Composition and Use of Sirobin and Cyrosine

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 silybin and silibinin. The present disclosure further provides a method of stimulating neurogenesis or neurite outgrowth to effect an increase in the length of nerve cells.

Description

Technical Field

[0001] The present invention relates to crystalline forms of compounds of psilocybin and psilocin, and to 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 natural plants and fungi contain compounds with hallucinogenic effects ( "neuroactive" compounds) that can cause changes in brain function or activity, and may cause hallucinations or similar experiences in an individual ( "hallucinogenic" compounds). The most common naturally occurring hallucinogen is psilocybin, which has been found in over 180 species of mushrooms worldwide. Mushrooms containing psilocybin also contain other neuroactive and hallucinogenic compounds, the most abundant of which is psilocin, the main metabolite of psilocybin. In the human body, psilocybin is mainly metabolized to psilocin in the digestive system, which is then absorbed and causes hallucinogenic effects.

[0003] These hallucinogenic effects are dose-dependent and usually involve changes in visual, auditory, and cognitive experiences. These psilocybin experiences may occur because both psilocybin and psilocin are structurally similar to the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) and both bind to various 5-HT receptors.

[0004] In contrast to psilocybin, psilocin is chemically unstable and rapidly oxidizes when exposed to air. For this reason, few clinical or investigational studies have been conducted on the effects of administering psilocin alone or in comparison to psilocybin. Preclinical studies that have been conducted suggest that psilocin has a faster absorption rate and onset of action than psilocybin. Psilocin binds to a different range of 5-HT receptors at different concentrations, resulting in a different range of effects.

[0005] Since the properties of silibinin and silybin are different, a compound combining both silibinin and silybin can be expected to have unique beneficial properties compared to the case of only one of the compounds.

[0006] Hallucinogens such as silibinin and silybin have been suggested to be effective in the treatment of certain mental health and central nervous system diseases. This is particularly thought to be the case for disorders that are 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] There is a need for new treatments for a wide variety of mental health and central nervous system diseases. One such treatment could potentially be crystalline forms of silibinin and silybin, particularly for use in diseases that are currently resistant to treatment.

Summary of the Invention

[0008] The present disclosure provides crystalline forms of silybin and silibinin:

Chemical

[0009] In this specification, they are described and identified as Crystal Form A, B, and C. Crystal Form A is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 10.1°. The XRPD pattern of Crystal Form A may further include a prominent peak at a 2θ angle of about 19.16°. The XRPD pattern of Crystal Form A may further include prominent peaks at 2θ angles of about 10.74°, about 25.3°, and about 24.07°. Further, the XRPD pattern of Crystal Form A may further include prominent peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. Crystal Form B may be characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 18.54°. The XRPD pattern of Crystal Form B may further include a prominent peak at a 2θ angle of about 8.54°. The XRPD pattern of Crystal Form B may further include prominent peaks at 2θ angles of about 22.78°, about 14.27°, and about 21.12°. Further, the XRPD pattern of Crystal Form B may further include prominent peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94°, and about 25.02°. Crystal Form C may be characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 9.18°. The XRPD pattern of Crystal Form C may further include a prominent peak at a 2θ angle of about 17.95°. The XRPD pattern of Crystal Form C may further include prominent peaks at 2θ angles of about 10.42°, about 24.22°, and about 18.38°. Further, the XRPD pattern of Crystal Form C may further include prominent peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°.

[0010] In one embodiment, the present application provides a pharmaceutical composition comprising a crystalline form of silosine and silibinin, 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 by an XRPD pattern comprising a prominent peak at a 2θ angle of about 10.1°, said XRPD pattern further comprising prominent peaks at 2θ angles of about 19.16°, about 10.74°, about 25.3° and about 24.07°, and / or said XRPD pattern further comprising prominent peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42° and about 8.62°. In one embodiment, crystalline Form A has a ratio of silibinin to silosine of about 1:1. In one embodiment, crystalline Form A has a chemical purity of about 95% or more. In some embodiments, crystalline Form A comprises about 5 mol% or less of other solid forms. In some embodiments, said composition of crystalline Form A of silosine and silibinin comprises about 95 mol% of crystalline Form A, about 2.5 mol% of silosine, and about 2.5 mol% of silibinin. In one embodiment, crystalline Form A is a co-crystal formed between silosine and silibinin. In one embodiment, crystalline Form A is a salt formed between silosine and silibinin.

[0011] In some embodiments, the crystalline Form B is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 18.54°, said XRPD pattern further including a prominent peak at a 2θ angle of about 8.54°, said XRPD pattern further including prominent peaks at 2θ angles of about 22.78°, about 14.27° and about 21.12°, and / or said XRPD pattern further including prominent peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94° and about 25.02°. In one embodiment, the crystalline Form B has a ratio of syrosingopine to syrosingopyranoside of about 1.3:1. In one embodiment, the crystalline Form B has a ratio of syrosingopine to syrosingopyranoside of about 1:1. In one embodiment, the crystalline Form B has a chemical purity of about 95% or greater. In some embodiments, the crystalline Form B comprises about 5 mol% or less of other solid forms. In some embodiments, the composition of the crystalline Form B of syrosingopine and syrosingopyranoside comprises about 95 mol% of the crystalline Form B, about 2.5 mol% of syrosingopine, and about 2.5 mol% of syrosingopyranoside. In one embodiment, the crystalline Form B is a eutectic formed between syrosingopine and syrosingopyranoside. In one embodiment, the crystalline Form B is a salt formed between syrosingopine and syrosingopyranoside.

[0012] In some embodiments, polymorph C is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 9.18°, said XRPD pattern further including a prominent peak at a 2θ angle of about 17.95°, said XRPD pattern further including prominent peaks at 2θ angles of about 10.42°, about 24.22° and about 18.38°, and / or said XRPD pattern further including prominent peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38° and about 14.06°. In one embodiment, polymorph C has a ratio of syringobin to syringosine of about 1:1. In one embodiment, polymorph C has a chemical purity of about 95% or more. In some embodiments, polymorph C contains about 5 mol% or less of other solid forms. In some embodiments, said composition of polymorph C of syringosine and syringobin contains about 95 mol% of polymorph C, about 2.5 mol% of syringosine, and about 2.5 mol% of syringobin. In one embodiment, polymorph C is a co-crystal formed between syringosine and syringobin. In one embodiment, polymorph C is a salt formed between syringosine and syringobin.

[0013] In one embodiment, the present invention provides a method of treating or ameliorating a disease or disorder, the method comprising administering to a subject a composition comprising a crystalline form of syringosine and syringobin, thereby treating said disease or disorder.

[0014] In one embodiment, said disease or disorder is a mental health disorder or a central nervous system (CNS) disorder. In one embodiment, said mental health disorder is selected from depressive disorders, anxiety disorders, post-traumatic stress disorder and addiction disorders. In one embodiment, said CNS disorder is selected from chronic pain disorders and cognitive impairments.

[0015] In one embodiment, the present invention provides a method of stimulating neurogenesis or neurite outgrowth, the method comprising administering to a subject a composition comprising a crystalline form of syringosine and syringobin, thereby stimulating neurogenesis or neurite outgrowth. In some embodiments, stimulating neurogenesis or neurite outgrowth results in an increase in the length of nerve cells.

Brief Description of the Drawings

[0016]

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[0100] direction in the crystal of crystalline Form A.

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Mode for Carrying Out the Invention

[0017] The present invention is based on the epoch-making discovery that silibinin and silybin form a crystal form, and specifically, the crystal form of the composition containing silibinin and silybin may be useful for the treatment of certain mental health diseases and central nervous system diseases, as well as for stimulating neurogenesis.

[0018] Before explaining 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 methodologies described. This is because they may change. Also, the terms used in the description are for the purpose of describing a particular version or embodiment only, and are not intended to limit the scope of the embodiments herein. It is also understood that the scope of the embodiments is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments described herein, but the preferred methods, devices, and materials are described herein. All publications described herein are incorporated by reference in their entirety. Nothing in this specification should be construed as an admission that the embodiments herein have a right to antedate the disclosure of the present invention by virtue of prior invention.

[0019] It should also be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[0020] The transitional term "comprising", which is synonymous with "including", "containing", or "characterized by", is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0021] As used herein, the term "consist of" or "consisting of" means that a composition, formulation, or method includes only the specifically recited elements, steps, or components of a particular claimed embodiment or claim.

[0022] As used herein, the term "consisting essentially of" or "consisting essentially of" means that a composition, formulation, or method includes only the specifically recited elements, steps, or components of a particular claimed embodiment or claim, optionally including additional elements, steps, or components that do not materially affect the basic and novel characteristics of the particular embodiment or claim. For example, the only active ingredient in a formulation or method for treating a particular condition (e.g., nutrient depletion) is the therapeutic agent specifically recited in a particular embodiment or claim.

[0023] As used herein, two embodiments are "mutually exclusive" if one is defined as being different from the other.

[0024] When a range of values is disclosed and the notation "n1 to n2" or "between n1 and n2" is used (where n1 and n2 are numerical values), unless otherwise specified, this notation is intended to include the numerical values themselves and the ranges between them. This range can be integers or continuous numbers between, including the end values. For example, within the range of "1 °C to 3 °C", 1 °C, 3 °C, and any significant figures in between (e.g., 1.255 °C, 2.1 °C, 2.9999 °C, etc.) are all intended to be included.

[0025] The term "about" as used in this document means ±10% of the numerical value for which it is used. Thus, about 50% means within the range of 45% to 55%. For example, "about 100 °C" means a temperature within the range of 90 °C to 110 °C. For example, "the 2θ angle is about 10°" means that the 2θ angle is in the range of 9° to 11°.

[0026] The term "substantially free of" is used herein either alone or in combination and is used interchangeably with the term "substantially pure" and refers to a compound that contains no other compounds within the detection limit 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 of can 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%.

[0027] Crystal form This disclosure relates to embodiments of compositions comprising:

Chemical formula

[0028] In some embodiments, the crystal form of the composition comprising silosine and silibinin is crystal form A.

[0029] In some embodiments, crystalline Form A is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 10.1°. In some embodiments, the XRPD pattern of crystalline Form A may further include a prominent peak at a 2θ angle of about 19.16°. In some embodiments, the XRPD pattern of crystalline Form A may further include prominent 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 further include prominent 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 by the XRPD pattern of FIG. 1.

[0030] In one embodiment, crystalline Form A has a TGMS thermogram that substantially corresponds to the representative TGMS thermogram shown in FIG. 4. In some embodiments, a negligible weight loss is observed. For crystalline Form A, a weight loss (1.3%) is observed between 40°C and 200°C by TGMS.

[0031] In one embodiment, crystalline Form A has a DSC thermogram that substantially coincides with that shown in FIG. 5. In certain embodiments, crystalline Form A is characterized by a DSC plot that includes a sharp endothermic event at a temperature of about 255°C.

[0032] In some embodiments, crystalline Form A has a ratio of syringobillin to syringosine of 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, crystalline Form A has a ratio of syringobillin to syringosine of about 1:1.

[0033] In some embodiments, crystalline Form A has a chemical purity of about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In some embodiments, crystalline Form A is substantially pure.

[0034] In some embodiments, crystalline Form A contains other solid forms, such as amorphous forms, of 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 0.7 mol%, about 0.75 mol%, about 0.8 mol%, about 0.85 mol%, about 0.9 mol%, about 0.95 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol% or less. In some embodiments, crystalline Form A is substantially free of other solid forms.

[0035] In some embodiments, the composition of crystalline form A of silybin and silibinin comprises about 99 mol% crystalline form A, about 0.5 mol% silybin and about 0.5 mol% silibinin, about 98 mol% crystalline form A, about 1.0 mol% silybin and about 1.0 mol% silibinin, about 97 mol% crystalline form A, about 1.5 mol% silybin and about 1.5 mol% silibinin, about 96 mol% crystalline form A, about 2.0 mol% silybin and about 2.0 mol% silibinin, about 95 mol% crystalline form A, about 2.5 mol% silybin and about 2.5 mol% silibinin, about 94 mol% crystalline form A, about 3.0 mol% silybin and about 3.0 mol% silibinin, about 93 mol% crystalline form A, about 3.5 mol% silybin and about 3.5 mol% silibinin, about 92 mol% crystalline form A, about 4.0 mol% silybin and about 4.0 mol% silibinin, about 91 mol% crystalline form A, about 4.5 mol% silybin and about 4.5 mol% silibinin, or about 90 mol% crystalline form A, about 5.0 mol% silybin and about 5.0 mol% silibinin.

[0036] In some embodiments, crystalline form A is anhydrous.

[0037] In some embodiments, crystalline form A is a salt formed between silybin and silibinin.

[0038] In some embodiments, crystalline form A is a co-crystal formed between silybin and silibinin.

[0039] Some embodiments relate to a crystalline form of silybin and silibinin: [Chemical formula] A composition comprising wherein crystalline form A is characterized by unit cell parameters that are substantially equal to the following: Unit cell dimensions: a = 9.3674(3) Å b = 11.2660(6) Å c = 24.2741(9) Å α = 90 degrees β = 90 degrees γ = 90 degrees Space group = P212121 Molecule / asymmetric unit = 1.

[0040] In some embodiments, the unit cell parameters were measured at about 296K.

[0041] In some embodiments, Crystal Form A substantially has the hydrogen bond geometries listed in Table A. [Table 1]

[0042] In some embodiments, Crystal Form A substantially has the atomic coordinates of non-hydrogen atoms listed in Table B. [Table 2-1]

Table 2-2

[0043] In some embodiments, Crystal Form A substantially has the atomic coordinates of hydrogen atoms listed in Table C.

Table 3-1

Table 3-2

[0044] In some embodiments, the crystal form of the composition containing cyrosine and sirobirubin is Crystal Form B.

[0045] In some embodiments, crystalline Form B is characterized by an XRPD pattern that includes a prominent 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 further include a prominent 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 further include prominent peaks at 2θ angles 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 further include prominent peaks at 2θ angles 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 by the XRPD pattern of FIG. 2.

[0046] In one embodiment, crystalline Form B has a TGMS thermogram that substantially corresponds to the representative TGMS thermogram shown in FIG. 6. In some embodiments, a negligible weight loss is observed. In the case of crystalline Form B, a weight loss (15.8%) is observed between 40°C and 200°C by TGMS.

[0047] In one embodiment, crystalline Form B has a DSC thermogram that substantially coincides with that shown in FIG. 7. In certain embodiments, crystalline Form B is characterized by a DSC plot that includes a broad endothermic event at a temperature of about 168.2°C.

[0048] In some embodiments, crystalline Form B has a ratio of synephrine to sinensetin of 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, crystalline Form B has a ratio of synephrine to sinensetin of about 1.3:1. In some embodiments, crystalline Form B has a ratio of synephrine to sinensetin of about 1:1.

[0049] In some embodiments, crystalline Form B has a chemical purity of 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.

[0050] In some embodiments, crystalline Form B contains other solid forms, such as amorphous forms, of 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 0.7 mol%, about 0.75 mol%, about 0.8 mol%, about 0.85 mol%, about 0.9 mol%, about 0.95 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol% or less. In some embodiments, crystalline Form B is substantially free of other solid forms.

[0051] In some embodiments, crystalline Form B is anhydrous.

[0052] In some embodiments, crystalline Form B is a salt formed between silybin and silibinin.

[0053] In some embodiments, crystalline Form B is a co-crystal formed between silybin and silibinin.

[0054] In some embodiments, the crystalline form of a composition comprising silybin and silibinin is crystalline Form C.

[0055] In some embodiments, the crystalline Form C is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 9.18°. In some embodiments, the crystalline Form C is characterized in that the XRPD pattern of the crystalline Form C may further include a prominent peak at a 2θ angle of about 17.95°. In some embodiments, the crystalline Form C is characterized in that the XRPD pattern of the crystalline Form C may further include prominent peaks at 2θ angles of about 10.42°, about 24.22°, and about 18.38°. In some embodiments, the crystalline Form C is characterized in that the XRPD pattern of the crystalline Form C may further include prominent peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°. In some embodiments, the crystalline Form C is characterized by the XRPD pattern of FIG. 3.

[0056] In one embodiment, the crystalline Form C has a TGMS thermogram that substantially corresponds to the representative TGMS thermogram shown in FIG. 8. In some embodiments, a negligible weight loss is observed. In the case of the crystalline Form C, a weight loss (13.5%) is observed between 40°C and 160°C by TGMS.

[0057] In one embodiment, the crystalline Form C has a DSC thermogram that substantially coincides with that shown in FIG. 9. In certain embodiments, the crystalline Form C is characterized by a DSC plot that includes a broad endothermic event at a temperature of about 25 - 140°C, together with a peak at 98.7°C.

[0058] In some embodiments, crystalline Form C has a ratio of silybin to silicic acid of 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, crystalline Form C has a ratio of silybin to silicic acid of about 1:1.

[0059] In some embodiments, crystalline Form C has a chemical purity of about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In some embodiments, crystalline Form C is substantially pure.

[0060] In some embodiments, crystalline Form C contains other solid forms, such as amorphous forms, of 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 0.7 mol%, about 0.75 mol%, about 0.8 mol%, about 0.85 mol%, about 0.9 mol%, about 0.95 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol% or less. In some embodiments, crystalline Form C is substantially free of other solid forms.

[0061] In some embodiments, crystalline Form C is anhydrous.

[0062] In some embodiments, crystalline Form C is a salt formed between silosine and siloxibine.

[0063] In some embodiments, crystalline Form C is a co-crystal formed between silosine and siloxibine.

[0064] Pharmaceutical composition In one embodiment, the present application provides a pharmaceutical composition comprising a crystalline form of silosine and siloxibine, and a pharmaceutically acceptable excipient.

[0065] 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 prominent peak at a 2θ angle of about 10.1°, said XRPD pattern further comprising prominent peaks at 2θ angles of about 19.16°, about 10.74°, about 25.3°, and about 24.07°, and / or said XRPD pattern further comprising prominent peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. In one embodiment, crystalline Form A has a ratio of siloxibine to silosine of about 1:1. In one embodiment, crystalline Form A has a chemical purity of about 95% or more. In some embodiments, the pharmaceutical composition of crystalline Form A comprises about 5 mol% or less of other solid forms. In some embodiments, the pharmaceutical composition of crystalline Form A of silosine and siloxibine comprises about 95 mol% of crystalline Form A, about 2.5 mol% of silosine, and about 2.5 mol% of siloxibine. In one embodiment, crystalline Form A is a co-crystal formed between silosine and siloxibine. In one embodiment, crystalline Form A is a salt formed between silosine and siloxibine.

[0066] In one embodiment, crystalline Form A is characterized by unit cell parameters that are substantially equal to the following: Unit cell dimensions: a = 9.3674(3) Å b = 11.2660(6) Å c = 24.2741(9) Å α = 90 degrees β = 90 degrees γ = 90 degrees Space group = P212121 Molecule / asymmetric unit = 1.

[0067] In one embodiment, the unit cell parameters were measured at about 296K. In one embodiment, Crystal A substantially has the hydrogen bond geometry listed in Table A. In one embodiment, Crystal A substantially has the atomic coordinates of the non-hydrogen atoms listed in Table B. In one embodiment, Crystal A substantially has the atomic coordinates of the hydrogen atoms listed in Table C. In one embodiment, Crystal A is a co-crystal formed between cytisine and scoparone. In one embodiment, Crystal A is a salt formed between cytisine and scoparone.

[0068] In some embodiments, Crystal B is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 18.54°, the XRPD pattern further includes a prominent peak at a 2θ angle of about 8.54°, the XRPD pattern further includes prominent peaks at 2θ angles of about 22.78°, about 14.27° and about 21.12°, and / or the XRPD pattern further includes prominent peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94° and about 25.02°. In one embodiment, Crystal B has a ratio of scoparone to cytisine of about 1.3:1. In one embodiment, Crystal B has a ratio of scoparone to cytisine of about 1:1. In one embodiment, Crystal B has a chemical purity of about 95% or more. In some embodiments, the pharmaceutical composition of Crystal B contains about 5 mol% or less of other solid forms. In some embodiments, the pharmaceutical composition of Crystal B of cytisine and scoparone contains about 95 mol% of Crystal B, about 2.5 mol% of cytisine, and about 2.5 mol% of scoparone. In one embodiment, Crystal B is a co-crystal formed between cytisine and scoparone. In one embodiment, Crystal B is a salt formed between cytisine and scoparone.

[0069] In some embodiments, crystalline Form C is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 9.18°, said XRPD pattern further including a prominent peak at a 2θ angle of about 17.95°, said XRPD pattern further including prominent peaks at 2θ angles of about 10.42°, about 24.22°, and about 18.38°, and / or said XRPD pattern further including prominent peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38°, and about 14.06°. In one embodiment, crystalline Form C has a ratio of silybin to silicolin of about 1:1. In one embodiment, crystalline Form C has a chemical purity of about 95% or greater. In some embodiments, said pharmaceutical composition of crystalline Form C contains about 5 mol% or less of other solid forms. In some embodiments, said pharmaceutical composition of crystalline Form C of silicolin and silybin contains about 95 mol% of crystalline Form C, about 2.5 mol% of silicolin, and about 2.5 mol% of silybin. In one embodiment, crystalline Form C is a co-crystal formed between silicolin and silybin. In one embodiment, crystalline Form C is a salt formed between silicolin and silybin.

[0070] As used herein, "pharmaceutical composition" refers to a formulation that includes an active ingredient and optionally a pharmaceutically acceptable carrier, diluent, or excipient. The term "active ingredient" can be used interchangeably with "active ingredient" and refers to any agent that can induce the desired effect upon administration. Examples of active ingredients include, but are not limited to, compounds, drugs, therapeutic agents, small molecules, etc. In one embodiment, said active ingredient is a crystalline form of silicolin and silybin, such as crystalline Form A, crystalline Form B, or crystalline Form C described herein.

[0071] The terms "excipient" and "pharmaceutically acceptable excipient" as used herein are intended to be 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 is compatible with the other ingredients of the formulation and must not be harmful to the recipient or to the activity of the active ingredient of the formulation. Pharmaceutically acceptable carriers, excipients, or stabilizers are well known in the art and are described, for example, in Remington’s Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dosages and concentrations employed and may include the following: buffers such as phosphoric acid, citric acid, and other organic acids; antioxidants such as ascorbic acid and methionine; preservatives (octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants such as TWEEN™, PLURONICS™, or 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, anti-adhesion agents such as magnesium stearate, binders such as saccharides and their derivatives (sucrose, lactose, starch, cellulose, sugar alcohols, and the like), proteins such as gelatin, synthetic polymers, lubricants such as talc and silica, and preservatives such as antioxidants, vitamin A, vitamin E, vitamin C, retinol palmitate, selenium, cysteine, methionine, citric acid, sodium sulfate, and parabens. Examples of diluents include, but are not limited to, water, alcohol, physiological saline, glycol, mineral oil, and dimethyl sulfoxide (DMSO).

[0072] In one embodiment, the pharmaceutically acceptable excipients are selected from phosphate buffer, citrate buffer, ascorbic acid, methionine, octadecyldimethylbenzylammonium 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, immunoglobulins, polyvinylpyrrolidone, glycine, glutamine, asparagine, histidine, arginine, lysine, monosaccharides, disaccharides, glucose, mannose, dextrin, EDTA, trehalose, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose (including eutectic solvents, eutectic ionic liquids, ionic liquids, and sorbitol), sodium, physiological saline, metal surfactants, nonionic surfactants, polyethylene glycol (PEG), magnesium stearate, water, alcohol, physiological saline, glycol, mineral oil, and dimethyl sulfoxide (DMSO).

[0073] The active compound can exert its effects over a wide dosage range and can generally be administered in a therapeutically effective amount. However, the amount of the compound actually administered will usually be determined by a physician according to circumstances related to the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, response of the individual patient, the severity of the patient's condition, etc.

[0074] Treatment method In one embodiment, the present invention provides a method for treating or ameliorating a disease or disorder, comprising administering to a subject a composition comprising a crystalline form of thyrosine and silosibin, thereby treating the disease or disorder.

[0075] In one embodiment, the disease or disorder is selected from mental health disorders or central nervous system (CNS) disorders. In one embodiment, the mental health disorder is selected from depressive disorders, anxiety disorders, post-traumatic stress disorder, and addiction disorders. In one embodiment, the CNS disorder is selected from chronic pain disorders and cognitive impairments.

[0076] In one embodiment, the present invention provides a method for stimulating neurogenesis or neurite outgrowth, comprising administering to a subject a composition comprising a crystalline form of thyrosine and silosibin, thereby stimulating neurogenesis or neurite outgrowth. In some embodiments, stimulating neurogenesis or neurite outgrowth results in an increase in the length of nerve cells.

[0077] In some embodiments, stimulating neurogenesis or neurite outgrowth results in an improvement in cognitive ability or other neurological dysfunctions associated with the state of the central nervous system. In some embodiments, the state of the central nervous system is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, senile dementia, Pick's disease, Parkinsonism-dementia complex, progressive subcortical gliosis, progressive supranuclear palsy, thalamic degeneration syndrome, hereditary aphasia, myoclonic epilepsy, sleep deprivation, depression, stroke, ischemia, traumatic brain injury, psychological and physical trauma, chronic pain due to any cause, cognitive impairment, and cognitive decline.

[0078] 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 that includes a prominent peak at a 2θ angle of about 10.1°, said XRPD pattern further including prominent peaks at 2θ angles of about 19.16°, about 10.74°, about 25.3°, and about 24.07°, and / or said XRPD pattern further including prominent peaks at 2θ angles of about 14.54°, about 16.5°, about 13.44°, about 23.42°, and about 8.62°. In one embodiment, crystalline Form A has a ratio of syringobillin to syringosine of about 1:1. In one embodiment, crystalline Form A has a chemical purity of about 95% or more. In some embodiments, crystalline Form A contains about 5 mol% or less of other solid forms. In some embodiments, said composition of crystalline Form A of syringosine and syringobillin contains about 95 mol% of crystalline Form A, about 2.5 mol% of syringosine, and about 2.5 mol% of syringobillin. In one embodiment, crystalline Form A is a co-crystal formed between syringosine and syringobillin. In one embodiment, crystalline Form A is a salt formed between syringosine and syringobillin.

[0079] In one embodiment, crystalline Form A is characterized by unit cell parameters that are substantially equal to the following: Unit cell dimensions: a = 9.3674(3) Å b = 11.2660(6) Å c = 24.2741(9) Å α = 90 degrees β = 90 degrees γ = 90 degrees Space group = P212121 Molecules / Asymmetric unit = 1.

[0080] In one embodiment, the unit cell parameters were measured at about 296K. In one embodiment, Crystal Form A substantially has the hydrogen bond geometry listed in Table A. In one embodiment, Crystal Form A substantially has the atomic coordinates of non-hydrogen atoms listed in Table B. In one embodiment, Crystal Form A substantially has the atomic coordinates of hydrogen atoms listed in Table C. In one embodiment, Crystal Form A is a co-crystal formed between cytosine and syrosingopine. In one embodiment, Crystal Form A is a salt formed between cytosine and syrosingopine.

[0081] In some embodiments, Crystal Form B is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 18.54°, the XRPD pattern further includes a prominent peak at a 2θ angle of about 8.54°, the XRPD pattern further includes prominent peaks at 2θ angles of about 22.78°, about 14.27° and about 21.12°, and / or the XRPD pattern further includes prominent peaks at 2θ angles of about 14.12°, about 10.05°, about 9.94°, about 24.94° and about 25.02°. In one embodiment, Crystal Form B has a ratio of syrosingopine to cytosine of about 1.3:1. In one embodiment, Crystal Form B has a ratio of syrosingopine to cytosine of about 1:1. In one embodiment, Crystal Form B has a chemical purity of about 95% or greater. In some embodiments, Crystal Form B contains about 5 mol% or less of other solid forms. In some embodiments, the composition of Crystal Form B of cytosine and syrosingopine contains about 92 mol% of Crystal Form B, about 2.5 mol% of cytosine, and about 2.5 mol% of syrosingopine. In one embodiment, Crystal Form B is a co-crystal formed between cytosine and syrosingopine. In one embodiment, Crystal Form B is a salt formed between cytosine and syrosingopine.

[0082] In some embodiments, the crystalline Form C is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of about 9.18°, said XRPD pattern further including a prominent peak at a 2θ angle of about 17.95°, said XRPD pattern further including prominent peaks at 2θ angles of about 10.42°, about 24.22° and about 18.38°, and / or said XRPD pattern further including prominent peaks at 2θ angles of about 19.82°, about 17.46°, about 14.82°, about 22.38° and about 14.06°. In one embodiment, the crystalline Form C has a ratio of syrosingopine to syrosingopyranose of about 1:1. In one embodiment, the crystalline Form C has a chemical purity of about 95% or more. In some embodiments, the crystalline Form C contains about 5 mol% or less of other solid forms. In some embodiments, the composition of the crystalline Form C of syrosingopine and syrosingopyranose contains about 95 mol% of the crystalline Form C, about 2.5 mol% of syrosingopine, and about 2.5 mol% of syrosingopyranose. In one embodiment, the crystalline Form C is a co-crystal formed between syrosingopine and syrosingopyranose. In one embodiment, the crystalline Form C is a salt formed between syrosingopine and syrosingopyranose.

[0083] As used herein, the terms "treating", "treated", "treatment", or "treat" refer to both therapeutic and prophylactic or preventive measures, the purpose of which is to prevent or delay (mitigate) an undesirable physiological condition, disease, or illness, or to obtain a beneficial or desirable clinical outcome. For the purposes of the present invention, beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of symptoms, disease, or illness; stabilization of the state of symptoms, disease, or illness (i.e., does not worsen); delay in the onset or reduction in the progression of symptoms, disease, or illness; improvement in symptoms, disease, or medical condition; and remission (partial or complete, induction or maintenance), detectable or undetectable, or enhancement or improvement of a condition, disease, or illness. Treatment includes eliciting a clinically significant response without undue side effects. Treatment also includes extending the survival period as compared to the expected survival period in the absence of treatment. Treatment may be essentially prophylactic, i.e., may include prevention of disease. Prevention of disease may include complete protection from a disease, such as prevention of infection by a pathogen, or may include prevention of the progression of a disease. For example, prevention of disease does not mean completely eliminating all effects associated with the disease at all levels, but may mean preventing the symptoms of the disease to a clinically significant or detectable level. Prevention of disease also means preventing the progression of the disease to a later stage and extending the disease-free survival period as compared to the disease-free survival period in the absence of treatment, and extending the disease-free survival period as compared to the disease-free survival period in the absence of treatment.

[0084] As used herein, the term "treatment" is used interchangeably with the term "therapy" and refers to both 1) therapeutic measures or means for curing, delaying, reducing, and / or halting the progression of the symptoms of a diagnosed pathogenic medical condition or disease, and 2) prophylactic / preventive means. Those in need of treatment include not only those already suffering from a specific medical disease, but also those who may ultimately develop the disease (i.e., those in need of preventive measures).

[0085] The terms "therapeutically effective amount", "effective dosage", "therapeutically effective dosage", "effective amount", or like terms refer to the amount of a subject compound that elicits a biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. Generally, the response is either an improvement in the patient's symptoms or a desirable biological outcome (e.g., improvement of symptoms of PTSD). The effective amount can be determined as described herein.

[0086] The terms "administer" and / or "administering" should be understood to mean providing a therapeutically effective amount of a pharmaceutical composition to a subject in need of treatment. The route of administration is enteral, topical, or parenteral. Thus, routes of administration include, but are not limited to, intradermal, subcutaneous, intravenous, intraarterial, intraorbital, intracardiac, intradermal, transdermal, subdural, intraspinal, oral, sublingual, buccal, rectal, nasal administration, and infusion. Suitable unit dosage forms include, but are not limited to, powders, tablets, pills, capsules, troches, suppositories, patches, nasal sprays, injections, implantable sustained release formulations, lipid complexes, etc.

[0087] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, as well as domestic animals such as cows, goats, sheep, pigs, rabbits, and pet animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0088] Mental health disorders or mental impairments refer to a wide range of disorders including, but not limited to, mood disorders, depression, mood instability disorder, mixed anxiety-depression disorder, bipolar disorder, anxiety disorders, generalized anxiety disorder, social anxiety disorder, phobias, panic attack disorder, schizophrenia, psychosis, schizoaffective disorder, eating disorders, anorexia nervosa, bulimia nervosa, substance use disorders, addiction disorders, alcohol use or dependence disorder, opioid use or dependence disorder, cocaine use or dependence disorder, polysubstance use or dependence disorder, behavioral addiction, gambling disorder, trauma-related disorders, post-traumatic stress disorder, grief-related disorders, loss-related disorders, end-of-life-related disorders, cancerous disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), personality disorders, obsessive-compulsive disorder, and combinations thereof. The complete list of currently recognized mental health disorders is described in the "Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM5)", which is hereby incorporated by reference in its entirety herein. Central nervous system (CNS) disorders include burns, injuries, other physical causes, post-traumatic, post-brain injury, post-stroke, post-heart attack, post-diabetes, chronic pain disorders, migraines, chronic headaches, chronic low back pain, chronic arthritis pain, chronic pain from any cause, cognitive disorders, cognitive decline, Alzheimer's disease, dementia at any stage, dementia from any cause, age-related memory impairment, neuropsychiatric disorders, fetal alcohol spectrum disorder (FAS) disorders, autism spectrum disorder, multiple sclerosis, Parkinson's disease, fragile X syndrome, Down syndrome, fatigue, chronic fatigue, insomnia from any cause, and psychological and physical trauma from all post-COVID syndromes, but are not limited thereto. The severity of symptoms varies, with some people experiencing debilitating diseases that interfere with normal social life, while others experience intermittent and recurrent episodes throughout their lives. The symptoms and diagnostic criteria for mental disorders and CNS conditions are partially different, but there are notable endophenotypes common to both disorders, and co-occurring disorders are also common.

[0089] Specifically, there are endophenotypes of phenotypes related to changes in mood, cognition, and behavior. Interestingly, many of these endophenotypes are also extended to neurological diseases. For example, attention deficit has 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 syndrome, Alzheimer's disease, Parkinson's disease, and frontotemporal dementia.

[0090] Depressive disorders are characterized by mood depression, sadness or a sense of despair, increased irritability, sleep disorders, decreased energy and fatigue, decreased concentration, decreased self-esteem or a sense of worthlessness, lack of interest or pleasure in things, slowing of movements, thoughts of being better off dead and self-harm behavior, and actively thinking about or attempting suicide, and include major depressive disorder, bipolar depression, treatment-resistant depression, and mood-cycling disorders.

[0091] Anxiety disorders are characterized by feelings of tension, anxiety, difficulty breathing, avoidance of people or activities, excessive worry, chest pain, palpitations, sweating, nausea, stomachache, headache, neck pain, lack of sleep, decreased concentration, sweating, dizziness and other physical symptoms, and include generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, phobias, and separation anxiety disorder.

[0092] Post-traumatic stress disorder (PTSD) is characterized by flashbacks, nightmares, involuntary memories, mental or physical reactions after recalling a trauma, avoidance of things that may trigger such memories, avoidance of activities, social isolation, increased anger or aggression, increased irritability, participation in risky behaviors, decreased concentration, sleep disorders, and increased startle responses, and can be further described as those accompanied by dissociative experiences.

[0093] Substance abuse and addiction disorders are identified when an individual repeatedly uses alcohol or drugs, causing significant disorders that have an adverse impact on health, work, school, and family. The severity varies depending on the type and frequency of drug use, as well as the social and interpersonal problems associated with this use. It affects family, friends, work, school, relationships, withdrawal symptoms, tolerance, failed attempts to quit, physical and mental health problems caused by drug use, and cravings, including 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, unknown substance use disorder, and these disorders can occur alone or in combination.

[0094] Chronic pain disorders are characterized by pain occurring in one or more parts of the body, such as headache, low back pain, neck pain, arthritis pain, pain associated with cancer, neuropathic pain, psychogenic pain, etc., and symptoms include chronic arthritis, osteoarthritis, chronic fatigue syndrome, endometriosis, fibromyalgia, inflammatory bowel disease, interstitial cystitis, temporomandibular joint disorder, vulvodynia, cluster headache, migraine, herpes zoster, painful shoulder contracture, complex regional pain syndrome, gout, postoperative pain syndrome, herniated disc, sciatica, and trigeminal neuralgia.

[0095] Cognitive impairment is characterized by a decline in brain function, including memory and other functions, such as movement, speech, concentration, problem-solving, sleep analysis, tremors, fatigue, dizziness, headache, hallucinations, and confabulation, and includes memory impairment associated with aging, Alzheimer's disease, Pick's disease, vascular dementia, post-stroke dementia, multi-infarct dementia, Parkinson's disease, frontotemporal dementia, alcohol-related dementia, and amnestic disorders such as Korsakoff syndrome.

[0096] Neurogenesis is an important process in the brains of animals and humans, where new neurons are continuously generated throughout the life of the organism. The newly born cells can differentiate into functional cells of the central nervous system and integrate into the existing neural circuits in the brain. Stimulating neurogenesis or neurite growth may improve cognitive abilities related to various symptoms of the central nervous system, such as depression and anxiety.

[0097] In one embodiment, crystalline forms of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof are provided for use in the treatment of post-traumatic stress disorder (PTSD). In one embodiment, crystalline forms of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof are provided for use in the treatment of treatment-resistant PTSD. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form A is provided for use in the treatment of treatment-resistant PTSD. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form B is provided for use in the treatment of treatment-resistant PTSD. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form C is provided for use in the treatment of treatment-resistant PTSD. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form A is provided for use in the treatment of treatment-resistant PTSD. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form B is provided for use in the treatment of treatment-resistant PTSD. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form C is provided for use in the treatment of treatment-resistant PTSD.

[0098] In one embodiment, a method of treating PTSD is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof. In one embodiment, a method of treating treatment-resistant PTSD is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof. In one embodiment, a method of treating treatment-resistant PTSD is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form A. In one embodiment, a method of treating treatment-resistant PTSD is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form B. In one embodiment, a method of treating treatment-resistant PTSD is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form C.

[0099] In one embodiment, crystalline forms of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof for use in the treatment of depression are provided. In one embodiment, crystalline forms of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof for use in the treatment of treatment-resistant depression are provided. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form A for use in the treatment of treatment-resistant depression is provided. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form B for use in the treatment of treatment-resistant depression is provided. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form C for use in the treatment of treatment-resistant depression is provided. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form A for use in the treatment of treatment-resistant depression is provided. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form B for use in the treatment of treatment-resistant depression is provided. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form C for use in the treatment of treatment-resistant depression is provided.

[0100] In one embodiment, a method of treating depression is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof. In one embodiment, a method of treating treatment-resistant depression is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof. In one embodiment, a method of treating treatment-resistant depression is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form A. In one embodiment, a method of treating treatment-resistant depression is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form B. In one embodiment, a method of treating treatment-resistant depression is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form C.

[0101] In one embodiment, crystalline forms of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof are provided for use in the treatment of anxiety. In one embodiment, crystalline forms of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof are provided for use in the treatment of treatment-resistant anxiety. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form A is provided for use in the treatment of treatment-resistant anxiety. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form B is provided for use in the treatment of treatment-resistant anxiety. In one embodiment, a crystalline form of cyrosine and silibinin that is crystalline Form C is provided for use in the treatment of treatment-resistant anxiety. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form A is provided for use in the treatment of treatment-resistant anxiety. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form B is provided for use in the treatment of treatment-resistant anxiety. In one embodiment, a high-purity crystalline form of cyrosine and silibinin that is crystalline Form C is provided for use in the treatment of treatment-resistant anxiety.

[0102] In one embodiment, a method of treating anxiety is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof. In one embodiment, a method of treating treatment-resistant anxiety is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin, crystalline Form A, crystalline Form B, crystalline Form C, or combinations thereof. In one embodiment, a method of treating treatment-resistant anxiety is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form A. In one embodiment, a method of treating treatment-resistant anxiety is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form B. In one embodiment, a method of treating treatment-resistant anxiety is provided that includes administering to a subject an effective amount of a crystalline form of cyrosine and silibinin that is crystalline Form C.

[0103] In one embodiment, a crystalline form of silosine and siloxibine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof for use in the treatment of pain is provided. In one embodiment, a crystalline form of silosine and siloxibine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof for use in the treatment of treatment-resistant pain is provided. In one embodiment, a crystalline form of silosine and siloxibine that is crystalline form A for use in the treatment of treatment-resistant pain is provided. In one embodiment, a crystalline form of silosine and siloxibine that is crystalline form B for use in the treatment of treatment-resistant pain is provided. In one embodiment, a crystalline form of silosine and siloxibine that is crystalline form C for use in the treatment of treatment-resistant pain is provided. In one embodiment, a high-purity crystalline form of silosine and siloxibine that is crystalline form A for use in the treatment of treatment-resistant pain is provided. In one embodiment, a high-purity crystalline form of silosine and siloxibine that is crystalline form B for use in the treatment of treatment-resistant pain is provided. In one embodiment, a high-purity crystalline form of silosine and siloxibine that is crystalline form C for use in the treatment of treatment-resistant pain is provided.

[0104] In one embodiment, a method of treating pain is provided that includes administering to a subject an effective amount of a crystalline form of silosine and siloxibine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof. In one embodiment, a method of treating treatment-resistant pain is provided that includes administering to a subject an effective amount of a crystalline form of silosine and siloxibine, crystalline form A, crystalline form B, crystalline form C, or a combination thereof. In one embodiment, a method of treating treatment-resistant pain is provided that includes administering to a subject an effective amount of a crystalline form of silosine and siloxibine that is crystalline form A. In one embodiment, a method of treating treatment-resistant pain is provided that includes administering to a subject an effective amount of a crystalline form of silosine and siloxibine that is crystalline form B. In one embodiment, a method of treating treatment-resistant pain is provided that includes administering to a subject an effective amount of a crystalline form of silosine and siloxibine that is crystalline form C.

[0105] In some embodiments, the composition is administered via an intracutaneous, subcutaneous, intravenous, intraarterial, intradermal, transdermal, oral, sublingual, buccal, or nasal route of administration.

[0106] In some embodiments, the method further comprises administering a second pharmaceutically active compound.

[0107] In some embodiments, the second pharmaceutically active compound is one or more of an anxiolytic, antidepressant, or pain reliever.

[0108] In some embodiments, the second pharmaceutically active compound is a psychoactive alkaloid. In some embodiments, the psychoactive compound or alkaloid is psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, bufotenin, bufotenidine, 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), N,N-dimethyltryptamine (DMT), 4-hydroxytryptamine, N,N,N-trimethyl-4-hydroxytryptamine elymoclavine (LSA), ergonovine, ergometrine, muscimol, ibotenic acid, lysergic acid hydroxyethylamide (LSH), elymoclavine, ergometrinine, or chanoclavine, or any combination thereof.

[0109] In some embodiments, the second pharmaceutically active compound is administered concurrently with the composition.

[0110] In some embodiments, the second pharmaceutically active compound is administered sequentially with the composition.

[0111] In some embodiments, the method further comprises administration of guided therapy.

[0112] In some embodiments, the guided therapy is administered simultaneously with the composition.

[0113] In some embodiments, the guided therapy is administered consecutively with the composition.

[0114] In some embodiments, the guided therapy is administered simultaneously with the second pharmaceutically active compound.

[0115] In some embodiments, the guided therapy is administered consecutively with the second pharmaceutically active compound.

[0116] The following examples are provided to further illustrate embodiments of the invention and are not intended to limit the scope of the invention. These are typical of those that may be used, but other procedures, methodologies, or techniques known to those skilled in the art may be used instead.

Example

[0117] Example 1 Salt screening Freeze-drying / Recrystallization: A physical mixture of silybin and silibinin 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, and each vial achieved a silybin content of 30 mg. The solvent was removed by freeze-drying. The resulting amorphous material was resuspended in 10 solvents, and the samples were heated to 50 °C and cooled to 5 °C at a constant heating rate of 10 °C / h and variable cooling rates of -20 °C / h, -10 °C / h, and -5 °C / h in the first to third cycles. After the temperature profile, the solids were collected, dried under ambient conditions and in vacuo, and analyzed by XPRD. Subsequently, all solids were exposed to 40 °C / 75% relative humidity (RH) (AAC) for 2 days and re-measured by XRPD. The results are shown in Table 1.

Table 4

[0118] Slurry Conversion: A physical mixture of silybin and silibinin in a molar ratio was prepared in an organic solvent mixture to form a suspension. The samples were heated to 50 °C and cooled to 5 °C at a constant heating rate of 10 °C / h and variable cooling rates of -20 °C / h, -10 °C / h, and -5 °C / h in the first to third cycles. Subsequently, the samples were aged at room temperature for 72 h. At the end of the aging period, the solids were separated from the liquid phase by centrifugation, dried under ambient conditions and in vacuo, and then analyzed by HT-XRPD. All solids were exposed to 40 °C / 75% RH (AAC) for 2 days and re-measured by XRPD. The results are shown in Table 2.

Table 5

[0119] Example 2 XRPD Analysis The XRPD pattern was obtained using an Ardena T2 high-throughput XRPD setup. The plate was mounted on a Bruker General Area Detector Diffraction System (GADDS) equipped with a VÅNTEC-500 gas area detector that corrected for intensity and geometric variations. Calibration of the measurement accuracy (peak position) was performed using the NIST SRM1976 standard (corundum).

[0120] Data collection was performed at room temperature using monochromatic Cu Kα radiation in the 2θ range of 1.5° to 41.5°, which is the most characteristic part of the XRPD pattern. The diffraction pattern of each well was collected at an exposure time of 90 seconds per frame in two 2θ ranges (1.5° ≤ 2θ ≤ 21.5° for the first frame and 19.5° ≤ 2θ ≤ 41.5° for the second frame). No background subtraction or curve smoothing was applied to the XRPD pattern.

[0121] The lattice 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 density of the crystal. The lattice parameters, purity, and instrument parameters were refined using the whole powder pattern decomposition method.

[0122] In the Rietveld calculation, the lattice parameters, crystal system, and atomic positions were obtained from a single crystal file (cif). During refinement, the following parameters were refined: lattice constant, background, instrument shape, zero shift, and absorption.

[0123] Throughout the process, neither the atomic positions nor the thermal motion parameters were refined. The following goodness-of-fit criteria were used. Y o,m and Y c,m are the observed data and calculated data at data point m, respectively, M is the number of data points, P is the number of parameters, wm is the weight given to data point m, and in the count statistics, wm = 1 / σ(Y o,m ) 2 is given, and σ(Y o,m ) is the error of Y o,m .

Number

[0124] The XRPD of crystal type A from experiment ID TCS2 is shown in Figure 1, and the peak table is shown in Table 3.

Table 6

[0125] The XRPD of crystal type B from experiment ID TCS24 is shown in Figure 2, and the peak table is shown in Table 4.

Table 7

[0126] The XRPD of crystal type C from experiment ID TCS26 is shown in Figure 3, and the peak table is shown in Table 5.

Table 8

[0127] Example 3 TGMS and DSC Analysis The mass loss due to the loss of solvent or water from the crystal was measured by TGA / DSC. When monitoring the weight of the sample during heating with a TGA / DSC 3+ STARe System (Mettler-Toledo GmbH, Switzerland), a weight versus temperature curve and a heat flow signal were obtained. The TGA / DSC 3+ was temperature-calibrated using samples of indium and aluminum. The sample (about 2 mg) was weighed into a 100 μL aluminum crucible and sealed. A pinhole was opened in the seal, and the crucible was heated in the TGA from 25 to 300 °C at a heating rate of 10 °C / min. Dry N2 gas was used for purging.

[0128] The gas generated from the TGA sample was analyzed by a mass spectrometer Omnistar GSD 350 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer that analyzes mass within a temperature range of 0 - 200 amu.

[0129] The thermal events were obtained from the DSC thermograms recorded by a heat flux DSC3 + STARe System (Mettler - Toledo GmbH, Switzerland). The temperature and enthalpy of DSC3 + were calibrated using small pieces of indium (m.p. = 156.6 °C, δHf = 28.45 J / g) and zinc (m.p. = 419.6 °C, δHf = 107.5 J / g). The sample (about 2 mg) was sealed in a standard 40 μL aluminum pan, with a pinhole opened, and heated from 25 °C to 300 °C at a heating rate of 10 °C / min using a DSC. During the measurement, dry N2 gas with a flow rate of 50 mL / min was used to purge the DSC apparatus.

[0130] In the TGMS analysis of crystalline Form A, a 1.3% mass loss was shown between 40 °C and 200 °C due to residual ethanol / water. Thermal decomposition started above 200 °C. The DSC trace showed a single endothermic event at T peak (252.5 °C of T onset ). This corresponds to the melting of crystalline Form A. The TGMS thermogram of crystalline Form A is shown in Figure 4, and the DSC thermogram of crystalline Form A is shown in Figure 5.

[0131] In the TGMS analysis of crystalline Form B, based on the MS signal, a 15.8% mass loss was shown between 40 °C and 200 °C due to TFE and toluene. Thermal decomposition started above 200 °C. The DSC trace showed a broad endothermic event at T peak (156.1 °C of T onset ). This corresponds to the desolvation of crystalline Form B. The TGMS thermogram of crystalline Form B is shown in Figure 6, and the DSC thermogram of crystalline Form B is shown in Figure 7.

[0132] TGMS analysis of crystalline form C showed a mass loss of 13.5% due to water between 40 and 160 °C based on the MS signal. Thermal decomposition began above 160 °C. The DSC trace showed a broad endothermic event between 25 and 140 °C (T of 98.7 °C). peak , T of 84.7 °C onset ), which corresponds to the dehydration of crystalline form C. The TGMS thermogram of crystalline form B is shown in Figure 8, and the DSC thermogram of crystalline form B is shown in Figure 9.

[0133] Example 4 NMR spectroscopy At D2O 1 Compound integrity was characterized for psilocybin and psilocybin-psilocin polymorphs (crystalline forms A and B) using H-NMR spectroscopy. Spectra were recorded at room temperature on a 500 MHz instrument (Bruker BioSpin GmbH) using standard pulse sequences. Data were processed using ACD Labs software Spectrus Processor 2016.2.2 (Advanced Chemistry Development Inc., Canada).

[0134] Figure 10 shows the structure of crystal type A and psilocybin. 1 The H-NMR spectra of crystalline form A and psilocybin between 6 ppm and 7.5 ppm are shown in FIG. 1 H-NMR of crystalline form A, crystalline form B, and psilocybin are shown in FIG. 1 The H-NMR spectra of crystalline form A, crystalline form B, and psilocybin between 6 ppm and 7.5 ppm are shown in FIG. 1 The H-NMR spectra are overlaid.

[0135] Example 5 DVS analysis The moisture sorption isotherm was collected using a DVS Adventure system from Surface Measurement Systems (London, UK). The sample size was approximately 10 mg of solid material. The relative humidity was changed in 10% increments from 40% to 95% to 0% to 40% at a constant temperature of 25 °C to record the complete adsorption and desorption isotherms. The weight equilibrium per step was set at a dm / dt of 0.002% / min. Subsequently, the sample was measured by HT-XRPD.

[0136] Crystal Form A: The total mass difference from RH 0% to 95% was 3.6%, and the mass absorption at RH 80% was 2.4%. According to the EP hygroscopicity classification, this substance shows medium hygroscopicity. The solid recovered after DVS was analyzed by XRPD, and it was confirmed that PSY1 was physically stable after the adsorption-desorption cycle. The DVS isotherm of Crystal Form A is shown in Figure 14.

[0137] Crystal Form B: The total mass difference from RH 0% to 95% was 8.0%, and the mass absorption at RH 80% was 4.3%. According to the EP hygroscopicity classification, this substance shows medium hygroscopicity. The solid recovered after DVS was analyzed by XRPD, and it was confirmed that PSY5 was physically stable after the adsorption-desorption cycle. The DVS isotherm of Crystal Form B is shown in Figure 15.

[0138] Crystal Form C: The total mass difference from RH 0% to 95% was 16.4%, and the mass absorption at RH 80% was 1.8%. According to the EP hygroscopicity classification, this substance shows slight hygroscopicity. The solid recovered after DVS was analyzed by XRPD, and it was confirmed that Crystal Form C was physically stable after the adsorption-desorption cycle. The stepwise moisture absorption between RH 20% and 95% was 5.2%, which corresponds to 1.5 molecules of water. The DVS isotherm of Crystal Form B is shown in Figure 16.

[0139] Example 6 UPLC Analysis UPLC Analytical Method UPLC System: · UPLC: Agilent 1290 · Detector 1: Set the UV detector to 267 nm · Detector 2: MSD XT in positive scan mode UPLC conditions: · Autosampler temperature: Room temperature · Column: ACE Avanor C18 - PVP (100×2.1 mm, 1.7 μm) · Column temperature: 40 °C · Gradient: · Mobile phase A: 0.7 grams of ammonium formate, 0.1% formic acid aqueous solution · Mobile phase B: 0.1% formic acid in methanol · Flow rate: 0.27 mL / min · Run time: 25 minutes · Gradient: Time [min]: Eluent A: Eluent B: 0 95% 5% 4 95% 5% 16.5 30% 70% 20 30% 70% 20.1 95% 5% 25 95% 5% Sample preparation · Concentration: Approximately 1.0 mg / mL · Solvent: Water: Acetonitrile (60:40 volume ratio) + 0.1% formic acid · Injection volume: 1 μL

[0140] Crystal A type: A reference solution of syrosine was prepared at a concentration of approximately 1 mg / mL. An approximately 2 mg / mL crystal A type solution was prepared with ACN / water (40 / 60 volume percent ratio) + 0.01% formic acid. The stoichiometry of crystal A type (syrobine:syrosine) was determined to be 1:1. The HPLC chromatogram is shown in Figure 17.

[0141] Crystal B type: A reference solution of syrosine was prepared at a concentration of approximately 1 mg / mL. An approximately 2 mg / mL crystal B type solution was prepared with ACN / water (40 / 60 volume percent ratio) + 0.01% formic acid. Applying the following formula (1), the stoichiometry of crystal B type (syrobine:syrosine) was determined to be 1.3:1. The HPLC chromatogram is shown in Figure 18.

[0142] Crystal Form C: A reference solution of syrosingopine was prepared at a concentration of about 1 mg / mL. A solution of crystal form C at about 2 mg / mL was prepared with ACN / water (40 / 60 volume percent ratio) + 0.01% formic acid. The stoichiometry of crystal form C (syrobirubin:syrosingopine) was determined to be 1:1. The HPLC chromatogram is shown in Figure 19.

[0143] Example 7 Crystal Structure High-Resolution Powder X-Ray Diffraction (HR-XRPD): The HR-XRPD data of crystal form A were collected on a D8 Advance diffractometer using Cu Kα1 radiation (1.54056 Å) with a germanium monochromator at room temperature. The diffraction data were collected in the 2θ range of 2.15° to 41.5°. The detector scan of the LynxEye detector for solids was performed using 0.0157° per step at a scan speed of 5 seconds / step. The sample was measured in a glass capillary with an outer diameter of 0.3 mm and a length of 8 mm. Before transferring to the capillary, the analyzed solid (from Example 1: experimental ID TCS2) was ground in an agate mortar until all visible crystals disappeared and the substance became a fine powder.

[0144] The lattice parameters and crystal system were obtained using the LSI-Index indexing program. The space group was selected based on the reflection conditions and density of the crystal. The lattice parameters, purity, and instrument parameters were refined using the Whole Powder Pattern Decomposition (WPPD) method.

[0145] This structure was analyzed using the simulated annealing technique implemented in TOPAS6. For both components of syrosingopine and syrobirubin, Z-Matrix models were created using cif files from the Cambridge Structural Data Base (CCDC1238288 for syrosingopine and CCDC2128419 for syrobirubin).

[0146] Rietveld analysis was performed using TOPAS6 (Bruker, 2017). All bond distances and angles were fixed, and only the rotation and translation of the molecule were possible, except for the following torsion angles (C6-O5-P4-O2, C16-C15-C13-C14, C25-C24-N23-C22, C26-C25-C24-N23).

[0147] The following fitting criteria were used. · Y o,m and Y c,m are the observed data and the calculated data at data point m, respectively. · M is the number of data points. · P is the number of parameters. · wm is the weight given to data point m, and in counting statistics, wm = 1 / σ(Y o,m ) 2 is given by, and σ(Y o,m ) is the error of Y o,m . [Number]

[0148] The structure was determined using the rigid body simulated annealing method so that both molecules could rotate and translate freely within the unit cell. Furthermore, the torsion angles of the phosphate and both amine groups were also treated as variables. After obtaining a chemically reasonable solution, the model was refined using the Rietveld algorithm.

[0149] Crystal A crystallized in the orthorhombic primitive space group based on the reflection conditions, and in the final result of simulated annealing, the space group P212121 was selected. Table 6 shows the final crystal and analysis data of the selected model. [Table 9]

[0150] The solution revealed that there is one cytosine - syrosinganine pair in the asymmetric unit without additional solvent or API molecules. All of the x, y, z positions of the atoms can be found. Figure 20 shows the molecular structure of crystalline form A cytosine - syrosinganine. It can be seen that the phosphate group of syrosinganine interacts directly with the N - amine atom of cytosine. The crystal is held together by an extensive network of intermolecular hydrogen bonds, in which all non - protonated O or N atoms function as acceptors and all N - H and O - H function as donors. Table 7 shows the geometry of all the hydrogen bonds found in the analyzed crystal.

Table 10

[0151] The hydrogen - bond network of crystalline form A forms a layered structure with intercalated layers composed of molecules of cytosine and syrosinganine. These layers are parallel to the ab plane, as shown in Figure 21.

[0152] Atomic coordinates and equivalent isotropic displacement parameters (Å 2x 10 3 ) of non - hydrogen atoms of form A are shown in Table 8. U(eq) is defined as one - third of the trace of the orthogonalized U ij tensor.

Table 11 - 1

Table 11 - 2

[0153] Hydrogen coordinates and isotropic displacement parameters (Å 2x 10 3 ) of form A are shown in Table 9. U(eq) is defined as one - third of the trace of the orthogonalized U ij tensor.

Table 12 - 1

Table 12 - 2

[0154] Figure 22 shows the graphical representation of the final cycle of the Rietveld analysis, and it is confirmed that the model fits very well with the collected diffraction pattern of crystalline form A.

[0155] Example 8 Ca 2+ Release assay The AequoScreen CHO-K1 cells that stably express h5HT2a contain the aequorin protein that can catalyze the decomposition of the coelenterazine molecule to generate light when binding to Ca 2+ . The level of light emitted is proportional to the endoplasmic reticulum calcium ion (Ca 2+ 2+) release. Before recording the chemiluminescence, the CHO-K1 cells were treated with each compound at 0.1 nM to 10 μM for 1 minute. Next, the obtained data was fitted to a three-parameter non-linear regression to determine the potency (EC 50 ) and efficacy (E max ). The results are shown in Figure 23. The data was fitted to a three-parameter non-linear regression of GraphPad (version 9). Independent experiments with n = 3 - 29 were performed in duplicates or triplicates. The data is presented as mean ± SEM. EC 50 and E max are reported in Table 10.

Table 13

[0156] Thyrosine is a potent activator of calcium ion (Ca 2+ 2+) release. Syrosingopine is clearly low in potency and efficacy. The 1:1 equimolar mixture of tyrosine and syrosingopine causes an intermediate Ca2+ release reaction between either compound alone.

[0157] Example 9 β-Arrestin 2 recruitment assay CHO-K1 cells express a fusion protein of h5HT2a-smBiT and β-arrestin 2-lgBiT. When h5HT2a and β-arrestin 2 come into contact with each other, the smBiT peptide and the lgBiT peptide complement each other, generating a complete NanoBit luciferase enzyme. Upon completion, the enzyme can catalyze the decomposition of the coelenterazine molecule to generate light. The level of light emitted is proportional to the interaction between h5HT2a and β-arrestin 2. CHO-K1 cells were treated with each compound at 0.1 nM to 10 μM for 2 hours, during which chemiluminescence was recorded. Next, the area under the curve data of the cumulative chemiluminescence was fitted to a three-parameter non-linear regression to determine the potency (EC 50 ) and efficacy (E max ). The results are shown in Figure 24. The data were fitted to a three-parameter non-linear regression using GraphPad (version 9). Independent experiments with n = 3 to 13 were performed in duplicates or triplicates. The data are presented as mean ± SEM. EC 50 and E max are reported in Table 11.

Table 14

[0158] Serotonin is an activator of β-arrestin 2 mobilization. Silibinin has no potency or efficacy. The potency of serotonin and silibinin is greater in the Ca 2+ release assay than in the β-arrestin 2 mobilization assay.

[0159] Example 10 β-Arrestin 2 Mobilization (Recruitment) Assay CHO-K1 cells stably expressing h5HT2a are grown, harvested, and frozen at -80°C. The cells are thawed as needed and subjected to pressure cavitation using a Dounce homogenizer to disrupt the cell membrane. Next, the cell lysate is centrifuged at 20,000 × g for 30 minutes at 4°C to collect the cell membrane. Homogenization and centrifugation are repeated to concentrate the sample of receptor-containing cell membrane. CHO-K1 cell membranes are at 1 nM 3Incubate with ketanserin and each compound at 0.1 nM to 10 μM for 2 hours. Next, pipette the sample onto filter paper, rinse, wash 3 times by vacuum filtration, dry, and incubate overnight in scintillation fluid. Residual bound radioactivity is then read on a liquid scintillation counter and normalized to the maximum LSD response (i.e., 0%). The data obtained are then fitted to a three-parameter non-linear regression to determine the affinity (K i ). The results are shown in Figure 25. The data were fitted to a three-parameter non-linear regression using GraphPad (version 9). n = 3 - 6 independent experiments. Data are presented as mean ± SEM. EC 50 and E max are reported in Table 12.

Table 15

[0160] Example 11 Physiology: Catalepsy, Body Temperature, and Pain Sensation C57BL / 6 mice were treated with the indicated escalating doses of the compound by intraperitoneal injection. The tests were as follows: As a baseline, body temperature was measured before the first administration of the compound. Catalepsy - bar grip assay 10 minutes after compound administration. Mice were placed to grasp a 0.7 cm ring clamp positioned 4.5 cm above the surface of the test space with their forelimbs. Record the length of time (seconds) the ring is grasped. The test is terminated if the mouse changes the orientation of its head or body or attempts to escape 3 times consecutively within a maximum of 60 seconds. Pain Sensation - Immerse the mouse's tail in water at 52 °C 15 minutes after compound administration. Record the waiting time until the tail is removed from the water up to a maximum of 20 seconds. Body Temperature - Measure with a rectal thermometer 20 minutes after compound administration. The results are shown in Figure 26. The data were plotted using GraphPad (version 9). n ≥ 6 animals per dose. Data are presented as mean ± SEM.

[0161] Psilocin and psilobin do not cause catalepsy. Neither drug, or combination thereof, is expected to cause freezing behavior or convulsions. Psilocin and psilobin cause hypothermia in a dose-dependent manner. Ultimately, psilocin at 1 mg / kg significantly reduces the peak of pain sensation.

[0162] Example 12 Rodent hallucination model: head-twitch response (HTR) C57BL / 6 mice were treated with the indicated escalating doses of the compound by intraperitoneal injection. The mice were placed in a transparent cylinder and video-recorded for 10 minutes immediately after compound administration. Head twitches were recorded by an individual blind to the treatment as lateral rhythmic head shakes distinct from grooming or vertical head nods. The results are shown in Figure 27. Data were plotted in GraphPad (version 9). Animals with n ≥ 3 individuals per dose. Data are presented as mean ± SEM.

[0163] Psilocin and psilobin cause a time-dependent head-twitch response as a model of hallucination or dissociation in rodents. At several test doses, the peak effect was seen 3 - 4 minutes after compound administration. In contrast, the peak effect of LSD was seen approximately 7 minutes after administration.

[0164] Example 13 Increasing spontaneous locomotor activity: open field task (OFT) C57BL / 6 mice were treated with the indicated escalating doses of the compound by intraperitoneal injection. The mice were placed in an open field 30 minutes after compound administration. The size of the open field is 1 m × 1 m and the test lasts for 5 minutes. The total distance traveled, speed, and time spent in the central quadrant of the field are recorded and analyzed using EthoVision XT (Noldus, version 17). The results are shown in Figure 28. Data were plotted in GraphPad (version 9). Animals with n ≥ 4 individuals per dose. Data are presented as mean ± SEM.

[0165] Sirocin and sirobine decreased movement, speed, and time required in the center of the open field in a dose-dependent manner. At the highest doses tested (i.e., 7 or 10 mg / kg), significant effects on movement and speed were observed, but no effect on the time required in the center.

[0166] Example 14 Recognition ability and anxiety: Elevated Plus Maze (EPM) C57BL / 6 mice were administered 3 mg / kg of the compound by intraperitoneal injection. Mice were placed in the EPM 30 minutes after compound administration. The size of the EPM is 1 m × 1 m, and the test continues for 5 minutes. The total distance moved, speed, number of arm entries, and time in each arm were recorded and analyzed using EthoVision XT (Noldus, version 17). The results are shown in Figure 29. The data were plotted in GraphPad (version 9). n = 3 - 5 animals per treatment. Data are presented as mean ± SEM.

[0167] According to preliminary evidence requiring additional animals, intraperitoneal administration of 3 mg / kg sirocin significantly shortened the closed arm time (p = 0.029, independent t - test), but did not shorten the open arm time (p = 0.12, independent t - test). There was no significant difference in arm entries. The data, consistent with the OFT data, showed a tendency for overall movement and speed to decrease.

[0168] Example 15 Pharmacokinetics (PK) Silosine-D10 was prepared as an internal standard for the quantification of silosine in mouse plasma samples (Figure 30, upper left). The quantification of the compound was optimized for high-performance liquid chromatography tandem mass spectrometry (HPLC-MS / MS) (AB SciEx 4000 QTRAP®) with respect to voltage (Figure 30, upper 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 + 0.1% formic acid) (Figure 30, upper middle left), injection volume, and flow rate, and a standard curve was prepared (Figure 30, upper middle right). The selected organic solvent was 100% acetonitrile + 0.1% formic acid (red line in Figure 30, upper right). This is because the signal-to-noise ratio is the highest and the peak is the narrowest. The most effective injection volume and flow rate are 5 μL at 0.2 mL / min. The fragmentation pattern and mass-to-charge ratio (m / z) of silosine-D10 were determined (Figure 30, lower middle left). A standard curve for the detection of silosine in mouse plasma was prepared, and the upper and lower quality controls were set at 2.5 ng / mL and 400 ng / mL, respectively (Figure 30, lower middle right).

[0169] Example 16 Neurogenesis and Plasticity in Healthy Brain Organoids In three experiments, the effects of 16 nM, 50 nM, 160 nM, 500 nM, and 1600 nM of shirosibirine, silosine, or shirosibirine + silosine in a 1:1 molar ratio were measured after one exposure (6 hours later, followed by washing). Starting with control brain organoids, the results were verified in patient-derived organoids.

[0170] Three-month-old human brain organoids were exposed to an EdU pulse 6 hours after the final drug administration. Newborn neurons were quantified (e.g., EdU+ / NeuN+ / EdU+), and the degree of neurogenesis was determined. Ki67+ / Sox2+ co-labeling was used to study changes in the progenitor cell pool. EdU+ / NeuN+ / EdU+ data are shown in Figure 31, Ki67+ data are shown in Figure 32, and Sox2-positive cell data are shown in Figure 33.

[0171] Three-month-old organoids were exposed to silibinin, silychristin, or silibinin + silychristin at a 1:1 molar ratio for 6 hours, then dissected into small pieces and placed on Matrigel™ for 2 days. TUJ1 was used to label neurite outgrowth, and the length (μm) and number of branches were quantified. The results of neurite outgrowth are shown in Figure 34.

[0172] When silibinin + silychristin was administered in a 1:1 molar ratio combination, it was found that a single administration over 6 hours increased neurogenesis by approximately 20% and decreased proliferation to a similar extent. It was observed that the length of nerve cells was maximized 2 days after administration of silibinin + silychristin in a 1:1 molar ratio combination, reaching approximately twice as long as that in the case of silibinin alone at the highest dose.

[0173] The present invention has been described with reference to the above examples, but it will be understood that modifications and changes are possible within the spirit and scope of the present invention. Accordingly, the present invention is limited only by the following claims.

Claims

【Request Item 1】 【Chemistry 1】

2. The crystal type according to claim 1, wherein the crystal type is type A.

3. The crystal type according to claim 2, wherein type A is characterized by a powder X-ray diffraction (XRPD) pattern that includes a prominent peak at a 2θ angle of approximately 10.1°.

4. The crystal type according to claim 3, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 19.16°.

5. The crystal form according to claim 4, wherein the XRPD pattern further includes significant peaks at 2θ angles of approximately 10.74°, approximately 25.3°, and approximately 24.07°.

6. The crystal form according to claim 5, wherein the XRPD pattern further includes significant peaks at 2θ angles of approximately 14.54°, approximately 16.5°, approximately 13.44°, approximately 23.42°, and approximately 8.62°.

7. The crystal type according to claim 2, wherein type A is characterized by a DSC plot that includes a sharp endothermic event at a temperature of approximately 255°C.

8. The crystalline form according to any one of claims 2 to 7, wherein type A has a psilocybin-to-psilocine ratio of approximately 1:

1.

9. The crystal type according to any one of claims 2 to 7, wherein type A has a chemical purity of approximately 95% or more.

10. The crystal form according to any one of claims 2 to 7, wherein type A contains about 5 mol% or less of other solid forms.

11. The crystalline form according to any one of claims 2 to 7, wherein type A is a salt formed between psilocine and psilocybin.

12. The crystal type according to claim 1, wherein the crystal type is type B.

13. The crystal type according to claim 12, wherein type B is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of approximately 18.54°.

14. The crystal type according to claim 13, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 8.54°.

15. The crystal form according to claim 14, wherein the XRPD pattern further includes significant peaks at 2θ angles of approximately 22.78°, approximately 14.27°, and approximately 21.12°.

16. The crystal form according to claim 15, wherein the XRPD pattern further includes significant peaks at 2θ angles of approximately 14.12°, approximately 10.05°, approximately 9.94°, approximately 24.94°, and approximately 25.02°.

17. The crystal type according to claim 12, wherein type B is characterized by a DSC plot including a broad endothermic event at a temperature of approximately 168.2°C.

18. The crystalline form according to any one of claims 12 to 17, wherein type B has a psilocybin-to-psilocine ratio of approximately 1.3:

1.

19. The crystal type according to any one of claims 12 to 17, wherein type B has a chemical purity of approximately 95% or more.

20. The crystal form according to any one of claims 12 to 17, wherein type B includes other solid forms in an amount of about 5 mol% or less.

21. The crystalline form according to any one of claims 12 to 17, wherein type B is a salt formed between psilocine and psilocybin.

22. The crystal type according to claim 1, wherein the crystal type is C type.

23. The crystal type according to claim 22, wherein type C is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of approximately 9.18°.

24. The crystal type according to claim 23, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 17.95°.

25. The crystal form according to claim 24, wherein the XRPD pattern further includes significant peaks at 2θ angles of approximately 10.42°, approximately 24.22°, and approximately 18.38°.

26. The crystal form according to claim 25, wherein the XRPD pattern further includes significant peaks at 2θ angles of approximately 19.82°, approximately 17.46°, approximately 14.82°, approximately 22.38°, and approximately 14.06°.

27. The crystal type according to claim 22, characterized by a DSC plot in which type C is characterized by a broad endothermic event at temperatures of approximately 25 to 140°C, with a peak at 98.7°C.

28. The crystalline form according to any one of claims 22 to 27, wherein type C has a psilocybin-to-psilocine ratio of approximately 1:

1.

29. The crystal type according to any one of claims 22 to 27, wherein type C has a chemical purity of approximately 95% or more.

30. The crystal form according to any one of claims 22 to 27, wherein the C-type includes other solid forms in an amount of about 5 mol% or less.

31. The crystalline form according to any one of claims 22 to 27, wherein type C is a salt formed between psilocine and psilocybin.

32. A pharmaceutical composition comprising a crystalline form of a composition containing psilocin and psilocybin, and a pharmaceutically acceptable excipient. 【Chemistry 2】

33. The pharmaceutical composition according to claim 32, wherein the crystalline form is type A.

34. The pharmaceutical composition according to claim 33, wherein type A is characterized by an XRPD pattern that includes a significant peak at a 2θ angle of approximately 10.1°.

35. The pharmaceutical composition according to claim 34, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 19.16°.

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

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

38. The pharmaceutical composition according to any one of claims 33 to 37, wherein type A has a ratio of psilocybin to psilocine of approximately 1:

1.

39. The pharmaceutical composition according to any one of claims 33 to 37, wherein type A has a chemical purity of approximately 95% or more.

40. The pharmaceutical composition according to any one of claims 33 to 37, wherein type A is a salt formed between psilocin and psilocybin.

41. The pharmaceutical composition according to claim 32, wherein the crystalline form is type B.

42. The pharmaceutical composition according to claim 41, wherein type B is characterized by an XRPD pattern that includes a significant peak at a 2θ angle of approximately 18.54°.

43. The pharmaceutical composition according to claim 42, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 8.54°.

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

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

46. The pharmaceutical composition according to any one of claims 41 to 45, wherein type B has a psilocybin to psilocin ratio of approximately 1.3:

1.

47. The pharmaceutical composition according to any one of claims 41 to 45, wherein type B has a chemical purity of approximately 95% or more.

48. The pharmaceutical composition according to any one of claims 41 to 45, wherein type B is a salt formed between psilocin and psilocybin.

49. The pharmaceutical composition according to claim 32, wherein the crystalline form is type C.

50. The pharmaceutical composition according to claim 49, wherein type C is characterized by an XRPD pattern that includes a significant peak at a 2θ angle of approximately 9.18°.

51. The pharmaceutical composition according to claim 50, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 17.95°.

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

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

54. The pharmaceutical composition according to any one of claims 49 to 53, wherein type C has a ratio of psilocybin to psilocine of approximately 1:

1.

55. The pharmaceutical composition according to any one of claims 49 to 53, wherein type C has a chemical purity of approximately 95% or more.

56. The pharmaceutical composition according to any one of claims 49 to 53, wherein type C is a salt formed between psilocine and psilocybin.

57. A composition comprising crystalline forms of psilocine and psilocybin, 【Transformation 3】 Here, the crystal type is type A, Crystal type A is a composition characterized by unit cell parameters substantially equivalent to the following: Unit cell dimension: a=9.3674(3)Å b=11.2660(6)Å c=24.2741(9)Å α = 90 degrees β=90 degrees γ = 90 degrees Space group = P2 １ 2 １ 2 １ Molecular / Asymmetric Unit = 1.

58. The composition according to claim 57, wherein the unit cell parameter of crystal type A was measured at approximately 296 K.

59. The composition according to claim 57, wherein the crystal type A substantially has the hydrogen bonding geometry listed in Table A.

60. The composition according to claim 57, wherein the crystal type A substantially has the atomic coordinates of non-hydrogen atoms listed in Table B.

61. The composition according to claim 57, wherein the crystal type A substantially has the atomic coordinates of the hydrogen atoms listed in Table C.

62. A pharmaceutical composition comprising crystalline forms of psilocybin and psilocybin, and pharmaceutically acceptable excipients, 【Chemistry 4】 Here, the crystal type is crystal type A, and Crystal type A is a pharmaceutical composition characterized by unit cell parameters substantially equivalent to the following: Unit cell dimension: a=9.3674(3)Å b=11.2660(6)Å c=24.2741(9)Å α = 90 degrees β=90 degrees γ = 90 degrees Space group = P2 １ 2 １ 2 １ Molecular / Asymmetric Unit = 1.

63. The pharmaceutical composition according to claim 62, wherein the unit cell parameter of crystal type A was measured at approximately 296 K.

64. The pharmaceutical composition according to claim 62, wherein the crystal type A substantially has the hydrogen bonding geometry listed in Table A.

65. The pharmaceutical composition according to claim 62, wherein the crystal type A substantially has the atomic coordinates of non-hydrogen atoms listed in Table B.

66. The pharmaceutical composition according to claim 62, wherein the crystal type A substantially has the atomic coordinates of the hydrogen atoms listed in Table C.

67. Crystalline form of a composition containing psilocine and psilocybin 【Transformation 5】 A method for treating or improving a disease or disorder, comprising administering a substance to a target and thereby treating the disease or disorder.

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

69. The method according to claim 68, wherein the mental health disorder is selected from depressive disorder, anxiety disorder, post-traumatic stress disorder, and addiction disorder.

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

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

72. The method according to claim 68, wherein the CNS disease is a chronic pain disease.

73. Crystalline forms of psilocybin and psilocybin 【Transformation 6】 A composition containing the following is administered to the target, thereby stimulating neurogenesis. A method for stimulating neurogenesis or neurite growth.

74. The method according to claim 73, wherein stimulating neurogenesis or neurite growth results in an increase in the length of nerve cells.

75. The method according to claim 73, wherein stimulating neurogenesis or neurite growth results in improvement of cognitive abilities or other neurological functional impairments related to the state of the central nervous system.

76. The method according to claim 75, wherein the central nervous system condition is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, senile dementia, Pick's disease, parkinsonian dementia syndrome, progressive subcortical gliosis, progressive supranuclear palsy, thalamic degenerative syndrome, hereditary aphasia, myoclonus epilepsy, sleep deprivation, depression, stroke, ischemia, traumatic brain injury, psychological or physical trauma, chronic pain of any cause, cognitive impairment and cognitive decline.

77. The method according to claims 67 to 76, wherein the crystal type is type A.

78. The method according to claim 77, wherein type A is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of approximately 10.1°.

79. The method according to claim 78, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 19.16°.

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

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

82. The method according to claim 77, wherein type A is characterized by a DSC plot including a sharp endothermic event at a temperature of approximately 255°C.

83. The method according to claim 77, wherein type A has a psilocybin-to-psilocine ratio of approximately 1:

1.

84. The method according to claim 77, wherein type A has a chemical purity of approximately 95% or more.

85. The method according to claim 77, wherein type A comprises another solid type in an amount of about 5 mol% or less.

86. The method according to claim 77, wherein type A is a salt formed between psilocine and psilocybin.

87. The method according to any one of claims 67 to 76, wherein the crystal type is type B.

88. The method according to claim 87, wherein type B is characterized by an XRPD pattern that includes a prominent peak at a 2θ angle of approximately 18.54°.

89. The method according to claim 88, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 8.54°.

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

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

92. The method according to claim 87, wherein type B is characterized by a DSC plot including a broad endothermic event at a temperature of approximately 168.2°C.

93. The method according to claim 87, wherein type B has a psilocybin-to-psilocine ratio of approximately 1.3:

1.

94. The method according to claim 87, wherein type B has a chemical purity of approximately 95% or more.

95. The method according to claim 87, wherein type B comprises another solid type in an amount of about 5 mol% or less.

96. The method according to claim 87, wherein type B is a salt formed between psilocine and psilocybin.

97. The method according to any one of claims 67 to 76, wherein the crystal form is C-type.

98. The method according to claim 97, wherein type C is characterized by an XRPD pattern including a prominent peak at a 2θ angle of approximately 9.18°.

99. The method according to claim 98, wherein the XRPD pattern further includes a significant peak at a 2θ angle of approximately 17.95°.

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

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

102. The method according to claim 97, wherein type C is characterized by a DSC plot that includes a broad endothermic event at temperatures of about 25 to 140°C, with a peak at 98.7°C.

103. The method according to claim 97, wherein type C has a psilocybin to psilocine ratio of approximately 1:

1.

104. The method according to claim 97, wherein type C has a chemical purity of approximately 95% or more.

105. The method according to claim 97, wherein type C comprises another solid type in an amount of about 5 mol% or less.

106. The method according to claim 97, wherein type C is a salt formed between psilocine and psilocybin.

107. The method according to claim 67, wherein the composition further comprises a pharmaceutically acceptable excipient.

108. The method according to claim 67, wherein the composition is administered via an intradermal, subcutaneous, intravenous, intra-arterial, intradermal, transdermal, oral, sublingual, buccal, or nasal route of administration.

109. The method according to claim 67, further comprising the administration of a second pharmaceutically active compound.

110. The method according to claim 109, wherein the second pharmaceutically active compound is one or more anxiolytics, antidepressants, or painkillers.

111. The second pharmaceutically active compound is psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, bufotenin, bufotenidine, 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), N,N-dimethyltryptamine (DMT), 4-hydroxytryptamine, N,N,N-trimethyl-4-hydroxytryptamine ergin (LSA), ergonovine, ergometrine, muscimol, ibotenic acid, The method according to claim 109, wherein lysergic acid hydroxyethylamide (LSH), elymoclavine, ergometrinine, or chanoclavine, or any combination thereof.

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

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

114. The method according to claim 67, further comprising the administration of guided therapy.

115. The method according to claim 114, wherein the induction therapy is administered simultaneously with the composition.

116. The method according to claim 114, wherein the induction therapy is administered in succession with the composition.

117. The method according to claim 114, wherein the induction therapy is administered simultaneously with the second pharmaceutically active compound.

118. The method according to claim 114, wherein the induction therapy is administered sequentially with the second pharmaceutically active compound.

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