Treatment of depression and other various disorders with psilocybin

Abstract

To provide treatment of depression and other various 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 depression, neurocognitive disorder, autism spectrum disorder, and / or attention-deficit / hyperactivity disorder.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] Depression is one of the most common mental illnesses, affecting more than 264 million people worldwide. It is characterized by a low mood and a marked decrease in interest or pleasure in activities. Other symptoms include significant weight loss or weight gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or slowness, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate or indecisiveness, recurring thoughts of death, suicidal ideation, or suicide attempts.

[0003] Current treatments for depression often consist of a combination of psychotherapy and one or more daily medications that modulate neurotransmitters such as dopamine, serotonin, and norepinephrine. These medications often take weeks to months to achieve their full effect, during which time individuals continue to suffer from symptoms and are at risk of self-harm and harm to their personal and professional lives.

[0004] There remains a need in the art for an effective treatment for depression that provides rapid onset of antidepressant action within hours or days, and that is long-lasting. 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] In some embodiments, the present disclosure provides a method of treating depression 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 subject has major depressive disorder, atypical depression, bipolar disorder, catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder. In some embodiments, the subject has a depressive disorder that is resistant to treatment.

[0007] In some embodiments, the method of the present disclosure reduces at least one sign or symptom of depression.In some embodiments, the sign or symptom of depression is depressed mood, decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or slowness, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, poor concentration or indecisiveness, or suicidal thoughts or behaviors.

[0008] In some embodiments, signs or symptoms of depression are measured according to a diary assessment, a clinician or caregiver assessment, a clinical rating scale, or by functional MRI. In some embodiments, the functional MRI measures the amygdala blood oxygen level-dependent (BOLD) response in the subject.

[0009] In some embodiments, signs or symptoms of depression are measured using a clinical depression rating scale, which is the Brief Inventory of Depressive Symptoms (QIDS)-16 scale, the QIDS-16 Daily Scale, the Hamilton Depression Rating Scale, the Beck Depression Inventory Scale, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impressions Scale, the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, and / or the Young Mania Rating Scale.

[0010] In some embodiments, the signs or symptoms of depression are assessed using the Spielberger Trait and Anxiety Inventory, Generalized Anxiety Disorder 7-Item Scale, Warwick-Edinburgh Mental Well-Being Scale, the Flourishing Scale, the Snaith Hamilton Anhedonia Pleasure Scale, the Life Orientation Test, the Meaning in Life Questionnaire, the Brief Resilience Scale, the Dysfunctional Attitudes Scale, the 44-item Big Five Inventory, the Peters 21-item Delusions Inventory, the Aberrant Self-Experiences Inventory, the Preoccupied Responsiveness Scale, the Polar Bear Inhibition Inventory, the Barrett Impulsivity Scale, the Brief Experiential Avoidance Questionnaire, the Modified Tellegen Preoccupation Questionnaire, the Scale for Assessing the Therapeutic Relationship, the Trust / Expectancy Questionnaire, the Nature Connectedness Scale, the Political Perspective Questionnaire, the Social Connectedness Scale, the Bech-Rafaelsen Mania Rating Scale, the Revised Santa Fe Inventory ... The Clara Brief Compassion Scale, Gratitude Questionnaire, Short Recommendation Scale, Rosenberg Self-Esteem Scale, Universality Subscale of the Spiritual Transcendence Scale, Oxford Questionnaire on Emotional Side Effects of Antidepressants, Lauks Emotion Intensity Scale, Sexual Dysfunction Questionnaire, Brief Index of Female Sexual Function, Gender Awareness Questionnaire, Barnes Akathisia Rating Scale, Work Productivity and Activity Impairment Questionnaire, Work and Social Adjustment Scale, Connectedness Questionnaire, Standard Assessment of Personality, Positive and Negative Syndrome Scale, Mastery Insight Scale, Self-Reflection and Insight Scale, Psychological Insight Scale, Metaphysical Beliefs Questionnaire, Spiritual Bypassing Scale, Adverse Childhood Experiences Questionnaire, Therapeutic Music Experiences Questionnaire, Setting Questionnaire, Music Immersion Scale, Psychedelic Predictor Scale, Surrender Scale, EuroQOL-5 Dimension-3 Level Scale, Columbia Suicide Severity Rating Scale, Suicidal Ideation Attribution Scale, or any combination thereof.

[0011] In some embodiments, at least one sign or symptom of depression is alleviated within 24 hours after administration of psilocybin. In some embodiments, at least one symptom of depression is alleviated within one week after administration of psilocybin. In some embodiments, at least one symptom of depression is alleviated for at least one month after administration of psilocybin. In some embodiments, at least one symptom of depression is alleviated for at least three months after administration of psilocybin. In some embodiments, at least one symptom of depression is alleviated for at least 12 months after administration of psilocybin.

[0012] In some embodiments, after administration of psilocybin, the subject is not administered any other treatment for reducing the signs or symptoms of depression.

[0013] In some embodiments, the methods of the present disclosure further include administering to the subject at least one additional therapeutic agent for reducing signs or symptoms of depression. In some embodiments, the at least one additional therapeutic agent is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic receptor antagonist. In some embodiments, the at least one additional therapeutic agent is administered before, on the same day as, or after the administration of psilocybin.

[0014] In some embodiments, the subject with depressive disorder has an additional comorbid disease or disorder. In some embodiments, the additional comorbid disease or disorder is anxiety disorder, obsessive-compulsive disorder, alcoholism, personality disorder, cardiovascular disease, neurological disease, or cancer. In some embodiments, the subject has dementia, Alzheimer's disease, or Parkinson's disease. In some embodiments, using the method of the present disclosure to reduce at least one sign or symptom of depression in a subject prevents one or more comorbid diseases or disorders in the subject.

[0015] In some embodiments, the disclosure provides methods of treating a subject in need of treatment, the methods comprising administering to the subject a therapeutically effective dose of psilocybin or an active metabolite thereof, wherein the subject is suffering from one of the following diseases, disorders, or conditions: severe mood dysregulation disorder, major depressive disorder (MDD), treatment-resistant depression, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, postpartum depression, depressive disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance-drug-induced anxiety disorder, anxiety disorder due to another medical condition, somatic symptom disorder, illness anxiety disorder (hypochondriasis), conversion disorder (functional neurological symptom disorder), factitious disorder, post-traumatic stress disorder (PTSD). ), adjustment disorder, acute distress disorder, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling) disorder, excoriation (skin picking) disorder, substance / drug-induced compulsive and related disorder, obsessive-compulsive and related disorder due to another medical condition, substance-related disorder, alcohol-related disorder, cannabis-related disorder, hallucinogen-related disorder, inhalant-related disorder, cocaine-related disorder, opioid-related disorder, sedative-related, hypnotic-related, or anxiolytic-related disorder, stimulant-related disorder, tobacco-related disorder, non-substance-related disorder (gambling or gaming disorder), migraine, cluster headache (including chronic cluster headache), cyclic vomiting, tension-type headache, dysphasia, pica, anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathy, pyromania, or kleptomania.

[0016] In some embodiments, the disclosure provides methods of treating a subject in need of treatment, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: Alzheimer's disease, Lewy bodies, traumatic brain injury, prion disease, HIV infection, Parkinson's disease, neurocognitive disorder due to Huntington's disease, concussion, chronic traumatic encephalopathy (CTE), language impairment, speech disorder (voice disorder), childhood-onset dysfluency disorder (stuttering), social (pragmatic) communication disorder, Tourette's syndrome, persistent (chronic) motor or vocal tic disorder, amnesic disorder due to a known physiological condition (perhaps in an electroconvulsive therapy (ECT)-resistant subject), transient ischemic attack, cerebral infarction, cerebral hemorrhage, progressive multinuclear ophthalmoplegia, or retrograde amnesia.

[0017] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one or more of the following diseases, disorders, or conditions: autism spectrum disorder or antisocial personality disorder.

[0018] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one or more of the following diseases, disorders, or conditions: attention-deficit / hyperactivity disorder, other specified attention-deficit / hyperactivity disorder, or attention-deficit / hyperactivity disorder not otherwise specified.

[0019] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one or more of the following diseases, disorders, or conditions: schizotypal (personality) disorder, delusional disorder, schizophrenia, or schizoaffective disorder.

[0020] In some embodiments, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has one or more diseases, disorders, or conditions selected from insomnia disorder, hypersomnia disorder, narcolepsy, or primary central sleep apnea.

[0021] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one or more of the following diseases, disorders, or conditions: schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, or obsessive-compulsive personality disorder.

[0022] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one or more of the following diseases, disorders, or conditions: Female Sexual Interest / Arousal Disorder, Male Hypoactive Sexual Desire Disorder, or Excessive Sexual Drive.

[0023] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has one or more of the following diseases, disorders, or conditions: bipolar I disorder, bipolar II disorder, or cyclothymic disorder.

[0024] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has one or more of the following diseases, disorders, or conditions: age-related hearing loss or tinnitus.

[0025] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one or more of the following diseases, disorders, or conditions: multiple sclerosis, cranial neuropathy, neuromyelitis optica, Bell's palsy, Guillain-Barré syndrome, a demyelinating disease of the central nervous system, or chronic inflammatory demyelinating polyneuropathy.

[0026] In some embodiments, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject is suffering from pain, such as phantom pain, chronic pain, or pain associated with another disease or disorder.

[0027] In some embodiments, the disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one or more of the following diseases, disorders, or conditions: myelopathy, traumatic brain injury, intellectual disability, mania, neurodegeneration, paraphilia disorder (e.g., pedophilic disorder), suicidal behavior disorder, non-suicidal self-injury disorder, persistent complex death disorder, gastrointestinal-related disease (e.g., irritable bowel syndrome (IBS)), epilepsy, sickle cell disease, locked-in syndrome, restless legs syndrome, stroke (ischemic stroke or hemorrhagic stroke), or amyotrophic lateral sclerosis (ALS).

[0028] In some embodiments, the disclosure provides methods of treating a subject, the methods comprising administering to the subject a therapeutically effective dose of psilocybin, wherein after administration, the subject exhibits improved cognition, in some embodiments, the improved cognition is improved attention, episodic memory, working memory, spatial memory, social cognition, executive function, and / or cognitive flexibility.

[0029] In some embodiments, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has treatment-resistant depression (TRD).

[0030] In some embodiments, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has major depressive disorder (MDD).

[0031] 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 no single impurity greater than 1%.

[0032] 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.

[0033] 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.

[0034] 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]

[0035] [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 diffractogram of the product obtained during the development of the process (CB646-E) (top) compared to the diffractograms of 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- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9G] 1 shows a graph of the least squares 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. A positive score indicates treatment performed better than placebo. A negative score indicates 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 10A] 1 shows the study design for a clinical trial testing psilocybin in major depressive disorder. [Figure 10B] 1 shows a trial timeline for testing psilocybin in major depressive disorder. [Figure 10C] 1 shows the timeline for the first dosing session (Visit 3) in the clinical trial. [Figure 11] 1 shows the study design for a clinical trial testing psilocybin in treatment-resistant depression. [Figure 12] 1 shows the study design for a clinical trial testing psilocybin in bipolar disorder. [Figure 13A]

[0023] Figure 1 is 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 in the rat Wistar-Kyoto model of TRD following psilocybin administration. The black arrow indicates the time of administration. The gray background indicates the dark phase (the period of wakefulness in rodents). [Figure 13B]

[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, the sleep period in rodents) following psilocybin administration in the rat Wistar-Kyoto model of treatment-resistant depression. Statistical analysis by repeated measures ANOVA followed by Dunnett's post-hoc test; *p<0.05. [Figure 13C]

[0023] Figure 1 is a series of graphs showing the amount of wakefulness, NREM sleep, and REM sleep 11-19 hours (dark phase, the wakefulness period in rodents) following psilocybin administration in the rat Wistar-Kyoto model of treatment-resistant depression. Statistical analysis by repeated measures ANOVA followed by Dunnett's post-hoc test; *p<0.05. [Figure 13D]

[0023] Figure 1 is a series of graphs showing changes in absolute and relative waking electroencephalogram (EEG) power frequency and amount of gamma oscillations in the rat Wistar-Kyoto model of treatment-resistant depression. Statistical analysis by repeated measures ANOVA followed by Dunnett's post-hoc test, *p<0.05. [Figure 13E-1] 1 is a series of graphs showing changes in frequency of absolute and relative wake, NREM and REM sleep EEG power in the rat Wistar-Kyoto model of TRD. [Figure 13E-2] 1 is a series of graphs showing changes in frequency of absolute and relative wake, NREM and REM sleep EEG power in the rat Wistar-Kyoto model of TRD. DETAILED DESCRIPTION OF THE INVENTION

[0036] 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.

[0037] The singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] Unless the context dictates otherwise, it is specifically contemplated that the various features described herein can be used in any combination.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] XRPD diffractograms and XRPD peak positions may be obtained using Cu Kα radiation.

[0048] DSC and TGA thermograms can be obtained using a heating rate of 20°C / min.

[0049] 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.

[0050] 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.

[0051] As used herein, the terms "subject" and "patient" are used interchangeably.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] As used herein, a subject who is "psilocybin-naive" has not previously been exposed to psilocybin.

[0056] 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.

[0057] depressive disorder In some embodiments, the methods provided herein are used to treat a subject with a depressive disorder. As used herein, the terms "depressive disorder," "depressive disorder," or "depression" refer to a group of disorders characterized by a persistent low mood that can affect a person's thoughts, behaviors, emotions, and sense of well-being. In some embodiments, a depressive disorder disrupts a person's physical and psychological functioning. In some embodiments, a depressive disorder causes physical symptoms such as weight loss, aches or pains, headaches, cramps, or digestive problems. In some embodiments, a depressive disorder causes mental symptoms such as persistent feelings of sadness, anxiety, hopelessness, and irritability, guilt, worthlessness, or helplessness, loss of interest or enjoyment in hobbies and activities, difficulty concentrating, remembering, or making decisions.

[0058] In some embodiments, the depressive disorder is major depressive disorder, atypical depression, bipolar disorder, catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder.

[0059] As used herein, the term "major depressive disorder" refers to a condition characterized by periods of low mood present across most circumstances. Major depressive disorder is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause. In some cases, major depressive disorder is characterized by periods of depression lasting for two weeks. In some cases, individuals experience periods of depression separated by years. In some cases, individuals experience nearly constant depressive symptoms. Major depressive disorder can adversely affect a person's personal, work, or school life, as well as sleep, eating habits, and general health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of those who commit suicide also had major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder that consists of the same cognitive and physical problems as major depressive disorder, but with less severe but longer-lasting symptoms. Exemplary symptoms of major depressive disorder include, but are not limited to, feelings of sadness, tearfulness, emptiness, or hopelessness, angry outbursts over small things, irritability or frustration, loss of interest or pleasure in most or all usual activities, sleep disturbances including insomnia or excessive sleeping, fatigue and lack of energy, loss of appetite, weight loss or gain, anxiety, agitation or restlessness, slowness of thinking, speaking, or physical movements, feelings of worthlessness or guilt, preoccupation with past failures or self-blame, difficulty thinking, concentrating, making decisions, and remembering things, frequent thoughts of death, thoughts of suicide, suicide attempts, or suicide, and unexplained physical problems such as back pain or headaches.

[0060] As used herein, the term "atypical depression" refers to a condition in which an individual exhibits a long-standing pattern of mood reactivity (i.e., mood brightening in response to actual or potential positive events), significant weight gain, increased appetite, hypersomnia, a heavy, leaden feeling in the arms or legs, and / or interpersonal rejection sensitivity that results in significant social or occupational impairment. Exemplary symptoms of atypical depression include, but are not limited to, daily sadness or depressed mood, loss of enjoyment in things that were once enjoyable, significant changes in weight (gain or loss) or appetite, near-daily insomnia or excessive sleep, physical restlessness or fatigue that is apparent to others, daily fatigue or loss of energy, feelings of hopelessness, worthlessness, or excessive guilt, near-daily concentration or decision-making problems, recurring thoughts of death or suicide, suicide plans, or suicide attempts.

[0061] As used herein, the term "bipolar disorder" refers to a condition that causes an individual to experience abnormal changes in mood, energy, activity level, and ability to perform everyday tasks. Individuals with bipolar disorder experience periods of abnormally intense emotions, changes in sleep patterns and activity levels, and abnormal behavior. These distinct periods are called "mood episodes." Mood episodes differ significantly from a person's typical mood and behavior. Exemplary symptoms of manic, excessive behavior include, but are not limited to, abnormally cheerful, excitable, or nervous behavior; increased activity, energy, or agitation; exaggerated feelings of happiness and confidence; decreased need for sleep; abnormal talkativeness; rapid-fire thinking; distractibility; and poor decision-making, such as buying sprees, sexual risk-taking, or unwise investments. Exemplary symptoms of a depressive episode or low mood include, but are not limited to, depressed mood such as sadness, emptiness, hopelessness, or tearfulness; loss of interest or pleasure in all or almost all activities; significant weight loss, weight gain, or decreased or increased appetite; insomnia or hypersomnia (excessive sleeping or excessive sleepiness); restlessness or sluggishness; fatigue or loss of energy; lethargy or excessive or inappropriate feelings of guilt; difficulty thinking or concentrating or indecisiveness; and thoughts, plans, or attempts of suicide.

[0062] Bipolar disorders include bipolar I disorder, bipolar II disorder, and cyclothymic disorder. Bipolar I disorder is defined by a manic episode lasting at least 7 days or severe manic symptoms requiring hospitalization. Subjects with bipolar I disorder may also typically experience depressive episodes lasting at least 2 weeks. Depression with mixed characteristics, i.e., simultaneous depressive and manic episodes, is also possible. Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but without the severe manic episodes typical of bipolar I disorder. Cyclothymic disorder (also known as cyclothymia) is characterized by periods of hypomanic symptoms (elevated elevation and euphoria) and depressive symptoms lasting at least 2 years. The number, severity, or duration of mood swings is not sufficient to meet the full criteria for a hypomanic or depressive episode.

[0063] As used herein, the term "catatonic depression" refers to a condition in which an individual remains silent and immobile for an extended period of time. Exemplary symptoms of catatonic depression include, but are not limited to, feelings of sadness that may occur daily, loss of interest in most activities, sudden weight gain or loss, changes in appetite, difficulty falling asleep, difficulty getting out of bed, feelings of restlessness, agitation, feelings of worthlessness, guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or dying, and / or attempted suicide.

[0064] As used herein, the term "depressive disorder due to a medical condition" refers to a condition in which an individual experiences depressive symptoms caused by another disease. Examples of medical conditions known to cause depressive disorders include, but are not limited to, HIV / AIDS, diabetes, arthritis, stroke, brain disorders such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease, metabolic conditions (e.g., vitamin B12 deficiency), autoimmune conditions (e.g., lupus and rheumatoid arthritis), viral or other infectious diseases (hepatitis, mononucleosis, herpes), back pain, and certain cancers (e.g., pancreatic cancer).

[0065] As used herein, the term "postpartum depression" refers to a condition resulting from childbirth and hormonal changes, psychological adjustment to parenthood, and / or fatigue. Although postpartum depression is often associated with women, men can also suffer from postpartum depression. Exemplary symptoms of postpartum depression include, but are not limited to, feeling sad, hopeless, empty, or overwhelmed; crying more often than usual or for no apparent reason; feeling anxious or excessively anxious; being moody, irritable, or restless; oversleeping or not being able to fall asleep even when the baby is asleep; impaired concentration, memory for details, and judgment; feeling angry or resentful; losing interest in usually enjoyable activities; experiencing physical aches and pains, including frequent headaches, upset stomach, and muscle aches; eating too little or too much; withdrawing from or avoiding friends and family; having trouble bonding or emotionally connecting with the baby; persistent doubts about one's ability to care for the baby; and thoughts of harming oneself or the baby.

[0066] As used herein, the term "premenstrual dysphoric disorder" refers to a condition in which an individual experiences mood lability, irritability, discomfort, and anxiety symptoms that recur before menstruation and then subside around the onset of menstruation. Exemplary symptoms of premenstrual dysphoric disorder include, but are not limited to, lability (e.g., mood swings), irritability or anger, depressed mood, anxiety and tension, decreased interest in usual activities, decreased concentration, lethargy and lack of energy, appetite changes (e.g., overeating or craving certain foods), hypersomnia or insomnia, feeling overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, a feeling of "bloating" and weight gain), self-loathing thoughts, feeling depressed or irritable, decreased interest in usual activities (e.g., work, school, friends, hobbies), subjective decreased ability to concentrate, and easy fatigue.

[0067] As used herein, the term "seasonal affective disorder" refers to a condition in which an individual experiences mood changes based on the time of year. In some cases, individuals experience low mood, low energy, or other depressive symptoms during the fall and / or winter seasons. In some cases, individuals experience low mood, low energy, or other depressive symptoms during the spring and / or summer seasons. Exemplary symptoms of seasonal affective disorder include, but are not limited to, feeling depressed for most of the day or almost every day, losing interest in once-enjoyable activities, having low energy, having trouble sleeping, experiencing changes in appetite or weight, feeling sluggish or agitated, having difficulty concentrating, feeling hopeless, worthless, or guilty, and having frequent thoughts of death or suicide.

[0068] In some embodiments, a depressive disorder comprises a medical diagnosis based on the criteria and classification of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, hi some embodiments, a depressive disorder comprises a medical diagnosis based on an independent medical evaluation.

[0069] In some embodiments, the methods described herein are provided to a subject with treatment-resistant depression. In some embodiments, the subject has been diagnosed with "treatment-resistant depression." The term "treatment-resistant depression" refers to a type of depression that does not respond or is resistant to at least one or more treatment attempts of appropriate dosage and duration. In some embodiments, a subject with treatment-resistant depression has failed to respond to one treatment attempt, two treatment attempts, three treatment attempts, four treatment attempts, or five treatment attempts. In some embodiments, a subject with treatment-resistant depression has been diagnosed with major depressive disorder and has failed to respond to three or more treatment attempts. In some embodiments, a subject with treatment-resistant depression has been diagnosed with bipolar disorder and has failed to respond to one treatment attempt.

[0070] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder 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.

[0071] In some embodiments, the methods provided herein reduce at least one sign or symptom of major depressive disorder 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.

[0072] In some embodiments, the methods provided herein reduce at least one sign or symptom of atypical depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of atypical depression 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.

[0073] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder 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.

[0074] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder Type I. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder Type I 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.

[0075] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar II disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar II disorder 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.

[0076] In some embodiments, the methods provided herein reduce at least one sign or symptom of catatonic depression 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.

[0077] In some embodiments, the methods provided herein reduce at least one sign or symptom of a medically-associated depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a medically-associated depressive disorder 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.

[0078] In some embodiments, the methods provided herein reduce at least one sign or symptom of postpartum depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of postpartum depression 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.

[0079] In some embodiments, the methods provided herein reduce at least one sign or symptom of premenstrual dysphoric disorder 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.

[0080] In some embodiments, the methods provided herein reduce at least one sign or symptom of seasonal affective disorder 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.

[0081] In some embodiments, signs or symptoms of depression are reduced or eliminated in a subject within 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 3 months after administration of psilocybin or an active metabolite thereof.

[0082] In some embodiments, signs or symptoms of depression are reduced or eliminated in a subject for 1 day, 3 days, 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or 48 months after administration of psilocybin or its active metabolite. In some embodiments, the subject does not experience a recurrence of depression upon administration of psilocybin or its active metabolite.

[0083] In some embodiments, after administration of psilocybin, the subject is not administered any other treatment for reducing the signs or symptoms of depression.

[0084] In some embodiments, the methods of the present disclosure further include administering to the subject at least one additional therapeutic agent for reducing signs or symptoms of depression. In some embodiments, the at least one additional therapeutic agent is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic receptor antagonist. In some embodiments, the at least one additional therapeutic agent is administered before, on the same day as, or after the administration of psilocybin.

[0085] In some embodiments, the subject with depressive disorder has an additional comorbid disease or disorder. In some embodiments, the additional comorbid disease or disorder is anxiety disorder, obsessive-compulsive disorder, alcoholism, personality disorder, cardiovascular disease, neurological disease, or cancer. In some embodiments, the subject has dementia, Alzheimer's disease, or Parkinson's disease. In some embodiments, using the method of the present disclosure to reduce at least one sign or symptom of depression in a subject prevents one or more comorbid diseases or disorders in the subject.

[0086] 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.

[0087] The numbered structural formula of psilocybin is shown in Figure 1. Novel polymorphs and hydrates of psilocybin, and their preparation and formulations, are described in U.S. Application US2019 / 0119310 A1, which is incorporated herein by reference in its entirety. US2019 / 0119310 discloses some formulations and the challenges of formulating psilocybin due to, for example, its hygroscopicity and poor flow properties. US2019 / 0119310 also discloses the importance of a controlled aqueous crystallization process.

[0088] 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 of 145°C to 165°C and a second onset temperature of 205°C to 220°C. Exemplary DSC thermograms are provided as Figures 3A and 3B.

[0089] 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.

[0090] 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.

[0091] 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, peaks in an XRPD diffractogram at 11.5, 12.0, 14.5, and 17.5 °2θ ± 0.2 °2θ, further characterized by at least one additional 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.

[0092] 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 peaks listed in Table A, or equivalent peaks within about ±0.1 degrees 2θ of the peaks listed in Table A. 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 peaks listed in Table A, or equivalent peaks within about ±0.2 degrees 2θ of the peaks listed in Table A. 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 A]

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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 in FIG. 3A.

[0097] 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.

[0098] 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.

[0099] In some embodiments, crystalline psilocybin polymorph A is a white to off-white solid.

[0100] In some embodiments, the crystalline psilocybin polymorph A is chemically pure, e.g., For example, 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.

[0101] Method for Producing Crystalline Psilocybin Polymorph A In another embodiment, the present disclosure provides a method for large-scale production of psilocybin, comprising subjecting psilocybin to a water crystallization step accompanied by controlled drying to produce crystalline psilocybin polymorph A.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] In some embodiments, the stirring is performed by stirring at about 400-500 rpm, typically about 450 rpm.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] In some embodiments, the psilocybin of the crystalline psilocybin is isolated by vacuum filtration.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] In contrast, crystals obtained without controlled cooling are much smaller in size (typically 5-50 microns) when viewed under a 10x microscope.

[0114] In some embodiments, provided is psilocybin obtained by the crystallization methods described herein.

[0115] In some embodiments, pharmaceutical formulations are provided that include psilocybin polymorph A obtained by the crystallization methods described herein.

[0116] 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 methods described in U.S. Application No. 2019 / 0119310 A1, which is incorporated herein by reference in its entirety.

[0117] 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.

[0118] 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.

[0119] In some embodiments, psilocybin polymorph A' exhibits the XRPD diffractogram summarized in Table B. 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 B]

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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'.

[0126] In some embodiments, crystalline psilocybin polymorph A' is a white to off-white solid.

[0127] 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.

[0128] 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 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.

[0129] 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.

[0130] Polymorph A (including its isostructural variant polymorph A') (Figures 2A and 2B) differs 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.

[0131] 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.

[0132] 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).

[0133] Hydrate A In some embodiments, the disclosure provides a crystalline form of psilocybin hydrate A. 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.

[0134] 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 C, or equivalent peaks within about ±0.1° 2θ. [Table C]

[0135] 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 .

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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 D, or equivalent peaks within about ±0.1 degrees 2θ. [Table D-1]

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] In some embodiments, the psilocybin of the present disclosure in the form of Polymorph A or A' has the general properties shown in Table D. [Table D-2]

[0148] In some embodiments, the psilocybin fits the spectrum as shown in Table E and illustrated in the spectra of Figures 5-8. [Table E]

[0149] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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%.

[0159] In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, where 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, where the ratio of SMCC 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%.

[0160] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, where 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, where the ratio of SMCC 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% to 1.0%.

[0161] 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.

[0162] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0163] 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.

[0164] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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%.

[0171] In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, where 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, where the ratio of SMCC 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%.

[0172] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, where 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, where the ratio of SMCC 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% to 1.0%.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] It should be noted that the formulations may contain psilocybin in any form, not just the polymorphic forms disclosed herein.

[0177] 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.

[0178] 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.

[0179] In some embodiments, the formulated dose contains about 2 to about 50 mg of crystalline psilocybin. In some embodiments, the formulated dose contains 2 to 40 mg, 2 to 10 mg, 5 to 30 mg, 5 to 15 mg, or 20 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.

[0180] 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 2-40 mg, 2-10 mg, 5-30 mg, 5-15 mg, or 20-30 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.

[0181] 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.

[0182] In some embodiments, the formulated dose contains about 2 to about 50 mg of crystalline psilocybin polymorph A'. In some embodiments, the formulated dose contains 2 to 40 mg, 2 to 10 mg, 5 to 30 mg, 5 to 15 mg, or 20 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'.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] Route of administration 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.

[0194] 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.

[0195] 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.

[0196] 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).

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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).

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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 who supervised 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 can be in the form of touch therapy, verbal reassurance, guided imagery, and / or relaxation or breathing exercises. In some embodiments, assistance can 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.

[0211] 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 pure 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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 willingness to accept and not mind the psychedelic experience.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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 a request 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 might 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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").

[0231] 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.

[0232] 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.

[0233] 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 patients to continue self-directed integration outside of clinical trial visits.

[0234] 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.

[0235] 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.

[0236] 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).

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] In some embodiments, the room comprises a sofa. In some embodiments, the room comprises a bed. In some embodiments, the room comprises more than one sofa or bed, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 sofas or beds. In some embodiments, the subject sits or lies on the sofa or bed for about 4-8 hours, or a substantial portion thereof, immediately after administration of psilocybin. In some embodiments, the subject listens to music for about 4-8 hours, or a substantial portion thereof, immediately after administration of psilocybin. In some embodiments, the subject wears an eye mask for about 4-8 hours, or a substantial portion thereof, immediately after administration of psilocybin. In some embodiments, the subject is provided with a weighted blanket.

[0250] 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.

[0251] 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.

[0252] 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 calls / emails / texts, word length in text communications, gestures used (tap, swipe, 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. For example, in one embodiment, a digital health product may be utilized to track compliance, determine medication dosage and / or frequency, indications of need for re-dosing, re-dosing amounts, alerts, or warnings.

[0253] 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 a concomitant compound or drug, 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 (cannabicyclomevarin), 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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).

[0267] 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.

[0268] 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.

[0269] 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).

[0270] 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.

[0271] 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.

[0272] 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.

[0273] Diseases, disorders, and / or conditions to be treated Provided herein are methods of treating a subject in need thereof, comprising administering to the subject a therapeutically effective dose of psilocybin.

[0274] The methods described herein can be used to treat diseases, disorders, and conditions, including certain psychiatric and neurological aspects of various diseases, disorders, or conditions.

[0275] In some embodiments, the disclosure provides methods of treating a subject in need of treatment, the methods comprising administering to the subject a therapeutically effective dose of psilocybin or an active metabolite thereof, wherein the subject is suffering from one of the following diseases, disorders, or conditions: severe mood dysregulation disorder, major depressive disorder (MDD), treatment-resistant depression, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, postpartum depression, depressive disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance-drug-induced anxiety disorder, anxiety disorder due to another medical condition, somatic symptom disorder, illness anxiety disorder (hypochondriasis), conversion disorder (functional neurological symptom disorder), factitious disorder, post-traumatic stress disorder (PTS). D), adjustment disorder, acute distress disorder, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling) disorder, excoriation (skin picking) disorder, substance / drug-induced compulsive and related disorder, obsessive-compulsive and related disorder due to another medical condition, substance-related disorder, alcohol-related disorder, cannabis-related disorder, hallucinogen-related disorder, inhalant-related disorder, cocaine-related disorder, opioid-related disorder, sedative-related, hypnotic-related, or anxiolytic-related disorder, stimulant-related disorder, tobacco-related disorder, non-substance-related disorder (gambling or gaming disorder), migraine, cluster headaches such as chronic cluster headache, cyclic vomiting, tension-type headache, dysphasia, pica, anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathy, pyromania, or kleptomania.

[0276] In some embodiments, the disclosure provides methods of treating a subject in need of treatment, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: Alzheimer's disease, Lewy bodies, traumatic brain injury, prion disease, HIV infection, Parkinson's disease, neurocognitive disorder due to Huntington's disease, concussion, chronic traumatic encephalopathy (CTE), language impairment, speech disorder (voice disorder), childhood-onset dysfluency disorder (stuttering), social (pragmatic) communication disorder, Tourette's syndrome, persistent (chronic) motor or vocal tic disorder, amnesic disorder due to a known physiological condition (perhaps in an ECT shock-resistant subject), transient ischemic attack, cerebral infarction, cerebral hemorrhage, progressive multinuclear ophthalmoplegia, or retrograde amnesia.

[0277] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: autism, autism spectrum disorder, or antisocial personality disorder.

[0278] In some embodiments, the disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: attention-deficit / hyperactivity disorder, other specified attention-deficit / hyperactivity disorder, or attention-deficit / hyperactivity disorder not otherwise specified.

[0279] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: schizotypal (personality) disorder, delusional disorder, schizophrenia, or schizoaffective disorder.

[0280] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: insomnia disorder, hypersomnia disorder, narcolepsy, or primary central sleep apnea.

[0281] In some embodiments, the present disclosure provides methods of treating a subject in need of treatment, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, or obsessive-compulsive personality disorder.

[0282] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: Female Sexual Interest / Arousal Disorder, Male Hypoactive Sexual Desire Disorder, and Excessive Sexual Drive.

[0283] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: bipolar I disorder, bipolar II disorder, or cyclothymic disorder.

[0284] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: age-related hearing loss or tinnitus.

[0285] In some embodiments, the present disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: multiple sclerosis, cranial neuropathy, neuromyelitis optica, Bell's palsy, Guillain-Barré syndrome, a demyelinating disease of the central nervous system, or chronic inflammatory demyelinating polyneuropathy.

[0286] In some embodiments, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject is suffering from pain, such as phantom pain, chronic pain, or pain associated with another disease or disorder.

[0287] In some embodiments, the disclosure provides methods of treating a subject in need thereof, the methods comprising administering a therapeutically effective dose of psilocybin to the subject, wherein the subject has at least one of the following diseases, disorders, or conditions: myelopathy, traumatic brain injury, intellectual disability, mania, neurodegeneration, paraphilia disorder (e.g., pedophilic disorder), suicidal behavior disorder, non-suicidal self-injury disorder, persistent complex death disorder, gastrointestinal-related disease (e.g., IBS), epilepsy, sickle cell disease, locked-in syndrome, restless legs syndrome, stroke (such as ischemic stroke or hemorrhagic stroke), or amyotrophic lateral sclerosis (ALS).

[0288] In some embodiments, the disclosure provides methods of treating a subject, the methods comprising administering to the subject a therapeutically effective dose of psilocybin, wherein after administration, the subject exhibits improved cognition, in some embodiments, the improved cognition is improved attention, episodic memory, working memory, spatial memory, social cognition, executive function, and / or cognitive flexibility.

[0289] In some embodiments, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has treatment-resistant depression (TRD).

[0290] In some embodiments, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has major depressive disorder (MDD).

[0291] 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.

[0292] 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.

[0293] 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).

[0294] In some embodiments, the present disclosure provides a method of reducing anxiety in a subject receiving treatment with psilocybin, the method comprising administering to the subject: i) psilocybin or a precursor or derivative thereof, and ii) one or more benzodiazepines.

[0295] 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.

[0296] 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.

[0297] 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, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam , 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, rilmazefone, temazepam, tetrazepam, and triazolam.

[0298] 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 patient 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 patient 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 patient experiences a decrease in one or more 5-HT receptor agonists or antagonists at 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, including, 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.

[0299] 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.

[0300] 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).

[0301] Preferred 5-HT 2A Inverse agonists include, but are not limited to, AC-90179, nerotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and vorinaserin.

[0302] In certain embodiments, 5-HT 2A The antagonist is selected from the compounds of Table I. [Table I]

[0303] In some embodiments, the present disclosure provides a method for reducing negative side effects associated with a traumatic psychedelic experience in a patient undergoing treatment with psilocybin, the method comprising administering to the patient: i) psilocybin or a precursor or derivative thereof, and ii) one or more cannabinoids or cannabinoid derivatives.

[0304] In some embodiments, the cannabinoid is selected from the group consisting of 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), and CBT (cannabicitran). In certain embodiments, the cannabinoid is CBD (cannabidiol).

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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 a 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, neuroimaging studies in healthy volunteers have shown that performance on SWM is associated with activation of the dorsal and ventral prefrontal cortex. The test takes approximately 4 minutes to complete.

[0310] 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 pre-treatment.

[0311] In some embodiments, the efficacy of psilocybin is assessed using a Spatial Working Memory Strategy (SWMS) score. In some embodiments, after treatment with a method 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.

[0312] 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-manner 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 indicated better performance. In some embodiments, after treatment with the methods of the present disclosure, the subject's RVPA 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%, 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.

[0313] 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 in which 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.

[0314] In some embodiments, the efficacy and / or safety of psilocybin is assessed using a cognitive flexibility panel test.

[0315] 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: One at a time, subjects are presented with computer-generated images on a screen, each derived from the facial features of a real individual, each representing a specific 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 subjects' 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.

[0316] 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 IEDYERT 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.

[0317] 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.

[0318] 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 endpoint 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%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 200%, about 210%, about 215%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 300%, about 310%, about 315%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 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.

[0319] 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.

[0320] 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, anxious ego annihilation, 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 "unifying experiences," "spiritual experiences," "euphoric states," "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.

[0321] 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.

[0322] 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.

[0323] 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%.

[0324] 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.

[0325] 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).

[0326] In some embodiments, the Pictorial Empathy Test (PET) is utilized to assess the effects of psilocybin on emotional empathy.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] In some embodiments, the Tellegen Preoccupation Scale is utilized to assess the safety and / or efficacy of psilocybin. The Tellegen Preoccupation Scale is a 34-item multidimensional scale assessing imaginative involvement and the tendency to become mentally absorbed in everyday activities.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] In some embodiments, clinical tests are utilized to assess the safety and / or efficacy of psilocybin. In some embodiments, clinical 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.

[0341] In some embodiments, urine is tested for pregnancy and / or illicit drugs.

[0342] 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.

[0343] Depression assessment In some embodiments, signs or symptoms of depression are measured in subjects before, during or after treatment with the methods described herein.In some embodiments, signs or symptoms of depression are measured according to diary assessment, clinician or caregiver assessment, clinical rating scale, imaging test, blood or CSF test.

[0344] In some embodiments, the sign or symptom of depression in the subject is measured using neuropsychological assessment or clinical assessment scale.In some embodiments, the neuropsychological assessment or clinical assessment scale is Hamilton Depression Rating Scale, Clinical Global Impression (CGI) scale, Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Rating Scale (BDI), Zung Self-Rating Depression Scale, Raskin Depression Rating Scale, Depressive Symptom Scale (IDS), Brief Depressive Symptom Scale (QIDS), Columbia Suicide Severity Rating Scale or Suicidal Ideation Attribution Scale.

[0345] In some embodiments, signs or symptoms of depression in a subject are measured using the Hamilton Assessment for Depression (HAM-D) scale. The HAM-D scale is a 17-item scale that measures the severity of depression before, during, and after treatment. Scoring is based on the 17 items, and it typically takes 15-20 minutes to complete the interview and score the results. Eight items are scored on a 5-point scale ranging from 0 = absent to 4 = severe. Nine items are scored on a 3-point scale ranging from 0 = absent to 2 = severe. A score of 10-13 indicates mild depression, a score of 14-17 indicates mild to moderate depression, and a score above 17 indicates moderate to severe depression. In some embodiments, after treatment with the methods described herein, the subject's HAM-D 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.

[0346] In some embodiments, the signs or symptoms of depression in a subject are measured using the Clinical Global Impression (CGI) scale. The CGI scale is a three-item scale that measures disease severity, overall improvement or change, and treatment response. The CGI is rated on a 7-point scale, with disease severity measured using a range of responses from 1 (normal) to 7 (among the most severely affected subjects). In some embodiments, after treatment with the methods described herein, the subject's CGI 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.

[0347] In some embodiments, signs or symptoms of depression in a subject are measured using the Montgomery-Asberg Depression Rating Scale (MADRS). The MADRS scale is a 10-item scale that measures the core symptoms of depression. Nine of the items are based on patient report and one is based on evaluator observation during the assessment interview. A score of 7-19 indicates mild depression, a score of 20-34 indicates moderate depression, and a score above 34 indicates severe depression. MADRS items are rated on a continuous range from 0 to 6, with 0 = no abnormalities and 6 = severe abnormalities. In some embodiments, after treatment with the methods described herein, the subject's MADRS 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.

[0348] In some embodiments, signs or symptoms of depression in a subject are measured using the Beck Depression Scale (BDI). The BDI is a 21-item self-report rating scale that measures attitudes and symptoms characteristic of depression. Items are rated on a continuous range from 0 to 3, with 0 = no abnormalities and 3 = severe abnormalities. A score of 17-20 indicates borderline clinical depression, a score of 21-30 indicates moderate depression, a score of 31-40 indicates severe depression, and a score above 40 indicates extreme depression. In some embodiments, after treatment with the methods described herein, the subject's BDI 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.

[0349] In some embodiments, signs or symptoms of depression in a subject are measured using the Zung Self-Rating Depression Scale. The Zung Self-Rating Depression Scale is a 20-item self-report questionnaire that measures psychological and physical symptoms associated with depression. The questionnaire takes approximately 10 minutes to complete, and items include both positive and negative statements. Each item is scored on a Likert scale of 1 to 4. A total score is obtained by adding up the individual item scores and ranges from 20 to 80. Most depressed patients score between 50 and 69, but a score of 70 or higher indicates severe depression. In some embodiments, after treatment with the methods described herein, the subject's Zung Self-Rating Depression 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.

[0350] In some embodiments, signs or symptoms of depression in a subject are measured using the Raskin Depression Rating Scale. The Raskin Depression Rating Scale measures baseline levels of depression and changes in depression severity over time. Each item is scored on a scale ranging from 1 to 5, with 1 = not at all to 5 = very much. A total score is obtained by adding up the individual item scores, with a score of 9 or higher representing moderate depression. In some embodiments, after treatment with the methods described herein, the subject's Raskin Depression Rating Scale 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.

[0351] In some embodiments, signs or symptoms of depression in a subject are measured using the Inventory of Depressive Symptoms Scale (IDS). The IDS is a 30-item rating scale that measures signs and symptoms of depression. Each item is scored on a scale of 0 to 3, with 0 = no symptoms and 3 = severe symptoms. A total score is obtained by summing the scores of the individual items, with a score of 26 to 38 indicating mild depression, a score of 39 to 48 indicating moderate depression, and a score of 49 or greater indicating severe depression. In some embodiments, after treatment with the methods described herein, the subject's IDS 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.

[0352] In some embodiments, signs or symptoms of depression in a subject are measured using the Brief Inventory of Depressive Symptoms (QIDS). The QIDS is a 16-item rating scale that measures signs and symptoms of depression. Each item is scored on a scale of 0 to 3, with 0 = no symptoms and 3 = severe symptoms. A total score is obtained by summing the scores of the individual items, with a score of 11 to 15 indicating moderate depression, a score of 16 to 20 indicating severe depression, and a score of 21 or greater indicating very severe depression. In some embodiments, after treatment with the methods described herein, the subject's QIDS 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.

[0353] In some embodiments, the subject's signs or symptoms of depression are measured using the Young Mania Rating Scale (YMRS). The YMRS is an 11-item rating scale that measures signs and symptoms of mania. Four items are scored on a 0-8 scale, ranging from 0 = absent to 8 = severe. The remaining seven items are scored on a 0-4 scale, ranging from 0 = absent to 4 = severe. A total score is obtained by summing the scores on the individual items, with a score of 9-15 indicating mild mania, a score of 16-25 indicating moderate mania, and a score of 26 or greater indicating severe mania. In some embodiments, after treatment with the methods described herein, the subject's YMRS 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.

[0354] In some embodiments, the signs or symptoms of depression in a subject are measured using the Columbia-Suicide Severity Rating Scale (C-SSRS). The C-SSRS measures the severity of suicidal ideation and behavior. The scale includes 10 multiple-choice questions (no = 0 points, yes = 1 point), each of which corresponds to a different component of the severity of the subject's suicidal ideation and behavior. A subject is considered to have suicidal ideation and / or behavior if they answer "yes" to any of the 10 questions. In some embodiments, after treatment with the methods described herein, the subject's C-SSRS 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.

[0355] In some embodiments, signs or symptoms of depression in a subject are measured using the Suicidal Ideation Attribution Scale (SIDAS). The SIDAS measures the presence and severity of suicidal thoughts. The scale includes five questions measured on a 10-point scale, with 0 = never and 10 = always. A total score is calculated as the sum of the five items and ranges from 0 to 50. A score of 21 or higher indicates an increased risk of suicidal behavior. In some embodiments, after treatment with the methods described herein, the subject's SIDAS 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.

[0356] In some embodiments, the signs or symptoms in a subject with depression are assessed using the Spielberger Trait and Anxiety Inventory, Generalized Anxiety Disorder 7-Item Scale, Warwick-Edinburgh Mental Well-Being Scale, the Flourishing Scale, the Snaith Hamilton Anhedonia Pleasure Scale, the Life Orientation Test, the Meaning in Life Questionnaire, the Brief Resilience Scale, the Dysfunctional Attitudes Scale, the 44-item Big Five Inventory, the Peters 21-item Delusions Inventory, the Aberrant Self-Experiences Test, the Preoccupied Responding Scale, the Polar Bear Inhibition Inventory, the Barrett Impulsivity Scale, the Brief Experiential Avoidance Questionnaire, the Modified Tellegen Preoccupation Questionnaire, the Scale for Assessing the Therapeutic Relationship, the Trust / Expectancy Questionnaire, the Nature Connectedness Scale, the Political Perspective Questionnaire, the Social Connectedness Scale, the Bech-Rafaelsen Mania Rating Scale, the Revised Santa Fe Inventory, the ... Clara Brief Compassion Scale, Gratitude Questionnaire, Short Recommendation Scale, Rosenberg Self-Esteem Scale, Universality Subscale of the Spiritual Transcendence Scale, Oxford Questionnaire on Emotional Side Effects of Antidepressants, Lauks Emotion Intensity Scale, Sexual Dysfunction Questionnaire, Brief Index of Female Sexual Function, Gender Awareness Questionnaire, Barnes Akathisia Rating Scale, Work Productivity and Activity Impairment Questionnaire, Work and Social Adjustment Scale, Connection Questionnaire, Standard Assessment of Personality, Positive and Negative Syndrome Scale, Mastery Insight Scale, Self-Reflection and Insight Scale, Psychological Insight Scale, Metaphysical Beliefs Questionnaire, Spiritual Bypassing Scale, Adverse Childhood Experiences Questionnaire, Therapeutic Music Experiences Questionnaire, Setting Questionnaire, Music Immersion Scale, Psychedelic Predictor Scale, Surrender Scale, EuroQOL-5 Dimensions-3 Level Scale, or any combination thereof.In some embodiments, after treatment with the methods described herein, signs or symptoms of depression, as measured using any of the above assessments, are 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.

[0357] In some embodiments, signs or symptoms of depression in a subject are measured using imaging before, during, or after treatment with the methods described herein. In some embodiments, the imaging is a CT scan. In some embodiments, the imaging is a functional MRI scan. In some embodiments, the functional MRI scan measures blood oxygen level-dependent (BOLD) response as an index of brain activity and / or functional connectivity. In some embodiments, BOLD response is measured in a subject in a resting state, in response to emotional faces, or in response to music. In some embodiments, after treatment with the methods described herein, the BOLD response in a brain region increases 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. In some embodiments, after treatment with the methods described herein, the BOLD response in the amygdala increases 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. In some embodiments, after treatment with the methods described herein, the BOLD response in a brain region 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. In some embodiments, after treatment with the methods described herein, the BOLD response in the amygdala 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.

[0358] In some embodiments, signs or symptoms of depression are measured using a marker of depression in blood or cerebrospinal fluid. In some embodiments, the marker of depression is measured in a subject before, during, or after treatment with a method or composition described herein. In some embodiments, the marker of depression is one or more tests of erythrocyte folate, serum folate, vitamin B12, plasma homocysteine, serum methylfolate, and / or brain-derived neurotrophic factor (BDNF) Val66Met, bone morphogenetic protein rs41271330, and / or 5-HTTLPR polymorphism. In some embodiments, the depression marker is increased by about 5% to about 300%, for example, 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 A decrease of 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. In other embodiments, the depression marker is increased by about 5% to about 300%, for example, 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 120%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, about 510%, about 520%, about 530%, about 540%, about 550%, about 560%, about 570%, about 580%, about 590%, about 610%, about 620%, about 630%, about 640%, about 650%, about 660%, about 670%, about 680%, about 690%, about 710%, about 720%, about 730%, about 740%, about 750%, about 760%, about 770%, about 780%, about 790%, about 810%, about 820%, about 830%, about 00%, 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.

[0359] 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:

[0360] 1. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject is suffering from one of the following diseases, disorders, or conditions: severe mood dysregulation disorder, major depressive disorder (MDD), treatment-resistant depression, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, postpartum depression, or depressive disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance-drug-induced anxiety disorder, anxiety disorder due to another medical condition, somatic symptom disorder, illness anxiety disorder (hypochondriasis), conversion disorder (functional neurological symptom disorder), factitious disorder, post-traumatic stress disorder (PTSD), adjustment disorder, acute distress disorder, the patient has at least one of the following: obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation (skin picking) disorder, substance / drug-induced compulsive and related disorders, obsessive-compulsive and related disorders due to another medical condition, a substance-related disorder, an alcohol-related disorder, a cannabis-related disorder, a hallucinogen-related disorder, an inhalant-related disorder, a cocaine-related disorder, an opioid-related disorder, a sedative-related, hypnotic-related, or anxiolytic-related disorder, a stimulant-related disorder, a tobacco-related disorder, a non-substance-related disorder (gambling or gaming disorder), migraine, cluster headaches such as chronic cluster headache, cyclic vomiting, tension-type headache, dysphasia, pica, anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathy, pyromania, or kleptomania.

[0361] 2. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Alzheimer's disease, neurocognitive disorders due to Lewy bodies, traumatic brain injury, prion disease, HIV infection, Parkinson's disease, or Huntington's disease; concussion; chronic traumatic encephalopathy (CTE); speech impediment; speech disorder (voice disorder); childhood-onset dysfluency disorder (stuttering); social (pragmatic) communication disorder; Tourette's syndrome; persistent (chronic) motor or vocal tic disorder; amnesic disorder due to a known physiological condition; transient ischemic attack; cerebral infarction; cerebral hemorrhage; progressive multinuclear ophthalmoplegia; or retrograde amnesia.

[0362] 3. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, said subject having at least one or more of the following diseases, disorders, or conditions: autism spectrum disorder or antisocial personality disorder.

[0363] 4. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject has at least one of the following diseases, disorders, or conditions: attention-deficit / hyperactivity disorder, other specified attention-deficit / hyperactivity disorder, or attention-deficit / hyperactivity disorder not otherwise specified.

[0364] 5. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject has at least one of the following diseases, disorders, or conditions: schizotypal (personality) disorder, delusional disorder, schizophrenia, or schizoaffective disorder.

[0365] 6. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject has at least one of the following diseases, disorders, or conditions: Female Sexual Interest / Arousal Disorder, Male Hypoactive Sexual Desire Disorder, or Excessive Sexual Drive.

[0366] 7. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject has at least one of the following diseases, disorders, or conditions: bipolar I disorder, bipolar II disorder, or cyclothymic disorder.

[0367] 8. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: insomnia disorder, hypersomnia disorder, narcolepsy, or primary central sleep apnea.

[0368] 9. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: schizotypal personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, or obsessive-compulsive personality disorder.

[0369] 10. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject has at least one of the following diseases, disorders, or conditions: age-related hearing loss or tinnitus.

[0370] 11. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: multiple sclerosis, cranial neuropathy, neuromyelitis optica, Bell's palsy, Guillain-Barré syndrome, a demyelinating disease of the central nervous system, or chronic inflammatory demyelinating polyneuropathy.

[0371] 12. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject is suffering from pain.

[0372] 13. A method of treating a subject in need thereof, comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: myelopathy, traumatic brain injury, intellectual disability, mania, neurodegeneration, paraphilia disorder (e.g., pedophilic disorder), suicidal behavior disorder, non-suicidal self-injury disorder, persistent complex death disorder, gastrointestinal-related disease, epilepsy, sickle cell disease, locked-in syndrome, restless legs syndrome, stroke, or amyotrophic lateral sclerosis (ALS).

[0373] 14. A method of treating a subject, comprising administering to the subject a therapeutically effective dose of psilocybin, wherein after administration, the subject exhibits improved cognition.

[0374] 15. The method of embodiment 14, wherein said cognitive improvement is improvement in attention, episodic memory, working memory, spatial memory, social cognition, executive function, and / or cognitive flexibility.

[0375] 16. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject has treatment-resistant depression (TRD).

[0376] 17. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective dose of psilocybin, wherein said subject has major depressive disorder (MDD).

[0377] 18. The method of any one of embodiments 1 to 17, wherein the subject is a mammal.

[0378] 19. The method of embodiment 18, wherein the subject is a human.

[0379] 20. The method of any one of embodiments 1-19, wherein the psilocybin is administered in a dosage form comprising a therapeutically effective amount of high-purity crystalline psilocybin in the form of Polymorph A, wherein the crystalline psilocybin comprises at least 90% Polymorph A by weight.

[0380] 21. The method of embodiment 20, wherein the crystalline psilocybin comprises at least 95% by weight of polymorph A.

[0381] 22. The method of embodiment 20 or 21, wherein said crystalline psilocybin has a chemical purity of greater than 97% by HPLC and no single impurity greater than 1%.

[0382] 23. The method of any one of embodiments 1-22, wherein 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 has a chemical purity of greater than 97% by HPLC and no single impurity greater than 1%.

[0383] 24. The method of embodiment 23, wherein the high-purity crystalline psilocybin comprises at least 90% by weight of Polymorph A.

[0384] 25. The method of embodiment 24, wherein the high-purity crystalline psilocybin comprises at least 95% by weight of Polymorph A.

[0385] 26. The high-purity crystalline psilocybin is: (i) a water content of less than 0.5 w / w%, or 26. The method of any one of embodiments 20 to 25, further characterized by having either (ii) a weight loss in a TGA thermogram from 25°C to 200°C of less than 0.5 w / w%.

[0386] 27. The method of any of embodiments 20-26, wherein the high-purity crystalline psilocybin is further characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 145°C and 155°C and a second onset temperature of between 205°C and 220°C.

[0387] 28. The method of any one of embodiments 20-27, wherein the high-purity crystalline psilocybin is further characterized by one or more of the following: (a) loss on drying of 2 w / w% or less; (b) residue on ignition of 0.5 w / w% or less; (c) an assay of 95-103 wt% (dry basis) as measured by HPLC; (d) a residual solvent content of 3000 ppm or less of methanol, 5000 ppm of ethanol, 720 ppm of THF, and 890 ppm of toluene as measured by HRGC; (e) 31 (f) an inductively coupled plasma mass spectrometry (ICP-MS) elemental analysis of: (i) Cd equal to or less than 1.5 ppm, (ii) Pb equal to or less than 1.5 ppm, (iii) As equal to or less than 4.5 ppm, (iv) Hg equal to or less than 9.0 ppm, (v) Co equal to or less than 15 ppm, (vi) V equal to or less than 30 ppm, (vii) Ni equal to or less than 60 ppm, (viii) Li equal to or less than 165 ppm, and (ix) Pd equal to or less than 30 ppm.

[0388] 29. The method of any one of embodiments 20-28, wherein the high-purity crystalline psilocybin does not have more than 0.5% of a single impurity.

[0389] 30. The method of any of embodiments 20-29, wherein the dosage form further comprises about 5-40 mg of the high-purity crystalline psilocybin.

[0390] 31. The method of embodiment 30, wherein the dosage form comprises 5 mg of high-purity crystalline psilocybin.

[0391] 32. The method of embodiment 30, wherein the dosage form comprises about 10 mg of high-purity crystalline psilocybin.

[0392] 33. The method of embodiment 30, wherein the dosage form comprises about 35 mg of high-purity crystalline psilocybin.

[0393] 34. The method of any of embodiments 20-33, wherein the dosage form comprises silicified microcrystalline cellulose.

[0394] 35. The method of embodiment 34, wherein the silicified microcrystalline cellulose has a particle size range of about 45 to 150 microns.

[0395] 36. The method of any of embodiments 20-35, 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.

[0396] 37. The method of embodiment 36, wherein about 30% or less of the microcrystalline cellulose is a first variant having a particle size of about 45 to 80 microns, and about 70% or more of the microcrystalline cellulose is a second variant having a particle size of about 90 to 150 microns.

[0397] 38. The method of embodiment 36, wherein about 20% or less of the microcrystalline cellulose is a first variant having a particle size of about 45 to 80 microns, and about 80% or more of the microcrystalline cellulose is a second variant having a particle size of about 90 to 150 microns.

[0398] 39. The method of embodiment 36, wherein about 15% or less of the microcrystalline cellulose is a first variant having a particle size of about 45 to 80 microns, and about 85% or more of the microcrystalline cellulose is a second variant having a particle size of about 90 to 150 microns.

[0399] 40. The method of embodiment 36, wherein about 15% or less of the microcrystalline cellulose is a first variant having a particle size of about 45 to 80 microns, and about 85% or more of the microcrystalline cellulose is a second variant having a particle size of about 90 to 150 microns.

[0400] 41. The method of embodiment 36, wherein the dosage form comprises 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.

[0401] 42. The method of embodiment 36, wherein the 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.

[0402] 43. The method of any one of embodiments 20-42, wherein the dosage form is an oral dosage form.

[0403] 44. The method of embodiment 43, wherein the dosage form is a capsule.

[0404] 45. The method of embodiment 43, wherein the dosage form is a tablet.

[0405] 46. ​​The method of any one of embodiments 1-45, wherein at least one dose of psilocybin is administered to the subject.

[0406] 47. The method of embodiment 46, wherein the at least one dose of psilocybin is in the range of about 0.1 mg to about 100 mg.

[0407] 48. The method of embodiment 47, wherein said dose of psilocybin is about 1 mg.

[0408] 49. The method of embodiment 47, wherein said dose of psilocybin is about 10 mg.

[0409] 50. The method of embodiment 47, wherein said dose of psilocybin is about 25 mg.

[0410] 51. The method of any one of embodiments 1-50, wherein more than one dose of psilocybin is administered to the subject.

[0411] 52. The method of embodiment 51, wherein at least two doses of psilocybin are administered to the subject.

[0412] 53. The method of any one of embodiments 51-52, wherein the psilocybin is administered once a day.

[0413] 54. The method of any one of embodiments 51-52, wherein the psilocybin is administered at least once a week.

[0414] 55. The method of any one of embodiments 51-52, wherein the psilocybin is administered at least twice a week.

[0415] 56. The method of any one of embodiments 51-52, wherein the psilocybin is administered at least once a month.

[0416] 57. The method of any one of embodiments 51-52, wherein the psilocybin is administered at least twice a month.

[0417] 58. The method of any one of embodiments 51-52, wherein the psilocybin is administered at least once every three months.

[0418] 59. The method of any one of embodiments 51-52, wherein the psilocybin is administered at least once every six months.

[0419] 60. The method of any one of embodiments 51-52, wherein the psilocybin is administered at least once every 12 months.

[0420] 61. The method of any one of embodiments 79-88, wherein each dose of psilocybin administered is in the range of about 0.1 mg to about 100 mg.

[0421] 62. The method of embodiment 61, wherein each dose of psilocybin administered is about 1 mg.

[0422] 63. The method of embodiment 61, wherein each dose of psilocybin administered is about 10 mg.

[0423] 64. The method of embodiment 61, wherein each dose of psilocybin administered is about 25 mg.

[0424] 65. The method of any one of embodiments 46-65, wherein the psilocybin is administered by one of the following routes: oral, parenteral, topical, inhalation, rectal, transmucosal, intranasal, buccal, vaginal, intrathecal, intraocular, transdermal, intrauterine, intralymphatic, or by direct tissue or organ injection.

[0425] 66. The method of embodiment 65, wherein the psilocybin is administered orally.

[0426] 67. The method of any one of embodiments 1-66, wherein the subject participates in at least one psychological support session prior to administration of the psilocybin.

[0427] 68. The method of embodiment 67, wherein the subject participates in at least three psychological support sessions prior to administration of the psilocybin.

[0428] 69. The method of any one of embodiments 67-68, wherein at least one therapeutic intent is discussed during a psychological support session.

[0429] 70. The method of any one of embodiments 67-69, wherein self-directed interviewing and experiential processing is performed during the psychological support session.

[0430] 71. The method of any one of embodiments 67-70, wherein the subject participates in at least one psychological support session after administration of the psilocybin.

[0431] 72. The method of embodiment 71, wherein the subject participates in at least three psychological support sessions after administration of the psilocybin.

[0432] 73. The method of any one of embodiments 67-72, wherein the psilocybin is administered to the subject in a room having a substantially non-clinical appearance.

[0433] 74. The method of embodiment 73, wherein the room is equipped with soft furniture.

[0434] 75. The method of any one of embodiments 73-74, wherein the room is decorated using muted colors.

[0435] 76. The method of any one of embodiments 73 to 75, wherein the room is equipped with a high-resolution sound system.

[0436] 77. The method of any one of embodiments 73-76, wherein the room comprises a bed or a sofa.

[0437] 78. The method of embodiment 77, wherein the subject lies in bed or on a couch for about 4 to 8 hours, or a substantial portion thereof, after administration of the psilocybin.

[0438] 79. The method of any one of embodiments 73-78, wherein the subject listens to music for about 4 to 8 hours, or a significant portion thereof, after administration of the psilocybin.

[0439] 80. The method of any one of embodiments 73-79, wherein the subject wears an eye mask for about 4 to 8 hours, or a substantial portion thereof, after administration of the psilocybin.

[0440] 81. The method of any one of embodiments 67-80, wherein a therapist provides psychological support to the subject for about 4 to 8 hours after administration of the psilocybin.

[0441] 82. The method of embodiment 81, wherein the therapist uses guided imagery and / or breathing exercises to calm the subject and / or focus the subject's attention.

[0442] 83. The method of embodiment 81, wherein the therapist provides reassuring physical contact with the subject.

[0443] 84. The method of embodiment 83, wherein the therapist touches the subject's hand, arm, or shoulder.

[0444] 85. The method of embodiment 81, wherein the therapist encourages the subject to perform self-directed interviews and experiential processing.

[0445] 86. The method of embodiment 81, wherein the therapist reminds the subject of at least one therapeutic intention.

[0446] 87. The method of embodiment 81, wherein 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.

[0447] 88. The method of embodiment 81, wherein the therapist does not initiate a conversation with the subject.

[0448] 89. The method of embodiment 81, wherein the therapist responds to the subject if the subject initiates a conversation.

[0449] Numbered embodiments for depression 1. A method of treating depression in a subject in need thereof, comprising administering to the subject an effective amount of psilocybin or an active metabolite thereof.

[0450] 2. The method of embodiment 1, wherein said subject has major depressive disorder, atypical depression, bipolar disorder, catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder.

[0451] 3. The method of embodiment 2, wherein the subject has major depressive disorder.

[0452] 4. The method of embodiment 2, wherein the subject has bipolar disorder.

[0453] 5. The method of embodiment 4, wherein the subject has bipolar I disorder.

[0454] 6. The method of embodiment 4, wherein the subject has bipolar disorder type II.

[0455] 7. The method of any one of embodiments 1-6, wherein the depression is resistant to treatment.

[0456] 8. The method of any one of embodiments 1-7, wherein at least one sign or symptom of depression is reduced.

[0457] 9. The method of embodiment 8, wherein said signs or symptoms of depression are depressed mood, decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or slowness, fatigue or decreased energy, feelings of worthlessness or excessive or inappropriate guilt, poor concentration or indecisiveness, or suicidal thoughts or behaviors.

[0458] 10. The method of embodiment 9, wherein said signs or symptoms of depression are measured according to a diary assessment, a clinician or caregiver assessment, a clinical rating scale, or by functional MRI.

[0459] 11. The method of embodiment 10, wherein the clinical depression rating scale is the Quick Inventory of Depressive Symptoms (QIDS)-16 scale, the QIDS-16 Daily Scale, the Hamilton Depression Rating Scale, the Beck Depression Inventory Scale, the Mongomery-Asberg Depression Rating Scale, the Clinical Global Impression Scale, the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, and / or the Young Mania Rating Scale.

[0460] 12. The signs or symptoms of depression are determined by the Spielberger Trait and Anxiety Inventory, Generalized Anxiety Disorder 7-item Scale, Warwick-Edinburgh Mental Well-Being Scale, Flourishing Scale, Snaith Hamilton Anhedonia Pleasure Scale, Life Orientation Test, Meaning in Life Questionnaire, Brief Resilience Scale, Dysfunctional Attitudes Scale, 44-item Big Five Inventory, Peters 21-item Delusions Inventory, Anomalous Self-Experiences Test, Preoccupied Responding Scale, Polar Bear Inhibition Inventory, Barrett Impulsivity Scale, Brief Experiential Avoidance Questionnaire, Modified Tellegen Preoccupation Questionnaire, Scale for Assessing the Therapeutic Relationship, Trust / Expectancy Questionnaire, Nature Connectedness Scale, Political Perspective Questionnaire, Social Connectedness Scale, Bech-Rafaelsen Mania Rating Scale, Revised Santa Clara Inventory Clara Brief Compassion Scale, Gratitude Questionnaire, Short Recommendation Scale, Rosenberg Self-Esteem Scale, Universality Subscale of the Spiritual Transcendence Scale, Oxford Questionnaire on Emotional Side Effects of Antidepressants, Lauks Emotion Intensity Scale, Sexual Dysfunction Questionnaire, Brief Index of Female Sexual Function, Gender Awareness Questionnaire, Barnes Akathisia Rating Scale, Work Productivity and Activity Impairment Questionnaire, Work and Social Adjustment Scale, Connectedness Questionnaire, Standardized Assessment of Personality, Positive and Negative Syndrome Scale, Mastery Insight Scale, Self-Reflection and Insight Scale, Psychological Insight Scale, Metaphysical Beliefs Questionnaire, Spiritual Bypass 11. The method of embodiment 10, wherein the cognitive impairment is measured using the Adverse Childhood Experiences Bypassing Scale, Adverse Childhood Experiences Questionnaire, Therapeutic Music Experiences Questionnaire, Setting Questionnaire, Music Immersion Scale, Psychedelic Predictor Scale, Surrender Scale, EuroQOL-5 Dimensions-3 Level Scale, Columbia-Suicide Severity Rating Scale, Suicidal Ideation Attribution Scale, or any combination thereof.

[0461] 13. The method of embodiment 10, wherein said functional MRI measures amygdala blood oxygen level dependent (BOLD) response.

[0462] 14. The method of embodiment 13, wherein the BOLD response is measured in a resting state and in response to emotional faces and / or music as hedonic stimuli.

[0463] 15. The method of any one of embodiments 1-14, wherein at least one sign or symptom of depression is alleviated within 24 hours of administering the psilocybin.

[0464] 16. The method of any one of embodiments 1-14, wherein at least one symptom of depression is alleviated within 1 week of administering the psilocybin.

[0465] 17. The method of any one of embodiments 1-14, wherein at least one symptom of depression is alleviated for at least 1 month after administration of said psilocybin.

[0466] 18. The method of any one of embodiments 1-14, wherein at least one symptom of the depression is alleviated for at least 3 months after administration of the psilocybin.

[0467] 19. The method of any one of embodiments 1-14, wherein at least one symptom of the depression is alleviated for at least 12 months following administration of the psilocybin.

[0468] 20. The method of any one of embodiments 1-19, wherein after administration of the psilocybin, no other treatment for reducing signs or symptoms of depression is administered to the subject.

[0469] 21. The method of any one of embodiments 1-19, further comprising administering to the subject at least one additional therapeutic agent for reducing signs or symptoms of depression.

[0470] 22. The method of embodiment 21, wherein the at least one additional therapeutic agent is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic receptor antagonist.

[0471] 23. The method of embodiment 21 or 22, wherein the at least one additional therapeutic agent is administered prior to administration of psilocybin.

[0472] 24. The method of embodiment 21 or 22, wherein the at least one additional therapeutic agent is administered after administration of psilocybin.

[0473] 25. The method of embodiment 21 or 22, wherein the at least one additional therapeutic agent is administered on the same day as the psilocybin.

[0474] 26. The method of any one of embodiments 1-25, wherein the subject has not been previously exposed to psilocybin.

[0475] 27. The method of any one of embodiments 1-25, wherein the subject has previously been exposed to psilocybin.

[0476] 28. The method of any one of embodiments 1-27, wherein the subject has an additional co-morbidity or disorder.

[0477] 29. The method of embodiment 28, wherein the subject has an anxiety disorder, obsessive-compulsive disorder, alcoholism, a personality disorder, a cardiovascular disease, a neurological disease, or cancer.

[0478] 30. The method of embodiment 29, wherein the neurological disease is dementia, Alzheimer's disease, or Parkinson's disease.

[0479] 31. The method of any one of embodiments 28-30, wherein reducing at least one sign or symptom of depression in the subject treats or prevents one or more co-morbid diseases or disorders in the subject.

[0480] 32. The method of any one of embodiments 1-31, wherein the subject is a mammal.

[0481] 33. The method of embodiment 32, wherein the subject is a human.

[0482] 34. The method of any one of embodiments 1-33, wherein the psilocybin is administered in a dosage form comprising a therapeutically effective amount of high-purity crystalline psilocybin in the form of Polymorph A, wherein the crystalline psilocybin comprises at least 90% Polymorph A by weight.

[0483] 35. The method of embodiment 34, wherein the crystalline psilocybin comprises at least 95% by weight of polymorph A.

[0484] 36. The method of embodiment 34 or 35, wherein said crystalline psilocybin has a chemical purity of greater than 97% by HPLC and no single impurity greater than 1%.

[0485] 37. The method of any one of embodiments 1-33, wherein 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 has a chemical purity of greater than 97% by HPLC and no single impurity greater than 1%.

[0486] 38. The method of embodiment 37, wherein the high-purity crystalline psilocybin comprises at least 90% by weight of polymorph A.

[0487] 39. The method of embodiment 38, wherein the high-purity crystalline psilocybin comprises at least 95% by weight of polymorph A.

[0488] 40. The method of any one of embodiments 34-39, wherein the high-purity crystalline psilocybin is further characterized by having either (i) a water content of less than 0.5 w / w%, or (ii) a weight loss in a TGA thermogram from 25°C to 200°C of less than 0.5 w / w%.

[0489] 41. The method of any one of embodiments 34-40, wherein the high-purity crystalline psilocybin is further characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 145°C and 155°C and a second onset temperature of between 205°C and 220°C.

[0490] 42. The method of any one of embodiments 34-41, wherein the high-purity crystalline psilocybin is further characterized by one or more of the following: (a) loss on drying of 2 w / w% or less; (b) residue on ignition of 0.5 w / w% or less; (c) an assay of 95-103 wt% (dry basis) as measured by HPLC; (d) a residual solvent content of 3000 ppm or less of methanol, 5000 ppm of ethanol, 720 ppm of THF, and 890 ppm of toluene as measured by HRGC; (e) 31 (f) an inductively coupled plasma mass spectrometry (ICP-MS) elemental analysis of: (i) Cd equal to or less than 1.5 ppm, (ii) Pb equal to or less than 1.5 ppm, (iii) As equal to or less than 4.5 ppm, (iv) Hg equal to or less than 9.0 ppm, (v) Co equal to or less than 15 ppm, (vi) V equal to or less than 30 ppm, (vii) Ni equal to or less than 60 ppm, (viii) Li equal to or less than 165 ppm, and (ix) Pd equal to or less than 30 ppm.

[0491] 43. The method of any one of embodiments 34-42, wherein the high-purity crystalline psilocybin does not have more than 0.5% of a single impurity.

[0492] 44. The method of any of embodiments 34-43, wherein the dosage form further comprises about 5-40 mg of the high-purity crystalline psilocybin.

[0493] 45. The method of embodiment 44, wherein the dosage form comprises 5 mg of high-purity crystalline psilocybin.

[0494] 46. ​​The method of embodiment 44, wherein the dosage form comprises about 10 mg of high-purity crystalline psilocybin.

[0495] 47. The method of embodiment 44, wherein the dosage form comprises about 35 mg of high-purity crystalline psilocybin.

[0496] 48. The method of any one of embodiments 34-47, wherein the dosage form comprises silicified microcrystalline cellulose.

[0497] 49. The method of embodiment 48, wherein the silicified microcrystalline cellulose has a particle size range of about 45 to 150 microns.

[0498] 50. The method of any one of embodiments 34-49, 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.

[0499] 51. The method of embodiment 50, wherein about 30% or less of the microcrystalline cellulose is a first variant having a particle size of about 45 to 80 microns, and about 70% or more of the microcrystalline cellulose is a second variant having a particle size of about 90 to 150 microns.

[0500] 52. The method of embodiment 50, wherein about 20% or less of the microcrystalline cellulose is a first variant having a particle size of about 45 to 80 microns, and about 80% or more of the microcrystalline cellulose is a second variant having a particle size of about 90 to 150 microns.

[0501] 53. The method of embodiment 50, wherein about 15% or less of the microcrystalline cellulose is a first variant having a particle size of about 45 to 80 microns, and about 85% or more of the microcrystalline cellulose is a second variant having a particle size of about 90 to 150 microns.

[0502] 54. The method of embodiment 53, wherein the dosage form comprises 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.

[0503] 55. The method of embodiment 53, wherein the 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.

[0504] 56. The method of any one of embodiments 34-55, wherein the dosage form is an oral dosage form.

[0505] 57. The method of embodiment 56, wherein the dosage form is a capsule.

[0506] 58. The method of embodiment 56, wherein the dosage form is a tablet.

[0507] 59. The method of any one of embodiments 1-58, wherein at least one dose of psilocybin is administered to the subject.

[0508] 60. The method of embodiment 59, wherein the at least one dose of psilocybin is in the range of about 0.1 mg to about 100 mg.

[0509] 61. The method of embodiment 60, wherein said dose of psilocybin is about 1 mg.

[0510] 62. The method of embodiment 60, wherein said dose of psilocybin is about 10 mg.

[0511] 63. The method of embodiment 60, wherein said dose of psilocybin is about 25 mg.

[0512] 64. The method of any one of embodiments 1-58, wherein more than one dose of psilocybin is administered to the subject.

[0513] 65. The method of embodiment 65, wherein at least two doses of psilocybin are administered to the subject.

[0514] 66. The method of any one of embodiments 64-65, wherein the psilocybin is administered once a day.

[0515] 67. The method of any one of embodiments 64-65, wherein the psilocybin is administered at least once a week.

[0516] 68. The method of any one of embodiments 64-65, wherein the psilocybin is administered at least twice a week.

[0517] 69. The method of any one of embodiments 64-65, wherein the psilocybin is administered at least once a month.

[0518] 70. The method of any one of embodiments 64-65, wherein the psilocybin is administered at least twice a month.

[0519] 71. The method of any one of embodiments 64-65, wherein the psilocybin is administered at least once every three months.

[0520] 72. The method of any one of embodiments 64-65, wherein the psilocybin is administered at least once every six months.

[0521] 73. The method of any one of embodiments 64-65, wherein the psilocybin is administered at least once every 12 months.

[0522] 74. The method of any one of embodiments 64-73, wherein each dose of psilocybin administered is in the range of about 0.1 mg to about 100 mg.

[0523] 75. The method of embodiment 74, wherein each dose of psilocybin administered is about 1 mg.

[0524] 76. The method of embodiment 74, wherein each dose of psilocybin administered is about 10 mg.

[0525] 77. The method of embodiment 74, wherein each dose of psilocybin administered is about 25 mg.

[0526] 78. The method of any one of embodiments 59-77, wherein the psilocybin is administered by one of the following routes: oral, parenteral, topical, inhalation, rectal, transmucosal, intranasal, buccal, vaginal, intrathecal, intraocular, transdermal, intrauterine, intralymphatic, or by direct tissue or organ injection.

[0527] 79. The method of embodiment 78, wherein the psilocybin is administered orally.

[0528] 80. The method of any one of embodiments 1-79, wherein the subject participates in at least one psychological support session prior to administration of the psilocybin.

[0529] 81. The method of embodiment 80, wherein the subject participates in at least three psychological support sessions prior to administration of the psilocybin.

[0530] 82. The method of any one of embodiments 80-81, wherein at least one therapeutic intent is discussed during the psychological support session.

[0531] 83. The method of any one of embodiments 80-82, wherein self-directed interviewing and experiential processing is performed during the psychological support session.

[0532] 84. The method of any one of embodiments 80-83, wherein the subject participates in at least one psychological support session after administration of the psilocybin.

[0533] 85. The method of embodiment 84, wherein the subject participates in at least three psychological support sessions after administration of the psilocybin.

[0534] 86. The method of any one of embodiments 80-85, wherein the psilocybin is administered to the subject in a room having a substantially non-clinical appearance.

[0535] 87. The method of embodiment 86, wherein the room is equipped with soft furniture.

[0536] 88. The method of embodiment 86, wherein the room is decorated using muted colors.

[0537] 89. The method of embodiment 86, wherein the room is equipped with a high-resolution sound system.

[0538] 90. The method of any one of embodiments 86-89, wherein the room comprises a bed or a sofa.

[0539] 91. The method of embodiment 90, wherein the subject lies in bed or on a couch for about 4 to 8 hours, or a substantial portion thereof, after administration of the psilocybin.

[0540] 92. The method of any one of embodiments 86-91, wherein the subject listens to music for about 4 to 8 hours, or a significant portion thereof, after administration of the psilocybin.

[0541] 93. The method of any one of embodiments 86-92, wherein the subject wears an eye mask for about 4 to 8 hours, or a significant portion thereof, after administration of the psilocybin.

[0542] 94. The method of any one of embodiments 87-93, wherein a therapist provides psychological support to the subject for about 4 to 8 hours after administration of the psilocybin.

[0543] 95. The method of embodiment 94, wherein the therapist uses guided imagery and / or breathing exercises to calm the subject and / or focus the subject's attention.

[0544] 96. The method of embodiment 94, wherein the therapist provides reassuring physical contact with the subject.

[0545] 97. The method of embodiment 96, wherein the therapist touches the subject's hand, arm, or shoulder.

[0546] 98. The method of embodiment 94, wherein the therapist encourages the subject to perform self-directed interviews and experiential processing.

[0547] 99. The method of embodiment 94, wherein the therapist reminds the subject of at least one therapeutic intention.

[0548] 100. The method of embodiment 94, wherein 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.

[0549] 101. The method of embodiment 94, wherein the therapist does not initiate a conversation with the subject.

[0550] 102. The method of embodiment 94, wherein the therapist responds to the subject if the subject initiates a conversation.

[0551] 103. The method of any one of embodiments 80-102, wherein the psychological support is provided to the subject remotely.

[0552] 104. The method of embodiment 103, wherein the psychological support is provided via a digital or electronic system.

[0553] 105. The method of embodiment 104, wherein the digital or electronic system is a mobile phone app.

[0554] 106. The method of embodiment 105, wherein the digital or electronic system is a website.

[0555] 107. The method claimed herein.

[0556] 108. A formulation as claimed herein.

[0557] 109. Crystalline psilocybin as claimed in the present application.

[0558] Numbered Embodiments for Co-Administration of Psilocybin and Benzodiazepines 1. A method of reducing anxiety in a subject receiving treatment with psilocybin, comprising administering to the subject: i) psilocybin or a precursor or derivative thereof, and ii) administering one or more benzodiazepines.

[0559] 2. The subject is diagnosed with: Disruptive Mood Dysfunction Disorder, Major Depressive Disorder (MDD), Treatment-Resistant Depression, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance / Medication-Induced Depressive Disorder, Postpartum Depression, or Depressive Disorder Due to Another Medical Condition, Separation Anxiety Disorder, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Panic Disorder, Panic Attacks, Agoraphobia, Generalized Anxiety Disorder, Substance- or Medication-Induced Anxiety Disorder, Anxiety Disorder Due to Another Medical Condition, Somatic Symptom Disorder, Illness Anxiety Disorder (Hypochondriasis), Conversion Disorder (Functional Neurological Symptom Disorder), Factitious Disorder, Post-Traumatic Stress Disorder (PTSD), Adjustment Disorder, Acute Distress Disorder, Obsessive-Compulsive Disorder, Body Dysmorphic Disorder, Hoarding Disorder, Trichotillomania (Hair Pulling Disorder), Excoriation (Skin Picking Disorder), 2. The method of embodiment 1, wherein the patient is suffering from a disease, disorder, or condition selected from: obsessive-compulsive and related disorders, substance / drug-induced obsessive-compulsive and related disorders, obsessive-compulsive and related disorders due to another medical condition, substance-related disorders, alcohol-related disorders, cannabis-related disorders, hallucinogen-related disorders, inhalant-related disorders, cocaine-related disorders, opioid-related disorders, sedative-, hypnotic-, or anxiolytic-related disorders, stimulant-related disorders, tobacco-related disorders, non-substance-related disorders (gambling or gaming disorders), migraine, cluster headaches such as chronic cluster headaches, cyclic vomiting, tension-type headaches, dysphagia, pica, anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathy, pyromania, and kleptomania.

[0560] 3. The method of embodiment 1 or 2, wherein the one or more benzodiazepines are administered to the subject simultaneously or contemporaneously with the psilocybin, or a precursor or derivative thereof.

[0561] 4. The method of embodiment 1 or 2, wherein the one or more benzodiazepines are administered to the subject prior to administration of the psilocybin, or a precursor or derivative thereof.

[0562] 5. The method of embodiment 4, wherein the one or more benzodiazepines are administered to the 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 prior to administration of the psilocybin, or a precursor or derivative thereof.

[0563] 6. The method of embodiment 1 or 2, wherein the one or more benzodiazepines are administered to the subject after the psilocybin, or a precursor or derivative thereof.

[0564] 7. The method of embodiment 6, wherein the one or more benzodiazepines are administered to the 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 the psilocybin, or a precursor or derivative thereof.

[0565] 8. The method of any one of embodiments 1-7, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject at a dose of from about 0.1 mg to about 100 mg.

[0566] 9. The method of embodiment 8, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject in a dose of between about 1 mg and about 50 mg.

[0567] 10. The method of embodiment 9, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject in a dose of about 1 mg, about 10 mg, or about 25 mg.

[0568] 11. The method of any one of embodiments 1-10, wherein the one or more benzodiazepines are administered at a dose lower than that typically used to treat anxiety.

[0569] 12. The method of embodiment 11, wherein said dose is about 10%, 20%, 25%, 30%, 40%, 50%, or 75% of a typical dose.

[0570] 13. The method of any one of embodiments 1-10, wherein said one or more benzodiazepines are administered at a dose approximately equivalent to that typically used to treat anxiety.

[0571] 14. The method of any one of embodiments 1-10, wherein the one or more benzodiazepines are administered at a dose higher than that typically used to treat anxiety.

[0572] 15. The method of embodiment 14, wherein the dose is about 125%, 150%, 175%, 200%, 250%, or 300% of a typical dose.

[0573] 16. 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, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam, flunitrazolam, flurazepam 16. The method of any one of embodiments 1-15, wherein the agonist is selected from the group consisting of 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.

[0574] 17. The method of embodiment 16, wherein the benzodiazepine is alprazolam.

[0575] 18. The method of embodiment 16, wherein the benzodiazepine is diazepam.

[0576] 19. The method of any one of embodiments 1-18, wherein the psilocybin is crystalline psilocybin in the form of Polymorph A, Polymorph A', Polymorph B, or Hydrate A.

[0577] 20. The method of embodiment 19, wherein the crystalline psilocybin is polymorph A, characterized by one or more of the following: a. Peaks at 11.5, 12.0, 14.5, and 17.5° 2θ ± 0.1° 2θ in the XRPD diffractogram; b. peaks at 11.5, 12.0, 14.5, and 17.5 °2θ ± 0.1 °2θ in an XRPD diffractogram, further characterized by at least one additional peak at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ; c. an XRPD diffractogram substantially as shown in Figure 2a; and / or d. 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.

[0578] 21. The method of embodiment 19, wherein the crystalline psilocybin is polymorph A', characterized by one or more of the following: a. Peaks in an XRPD diffractogram at 11.5, 12.0, and 14.5°2θ±0.1°2θ, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent; b. peaks at 11.5, 12.0, and 14.5 °2θ ± 0.1 °2θ, but with the absence or substantial absence of a peak at 17.5 °2θ ± 0.1 °2θ in an XRPD diffractogram, 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; c. an XRPD diffractogram substantially as shown in Figure 2b; and / or d. 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 3b.

[0579] 22. The method of any one of embodiments 1-21, wherein the psilocybin, or a precursor or derivative thereof, is administered orally to the subject.

[0580] 23. The method of any one of embodiments 1-22, wherein the one or more benzodiazepines are administered orally to the subject.

[0581] 24. The method of any one of embodiments 1-23, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject at least once.

[0582] 25. The method of embodiment 24, wherein the psilocybin is administered to the subject at least twice at therapeutically effective intervals.

[0583] 26. The method of embodiment 25, wherein the therapeutically effective interval is 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.

[0584] 27. The method of any one of embodiments 1-16, wherein the subject has not previously taken psilocybin.

[0585] 28. The method of any one of embodiments 1-26, wherein the subject has previously taken psilocybin.

[0586] 29. The method of any one of embodiments 1-28, wherein the subject is supervised during the administration and for at least 4-12 hours thereafter.

[0587] 30. The method of any one of embodiments 1-29, wherein the subject receives psychological support during the administration and for at least 4-12 hours thereafter.

[0588] 31. The method of any one of embodiments 1-30, wherein the subject has not been taking any serotonergic antidepressants for at least 2 weeks, at least 4 weeks, or at least 6 weeks prior.

[0589] 32. The method of any one of embodiments 1-31, wherein the subject receives counseling regarding the expected effects of the psilocybin.

[0590] 33. The method of any one of embodiments 1-32, wherein the subject is male.

[0591] 34. The method of any one of embodiments 1-32, wherein the subject is a female.

[0592] 35. Disruptive mood dysregulation disorder, major depressive disorder (MDD), treatment-resistant depression, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, postpartum depression, or depressive disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance- or drug-induced anxiety disorder, anxiety disorder due to another condition, somatic symptom disorder, illness anxiety disorder (hypochondriasis), conversion disorder (functional neurological symptom disorder), factitious disorder, post-traumatic stress disorder (PTSD), adjustment disorder, acute distress disorder, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation (skin picking) disorder, substance / Combination therapy for treating or preventing a disease, disorder, or condition selected from drug-induced obsessive-compulsive and related disorders, obsessive-compulsive and related disorders due to another condition, substance-related disorders, alcohol-related disorders, cannabis-related disorders, hallucinogen-related disorders, inhalant-related disorders, cocaine-related disorders, opioid-related disorders, sedative-, hypnotic-, or anxiolytic-related disorders, stimulant-related disorders, tobacco-related disorders, non-substance-related disorders (gambling or gaming disorders), migraine, cluster headaches such as chronic cluster headache, cyclic vomiting, tension-type headache, dysphagia, pica, anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathy, pyromania, and kleptomania, wherein the subject is i) psilocybin or a precursor or derivative thereof, and ii) The combination therapy described above, which comprises administering one or more benzodiazepines.

[0593] 36. A kit for treating a subject in need thereof, comprising: a first pharmaceutical composition comprising psilocybin or a precursor or derivative thereof; a second pharmaceutical composition comprising one or more benzodiazepines.

[0594] 37. The kit of embodiment 36, further comprising instructions for administering the first pharmaceutical composition and the second pharmaceutical composition to the subject.

[0595] Numbered embodiments for the simultaneous administration of psilocybin and a 5-HT2A-specific antagonist and / or inverse agonist. 1. A method of reducing negative side effects associated with a traumatic psychedelic experience in a subject treated with psilocybin, comprising administering to the subject: i) psilocybin or a precursor or derivative thereof, and ii) one or more 5-HT 2A The method further comprising administering a specific antagonist and / or inverse agonist.

[0596] 2. The subject is diagnosed with major mood dysregulation disorder, major depressive disorder (MDD), treatment-resistant depression, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / drug-induced depressive disorder, postpartum depression, or depressive disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance-drug induced anxiety disorder, anxiety disorder due to another condition, somatic symptom disorder, illness anxiety disorder (hypochondriasis), conversion disorder (functional neurological symptom disorder), factitious disorder, post-traumatic stress disorder (PTSD), adjustment disorder, acute distress disorder, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation (skin picking) disorder, substance / drug-induced obsessive-compulsive disorder, or substance / drug-induced obsessive-compulsive disorder. 2. The method of embodiment 1, wherein the patient suffers from a disease, disorder, or condition selected from: obsessive-compulsive and related disorders, obsessive-compulsive and related disorders due to another condition, substance-related disorders, alcohol-related disorders, cannabis-related disorders, hallucinogen-related disorders, inhalant-related disorders, cocaine-related disorders, opioid-related disorders, sedative-, hypnotic-, or anxiolytic-related disorders, stimulant-related disorders, tobacco-related disorders, non-substance-related disorders (gambling or gaming disorders), migraine, cluster headaches such as chronic cluster headaches, cyclic vomiting, tension-type headache, dysphasia, pica, anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathy, pyromania, kleptomania, mental fatigue, vegetative state, and asthma (and other inflammatory diseases).

[0597] 3. One or more of the above 5-HT 2A 3. The method of embodiment 1 or 2, wherein a specific antagonist and / or inverse agonist is administered to the subject simultaneously or contemporaneously with the psilocybin, or a precursor or derivative thereof.

[0598] 4. One or more of the above 5-HT 2A 3. The method of embodiment 1 or 2, wherein a specific antagonist and / or inverse agonist is administered to the subject prior to administration of the psilocybin, or a precursor or derivative thereof.

[0599] 5. One or more of the above 5-HT 2A5. The method of embodiment 4, wherein the specific antagonist and / or inverse agonist is administered to the 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 prior to administration of the psilocybin, or a precursor or derivative thereof.

[0600] 6. One or more of the above 5-HT 2A 3. The method of embodiment 1 or 2, wherein a specific antagonist and / or inverse agonist is administered to the subject after the psilocybin, or a precursor or derivative thereof.

[0601] 7. One or more of the above 5-HT 2A 7. The method of embodiment 6, wherein the specific antagonist and / or inverse agonist is administered to the 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 the psilocybin, or a precursor or derivative thereof.

[0602] 8. The method of any one of embodiments 1-7, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject at a dose of from about 0.1 mg to about 100 mg.

[0603] 9. The method of embodiment 8, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject in a dose of between about 1 mg and about 50 mg.

[0604] 10. The method of embodiment 9, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject in a dose of about 1 mg, about 10 mg, or about 25 mg.

[0605] 11. One or more of the above 5-HT 2A 11. The method of any one of embodiments 1-10, wherein the specific antagonist and / or inverse agonist is administered at a dose lower than a typical dose.

[0606] 12. The method of embodiment 11, wherein said dose is about 10%, 20%, 25%, 30%, 40%, 50%, or 75% of a typical dose.

[0607] 13. One or more of the following: 5-HT 2A 11. The method of any one of embodiments 1-10, wherein the specific antagonist and / or inverse agonist is administered at a dose that is approximately equivalent to a typical dose.

[0608] 14. One or more of the following: 5-HT 2A 11. The method of any one of embodiments 1-10, wherein the specific antagonist and / or inverse agonist is administered at a dose higher than a typical dose.

[0609] 15. The method of embodiment 14, wherein the dose is about 125%, 150%, 175%, 200%, 250%, or 300% of a typical dose.

[0610] 16. 5-HT 2ASpecific antagonists 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, or 7-[[4-[2-(4-fluorophenyl)ethyl]-1-piperazinyl]carbonyl]-1H-indole-3-carbonitrile (EMD281014).

[0611] 17. 5-HT 2A 17. The method of embodiment 16, wherein the specific antagonist is ketanserin.

[0612] 18. 5-HT 2A16. The method of any one of embodiments 1-15, wherein the inverse antagonist is AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), or vorinaserin.

[0613] 19. 5-HT 2A 19. The method of embodiment 18, wherein the inverse antagonist is pimavanserin.

[0614] 20. The method of any one of embodiments 1-19, wherein the psilocybin is crystalline psilocybin in the form of Polymorph A, Polymorph A', Polymorph B, or Hydrate A.

[0615] 21. The method of embodiment 20, wherein the crystalline psilocybin is polymorph A, characterized by one or more of the following: e. Peaks at 11.5, 12.0, 14.5, and 17.5° 2θ ± 0.1° 2θ in the XRPD diffractogram; f. peaks at 11.5, 12.0, 14.5, and 17.5 °2θ ± 0.1 °2θ in an XRPD diffractogram, further characterized by at least one additional peak at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ; g. an XRPD diffractogram substantially as shown in Figure 2A; and / or h. 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.

[0616] 22. The method of embodiment 20, wherein the crystalline psilocybin is polymorph A', characterized by one or more of the following: e. peaks at 11.5, 12.0, and 14.5°2θ±0.1°2θ in an XRPD diffractogram, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent; f. peaks at 11.5, 12.0, and 14.5 °2θ ± 0.1 °2θ, but with the absence or substantial absence of a peak at 17.5 °2θ ± 0.1 °2θ in an XRPD diffractogram, 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; g. an XRPD diffractogram substantially as shown in Figure 2B; and / or h. 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 3B.

[0617] 23. The method of any one of embodiments 1-22, wherein the psilocybin, or a precursor or derivative thereof, is administered orally to the subject.

[0618] 24. One or more of the following: 5-HT 2A 24. The method of any one of embodiments 1-23, wherein the specific antagonist and / or inverse agonist is orally administered to said subject.

[0619] 25. The method of any one of embodiments 1-24, wherein the psilocybin, or a precursor or derivative thereof, is administered to the subject at least once.

[0620] 26. The method of embodiment 25, wherein the psilocybin is administered to the subject at least twice at therapeutically effective intervals.

[0621] 27. The method of embodiment 26, wherein the therapeutically effective interval is 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.

[0622] 28. The method of any one of embodiments 1-27, wherein the subject has never taken psilocybin before.

[0623] 29. The method of any one of embodiments 1-27, wherein the subject has previously taken psilocybin.

[0624] 30. The method of any one of embodiments 1-29, wherein the subject is supervised during the administration and for at least 4-12 hours thereafter.

[0625] 31. The method of any one of embodiments 1-30, wherein the subject receives psychological support during said administering and for at least 4-12 hours thereafter.

[0626] 32. The method of any one of embodiments 1-31, wherein the subject has not taken any serotonergic antidepressants for at least 2 weeks, at least 4 weeks, or at least 6 weeks prior.

[0627] 33. The method of any one of embodiments 1-32, wherein the subject receives counseling regarding the expected effects of the psilocybin.

[0628] 34. The method of any one of embodiments 1-33, wherein the subject is male.

[0629] 35. The method of any one of embodiments 1-33, wherein the subject is a female.

[0630] 36. Disruptive mo...

Claims

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

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