Methods for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

Abstract

To provide methods for treating anxiety disorders, headache disorders, and eating disorders with psilocybin.SOLUTION: The disclosure provides methods for treating a subject in need thereof, comprising administering to the subject a therapeutically-effective dose of psilocybin. The methods described herein may be used to treat a variety of diseases, disorders, and conditions. For example, the methods may be used to treat anxiety disorders, eating disorders, and headache disorders.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application is a continuation of U.S. application Ser. Nos. 62 / 835,449, 62 / 835,450, 62 / 835,458, 62 / 835,460, 62 / 835,464, 62 / 835,465, 62 / 835,472, 62 / 835,474, 62 / 835,476, 62 / 835,477, 62 / 835,478, 62 / 835,479, 62 / 835,480, 62 / 835,481, 62 / 835,482, 62 / 835,483, 62 / 835,484, 62 / 835,485, 62 / 835,486, 62 / 835,487, 62 / 835,488, 62 / 835,489, 62 / 835,490, 62 / 835,491, 62 / 835,492, 62 / 835,493, 62 / 835,494, 62 / 835,495, 62 / 835,496, 62 / 835,497, 62 / 835,498, 62 / 835,499, 62 / 835,499, 62 / 835,490, 62 / 835,491, 62 / 835,492, 62 / 835,493, 62 / 835,494, 62 / 835,495, 62 / 835,496, 62 / 835,497, This application claims priority to and benefit of U.S. Application Nos. 2 / 835,482, 62 / 835,484, and 62 / 835,485 (all filed April 17, 2019), U.S. Application No. 62 / 893,110 (filed August 28, 2019), U.S. Application No. 62 / 893,611 (filed August 29, 2019), and U.S. Application No. 62 / 946,159 (filed December 10, 2019), each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Psilocybin belongs to a class of drugs called psychedelics ("mind-manifesting" drugs). Specifically, psilocybin is considered a 5-hydroxytryptaminergic (serotonergic) psychedelic, as distinguished from other tryptamines such as dimethyltryptamine (DMT), ergolines such as lysergic acid diethylamide (LSD), and phenethylamines such as mescaline. Psilocybin was first isolated from psilocybe mushrooms and later synthesized in the laboratory.

[0003] There are several common diseases, disorders, and conditions for which no adequate treatment, therapy, or cure exists, including: Anxiety Disorders: Anxiety disorders are a class of mental disorders involving extreme fear or worry. Anxiety disorders often interfere with daily activities such as work performance, schoolwork, and relationships. Anxiety disorders have a variety of causes, including brain changes, environmental stress, and genetics. Examples of anxiety disorders include acute stress disorder, anxiety due to medical conditions, generalized anxiety disorder, panic disorder, panic attacks, phobias, post-traumatic stress disorder, obsessive-compulsive disorder, separation anxiety disorder, social anxiety disorder, substance-induced anxiety disorder, and selective mutism. Headache disorders: Headache disorders are characterized by recurrent headaches and are one of the most common disorders of the nervous system. Headaches are a disabling feature of headache disorders such as migraine, tension headache, and cluster headache. Eating disorder: An eating disorder is characterized by irregular eating habits and severe distress or concern about weight or body shape. Eating disturbances can involve inadequate or excessive food intake that may ultimately impair an individual's physical and / or psychological health. Examples of eating disorders include pica, anorexia nervosa, bulimia nervosa, rumination disorder, avoidant / restrictive food intake disorder, and binge eating disorder.

[0004] There remains a need in the art for improved compositions and methods for treating subjects using psilocybin. Summary of the Invention

[0005] Psilocybin may provide many clinical benefits, such as benefits in neuroplasticity and cognitive function (e.g., as measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) test), with improvements in working memory and executive function, sustained attention, and episodic memory. These benefits have important implications for the use of psilocybin in the treatment of various diseases, disorders, and conditions, including both psychiatric and neurological aspects thereof.

[0006] Disclosed herein, in some embodiments, are methods for treating one or more of an anxiety disorder, an eating disorder, and a headache disorder, comprising administering to said subject an effective amount of psilocybin or an active metabolite thereof.

[0007] Provided herein are methods for treating an anxiety disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0008] Also provided herein are methods for treating obsessive-compulsive and related disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0009] Also provided herein is a method for treating post-traumatic stress disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0010] Provided herein are methods for treating a headache disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0011] Also provided herein is a method for treating cluster headache in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0012] Also provided herein is a method for treating migraine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0013] Provided herein are methods for treating an eating disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0014] Also provided herein is a method for treating binge eating disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0015] Also provided herein is a method for treating anorexia nervosa in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0016] In some embodiments, the psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly pure crystalline psilocybin in the form of Polymorph A, wherein the crystalline psilocybin comprises at least 90% by weight Polymorph A. In some embodiments, the crystalline psilocybin comprises at least 95% by weight Polymorph A. In some embodiments, the crystalline psilocybin has a chemical purity of greater than 97% by high performance liquid chromatography (HPLC) and does not have a single impurity greater than 1%.

[0017] In some embodiments, psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly purified crystalline psilocybin in the form of Polymorph A, the crystalline psilocybin having a chemical purity of greater than 97% by HPLC and not having a single impurity greater than 1%. In some embodiments, psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly purified crystalline psilocybin in the form of Polymorph A, the crystalline psilocybin having a chemical purity of greater than 97% by HPLC and not having a single impurity greater than 1%, and further comprising a mixture of two silicified microcrystalline cellulose variants, the first variant having a particle size of about 45-80 microns and the second variant having a particle size of about 90-150 microns. In some embodiments, not more than about 30% of the microcrystalline cellulose is the first variant having a particle size of about 45-80 microns, and not less than about 70% of the microcrystalline cellulose is the second variant having a particle size of about 90-150 microns. In some embodiments, the psilocybin is administered in an oral dosage form. In some embodiments, the psilocybin is administered in a capsule. In some embodiments, the psilocybin is administered in a tablet.

[0018] In some embodiments, at least one dose of psilocybin is administered to the subject. In some embodiments, the dose of psilocybin is within the range of about 0.1 mg to about 100 mg. In some embodiments, the dose of psilocybin is about 25 mg.

[0019] In some embodiments, the subject participates in at least one psychological support session prior to administration of psilocybin. In some embodiments, the subject participates in at least one psychological support session after administration of psilocybin. In some embodiments, the therapist provides psychological support to the subject for about 4-8 hours after administration of psilocybin. [Brief explanation of the drawings]

[0020] [Figure 1] The numbered structural formula of psilocybin. [Figure 2A] FIG. 1 is an XRPD diffractogram of Polymorph A (GM764B). [Figure 2B] FIG. 1 is an XRPD diffractogram of polymorph A′ (JCCA2160F). [Figure 2C] FIG. 1 is an XRPD diffractogram of polymorph B (JCCA2160-F-TM2). [Figure 2D] FIG. 1 is an XRPD diffractogram of Hydrate A (JCCA2157E). [Figure 2E] FIG. 1 is an XRPD diffractogram of the ethanol solvate (JCCA2158D). [Figure 2F] XRPD diffractograms of the product obtained during the development of the process (CB646-E) (top) compared to polymorph A' (JCCA2160F) (center) and polymorph B (JCCA2160-TM2) (bottom). [Figure 3A] 1 is a DSC and TGA thermograph of polymorph A (GM764B). [Figure 3B] 1 is a DSC and TGA thermograph of polymorph A' (JCCA2160F). [Figure 3C] 1 is a DSC thermograph of polymorph B (GM748A). [Figure 3D] 1 shows DSC and TGA thermographs of Hydrate A (JCCA2157E). [Figure 3E] 1 is a DSC and TGA thermograph of the ethanol solvate (JCCA2158D). [Figure 4] FIG. 1 is a morphology phase diagram showing the interrelationships of morphologies in water-based systems. [Figure 5] This is the 1H NMR (nuclear magnetic resonance) spectrum of psilocybin. [Figure 6] This is the 13C NMR spectrum of psilocybin. [Figure 7] FT-IR spectrum of psilocybin. [Figure 8] Mass spectrum of psilocybin. [Figure 9A] 1 shows a timeline of a Phase 1 exploratory study evaluating psilocybin treatment in healthy volunteer subjects. [Figure 9B]The number of subjects who completed screening (Visit 1), baseline measurements (Visit 2), and drug administration (Visit 3) for the Phase 1 exploratory study is shown. [Figure 9C] Group sizes for dosing sessions of the Phase 1 exploratory study are shown. [Figure 9D] The most frequently reported adverse events from the exploratory phase 1 trials are shown. [Figure 9E] The duration of adverse events in the Phase 1 exploratory study is shown. [Figure 9F] FIG. 1 shows a graph of Paired-Associate Learning Total Errors (Adjustments) (PALTEA) scores over time on the Cambridge Neuropsychological Test Automated Battery (CANTAB) in psilocybin-treated and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9G] 1 shows a graph of the least squares (LS) mean difference from placebo in PALTEA scores over time for CANTAB in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9H] 1 shows a graph of spatial working memory between errors over time (SWMBE) scores for CANTAB in psilocybin-treated and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9I] 1 shows a graph of the least squares mean difference from placebo in SWMBE scores over time for CANTAB in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9J] FIG. 1 shows a graph of spatial working memory strategy (SWM strategy) scores over time on CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9K] 1 shows a graph of the least squares mean difference from placebo in SWM strategy scores over time for CANTAB in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9L] FIG. 1 shows a graph of rapid visual processing A-prime (RVPA) scores over time for CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9M]Figure 1 shows a graph of least squares (LS) mean differences for the psilocybin groups (10 mg and 25 mg) compared to the placebo group over time. Psilocybin was administered on day 0. Data were collected remotely on days 7 and 28. Positive scores indicate that psilocybin performed better than placebo. Negative scores indicate that placebo performed better than psilocybin. LS means were calculated using repeated measures analysis of variance and compared with placebo. *p≦0.05. Data are presented as LS means ± SEM. [Figure 9N] FIG. 1 shows a graph of the Emotion Recognition Task Percent Correct (ERTPC) of CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9O] 1 shows graphs of the CANTAB first-choice One Touch Stocking Problem Solved (OTSPSFC) in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9P] FIG. 1 shows a graph of the intra- and extra-dimensional set-shifting total errors (IEDYERT) of the CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9Q] FIG. 1 shows a graph of the CANTAB global composite score over time in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9R] 1 shows a graph of the least squares mean difference from placebo over time in the CANTAB global composite score in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9S] 1 shows graphs of verbal fluency testing in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9T] FIG. 1 shows a graph of the Digit Span Forward test in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9U] FIG. 1 shows a graph of 5-Dimensional Altered States of Consciousness (5D-ASC), which measures changes in mood, perception, and experience of self after administration of psilocybin or placebo in a Phase 1 exploratory study. [Figure 9V]The difference in CANTAB composite scores between "psilocybin-naive" (0, left) subjects and subjects with prior psilocybin experience (1, right) is shown. [Figure 10] Calsyntenin 2 (Clstn2) expression levels are shown at 1 hour, 24 hours, and 8 days after a single dose of psilocybin in naive mice compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test, *<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 11] Figure 1 shows receptor tyrosine-protein kinase erbB-4 (Erbb4) expression levels in naive mice 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 12] Figure 1 shows glucagon (Gcg) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 13] Figure 1 shows chemokine ligand 1 (Cxcl1) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 14]Activin A receptor-like type 1 (Acvrl1) expression levels are shown at 1 hour, 24 hours, and 8 days after a single dose of psilocybin in naive mice compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 15] The experimental conditions for the marble burying test are shown. [Figure 16] The number of buried marbles 1 hour after psilocybin (PS) treatment is shown. Fluoxetine (Fluox, 30 minutes before treatment) was used as a positive control. Data are presented as mean ± SEM. Statistical significance was determined using an unpaired t-test for vehicle FL and fluoxetine, ****p<0.0001. Statistical significance was determined using one-way ANOVA and Tukey's correction test for vehicle PS and psilocybin, **p<0.001. FL=fluoxetine, PS=psilocybin. [Figure 17] A series of graphs showing the change in the amount of wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep over a 24-hour period following psilocybin administration. The black arrows indicate the time of administration. The gray background indicates the dark period (the wakeful period for rodents). [Figure 18]

[0023] Figure 1 is a series of graphs showing the amount of wakefulness, NREM sleep, and REM sleep from 1 to 7 hours (light phase, sleep phase for rodents) after psilocybin administration. Statistical analysis by repeated measures ANOVA, *p<0.05. [Figure 19]

[0023] Figure 1 is a series of graphs showing the amount of wakefulness, NREM sleep, and REM sleep from 11 to 19 hours (dark phase) following psilocybin administration. Statistical analysis by repeated measures ANOVA, *p<0.05. [Figure 20]

[0023] Figure 1 is a set of graphs showing changes in absolute and relative waking electroencephalogram (EEG) power frequency and amount of gamma oscillations. Statistical analysis by repeated measures ANOVA, *p<0.05. [Figure 21] 1 is a series of graphs showing frequency changes in absolute and relative wake, NREM and REM sleep EEG power. [Figure 22]The number of entries into the open arms (left panel) and the time spent in the open arms (right panel) 2 hours after administration of psilocybin are shown. Diazepam was used as a positive control. Data are expressed as mean ± SEM. Statistical significance was determined using one-way ANOVA followed by Fisher's least significant difference for paired comparisons, *p≦0.05. [Figure 23] The number of entries into the open arms (left panel) and the time spent in the open arms (right panel) 24 hours after administration of psilocybin are shown. Diazepam was used as a positive control. [Figure 24]

[0023] Figure 1 shows the change in Social Connectedness Scale scores following administration of psilocybin to healthy human volunteers. Two-way repeated measures ANOVA with Bonferroni correction, **p<0.01, #<0.05. Data are expressed as mean ± SEM. [Figure 25]

[0023] Figure 1 shows reaction times of healthy human volunteers in a facial expression recognition task after administration of psilocybin. One-way ANOVA repeated measures, *p<0.05, **p<0.01, ***p<0.001. Data are expressed as mean ± SEM. [Figure 26] Figure 1 shows activation of the left amygdala, represented by the mean Z change in the left amygdala in healthy volunteers after administration of psilocybin. One-way ANOVA repeated measures, *p<0.05, **p<0.01, ***p<0.001. Data are expressed as mean ± SEM. [Figure 27] 1 shows the timeline of the chronic cluster headache study. [Figure 28] FIG. 1 shows the timeline of visits for a Phase 2 clinical trial to evaluate the use of psilocybin for the treatment of anorexia. [Figure 29] 1 shows a timeline of an in vivo study evaluating the use of psilocybin for the treatment of binge eating. [Figure 30]The amounts of food, chocolate, and total food consumed 1 hour after administration of 1 mg / kg psilocybin, 3 mg / kg psilocybin, 10 mg / kg psilocybin, saline vehicle, or lisdexamfetamine (LDX) are shown. Multiple comparisons with vehicle were performed by Williams' test for psilocybin and multiple t-test for LDX. **p<0.01, ***p<0.001. Data are presented as corrected mean ± SEM. [Figure 31] The amounts of chow, chocolate, and total food consumed 24 hours after administration of 1 mg / kg psilocybin, 3 mg / kg psilocybin, 10 mg / kg psilocybin, saline vehicle, or LDX are shown. Multiple comparisons with vehicle were performed by Williams' test for psilocybin and multiple t-test for LDX. *p<0.05, ***p<0.001. Data are presented as corrected mean ± SEM. [Figure 32] The effects of psilocybin on 24-hour food intake compared to the vehicle / binge treatment group are shown. One-way repeated measures ANOVA followed by Williams' test and multiple t-test for LDX, *p<0.05, **p<0.01, and ***p<0.001. Data are presented as corrected mean ± SEM. Arrows indicate binge days. [Figure 33] The effects of psilocybin on mean 24-hour food intake are shown. One-way repeated measures ANOVA followed by Williams' test and multiple t-test for f or LDX, *p<0.05, **p<0.01, and ***p<0.001. Vehicle / no chocolate data are presented as mean±SEM, and all other groups are presented as corrected mean±SEM. [Figure 34] The effect of psilocybin on body weight change compared to the vehicle / binge treatment group is shown. One-way repeated measures ANOVA followed by Williams' test and multiple t-test for f or LDX, *p<0.05, **p<0.01, and ***p<0.001. Vehicle / no chocolate data are presented as mean±SEM, and all other groups are presented as corrected mean±SEM. [Figure 35]

[0023] Figure 1 shows the effect of psilocybin on Life Change Inventory proprioception scores in a healthy volunteer study. Least squares (LS) means were calculated using a mixed model for repeated measures, followed by pairwise comparisons with the placebo group. ***p<0.001. Data are presented as LS means ± SEM. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition 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 to which this disclosure belongs. The terminology used in the detailed description is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0022] The singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0023] Additionally, as used herein, the term "about," when referring to a measurable value (dosage, time, temperature, etc.), is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or in some cases ±0.1% of the stated amount.

[0024] The term "and / or," as used herein in the specification and embodiments, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are present conjunctively in some cases and separately in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" elements so conjoined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, which may or may not be related to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0025] As used in this specification and in the embodiments, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., the inclusion of at least one, but also includes more than one element or list of elements, and optionally, further unlisted items. "Only one of" Only terms clearly indicated to the contrary, such as "one of," "exactly one of," or, when used in an embodiment, "consisting of," refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" should be construed only as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in an embodiment, should have its ordinary meaning as used in the field of patent law.

[0026] As used in this specification and in the embodiments, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, which may or may not be related to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally more than one, A, with no B (and optionally including elements other than B); in another embodiment to at least one, optionally more than one, B, with no A (and optionally including elements other than A); in yet another embodiment to at least one, optionally more than one, A, and at least one, optionally more than one, B (and optionally including other elements); etc.

[0027] Unless the context dictates otherwise, it is specifically contemplated that the various features described herein can be used in any combination.

[0028] As used herein, the terms "reduce," "decrease," "lessen," and similar terms refer to a reduction of at least about 10%, about 15%, about 20%, about 25%, about 35%, about 50%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, or more.

[0029] As used herein, the terms "improve," "increase," "enhance," and similar terms refer to an increase of at least about 10%, about 15%, about 20%, about 25%, about 50%, about 75%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more.

[0030] Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values ​​is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, reference to values ​​stated in ranges includes each and every value within that range. All ranges are inclusive and combinable.

[0031] As used herein, "substantially absent" with respect to an XRPD diffractogram peak means that, compared to a reference peak present in the diffractogram, the peak has a relative intensity of less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the intensity of the reference peak, or the peak is not detectable.

[0032] XRPD diffractograms and XRPD peak positions may be obtained using Cu Kα radiation.

[0033] DSC and TGA thermograms can be obtained using a heating rate of 20°C / min.

[0034] As used herein, the term "diffusion tensor imaging" or "DTI" refers to a technique that detects how water moves along white matter tracts in the brain. In some embodiments, DTI is used to characterize microstructural changes associated with psychiatric disorders (e.g., major depressive disorder) and / or response to treatment in subjects with psychiatric disorders.

[0035] All diseases and disorders listed herein are defined as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

[0036] As used herein, the terms "subject" and "patient" are used interchangeably.

[0037] As used herein, "treating" and like terms refer to reducing the severity and / or frequency of one or more symptoms, eliminating one or more symptoms and / or the underlying cause of said symptoms, reducing the frequency or likelihood of one or more symptoms and / or their underlying causes, delaying, preventing, and / or slowing the progression of a disease and / or disorder, and ameliorating or correcting damage caused directly or indirectly by a disease and / or disorder.

[0038] As used herein, a "therapeutically effective dose" means a dose sufficient to achieve the intended therapeutic purpose, such as alleviating the signs or symptoms of a disease or disorder in a subject.

[0039] As used herein, "precursors" and / or "derivatives" of psilocybin include, but are not limited to, prodrugs of psilocybin, prodrugs of active metabolites of psilocybin, and active metabolites of psilocybin.

[0040] As used herein, a subject who is "psilocybin-naive" has not previously been exposed to psilocybin.

[0041] As used herein, the following Medical Dictionary of Clinical Terms (MedDRA) terms are considered to be adverse events that are psychotomimetic in nature: mood changes, altered states of consciousness, self-image hallucinations, delusional perceptions, inhibition, dissociation, dissociative identity disorder, dream state, affective disorder, euphoric mood, abnormal sensations, hallucinations, hyperacusis, hyperesthesia, hypoesthesia, illusions, paranoia, olfactory paraesthesia, photophobia, paresthesia, altered time perception, thought disorder, synesthesia, substance-induced psychotic distress, and somatic hallucinations.

[0042] As used herein, the term "anxiety disorder" refers to a state of apprehension, uncertainty, and / or fear resulting from anticipation of an event and / or situation. Non-limiting examples of anxiety disorders include acute stress disorder, anxiety due to a medical condition, generalized anxiety disorder, panic disorder, panic attacks, phobias, post-traumatic stress disorder, obsessive-compulsive disorder, separation anxiety disorder, social anxiety disorder, substance-induced anxiety disorder, or selective mutism.

[0043] As used herein, the term "post-traumatic stress disorder" refers to a condition that develops after experiencing and / or witnessing a traumatic event, or learning that a traumatic event has happened to a loved one. Non-limiting examples of traumatic events include war, rape or sexual violence, physical attack, illness, robbery, childhood physical or sexual violence, kidnapping or hostage-taking, terrorist attack, torture, natural disaster, and / or exposure to a severe accident.

[0044] As used herein, "obsessive-compulsive and related disorders" refers to conditions involving compulsions or compulsions. Non-limiting examples of obsessive-compulsive and related disorders are obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, skin-picking disorder, trichotillomania, excoriation, substance-induced obsessive-compulsive and related disorders, or obsessive-compulsive disorder due to another medical condition, or a combination thereof.

[0045] As used herein, the term "eating disorder" refers to any of a range of psychological disorders characterized by abnormal or disturbed eating habits. Non-limiting examples of eating disorders include pica, anorexia nervosa, bulimia nervosa, rumination disorder, avoidant / restrictive food intake disorder, binge eating disorder, other specified feeding or eating disorder, unspecified feeding or eating disorder, or a combination thereof.

[0046] As used herein, the term "headache disorder" refers to a disorder characterized by recurrent headaches.

[0047] As used herein, "antidepressant" refers to any drug used to relieve depression. Non-limiting examples of antidepressants include, in some embodiments, the following antidepressants: adatanserin hydrochloride, adinazolam, adinazolam mesylate, alaproclate, arethamine hydrochloride, amidaline hydrochloride, amitriptyline hydrochloride, amoxapine, aphthazapine maleate, amitriptyline, azaroxan fumarate, azepindole, adipramine hydrochloride, bifenanol hydrochloride, bupropion hydrochloride, butacetin, butriftyline hydrochloride. hydrochloride), caroxazone, cartazolate, cyclazindol, cidoxepin hydrochloride, cilobamine mesylate, citalipram, clodazone hydrochloride, clomipramine hydrochloride, cotinine fumarate, cyclindol, cyphenamine hydrochloride, cyprolidol hydrochloride, ciproximide, darledintosilatetosylate), dapoxetine hydrochloride, dazadrol maleate, dazefinil hydrochloride, desipramine hydrochloride, dexamidazole, deximafen, dibenzepin hydrochloride, dioxadrol hydrochloride, dothipine hydrochloride, doxepin hydrochloride, duloxetine hydrochloride, eclanamine maleate, encyclate, etoferidone hydrochloride, pantridone hydrochloride, femetozole hydrochloride, penmethamide, bezolamine fumarate, fluorothracene hydrochloride, fluoxetine hydrochloride, fluparoxane hydrochloride, gammapexin, guanoxyfen sulfate, imafen hydrochloride, imilox hydrochloride, imipramine hydrochloride, indeloxazine hydrochloride, intriptyline hydrochloride, iflindole, isocalazide (iso cacarazide, ketipramine fumarate, lofepramine hydrochloride, lortalamine, mapprotiline, mapprotiline hydrochloride, melitracen hydrochloride, milacemide hydrochloride, minalin hydrochloride, mirtazapine, moclobemide, modal sulfate, napactadine hydrochloride, napamezole hydrochloride, nefazodone hydrochloride, nisoxetine, nitroputam hydrochloride, nomifensine maleate, nortriptyline hydrochloride, octriptyline phosphate, opipramol hydrochloride, oxaprotiline hydrochloride, oxypertine, paroxetine, phenelazine sulfate, pirandamine hydrochloride, piezotyline, pridepine hydrochloride, prolinetane hydrochloride hydrochloride, protriptyline hydrochloride, quipazine maleate, rolicillin, seproxetine hydrochloride, sertraline hydrochloride, sibutramine hydrochloride, sulfide, hydrotosol, tamethalin hydrochloride, tampramine fumarate, tandamine hydrochloride, thiazime hydrochloride, thozalinone, diosetin hydrochloride, trazodone hydrochloride, trebenzomine hydrochloride, trimimipramine, trimimipramine maleate, venlafaxine hydrochloride, viloxazine hydrochloride, zimeldine hydrochloride, and zometapine.

[0048] Psilocybin In some embodiments, the method of treatment comprises administering to a subject in need of treatment a therapeutically effective amount of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin, as described herein. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of psilocybin, as described herein. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of psilocin, as described herein. Some embodiments comprise psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin, as described herein, for use in treating an indication. Some embodiments comprise psilocybin for use in treating an indication, as described herein. Some embodiments comprise psilocin for use in treating an indication, as described herein. Some embodiments comprise the use of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin, as described herein, in the manufacture of a medicament for treating an indication.

[0049] The numbered structural formula of psilocybin is shown in Figure 1. Novel polymorphs and hydrates of psilocybin, and their preparation and formulations, are disclosed in U.S. Application No. US2019 / 0119310 A1, which is incorporated herein by reference in its entirety. US2019 / 0119310 discloses several formulations and challenges in formulating psilocybin due to, for example, its hygroscopicity and poor flow properties. US2019 / 0119310 also discloses the importance of a controlled aqueous crystallization process.

[0050] In some embodiments, the psilocybin comprises crystalline psilocybin in the form of polymorph A or polymorph A', as described herein, wherein the crystalline psilocybin exhibits peaks at 11.5, 12.0, and 14.5°2θ±0.1°2θ in an X-ray powder diffraction (XRPD) diffractogram. In some embodiments, the crystalline psilocybin further exhibits at least one peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ in an XRPD diffractogram. Exemplary XRPD diffractograms are provided as Figures 2A and 2B. In some embodiments, the crystalline psilocybin exhibits an endothermic event in a DSC thermogram having a first onset temperature between 145°C and 165°C and a second onset temperature between 205°C and 220°C. Exemplary DSC thermograms are provided as Figures 3A and 3B.

[0051] Polymorph A In some embodiments, the present disclosure provides crystalline psilocybin in the form of Polymorph A, which is characterized by one or more of the following: Peaks at 11.5, 12.0, 14.5, and 17.5°2θ±0.1°2θ in the XRPD diffractogram, a peak characterized by peaks at 11.5, 12.0, 14.5, and 17.5°2θ±0.1°2θ in an XRPD diffractogram, as well as at least one further peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ; an XRPD diffractogram substantially as shown in Figure 2A; or An endothermic event in a DSC thermogram having a first onset temperature of 145°C to 165°C and a second onset temperature of 205°C to 220°C, substantially as shown in Figure 3A.

[0052] In some embodiments, the peak at 17.5°2θ±0.1°2θ has a relative intensity that is at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% greater than the peak at 14.5°2θ±0.1°2θ.

[0053] In some embodiments, the present disclosure provides crystalline psilocybin in the form of Polymorph A, which is characterized by one or more of the following: Peaks at 11.5, 12.0, 14.5, and 17.5°2θ±0.2°2θ in the XRPD diffractogram, a peak in an XRPD diffractogram characterized by peaks at 11.5, 12.0, 14.5, and 17.5°2θ±0.2°2θ and at least one further peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.2°2θ, an XRPD diffractogram substantially as shown in Figure 2A; or An endothermic event in a DSC thermogram having a first onset temperature of 145°C to 165°C and a second onset temperature of 205°C to 220°C, substantially as shown in Figure 3A.

[0054] In some embodiments, crystalline psilocybin of Polymorph A exhibits an XRPD diffractogram having at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of the peaks listed in Table 1, or equivalent peaks within about ±0.1 degrees 2θ of the peaks listed in Table 1. In some embodiments, crystalline psilocybin of Polymorph A exhibits an XRPD diffractogram having at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of the peaks listed in Table 1, or equivalent peaks within about ±0.2 degrees 2θ of the peaks listed in Table 1. In some embodiments, Polymorph A exhibits a peak at 17.5 degrees 2θ ±0.1 degrees 2θ that is substantially absent in Polymorph A′. In some embodiments, polymorph A exhibits a peak at 17.5° 2θ±0.2° 2θ that is substantially absent in polymorph A′. [Table 1]

[0055] In some embodiments, crystalline psilocybin polymorph A exhibits XRPD diffractogram peaks at 11.5, 12.0, 14.5, and 17.5 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least one additional peak occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least two additional peaks occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least three additional peaks occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in Figure 2A.

[0056] In some embodiments, crystalline psilocybin polymorph Form A is characterized by XRPD diffractogram peaks at 14.5 and 17.5°2θ±0.1°2θ, wherein the peak at 17.5°2θ has an intensity that is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% of the intensity of the peak at 14.5°2θ.

[0057] In some embodiments, crystalline psilocybin polymorph A does not exhibit a peak at 10.1, i.e., the peak at 10.1 is absent or substantially absent.

[0058] In some embodiments, crystalline psilocybin polymorph A is characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 145° C. and 165° C., e.g., between 145° C. and 160° C., or e.g., between 145° C. and 155° C., and a second onset temperature of between 205° C. and 220° C., e.g., between 210° C. and 220° C., e.g., between 210° C. and 218° C., or e.g., between 210° C. and 216° C. In some embodiments, crystalline psilocybin polymorph A exhibits an endothermic event in a DSC thermogram having an onset temperature of about 205° C. to about 220° C., about 210° C. to about 220° C., about 210° C. to about 218° C., or about 210° C. to about 216° C. In some embodiments, crystalline psilocybin polymorph A further exhibits an endothermic event in a DSC thermogram with an onset temperature of about 145° C. to about 165° C., about 145° C. to about 160° C., or about 145° C. to about 155° C. In some embodiments, crystalline psilocybin polymorph A exhibits an endothermic event in a DSC thermogram with an onset temperature of about 205° C. to about 220° C., about 210° C. to about 220° C., about 210° C. to about 218° C., or about 210° C. to about 216° C., and an endothermic event with an onset temperature of about 145° C. to about 165° C., about 145° C. to about 160° C., or about 145° C. to about 155° C. In some embodiments, crystalline psilocybin polymorph A exhibits a DSC thermogram substantially the same as the DSC thermogram of FIG. 3A.

[0059] In some embodiments, crystalline psilocybin polymorph A exhibits a water content of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight. The water content of a crystalline compound can be determined by known methods, such as Karl Fischer titration. In some embodiments, crystalline psilocybin polymorph A exhibits a weight loss of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight in a TGA thermogram at ambient temperatures, e.g., between about 25°C and 200°C. In some embodiments, crystalline psilocybin polymorph A loses less than 2%, less than 1%, or less than 0.5% by weight in a loss-on-drying test, e.g., a loss-on-drying test performed at 70°C.

[0060] In some embodiments, the crystalline psilocybin polymorph A is a highly pure crystalline form of polymorph A, e.g., in a loss on drying test, the psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of crystalline psilocybin polymorph A.

[0061] In some embodiments, crystalline psilocybin polymorph A is a white to off-white solid.

[0062] In some embodiments, the crystalline psilocybin polymorph A is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph A contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A does not contain levels of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, the crystalline psilocybin polymorph A has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0063] Method for Producing Crystalline Psilocybin Polymorph A In another embodiment, the present disclosure provides a method for large-scale production of psilocybin, the method comprising subjecting psilocybin to a water crystallization step accompanied by controlled drying to produce crystalline psilocybin polymorph A.

[0064] In another embodiment, the disclosure provides a method for the large-scale production of psilocybin, the method comprising subjecting psilocybin to a water crystallization step with controlled drying to produce crystalline psilocybin polymorph A, which exhibits the XRPD diffractogram shown in Figure 2A and the DSC and TGA thermograms shown in Figure 3A. In another embodiment, the disclosure provides a method for the large-scale production of psilocybin, the method comprising subjecting psilocybin to a water crystallization step with controlled drying to produce high-purity crystalline psilocybin polymorph A, which exhibits the XRPD diffractogram shown in Figure 2A and the DSC thermogram shown in Figure 3A.

[0065] In another embodiment of the present disclosure, psilocybin is recrystallized in about 10-20 volumes of water, stirred and heated to a temperature of at least 70°C, polish filtered to a suitable cutoff (typically less than 5 μm), seeded at a temperature of about 70°C, and cooled in a controlled manner to about 5°C over a period of more than two hours.

[0066] In some embodiments, recrystallization of psilocybin involves controlled cooling, decreasing the temperature by about 5°C to 15°C per hour, more preferably about 10°C per hour. In certain embodiments, the polish filtration step is performed through an appropriately sized filter, such as, but not limited to, a 1.2 μm line filter.

[0067] In some embodiments, the stirring is performed by stirring at about 400-500 rpm, typically about 450 rpm.

[0068] In some embodiments, the psilocybin is dissolved in water heated to no more than 90° C. In some embodiments, the psilocybin is dissolved in water heated to no more than 85° C. Without being bound to any particular mechanism, this dissolution step is intended to solubilize the psilocybin while minimizing the formation of hydrolysis products.

[0069] In some embodiments, the psilocybin solution is agitated to speed solubilization and reduce the amount of time the solution is at elevated temperatures, i.e., 80° C. or higher.

[0070] In some embodiments, the seed is psilocybin hydrate A. In one embodiment, no more than 0.1% by weight of the seed is added to the process.

[0071] In some embodiments, the psilocybin of the crystalline psilocybin is isolated by vacuum filtration.

[0072] In some embodiments, the isolated crystals are vacuum dried at a temperature of at least 30°C, e.g., 30-50°C, or e.g., 40-50°C. In some embodiments, the isolated crystals are vacuum dried for at least 10 hours, e.g., 12-18 hours, or e.g., about 30 hours. In some embodiments, the isolated crystals are vacuum dried at a temperature of at least 30°C, e.g., 30-50°C, or 40-50°C, for at least 10 hours, e.g., 12-18 hours, or e.g., about 30 hours. In some embodiments, the isolated crystals are dried until the isolated crystals lose less than 2% by weight, e.g., less than 0.5% by weight, in a loss-on-drying test.

[0073] In some embodiments, the isolated crystals are washed several times in water and dried under vacuum at about 50° C. for at least 12 hours.

[0074] In some embodiments, the resulting crystals are typically relatively large (in the range of 50-200 microns) and uniform when viewed under a 10x microscope.

[0075] In contrast, crystals obtained without controlled cooling are much smaller in size (typically 5-50 microns) when viewed under a 10x microscope.

[0076] In some embodiments, provided is psilocybin obtained by the crystallization methods described herein.

[0077] In some embodiments, pharmaceutical formulations are provided that include psilocybin polymorph A obtained by the crystallization methods described herein.

[0078] In some embodiments, the pre-crystallization-produced psilocybin may be produced using one of a synthetic or biological method, for example, by fermentation, or may be obtained by extraction from mushrooms. In some embodiments, the pre-crystallization-produced psilocybin is produced according to all or part of the method described in U.S. Application No. 2019 / 0119310 A1, which is incorporated herein by reference in its entirety.

[0079] Polymorph A' The present disclosure provides crystalline psilocybin in the form of Polymorph A′, characterized by one or more of the following: (i) peaks in an XRPD diffractogram at 11.5, 12.0, and 14.5°2θ±0.1°2θ, but with the peak at 17.5°2θ±0.1°2θ absent or substantially absent; (ii) peaks in an XRPD diffractogram at 11.5, 12.0, and 14.5 °2θ ± 0.1 °2θ, but with the peak at 17.5 °2θ ± 0.1 °2θ absent or substantially absent, and further characterized by at least one additional peak at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ; (iii) an XRPD diffractogram substantially as shown in Figure 2B; or (iv) An endothermic event in a DSC thermogram having a first onset temperature between 145°C and 165°C and a second onset temperature between 205°C and 220°C, substantially as shown in Figure 3B.

[0080] In some embodiments, the crystalline psilocybin comprises crystalline psilocybin polymorph A'. Crystalline psilocybin polymorph A' exhibits peaks at 11.5, 12.0, and 14.5°2θ±0.1°2θ in an XRPD diffractogram, with the peak at 17.5°2θ±0.1°2θ being absent or substantially absent. In some embodiments, crystalline psilocybin polymorph A' further exhibits one, two, three, four, or five peaks selected from 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ. An exemplary XRPD diffractogram for Polymorph A' is provided as Figure 2B. An exemplary DSC thermogram for Polymorph A' having an onset temperature of 205-220°C is provided as Figure 3B.

[0081] In some embodiments, psilocybin polymorph A' exhibits an XRPD diffractogram summarized in Table 2. In some embodiments, crystalline psilocybin polymorph A' exhibits at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks listed in Table B, or equivalent peaks within about ±0.1 degrees 2θ, with the peak at 17.5 degrees 2θ ±0.1 degrees 2θ being absent or substantially absent. [Table 2]

[0082] In some embodiments, crystalline psilocybin polymorph A' exhibits XRPD diffractogram peaks at 11.5, 12.0, and 14.5 degrees 2θ ± 0.1 degrees 2θ, with the peak at 17.5 degrees 2θ ± 0.1 degrees 2θ being substantially absent. In some embodiments, crystalline psilocybin polymorph A' further exhibits at least one additional peak occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 degrees 2θ ± 0.1 degrees 2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least two additional peaks occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 degrees 2θ ± 0.1 degrees 2θ. In some embodiments, crystalline psilocybin polymorph A' exhibits polymorph A and is distinguished from polymorph A by the presence of a peak occurring at 10.1 degrees 2θ ± 0.1 degrees 2θ. In yet another embodiment, crystalline psilocybin polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in Figure 2B.

[0083] In some embodiments, crystalline psilocybin polymorph A' exhibits XRPD diffractogram peaks at 14.5 and 17.5°2θ±0.1°2θ, wherein the intensity of the peak at 17.5°2θ is less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the intensity of the peak at 14.5°2θ.

[0084] In some embodiments, crystalline psilocybin polymorph Form A' exhibits XRPD diffractogram peaks at 10.1 and 14.5°2θ±0.1°2θ, wherein the intensity of the peak at 10.1°2θ is at least 1%, at least 2%, at least 3%, or at least 4% of the intensity of the peak at 14.5°2θ.

[0085] In some embodiments, crystalline psilocybin polymorph A' is characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 145° C. and 165° C., e.g., between 145° C. and 160° C., or e.g., between 145° C. and 155° C., and a second onset temperature of between 205° C. and 220° C., e.g., between 210° C. and 220° C., e.g., between 210° C. and 218° C., or e.g., between 210° C. and 216° C. In some embodiments, crystalline psilocybin polymorph A' is characterized by an endothermic event in a DSC thermogram having an onset temperature of about 205° C. to about 220° C., about 210° C. to about 220° C., about 210° C. to about 218° C., or about 210° C. to about 216° C. In some embodiments, crystalline psilocybin polymorph A' exhibits an endothermic event in a DSC thermogram with an onset temperature of about 145°C to about 165°C, about 145°C to about 160°C, or about 145°C to about 155°C. In some embodiments, crystalline psilocybin polymorph A' exhibits an endothermic event in a DSC thermogram with an onset temperature of about 205°C to about 220°C, about 210°C to about 220°C, about 210°C to about 218°C, or about 210°C to about 216°C, and an endothermic event with an onset temperature of about 145°C to about 165°C, about 145°C to about 160°C, or about 145°C to about 155°C. In some embodiments, crystalline psilocybin polymorph A' exhibits a DSC thermogram substantially the same as the DSC thermogram in FIG. 3B.

[0086] In some embodiments, crystalline psilocybin polymorph A' exhibits a water content of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight. Methods for determining the water content of crystalline compounds are known, such as Karl Fischer titration. In some embodiments, crystalline psilocybin polymorph A' exhibits a weight loss of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight in a TGA thermogram at ambient temperatures, e.g., between 25°C and 200°C. In some embodiments, crystalline psilocybin polymorph A' loses less than 2%, less than 1%, or less than 0.5% by weight in a loss-on-drying test. In some embodiments, the loss-on-drying test is performed at 70°C.

[0087] In some embodiments, the crystalline psilocybin polymorph A' is a highly purified crystalline form of Polymorph A'. In some embodiments, the crystalline psilocybin comprises at least 90%, 95%, 99%, or 99.5% by weight of Polymorph A'.

[0088] In some embodiments, crystalline psilocybin polymorph A' is a white to off-white solid.

[0089] In some embodiments, the crystalline psilocybin polymorph A' is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, greater than 98%, or greater than 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph A' contains greater than 1% or greater than 0.5% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or no impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A' has no single impurity greater than 1 area%, or greater than 0.5 area%, as measured, for example, by HPLC. In some embodiments, crystalline psilocybin polymorph A' does not contain a level of psilocin greater than 1 area%, or greater than 0.5 area%, as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has 31 It does not contain levels of phosphate greater than 1% or greater than 0.5% by weight as measured by P NMR. In some embodiments, crystalline psilocybin polymorph A' has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0090] In some embodiments, the crystalline psilocybin polymorph A' is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph A' has greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A' has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' does not contain a level of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin polymorph A' has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0091] Exemplary XRPD diffractograms of high-purity crystalline psilocybin, Polymorph A, or Polymorph A' are provided in Figures 2A and 2B. Exemplary DSC thermographs of high-purity crystalline psilocybin, Polymorph A, or Polymorph A' are provided in Figures 2A and 2B.

[0092] Polymorph A (including its isostructural variant Polymorph A') (Figures 2A and 2B) is distinct from Polymorph B (Figure 2C), Hydrate A (Figure 2D), and the ethanol solvate (Figure 2E: Solvate A), and the relationships between some of the different forms are shown in Figure 4.

[0093] In some embodiments, crystalline psilocybin polymorph A or polymorph A' is a white to off-white solid and / or has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, such as 31 It has no impurity phosphate as measured by P NMR or no impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' does not contain a level of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin Polymorph A or Polymorph A' has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0094] Heating of Form A or A' results in an endothermic event with an onset temperature of approximately 150 °C, corresponding to the solid-solid transition of Form A or Form A' to Form B. Continued heating of the resulting solid, Form B, results in a second endothermic event corresponding to the melting point with an onset temperature of 205-220 °C (see Figures 3A and 3B).

[0095] Hydrate A In some embodiments, the disclosure provides psilocybin hydrate A in a crystalline form. In some embodiments, crystalline psilocybin hydrate A exhibits peaks at 8.9, 12.6, and 13.8 °2θ ± 0.1 °2θ in an XRPD diffractogram. In some embodiments, crystalline psilocybin hydrate A further exhibits at least one, two, three, four, or five additional peaks at 6.5, 12.2, 19.4, 20.4, or 20.8 °2θ ± 0.1 °2θ. An exemplary XRPD diffractogram is provided as FIG. 2D . In some embodiments, crystalline psilocybin hydrate A further exhibits endothermic events in a DSC thermogram having a first onset temperature between 90°C and 100°C, a second onset temperature between 100°C and 120°C, and a third onset temperature between 210°C and 220°C. An exemplary DSC thermogram is provided as FIG. 2D .

[0096] In some embodiments, psilocybin hydrate A exhibits an XRPD diffractogram comprising at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks listed in Table 3, or equivalent peaks within about ±0.1° 2θ. [Table 3]

[0097] In some embodiments, crystalline psilocybin hydrate A exhibits XRPD diffractogram peaks at 8.9, 12.6, and 13.8 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin hydrate A exhibits at least one peak occurring at 6.5, 12.2, 19.4, 20.4, or 20.8 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin hydrate A exhibits at least two peaks occurring at 6.5, 12.2, 19.4, 20.4, or 20.8 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin hydrate A exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in FIG. 2D .

[0098] In certain embodiments, crystalline psilocybin hydrate A is characterized by an endothermic event in a DSC thermogram having a first onset temperature between 85° C. and 105° C., e.g., between 90° C. and 100° C., and most preferably about 96° C., a second onset temperature between 100° C. and 120° C., e.g., between 105° C. and 115° C., and most preferably about 109° C., and a third onset temperature between 205° C. and 220° C., e.g., between 210° C. and 220° C., e.g., between 210° C. and 218° C., or between 210° C. and 216° C., or about 216° C. In some embodiments, crystalline psilocybin hydrate A exhibits an endothermic event in a DSC thermogram having an onset temperature between about 205° C. and about 220° C., between about 210° C. and about 220° C., between about 210° C. and about 218° C., or between about 210° C. and about 216° C. In some embodiments, crystalline psilocybin hydrate A exhibits an endothermic event in a DSC thermogram with an onset temperature of about 85° C. to about 105° C., or about 90° C. to about 100° C. In some embodiments, crystalline psilocybin hydrate A exhibits an endothermic event in a DSC thermogram with an onset temperature of about 205 to about 220° C., about 210 to about 220° C., about 210 to about 218° C., or about 210 to about 216° C., and an endothermic event with an onset temperature of about 85 to about 105° C., or about 90 to about 100° C. In some embodiments, crystalline psilocybin hydrate A exhibits a DSC thermogram substantially the same as the DSC thermogram of FIG. 3D.

[0099] In some embodiments, crystalline psilocybin hydrate A exhibits a water content of about 10% to about 18%, about 12% to about 16%, or about 13%. Methods for determining the water content of crystalline compounds are known, such as Karl Fischer titration. In some embodiments, crystalline psilocybin hydrate A exhibits a weight loss of about 10% to about 18%, about 12% to about 16%, or about 13% in a TGA thermogram at ambient temperatures, between about 25°C and 120°C.

[0100] In some embodiments, crystalline psilocybin hydrate A is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, crystalline psilocybin hydrate A contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin hydrate A has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin hydrate A has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin hydrate A does not contain a level of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin hydrate A has 31 It does not contain phosphoric acid at levels greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin hydrate A has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0101] In some embodiments, the crystalline psilocybin hydrate A is a highly purified crystalline form of hydrate A. In some embodiments, the crystalline psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of hydrate A.

[0102] Polymorph B In some embodiments, the present disclosure provides crystalline psilocybin polymorph B. In some embodiments, crystalline psilocybin polymorph B exhibits peaks at 11.1, 11.8, and 14.3°2θ ± 0.1°2θ in an XRPD diffractogram. In some embodiments, crystalline psilocybin polymorph B exhibits at least one, two, three, four, or five peaks at 14.9, 15.4, 19.3, 20.0, or 20.6°2θ ± 0.1°2θ in an XRPD diffractogram. An exemplary XRPD diffractogram of crystalline psilocybin polymorph B is provided as Figure 2C. In some embodiments, crystalline psilocybin polymorph B exhibits a single endothermic event in a DSC thermogram with an onset temperature of about 205 to about 220°C. An exemplary DSC thermogram of crystalline psilocybin polymorph B is provided as Figure 3C.

[0103] In some embodiments, psilocybin polymorph Form B exhibits an XRPD diffractogram comprising at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks listed in Table 4, or equivalent peaks within about ±0.1 degrees 2θ. [Table 4]

[0104] In some embodiments, crystalline psilocybin polymorph B exhibits XRPD diffractogram peaks at 11.1, 11.8, and 14.3 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph B exhibits at least one peak at 14.9, 15.4, 19.3, 20.0, or 20.6 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph B exhibits at least two peaks occurring at 14.9, 15.4, 19.3, 20.0, or 20.6 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph B exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in FIG. 2C.

[0105] In some embodiments, crystalline psilocybin polymorph B is characterized by a single endothermic event in a DSC thermogram having an onset temperature of about 205 to about 220° C., about 210 to about 220° C., about 210 to about 218° C., or about 210 to about 216° C. In some embodiments, crystalline psilocybin polymorph B exhibits a DSC thermogram substantially the same as the DSC thermogram in FIG. 3C.

[0106] In some embodiments, crystalline psilocybin polymorph B exhibits a water content of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight. Methods for determining the water content of crystalline compounds are known, such as Karl Fischer titration. In some embodiments, crystalline psilocybin polymorph B exhibits a weight loss of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight in a TGA thermogram at ambient temperatures, e.g., between 25°C and 200°C. In some embodiments, crystalline psilocybin polymorph B loses less than 2%, less than 1%, or less than 0.5% by weight in a loss-on-drying test. In some embodiments, the loss-on-drying test is performed at 70°C.

[0107] In some embodiments, the crystalline psilocybin polymorph B is a highly purified crystalline form of polymorph B, e.g., the psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of polymorph B.

[0108] In some embodiments, the crystalline psilocybin polymorph B is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph B contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph B has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph B has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph B does not contain levels of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph B has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin polymorph B has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0109] In some embodiments, the psilocybin of the present disclosure in the form of Polymorph A or A' has the general properties shown in Table 5. [Table 5]

[0110] In some embodiments, the psilocybin fits the spectrum as shown in Table 6 and illustrated in the spectra of Figures 5-8. [Table 6]

[0111] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0112] In some embodiments, the disclosure provides crystalline psilocybin in the form of Polymorph A or Polymorph A' for use in medicine. In some embodiments, the disclosure provides crystalline psilocybin Polymorph A for use in medicine. In some embodiments, the disclosure provides crystalline psilocybin Polymorph A' for use in medicine. In some embodiments, the disclosure provides high-purity crystalline psilocybin Polymorph A for use in medicine. In some embodiments, the disclosure provides high-purity crystalline psilocybin Polymorph A' for use in medicine. Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0113] In some embodiments, the present disclosure provides crystalline psilocybin in the form of Polymorph A or Polymorph A' for use in treating a subject in need thereof. Alternatively, independently, the crystalline psilocybin may be in the form of Hydrate A or Polymorph B.

[0114] In some embodiments, the present disclosure provides crystalline psilocybin polymorph A or polymorph A' for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides crystalline psilocybin polymorph A or polymorph A' for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides crystalline psilocybin polymorph A for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides crystalline psilocybin polymorph A' for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides high-purity crystalline psilocybin polymorph A for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides high-purity crystalline psilocybin polymorph A' for use in treating a subject in need of treatment.

[0115] Pharmaceutical Compositions and Formulations In some embodiments, the present disclosure provides pharmaceutical compositions comprising crystalline psilocybin and one or more pharmaceutically acceptable carriers or excipients.

[0116] In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity psilocybin and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising crystalline psilocybin polymorph A and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising crystalline psilocybin polymorph A' and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity crystalline psilocybin, Polymorph A, or Polymorph A' and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity crystalline psilocybin polymorph A and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity crystalline psilocybin polymorph A' and one or more pharmaceutically acceptable carriers or excipients.

[0117] Preferred pharmaceutical excipients for oral formulations include diluents such as microcrystalline cellulose, starch, mannitol, anhydrous calcium hydrogen phosphate, or a co-mixture of silicon dioxide, calcium carbonate, microcrystalline cellulose, and talc; disintegrants such as sodium starch glycolate or croscarmellose sodium; binders such as povidone, copovidone, or hydroxyl propyl cellulose; lubricants such as magnesium stearate or stearyl fumulate; glidants such as colloidal silicon dioxide; and film coats such as Opadry II white or PVA-based Opadry II brown.

[0118] In some embodiments, the oral dosage form also includes a disintegrant such as, but not limited to, starch glycolate, croscarmellose sodium, and / or mixtures thereof. In some embodiments, the oral dosage form includes 3% or less by weight of disintegrant, less than 3% by weight of disintegrant, and more than 0.001% by weight of disintegrant, about 2.5% or less by weight of disintegrant, 2% or less by weight of disintegrant, 1.5% or less by weight of disintegrant, 1% or less by weight of disintegrant, 0.7% or less by weight of disintegrant, 0.5% or less by weight of disintegrant, or 0.3% or less by weight of disintegrant.

[0119] In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the sodium starch glycolate is present at less than 3% by weight. In other embodiments, the sodium starch glycolate is present at about 2% by weight or less, about 2% by weight, about 1% by weight or less, about 1% by weight or less, about 0.7% by weight or less, about 0.7% by weight, about 0.5% by weight or less, or about 0.5% by weight. In still other embodiments, the sodium starch glycolate is present at about 0.5% to 1% by weight.

[0120] In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0121] In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0122] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%-1.0%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0123] In some embodiments, crystalline psilocybin in the form of Polymorph A or Polymorph A' is provided for use in medicine. In some embodiments, crystalline psilocybin Polymorph A is provided for use in medicine. In some embodiments, crystalline psilocybin Polymorph A' is provided for use in medicine. In some embodiments, high-purity crystalline psilocybin Polymorph A is provided for use in medicine. In some embodiments, high-purity crystalline psilocybin Polymorph A' is provided for use in medicine.

[0124] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0125] In some embodiments, there is provided crystalline psilocybin, particularly, but not essentially, in the form of Polymorph A or Polymorph A', for use in treating a central nervous system disorder.

[0126] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0127] In some embodiments, the pharmaceutical formulation is a parenteral dosage form. In some embodiments, the pharmaceutical formulation is an oral dosage form. In some embodiments, the pharmaceutical composition comprises a tablet. In some embodiments, the pharmaceutical composition comprises a capsule. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, two or more dosage forms are administered to a subject substantially simultaneously. In some embodiments, a subject may receive an entire therapeutic dose in one tablet or capsule. In some embodiments, a therapeutic dose may be divided among multiple tablets or capsules. For example, for a 25 mg dose, a subject may receive five tablets or capsules each containing 25 mg of psilocybin. Alternatively, for a 10 mg dose, a subject may receive two tablets or capsules each containing 5 mg of psilocybin.

[0128] In some embodiments, the oral dosage form includes a functional filler. The functional filler can be a silicified filler, such as, but not limited to, silicified microcrystalline cellulose (SMCC). In some embodiments, the oral dosage form includes a highly compressible grade of SMCC having a particle size range of about 45 to 150 microns. A mixture of two functional fillers with different particle size ranges can be used at two weight percentages, with the larger size particles predominating.

[0129] In some embodiments, the silicided microcrystalline filler may comprise a first filler having a particle size range of about 45-80 microns in an amount of up to 30%, up to 20%, up to 15% or less by weight of the filler, and a second filler having a particle size range of about 90-150 microns in an amount of up to 70%, up to 80%, up to 85% or more by weight of the filler.

[0130] In some embodiments, the oral dosage form may comprise silicified microcrystalline cellulose (SMCC 50) having a particle size of about 45-80 microns, such as Prosolv 50, silicified microcrystalline cellulose (SMCC 90) having a particle size of about 90-150 microns, such as Prosolv 90, or a mixture thereof. In other embodiments, the oral dosage form may comprise a mixture of SMCC 50 and SMCC In other embodiments, the oral dosage form may comprise SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:5 to 1:8 wt%. In still other embodiments, the ratio of SMCC 50 to SMCC 90 is 1:5 to 1:7, 1:6 to 1:7, 1:6 to 1:8, or 1.7 to 1.8. In still other embodiments, the ratio of SMCC 50 to SMCC 90 is 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, or 1:7. The formulation may further comprise or consist essentially of disintegrants, including but not limited to sodium starch glycolate, glidants, including but not limited to colloidal silicon dioxide, and lubricants, including but not limited to sodium stearyl fumarate.

[0131] In some embodiments, the oral dosage form may contain less than 3% (by weight), less than 2%, or 1% or less of a disintegrant, such as sodium starch glycolate.

[0132] In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0133] In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0134] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%-1.0%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0135] In some embodiments, the oral dosage form contains 5 mg of crystalline psilocybin in the form of Polymorph A, 12.5 mg of SMCC 50, 79.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate. In some embodiments, the tablet or capsule contains 5 mg of crystalline psilocybin in the form of Polymorph A, 12.5 mg of SMCC 50, 79.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate.

[0136] In some embodiments, the oral dosage form comprises 1 mg of crystalline psilocybin in the form of Polymorph A, 20.5 mg of SMCC 50, 75.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate. In some embodiments, the tablet or capsule comprises 1 mg of crystalline psilocybin in the form of Polymorph A, 20.5 mg of SMCC 50, 75.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate.

[0137] In some embodiments, the tablet or capsule comprises one or more excipients. Non-limiting exemplary excipients include microcrystalline cellulose, including but not limited to silicified microcrystalline cellulose, and starch.

[0138] It should be noted that the formulations may contain psilocybin in any form, not just the polymorphic forms disclosed herein.

[0139] As used herein, oral doses of psilocybin are categorized as "very low doses" (about 0.045 mg / kg or less), "low doses" (about 0.115 to about 0.125 mg / kg), "moderate doses" (about 0.115 to about 0.260 mg / kg), and "high doses" (about 0.315 mg / kg or more). See Studerus et al (2011) J Psychopharmacol 25(11) 1434-1452.

[0140] In some embodiments, the formulated dose of psilocybin comprises from about 0.01 mg / kg to about 1 mg / kg, and in some embodiments, a human dose (for an adult weighing 60-80 kg) comprises from about 0.60 mg to about 80 mg.

[0141] In some embodiments, the formulated dose contains about 2 mg to about 50 mg of crystalline psilocybin. In some embodiments, the formulated dose contains 2 mg to 40 mg, 2 mg to 10 mg, 5 mg to 30 mg, 5 mg to 15 mg, or 20 mg to 30 mg of crystalline psilocybin. In some embodiments, the formulated dose contains about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin.

[0142] In some embodiments, the formulated dose contains about 2 mg to about 50 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof. In some embodiments, the formulated dose contains 2 mg to 40 mg, 2 mg to 10 mg, 5 mg to 30 mg, 5 mg to 15 mg, or 20 mg to 30 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof. In some embodiments, the formulated dose contains about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof. In some embodiments, the formulated dose contains about 5 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof.

[0143] In some embodiments, the formulated dose contains about 2 mg to about 50 mg of crystalline psilocybin polymorph A. In some embodiments, the formulated dose contains 2 mg to 40 mg, 2 mg to 10 mg, 5 mg to 30 mg, 5 mg to 15 mg, or 20 mg to 30 mg of crystalline psilocybin polymorph A. In some embodiments, the formulated dose contains about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin polymorph A.

[0144] In some embodiments, the formulated dose contains about 2 mg to about 50 mg of crystalline psilocybin polymorph A'. In some embodiments, the formulated dose contains 2 mg to 40 mg, 2 mg to 10 mg, 5 mg to 30 mg, 5 mg to 15 mg, or 20 mg to 30 mg of crystalline psilocybin polymorph A'. In some embodiments, the formulated dose contains about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin polymorph A'.

[0145] In some embodiments, the formulated dose comprises about 2 mg to about 50 mg of crystalline psilocybin polymorph B. In some embodiments, the formulated dose comprises 2 mg to 40 mg, 2 mg to 10 mg, 5 mg to 30 mg, 5 mg to 15 mg, or 20 mg to 30 mg of crystalline psilocybin polymorph B. In some embodiments, the formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin polymorph B.

[0146] In some embodiments, the formulated dose contains about 2 mg to about 50 mg of crystalline psilocybin hydrate A. In some embodiments, the formulated dose contains 2 mg to 40 mg, 2 mg to 10 mg, 5 mg to 30 mg, 5 mg to 15 mg, or 20 mg to 30 mg of crystalline psilocybin hydrate A. In some embodiments, the formulated dose contains about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin hydrate A.

[0147] Dosage In some embodiments, a therapeutically effective amount of psilocybin is administered to the subject. In some embodiments, each dose of psilocybin administered to the subject is a therapeutically effective dose.

[0148] In some embodiments, a dose of psilocybin may be in the range of about 1 mg to about 100 mg. For example, the dose may be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some embodiments, the dose of psilocybin is about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg. In some embodiments, the dose of psilocybin is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, the dose of psilocybin is in the range of about 0.001 mg to about 1 mg. In some embodiments, the dose of psilocybin is in the range of about 100 mg to about 250 mg. In some embodiments, the dose of psilocybin is about 25 mg. In some embodiments, the psilocybin is in the form of polymorph A.

[0149] In some embodiments, an adult oral dose contains about 1 mg to about 40 mg, about 2 mg to about 30 mg, or about 15 mg to about 30 mg of crystalline psilocybin, e.g., about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin. In some embodiments, an adult oral dose contains about 25 mg of crystalline psilocybin. In some embodiments, the crystalline psilocybin is in the form of Polymorph A.

[0150] In some embodiments, a "microdose" of psilocybin is administered to a subject. A microdose may contain, for example, about 0.05 mg to about 2.5 mg of crystalline psilocybin, such as about 1.0 mg. In the case of microdosing, the regime may include, for example, a regular, continuous regime of daily administration, every other day administration, or weekly administration. Such administration may be without psychological support.

[0151] In some embodiments, one dose of psilocybin is administered to the subject. In some embodiments, multiple doses of psilocybin are administered to the subject. For example, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, at least 30, or at least 50 doses of psilocybin can be administered to the subject. In some embodiments, the same dose of psilocybin is administered to the subject during each administration. In some embodiments, different doses of psilocybin are administered to the subject during each administration. In some embodiments, the dose of psilocybin administered to the subject increases over time. In some embodiments, the dose of psilocybin administered to the subject decreases over time.

[0152] In some embodiments, psilocybin is administered at a therapeutically effective interval. In some embodiments, the therapeutically effective interval may be about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, the therapeutically effective interval may be about 1 month, about 3 months, about 6 months, or about 12 months. In some embodiments, psilocybin is administered once daily. In some embodiments, psilocybin is administered at least once per week or at least twice per week. In some embodiments, psilocybin is administered at least once per month or at least twice per month. In some embodiments, psilocybin is administered at least once every 3 months, at least once every 6 months, or at least once every 12 months.

[0153] In some embodiments, a first dose and a second dose of psilocybin are administered to a subject. In some embodiments, the first dose is about 1 mg and the second dose is about 1 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 1 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 1 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 1 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 1 mg.

[0154] In some embodiments, the second dose of psilocybin is administered about 1 week to about 12 weeks after the first dose. In some embodiments, the second dose of psilocybin is administered about 1 week after the first dose. In some embodiments, the second dose of psilocybin is administered about 2 weeks after the first dose. In some embodiments, the second dose of psilocybin is administered about 3 weeks after the first dose. In some embodiments, the second dose of psilocybin is administered about 4 weeks after the first dose. In some embodiments, the second dose of psilocybin is administered about 5 weeks after the first dose. In some embodiments, the second dose of psilocybin is administered about 6 weeks after the first dose.

[0155] Administration route Exemplary modes for administration of psilocybin include oral, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular [including administration to skeletal muscle, diaphragm muscle, and / or cardiac muscle], intradermal, intrapleural, intracerebral, and intra-articular), topical (e.g., to both cutaneous and mucosal surfaces, including respiratory tract surfaces, and transdermal), inhalation (e.g., via aerosol), rectal (e.g., via suppository), transmucosal, intranasal, buccal (e.g., sublingual), intravaginal, intrathecal, intraocular, transdermal, intrauterine (or intraovo), intralymphatic, and direct tissue or organ injection (e.g., into the liver, skeletal muscle, cardiac muscle, diaphragm muscle, or brain). In some embodiments, psilocybin is administered orally to a subject.

[0156] Treatment method Those skilled in the art will understand that methods of treatment comprising administering psilocybin, a psilocybin prodrug, a psilocybin metabolite, and / or a psilocybin metabolite prodrug for the treatment of one or more of the indications described herein also include the use of psilocybin, a psilocybin prodrug, a psilocybin metabolite, and / or a psilocybin metabolite prodrug in the manufacture of a medicament for the treatment of one or more of the indications described herein, as well as the use of psilocybin, a psilocybin prodrug, a psilocybin metabolite, and / or a psilocybin metabolite prodrug for the treatment of one or more of the indications described herein.

[0157] In some embodiments, a method for treating a subject in need of treatment comprises administering to the subject a therapeutically effective amount of psilocybin. In some embodiments, a method for treating a subject in need of treatment comprises administering to the subject a therapeutically effective amount of psilocybin in a controlled environment, wherein the subject is provided with psychological support.

[0158] In some embodiments, the method for treating a subject in need thereof comprises at least one of the following: (i) administering to a subject a therapeutically effective amount of psilocybin in a controlled environment, and providing the subject with psychological support; (ii) having the subject participate in one or more pre-administration psychological support session(s); and / or (ii) The subject participates in one or more post-administration psychological support session(s).

[0159] After administration of psilocybin, the subject may not feel the effects of the drug for about 30 minutes to about 90 minutes. In some embodiments, the subject may not feel the effects of the drug for about 60 minutes. This period after administration and before the onset of effects is referred to herein as the early phase of the psilocybin session. The time period characterized by the onset of the drug's effects is referred to herein as the early phase of the psilocybin session.

[0160] In some embodiments, the subject experiences the peak effects of the psilocybin between about 1.5 hours and about 3.5 hours after administration of the psilocybin. The period characterized by the peak psilocybin experience is referred to herein as the peak phase of the psilocybin session.

[0161] In some embodiments, the effects of psilocybin may substantially wear off between about 4 hours and about 6 hours after administration, a period referred to as the late phase of a psilocybin session.

[0162] In some embodiments, non-dual states (e.g., mystical experiences), or feelings of oneness, infinity, ego-annihilation, or transcendence correlate with positive clinical outcomes. Each of these terms can be generally defined as a breakdown of normal relationships between self and others, whereby a subject can feel a sense of oneness and increased connectedness to their surroundings and / or the world at large.

[0163] Low levels of emotional arousal, lack of engagement or intellectualization, which may in some embodiments indicate avoidance, may in some embodiments correlate with little or no improvement in treatment outcome.

[0164] Factors that may influence the subjective experience of psilocybin include, for example, (i) the dose, (ii) the participant's mood before the session, (iii) the setting of the session, (iv) the subject's ability to focus and stay with the experience, and / or (v) the subject's previous experience with psychedelics. These and other factors are described in more detail below, along with methods for maximizing the therapeutic benefit of a psilocybin session.

[0165] Pre-administration psychological support session In some embodiments, the subject participates in at least one psychological support session prior to administration of psilocybin (the "pre-administration psychological support session"). In some embodiments, the pre-administration psychological support session may occur about one month prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about two weeks prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about one week prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about three days prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about one day prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur on the same day as administration of psilocybin, prior to administration.

[0166] In some embodiments, the subject may participate in one, two, three, four, five, six, seven, or eight pre-administration psychological support sessions. In some embodiments, the subject may participate in at least two pre-administration psychological support sessions. In some embodiments, the subject may participate in at least three pre-administration psychological support sessions. In some embodiments, the subject may participate in a pre-administration psychological support session at least once a week for at least two or three weeks before the psilocybin session. In some embodiments, the subject may participate in an additional pre-administration psychological support session the day before the psilocybin session.

[0167] The pre-administration psychological support session may be an individual session, with the subject meeting one-on-one with a therapist. In some embodiments, the psychological support session may be a group session, with two or more subjects meeting with one therapist, or two or more therapists. In some embodiments, one or more of the subject's family members or friends may attend the pre-administration psychological support session(s).

[0168] In some embodiments, the purpose of the pre-administration session may include (i) building a therapeutic alliance between the subject and the therapist, (ii) answering the subject's questions and addressing any concerns, and / or (iii) demonstrating and demonstrating self-directed inquiry and experiential processing skills. In some embodiments, the pre-administration psychological support session focuses on discussing possible psilocybin effects and / or preparing the subject for the administration session by implementing relevant therapeutic techniques for reducing avoidance and anxiety, eliciting appropriate treatment goals, building rapport, and / or building a therapeutic alliance. During the psychological support session, self-directed inquiry and experiential processing skills may be demonstrated and / or demonstrated.

[0169] In some embodiments, breathing exercises aimed at promoting calmness and / or relieving anxiety may be demonstrated and / or performed. In some embodiments, the breathing exercises include instructing the subject to focus on whole-body breathing and / or breathing-related sensations. For example, the subject may be instructed to breathe in for a count of four, hold the breath briefly, and then breathe out for a count of eight. In some embodiments, the therapist and subject may discuss the most beneficial ways to assist in case of emotional distress during the psilocybin session. In some embodiments, the subject is given access (e.g., online access) to materials regarding the safety and mechanism of action of psilocybin.

[0170] In some embodiments, the pre-administration psychological support session helps to establish the therapeutic goals of the psilocybin session. In some embodiments, the subject proposes their own therapeutic goals. In some embodiments, the therapist proposes therapeutic goals to the subject. In some embodiments, the subject is reminded of the therapeutic goals during the pre-administration psychological support session.

[0171] In some embodiments, the therapist is trained to counsel the subject before, during, and / or after the psilocybin session. In some embodiments, the therapist has mental health training. In some embodiments, the therapist is a clinical psychologist, psychiatrist, social worker, physician, or nurse. In some embodiments, the therapist meets the following criteria: ·Demonstrate independent clinical experience in direct subject care in areas requiring counseling and psychotherapeutic skills; · A current unrestricted professional license and / or good professional standing with no history of suspension, professional misconduct, or disciplinary action; and / or ·High level of openness to learning new approaches and receiving feedback.

[0172] Psychological support during psilocybin sessions During the treatment session, the subject may be supervised by one or more trained therapists. The therapist supervising the subject during the psilocybin session may be the same therapist as the subject's pre-administration psychological support session(s), or may be a different therapist. The therapist(s) may provide psychological support to the subject as needed. As used herein, the term "psychological support" refers to any measure(s) taken by the therapist during the subject's psilocybin session to ensure the subject's safety and maximize the clinical effectiveness of the psilocybin session. For example, psychological support may be provided by the therapist to (1) ensure the subject's psychological safety, (2) allow the subject's subjective experience to unfold naturally within the boundaries of the therapeutic intent established in the preparation, (3) maintain attention and awareness of the participant's current experience, thereby allowing the exposure and processing of difficult emotional states and personal memories, and / or (4) generate insights and solutions for the resolution of difficult personal situations, conflicts, and traumatic experiences. In some embodiments, assistance may be in the form of touch therapy, verbal reassurance, guided imagery, and / or relaxation or breathing exercises. In some embodiments, assistance may include reminders, encouragement, or active guidance. Typically, only one technique is applied at a time to allow for minimal intervention and interference with the subject's intrinsic processes.

[0173] In some embodiments, the therapist's primary therapeutic goals during a psilocybin session are (i) minimizing extreme anxiety and (ii) providing appropriate support to enable self-directed inquiry and experiential processing skills and processes. In some embodiments, the therapist demonstrates true presence, patience, curiosity, and / or openness during the psilocybin session. "Presence" refers to being fully available and present with the subject at all stages of the psilocybin session, and always exhibiting calmness. "Curiosity" refers to interest and willingness to understand the subject's experience without preconceptions. "Patience" refers to the therapist facilitating the participant's exploration of the experience, taking the time necessary to do so without suppressing the participant's natural impulse to assist or direct the experience. "Openness" refers to the therapist's ability to maintain a cognitively and experientially open state, including the ability to recognize how the subject's mind will uniquely orchestrate the unfolding content of the session. This includes welcoming all emotions and expressions that may arise.

[0174] In some embodiments, psychological support may include inquisitive questioning, in which brief yet detailed questions are asked of the subject ("How does that make you feel?") to help the subject shift and maintain attention across different levels of cognition and emotion. Because of its applicability across a wide range of mental states and in various settings, the inquisitive questioning technique can typically be used safely and consistently during psilocybin sessions, regardless of the quality or intensity of each subject's experience.

[0175] In some embodiments, the level of psychological support varies during different stages of a subject's psilocybin experience (e.g., initial, early, peak, and late). In some embodiments, the type of psychological support varies during different stages of a subject's psilocybin experience (e.g., initial, early, peak, and late). Because non-dual, ego-annihilating, or "integrative" experiences have been shown to positively correlate with the magnitude and durability of clinical response, in some embodiments, therapists pay particular attention to addressing such states.

[0176] In some embodiments, a subject may experience a compromised sense of self during their psilocybin experience. In some embodiments, this experience is interpreted from a psychoanalytic perspective as a breakdown of ego boundaries, resulting in a blurring of the distinction between self and object representations and preventing the integration of self representations into a coherent whole. In some embodiments, a non-dual, ego-annihilated, or "integrative" experience refers to an altered state of consciousness in which there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a loss of a sense of "self," and instead, only an undivided background awareness, often characterized by a sense of unity or "oneness" that transcends sensory or cognitive comprehension. In some embodiments, a non-dual experience is a state of consciousness in which the subject-object dichotomy of normal waking consciousness is replaced by a non-centered, undivided, integrated background awareness. In some embodiments, an ego-annihilated experience is a spontaneously occurring state of consciousness in which there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a loss of a sense of "self." In some embodiments, an integrative experience is one characterized by a sense of unity or "oneness" that goes beyond sensory or cognitive understanding.

[0177] During the initial and early stages of psilocybin sessions, psychological support may be used to reduce severe and / or prolonged anxiety. Anxiety before or during the onset of psilocybin effects is not uncommon, and therapists can be specially trained to recognize and actively manage the subject through such periods of anxiety until the subject feels comfortable enough to continue on their own. In some embodiments, the therapist validates the subject's anxiety without providing an interpretation of perceptual disturbances or directing the subject toward specific images or memories, other than encouraging the subject to relax and open up to emergent experiences. For example, in some embodiments, the therapist may use grounding exercises to help alleviate anxiety. In such exercises, the subject may be encouraged to pay attention to surrounding sounds or sensations on the skin when touching the bed / sofa, the ground, or other objects.

[0178] During the initial and early stages of a psilocybin session, the therapist may encourage the subject to lie down, practice relaxation and breathing exercises, and / or listen to calming music. In some embodiments, the therapist may remind the subject of the intent of the treatment session. For example, the therapist may ask the subject, "What does it feel like when you feel better or recovered?" or any number of similar questions. Such reminders provide an implicit orientation to the subjective experience during the psilocybin session, before or during the onset of the psilocybin effect. In some embodiments, the therapist may remind the subject that their primary task during this session is simply to gather new and interesting experiences that can be discussed with the therapist after the session. The therapist may remind the participant of the purpose of psilocybin therapy and the role of experiential processing, i.e., allowing the participant to be open and curious about whatever arises and to encounter thoughts and feelings previously unknown to the participant. In some embodiments, the therapist emphasizes that this process essentially requires a willing passivity to, and no mindfulness of, the psychedelic experience.

[0179] During acute behavioral onset, the subject may experience perceptual changes in visual, auditory, or olfactory modes, as well as a series of unusual physical sensations. These experiences may be anxiety-provoking. In some embodiments, the therapist may perform a reassuring "arm holding," where, at the subject's request, the therapist places a hand on the subject's wrist, arm, hand, or shoulder to help the subject feel at ease during this phase. This training may have been previously conducted in a pre-administration psychological support session.

[0180] In some embodiments, the therapist may encourage the subject to wear an eye mask, such as a Mindfold blindfold, hi some embodiments, the therapist encourages the subject to wear an eye mask before, during, or after the onset of the effects of psilocybin.

[0181] In some embodiments, the therapist may encourage the subject to wear headphones and listen to music. In some embodiments, the headphones reduce external noise (e.g., "noise-canceling" headphones). In some embodiments, the music is calming music, such as instrumental (e.g., classical) music. In some embodiments, the music includes nature sounds and / or the sounds of moving water (e.g., ocean sounds). In some embodiments, the music includes isochronic sounds. In some embodiments, the music includes periods of silence. In some embodiments, the music is emotionally evocative. In some embodiments, the music includes a playlist that reflects the pharmacodynamics of a typical high-dose psilocybin session: early phase, early stage, peak phase, and late phase. In some embodiments, listening to music helps the subject focus on their internal experience.

[0182] In cases of long-term anxiety or distress, in some embodiments, the therapist may actively guide the participant through such an experience without interpreting or judging the experience or offering advice. Once the participant is comfortable, the therapist can encourage them to reconnect with introspection.

[0183] During the peak and later stages of psilocybin sessions, the therapist can encourage the subject to confront and explore their experiences, including difficult ones. The therapist can guide the subject to engage in self-directed inquiry and experiential processing to develop different perspectives on personal challenges and conflicts and generate unique solutions. Such self-generated insights can provide the subject with self-confidence as well as emotional resolution.

[0184] As used herein, the term "self-directed inquiry" refers to paying attention to internal states. The subject is encouraged to be curious about their moment-to-moment present experience, including foreground and background thoughts, feelings, and physical sensations. During the preparation and integration phases, this inquiry may mean asking specific, detailed questions that help direct attention to internal states. However, during periods of drug behavior, inquiry may simply mean being open to inner experiences.

[0185] As used herein, "experiential processing" refers to a participant's ability to maintain full attention to an experience that is recognized through self-directed inquiry. This includes the willingness and ability to stay with and / or move through uncomfortable or difficult thoughts, feelings, sensations, or emotions until the discomfort is alleviated or resolved.

[0186] In some embodiments, the therapist uses transdiagnostic therapy. In some embodiments, transdiagnostic therapy is Method of Level (MOL) therapy. In yet further embodiments, MOL therapy involves self-directed inquiry and experiential processing. Typically, MOL uses brief, yet detailed, and inquisitive questions to help the subject shift and maintain attention across different levels of cognition and emotion (Carey, 2006; Carey, Mansell, & Tai, 2015). The emphasis within MOL is to identify and address the subject's underlying distress, not just symptoms. Such MOL-related methods and techniques can include the following: (1) Self-Directed Inquiry—Attention to Inner State. Participants are encouraged to be curious about their present-moment experience, including foreground and background thoughts, emotions, and bodily sensations. During the preparation and integration phases, such inquiry can mean asking specific and detailed questions that help direct attention to inner state; however, in some embodiments, during periods of drug effect, inquiry can refer to an attitude of openness to inner experience. (2) Experiential Processing - refers to the ability to sustain a sustained focus on experience and maintain full attention on experiences that participants bring to consciousness through self-directed inquiry. This includes the willingness and ability to stay with and / or move through uncomfortable or difficult thoughts, feelings, sensations, or emotions until the discomfort is reduced or resolved.

[0187] In some embodiments, the psychological support comprises mindfulness-based therapy or cognitive behavioral therapy (CBT). In some embodiments, the psychological support is provided by a functional theory of human behavior called perceived control theory.

[0188] Occasionally, subjects seek distraction while avoiding new experiences or attempting to regain cognitive control over their abnormal state of mind. Such distraction can take different forms. For example, a subject may be premature to engage in conversation or to elaborate on their experiences, perspectives, or insights. When this occurs, the therapist can aim to remain silent as much as possible, thereby allowing the subject and their internal experiences to direct the course of the psilocybin session. In some embodiments, the therapist may use active listening skills paired with prompts to encourage the subject to remain focused on the current experience, especially if the participant engages the therapist in the conversation. In another example, a subject may request to go to the bathroom or get a drink of water. The sudden, urgent nature of such requests may suggest that they are truly trying to avoid the new material. In such cases, the therapist can encourage the subject to linger in the experience by simply redirecting their attention. For example, the therapist could say something like: "Let's take a bathroom break at the end of this music," or "We'll be handing out water shortly. Why don't you put the eye mask back on and relax for a few minutes?" If the subject is trying to avoid a difficult experience, they may listen to the suggestion and relax.

[0189] In some embodiments, spontaneous movement such as rocking, stretching, or dancing while engaging in an experience is acceptable and often encouraged, unless the movement is perceived as a way to distract from the experience. In some embodiments, if the subject is frequently constantly moving, they may be periodically provided with cues to return to a lying position and actively focus inward.

[0190] The therapist need not understand, endorse, or have an opinion about the nature or content of the subject's experiences, but the therapist can validate them and communicate openness to the subject's own perspective on them without denying or pathologizing any experiences based on their abnormal content. These experiences may offer the subject a perspective beyond identification with a personal narrative. In some embodiments, the therapist validates one or more of the subject's experiences. In some embodiments, validating an experience simply means having the courage to be open to the experience and acknowledging the possibility that any experience may serve the intent of the session.

[0191] In some embodiments, the therapist provides psychological support for approximately 4-8 hours immediately after administration of psilocybin. In some embodiments, the therapist uses guided imagery and / or breathing exercises to calm the subject and / or focus the subject's attention. In some embodiments, the therapist touches the subject's hand, arm, or shoulder. In some embodiments, the therapist counsels the subject to do one or more of the following: (1) accept feelings of anxiety, (2) allow the experience to unfold naturally, (3) avoid psychological resistance to the experience, (4) relax, and / or (5) explore the subject's own mental space.

[0192] In some embodiments, the therapist avoids initiating conversation with the subject but responds if the subject initiates a conversation. Typically, active intervention is kept to a minimum during the therapeutic experience. In some embodiments, the subject is encouraged to explore their own mental space, and simple guided imagery may be used to assist relaxation. "Guided imagery" refers to exercises that ask the subject to imagine a scene (e.g., "Picture a scene, perhaps a landscape, and tell me where you are," "Imagine a place where you feel safe").

[0193] Post-administration psychological support session In some embodiments, subjects may be encouraged to participate in a post-administration integration session with their therapist. Integration is a process that involves processing or embodying the psychedelic experience within a therapeutic context. This process begins with the subject verbalizing, reflecting on, and openly discussing with the therapist any experiences from the psilocybin session. Successful integration of the psilocybin experience involves addressing emotional changes and transforming the experience into new insights, perspectives, and new behaviors that can be used to benefit the subject's quality of life thereafter. New perspectives may then influence the participant's current knowledge or values, leading to new ways of relating to cognition, emotions, behavior, and physical experiences.

[0194] In some embodiments, the goals and support methods used by the therapist throughout an integrated session should remain consistent regardless of the intensity or content of the subjective experiences explored by the subject. Nevertheless, the support methods used by the therapist should accommodate all experiences the subject may have encountered.

[0195] The integration process should not be limited to sessions with the therapist and is likely to continue unfolding beyond clinic visits. Therapists may encourage participants to use methods such as spending time in nature, exercise, or creative expression to help further the process. Subjects may also be encouraged to discuss their experiences with friends, family, and / or support networks. The role of the integration session is not to comprehensively address the entire experience, but to empower participants by building their capacity to safely process information experientially. This allows participants to continue self-directed integration outside of clinical study visits.

[0196] In some embodiments, the subject participates in at least one psychological support session after administration of psilocybin (the "post-administration psychological support session"). In some embodiments, the post-administration psychological support session may occur on the same day as the psilocybin session, after the effects of the psilocybin have substantially worn off. In some embodiments, the post-administration psychological support session may occur the day after the psilocybin session. In some embodiments, the post-administration psychological support session may occur two days after the psilocybin session. In some embodiments, the post-administration psychological support session may occur three days after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about one week after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about two weeks after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about one month after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about three months after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about six months after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about 12 months after the psilocybin session.

[0197] In some embodiments, a subject may participate in 1, 2, 3, 4, 5, 6, 7, or 8 post-administration psychological support sessions, hi some embodiments, a subject may participate in at least 2, or at least 3 post-administration psychological support sessions.

[0198] The post-administration psychological support session may be an individual session, with the subject meeting one-on-one with a therapist. In some embodiments, the psychological support session may be a group session, with two or more subjects meeting with one therapist, or two or more therapists. In some embodiments, one or more of the subject's family members or friends may attend the post-administration psychological support session(s).

[0199] In some embodiments, post-administration psychological support sessions may focus on integrating the psilocybin experience. Integration may include processing the psychedelic experience in a therapeutic context. Integration may include psychological and somatic processing of the experience and successful assimilation of insights into the subject's life for the purposes of growth, healing, and / or well-being. In integration sessions, subjects may be encouraged to discuss and reflect on their experiences during the psilocybin session. In some embodiments, integration may include external expression of the psilocybin experience, such as word choice, tone of voice, gestures, and / or specific physical activities (e.g., yoga, exercise, bodywork, etc.). In some embodiments, integration includes creatively expressing any insights or experiences gained during the psilocybin experience, for example, through poetry, art, music / singing, dance, writing, or drawing.

[0200] In some embodiments, the subject may be encouraged to reflect on both the thoughts and emotions experienced during the psilocybin session and to express those thoughts and emotions in a tangible form that can serve as a tool for remembering and continuing to integrate those lessons in the future. In some embodiments, the subject may be encouraged to recognize and connect the range of emotional, cognitive, and physical experiences of the psilocybin session and relate them to current experiences in the subject's life situation. This may be achieved, for example, by discussing them initially with the therapist and perhaps later with family, friends, and supportive circles. Integration helps to respond to changes in emotional state as new insights are generated and integrated. When further explored through oscillating attention between foreground and background thoughts and emotions, such insights may lead to natural and effortless changes in perspective or behavior. In some embodiments, the integration process is not limited to the initial integration meeting with the therapist but continues to unfold spontaneously through the participant's own processing and behavior in everyday life.

[0201] In the case of low-intensity experiences, the integration process may focus on mental content that emerged during periods of relaxation and reflection, including reactions to what may have been unremarkable experiences such as disappointment, anger, or relief.

[0202] Psychological support provided remotely In some embodiments, psychological support can be provided to the subject remotely.For example, the therapist who provides psychological support does not need to be in the same room, building, or facility as the subject.Remote psychological support can be provided, for example, by telephone (i.e., voice call), video call or video conference, text, or email.

[0203] In some embodiments, the pre-administration therapy session is conducted remotely. In some embodiments, the post-administration therapy session (e.g., the integration session) is conducted remotely.

[0204] In some embodiments, psychological support is provided remotely during a subject's psilocybin session. For example, in some embodiments, the subject takes psilocybin at home, and a therapist provides psychological support via voice call, video call, text, email, etc., for at least 4-8 hours after the subject has taken the drug. In some embodiments, the subject takes psilocybin at a dosing facility described herein, and a therapist provides psychological support to the subject, and the therapist provides psychological support via voice call, video call, text, email, etc., for at least 4-8 hours after the subject has taken the drug.

[0205] In some embodiments, remote psychological support is provided to a subject using a digital or electronic system. In some embodiments, the digital or electronic system may include one or more of the following features: Digital or electronic systems securely connect patients with one or more therapists or physicians for “virtual visits.” These virtual visits can be introductory or routine. A digital or electronic system allows subjects to qualify, pre-qualify, or enroll in a psilocybin-based clinical trial or a psilocybin-based psychological support session. A digital or electronic system is configured to help therapists and / or physicians manage and interact with patients. For example, the electronic system may allow therapists to share documents with subjects, leave notes about sessions, or schedule future sessions. The digital or electronic system may be configured to provide an alert for crisis intervention. For example, the digital or electronic system may allow a subject to contact a therapist if the subject is feeling anxious or otherwise needs to urgently speak with a therapist. The digital or electronic system is configured to help the subject prepare for a visit with a therapist and / or physician. For example, the digital or electronic system may include information about psilocybin, treatment protocols, etc. Digital or electronic systems are configured to allow therapists to provide psychological support during a subject's psilocybin session. For example, the systems may include video calling or chat functionality. Digital or electronic systems are set up to enable therapists to provide psychological support during post-administration sessions (e.g., consolidation sessions). A digital or electronic system is configured to track a subject's adherence to a treatment regimen or goal. The digital or electronic system is configured to assess one or more clinical endpoints in a subject. For example, the system may include one or more questionnaires or tasks for the subject to complete. The results may be available to the subject's physician and / or therapist.

[0206] In some embodiments, the digital or electronic system is an "app" for use on a mobile phone or computer. In some embodiments, the digital or electronic system is a website. In some embodiments, the digital or electronic system includes a "chat" feature that allows real-time communication between the subject and the therapist. In some embodiments, the website includes a video call feature that allows the therapist to communicate with the subject using video communication. In some embodiments, the digital or electronic system is configured to allow a single therapist to provide psychological support to one or more subjects simultaneously or contemporaneously.

[0207] In some embodiments, psychological support sessions may be pre-recorded (e.g., audio or video recorded) and provided to the subject via a digital or electronic system for use at the subject's convenience.

[0208] Management facilities, "Sets and Settings" As used herein, the term "set and setting" refers to the subject's perspective ("set") and the physical and social environment ("setting") in which a user has a psilocybin session. In some embodiments, psilocybin may be administered in a particular set and setting. In some embodiments, the set and setting are controlled to maximize, to the extent possible, the therapeutic benefit of the psilocybin session.

[0209] In some embodiments, psilocybin is administered by a facility specifically designed for psilocybin administration. Administering psilocybin to a subject in a facility where the subject feels safe and comfortable can help alleviate the subject's anxiety and promote maximum clinical benefit. For example, psilocybin may be administered to a subject in their own home or in a clinical facility.

[0210] In some embodiments, psilocybin is administered to a subject in a facility (e.g., a room) that has a substantially non-clinical appearance. For example, psilocybin can be administered in a room equipped with soft furniture (e.g., plush sofas, chairs, or pillows) and / or plants. In some embodiments, the room can be decorated using subdued colors (e.g., gray, dull, or unsaturated colors). In some embodiments, the light in the room is dimmed and / or the light level is kept relatively low or adjusted. In some embodiments, the room lighting is adjusted for intensity and / or color. In some embodiments, a virtual reality or augmented reality system (e.g., a computer with visual / graphical and auditory output) is used. In some embodiments, the room is equipped with a sound system, e.g., a high-resolution sound system. In some embodiments, the sound system can allow for simultaneous ambient and earphone listening. In some embodiments, the subject can bring a meaningful photo or object into the administration room.

[0211] In some embodiments, the room comprises a couch. In some embodiments, the room comprises a bed. In some embodiments, the room comprises more than one couch or bed, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 couches or beds. In some embodiments, the subject sits or lies on the couch or bed for about 4-8 hours, or a substantial portion thereof, immediately after administration of the psilocybin. In some embodiments, the subject listens to music for about 4-8 hours, or a substantial portion thereof, immediately after administration of the psilocybin. In some embodiments, the subject wears an eye mask for about 4-8 hours, or a substantial portion thereof, immediately after administration of the psilocybin. In some embodiments, the subject is provided with a weighted blanket.

[0212] In some embodiments, each subject is supervised by one therapist during the psilocybin session. In some embodiments, each subject is supervised by more than one therapist during the psilocybin session, such as two therapists, three therapists, four therapists, or five therapists. In some embodiments, one therapist has multiple subjects, and each subject participates in the psilocybin session. For example, one therapist can supervise two, three, four, five, six, seven, eight, nine, or ten subjects.

[0213] Embodiments of the present disclosure include the use of additional tools and / or techniques in conjunction with medication / administration, including various transcranial magnetic stimulation (TMS) methods and protocols, e.g., before or after one or more medication(s), biofeedback devices, etc.

[0214] Some embodiments can be used in conjunction with digital health products or digital solutions. The teachings of the present disclosure include utilizing such digital health products and / or associated digital biomarkers as diagnostic and / or prognostic assessment tools for patient monitoring and management before, during, and / or after treatment. Digital biomarkers may include, by way of non-limiting example, the number and / or duration of phone calls / emails / texts, word length in text communications, gestures used (taps, swipes, or other), gyroscope-derived information such as phone orientation, phone acceleration, keystroke patterns, location-derived information from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media use, sleep patterns, specific words or emojis used or not used, and / or the like. For example, in one embodiment, a digital health product can be utilized to track compliance, determine medication dosage and / or frequency, indications of need for re-dosing, re-dosing amounts, alerts, or warnings.

[0215] In some embodiments, the treatment method can include providing a clearance period for the subject or patient, during which such one or more drugs are absent or substantially removed from the subject's / patient's system. For example, the treatment method can be configured such that, at the time of administration, the subject is not taking other serotonergic agents, such as selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and / or antipsychotics. In some embodiments, the treatment method includes concurrent treatment with one or more drugs, including, but not limited to, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and / or monoamine oxidase inhibitors. In some embodiments, the methods include treatments in which the subject or patient takes concomitant compounds or medications including, but not limited to, benzodiazepines, cannabidiol (CBD) and / or other cannabinoids (e.g., THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), CBT (cannabicitran), and / or the like), magnesium, levomefolic acid, for example, prior to, immediately prior to, and / or concurrently with receiving psilocybin.

[0216] In some embodiments, the methods include treatment in which the subject has not been taking one or more medications, particularly one or more serotonergic medications for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, 3 weeks, or 4 weeks prior to administration of the disclosed psilocybin compounds.

[0217] In some embodiments, the methods and / or treatments can include sub-perceptual dosing (e.g., doses of less than 3 mg, 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, or 0.1 mg) before and / or after administration of a single or multiple relatively large dose (given days to weeks apart), where the single or multiple relatively large dose is one or more of 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg or more, 45 mg or more, 50 mg or more.

[0218] Embodiments of the present disclosure include methods of utilizing digital biomarkers as diagnostic and / or prognostic tools for patient management, for example, before, during, and / or after treatment with psilocybin, where the digital biomarker is one or more biomarkers related to executive function, cognitive control, working memory, processing speed, and / or emotional valence.

[0219] In some embodiments, digital biomarkers may be identified from patterns in smartphone use, such as swipes, taps, and other touchscreen activity, and scientifically validated to provide measurements of subjective states, such as cognition and mood, including, by way of non-limiting example, those disclosed in one or more of the following, each of which is expressly incorporated by reference herein for all purposes: US2017 / 0086727, US2017 / 0258382, US2017 / 0258383, US2017 / 0287348, US10 / 148534, US97 / 37759, and / or US10 / 231651.

[0220] Biomarkers that may serve as diagnostic and / or prognostic tools for pre-treatment, during treatment, and / or post-treatment patient management may be identified using one or more of the following: number and / or duration of calls / emails / texts, word length in text communications, gestures used (taps, swipes, or other), information derived from a gyroscope, such as phone orientation, phone acceleration, keystroke patterns, location derived from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media use, sleep patterns, specific words or emojis used or not used, and / or the like. In some embodiments, health components and / or connected biomonitors and / or smart devices / wearables may be utilized to gather information used in the diagnostic and / or prognostic output. For example, in some embodiments, a heart rate monitor or similar device can collect subject data and heart rate variability (e.g., as disclosed in US10058253, which is incorporated herein by reference in its entirety) can be used to assess / determine metrics related to the subject's current emotional state, relative changes in emotional state, etc., which can be used to determine new or subsequent treatment regimens, adjust treatment regimens, etc.

[0221] According to a further aspect of the present disclosure, there is provided a method of evaluating a subject before, during, and / or after treatment for a central nervous system disorder to determine whether to provide psilocybin treatment or further psilocybin treatment, the method comprising monitoring one or more biomarkers related to executive function, cognitive control, working memory, processing speed, and emotional valence, and determining treatment based on the outcome. The method can further include administering psilocybin for the first time or thereafter.

[0222] In some embodiments, biomarkers are identified from patterns in smartphone use, such as swipes, taps, and other touchscreen activity, and scientifically validated to provide measures of cognition and mood. For example, in some instances, patterns may be identified using one or more of the following: number and / or duration of calls / emails / texts, word length in text communications, gestures used (taps, swipes, or other), information derived from the gyroscope, such as phone orientation, phone acceleration, keystroke patterns, location derived from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media use, sleep patterns, specific words or emojis used or not used, and / or the like.

[0223] Embodiments include methods of evaluating a subject before, during, and / or after treatment for a central nervous system disorder to determine whether to provide psilocybin treatment or further psilocybin treatment, comprising monitoring one or more biomarkers related to executive function, cognitive control, working memory, processing speed, and emotional valence, and determining treatment based on the outcome, which may further include administering psilocybin for the first time or subsequently.

[0224] In some embodiments, the disclosure provides for treating two or more subjects, the method comprising administering a therapeutically effective dose of psilocybin to each subject simultaneously or at substantially the same time (e.g., within minutes of each other, within 5, 10, 15, 20, 25, or 30 minutes of each other), wherein each subject is aware of the other subjects receiving treatment. In some embodiments, the subjects are in the same room. In some embodiments, the subjects are in different rooms.

[0225] In some embodiments, the present disclosure provides a method of treating a subject, the method comprising administering to the subject a therapeutically effective dose of psilocybin and providing a virtual reality / immersive virtual reality digital tool. In some embodiments, the lights in the room are dimmed and / or the light level is kept relatively low or adjusted. In some embodiments, darkened glasses or eye shades are provided. In some embodiments, the room lighting is adjusted for intensity and / or color. In some embodiments, a virtual reality or augmented reality system (e.g., a computer with visual / graphical and audio output) is used.

[0226] subject In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the female subject is pregnant or postpartum. In some embodiments, the subject is attempting to reduce or eliminate the use of a medication, such as an antidepressant or antiepileptic drug. In some embodiments, the subject is attempting to reduce or eliminate the use of a medication before becoming pregnant, undergoing surgery or other medical procedure, or starting the use of a different medication.

[0227] The subject can be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject. In some embodiments, the subject is under about 18 years of age. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10 years of age, about 10-15 years of age, about 15-20 years of age, about 20-25 years of age, about 25-30 years of age, about 30-35 years of age, about 35-40 years of age, about 40-45 years of age, about 45-50 years of age, about 50-55 years of age, about 55-60 years of age, about 60-65 years of age, about 65-70 years of age, about 70-75 years of age, about 75-80 years of age, about 85-90 years of age, about 90-95 years of age, or about 95-100 years of age.

[0228] The subject may have a chronic or terminal illness, hi some embodiments, the subject may have a life-altering illness or condition (such as losing a limb or developing blindness).

[0229] The subject may have recently been diagnosed with disease, disorder or condition.For example, the subject may have been diagnosed within 1 month, 3 months, 6 months or 1 year.In some embodiments, the subject may have been living with disease, disorder or condition for a long period, such as at least 6 months, at least 1 year, at least 3 years, at least 5 years or at least 10 years.

[0230] In some embodiments, the subject may be a cancer patient, such as a stage 4 or terminal cancer patient. In some embodiments, the subject may have been determined to have a limited survival time, such as less than 1 year, less than 6 months, or less than 3 months.

[0231] The subject may have previously taken a psychedelic drug or may have never previously taken a psychedelic drug, for example, the subject may have previously taken psilocybin, psilocybin mushrooms ("magic mushrooms"), LSD (lysergic acid diethylamide or acid), mescaline, or DMT (N,N-dimethyltryptamine).

[0232] In some embodiments, the subject may have previously taken one or more serotonergic antidepressants (e.g., selective serotonin reuptake inhibitors (SSRIs)). In some embodiments, the subject has not previously taken a serotonergic antidepressant. In some embodiments, the subject has not taken any serotonergic antidepressants for at least 2 weeks, at least 4 weeks, or at least 6 weeks prior to receiving psilocybin.

[0233] In some embodiments, the subject may have previously undergone electroconvulsive therapy (ECT), hi some embodiments, the subject has not undergone any ECT for at least 2 weeks, at least 4 weeks, or at least 6 weeks prior to receiving psilocybin.

[0234] The subject may have a medical condition that prevents the subject from receiving a particular medical therapy (such as an SSRI or ECT). In some embodiments, the subject may have previously had an adverse reaction to a particular medical therapy (such as an SSRI or ECT). In some embodiments, the prior medical therapy (such as an SSRI or ECT) was not effective in treating the disease, disorder, or condition in the subject.

[0235] Diseases, disorders, and / or conditions to be treated Provided herein are methods of treating a subject in need thereof, the methods comprising administering to the subject a therapeutically effective dose of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin.

[0236] Anxiety disorders In some embodiments, disclosed herein are methods for treating one or more anxiety disorders in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, the active metabolite is psilocybin.

[0237] As used herein, the term "anxiety disorder" refers to a state of apprehension, uncertainty, and / or fear resulting from anticipation of an event and / or situation. Anxiety disorders cause physiological and psychological signs or symptoms. Non-limiting examples of physiological symptoms include muscle tension, heart palpitations, sweating, dizziness, shortness of breath, tachycardia, tremors, fatigue, worry, irritability, and sleep disturbances. Non-limiting examples of psychological symptoms include fear of death, fear of embarrassment or humiliation, fear of an event occurring, and the like. Anxiety disorders also impair a subject's cognition, information processing, stress levels, and immune response. In some embodiments, the methods disclosed herein treat chronic anxiety disorders. As used herein, a "chronic" anxiety disorder is recurrent.

[0238] Anxiety disorders are considered to be the most common class of mental disorders, affecting more than 60 million people annually in Europe, while epidemiological studies estimate that one-third of the population will suffer from an anxiety disorder during their lifetime.

[0239] Non-limiting examples of anxiety disorders include acute stress disorder, anxiety due to a medical condition, generalized anxiety disorder, panic disorder, panic attacks, phobias, post-traumatic stress disorder, obsessive-compulsive disorder, separation anxiety disorder, social anxiety disorder, substance-induced anxiety disorder, or selective mutism.

[0240] In some embodiments, the subject in need of treatment develops an anxiety disorder after experiencing the consequences of a disease. The consequences of a disease include the individual being diagnosed with the disease, the diagnosis of a relative of the individual with the disease, social isolation due to the disease, isolation from the disease, or social distancing as a result of the disease. In some embodiments, the individual is quarantined to prevent the spread of the disease. In some embodiments, the disease is COVID-19, SARS, or MERS. In some embodiments, the subject develops an anxiety disorder after losing a job, losing a home, or fearing not being able to find employment.

[0241] In some embodiments, the anxiety disorder comprises a medical diagnosis based on the criteria and classification of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. In one embodiment, the anxiety disorder comprises a medical diagnosis based on an independent medical evaluation.

[0242] Disclosed herein, in some embodiments, are methods for treating generalized anxiety disorder in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Generalized anxiety disorder is characterized by excessive anxiety and worry, fatigue, restlessness, increased muscle aches or pains, impaired concentration, irritability, and / or difficulty sleeping. In some embodiments, the subject with generalized anxiety disorder does not have associated panic attacks.

[0243] In some embodiments, disclosed herein are methods for treating social anxiety disorder in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. As used herein, "social anxiety disorder" refers to marked fear or anxiety associated with one or more social situations in which the individual is exposed to potential scrutiny by others. Non-limiting examples of situations that induce social anxiety include social interactions (e.g., having a conversation, meeting unfamiliar people), being observed (e.g., eating or drinking), and performing in front of others (e.g., giving a speech). In some embodiments, the social anxiety disorder is limited to public speaking or acting. In some embodiments, treatment with the disclosed methods reduces or improves symptoms of social anxiety disorder. In some embodiments, the reduction / improvement in symptoms of social anxiety disorder can be measured using any one of the assessments described herein. In some embodiments, after treatment, symptoms are reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0244] In some embodiments, disclosed herein are methods for treating panic disorder in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Subjects with panic disorder experience panic attacks, which are sudden feelings of fear in the absence of real danger. Subjects experiencing panic attacks may feel as if they are losing control. In some embodiments, subjects with panic disorder have physical symptoms, including, but not limited to, rapid heartbeat, chest or stomach pain, difficulty breathing, weakness or dizziness, sweating, hot or cold sensations, and tingling or numb hands. In some embodiments, treatment with the disclosed methods reduces the incidence of panic attacks compared to before the treatment. In some embodiments, treatment with the disclosed methods reduces the number of panic attacks per month by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0245] Disclosed herein in some embodiments is a method for treating a phobia in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. A phobia is an irrational fear of something with a low likelihood of causing harm. A phobia causes anxiety, fear, and panic. In some embodiments, the phobia is agoraphobia, acrophobia, aerophobia, arachnophobia, thunder phobia, kotophobia, claustrophobia, homophobia, hydrophobia, snake phobia, animal phobia, chicken phobia, name phobia, beard phobia, cloud phobia, and freezing phobia. In some embodiments, the subject has agoraphobia. In some embodiments, the phobia is a specific phobia. In some embodiments, the specific phobia is animal phobia, natural environment phobia, blood injection injury phobia, or situational phobia. In some embodiments, one or more symptoms of the phobia are reduced after treatment with the present disclosure.

[0246] In some embodiments, disclosed herein are methods for treating post-traumatic stress disorder (PTSD) in a subject in need of treatment, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. As used herein, the term "post-traumatic stress disorder" refers to a condition that develops after experiencing and / or witnessing a traumatic event, or learning that a traumatic event has occurred to a loved one. Non-limiting examples of traumatic events include exposure to war, rape or sexual violence, physical assault, disease, robbery, childhood physical or sexual violence, kidnapping or hostage-taking, terrorist attack, torture, natural disaster, and / or severe accident. In some embodiments, post-traumatic stress disorder is caused by trauma associated with an infectious disease pandemic, such as, but not limited to, COVID-19. For example, trauma can be caused by a pandemic such as COVID-19, forced quarantine, social isolation, damage to personal health, or damage to family health as a result of an infectious disease. In some embodiments, trauma results from unemployment. In some embodiments, the trauma results from the loss of housing. In some embodiments, the trauma results from the fear of not being able to find employment.

[0247] In some cases, a person exhibits symptoms of post-traumatic stress disorder within one week of experiencing the traumatic event. In some cases, a person exhibits symptoms of post-traumatic stress disorder within one month of experiencing the traumatic event. In some cases, a person exhibits symptoms of post-traumatic stress disorder within one year of experiencing the traumatic event. In some cases, a person exhibits symptoms of post-traumatic stress disorder more than one year after experiencing the traumatic event. In some cases, post-traumatic stress disorder involves a person reliving the traumatic event through intrusive and distressing recollections, flashbacks, and / or nightmares of the event. In some cases, symptoms of post-traumatic stress disorder include emotional numbness and avoidance of places, people, and activities that remind one of the trauma. In some cases, symptoms of post-traumatic stress disorder include difficulty sleeping and concentrating, anxiety, and increased arousal, such as being easily irritated or angry.

[0248] In some embodiments, disclosed herein are methods for treating moral injury in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Moral injury can occur in individuals / populations with PTSD or individuals / populations at risk for developing PTSD (e.g., veterans or physicians). Moral injury can occur when individuals transgress their own moral boundaries, often in high-stakes situations, when pressure is exerted by higher authorities.

[0249] In some embodiments, disclosed herein are methods for treating acute stress disorder in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. A subject may be determined to have acute stress disorder if the subject exhibits PTSD symptoms that have been present for about 3 days to about 1 month.

[0250] In some embodiments, disclosed herein are methods for treating an adjustment disorder in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. A subject can be determined to have an adjustment disorder if the traumatic event experienced by the subject and / or the subject's symptoms do not meet the criteria required for a diagnosis of PTSD.

[0251] In some embodiments, disclosed herein are methods for treating an obsessive-compulsive and related disorder in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, the obsessive-compulsive and related disorder is obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, skin-picking disorder, trichotillomania, excoriation, substance-induced obsessive-compulsive and related disorder, or obsessive-compulsive disorder due to another medical condition, or a combination thereof.

[0252] Disclosed herein, in some embodiments, is a method for treating obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Approximately 2-4% of adults meet DSM criteria for OCD. While there are mixed findings regarding gender differences, OCD appears to be more prevalent in males during childhood and females during adolescence and adulthood. Up to 15% of individuals diagnosed with OCD have a history of suicide attempts. Pregnant and postpartum women have been found to have a higher prevalence of OCD than the general population. In Canada, the prevalence of OCD in individuals aged 15 years and older is estimated at 1 in 100, and this diagnosis has been associated with adverse childhood experiences and low income. Mortality rates in OCD patients are significantly higher, even after adjusting for physical comorbidities. Quality of life is significantly lower in OCD patients.

[0253] OCD involves the presence of repetitive behaviors or mental acts that exist in response to urges or compulsions related to anxiety (obsessions) and obsessions (compulsions).

[0254] A subject is diagnosed with obsessive-compulsive disorder when the obsessions and compulsions significantly affect daily life. In some embodiments, a subject with OCD is unaware that the obsessions and compulsions are excessive or irrational. As used herein, "obsessions" are intrusive, repetitive, and / or persistent thoughts, urges, and / or mental images that cause distress. In some embodiments, the obsessions cannot be suppressed or ignored. In some embodiments, a subject with OCD is unaware that these thoughts are not an actual threat but are generated by the subject's mind.

[0255] As used herein, a "compulsion" is an excessive and repetitive ritualistic behavior that must be performed to prevent something bad from happening. In some embodiments, the obsession is performed by the subject to reduce the anxiety caused by the obsessive thoughts. In some embodiments, a subject with OCD treated according to the methods described herein performs one or more compulsions for at least about 15 minutes to about 20 hours per day, e.g., about 15 minutes per day, about 30 minutes per day, about 45 minutes per day, about 1 hour per day, about 1.5 hours per day, about 2 hours per day, about 2.5 hours per day, about 3 hours per day, about 3.5 hours per day, about 4 hours per day, about 4.5 hours per day, about 5 hours per day, about 5.5 hours per day, about 6.0 hours per day, about 6.5 hours per day, about 7 hours per day, about 7.5 hours per day, about 8 hours per day, or about 9 hours per day. about 8.5 hours per day, about 9 hours per day, about 9.5 hours per day, about 10 hours per day, about 10.5 hours per day, about 11 hours per day, about 11.5 hours per day, about 12 hours per day, about 12.5 hours per day, about 13 hours per day, about 13.5 hours per day, about 14 hours, about 14.5 hours, about 15 hours, about 15.5 hours per day, about 16 hours per day, about 16.5 hours per day, about 17 hours per day, about 17.5 hours per day, about 18 hours per day, about 18.5 hours per day, about 19 hours per day, about 19.5 hours per day, or about 20 hours per day. In some embodiments, after treatment with the methods of the present disclosure, the amount of time a subject spends performing compulsions is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to before said treatment.

[0256] In some embodiments, the substance-induced compulsive and related disorder is trichotillomania. Trichotillomania is a disorder involving a recurrent, irresistible urge to pull hair from the scalp, eyebrows, or other parts of the body. In some embodiments, a subject with trichotillomania repeatedly attempts to reduce or stop the recurrent hair pulling. In some embodiments, a subject with trichotillomania experiences hair loss that can cause bald spots. In some embodiments, a subject with trichotillomania ingests the pulled hair or parts thereof. In some embodiments, a subject with trichotillomania who ingests the pulled hair or parts thereof develops trichobezoars or hairballs in the intestine or stomach. In some embodiments, after treatment with the methods of the present disclosure, the subject's trichotillomania improves compared to before the treatment.

[0257] In some embodiments, the subject with an anxiety disorder has one or more comorbid conditions. Non-limiting examples of comorbid conditions include endocrine and / or metabolic conditions, gastrointestinal conditions, cardiovascular conditions, psychiatric conditions, or neurological conditions. In some embodiments, the comorbid condition is an anxiety disorder, a depressive disorder, a psychotic disorder, a developmental disorder, an eating disorder, attention deficit hyperactivity disorder (ADHD), COVID-19, a COVID-19-related disorder, attention deficit disorder (ADD), autism spectrum disorder (ASD), a tic disorder, bipolar disorder, conduct disorder, mental retardation, or a combination thereof. In some embodiments, the comorbid condition is a mood disorder, major depressive disorder, bipolar disorder, schizophrenia, an eating disorder, attention deficit / hyperactivity disorder, epilepsy, cardiovascular conditions, migraine, irritable bowel syndrome, dementia, Alzheimer's disease, Parkinson's disease, or a combination thereof. In some embodiments, the comorbid condition is depression, generalized anxiety, agoraphobia, or panic disorder. In some embodiments, the comorbid condition is major depression. In some embodiments, the comorbid condition is an eating disorder. In some embodiments, the comorbid condition is ADHD. In some embodiments, the comorbid condition is ASD. In some embodiments, the comorbid condition is COVID-19, a COVID-19 related disorder, or both. In some embodiments, the comorbid condition is COVID-19. In some embodiments, the comorbid condition is a COVID-19 related disorder. Non-limiting examples of COVID-19 related disorders include post-traumatic stress disorder, anxiety disorder, acute stress disorder, adjustment disorder, or panic disorder. In some embodiments, the comorbid condition is major depressive disorder, bipolar disorder, irritable bowel disease, or irritable bowel syndrome.

[0258] In some embodiments, after administration of psilocybin, no other treatment for treating an anxiety disorder is administered to the subject.

[0259] In some embodiments, the subject with an anxiety disorder is administered at least one additional therapeutic and / or therapeutic agent. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs before the administration of psilocybin. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs after the administration of psilocybin. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs simultaneously with the administration of psilocybin.

[0260] In some embodiments, the additional therapeutic agent is an antidepressant, an anticonvulsant, lisdexamfetamine dimesylate, an antipsychotic, an anxiety medication, an anti-inflammatory agent, a benzodiazepine, an analgesic, a cardiovascular agent, or a combination thereof.

[0261] In some embodiments, the additional therapeutic agent is a benzodiazepine. In some embodiments, the benzodiazepine is diazepam or alprazolam.

[0262] In some embodiments, the additional therapeutic agent is an N-methyl-D-aspartate (NMDA) receptor antagonist. In some embodiments, the NMDA receptor antagonist is ketamine.

[0263] In some embodiments, the additional therapy is an antidepressant. In some embodiments, the antidepressant indirectly affects neurotransmitter receptors, for example, through interactions that affect the responsiveness of other molecules at the neurotransmitter receptor. In some embodiments, the antidepressant is an agonist. In one embodiment, the antidepressant is an antagonist. In some embodiments, the antidepressant acts (either directly or indirectly) on more than one neurotransmitter receptor. In some embodiments, the antidepressant is selected from bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.

[0264] In some embodiments, the antidepressant is a tricyclic antidepressant ("TCA"), a selective serotonin reuptake inhibitor ("SSRI"), a serotonin and noradrenaline reuptake inhibitor ("SNRI"), a dopamine reuptake inhibitor ("DRI"), a monoamine oxidase inhibitor ("MAOI"), including a noradrenaline reuptake inhibitor ("NRU"), a dopamine, serotonin and noradrenaline reuptake inhibitor ("DSNRI"), a reversible inhibitor of monoamine oxidase type A (RIMA), or a combination thereof. In some embodiments, the antidepressant is a TCA. In some embodiments, the TCA is imipramine or clomipramine. In some embodiments, the antidepressant is an SRI. In some embodiments, the SSRI is escitalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, or a combination thereof. In some embodiments, the SNRI is venlafaxine. In some embodiments, the additional therapeutic agent is pregabalin.

[0265] In some embodiments, the additional therapeutic agent is an anticonvulsant. In some embodiments, the anticonvulsant is gabapentin, carbamazepine, ethosuximide, lamotrigine, felbamate, topiramate, zonisamide, tiagabine, oxcarbazepine, levetiracetam, divalproex sodium, phenytoin, or fos-phenytoin. In some embodiments, the anticonvulsant is topiramate.

[0266] In some embodiments, the additional therapeutic agent is an antipsychotic drug, hi some embodiments, the antipsychotic drug is a phenothiazine, butryophenone, thioxanthene, clozapine, risperidone, olanzapine, or sertindole, quetiapine, aripiprazole, zotepine, perospirone, a neurokinin-3 antagonist such as osanthan and talnetant, rimonabant, or a combination thereof.

[0267] In some embodiments, the additional therapeutic agent is an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (NSAID), a steroid, acetaminophen (a COX-3 inhibitor), a 5-lipoxygenase inhibitor, a leukotriene receptor antagonist, a leukotriene A4 hydrolase inhibitor, an angiotensin-converting enzyme antagonist, a beta-blocker, an antihistamine, a histamine 2 receptor antagonist, a phosphodiesterase-4 antagonist, a cytokine antagonist, a CD44 antagonist, an anti-tumor agent, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor (a statin), an estrogen, an androgen, an antiplatelet agent, an antidepressant, a Helicobacter pylori inhibitor, a proton pump inhibitor, a thiazolidinedione, a dual-action compound, or a combination thereof.

[0268] In some embodiments, the additional therapeutic agent is an anti-anxiolytic. In one embodiment, the anti-anxiolytic is selected from alprazolam, an alpha-blocker, an antihistamine, a barbiturate, a beta-blocker, bromazepam, a carbamate, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, an opioid, oxazepam, temazepam, or triazolam.

[0269] In some embodiments, the subject with anxiety disorder is administered at least one therapy.Non-limiting examples of the therapy include transcranial magnetic stimulation, cognitive behavioral therapy, interpersonal therapy, dialectical behavioral therapy, mindfulness techniques, or acceptance and commitment therapy, or combinations thereof.

[0270] In some embodiments, at least one sign or symptom of an anxiety disorder is improved after administration of psilocybin or its active metabolite. In some embodiments, the sign or symptom of an anxiety disorder is measured by diary assessment, clinician or caregiver assessment, or clinical scale. In some embodiments, psilocybin treatment improves the symptoms of an anxiety disorder using the following measures: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale (HADS), Generalized Anxiety Disorder Questionnaire-IV (GADQ-IV), Hamilton Anxiety Rating Scale (HARS), Leibowitz Social Anxiety Scale (LSAS), Generalized Anxiety Severity and Impairment Scale (OASIS), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire-4 (PHQ-4), Social Phobia. Symptom Inventory (SPIN), Brief Trauma Questionnaire (BTQ), Combat Exposure Scale (CES), Mississippi Scale for Combat-Related PTSD (M-PTSD), Posttraumatic Maladaptive Beliefs Scale (PMBS), Perceived Threat Scale (DRRI-2 Section: G), Interview for PTSD Syndrome Scale-DSM-5 (PSS-I-5), Structured Interview for PTSD (SI-PTSD), Davidson Trauma Scale (DTS), Impact of Events Scale-Revised (IES-R), Posttraumatic Diagnostic Imaging The following items are included in the Scale for Trichotillomania (PDS-5), Potential Stressful Events Interview (PSEI), Stressful Life Events Screening Questionnaire (SLESQ), Spielberger Trait and Anxiety Scale, Generalized Anxiety Disorder 7-item Scale, Psychiatric Institute Trichotillomania Scale (PITS), MGH Trichotillomania Scale (MGH-HPS), NIMH Trichotillomania Severity Scale (NIMH-TSS), NIMH Trichotillomania Disorder Scale (NIMH-TIS), Clinical Global Impression (CGI), Brief Social Phobia Scale (BSPS), Panic Attack Questionnaire (PAQ), Panic Disorder Severity Scale, Florida Obsessive-Compulsive Inventory (FOCI), Leyton Obsessive-Compulsive Inventory Form, Vancouver Obsessive-Compulsive Inventory (VOCI), Schedule for Impulses, Compulsions, and Pathological Impulsive Behaviors (SCOPI), Padua Inventory-Revised (PI-R), Quality of Life (QoL), Clinical Global Improvement (CGI) Scale, and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS).Produces demonstrated improvement in one or more of the following: the Yale-Brown Obsessive-Compulsive Scale, Second Edition (Y-BOCS-II), the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS), the National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH-GOCS), the Yale-Brown Obsessive-Compulsive Scale Self-Report (Y-BOCS-SR), the Obsessive-Compulsive Inventory-Revised (OCI-R), and the Dimensional Obsessive-Compulsive Scale (DOCS), or a combination thereof.

[0271] In some embodiments, after treatment with psilocybin, the signs or symptoms of OCD improve as demonstrated by one of the following scales: Florida Obsessive-Compulsive Inventory (FOCI), Leyton Obsessive-Compulsive Inventory-Form, Vancouver Obsessive-Compulsive Inventory (VOCI), Schedule for Impulses, Compulsions, and Pathological Impulsive Behaviors (SCOPI), Padua Inventory-Revised (PI-R), Quality of Life (QoL), Clinical Global Improvement (CGI) scale, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Yale-Brown Obsessive-Compulsive Scale-Second Edition (Y-BOCS-II), Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS), National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH-GOCS), Yale-Brown Obsessive-Compulsive Scale-Self-Report (Y-BOCS-SR), Obsessive-Compulsive Inventory-Revised (OCI-R), and Dimensional Obsessive-Compulsive Scale (DOCS).

[0272] In some embodiments, after treatment with psilocybin, the signs or symptoms of trichotillomania are improved as demonstrated by one of the following scales: the Psychiatric Institute Trichotillomania Scale (PITS), the Massachusetts General Hospital (MGH) Hair Pulling Scale (MGH-HPS), the National Institute of Mental Health (NIMH) Trichotillomania Severity Scale (NIMH-TSS), or the NIMH Trichotillomania Injury Scale (NIMH-TIS).

[0273] In some embodiments, treatment with the methods of the present disclosure results in about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in anxiety disorder compared to before treatment according to any one of the diary assessments, clinician or caregiver assessments, or clinical scales described herein.

[0274] In some embodiments, treatment with the methods of the present disclosure results in about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in obsessive-compulsive and related disorders compared to before treatment according to any one of the diary assessments, clinician or caregiver assessments, or clinical scales described herein.

[0275] In some embodiments, treatment with the methods of the present disclosure results in about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in post-traumatic stress disorder compared to before treatment according to any one of the diary assessments, clinician or caregiver assessments, or clinical scales described herein.

[0276] In some embodiments, after administration of psilocybin or an active metabolite thereof, the subject has improved cognition, information processing, stress levels, immune system, or a combination thereof.

[0277] In some embodiments, following administration of psilocybin or an active metabolite thereof, at least one symptom of the anxiety disorder is alleviated for at least about 5 minutes to at least about 1 year, e.g., at least one symptom of the anxiety disorder is alleviated for at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, or at least In some embodiments, the alleviation of at least one symptom of the anxiety disorder is for at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, or longer. In some embodiments, at least one symptom of the anxiety disorder is alleviated for at least one month after administration of psilocybin. In some embodiments, at least one symptom of the anxiety disorder is alleviated for at least three months after administration of psilocybin. In some embodiments, at least one symptom of the anxiety disorder is alleviated for at least one year after administration of the psilocybin.

[0278] In some embodiments, after administration of psilocybin or an active metabolite thereof, at least one symptom of an anxiety disorder is alleviated within about 5 minutes to about 1 week, e.g., within about 5 minutes, within about 15 minutes, within about 30 minutes, within about 45 minutes, within about 1 hour, within about 2 hours, within at least 3 hours, within about 4 hours, within about 5 hours, within about 6 hours, within about 7 hours, within about 8 hours, within about 9 hours, within about 10 hours, within about 11 hours, within about 12 hours, within about 13 hours, within about 14 hours, within about 15 hours, within about 16 hours, within about 17 hours, within about 18 hours, within about 19 hours, within about 20 hours, within about 21 hours, within about 22 hours, within about 23 hours, within about 24 hours, within about 1 day, within about 2 days, within about 3 days, within about 4 days, within about 5 days, within about 6 days, or within about 7 days. In some embodiments, at least one symptom of anxiety is alleviated within 24 hours of administering the psilocybin, hi some embodiments, at least one symptom of anxiety is alleviated within one week of administering the psilocybin.

[0279] Eating disorders In some embodiments, disclosed herein are methods for treating one or more eating disorders in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, the active metabolite is psilocybin.

[0280] As used herein, the term "eating disorder" refers to any of a range of psychological disorders characterized by abnormal or neurotic eating habits. In some embodiments, the eating disorder is pica, anorexia nervosa, bulimia nervosa, rumination disorder, avoidant / restrictive food intake disorder, binge eating disorder, or a combination thereof.

[0281] In some embodiments, the presently disclosed methods treat chronic eating disorders. As used herein, a "chronic" eating disorder is one that is recurrent.

[0282] In some embodiments, the eating disorder comprises a medical diagnosis based on the criteria and classification of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. In one embodiment, the eating disorder comprises a medical diagnosis based on an independent medical evaluation.

[0283] In some embodiments, disclosed herein are methods for treating pica in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Pica is a disorder characterized by an appetite for primarily non-nutritional substances. Individuals with pica disorder compulsively ingest non-nutritional substances. Substances may include ice, hair, cigarette ash, glue, paper, drywall, paint, sharps, metal, stones, dirt, glass, feces, chalk, dust, or dirt. In some embodiments, individuals with pica also have intellectual disabilities, schizophrenia, or OCD. In some embodiments, individuals with pica have a nutritional deficiency. In some embodiments, the nutritional deficiency is low levels of zinc or iron.

[0284] In some embodiments, a subject with pica has been experiencing the disorder for at least 1 month, e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more.

[0285] In some embodiments, after treatment with the methods of the present disclosure, the individual with pica stops consuming non-nutritional substances for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 1 year, at least 2 years, or more. In some embodiments, after treatment with the methods of the present disclosure, the individual with pica stops consuming non-nutritional substances within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.

[0286] In some embodiments, disclosed herein is a method for treating anorexia nervosa (AN) in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. AN is a disorder characterized by an intense fear of weight gain, an abnormally low body weight, and a distorted perception of body weight. Individuals with AN often severely restrict the amount of food they eat. They may control calorie intake by vomiting after meals or misusing laxatives, dietary supplements, diuretics, or enemas. They may also attempt to lose weight by excessive exercise. In some embodiments, a subject with AN has signs and symptoms including, but not limited to, extreme weight loss or failure to gain expected developmental weight, thin appearance, abnormal blood counts, fatigue, insomnia, dizziness or fainting, pale discoloration of the fingers, thin hair that crumbles or falls out, soft downy hair covering the body, amenorrhea, constipation and abdominal pain, dry or yellowish skin, intolerance of cold, irregular heart rhythm, low blood pressure, dehydration, swelling of the arms or legs, or eroded teeth and calluses on the knuckles from induced vomiting.

[0287] In some embodiments, after treatment with the methods of the present disclosure, one or more symptoms of AN improve for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 1 year, at least 2 years, or more.

[0288] In some embodiments, after treatment with a method of the present disclosure, one or more symptoms of AN improve within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.

[0289] Disclosed herein, in some embodiments, are methods for treating bulimia nervosa (BN) in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. BN is a disorder characterized by distorted body image and extreme binge eating followed by a compulsive desire for weight loss, followed by depression and the use of self-induced vomiting, laxatives, laxatives, diuretics, or fasting. In some embodiments, both the binge eating and inappropriate compensatory behaviors occur, on average, at least once a week for three months. Signs and symptoms of BN include behaviors and attitudes that indicate weight loss, dieting, and food control are primary concerns; evidence of binge eating, including the disappearance of large amounts of food in a short period of time or the consumption of large amounts of food with many empty packages and containers; evidence of purging behaviors, including frequent trips to the bathroom after meals, signs and / or smells of vomiting, and the presence of laxative or diuretic wrappers or packaging; appearing uncomfortable eating around others; exhibiting ritualized eating (e.g., eating only certain foods or food groups [e.g., condiments], excessive chewing, not allowing food to touch); skipping meals or eating small amounts of food at regular meals; disappearing after meals and frequent trips to the bathroom; committing to food or fad diets, including eliminating entire food groups (e.g., no sugar, no carbohydrates, no dairy, vegetarianism / veganism) new habits; fear of eating in public or with others; stealing food or storing it in odd places; drinking excessive amounts of water or non-caloric beverages; using excessive amounts of mouthwash, mints, and gum; hiding the body in baggy clothing; maintaining an excessive and rigid exercise regimen due to the need to "burn" calories (regardless of weather, fatigue, illness, or injury); exhibiting abnormal swelling in the cheek or jaw area; having calluses on the backs of the hands and joints due to self-induced vomiting; discolored and stained teeth; creating a lifestyle schedule or ritual to make time for binge-purge sessions; withdrawing from usual friends and activities; appearing bloated from fluid retention; dieting frequently; exhibiting extreme anxiety about weight and body shape; frequently checking the mirror to recognize imperfections in appearance;Having covert, recurring episodes of binge eating (eating much more food at separate times than most individuals would eat under similar circumstances); feeling a lack of control over their ability to stop eating; purging after binges (e.g., self-induced vomiting, abuse of laxatives, weight loss drugs, and / or diuretics, excessive exercise, fasting); extreme mood swings; self-harm (cutting and other forms without suicidal intent), substance abuse, impulsivity, diabulimia, noticeable fluctuations in weight both up and down; weight is typically within the normal weight range; may be overweight; stomach cramps, other nonspecific gastrointestinal symptoms (e.g., constipation, acid reflux); difficulty concentrating; abnormal test results (anemia, low thyroid and hormone levels, low potassium) Symptoms include, but are not limited to: nausea, low blood counts, slow heart rate; dizziness; fainting / syncope; feeling cold all the time; trouble sleeping; cuts and calluses over the tops of the knuckles (resulting in vomiting); dental problems such as enamel erosion, tooth decay, and tooth sensitivity; dry skin; dry, brittle nails; swelling around the salivary glands; thinning body hair; thinning, dry, brittle hair on the head (vellus hair); tooth decay or tooth discoloration due to vomiting; muscle weakness; yellow skin (in the event of eating large amounts of carrots); cold, blotchy, swollen hands, feet, or legs; menstrual irregularities - missing periods or only having periods while taking hormonal contraceptives (this is not considered a "true" period); poor wound healing; or impaired immune function.

[0290] In some embodiments, after treatment with the methods of the present disclosure, one or more symptoms of BN improve for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 1 year, at least 2 years, or more.

[0291] In some embodiments, after treatment with a method of the present disclosure, one or more symptoms of BN improve within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.

[0292] In some embodiments, disclosed herein are methods for treating binge eating disorder (BED) in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Binge eating disorder (BED) is the most common eating disorder, characterized by uncontrollable consumption of large amounts of food over a short period of time, causing psychological distress. To qualify for diagnosis, these episodes must be recurrent, occur on average at least once per week for three months, and be accompanied by three of the following: consuming food more rapidly than usual; consuming food to the point of feeling uncomfortably full; consuming large amounts of food when not hungry; consuming food alone because of embarrassment; and feeling disgust, depression, or guilt after consuming large amounts of food. Compensatory behaviors associated with bulimia nervosa must not be involved, and binging should not occur during episodes of bulimia nervosa or anorexia nervosa.

[0293] Many factors have been implicated in the causes of BED: high levels of depressive symptoms, body dissatisfaction, low family cohesion, and low self-esteem are important predictors of binge eating behavior.

[0294] The global pooled prevalence of BED is estimated to be 0.9%. The prevalence is higher in women (1.4%) than men (0.4%). An online survey of 22,397 adults with BED in the United States found that only 3.2% reported receiving help from a healthcare provider.

[0295] A WHO mental health survey found that the lifetime prevalence of BED was 1.4%, with a mean age of onset in the late teens to early twenties. No ethnic differences have been found in the prevalence of eating disorders or the association of risk factors for future BED development. BED is more common in obese populations, with 20–50% of those seeking weight-control treatment reporting episodes of binge eating. However, only 1–2% of this population meets the full DSM criteria for BED.

[0296] In some embodiments, treatment with the disclosed methods improves one or more symptoms of BED, including eating abnormally large amounts of food in a specific period of time, feeling out of control about eating, eating when not full or hungry, eating rapidly during binge episodes, eating until uncomfortably full, eating alone or in secret, feeling depressed, disgusted, embarrassed, guilty, or upset about eating, or frequent dieting, possibly without weight loss.

[0297] In some embodiments, after treatment with the methods of the present disclosure, one or more symptoms of BED are improved for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 1 year, at least 2 years, or more.

[0298] In some embodiments, after treatment with the methods of the present disclosure, one or more symptoms of BED improve within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.

[0299] Disclosed herein, in some embodiments, are methods for treating a rumination disorder in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Rumination disorder is an eating disorder in which an individual vomits swallowed food. In some embodiments, a subject with a rumination disorder re-swallows vomited food. In some embodiments, a subject with a rumination disorder vomits vomited food. In some embodiments, a subject with a rumination disorder chews vomited food. In some embodiments, a subject with a rumination disorder chews and swallows vomited food. In some embodiments, rumination disorder can cause unhealthy weight loss, malnutrition, dental erosion, bad breath, embarrassment, and / or social isolation.

[0300] In some embodiments, after treatment with the methods of the present disclosure, rumination frequency is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, signs and symptoms of rumination disorder are improved for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 1 year, at least 2 years, or more.

[0301] In some embodiments, after treatment with the methods of the present disclosure, the signs and symptoms of a rumination disorder improve within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.

[0302] Disclosed herein, in some embodiments, is a method for treating avoidant / restrictive food eating disorder (ARFID) in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. ARFID is an eating or feeding disorder characterized by one or more of the following: a clear lack of interest in eating or food, avoidance based on the sensory characteristics of food, and concern about the aversive consequences of eating. ARFID manifests as an inability to meet adequate nutritional and / or energy needs, nutritional deficiencies, dependence on enteral or oral nutritional supplements, or significant interference with psychosocial functioning. In some embodiments, the subject with ARFID has ASD, ADH, or intellectual disability.

[0303] In some embodiments, after treatment with the methods of the present disclosure, one or more signs, symptoms, or consequences of ARFID are improved, hi some embodiments, the improvement is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0304] In some embodiments, the subject with an eating disorder has one or more comorbid conditions. Non-limiting examples of comorbid conditions include endocrine and / or metabolic conditions, gastrointestinal conditions, cardiovascular conditions, psychiatric conditions, or neurological conditions. In some embodiments, the comorbid condition is an anxiety disorder, a depressive disorder, a psychotic disorder, a developmental disorder, an eating disorder, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), autism spectrum disorder (ASD), a tic disorder, a bipolar disorder, a conduct disorder, mental retardation, or a combination thereof. In some embodiments, the comorbid condition is a mood disorder, a major depressive disorder, a bipolar disorder, schizophrenia, an eating disorder, an attention deficit / hyperactivity disorder, epilepsy, a cardiovascular condition, migraine, irritable bowel syndrome, dementia, Alzheimer's disease, Parkinson's disease, or a combination thereof. In some embodiments, the comorbid condition is depression, generalized anxiety, agoraphobia, or panic disorder. In some embodiments, the comorbidity is an anxiety disorder, a mood disorder, an impulse control disorder, a substance use disorder, or any disorder. In some embodiments, the comorbidity is hypertension, dyslipidemia, a sleep disorder / disorder, pain, a functional gastrointestinal symptom / disorder, a menstrual disorder, a pregnancy complication, intracranial hypertension, polycystic ovary syndrome, or a combination thereof. Table 7 shows the lifetime comorbidity of eating disorders with other core disorders. [Table 7]

[0305] In some embodiments, the co-morbidity is another eating disorder. In some embodiments, the subject in need of treatment has at least two eating disorders. In some embodiments, the subject in need of treatment has at least three eating disorders. In some embodiments, the subject in need of treatment has at least four eating disorders.

[0306] In some embodiments, the co-morbid condition is a psychiatric disorder selected from schizophrenia, schizoaffective disorder, bipolar disorder, major depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism, alcohol use disorder, substance use disorder, or suicide attempt.

[0307] In some embodiments, the comorbid condition is major depression. In some embodiments, the comorbid condition is an eating disorder. In some embodiments, the comorbid condition is obesity, one or more conditions associated with obesity, or both. In some embodiments, the one or more conditions associated with obesity are one or more of metabolic syndrome, diabetes, hypertension, dyslipidemia, a sleep disorder or disorder, or pain. In some embodiments, the comorbid condition is ADHD. In some embodiments, the comorbid condition is ASD. In some embodiments, the comorbid condition is major depressive disorder, bipolar disorder, irritable bowel disease, or irritable bowel syndrome. In some embodiments, the one or more comorbid conditions are reproductive dysfunction, polycystic ovary syndrome, or menstrual abnormalities. In some embodiments, the comorbid condition is a psychiatric disorder selected from schizophrenia, schizoaffective disorder, bipolar disorder, major depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism, alcohol use disorder, substance use disorder, or suicide attempt.

[0308] In some embodiments, after administration of psilocybin, no other therapy for treating the eating disorder is administered to the subject.

[0309] In some embodiments, at least one additional therapeutic and / or therapeutic agent is administered to a subject with an anxiety disorder. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs before the administration of psilocybin. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs after the administration of psilocybin. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs simultaneously with the administration of psilocybin.

[0310] In some embodiments, the additional therapeutic agent is an antidepressant, an anticonvulsant, lisdexamfetamine dimesylate, an antipsychotic, an anxiety medication, an anti-inflammatory agent, a benzodiazepine, an analgesic, a cardiovascular agent, an opioid antagonist, or a combination thereof.

[0311] In some embodiments, the additional therapeutic agent is a benzodiazepine. In some embodiments, the benzodiazepine is diazepam or alprazolam.

[0312] In some embodiments, the additional therapeutic agent is an N-methyl-D-aspartate (NMDA) receptor antagonist. In some embodiments, the NMDA receptor antagonist is ketamine.

[0313] In some embodiments, the additional therapy is an antidepressant. In some embodiments, the antidepressant indirectly affects neurotransmitter receptors, for example, through interactions that affect the responsiveness of other molecules at the neurotransmitter receptor. In some embodiments, the antidepressant is an agonist. In one embodiment, the antidepressant is an antagonist. In some embodiments, the antidepressant acts (either directly or indirectly) on more than one neurotransmitter receptor. In some embodiments, the antidepressant is selected from bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.

[0314] In some embodiments, the antidepressant is a tricyclic antidepressant ("TCA"), a selective serotonin reuptake inhibitor ("SSRI"), a serotonin and noradrenaline reuptake inhibitor ("SNRI"), a dopamine reuptake inhibitor ("DRI"), a monoamine oxidase inhibitor ("MAOI"), including a noradrenaline reuptake inhibitor ("NRU"), a dopamine, serotonin and noradrenaline reuptake inhibitor ("DSNRI"), a reversible inhibitor of monoamine oxidase type A (RIMA), or a combination thereof. In some embodiments, the antidepressant is a TCA. In some embodiments, the TCA is imipramine or clomipramine. In some embodiments, the antidepressant is an SRI. In some embodiments, the SSRI is escitalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, or a combination thereof. In some embodiments, the SNRI is venlafaxine. In some embodiments, the additional therapeutic agent is pregabalin.

[0315] In some embodiments, the additional therapeutic agent is an anticonvulsant. In some embodiments, the anticonvulsant is gabapentin, carbamazepine, ethosuximide, lamotrigine, felbamate, topiramate, zonisamide, tiagabine, oxcarbazepine, levetiracetam, divalproex sodium, phenytoin, or fos-phenytoin. In some embodiments, the anticonvulsant is topiramate.

[0316] In some embodiments, the additional therapeutic agent is an antipsychotic drug, hi some embodiments, the antipsychotic drug is a phenothiazine, butryophenone, thioxanthene, clozapine, risperidone, olanzapine, or sertindole, quetiapine, aripiprazole, zotepine, perospirone, a neurokinin-3 antagonist such as osanthan and talnetant, rimonabant, or a combination thereof.

[0317] In some embodiments, the additional therapeutic agent is an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (NSAID), a steroid, acetaminophen (a cyclooxygenase-3 (COX-3) inhibitor), a 5-lipoxygenase inhibitor, a leukotriene receptor antagonist, a leukotriene A4 hydrolase inhibitor, an angiotensin-converting enzyme antagonist, a beta-blocker, an antihistamine, a histamine 2 receptor antagonist, a phosphodiesterase-4 antagonist, a cytokine antagonist, a CD44 antagonist, an anti-tumor agent, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor (statin), an estrogen, an androgen, an antiplatelet agent, an antidepressant, a Helicobacter pylori inhibitor, a proton pump inhibitor, a thiazolidinedione, a dual-action compound, or a combination thereof.

[0318] In some embodiments, the additional therapeutic agent is an anxiolytic agent, hi one embodiment, the anxiolytic agent is selected from alprazolam, an alpha blocker, an antihistamine, a barbiturate, a beta blocker, bromazepam, a carbamate, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, an opioid, oxazepam, temazepam, or triazolam.

[0319] In some embodiments, the additional therapeutic agent is an opioid antagonist. Non-limiting examples of opioid antagonists include naloxone, naltrexone, nalmefene, nalorphine, nalorphine dinicotinate, levarfan, samidorphan, nalodine, alvimopan, methylnaltrexone, naloxegol, 6β-naltrexol, axerophrine, bebenoplan, methylsamidorphan, naldemedine, buprenorphine, decodine, butorphanol, levorphanol, nalbuphine, pentazocine, and phenazocine.

[0320] In some embodiments, the additional therapeutic agent is a cardiovascular drug. Non-limiting examples of cardiovascular drugs include digoxin or (3β,5β,12β)-3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl)-(1,4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl)-(1,4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]12,14-dihydroxy-card-20(22)-enolide, lisinopril, captopril, ramipril, trandolapril, benazepril, cilazapril, enalapril, moexipril, perindopril, quinapril, fludrocortisone, enalaprilate, quinapril, perindopril, apixaban, and dabigatran. , edoxaban, heparin, rivaroxaban, warfarin, aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, sacubitril, acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisolidipine, verapamil, statins, nicotinic acid, diuretics, vasodilators, and combinations thereof.

[0321] In some embodiments, a subject with an eating disorder is administered at least one therapy, non-limiting examples of which include transcranial magnetic stimulation, cognitive behavioral therapy, interpersonal psychotherapy, dialectical behavioral therapy, weight loss therapy, mindfulness techniques, acceptance and commitment therapy, and combinations thereof.

[0322] In some embodiments, at least one sign or symptom of an eating disorder improves after administration of psilocybin or its active metabolite. In some embodiments, the sign or symptom of an anxiety disorder is measured according to a diary assessment, a clinician or caregiver assessment, or a clinical scale. Non-limiting examples of clinical scales, diary assessments, and clinician or caregiver assessments include the Mini-International Neuropsychiatric Interview (MINI), the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), the Eating Disorder Examination (EDE), the Eating Disorder Questionnaire (EDE-Q), the Eating Disorder Examination Questionnaire Short Form (EDE-QS), the Physical Appearance State and Trait Anxiety Scale - State and Trait Version (PASTAS), the Spielberger State-Trait Anxiety Inventory (STAI), the Eating Disorder Readiness Scale (ED-RR), a visual analog rating scale (VAS), the Montgomery-Asberg Depression Rating Scale (MADRS), the Yale-Brown Cornell Eating Disorder Scale (YBC-EDS), the Yale-Brown These include the Cornell Eating Disorder Scale-Self-Report Questionnaire (YBC-EDS-SRQ), Body Image Status Scale (BISS), Clinical Impairment Assessment (CIA) Questionnaire, Eating Disorder Inventory (EDI) (e.g., version 3: EDI-3), Five-Dimensional Altered States of Consciousness Questionnaire (5D-ASC), Columbia-Suicide Severity Rating Scale (C-SSRS), Life Change Inventory (LCI), and combinations thereof.

[0323] In some embodiments, the Mini International Neuropsychiatric Interview (MINI) (e.g., version 7.0.2) is a diagnostic interview instrument for mental disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the International Classification of Diseases-10.

[0324] In some embodiments, the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) is utilized to diagnose borderline personality disorder (BPD). The MSI-BPD includes 10 items based on the DSM-5 BPD criteria, with the first eight items representing the first eight DSM-5 criteria for diagnosing BPD, and the last two questions assessing the delusional and dissociative criteria for BPD. The MSI-BPD is scored on a scale of 0 to 10, with each item rated "1" for present and "0" for absent. A score of 7 or greater indicates that the subject likely meets criteria for BPD. In some embodiments, after treatment with the methods of the present disclosure, the subject's MSI-BPD score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0325] In some embodiments, one or more of the Eating Disorder Examination (EDE), Eating Disorder Questionnaire (EDE-Q), or Eating Disorder Examination Questionnaire-Short Form (EDE-QS) are utilized to assess the extent and severity of an eating disorder. The EDE is a structured clinical interview (assessed by an investigator), while the EDE-Q and EDE-QS are self-report questionnaires. The EDE is a standardized interview used to measure the severity of psychopathology characteristic of eating disorders. In some embodiments, after treatment with the methods of the present disclosure, a subject's EDE score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0326] The EDE-Q is a self-report interview that assesses the severity of a subject's eating disorder over a 28-day period. In some embodiments, after treatment with a method of the present disclosure, the subject's EDE-Q score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0327] The EDE-QS is a self-report eating disorder severity interview that assesses the severity of a subject's eating disorder symptoms over a 7-day period. The EDE-QS assesses the frequency of different forms of problematic binge eating behavior, including binge eating (labeled objective binge eating episodes (OBEs)) and different forms of inappropriate weight-compensatory behaviors (e.g., laxative methods). In some embodiments, after treatment with the methods of the present disclosure, the subject's EDE-QS score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0328] In some embodiments, the Physical Appearance State and Trait Anxiety Scale - State and Trait Version (PASTAS) is utilized to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The PASTAS is a self-report 16-item scale assessing anxiety related to physical appearance. Subjects rate how often they experience anxiety about parts of their body on a Likert scale of 0 to 4, with a score of 0 being "never" and a score of 4 being "almost always." In some embodiments, the PASTAS is used to assess anxiety associated with eating disorders. In some embodiments, after treatment with the methods of the present disclosure, a subject's PASTAS score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0329] In some embodiments, the Spielberger State-Trait Anxiety Inventory (STAI) is utilized to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The STAI is a widely used instrument that includes separate self-report scales for measuring "state" and "trait" anxiety. "State" anxiety is the transient anxiety resulting from stressful stimuli, while "trait" anxiety is a subject's predisposition to respond anxiously to stressful situations. The STAI contains 40 items that are self-reported and scored on a 4-point Likert scale with a semantic guide, taking approximately 10 minutes. The STAI includes 20 questions related to state anxiety and 20 questions related to trait anxiety. Each section is scored between 20 and 80.

[0330] In some embodiments, the Eating Disorder Readiness Scale (ED-RR) is utilized to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The ED-RR is a self-reported, two-part, 18-item questionnaire that assesses readiness to change across nine dimensions of eating disorder behaviors (restriction, weight shape assessment, binge eating, vomiting, laxative use, fasting, diuretic use, fear of weight gain, and exercise). Part 1 of the ED-RR measures the subject's subjective readiness to change on a 1-10 Likert scale. Part 2 of the ED-RR measures whether the motivation to change is for others or for oneself. Part 2 of the ED-RR is scored on a 0% to 100% scale, with scores closer to 0% indicating the motivation to change is for others and scores closer to 100% indicating the motivation to change is for oneself. Higher readiness to change correlates with a decrease in eating disorder symptoms over time. In some embodiments, after treatment with the methods of the present disclosure, a subject's readiness to change improves by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, or more compared to before treatment. In some embodiments, a subject's ED-RR score increases by about 1 point, about 2 points, about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, or about 10 points after treatment with a method of the present disclosure.

[0331] In some embodiments, a visual analogue scale (VAS) is used to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The VAS is a self-reported assessment of hunger, fullness, and appetite. Subjects mark the intensity of their experience relative to anchors along a 100mm continuum. In some embodiments, after treatment with the methods of the present disclosure, the subject's VAS score improves by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300% or more compared to before said treatment.

[0332] In some embodiments, the Montgomery-Asberg Depression Rating Scale (MADRS) is utilized to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The MADRS is a clinician-rated scale measuring depression severity that includes 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. Higher scores indicate greater severity of depression. In some embodiments, after treatment with the methods of the present disclosure, a subject's MADRS score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0333] In some embodiments, the Yale-Brown Cornell Eating Disorder Scale (YBC-EDS) and / or the Yale-Brown Cornell Eating Disorder Scale Self-Report Questionnaire (YBC-EDS-SRQ) are utilized to assess the severity and type of symptoms observed to be present in a subject with an eating disorder. The YBC-EDS is a physician-administered interview, and the YBC-EDS-SRQ is a self-report questionnaire. The YBC-EDS-SRQ assesses the current severity of a subject's eating disorder and the worst severity of a subject's eating disorder.

[0334] In some embodiments, the Body Image Status Scale (BISS) is utilized to evaluate the safety and efficacy of psilocybin for the treatment of eating disorders. The BISS is a six-item self-report scale measuring a subject's affective / evaluative body image state. The BISS is used to investigate transient emotional experiences of body image in response to various hypothetical situations. The six items are: 1) dissatisfaction with physical appearance, 2) dissatisfaction with body size and shape, 3) dissatisfaction with weight, 4) feeling physically unattractive, 5) current feelings about one's appearance compared to how one normally feels, and 6) evaluation of one's appearance compared to how a normal person looks. Each item is rated on a nine-point bipolar Likert-like scale. The scale can be administered in natural contexts as well as in a series of positive or negative hypothetical situations. A higher BISS score indicates a better body image. In some embodiments, after a subject is treated with a method of the present disclosure, the subject's BISS score improves by about 5% to about 300%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% , about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 145%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% increase.

[0335] In some embodiments, the subject's body mass index is assessed to determine the safety and effectiveness of psilocybin for treating eating disorders.

[0336] In some embodiments, the Clinical Impairment Assessment (CIA) questionnaire is used to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The CIA is a self-report 16-item scale of the level of social and psychological impairment caused by the eating disorder over the past 28 days. Subscales include mood, self-perception, cognitive function, interpersonal function, and work preferences. Items are ranked on a 4-point Likert scale. In some embodiments, a score of 16 or higher indicates that the subject has an eating disorder. In some embodiments, after treatment with the methods of the present disclosure, the subject's CIA score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0337] In some embodiments, the Eating Disorder Inventory (EDI), e.g., Version 3 (EDI-3), is utilized to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The EDI-3 is a self-report questionnaire rated on a 0-4 Likert scale. The EDI-3 includes 12 subscales, three of which are specific to eating disorders (thinness, bulimia, and body dissatisfaction drives) and nine of which measure general psychological characteristics (low self-esteem, personal alienation, interpersonal security, interpersonal alienation, interoceptive deficits, emotion dysregulation, perfectionism, apathy, and fear of maturation). In some embodiments, after treatment with the methods of the present disclosure, the subject's EDI-3 complex is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0338] In some embodiments, the Five-Dimensional Altered States of Consciousness Questionnaire (5D-ASC) is utilized to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The 5D-ASC measures acute drug effects using five major dimensions and their respective subdimensions to assess changes in mood, perception, and experience of the self related to the environment and thought disorders. The five dimensions include oceanic infinity, anxious self-destruction, visual restructuring, auditory alterations, and reduced vigilance.

[0339] In some embodiments, the Columbia-Suicide Severity Rating Scale (C-SSRS) is utilized to assess the safety and efficacy of psilocybin for the treatment of eating disorders. The C-SSRS is used to assess suicidal potential or tendency as a study entry criterion and is monitored throughout the study. In some embodiments, after treatment with the methods of the present disclosure, a subject's C-SSRS score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to pre-treatment.

[0340] In some embodiments, qualitative interviews are utilized to assess the safety and effectiveness of psilocybin for the treatment of eating disorders.

[0341] In some embodiments, an electrocardiogram (ECG) is utilized to assess the safety and effectiveness of psilocybin for the treatment of eating disorders, hi some embodiments, the ECG is a standard 12-lead ECG.

[0342] In some embodiments, vital signs are utilized to assess the safety and effectiveness of psilocybin for the treatment of eating disorders. Non-limiting examples of vital signs include weight, blood pressure, respiratory rate, temperature, and pulse rate.

[0343] In some embodiments, laboratory tests are utilized to assess the safety and / or effectiveness of psilocybin for treating eating disorders. In some embodiments, the laboratory tests include liver function tests. In some embodiments, the laboratory tests utilize blood and / or urine samples. In some embodiments, blood is tested for hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count (with differential), and platelet levels. In some embodiments, blood is tested for albumin, alkaline phosphatase, alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect, and total), calcium, chloride, creatine kinase, creatinine, gamma-glutamyltransferase, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, total protein, sodium, urea (blood urea nitrogen), and uric acid levels. In some embodiments, the urine sample is tested for pregnancy, illicit drugs, blood, glucose, ketones, protein, pH, specific gravity, nitrites, white blood cells, bilirubin, and urobilinogen.

[0344] In some embodiments, adverse events (AEs) are measured to determine the safety and effectiveness of psilocybin for treating eating disorders. In some embodiments, adverse events are classified as mild, moderate, or severe. Mild AEs do not significantly interfere with a subject's normal level of functioning. Moderate AEs cause some functional impairment but are not dangerous to the subject's health. Severe AEs cause significant functional impairment or dysfunction and pose a definite risk to the subject's health. Non-limiting examples of adverse events include euphoric mood, euphoric mood, dissociative disorders, hallucinations, psychotic disorders, cognitive impairment, attention disorders, mood alterations, psychomotor skill impairment, inappropriate affect, overdose, and intentional product misuse. Serious adverse events include death, life-threatening adverse events, inpatient hospitalization or prolongation of current hospitalization, permanent or significant physical disability / incapacity, and congenital / birth defects in the offspring of the subject receiving psilocybin. An event is life-threatening if the subject was at immediate risk of death at the time the event occurred. That is, reactions that may cause death if they occur in a more severe form are not included. For example, although drug-induced hepatitis can be fatal, drug-induced hepatitis that resolves without evidence of liver failure is not considered life-threatening. Serious medical events that may result in death, threaten life, or do not require hospitalization may be considered serious adverse events if, based on appropriate medical judgment, they may endanger the subject and may require medical or surgical intervention to prevent one of the outcomes described in this definition. Such events include, but are not limited to, allergic bronchospasm requiring intensive care in the emergency room or at home, blood disorders or seizures that do not require hospitalization in hospitalized subjects, and the development of drug addiction or drug abuse.

[0345] In some embodiments, treatment with the methods of the present disclosure results in about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in eating disorder compared to before treatment according to any one of the diary assessments, clinician or caregiver assessments, or clinical scales described herein.

[0346] In some embodiments, after treatment with a method of the present disclosure, a subject in need of treatment has a decreased Eating Disorder Examination Short Form (EDE-QS) score compared to before said treatment. In some embodiments, after treatment with a method of the present disclosure, a subject in need of treatment has a decreased Physical Appearance State and Trait Anxiety Scale (PASTAS) score compared to before said treatment. In some embodiments, after treatment with a method of the present disclosure, a subject in need of treatment has a higher motivation for change as assessed by the Eating Disorder Readiness Scale (ED-RR) compared to before said treatment. In some embodiments, after treatment with a method of the present disclosure, a subject in need of treatment has a decreased Montgomery-Asberg Depression Rating Scale (MADRS) score compared to before said treatment. In some embodiments, after treatment with a method of the present disclosure, a subject in need of treatment has an increased Body Image State Scale (BISS) compared to before said treatment.

[0347] In some embodiments, after administration of psilocybin or an active metabolite thereof, a subject with an eating disorder has improved cognition, information processing, stress levels, immune system, or a combination thereof.

[0348] In some embodiments, following administration of psilocybin or an active metabolite thereof, the eating disorder, or at least one symptom thereof, is alleviated for at least about 5 minutes to at least about 1 year, e.g., at least one symptom of an anxiety disorder is alleviated for at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 25 hours, at least about 26 hours, at least about 27 hours, at least about 28 hours, at least about 29 hours, at least about 30 hours, at least about 31 hours, at least about 32 hours, at least about 33 hours, at least about 34 hours, at least about 35 hours, at least about 36 hours, at least about 37 hours, at least about 38 hours, at least about 39 hours, at least about 40 hours, at least about 41 hours, at least about 42 hours, at least about 43 hours, at least about 44 hours, at least about 45 hours, at least about 46 hours, at least about 47 hours, at least about 48 hours, at least about 49 hours, at least about 50 hours, at least about 51 hours, at least about 52 hours, at least about 5 The eating disorder or at least one symptom thereof is alleviated for at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, or longer. In some embodiments, the eating disorder or at least one symptom thereof is alleviated for at least one month after administration of psilocybin. In some embodiments, the eating disorder or at least one symptom thereof is alleviated for at least three months after administration of psilocybin. In some embodiments, the eating disorder, or at least one symptom thereof, is alleviated for at least one year following administration of the psilocybin.

[0349] In some embodiments, after administration of psilocybin or an active metabolite thereof, the eating disorder, or at least one symptom thereof, is alleviated within about 5 minutes to about 1 week, e.g., within about 5 minutes, within about 15 minutes, within about 30 minutes, within about 45 minutes, within about 1 hour, within about 2 hours, within at least 3 hours, within about 4 hours, within about 5 hours, within about 6 hours, within about 7 hours, within about 8 hours, within about 9 hours, within about 10 hours, within about 11 hours, within about 12 hours, within about 13 hours, within about 14 hours, within about 15 hours, within about 16 hours, within about 17 hours, within about 18 hours, within about 19 hours, within about 20 hours, within about 21 hours, within about 22 hours, within about 23 hours, within about 24 hours, within about 1 day, within about 2 days, within about 3 days, within about 4 days, within about 5 days, within about 6 days, or within about 7 days. In some embodiments, the eating disorder, or at least one symptom thereof, is alleviated within 24 hours of administering the psilocybin. In some embodiments, the eating disorder, or at least one symptom thereof, is alleviated within one week of administering the psilocybin.

[0350] Disclosed herein, in some embodiments, are methods for treating one or more headache disorders in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, the active metabolite is psilocybin.

[0351] As used herein, the term "headache disorder" refers to a disorder characterized by recurrent headaches. Headache disorders are among the most common disorders of the nervous system. Headache disorders include migraine, tension-type headache, cluster headache, and chronic daily headache syndrome.

[0352] In some embodiments, disclosed herein are methods for treating cluster headache in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, at least one sign or symptom of cluster headache is improved after administration of psilocybin or its metabolite. In some embodiments, the sign or symptom of cluster headache is measured according to a diary assessment, a physical or psychological evaluation by a clinician, an imaging test, or a neurological examination.

[0353] Cluster headache is a primary headache disorder and belongs to the trigeminal autonomic headache. Cluster headache is defined as a unilateral headache with at least one autonomic symptom on the same side as the headache. Attacks are characterized by severe unilateral pain, mainly in the first division of the trigeminal nerve, i.e., the fifth cranial nerve, whose main function is to provide sensory and motor innervation to the face. Attacks are also associated with prominent unilateral cranial autonomic symptoms, and patients often experience agitation and emotional restlessness during attacks.

[0354] In some embodiments, subjects with cluster headaches have cluster headache attacks lasting 15 to 180 minutes and occurring up to 8 times per day. Cluster headaches usually occur at approximately the same time each day, often at night. In some embodiments, cluster headaches are episodic. Episodic cluster headache (ECH) is experienced by 85 to 90% of subjects and occurs when a subject experiences daily attacks for several weeks to several months, followed by remission for several months to several years. Subjects often experience one to two episodes per year, often in the spring or fall. In some embodiments, the cluster headache is chronic cluster headache (CCH). Individuals with CCH experience attacks without remission lasting more than a year, or remissions lasting less than a month. CCH is experienced by 15 to 20% of subjects who experience cluster headaches.

[0355] Approximately 0.1% of the population suffers from cluster headache. This disorder has historically been considered to have a male predominance, with a high male-to-female ratio that differs between ECH and CCH. The ratio is highest in subjects aged 20 to 49 years with an onset age of 7.2:1 for ECH and 11.0:1 for CCH. The ratio is lowest in subjects aged 50 years or older with an onset age of 2.3:1 for ECH and 0.6:1 for CCH. These ratios were determined by observation of 554 cluster headache patients examined between 1963 and 1997. The authors suggested that these ratios may be related to sex hormone regulation and environmental factors. Recent studies have reported a decrease in the male predominance, with the ratio now at 2:1.

[0356] In some embodiments, subjects with cluster headaches also experience nausea and / or vomiting. In some embodiments, subjects with cluster headaches experience unilateral pain, excessive tearing, facial flushing, ptosis, constricted pupils, redness of the eyes, swelling under or around one or both eyes, sensitivity to light, nausea, agitation, and restlessness.

[0357] In some embodiments, after treatment with the methods of the present disclosure, the frequency of cluster headaches is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before said treatment.

[0358] In some embodiments, after treatment with the methods of the present disclosure, the duration of cluster headaches is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before said treatment.

[0359] In some embodiments, after treatment with the methods of the present disclosure, the signs or symptoms of cluster headache are reduced compared to before the treatment. In some embodiments, the signs or symptoms of migraine are measured according to a diary assessment, a physical or psychological evaluation by a clinician, imaging tests, electroencephalography, blood tests, neurological tests, or a combination thereof. In some embodiments, the blood tests evaluate blood chemistry and / or vitamins.

[0360] Disclosed herein in some embodiments is a method for treating migraine in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Migraine is a moderate to severe headache that affects one half or both sides of the head, is pulsating in nature, and lasts 2 to 72 hours. Migraine symptoms include headache, nausea, sensitivity to light, sound, or smell, dizziness, difficulty speaking, vertigo, vomiting, seizures, astigmatism, fatigue, or loss of appetite. Some subjects also experience a pre-symptomatic phase occurring hours or days before the headache and / or a post-symptomatic phase after the headache resolves. Pre-symptomatic and post-symptomatic symptoms include hyperactivity, hypoactivity, depression, cravings for certain foods, recurrent yawning, fatigue, and neck stiffness and / or pain.

[0361] In some embodiments, the migraine is migraine without aura, migraine with aura, chronic migraine, abdominal migraine, basilar migraine, menstrual migraine, ophthalmoplegic migraine, ocular migraine, ophthalmic migraine, or hemiplegic migraine. In some embodiments, the migraine is migraine without aura. Migraine without aura is associated with migraine without headache. In some embodiments, the migraine is migraine with aura. Migraine with aura is primarily characterized by transient focal neurological symptoms that usually precede or sometimes accompany the headache. Although uncommon, the aura can occur without headache or with non-migraine headaches. In some embodiments, the migraine is hemiplegic migraine. Hemiplegic migraine is migraine with aura and associated motor paralysis. In some embodiments, the hemiplegic migraine is familial hemiplegic migraine or sporadic hemiplegic migraine. In some embodiments, the migraine is a basilar artery migraine. Subjects with basilar artery migraine experience a migraine headache and aura accompanied by many other brainstem-related symptoms, including difficulty speaking, spinning of the world, tinnitus, or motor paralysis. In some embodiments, the migraine is a menstrual migraine. Menstrual migraines occur just before and during menstruation. In some embodiments, the subject has abdominal migraine. Abdominal migraine is often experienced by children. Abdominal migraine is not a headache, but instead a stomach ache. In some embodiments, subjects with abdominal migraine experience a migraine headache. In some embodiments, the subject has ophthalmic migraine, also known as "ocular migraine." Subjects with ocular migraine experience loss of vision or blindness in one eye for a short period of time during or after the migraine. In some embodiments, the subject has ophthalmoplegic migraine. Ophthalmoplegic migraine is a recurrent attack of migraine associated with paresis of one or more ophthalmic cranial nerves.

[0362] In some embodiments, the subject in need of treatment experiences chronic migraine. As defined herein, a subject with chronic migraine has headaches on more than 15 days per month. In some embodiments, the subject in need of treatment experiences episodic migraine. As defined herein, a subject with chronic migraine has headaches on less than 15 days per month.

[0363] In some embodiments, after treatment with the methods of the present disclosure, the frequency of migraines is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before treatment.

[0364] In some embodiments, after treatment with the methods of the present disclosure, the length of the migraine headache is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before the treatment.

[0365] In some embodiments, after treatment with the methods of the present disclosure, migraine signs or symptoms are reduced compared to before said treatment, hi some embodiments, migraine signs or symptoms are measured according to a diary assessment, a physical or psychological evaluation by a clinician, an imaging study, or a neurological examination.

[0366] In some embodiments, disclosed herein is a method for treating chronic daily headache syndrome (CDHS) in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof. Subjects with CDHS experience headaches lasting more than four hours for 15 or more days per month. Some subjects experience these headaches for 6 months or more. CDHS affects 4% of the general population. Chronic migraine, chronic tension-type headache, new-onset daily persistent headache, and medication overuse headache account for the majority of chronic daily headaches.

[0367] In some embodiments, after treatment with the methods of the present disclosure, the chronic daily headaches experienced by the subject in need of treatment are reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0368] In some embodiments, after treatment with the methods of the present disclosure, the number of chronic daily headaches experienced by a subject in need of treatment per month is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0369] In some embodiments, after treatment with the methods of the present disclosure, the number of chronic daily headaches experienced by a subject in need of treatment per month is reduced by about 1 headache per month, about 2 headaches per month, about 3 headaches per month, about 4 headaches per month, about 5 headaches per month, about 6 headaches per month, about 7 headaches per month, about 8 headaches per month, about 9 headaches per month, about 10 headaches per month, about 11 headaches per month, about 12 headaches per month, about 13 headaches per month, about 14 headaches per month, about 15 headaches per month, or more.

[0370] In some embodiments, the subject with headache has one or more comorbid conditions. Non-limiting examples of comorbid conditions include endocrine and / or metabolic conditions, gastrointestinal conditions, cardiovascular conditions, psychiatric conditions, or neurological conditions. In some embodiments, the comorbid condition is an anxiety disorder, a depressive disorder, a psychotic disorder, a developmental disorder, an eating disorder, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), autism spectrum disorder (ASD), a tic disorder, a bipolar disorder, a conduct disorder, mental retardation, or a combination thereof. In some embodiments, the comorbid condition is a mood disorder, a major depressive disorder, a bipolar disorder, schizophrenia, an eating disorder, an attention deficit / hyperactivity disorder, epilepsy, a cardiovascular condition, migraine, irritable bowel syndrome, dementia, Alzheimer's disease, Parkinson's disease, or a combination thereof. In some embodiments, the comorbid condition is depression, generalized anxiety, agoraphobia, or panic disorder. In some embodiments, the comorbid condition is major depression. In some embodiments, the comorbid condition is an eating disorder. In some embodiments, the comorbid condition is ADHD. In some embodiments, the comorbid condition is ASD. In some embodiments, the comorbid condition is major depressive disorder, bipolar disorder, irritable bowel disease, or irritable bowel syndrome.

[0371] In some embodiments, the comorbid condition is sleep apnea, depression, anxiety, aggressive behavior, suicidal ideation, or bipolar disorder. In some embodiments, the comorbid condition is smoking, sleep apnea, depression, anxiety, aggressive behavior, suicidal ideation, or bipolar disorder. In some embodiments, the comorbid condition is stroke, vascular cerebral lesions, coronary heart disease, patent foramen ovale, hypertension, depression, anxiety, bipolar disorder, panic disorder, suicide, restless legs syndrome, epilepsy, inflammatory bowel disease, or asthma.

[0372] In some embodiments, the subject in need of treatment is male. In some embodiments, the subject in need of treatment is female. In some embodiments, the subject in need of treatment is a pregnant woman. In some embodiments, the subject in need of treatment is a postpartum woman. In some embodiments, the subject in need of treatment is psilocybin naive. In some embodiments, the subject in need of treatment has previously experienced psilocybin.

[0373] In some embodiments, after administration of psilocybin, no other therapy for treating a headache disorder is administered to the subject.

[0374] In some embodiments, the subject with a headache disorder is administered at least one additional therapeutic and / or therapeutic agent. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs before the administration of psilocybin. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs after the administration of psilocybin. In some embodiments, the administration of the additional therapeutic and / or therapeutic agent occurs simultaneously with the administration of psilocybin.

[0375] In some embodiments, the additional therapeutic agent is oxygen therapy, triptans, ergotamine, lidocaine, somatostatin and somatostatin analogs, corticosteroids, methysergide, verapamil, lithium, topiramate, valproic acid, botulinum toxin, clomiphene, lysergic acid diethylamide, prednisolone, dihydroergotamine, beta-blockers, vitamins, antidepressants, anticonvulsants, lisdexamfetamine dimesylate, antipsychotics, anxiety medications, anti-inflammatory medications, benzodiazepines, analgesics, cardiovascular medications, or combinations thereof.

[0376] In some embodiments, the additional therapy is an antidepressant. In some embodiments, the antidepressant is amitriptyline. In some embodiments, the antidepressant indirectly affects neurotransmitter receptors, for example, through interactions that affect the responsiveness of other molecules at the neurotransmitter receptor. In some embodiments, the antidepressant is an agonist. In one embodiment, the antidepressant is an antagonist. In some embodiments, the antidepressant acts (either directly or indirectly) on more than one neurotransmitter receptor. In some embodiments, the antidepressant is selected from bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.

[0377] In some embodiments, the antidepressant is a tricyclic antidepressant ("TCA"), a selective serotonin reuptake inhibitor ("SSRI"), a serotonin and noradrenaline reuptake inhibitor ("SNRI"), a dopamine reuptake inhibitor ("DRI"), a monoamine oxidase inhibitor ("MAOI"), including a noradrenaline reuptake inhibitor ("NRU"), a dopamine, serotonin and noradrenaline reuptake inhibitor ("DSNRI"), a reversible inhibitor of monoamine oxidase type A (RIMA), or a combination thereof. In some embodiments, the antidepressant is a TCA. In some embodiments, the TCA is imipramine or clomipramine. In some embodiments, the antidepressant is an SRI. In some embodiments, the SSRI is escitalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, or a combination thereof. In some embodiments, the SNRI is venlafaxine. In some embodiments, the additional therapeutic agent is pregabalin.

[0378] In some embodiments, the antidepressant is amitriptyline.

[0379] In some embodiments, the additional therapeutic agent is an anticonvulsant. In some embodiments, the anticonvulsant is gabapentin, carbamazepine, ethosuximide, lamotrigine, felbamate, topiramate, zonisamide, tiagabine, oxcarbazepine, levetiracetam, divalproex sodium, phenytoin, or fos-phenytoin. In some embodiments, the anticonvulsant is topiramate.

[0380] In some embodiments, the additional therapeutic agent is a beta-blocker. Non-limiting examples of beta-blockers include acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propranolol, sotalol, or timolol. In some embodiments, the beta-blocker is propranolol.

[0381] In some embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drug, acetaminophen, caffeine, a triptan, dihydroergotamine, an opioid, an antinausea medication, an antihypertensive, an antidepressant, an antiseizure medication, Botox injections, a monoclonal antibody directed against calcitonin gene-related peptide, acupuncture, a black room, dietary modifications, heat / cold therapy, magnesium supplementation, massage, riboflavin / B2 supplementation, transcranial magnetic stimulation, or any combination thereof.

[0382] In some embodiments, at least one sign or symptom of the headache disorder is improved after administration of psilocybin or a metabolite thereof. In some embodiments, the sign or symptom of the headache disorder is measured according to a diary assessment, a clinician or caregiver assessment, or a clinical scale. In some embodiments, psilocybin treatment causes improvements as demonstrated by one or more of the following: visual analog scale, numeric rating scale, Short Form Health Survey, Profile of Mood States, Pittsburgh Sleep Quality Index, Major Depression Inventory, Perceived Stress Scale, 5-level EuroQoL-5D, Headache Impulse Test, ID-Migraine, 3-item screener, Minnesota Multiphasic Personality Inventory, Hospital Anxiety and Depression Scale (HADS), 50-Beck Depression Inventory (BDI, both the original BDI51 and the second edition, BDI-II52), 9-item Patient Health Questionnaire (PHQ-9), Migraine Disability Assessment Questionnaire (MIDAS), Migraine-Specific Quality of Life Questionnaire Version 2.1 (MSQ v2.1), European Quality of Life 5 Dimension (EQ-5D), Short Form 36 (SF-36), or a combination thereof.

[0383] In some embodiments, treatment with the methods of the present disclosure results in about a 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in headache disorder compared to before treatment according to any one of the diary assessments, clinician or caregiver assessments, or clinical scales described herein.

[0384] In some embodiments, treatment with the methods of the present disclosure results in about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% improvement in migraine headaches compared to before treatment according to any one of the diary assessments, clinician or caregiver assessments, or clinical scales described herein. In some embodiments, the assessment is a visual aura rating scale or an ID migraine questionnaire.

[0385] In some embodiments, treatment with the methods of the present disclosure results in about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% improvement in cluster migraine compared to before treatment according to any one of the diary assessments, clinician or caregiver assessments, or clinical scales described herein. In some embodiments, the assessment is a visual analog scale, a numerical rating scale, a Short Form Health Survey, a Profile of Mood States, a Pittsburgh Sleep Quality Index, a Major Depression Inventory, a Perceived Stress Scale, a 5-level EuroQoL-5D, a Headache Impulse Test, or a combination thereof.

[0386] In some embodiments, following administration of psilocybin or an active metabolite thereof, at least one symptom of a headache disorder is alleviated for at least about 5 minutes to at least about 1 year, e.g., at least one symptom of anxiety is alleviated for at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 25 hours, at least about 26 hours, at least about 27 hours, at least about 28 hours, at least about 29 hours, at least about 30 hours, at least about 31 hours, at least about 32 hours, at least about 33 hours, at least about 34 hours, at least about 35 hours, at least about 36 hours, at least about 37 hours, at least about 38 hours, at least about 39 hours, at least about 40 hours, at least about 41 hours, at least about 42 hours, at least about 43 hours, at least about 44 hours, at least about 45 hours, at least about 46 hours, at least about 47 hours, at least about 48 hours, at least about 49 hours, at least about 50 hours, at least about 51 hours, at least about 52 hours, at least about 53 hours, at least In some embodiments, at least one symptom of the headache disorder is alleviated for at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, or longer. In some embodiments, at least one symptom of the headache disorder is alleviated for at least one month after administration of psilocybin. In some embodiments, at least one symptom of the headache disorder is alleviated for at least three months after administration of psilocybin. In some embodiments, at least one symptom of the headache disorder is alleviated for at least one year following administration of the psilocybin.

[0387] In some embodiments, administration of psilocybin prevents the occurrence of a headache disorder for at least about 1 week or more, e.g., about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 1 month, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, or more. In some embodiments, administration of psilocybin prevents the occurrence of a headache disorder for at least about 1 month. In some embodiments, administration of psilocybin prevents the occurrence of a headache disorder for at least about 3 months. In some embodiments, administration of psilocybin prevents the occurrence of a headache disorder for at least about 6 months. In some embodiments, administration of psilocybin prevents the occurrence of a headache disorder for at least about 12 months.

[0388] In some embodiments, after administration of psilocybin or an active metabolite thereof, at least one symptom of a headache disorder is alleviated within about 5 minutes to about 1 week, e.g., within about 5 minutes, within about 15 minutes, within about 30 minutes, within about 45 minutes, within about 1 hour, within about 2 hours, within at least 3 hours, within about 4 hours, within about 5 hours, within about 6 hours, within about 7 hours, within about 8 hours, within about 9 hours, within about 10 hours, within about 11 hours, within about 12 hours, within about 13 hours, within about 14 hours, within about 15 hours, within about 16 hours, within about 17 hours, within about 18 hours, within about 19 hours, within about 20 hours, within about 21 hours, within about 22 hours, within about 23 hours, within about 24 hours, within about 1 day, within about 2 days, within about 3 days, within about 4 days, within about 5 days, within about 6 days, or within about 7 days. In some embodiments, at least one symptom of the headache disorder is alleviated or improved within 15 minutes of administering psilocybin. In some embodiments, at least one symptom of the headache disorder is alleviated or improved within 30 minutes of administering psilocybin. In some embodiments, at least one symptom of the headache disorder is alleviated or improved within 1 hour of administering psilocybin. In some embodiments, at least one symptom of the headache disorder is alleviated or improved within 3 hours of administering psilocybin. In some embodiments, at least one symptom of the headache disorder is alleviated or improved within 6 hours of administering psilocybin.

[0389] Prior and concomitant treatments In some embodiments, a treatment method comprising administering psilocybin to a subject in need thereof further comprises pretreating the subject with magnesium prior to administration of psilocybin. In some cases, magnesium is administered daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks prior to administration of psilocybin. In some embodiments, about 10 mg to about 500 mg of magnesium is administered to the subject per day. In some embodiments, about 30 mg, about 75 mg, about 80 mg, about 130 mg, about 240 mg, about 310 mg, about 320 mg, about 360 mg, about 410 mg, about 400 mg, or about 420 mg is administered to the subject per day. In some embodiments, magnesium is administered to the subject on the same day as psilocybin. In some embodiments, magnesium is administered to the subject immediately before, simultaneously with, or immediately after administration of psilocybin. In some embodiments, the magnesium supplement is administered to the subject until the subject's blood magnesium level is about 1.5 to about 2.5 mEq / L. In some embodiments, if the subject's blood magnesium level is less than about 1.5 to about 2.5 mEq / L, psilocybin is not administered to the subject.

[0390] In some embodiments, a method of treatment comprising administering psilocybin to a subject in need thereof further comprises pretreating the subject with niacin prior to administration of psilocybin. In some cases, niacin is administered daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks prior to administration of psilocybin. In some embodiments, about 1 mg to about 5,000 mg of niacin is administered to the subject per day, e.g., about 1 mg to about 50 mg, about 10 mg to about 100 mg, about 100 mg to about 200 mg, about 1 mg to about 200 mg, about 100 mg to about 200 mg, about 10 mg to about 50 mg, about 10 mg to about 35 mg, about 100 mg to about 500 mg, or about 1,000 mg to about 3,000 mg. In some embodiments, about 10 mg, about 14 mg, about 15 mg, about 16 mg, about 20 mg, about 30 mg, about 35 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg of niacin is administered to a subject per day (while avoiding any toxic exposure from excess niacin). In some embodiments, niacin is included as an ingredient / component, for example, to reduce the risk of abuse and / or improve efficacy. In some embodiments, the niacin is administered to the subject on the same day as the psilocybin. In some embodiments, the niacin is administered to the subject immediately before, simultaneously with, or immediately after the administration of the psilocybin.

[0391] In some embodiments, psilocybin is administered to a subject in combination with one or more additional therapeutic agents. In some embodiments, psilocybin is administered to a subject in combination with one or more antidepressants or anti-anxiety medications, such as an SSRI, a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), or a serotonin norepinephrine reuptake inhibitor (SNRI).

[0392] In some embodiments, the present disclosure provides a method of reducing anxiety in a subject undergoing treatment with psilocybin, the method comprising administering to the subject: i) psilocybin or a precursor or derivative thereof, and ii) one or more benzodiazepines.

[0393] In some embodiments, one or more benzodiazepines are administered to a subject simultaneously or nearly simultaneously with psilocybin or a precursor or derivative thereof. In some embodiments, one or more benzodiazepines are administered prior to administration of psilocybin or a precursor or derivative thereof, e.g., about 10, 15, 20, 30, 45, 60, 75, 90, 105, 120, 150, or 180 minutes prior to administration of psilocybin or a precursor or derivative thereof. In some embodiments, the one or more benzodiazepines are administered after administration of psilocybin or a precursor or derivative thereof, for example, to a subject about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after administration of psilocybin or a precursor or derivative thereof.

[0394] In some embodiments, one or more benzodiazepines are administered at a dose lower than that typically used to treat anxiety, such as about 10%, 20%, 25%, 30%, 40%, 50%, or 75% of the typical dose. In some embodiments, one or more benzodiazepines are administered at a dose approximately equal to that typically used to treat anxiety. In some embodiments, one or more benzodiazepines are administered at a dose higher than that typically used to treat anxiety, such as about 125%, 150%, 175%, 200%, 250%, or 300% of the typical dose. In some embodiments, one or more benzodiazepines are administered orally to the subject.

[0395] In some embodiments, the benzodiazepines are adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, fluralprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam ...

[0039] The agonist is selected from the group consisting of flunitrazepam, flurazepam, flutazolam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, meclonazepam, medazepam, metizolam, mexazolam, midazolam, nifoxipam, nimetazepam, nitemazepam, nitrazepam, nitrazolam, nordiazepam, norflurazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, rilmazepam, temazepam, tetrazepam, and triazolam.

[0396] In certain embodiments, a patient receives psilocybin, or a precursor or derivative thereof, as described herein, in combination with one or more 5-HT 2AIn some embodiments, the subject is administered psilocybin or a precursor or derivative thereof, along with one or more 5-HT specific antagonists and / or inverse agonists. 2A In other embodiments, the subject is administered one or more 5-HT specific antagonists and / or inverse agonists at the same time, such as, but not limited to, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes prior to psilocybin administration. 2A In some embodiments, the subject receives a specific antagonist and / or inverse agonist of one or more 5-HT agonists after psilocybin administration, such as, but not limited to, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after psilocybin administration. 2A Specific antagonists and / or inverse agonists are administered.

[0397] In certain embodiments, one or more 5-HT 2A The specific antagonist and / or inverse agonist is administered at a dose lower than typically used, e.g., about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 75% of the typical dose. 2A In yet another embodiment, the specific antagonist and / or inverse agonist is administered at a dose equivalent to that typically used. 2A The specific antagonist and / or inverse agonist is administered at a higher dose than typically used, for example, about 125%, about 150%, about 175%, about 200%, about 250%, or about 300% of the typical dose.

[0398] Adequate 5-HT 2AAntagonists include trazodone, mirtazapine, metergoline, ketanserin, ritanserin, nefazodone, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines, 9-aminomethyl-9,10-dihydroanthracene (AMDA), haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO- NBpBrT, niaprazine, altanserin, aripiprazole, etoperidone, cetoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rauwolscine, phenoxybenzamine, pulvanserin, deramciclane, nerotanserin, rubazodone, mepiprazole, xylamidine, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinemethanol (M100907), mianserin, AT 1015, DV 7028, eplivanserin, 4F 4PP, fanaserin, alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol (MDL 11,939), melperone, mesulergine, paliperidone, 1-[2-(3,4-dihydro-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine dihydrochloride (PNU 96415E), (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol (R-96544), sarpogrelate, spiperone, ziprasidone, zotepine, and 7-[[4-[2-(4-fluorophenyl)ethyl]-1-piperazinyl]carbonyl]-1H-indole-3-carbonitrile (EMD281014).

[0399] Preferred 5-HT 2A Inverse agonists include, but are not limited to, AC-90179, nerotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and vorinaserin.

[0400] In certain embodiments, 5-HT 2A The antagonist is selected from the compounds in Table 8: [Table 8-1] [Table 8-2]

[0401] In some embodiments, the present disclosure provides methods for reducing negative side effects associated with a traumatic psychedelic experience in a subject receiving treatment with psilocybin, the methods comprising administering to the subject i) psilocybin or a precursor or derivative thereof, and ii) one or more cannabinoids or cannabinoid derivatives.

[0402] In some embodiments, the cannabinoid is selected from THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabidiol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), or CBT (cannabicitran). In certain embodiments, the cannabinoid is CBD (cannabidiol).

[0403] In some embodiments, at least one symptom of a disease, disorder, or condition described herein is alleviated within 24 hours of administration of psilocybin. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within one week of administration. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within one month of administration. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within six months of administration. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within 12 months of administration.

[0404] In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least one month after administration of psilocybin. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least three months after administration. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least six months after administration. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least 12 months after administration.

[0405] In some embodiments, prior to administration of psilocybin, the subject is not administered other therapies for treating the disease, disorder, or condition, hi some embodiments, after administration of psilocybin, the subject is not administered other therapies for treating the disease, disorder, or condition.

[0406] Safety and efficacy of psilocybin The present disclosure also relates to the safety and efficacy of using psilocybin as disclosed herein. The following is a non-exhaustive list of tests that can be used to determine the effects of psilocybin, particularly psilocybin formulations, as disclosed herein, administered as disclosed herein.

[0407] In some embodiments, a spatial working memory (SWM) test is utilized to assess the safety and efficacy of psilocybin as disclosed herein. SWM requires the retention and manipulation of visuospatial information. Subjects must find blue tokens in "boxes" on the screen. Boxes are searched by touching them to determine whether they contain a token. Once a token is found, it is "stacked" in a column on the right side of the screen. The subject searches for more tokens until all are located. The remaining tokens are then found only in boxes that have not previously contained a token. Subjects are explicitly informed that this is the case, and revisiting a box in which a token was found constitutes a "between error," the usual key measure of this test. If a subject revisits a box during the same search, it is scored as a "within" error. Many subjects employ a search strategy that systematically searches through the array of boxes. This is also scored by the Cambridge Neuropsychological Test Automated Battery System, resulting in a "Strategy" score. SWM performance is impaired by damage to the prefrontal cortex, particularly the dorsofrontal cortex. Similarly, in neuroimaging studies of healthy volunteers, performance on SWM is associated with activation of the dorsal and ventral prefrontal cortex. The test takes approximately 4 minutes to complete.

[0408] In some embodiments, the efficacy of psilocybin is assessed using a spatial working memory between errors (SWMBE) score. In some embodiments, after treatment with a method of the present disclosure, the subject's SWMBE score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0409] In some embodiments, the effectiveness of psilocybin is assessed using a Spatial Working Memory Strategy (SWMS) score. In some embodiments, after treatment with the methods of the present disclosure, the subject's SWMS score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to pre-treatment.

[0410] In some embodiments, the Rapid Visual Processing (RVP) test is utilized to assess the safety and efficacy of psilocybin. RVP is a measure of sustained attention that outputs measurements of response accuracy, target sensitivity, and reaction time. In this test, subjects monitor a stream of two to nine digits for a specific sequence (e.g., 3-5-7) and must confirm detection of the sequence by touching an on-screen response button as quickly as possible after the presentation of the third digit. Numbers are presented in a pseudo-like fashion to create the possibility of a "false alarm" response, in which the first two digits of the sequence do not follow the true target. For example, a 3 follows a 5, but not a 7. To successfully complete the task, subjects must maintain continuous attention on a white box displaying the digits. Performance on this task is measured by the speed of response to the presentation of the final target digit, as well as the subject's ability to detect the specific sequence. This test takes approximately 7 minutes to complete. In some embodiments, performance on the Rapid Visual Processing test is reported using the RVP A Prime (RPVA) score. A higher RVPA score indicates better performance. In some embodiments, after treatment with the methods of the present disclosure, the subject's RVPA score is improved by about 5% to about 300%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or more, compared to before treatment. %, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more increase.

[0411] In some embodiments, the paired associative learning (PAL) test is used to assess the safety and / or efficacy of psilocybin. The PAL task is a measure of visuospatial memory, requiring subjects to remember the location of a visual stimulus. Boxes are displayed on the screen and "opened" in random order. One or more of them contain a pattern. The patterns are then displayed one at a time in the center of the screen, and the subject must select the box where the pattern was originally located. If the subject makes an error, the boxes are opened again in sequence to remind the subject of the pattern's location. A higher difficulty level can be used to test high-functioning, healthy individuals. The primary indicator of this test is the number of errors made. The test takes approximately 8 minutes to complete. Success with the PAL test depends on the functional integrity of the temporal lobe, particularly the entorhinal cortex. In some embodiments, the Paired Associate Learning Total Errors (Adjustments) (PALTEA) score is used to assess the efficacy of psilocybin. In some embodiments, after treatment with the methods of the present disclosure, the subject's PALTEA score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0412] In some embodiments, the efficacy and / or safety of psilocybin is assessed using a cognitive flexibility panel test.

[0413] In some embodiments, the Emotion Recognition Task (ERT) test is utilized to assess the safety and / or efficacy of psilocybin. The ERT measures the ability to identify six basic emotions in facial expressions along a continuum of different magnitudes. In some embodiments, the ERT is administered according to the following protocol: The subject is presented with computer-generated images on a screen, one at a time, derived from the facial features of real individuals that display a particular emotion. Each face is displayed for 200 milliseconds and then immediately obscured, and the subject must select which face is displayed from six options (happy, sad, anger, fear, surprise, disgust). The subject's correct responses (emotion selections) are assessed as ERT Correct Percentage (ERTPC). A higher score indicates better performance. In some embodiments, after treatment with the methods of the present disclosure, the subject's ERTPC is about 5% to about 300%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or greater than about 5% compared to before treatment. , about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more increase.

[0414] In some embodiments, the intra- and extra-dimensional set-shifting (IED) test is used to assess the safety and / or efficacy of psilocybin. The IED consists of four 7-item subscales, each tapping a distinct aspect of the global concept of "empathy." In some embodiments, the intra- and extra-dimensional set-shifting total error (IEDYERT) score is used to assess the efficacy of psilocybin. In some embodiments, after treatment with the methods of the present disclosure, a subject's IEDEYERT score is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to pre-treatment.

[0415] In some embodiments, the Cambridge Test of One Touch Stocking (OTS) is used to assess the safety and / or efficacy of psilocybin. The OTS is a test of executive function based on the Tower of Hanoi test. It assesses both spatial planning and working memory subdomains. This test takes approximately 10 minutes to administer. The OTS test reports a First-Choice Cambridge Problem Solved One Touch Stocking (OTSPSFC) score. Higher OTSPSFC scores are associated with better executive function. In some embodiments, after treatment with the methods of the present disclosure, the subject's OTSPSFC score improves by about 5% to about 300%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about An increase of 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more.

[0416] In some embodiments, verbal fluency is used to assess the safety and / or efficacy of psilocybin. In a verbal fluency test, subjects are asked to name as many examples of different categories (e.g., "animals") as possible in one minute, following specific scoring rules, such as repetition. Successful performance of this test depends on the integrity of several cognitive abilities, particularly those traditionally considered executive functions, such as planning and working memory. The primary measure of this test is the total number of acceptable words produced. In some embodiments, after treatment with psilocybin, subjects' verbal fluency category scores improve by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to pre-treatment. An improvement of 5%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more.

[0417] In some embodiments, the digit span forward (DSF) test is used to evaluate the safety and / or efficacy of psilocybin. DSF is used to measure numerical memory capacity. Subjects hear a series of digit sequences and are tasked with correctly recalling the sequences, with sequences of increasing length being tested on each trial. The subject's span is the longest consecutive number of digits they can accurately remember. The digit span task can be administered forward or backward, meaning that once the sequence is presented, the subject is asked to recall the sequence in normal or reverse order. In this test, the subject is asked to recall the sequence in the order in which it was presented, i.e., digit span forward order. The primary endpoint of this test is the number of digit sequences successfully recalled. In some embodiments, after treatment with psilocybin, the subject's digit span forward score improves by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about An improvement of 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more.

[0418] In some embodiments, the Five-Dimensional Altered States of Consciousness Questionnaire (5D-ASC) is utilized to assess the safety and / or efficacy of psilocybin. The 5D-ASC measures acute drug effects using five primary dimensions and 11 lower-order scales to assess changes in mood, perception, and experience of self related to the environment and thought disorders. The five dimensions include oceanic infinity, dissipation of anxious self, visual restructuring, auditory alterations, and reduced vigilance. In some embodiments, after treatment with the disclosed methods, subjects experience increases in a dimension or subscale compared to pre-treatment. Lower-order scales include "experience of unity," "spiritual experience," "euphoric state," "insight," "impaired execution," "impaired cognitive control," "anxiety," "complex imagery," "basic imagery," "auditory-visual synesthesia," and "altered meaning of perception." In some embodiments, the increase is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more compared to before treatment.

[0419] In some embodiments, the Positive and Negative Affect Schedule (PANAS) is used to assess the safety and / or efficacy of psilocybin. The PANAS measures acute emotional drug effects and includes two mood scales measuring positive and negative affect. Positive affect refers to the tendency to experience positive emotions and interact positively with others. Negative affect involves experiencing the world in a more negative way. Subjects answer 10 questions related to negative affect and 10 questions related to positive affect. Questions are scaled using a 5-point scale ranging from "slightly or not at all" (1) to "extremely" (5). A higher overall score on the positive affect questions indicates more positive affect, while a lower score on the negative affect questions indicates less negative affect. In some embodiments, after treatment with the methods of the present disclosure, the subject experiences a reduction in PANAS negative affect score of about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to before treatment. In some embodiments, after treatment with the methods of the present disclosure, the subject improves their PANAS positive affect score by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or more, compared to before treatment. %, about 95%, or about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more increase.

[0420] In some embodiments, the NEO-Five Factor Inventory (NEO-FFI) test is used to assess the safety and / or efficacy of psilocybin. The NEO-FFI assesses five broad personality domains: neuroticism, extraversion, openness, agreeableness, and conscientiousness.

[0421] In some embodiments, the Symptom Checklist-90 (SCL-90) questionnaire is used to assess the safety and / or efficacy of psilocybin. The SCL-90 is a relatively short, self-report psychometric instrument designed to assess a wide range of mental problems and symptoms of psychopathology. In some embodiments, the SCL-90 is used to assess somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety disorder, paranoid ideation, and psychotic tendencies in subjects treated according to the methods of the present disclosure. The 90 items of the questionnaire are scored on a 5-point Likert scale to indicate the incidence of symptoms during baseline. In some embodiments, after treatment with the methods of the present disclosure, the subject's SCL-90 score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0422] In some embodiments, the Life Change Inventory (LCI) questionnaire is utilized to assess the safety and / or efficacy of psilocybin. The LCI is designed to explore variables present in the everyday experiences of adults that may be associated with either stability or decline in intellectual ability.

[0423] In some embodiments, social cognition panel scales are utilized to assess the safety and / or efficacy of psilocybin, including the Pictorial Empathy Test (PET), the Reading the Mind in the Eyes Test (RMET), the Social Value Orientation (SVO) Test, the Toronto Empathy Questionnaire (TEQ), and the Social Responsibility Scale (SSR).

[0424] In some embodiments, the Pictorial Empathy Test (PET) is utilized to assess the effects of psilocybin on emotional empathy.

[0425] In some embodiments, the Reading the Mind from the Eyes Test (RMET) is utilized to assess the safety and / or efficacy of psilocybin. The RMET has 36 items in which subjects are presented with a photograph of the eye area of ​​a face and must select one of four adjectives or phrases to describe the mental state of the person in the photograph. A definition handout is provided at the beginning of the task, and practice items are provided prior to the first trial.

[0426] In some embodiments, the Social Value Orientation (SVO) test is utilized to assess the safety and / or efficacy of psilocybin. The SVO slider standard scale has six primary items and nine secondary (and optional) items. All items have the same general form. Each item is a resource allocation choice for a distinct set of joint payoffs.

[0427] In some embodiments, after treatment with the methods of the present disclosure, one or more of the subject's social cognition panel scale scores (i.e., PET, RMET, SVO, TEQ, and / or SSR scores) improves by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141%, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, An increase of 0%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, or more.

[0428] In some embodiments, the Toronto Empathy Questionnaire (TEQ) is utilized to assess the safety and / or efficacy of psilocybin. The TEQ primarily assesses empathy as an emotional process. The TEQ exhibits good internal consistency and high test-retest reliability. The TEQ is a brief, reliable, and valid tool for assessing empathy. In some embodiments, after treatment with the methods of the present disclosure, a subject's TEQ score increases by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, or more compared to before treatment.

[0429] In some embodiments, the Social Responsibility Scale (SSR) is utilized to assess the safety and / or efficacy of psilocybin. The SSR measures perceptions of the importance of ethics and social responsibility.

[0430] In some embodiments, the Sheehan Suicidality Tracking Scale (SSTS) is utilized to assess the safety and / or efficacy of psilocybin. The SSTS is a 16-item Likert-type (0-4) scale assessing the severity of suicidality phenomena, ranging from "not at all" (0) to "extremely." The SSTS assesses the frequency of major phenomena and the total treatment time spent on suicidality.

[0431] In some embodiments, the Mini International Neuropsychiatric Interview (MINI) (version 7.0.2) is utilized to assess the safety and efficacy of psilocybin. The MINI is a brief structured interview for Axis I psychiatric disorders in DSM-5 and the International Classification of Diseases 10. In some embodiments, the MINI is used to diagnose subjects with a disorder.

[0432] In some embodiments, the McLean Screening Instrument for Borderline Personality Disorder (MSIBPD) is utilized to assess the safety and / or efficacy of psilocybin. The MSIBPD is a useful screening tool for identifying the presence of DMS-IV borderline personality disorder.

[0433] In some embodiments, the Tellegen Absorption Scale is utilized to assess the safety and / or efficacy of psilocybin. The Tellegen Absorption Scale is a 34-item multidimensional scale assessing imaginative involvement and the tendency to become mentally absorbed in everyday activities.

[0434] In some embodiments, the safety and / or efficacy of psilocybin is assessed by a physical examination, which may include, but is not limited to, an examination of the subject's general appearance, including an examination of the skin, neck, eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and musculoskeletal system.

[0435] In some embodiments, the subject's weight and height are assessed, and in some embodiments, body mass index is used to assess the safety and / or efficacy of psilocybin.

[0436] In some embodiments, an electrocardiogram (ECG) is utilized to assess the safety and / or efficacy of psilocybin, hi some embodiments, a standard 12-lead ECG is obtained.

[0437] In some embodiments, the subject's vital signs are used to assess the safety and / or efficacy of psilocybin. Vital signs include, but are not limited to, blood pressure (BP), respiratory rate, oral temperature, and pulse. In some embodiments, BP is measured after the subject has been seated for at least 3 minutes.

[0438] In some embodiments, laboratory tests are utilized to assess the safety and / or efficacy of psilocybin. In some embodiments, laboratory tests include blood and / or urine samples. In some embodiments, hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count (with differential), and platelet count are measured to assess the safety and / or efficacy of psilocybin. In some embodiments, albumin, alkaline phosphatase, alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect, and total), calcium, chloride, creatine kinase, creatinine, gamma-glutamyltransferase, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, total protein, sodium, blood urea nitrogen, and / or uric acid are measured to assess the safety and / or efficacy of psilocybin.

[0439] In some embodiments, urine is tested for pregnancy and / or illicit drugs.

[0440] In some embodiments, the safety and / or efficacy of psilocybin is assessed by measuring adverse events. Adverse events are classified as mild, moderate, or severe. Mild adverse events do not significantly interfere with the subject's normal level of functioning. Moderate adverse events cause some functional impairment but are not dangerous to the subject's health. Serious adverse events result in significant functional impairment or dysfunction and pose a definite risk to the subject's health. Adverse events may include, for example, euphoric mood, dissociative disorders, hallucinations, psychotic disorders, cognitive impairment, attention disorders, mood alterations, psychomotor skill impairment, inappropriate affect, overdose, and intentional product misuse. In some embodiments, serious adverse events include death, life-threatening adverse events, inpatient hospitalization or prolongation of current hospitalization, permanent or significant physical disability / incapacity, and congenital anomalies / birth defects in the offspring of subjects receiving psilocybin. In some embodiments, serious adverse events include allergic bronchospasm requiring intensive care in an emergency room or at home, hematological disorders or seizures not requiring inpatient hospital care, or the development of drug addiction or drug abuse.

[0441] Numbered Embodiments of the Present Disclosure In addition to the above disclosure, the following examples, and the appended claims, the present disclosure describes the following numbered embodiments:

[0442] Numbered embodiments for the treatment of anxiety disorders with psilocybin 1. A method of treating an anxiety disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0443] 2. The method of embodiment 1, wherein the active metabolite is psilocin.

[0444] 3. The method of any one of embodiments 1-2, wherein ...

Claims

[Claim 1] The invention described in the present specification.

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