of claims 67-76, wherein the crystalline form is Form C.

98. The method of claim 97, wherein Form C is characterized by an XRPD pattern comprising a significant peak at an angle 2θ of about 9.18°.

99. The method of claim 98, wherein the XRPD pattern further comprises a significant peak at an angle 2θ of about 17.95°.

100. The method of claim 99, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 10.42°, about 24.22°, and about 18.38°.

101. The method of claim 100, wherein the XRPD pattern further comprises significant peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°.

102. The method of claim 97, wherein Form C is characterized by a DSC trace comprising a broad endothermic event at temperatures between about 25-140°C, with a peak at 98.7°C.

103. The method of any one of claims 97-102, wherein the ratio of psilocybin in Form C to dimethyl-4-hydroxytryptamine is about 1:

1.

104. The method of any one of claims 97-103, wherein the chemical purity of Form C is about 95% or greater.

105. The method of any one of claims 97-104, wherein Form C contains no more than about 5 mol% of other solid forms.

106. The method of any one of claims 97-105, wherein Form C is a salt formed between dimethylserotonin and psilocybin.

107. The method of claims 67-106, wherein the composition further comprises a pharmaceutically acceptable excipient.

108. The method of claims 67-107, wherein the composition is administered by an intradermal, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual, buccal, or nasal route of administration.

109. The method of claims 67-108, further comprising administering a second pharmaceutically active compound.

110. The method of claim 109, wherein the second pharmaceutically active compound is one or more of an antianxiety drug, an antidepressant drug, or an analgesic drug.

111. The method of claim 109, wherein the second pharmaceutically active compound is psilocybin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, toad tryptamine, toad tenidine, 5-MeO-DMT (5-methoxy-NN-dimethyltryptamine), N,N-dimethyltryptamine (DMT), 4-hydroxytryptamine, N,N,N-trimethyl-4-hydroxytryptamine sedative (LSA), ergonovine, ergometrine, muscimol, ibotenic acid, lysergic acid hydroxyethylamide (LSH), sedative, ergonovine, or sedative, or any combination thereof.

112. The method of claim 109, wherein the second pharmaceutically active compound is administered simultaneously with the composition.

113. The method of claim 109, wherein the second pharmaceutically active compound is administered sequentially with the composition.

114. The method of claims 67-111, further comprising administering a guided therapy.

115. The method of claim 114, wherein the directed therapy is administered concurrently with the composition.

116. The method of claim 114, wherein the lead-in therapy is administered sequentially with the composition.

117. The method of claim 114, wherein the directed therapy is administered concurrently with the second pharmaceutically active compound.

118. The method of claim 114, wherein the lead therapy is administered sequentially with the second pharmaceutically active compound.

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