Psilocybin and adjunctive serotonin reuptake inhibitors for use in the treatment of treatment-resistant depression - Patents.com

Abstract

The present disclosure provides a method for treating a subject in need of treatment, comprising administering to the subject a therapeutically effective dose of psilocybin. The methods described herein can be used to treat a variety of diseases, disorders, and conditions. For example, the methods can be used to treat depression, neurocognitive disorders, autism spectrum disorders, and / or attention-deficit / hyperactivity disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 288,938, filed December 13, 2021, the contents of which are incorporated by reference in their entirety herein. [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 retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate or indecisiveness, recurrent 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 for 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] The present disclosure provides methods of treating treatment-resistant depression in a subject in need thereof.

[0006] In some embodiments, the methods described herein comprise treating treatment-resistant depression in a subject in need of treatment thereof, comprising administering to the subject an effective amount of psilocybin, or an active metabolite thereof, as an adjunct to selective serotonin reuptake inhibitor (SSRI) therapy.

[0007] In some embodiments, the SSRI is selected from the group consisting of escitalopram, sertraline, fluoxetine, vilazodone, vortioxetine, paroxetine, or citalopram.

[0008] In some embodiments, the SSRI is administered prior to administration of psilocybin. In some embodiments, the SSRI is administered after administration of psilocybin. In some embodiments, the SSRI is administered on the same day as psilocybin.

[0009] In some embodiments, the subject is administered about 25 mg of psilocybin or an active metabolite thereof.

[0010] In some embodiments, administration of psilocybin reduces at least one sign or symptom of depression.In some embodiments, the sign or symptom of depression is depressed mood, decreased interest in activity, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased concentration or indecisiveness, or suicidal thoughts or behaviors.

[0011] 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 clinical 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 Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions scale, the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, and / or the Young Mania Rating Scale.

[0012] In some embodiments, the clinical assessment scale is MADRS. In some embodiments, administration of psilocybin results in about a 50% decrease in the patient's MADRS total score compared to before treatment with psilocybin. In some embodiments, administration of psilocybin results in a decrease in the patient's MADRS total score to 10 or less.

[0013] In some embodiments, the clinical assessment scale is the Clinical Global Impression Scale-Severity (CGI-S). In some embodiments, administration of psilocybin results in a reduction in the patient's CGI-S score to 2 or less. In some embodiments, the clinical assessment scale is the Clinical Global Impression Scale-Improvement (CGI-I). In some embodiments, administration of psilocybin results in a reduction in the patient's CGI-I score reported as "very improved" or "much improved" compared to before treatment with psilocybin.

[0014] In some embodiments, administration of psilocybin results in a reduction in the patient's anxiety compared to before treatment with psilocybin, hi some embodiments, administration of psilocybin results in a reduction in the patient's Generalized Anxiety Disorder 7-item (GAD-7) total score compared to before treatment with psilocybin.

[0015] In some embodiments, at least one sign or symptom of depression is alleviated within 24 hours of administration of psilocybin. In some embodiments, at least one symptom of depression is alleviated within 1 week of administration of psilocybin. In some embodiments, at least one symptom of depression is alleviated for at least 1 month after administration of psilocybin. In some embodiments, at least one symptom of depression is alleviated for at least 3 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.

[0016] In some embodiments, at least two doses of psilocybin are administered to the subject. In some embodiments, psilocybin is administered once a day. In some embodiments, psilocybin is administered at least once a week. In some embodiments, psilocybin is administered at least twice a week. In some embodiments, psilocybin is administered at least once a month. In some embodiments, psilocybin is administered at least twice a month. In some embodiments, psilocybin is administered at least once every three months. In some embodiments, psilocybin is administered at least once every six months. In some embodiments, psilocybin is administered at least once every twelve months. In some embodiments, each dose of psilocybin administered is about 25 mg.

[0017] In some embodiments, the psilocybin is administered by one of the following routes: oral, intravenous, intramuscular, parenteral, topical, inhalation, rectal, transmucosal, intranasal, buccal, vaginal, intrathecal, intraocular, transdermal, intrauterine, intralymphatic, or by direct tissue or organ injection. In some embodiments, the psilocybin is administered orally.

[0018] In some embodiments, the psilocybin comprises a crystalline polymorph of psilocybin. In some embodiments, the psilocybin comprises a crystalline polymorph of psilocybin. In some embodiments, the crystalline polymorph A of psilocybin is characterized by XRPD peaks at 11.5±0.1, 12.0±0.1, 14.5±0.1, 17.5±0.1, and 19.7±0.1 degrees 2θ. In some embodiments, polymorph A is further characterized by at least one peak selected from the group consisting of 20.4±0.1, 22.2±0.1, 24.3±0.1, and 25.7±0.1 degrees 2θ.

[0019] In some embodiments, the crystalline psilocybin comprises Hydrate A. In some embodiments, Hydrate A is characterized by X-ray powder diffraction (XRPD) peaks at 8.9±0.1, 13.8±0.1, 19.4±0.1, 23.1±0.1, and 23.5±0.1 degrees 2θ. In some embodiments, Hydrate A is further characterized by at least one peak selected from the group consisting of 6.5±0.1, 12.2±0.1, 12.6±0.1, 16.2±0.1, 20.4±0.1, 20.8±0.1, and 21.5±0.1 degrees 2θ.

[0020] In some embodiments, the psilocybin has no impurities greater than 1% as determined by HPLC analysis, hi some embodiments, the psilocybin has a chemical purity of greater than 97% as determined by HPLC analysis. [Brief description of the drawings]

[0021] [Figure 1] 1 is 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 (CB646-E) obtained during process development (top) compared to the diffractograms of polymorph A' (JCCA2160F) (middle) 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 is a DSC and TGA thermograph 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. [Diagram 5] This is the 1H NMR (nuclear magnetic resonance) spectrum of psilocybin. [Figure 6] This is the 13C NMR spectrum of psilocybin. [Figure 7] This is an FT-IR spectrum of psilocybin. [Figure 8] This is the mass spectrum of psilocybin. [Figure 9] 1 shows the study design for a clinical trial investigating psilocybin as an adjunctive therapy in participants with treatment-resistant depression. [Figure 10] 1 shows patient disposition from a clinical trial investigating psilocybin as an adjunctive therapy in participants with treatment-resistant depression. [Figure 11]Figure 1 shows the SSRIs that patients were taking at the time they were administered psilocybin in a clinical trial investigating psilocybin as an adjunctive therapy in participants with treatment-resistant depression. [Figure 12A] 1 shows the mean change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score observed during the clinical trial described in Example 2. [Figure 12B] 1 shows the mean MADRS total scores observed during the clinical trial described in Example 2. [Figure 13] 1 shows the proportion of MADRS responders by visit observed during the clinical trial described in Example 2. [Figure 14] 1 shows the proportion of MADRS remissions per visit observed during the clinical trial described in Example 2. [Figure 15A] 1 shows the mean change from baseline in Clinical Global Impression Scale-Severity (CGI-S) total score observed during the clinical trial described in Example 14. [Figure 15B] 1 shows the mean CGI-S total scores observed during the clinical trial described in Example 2. [Figure 16] 1 shows the percentage of CGI-S responders by visit observed during the clinical trial described in Example 2. [Figure 17A] 1 shows the mean change from baseline in Generalized Anxiety Disorder 7-item scale (GAD-7) total score observed during the clinical trial described in Example 2. [Figure 17B] 1 shows the mean GAD-7 total scores observed during the clinical trial described in Example 2. [Figure 18A] 1 shows the mean change from baseline in Positive and Negative Affect Schedule (PANAS) negative affect total score, as well as the mean PANAS negative affect total score observed during the clinical trial described in Example 2. [Figure 18B] 1 shows the mean change from baseline in PANAS positive affect total score, as well as the mean PANAS positive affect total score observed during the clinical trial described in Example 2. [Figure 19] 1 shows a summary of the Five-Dimensional Altered State of Consciousness Scale (5D-ASC) scores on Day 1 observed during the clinical trial described in Example 2. [Figure 20A] 1 shows the mean change from baseline in the 16-item Brief Depressive Symptoms Scale-Self-Report (QIDS-SR-16) total score observed during the clinical trial described in Example 2. [Figure 20B] 1 shows the mean QIDS-SR-16 total scores observed during the clinical trial described in Example 2. [Figure 21A] 1 shows the mean change from baseline in EuroQol-5 Dimension-3 Level scale (EQ-5D-3L) total score observed during the clinical trial described in Example 2. [Figure 21B] 1 shows the mean EQ-5D-3L total scores observed during the clinical trial described in Example 2. [Figure 22A] 1 shows the mean change from baseline in Euro QoL visual analogue scale (EQ-VAS) total score observed during the clinical trial described in Example 14. [Figure 22B] 1 shows the mean EQ-VAS total scores observed during the clinical trial described in Example 2. [Diagram 23] 1 shows the percentage of Clinical Global Impression Scale-Improvement (CGI-I) responders by visit observed during the clinical trial described in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] 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.

[0023] The singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0024] Additionally, as used herein, the term "about" when referring to measurable values ​​(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.

[0025] 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 in some cases conjunctive and in other cases disjoint. Multiple elements listed with "and / or" should be interpreted 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 only A (optionally including elements other than B), in another embodiment to only B (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0026] As used herein and in the embodiments, "or" should be understood to have the same meaning as "and / or" 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 including more than one element or list of elements, and optionally further unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the embodiments, "consisting of," refer to the inclusion of exactly one element of a number of elements or list of elements. In general, the term "or" as used herein should only be interpreted 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 the embodiments, shall have its ordinary meaning as used in the field of patent law.

[0027] As used herein 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.

[0028] Unless the context dictates otherwise, it is specifically contemplated that the various features described herein can be used in any combination.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] As used herein, "substantially absent" in reference to an XRPD diffractogram peak means that, compared to a reference peak present in the diffractogram, the peak has a relative intensity that is 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.

[0033] XRPD diffractograms and XRPD peak positions may be obtained using Cu Kα radiation.

[0034] DSC and TGA thermograms may be obtained using a heating rate of 20° C. / min.

[0035] 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 a psychiatric disorder (e.g., major depressive disorder) and / or response to treatment in subjects with a psychiatric disorder.

[0036] 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.

[0037] As used herein, the terms "subject" and "patient" are used interchangeably.

[0038] As used herein, "treating" and similar terms refer to reducing the severity and / or frequency of one or more symptoms, eliminating one or more symptoms and / or the underlying causes 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 remedying the damage caused directly or indirectly by a disease and / or disorder.

[0039] As used herein, a "therapeutically effective dose" means a dose sufficient to achieve the intended therapeutic purpose, such as alleviating a sign or symptom of a disease or disorder in a subject.

[0040] 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.

[0041] As used herein, a subject who is "psilocybin-naive" has not previously been exposed to psilocybin.

[0042] As used herein, the following Medical Dictionary for Drugs and Neurology (MedDRA) terms are considered to be adverse events that are psychotomimetic in nature: mood changes, altered state 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.

[0043] Depressive disorders In some embodiments, the methods provided herein are used to treat a subject with a depressive disorder. As used herein, the term "depressive disorder", "depressive disorder", or "depression" refers to a group of disorders characterized by a period of persistent low mood that can affect a person's thoughts, behavior, emotions, and 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, despair, and frustration, feelings of guilt, worthlessness, or helplessness, loss of interest or enjoyment in hobbies and activities, difficulty concentrating, remembering, or making decisions.

[0044] 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.

[0045] 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 with no clear cause. In some cases, major depressive disorder is characterized by periods of depression that are separated by years. In some cases, individuals experience symptoms of depression that are nearly always present. 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 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 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 disorders 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.

[0046] As used herein, the term "atypical depression" refers to a condition in which an individual shows signs of a long-standing pattern of mood reactivity (i.e., mood brightens in response to actual or potential positive events), significant weight gain, increased appetite, hypersomnia, 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 evident 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.

[0047] As used herein, the term "bipolar disorder" refers to a condition that causes an individual to experience abnormal changes in mood, energy, activity levels, 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 are significantly different from the person's typical moods and behaviors. Exemplary symptoms of mania, excessive behavior, include, but are not limited to, abnormally cheerful, excitable, or irritable behavior, increased activity, energy, or agitation, exaggerated feelings of happiness and self-confidence, decreased need for sleep, abnormal talkativeness, rapid-fire thinking, distractible nature, and poor decision-making, such as buying sprees, taking sexual risks, or making 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 nearly 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.

[0048] 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 that require hospitalization. Subjects with bipolar I disorder may also typically experience depressive episodes lasting at least 2 weeks. Depression with mixed characteristics, i.e., episodes of simultaneous depressive and manic symptoms, are also possible. Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but not the severe manic episodes typical of bipolar I disorder. Cyclothymic disorder (also called cyclothymia) is characterized by periods of hypomanic symptoms (elevated elevation and euphoria), and depressive symptoms that last for 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.

[0049] 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 or getting out of bed, feelings of restlessness, agitation, feelings of worthlessness, guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and / or suicide attempts.

[0050] As used herein, the term "depressive disorder caused by medical condition" refers to a condition in which an individual experiences depressive symptoms caused by another disease. Examples of medical conditions that are known to cause depressive disorder 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).

[0051] 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 sleep when the baby is asleep; impaired concentration, memory for details, and judgment; feeling anger or resentment; 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; constantly questioning one's ability to care for the baby; and thoughts of harming oneself or the baby.

[0052] As used herein, the term "premenstrual dysphoric disorder" refers to a condition in which an individual exhibits mood lability, irritability, discomfort, and anxiety symptoms that occur repeatedly before menstruation and then remit 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 normal 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, "bloating" and weight gain), self-loathing thoughts, feeling depressed or irritable, decreased interest in normal activities (e.g., work, school, friends, hobbies), subjective decreased concentration, and easy fatigue.

[0053] As used herein, the term "seasonal affective disorder" refers to a condition in which an individual experiences changes in mood based on the time of year. In some cases, an individual experiences low mood, low energy, or other depressive symptoms during the fall and / or winter seasons. In some cases, an individual experiences 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 most of the day or almost every day, losing interest in activities that were once enjoyable, 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.

[0054] 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, 5th Edition, hi some embodiments, a depressive disorder comprises a medical diagnosis based on an independent medical evaluation.

[0055] In some embodiments, the methods described herein are provided to a subject with depression that is resistant to treatment. In some embodiments, the subject has been diagnosed with "treatment-resistant depression". The term "treatment-resistant depression" refers to a type of depression that is unresponsive or resistant to at least one or more treatment attempts of appropriate dose 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.

[0056] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by about 5% to about 100%, 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%, or about 100% or more, compared to before treatment.

[0057] In some embodiments, the methods provided herein reduce at least one sign or symptom of major depressive disorder. 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.

[0058] 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%, 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%, or about 100% or more, compared to before treatment.

[0059] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder. 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.

[0060] 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.

[0061] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder type II. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder type II 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.

[0062] In some embodiments, the methods provided herein reduce at least one sign or symptom of catatonic depression. 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.

[0063] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder due to a medical condition. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder due to a medical condition by about 5% to about 100%, 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%, or about 100% or more, compared to before treatment.

[0064] 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%, 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%, or about 100% or more, compared to before treatment.

[0065] In some embodiments, the methods provided herein reduce at least one sign or symptom of premenstrual dysphoric disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of premenstrual dysphoric disorder by about 5% to about 100%, 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%, or about 100% or more, compared to before treatment.

[0066] In some embodiments, the methods provided herein reduce at least one sign or symptom of seasonal affective disorder. 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.

[0067] 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.

[0068] 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 an active metabolite thereof. In some embodiments, the subject does not experience a recurrence of depression upon administration of psilocybin or an active metabolite thereof.

[0069] In some embodiments, following administration of psilocybin, the subject is not administered any other treatment for reducing signs or symptoms of depression.

[0070] In some embodiments, the method of the present disclosure further comprises administering to the subject at least one additional therapeutic agent for reducing the 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 administration of psilocybin, on the same day as administration of psilocybin, or after administration of psilocybin.

[0071] In some embodiments, the subject with depressive disorder has additional comorbidities or disorders. In some embodiments, the additional comorbidities or disorders are 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 comorbidities or disorders in the subject.

[0072] Psilocybin In some embodiments, the method of treatment comprises administration of a therapeutically effective amount of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin, to a subject in need of treatment, as described herein. In some embodiments, the method of treatment comprises administration of a therapeutically effective amount of psilocybin, as described herein. In some embodiments, the method of treatment comprises administration of 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, for use in treating an indication, as described herein. 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, in the manufacture of a medicament for treating an indication, as described herein.

[0073] The numbered structural formula of psilocybin is shown in Figure 1. Novel polymorphs and hydrates of psilocybin, as well as their preparations and formulations, are disclosed in US Application US2019 / 0119310 A1, which is incorporated by reference in its entirety. US2019 / 0119310 discloses several formulations and the challenges of formulating psilocybin, for example, due to its hygroscopicity and poor flow properties. US2019 / 0119310 also discloses the importance of a controlled aqueous crystallization process.

[0074] In some embodiments, the psilocybin comprises crystalline psilocybin in the form of polymorph A or polymorph A' as described herein, the crystalline psilocybin exhibiting 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-165°C and a second onset temperature of 205°C-220°C. Exemplary DSC thermograms are provided as Figures 3A and 3B.

[0075] 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 FIG. 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 FIG. 3A .

[0076] 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% compared to the peak at 14.5°2θ±0.1°2θ.

[0077] 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 further peak at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.2 °2θ, an XRPD diffractogram substantially as shown in FIG. 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 FIG. 3A .

[0078] In some embodiments, the 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, the 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 1]

[0079] 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 FIG. 2A.

[0080] In some embodiments, crystalline psilocybin polymorph A is characterized by XRPD diffractogram peaks at 14.5 and 17.5°2θ±0.1°2θ, where 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 peak intensity at 14.5°2θ.

[0081] 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.

[0082] In some embodiments, crystalline psilocybin polymorph A is characterized by an endothermic event in a DSC thermogram having a first onset temperature of 145° C. to 165° C., e.g., 145° C. to 160° C., or e.g., 145° C. to 155° C., and a second onset temperature of 205° C. to 220° C., e.g., 210° C. to 220° C., e.g., 210° C. to 218° C., or e.g., 210° C. to 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 having 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 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., and an endothermic event having 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.

[0083] In some embodiments, the crystalline psilocybin polymorph A exhibits a water content of less than 0.5 w / w%, less than 0.4 w / w%, less than 0.3 w / w%, less than 0.2 w / w%, or less than 0.1 w / w%. The water content of the crystalline compound can be determined by known methods, for example, Karl Fischer titration. In some embodiments, the crystalline psilocybin polymorph A exhibits a weight loss of less than 0.5 w / w%, less than 0.4 w / w%, less than 0.3 w / w%, less than 0.2 w / w%, or less than 0.1 w / w% in a TGA thermogram at ambient temperatures, for example, between about 25° C. and 200° C. In some embodiments, the crystalline psilocybin polymorph A loses less than 2 wt%, less than 1 wt%, or less than 0.5 wt% in a loss on drying test, for example, a loss on drying test performed at 70° C.

[0084] In some embodiments, the crystalline psilocybin polymorph A is a high purity 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.

[0085] In some embodiments, crystalline psilocybin polymorph A is a white to off-white solid.

[0086] In some embodiments, the crystalline psilocybin polymorph A is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph A has greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A does not contain 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, crystalline psilocybin polymorph A has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0087] 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.

[0088] 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 thermograms shown in Figure 3A.

[0089] 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 greater than 2 hours.

[0090] In some embodiments, recrystallization of psilocybin involves controlled cooling to reduce 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.

[0091] In some embodiments, the stirring is performed by stirring at about 400-500 rpm, typically about 450 rpm.

[0092] 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, it is intended that this dissolution step solubilizes the psilocybin while minimizing the formation of hydrolysis products.

[0093] In some embodiments, the psilocybin solution is agitated to speed up solubilization and reduce the time the solution is at elevated temperatures, i.e., 80° C. or higher.

[0094] 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.

[0095] In some embodiments, the psilocybin of the crystalline psilocybin is isolated by vacuum filtration.

[0096] In some embodiments, the isolated crystals are vacuum dried at a temperature of at least 30° C., such as 30-50° C., or such as 40-50° C. In some embodiments, the isolated crystals are vacuum dried for at least 10 hours, such as 12-18 hours, or such as about 30 hours. In some embodiments, the isolated crystals are vacuum dried at a temperature of at least 30° C., such as 30-50° C., or 40-50° C., for at least 10 hours, such as 12-18 hours, or such as about 30 hours. In some embodiments, the isolated crystals are dried until the isolated crystals lose less than 2% by weight, such as less than 0.5% by weight, in a loss on drying test.

[0097] In some embodiments, the isolated crystals are washed several times in water and dried in vacuum at about 50° C. for at least 12 hours.

[0098] 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.

[0099] In contrast, crystals obtained without controlled cooling are much smaller in size (typically 5-50 microns) when viewed under a 10x microscope.

[0100] In some embodiments, there is provided psilocybin obtained by the crystallization methods described herein.

[0101] In some embodiments, pharmaceutical formulations are provided that include psilocybin polymorph A obtained by the crystallization methods described herein.

[0102] In some embodiments, the pre-crystallized produced psilocybin may be produced using one of the synthetic or biological methods, for example, by fermentation, or may be obtained by extraction from mushrooms. In some embodiments, the pre-crystallized produced psilocybin is produced according to all or a portion of the methods described in U.S. Application No. 2019 / 0119310 A1, which is incorporated herein by reference in its entirety.

[0103] Polymorph A' The present disclosure provides crystalline psilocybin in the form of polymorph A', characterized by one or more of the following: (a)(i) peaks 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 in an XRPD diffractogram; (b)(ii) peaks at 11.5, 12.0, and 14.5 °2θ ± 0.1 °2θ, but with the peak at 17.5 °2θ ± 0.1 °2θ being 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 in an XRPD diffractogram; (c)(iii) an XRPD diffractogram substantially as shown in FIG. 2B; or (d)(iv) 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 FIG. 3B.

[0104] In some embodiments, the crystalline psilocybin comprises crystalline psilocybin polymorph A'. Crystalline psilocybin polymorph A' exhibits peaks in an XRPD diffractogram at 11.5, 12.0, and 14.5°2θ±0.1°2θ, while a peak at 17.5°2θ±0.1°2θ is 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 FIG. 2B. An exemplary DSC thermogram for polymorph A' having an onset temperature of 205-220° C. is provided as FIG. 3B.

[0105] In some embodiments, psilocybin polymorph A' exhibits an 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, or equivalent peaks within about ±0.1 degrees 2θ, listed in Table B, with peaks at 17.5 degrees 2θ ±0.1 degrees 2θ being absent or substantially absent. [Table 2]

[0106] In some embodiments, crystalline psilocybin polymorph A' exhibits XRPD diffractogram peaks at 11.5, 12.0, and 14.5°2θ±0.1°2θ, with a peak at 17.5°2θ±0.1°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°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 polymorph A and is distinguished from polymorph A by the presence of a peak occurring at 10.1°2θ±0.1°2θ. In yet another embodiment, crystalline psilocybin polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in Figure 2B.

[0107] In some embodiments, crystalline psilocybin polymorph A' exhibits XRPD diffractogram peaks at 14.5 and 17.5°2θ±0.1°2θ, where 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.

[0108] In some embodiments, crystalline psilocybin polymorph A' exhibits XRPD diffractogram peaks at 10.1 and 14.5°2θ±0.1°2θ, where 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.

[0109] In some embodiments, the crystalline psilocybin polymorph A' is characterized by an endothermic event in a DSC thermogram having a first onset temperature of 145° C. to 165° C., e.g., 145° C. to 160° C., or e.g., 145° C. to 155° C., and a second onset temperature of 205° C. to 220° C., e.g., 210° C. to 220° C., e.g., 210° C. to 218° C., or e.g., 210° C. to 216° C. In some embodiments, the 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.

[0110] In some embodiments, the crystalline psilocybin polymorph A' exhibits a water content of less than 0.5 w / w%, less than 0.4 w / w%, less than 0.3 w / w%, less than 0.2 w / w%, or less than 0.1 w / w%. Methods for determining the water content of crystalline compounds are known, for example, Karl Fischer titration. In some embodiments, the crystalline psilocybin polymorph A' exhibits a weight loss of less than 0.5 w / w%, less than 0.4 w / w%, less than 0.3 w / w%, less than 0.2 w / w%, or less than 0.1 w / w% in a TGA thermogram at ambient temperatures, for example between 25°C and 200°C. In some embodiments, the crystalline psilocybin polymorph A' loses less than 2 wt%, less than 1 wt%, or less than 0.5 wt% in a loss on drying test. In some embodiments, the loss on drying test is performed at 70°C.

[0111] In some embodiments, the crystalline psilocybin polymorph A' is a highly pure 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'.

[0112] In some embodiments, crystalline psilocybin polymorph A' is a white to off-white solid.

[0113] 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 phosphate impurity as measured by P NMR or no psilocin impurity 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 levels of psilocin greater than 1 area%, or greater than 0.5 area%, as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has no phosphate impurity as measured by P NMR or no psilocin impurity as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has no psilocin impurity levels greater than 1 area%, or greater than 0.5 area%, as measured by HPLC. 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.

[0114] In some embodiments, the crystalline psilocybin polymorph A' is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph A' has greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A' has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' does not contain 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 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 ... 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.

[0115] 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.

[0116] Polymorph A (including its isostructural variant polymorph A') (Figures 2A and 2B) is distinct from polymorph B (Figure 2C), hydrate A (Figure 2D) and the ethanol solvate (Figure 2E; solvate A), and the relationships between some of the different forms are shown in Figure 4.

[0117] In some embodiments, the 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, the crystalline psilocybin polymorph A or polymorph A' has greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A 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 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 ... 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.

[0118] Heating of Form A or A' results in an endothermic event with an onset temperature of approximately 150 °C corresponding to a solid-solid transition of Form A or Form A' to Form B. Continued heating of the resulting solid, i.e., 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).

[0119] 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 an endothermic event in a DSC thermogram having a first onset temperature of 90° C.-100° C., a second onset temperature of 100° C.-120° C., and a third onset temperature of 210° C.-220° C. An exemplary DSC thermogram is provided as FIG. 2D.

[0120] 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 degrees 2θ. [Table 3]

[0121] 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.

[0122] In certain embodiments, crystalline psilocybin hydrate A is characterized by an endothermic event in a DSC thermogram having a first onset temperature of 85° C. to 105° C., e.g., 90° C. to 100° C., most preferably about 96° C., a second onset temperature of 100° C. to 120° C., e.g., 105° C. to 115° C., most preferably about 109° C., and a third onset temperature of 205° C. to 220° C., e.g., 210° C. to 220° C., e.g., 210° C. to 218° C., or 210° C. to 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 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 hydrate A exhibits an endothermic event in a DSC thermogram having 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 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., and an endothermic event having 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.

[0123] 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, for example, 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.

[0124] 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 has greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin 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 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 hydrate A has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin hydrate A has no impurity phosphate ... 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 hydrate A has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0125] In some embodiments, the crystalline psilocybin hydrate A is a high purity 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.

[0126] Polymorph B In some embodiments, the disclosure provides a crystalline form of psilocybin polymorph B. In some embodiments, the crystalline form of 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 FIG. 2C. In some embodiments, crystalline psilocybin polymorph B exhibits a single endothermic event in a DSC thermogram having an onset temperature of about 205 to about 220° C. An exemplary DSC thermogram of crystalline psilocybin polymorph B is provided as FIG. 3C.

[0127] In some embodiments, psilocybin polymorph 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 4]

[0128] 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.

[0129] 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.

[0130] In some embodiments, the crystalline psilocybin polymorph B exhibits a water content of less than 0.5 w / w%, less than 0.4 w / w%, less than 0.3 w / w%, less than 0.2 w / w%, or less than 0.1 w / w%. Methods for determining the water content of crystalline compounds are known, for example, Karl Fischer titration. In some embodiments, the crystalline psilocybin polymorph B exhibits a weight loss of less than 0.5 w / w%, less than 0.4 w / w%, less than 0.3 w / w%, less than 0.2 w / w%, or less than 0.1 w / w% in a TGA thermogram at ambient temperatures, for example between 25° C. and 200° C. In some embodiments, the crystalline psilocybin polymorph B loses less than 2 wt%, less than 1 wt%, or less than 0.5 wt% in a loss on drying test. In some embodiments, the loss on drying test is performed at 70° C.

[0131] In some embodiments, the crystalline psilocybin polymorph B is a highly pure crystalline form of polymorph B, e.g., the psilocybin comprises at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.5% by weight of polymorph B.

[0132] 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 has greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 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.

[0133] 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 5]

[0134] In some embodiments, the psilocybin fits the spectrum as shown in Table E and illustrated in the spectra of Figures 5-8. [Table 6]

[0135] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0136] 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.

[0137] In some embodiments, the disclosure provides crystalline psilocybin in the form of Polymorph A or Polymorph A' for use in treating a subject in need of treatment. Alternatively, independently, the crystalline psilocybin may be in the form of Hydrate A or Polymorph B.

[0138] In some embodiments, the disclosure provides crystalline psilocybin polymorph A or polymorph A' for use in treating a subject in need of treatment. In some embodiments, the disclosure provides crystalline psilocybin polymorph A or polymorph A' for use in treating a subject in need of treatment. In some embodiments, the disclosure provides crystalline psilocybin polymorph A for use in treating a subject in need of treatment. In some embodiments, the disclosure provides crystalline psilocybin polymorph A' for use in treating a subject in need of treatment. In some embodiments, the disclosure provides high purity crystalline psilocybin polymorph A for use in treating a subject in need of treatment. In some embodiments, the disclosure provides high purity crystalline psilocybin polymorph A' for use in treating a subject in need of treatment.

[0139] Pharmaceutical Compositions and Formulations In some embodiments, the present disclosure provides pharmaceutical compositions comprising crystalline psilocybin and one or more pharma- ceutically acceptable carriers or excipients.

[0140] In some embodiments, the disclosure provides a pharmaceutical formulation comprising high purity psilocybin and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising crystalline psilocybin polymorph A and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising crystalline psilocybin polymorph A' and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising high purity crystalline psilocybin, polymorph A or polymorph A' and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising high purity crystalline psilocybin polymorph A and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising high purity crystalline psilocybin polymorph A' and one or more pharma- ceutically acceptable carriers or excipients.

[0141] In some embodiments, the pharmaceutical compositions or formulations described herein comprise psilocybin, pregelatinized starch, and sodium stearyl fumarate. In some embodiments, the pharmaceutical compositions or formulations comprise about 1% to 10% by weight of psilocybin. In some embodiments, the pharmaceutical compositions or formulations comprise about 85% to 99% by weight of pregelatinized starch. In some embodiments, the pharmaceutical compositions or formulations comprise about 0.5% to 2% by weight of sodium stearyl fumarate.

[0142] In embodiments, the pharmaceutical compositions or formulations described herein include (a) about 1% to 10% by weight psilocybin; (b) about 85% to 99% by weight pregelatinized starch; and (c) about 0.5% to 2% by weight sodium stearyl fumarate. In some embodiments, the pharmaceutical compositions or formulations are one or more of the pharmaceutical compositions or formulations described in WIPO Patent Application Publication Nos. 2022 / 207746 and 2019 / 073379, the contents of which are incorporated herein by reference in their entireties.

[0143] 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.

[0144] 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 disintegrant by weight, less than 3% disintegrant by weight, and more than 0.001% disintegrant by weight, about 2.5% or less disintegrant by weight, 2% or less disintegrant by weight, 1.5% or less disintegrant by weight, 1% or less disintegrant by weight, 0.7% or less disintegrant by weight, 0.5% or less disintegrant by weight, or 0.3% or less disintegrant by weight.

[0145] 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 or less, 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.

[0146] In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, 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, 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, the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0147] In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, 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, the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0148] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, 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, 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 25 mg of psilocybin, SMCC 50, and SMCC 90, the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0149] 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.

[0150] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0151] In some embodiments, there is provided crystalline psilocybin, specifically, but not essentially, in the form of Polymorph A or Polymorph A', for use in treating a central nervous system disorder.

[0152] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0153] 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 the subject substantially simultaneously. In some embodiments, the subject may be administered the entire therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be divided among multiple tablets or capsules. For example, for a 25 mg dose, the subject may be administered five tablets or capsules, each containing 25 mg of psilocybin. Alternatively, for a 10 mg dose, the subject may be administered two tablets or capsules, each containing 5 mg of psilocybin.

[0154] 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.

[0155] In some embodiments, the silicided microcrystalline filler may include a first filler having a particle size range of about 45-80 microns in an amount 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 up to 70%, up to 80%, up to 85% or more by weight of the filler.

[0156] 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 SMCC 50 and SMCC 90. 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 weight percent. 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.

[0157] 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.

[0158] In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, 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, 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, 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, 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, the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0160] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, 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, 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 25 mg of psilocybin, SMCC 50, and SMCC 90, the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0161] 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.

[0162] In some embodiments, the oral dosage form contains 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 contains 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.

[0163] In some embodiments, the tablet or capsule comprises one or more excipients. Non-limiting exemplary excipients include, but are not limited to, microcrystalline cellulose and starch, including silicified microcrystalline cellulose.

[0164] It should be noted that the formulations may contain psilocybin in any form, not just the polymorphic forms disclosed herein.

[0165] As used herein, oral doses of psilocybin are classified as "very low doses" (about 0.045 mg / kg or less), "low doses" (about 0.115 to about 0.125 mg / kg), "medium 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.

[0166] In some embodiments, the formulated dose of psilocybin comprises from about 0.01 mg / kg to about 1 mg / kg, in some embodiments, a human dose (for an adult weighing 60-80 kg) comprises from about 0.60 mg to about 80 mg.

[0167] In some embodiments, the formulated dose comprises about 2 to about 50 mg of crystalline psilocybin. In some embodiments, the formulated dose comprises 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 comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin.

[0168] In some embodiments, the formulated dose comprises about 2 mg to about 50 mg of crystalline psilocybin polymorph A or polymorph A' or mixtures thereof. In some embodiments, the formulated dose comprises 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 mixtures thereof. In some embodiments, the formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin polymorph A or polymorph A' or mixtures thereof. In some embodiments, the formulated dose comprises about 5 mg of crystalline psilocybin polymorph A or polymorph A' or mixtures thereof.

[0169] 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.

[0170] 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'.

[0171] 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.

[0172] In some embodiments, the formulated dose comprises about 2 mg to about 50 mg of crystalline psilocybin hydrate A. 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 hydrate A. In some embodiments, the formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin hydrate A.

[0173] 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.

[0174] 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.

[0175] In some embodiments, an adult oral dose comprises 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 comprises about 25 mg of crystalline psilocybin. In some embodiments, the crystalline psilocybin is in the form of polymorph A.

[0176] In some embodiments, a "microdose" of psilocybin is administered to a subject. A microdose may include, 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 and continuous regime of daily dosing, every other day dosing, or weekly dosing. Such dosing may be absent of psychological support.

[0177] 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.

[0178] 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 a day. In some embodiments, psilocybin is administered at least once a week, or at least twice a week. In some embodiments, psilocybin is administered at least once a month, or at least twice a 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.

[0179] In some embodiments, a first dose and a second dose of psilocybin are administered to the 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 1 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 1 mg.

[0180] 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.

[0181] 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 airway 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 the subject.

[0182] Treatment method It will be understood by those of skill in the art that methods of treatment comprising administering psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and / or a prodrug of a metabolite of psilocybin for the treatment of one or more of the indications described herein also include the use of psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and / or a prodrug of a metabolite of psilocybin 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 prodrug of psilocybin, a metabolite of psilocybin, and / or a prodrug of a metabolite of psilocybin for the treatment of one or more of the indications described herein.

[0183] 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.

[0184] In some embodiments, the method for treating a subject in need of treatment includes 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 (iii) having the subject participate in one or more post-administration psychological support session(s).

[0185] 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 effects of the drug is referred to herein as the early phase of the psilocybin session.

[0186] In some embodiments, the subject experiences a peak effect of psilocybin about 1.5 hours to about 3.5 hours after administration of psilocybin. The period characterized by the peak psilocybin experience is referred to herein as the peak phase of the psilocybin session.

[0187] In some embodiments, the effects of psilocybin may substantially wear off between about 4 hours and about 6 hours after administration, this period being referred to as the late phase of a psilocybin session.

[0188] 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 may be generally defined as a breakdown of the usual relationships between self and others, whereby the subject may feel a sense of oneness and increased connectedness to the surrounding environment and / or the world at large.

[0189] 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.

[0190] Factors that may affect the subjective experience of psilocybin include, for example, (i) the dose, (ii) the participant's mood prior to 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.

[0191] 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 psilocybin administration. In some embodiments, the pre-administration psychological support session may occur about two weeks prior to psilocybin administration. In some embodiments, the pre-administration psychological support session may occur about one week prior to psilocybin administration. In some embodiments, the pre-administration psychological support session may occur about three days prior to psilocybin administration. In some embodiments, the pre-administration psychological support session may occur about one day prior to psilocybin administration. In some embodiments, the pre-administration psychological support session may occur prior to administration on the same day as psilocybin administration.

[0192] 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 additionally participate in a pre-administration psychological support session the day before the psilocybin session.

[0193] The pre-administration psychological support session may be an individual session, where the subject meets with the therapist one-on-one. In some embodiments, the psychological support session may be a group session, where two or more subjects meet with one therapist, or two or more therapists. In some embodiments, one or more of the subject's family or friends may attend the pre-administration psychological support session(s).

[0194] 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 preparing the subject for the discussion of possible psilocybin effects and / or dosing session by implementing relevant therapeutic techniques to reduce avoidance and anxiety, eliciting appropriate therapeutic 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.

[0195] In some embodiments, breathing exercises aimed at promoting calmness and / or relieving anxiety may be shown 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 for a moment, and then breathe out for a count of eight. In some embodiments, the therapist and subject may discuss the most beneficial way 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.

[0196] 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.

[0197] In some embodiments, the therapist is trained to counsel the subject before, during, and / or after the psilocybin session. In some embodiments, the therapist is trained in mental health. 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.

[0198] Psychological support during psilocybin sessions During the treatment session, the subject may be supervised by one or more trained therapists. The therapist who supervises the subject during the psilocybin session may be the same therapist as the subject's pre-administration psychological support session(s) or may be a different therapist. The therapist(s) may provide psychological support to the subject as needed. As used herein, the term "psychological support" refers to any measure(s) taken by the therapist during the subject's psilocybin session to ensure the subject's safety and maximize the clinical effectiveness of the psilocybin session. For example, psychological support may be undertaken 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 set in preparation, (3) maintain attention and awareness of the participant's current experience, thus allowing exposure and processing of tough emotional states and personal memories, and / or (4) generate insights and solutions for the resolution of tough personal situations, conflicts, and traumatic experiences. In some embodiments, the assistance may be in the form of touch therapy, verbal reassurance, guided imagery, and / or relaxation or breathing exercises. In some embodiments, the assistance may include reminders, encouragement, or active guidance. Typically, only one technique is applied at a time to allow for minimal intervention and interference with the subject's intrinsic processes.

[0199] In some embodiments, the therapist's primary therapeutic objectives during a psilocybin session are (i) to minimize extreme anxiety, and (ii) to provide 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 a psilocybin session. "Presence" refers to being fully available and with the subject at all stages of the psilocybin session, and exercising calm at all times. "Curiosity" refers to interest and willingness to understand the subject's experience without assumptions. "Patience" means that the therapist facilitates the participant, taking the time necessary to explore the experience, without controlling the natural urge to assist or direct the experience. "Openness" refers to the therapist's ability to remain cognitively and experientially open, including the ability to know how the subject's mind will uniquely direct the unfolding content of the session. This includes welcoming all emotions and expressions that may arise.

[0200] In some embodiments, psychological support may include inquisitive questioning, in which brief, yet detailed questions are used to help the subject shift and maintain attention to different levels of cognition and emotion ("How does that make you feel?"). Because of its applicability across a wide range of mental states and in a variety of 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.

[0201] In some embodiments, the level of psychological support varies during different stages of the subject's psilocybin experience (e.g., early, early, peak, and late). In some embodiments, the type of psychological support varies during different stages of the subject's psilocybin experience (e.g., early, 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 responses, in some embodiments, therapists pay particular attention to such conditions.

[0202] In some embodiments, a subject may experience a compromised sense of self during the subject's psilocybin experience. In some embodiments, this experience is interpreted from a psychoanalytic perspective as a collapse 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 consciousness that defines normal waking consciousness, resulting in a loss of a sense of "self", and instead only an undivided background consciousness that is often characterized by a sense of integration or "oneness" that goes beyond sensory or cognitive understanding. 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 an acentered, 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 consciousness that defines normal waking consciousness, resulting in a loss of a sense of "self". In some embodiments, an integrative experience is one that is characterized by a sense of unity or "oneness" that goes beyond sensory or cognitive understanding.

[0203] In the initial and early stages of a psilocybin session, psychological support may be used to reduce severe and / or long-term anxiety. Anxiety before or during the onset of psilocybin effects is not uncommon, and therapists may be specially trained to recognize and actively manage subjects 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 feelings of anxiety without providing an interpretation of the sensory disturbances or directing the subject toward specific images or memories, other than encouraging the subject to relax and open up to the emergent experience. 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 the sounds around them, or the sensations on their skin, when touching the bed / sofa, the ground, or other objects.

[0204] In the initial and early stages of the 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 intention of the treatment session. For example, the therapist may ask the subject, "What do you feel when you feel better or recovered?" or any number of similar questions. Such a reminder provides an implicit orientation of the subjective experience during the psilocybin session, before or at 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 collect 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., to allow the participant to be open and curious about whatever arises, as well as to encounter thoughts and feelings that were previously unknown to the participant. In some embodiments, the therapist emphasizes that this process essentially requires a willing passivity to, and no minding of, the psychedelic experience.

[0205] 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 cause anxiety. In some embodiments, the therapist may perform a reassuring "arm holding," in which, 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 at this stage. This training may have been previously conducted in a pre-administration psychological support session.

[0206] 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.

[0207] 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 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: initial, early, peak, and late phases. In some embodiments, listening to music helps the subject focus on their internal experience.

[0208] 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 giving advice. Once the participant feels comfortable, the therapist can encourage them to revisit introspection.

[0209] During the peak and later stages of the psilocybin session, the therapist can encourage the subject to confront and explore their experiences, including difficult ones. The therapist can guide the subject to participate in self-directed inquiry and experiential processing to develop different perspectives on their personal challenges and conflicts and generate unique solutions. Such self-generated insights provide the subject with self-confidence as well as emotional resolution.

[0210] As used herein, the term "self-directed inquiry" refers to paying attention to inner states. The subject is encouraged to be curious about moment-to-moment present experience, including foreground and background thoughts, feelings, and bodily sensations. During the preparation and integration phase, this inquiry may mean asking specific and detailed questions that help to pay attention to inner states. However, during the drug action period, inquiry may simply mean being open to inner experiences.

[0211] As used herein, "experiential processing" refers to the ability of a participant to maintain full attention to an experience that is recognized through self-directed enquiry. 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.

[0212] In some embodiments, the therapist uses transdiagnostic therapy. In some embodiments, the transdiagnostic therapy is Method of Levels (MOL) therapy. In still further embodiments, MOL therapy includes self-directed inquiry and experiential processing. Typically, MOL uses brief but detailed and inquisitive questions to help the subject shift and maintain attention to 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: (1) Self-Directed Inquiry - Attention to Inner States. Participants are encouraged to be curious about their present-moment experience, including foreground and background thoughts, feelings, and bodily sensations, and while in the preparation and integration phases, such inquiry can mean asking specific and detailed questions that help to direct attention to inner states, in some embodiments, during periods of drug action, inquiry can refer to an attitude of openness to inner experiences. (2) Experiential Processing - refers to the ability to sustain a sustained focus on an experience and maintain full attention on experiences that the participant brings to consciousness through self-directed inquiry. This includes the willingness and ability to stay with and / or move through unpleasant or difficult thoughts, feelings, sensations, or emotions until the discomfort is reduced or resolved.

[0213] In some embodiments, the psychological support includes 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.

[0214] Occasionally, subjects seek distraction while avoiding new experiences or trying to regain cognitive control over their abnormal state of mind. Such distraction can take different forms. For example, the subject may be premature in talking or detailing 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 inner 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 stay focused on the current experience, especially if the participant engages the therapist in the conversation. In another example, the subject may ask to go to the bathroom or get a drink of water. The sudden and urgent nature of such requests may suggest that they are truly trying to avoid the new material. In such cases, the therapist can encourage the subject to dwell on the experience by simply redirecting attention. For example, the therapist may 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.

[0215] In some embodiments, spontaneous movement such as rocking, stretching, or dancing while engaged in an experience is accepted and often encouraged, unless the movement is not seen as a way to distract from the experience. In some embodiments, if the subject continues to move a lot, they may be provided with cues to periodically return to a lying position and actively focus inward.

[0216] The therapist need not understand, endorse, or have an opinion on the nature or content of the subject's experiences, but the therapist can validate them and communicate openness to the subject's own take on them without denying or pathologizing any experience based on its aberrant 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 acknowledging the courage to be open to the experience and the possibility that any experience may serve the intent of the session.

[0217] In some embodiments, the therapist provides psychological support for approximately 4-8 hours immediately following 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.

[0218] 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 can be used to aid 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").

[0219] Post-treatment psychological support session In some embodiments, the subject 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 first verbalizing, reflecting on, and openly discussing with the therapist any experiences from the psilocybin session. Successful integration of the psilocybin experience involves responding to emotional changes and translating the experience into new insights, perspectives, and new behaviors that can be used for the subject's quality of life thereafter. New perspectives can then impact the participant's current knowledge or values, leading to new ways of relating to cognition, emotions, behavior, and physical experiences.

[0220] In some embodiments, the goals and support methods used by the therapist throughout the integrated session should remain consistent regardless of the intensity or content of the subjective experiences explored by the subject. Nonetheless, the support methods used by the therapist should accommodate all experiences the subject may have encountered.

[0221] The integration process should not be limited to sessions with the therapist, but is one that will likely continue to unfold 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 all experiences, but to empower participants by building their capacity to safely and experientially process information. This allows patients to continue self-directed integration outside of study visits.

[0222] In some embodiments, the subject participates in at least one psychological support session after administration of psilocybin ("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.

[0223] In some embodiments, a subject may participate in 1, 2, 3, 4, 5, 6, 7, or 8 post-administration psychological support sessions. In some embodiments, a subject may participate in at least 2, or at least 3 post-administration psychological support sessions.

[0224] The post-administration psychological support session may be an individual session, where the subject meets with the therapist one-on-one. In some embodiments, the psychological support session may be a group session, where two or more subjects meet 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).

[0225] In some embodiments, the post-administration psychological support session may focus on the integration of the psilocybin experience. Integration may include processing the psychedelic experience in a therapeutic context. Integration may include psychological and somatic processing of the experience, as well as successful assimilation of the insights into the subject's life for the purposes of growth, healing, and / or well-being. In the integration session, the subject may be encouraged to discuss and reflect on their experience during the psilocybin session. In some embodiments, integration may include external expressions of the psilocybin experience, such as word choice, tone of voice, gestures, and / or specific physical activities (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.

[0226] In some embodiments, the subject may be encouraged to reflect on both the thoughts and feelings the subject experienced during the psilocybin session, and to express those thoughts and feelings into a concrete form that can serve as a tool to remember those lessons and continue to integrate them 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 accomplished, for example, by discussing it first with the therapist, and perhaps later with family, friends, and support circles. Integration helps to accommodate changes in emotional state as new insights are generated and integrated. When further explored through attention oscillating between foreground and background thoughts and feelings, 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.

[0227] In the case of low-intensity experiences, the integration process may focus on mental contents that emerged during periods of relaxation and reflection, including reactions to what may have been unremarkable experiences such as feelings of disappointment, anger, or relief.

[0228] 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.

[0229] In some embodiments, the pre-administration therapy session is performed remotely. In some embodiments, the post-administration therapy session (e.g., the integration session) is performed remotely.

[0230] In some embodiments, the psychological support is provided remotely during the subject's psilocybin session. For example, in some embodiments, the subject takes psilocybin at home and the therapist provides the 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 the therapist provides the psychological support to the subject, and the therapist provides the psychological support via voice call, video call, text, email, etc. for at least 4-8 hours after the subject has taken the drug.

[0231] 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. The digital or electronic system enables subjects to qualify, pre-qualify, or enroll in a psilocybin-based clinical trial or a psilocybin-based psychological support session. The digital or electronic system is configured to help the therapist and / or physician manage the subject and interact with the patient. For example, the electronic system may allow the therapist to share documents with the subject, leave notes about the session, 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 enable 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 to a therapist and / or physician. For example, the digital or electronic system may include information about psilocybin, treatment protocols, etc. A digital or electronic system is set up to enable a therapist to provide psychological support to a subject during a psilocybin session. For example, the system 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.

[0232] 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 at the same time or contemporaneously.

[0233] In some embodiments, the psychological support sessions may be pre-recorded (e.g., audio or video recorded) and provided to the subject for use at the subject's convenience via a digital or electronic system.

[0234] Management facility, "Set and Setting" As used herein, the term "set and setting" refers to the subject's perspective (the "set") as well as the physical and social environment (the "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.

[0235] In some embodiments, psilocybin is administered by in a facility specifically designed for psilocybin administration. Administration of psilocybin to a subject in a facility where the subject feels safe and comfortable can help ease the subject's anxiety and promote maximum clinical benefit. Psilocybin may be administered to a subject, for example, in the subject's home or in a clinical facility.

[0236] 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 that includes soft furniture (e.g., plush sofas, chairs, or pillows) and / or plants. In some embodiments, the room can be decorated using muted 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 includes an audio system, e.g., a high-definition audio system. In some embodiments, the audio system can allow for simultaneous ambient and earphone listening. In some embodiments, the subject can bring meaningful pictures or objects into the administration room.

[0237] In some embodiments, the room comprises a couch. In some embodiments, the room comprises a bed. In some embodiments, the room comprises more than one couch or bed, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 couches or beds. In some embodiments, the subject sits or lies on the couch or bed for about 4-8 hours, or a significant portion thereof, immediately following administration of psilocybin. In some embodiments, the subject listens to music for about 4-8 hours, or a significant portion thereof, immediately following administration of psilocybin. In some embodiments, the subject wears an eye mask for about 4-8 hours, or a significant portion thereof, immediately following administration of psilocybin. In some embodiments, the subject is provided with a weighted blanket.

[0238] In some embodiments, each subject is supervised by one therapist during psilocybin session.In some embodiments, each subject is supervised by more than one therapist during 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 psilocybin session.For example, one therapist can supervise two, three, four, five, six, seven, eight, nine, or ten subjects.

[0239] Embodiments of the present disclosure include the use of additional tools and / or techniques(s) 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.

[0240] Some embodiments may be used 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 pre-treatment, during-treatment, and / or post-treatment patient monitoring and management. Digital biomarkers may include, by way of non-limiting examples, number and / or duration of calls / emails / texts, word length in text communication, gestures used (taps, swipes, or other), information derived from a gyroscope, such as phone orientation, phone acceleration, keystroke patterns, information derived from location from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media usage, sleep patterns, specific words or emojis used or not used, and / or the like. For example, in one embodiment, the digital health product may be utilized to determine medication dosage and / or frequency, indications of need for re-dosing, re-dosing amounts, alerts or warnings, as compliance tracking.

[0241] In some embodiments, the method of treatment can include providing a clearance time for the subject or patient, such that one or more drugs are not present or are substantially removed from the subject's / patient's system. For example, the method of treatment can be configured such that, at the time of administration, the subject is not taking other serotonin drugs, such as selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors and / or antipsychotics. In some embodiments, the method of treatment 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, levomefollic acid, for example, prior to, immediately prior to, and / or concurrently with receiving psilocybin.

[0242] In some embodiments, the methods include treatment where the subject has not been taking one or more medications, particularly, has not been taking 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.

[0243] 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 relatively large single dose or multiple doses (given days to weeks apart), where the relatively large single dose or multiple doses are 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.

[0244] 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.

[0245] In some embodiments, digital biomarkers can be identified from patterns in smartphone usage, 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.

[0246] 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 communication, gestures used (taps, swipes, or other), information derived from a gyroscope, such as phone orientation, phone acceleration, keystroke patterns, information derived from location from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media usage, sleep patterns, specific words or emojis used or not, 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, 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.

[0247] According to a further aspect of the present disclosure, there is provided a method of evaluating a subject before, during, and / or after treatment of a central nervous system disorder to determine whether to provide psilocybin treatment or further psilocybin treatment, comprising monitoring one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and emotional valence, and determining treatment based on the outcome. The method may further include administering psilocybin for the first or subsequent time.

[0248] In some embodiments, biomarkers are identified from patterns in smartphone usage, such as swipes, taps, and other touchscreen activity, and scientifically validated to provide measures of cognition and mood. For example, in some examples, patterns may be identified using one or more of the following: number and / or duration of calls / emails / texts, word length in text communication, gestures used (taps, swipes, or other), information derived from the gyroscope, such as phone orientation, phone acceleration, keystroke patterns, information derived from location from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media usage, sleep patterns, specific words or emojis used or not used, and / or the like.

[0249] 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 or subsequent time.

[0250] In some embodiments, the disclosure provides for treating two or more subjects, the method including administering a therapeutically effective dose of psilocybin to each subject at the same time 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), and each subject is aware of the other subject receiving treatment. In some embodiments, the subjects are in the same room. In some embodiments, the subjects are in different rooms.

[0251] In some embodiments, the disclosure provides a method of treating a subject, 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 levels are kept relatively low or adjusted. In some embodiments, darkened glasses or eye shades are provided. In some embodiments, the room lighting is adjusted in 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.

[0252] 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 medications, such as antidepressants or antiepileptic drugs. In some embodiments, the subject is attempting to reduce or eliminate the use of medications before becoming pregnant, undergoing surgery or other medical procedures, or before starting the use of a different medication.

[0253] The subject may 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 less than about 18 years old. In some embodiments, the subject is at least about 18 years old. In some embodiments, the subject is about 5-10 years old, about 10-15 years old, about 15-20 years old, about 20-25 years old, about 25-30 years old, about 30-35 years old, about 35-40 years old, about 40-45 years old, about 45-50 years old, about 50-55 years old, about 55-60 years old, about 60-65 years old, about 65-70 years old, about 70-75 years old, about 75-80 years old, about 85-90 years old, about 90-95 years old, or about 95-100 years old.

[0254] 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).

[0255] 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 of time, such as at least 6 months, at least 1 year, at least 3 years, at least 5 years, or at least 10 years.

[0256] 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 limited survival time, such as less than 1 year, less than 6 months, or less than 3 months.

[0257] 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).

[0258] 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.

[0259] 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.

[0260] 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.

[0261] Diseases, Disorders, and / or Conditions to be Treated Provided herein are methods of treating a subject in need of treatment, comprising administering to the subject a therapeutically effective dose of psilocybin.

[0262] The methods described herein can be used to treat diseases, disorders, and conditions, including certain psychiatric and neurological aspects of a variety of diseases, disorders, or conditions.

[0263] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method comprising administering to the subject a therapeutically effective dose of psilocybin or an active metabolite thereof, wherein the subject is suffering from or has a condition, such as major 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 obsessive-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 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, or kleptomania.

[0264] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method comprising administering to the subject a therapeutically effective dose of psilocybin, the subject having 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), speech disorder, speech production disorder (voice disorder), childhood onset dysphagia (stuttering), social (pragmatic) communication disorder, Tourette's disorder, persistent (chronic) motor or vocal tic disorder, amnesic disorder due to a known physiological condition (possibly in an ECT shock resistant subject), transient ischemic attack, cerebral infarction, cerebral hemorrhage, progressive multinuclear ophthalmoplegia, or retrograde amnesia.

[0265] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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.

[0266] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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: attention-deficit / hyperactivity disorder, other specified attention-deficit / hyperactivity disorder, or attention-deficit / hyperactivity disorder not otherwise specified.

[0267] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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, delusional disorder, schizophrenia, or schizoaffective disorder.

[0268] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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.

[0269] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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: schizophrenic personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, or obsessive-compulsive personality disorder.

[0270] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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: Female Sexual Interest / Arousal Disorder, Male Hypoactive Sexual Desire Disorder, and Excessive Sexual Drive.

[0271] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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.

[0272] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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: age-related hearing loss or tinnitus.

[0273] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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-Barre syndrome, a demyelinating disease of the central nervous system, or chronic inflammatory demyelinating polyneuropathy.

[0274] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, 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.

[0275] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method 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-harm 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).

[0276] In some embodiments, the disclosure provides a method of treating a subject, the method comprising administering to the subject a therapeutically effective dose of psilocybin, where 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.

[0277] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has treatment-resistant depression (TRD).

[0278] In some embodiments, the disclosure provides a method of treating a subject in need of treatment, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has major depressive disorder (MDD).

[0279] Prior and concomitant therapy In some embodiments, the method of treatment comprising administering psilocybin to a subject in need of treatment 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 concentration of magnesium is about 1.5 to about 2.5 mEq / L. In some embodiments, if the subject's blood concentration of magnesium is less than about 1.5 to about 2.5 mEq / L, psilocybin is not administered to the subject.

[0280] In some embodiments, the method of treatment comprising administering psilocybin to a subject in need of treatment 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, for example, 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 the 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 risk of abuse and / or improve efficacy. In some embodiments, the niacin is administered to the subject on the same day as the psilocybin, hi some embodiments, the niacin is administered to the subject immediately prior to, simultaneously with, or immediately after administration of the psilocybin.

[0281] 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 anxiolytics, such as SSRIs, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or serotonin norepinephrine reuptake inhibitors (SNRIs).

[0282] In some embodiments, psilocybin is administered to a subject in combination with an SSRI. In some embodiments, psilocybin is administered to a subject in combination with escitalopram, sertraline, fluoxetine, vilazodone, paroxetine, or citalopram. In some embodiments, psilocybin is administered to a subject in combination with escitalopram, sertraline, fluoxetine, paroxetine, citalopram, vilazodone, or vortioxetine.

[0283] In some embodiments, about 25 mg of psilocybin is administered to a subject in combination with an SSRI. In some embodiments, about 25 mg of psilocybin is administered to a subject in combination with escitalopram, sertraline, fluoxetine, vilazodone, paroxetine, or citalopram. In some embodiments, about 25 mg of psilocybin is administered to a subject in combination with escitalopram, sertraline, fluoxetine, paroxetine, citalopram, vilazodone, or vortioxetine.

[0284] In some embodiments, the disclosure provides a method of reducing anxiety in a subject undergoing treatment with psilocybin, the method comprising administering to the subject i) psilocybin or a precursor or derivative thereof, and ii) one or more benzodiazepines.

[0285] 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 to a subject prior to administration of psilocybin or a precursor or derivative thereof, for example, 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 psilocybin or a precursor or derivative thereof. In some embodiments, the one or more benzodiazepines are administered to the subject after administration of psilocybin or a precursor or derivative thereof, for example, 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.

[0286] In some embodiments, the one or more benzodiazepines are administered at a lower dose 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, the one or more benzodiazepines are administered at a dose approximately equal to that typically used to treat anxiety. In some embodiments, the one or more benzodiazepines are administered at a higher dose than that typically used to treat anxiety, such as about 125%, 150%, 175%, 200%, 250%, or 300% of the typical dose. In some embodiments, the one or more benzodiazepines are administered orally to the subject.

[0287] In some embodiments, the benzodiazepines are adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, fluralprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam. , flunitrazolam, 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.

[0288] In certain embodiments, the patient is administered psilocybin, or a precursor or derivative thereof, as described herein, in combination with one or more 5-HT 2A In some embodiments, the patient is administered psilocybin or a precursor or derivative thereof, and one or more 5-HT 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 administration of psilocybin. 2AIn some embodiments, the patient is administered a specific antagonist and / or inverse agonist of one or more 5-HT agonists after psilocybin administration, such as, but not limited to, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after psilocybin administration. 2A Specific antagonists and / or inverse agonists are administered.

[0289] In certain embodiments, one or more 5-HT 2A The specific antagonists and / or inverse agonists are administered at doses lower than those typically used, e.g., about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 75% of the typical dose. 2A Specific antagonists and / or inverse agonists are administered in doses that are equivalent to those typically used. 2A Specific antagonists and / or inverse agonists are administered at dosages higher than those typically used, for example, about 125%, about 150%, about 175%, about 200%, about 250%, or about 300% of the typical dosage.

[0290] 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, setoperone, chlorprothixene, cinaserine, 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).

[0291] Preferred 5-HT 2A Inverse agonists include, but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and vorinaserin.

[0292] In certain embodiments, 5-HT 2A The antagonist is selected from the compounds of Table I. [Table 7]

[0293] In some embodiments, the disclosure provides a method of 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.

[0294] 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).

[0295] In some embodiments, at least one symptom of the disease, disorder, or condition described herein is alleviated within 24 hours of administration of psilocybin. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated within 1 week of administration. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated within 1 month of administration. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated within 6 months of administration. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated within 12 months of administration.

[0296] 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 twelve months after administration.

[0297] In some embodiments, prior to administration of psilocybin, the subject is not administered other treatments for treating the disease, disorder, or condition, hi some embodiments, after administration of psilocybin, the subject is not administered other treatments for treating the disease, disorder, or condition.

[0298] Safety and efficacy of psilocybin The present disclosure also relates to the safety and efficacy of the use of 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.

[0299] In some embodiments, a spatial working memory (SWM) test is utilized to evaluate 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. To determine whether a box contains a token, it is searched by touching it. 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 obtained a token. Subjects are explicitly told that this is the case, and that if they revisit a box in which a token was found, they have committed a "between error," which is the usual primary measure of this test. If a subject revisits a box in the same search, it is scored as a "within" error. Many subjects employ a search strategy that systematically searches an 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 dorsal frontal cortex. Similarly, in neuroimaging studies of healthy volunteers, performance on SWM has been associated with activation of the dorsal and ventral prefrontal cortex. The test takes approximately 4 min to complete.

[0300] In some embodiments, the efficacy of psilocybin is assessed using a spatial working memory between errors (SWMBE) score. In some embodiments, after treatment with the methods of the present disclosure, the subject's SWMBE score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0301] In some embodiments, the efficacy of psilocybin is assessed using a spatial working memory strategy (SWMS) score. In some embodiments, after treatment with the methods of the present disclosure, the subject's SWMS score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0302] In some embodiments, the Rapid Visual Processing (RVP) test is utilized to evaluate 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 must monitor a stream of 2-9 digits for a specific sequence (e.g., 3-5-7) and confirm detection of the sequence by touching an on-screen response button as soon as possible after the presentation of the third digit. The digits are presented pseudo 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 then a 7. To successfully complete the task, subjects must continue to pay attention to the white box in which the digits are displayed. Performance on this task is measured by the speed of response to the presentation of the final digit of the target, as well as the subject's ability to detect the specific sequence. The 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 is increased by about 5% to about 300%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 100%, about 15 ... %, 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.

[0303] In some embodiments, the paired-associate learning (PAL) test is utilized to evaluate the safety and / or efficacy of psilocybin. The PAL task is a measure of visual spatial memory, where subjects are required to remember where a visual stimulus is located. Boxes are displayed on the screen and "opened" in a random order. One or more of them contain a pattern. The patterns are then displayed at once in the center of the screen, and the subject must select the box in which the pattern was originally located. If the subject makes a mistake, the boxes are opened again in sequence to remind the subject of the location of the pattern. A higher level of difficulty 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. The success of 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 (adjustment) (PALTEA) score is used to evaluate 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.

[0304] In some embodiments, the efficacy and / or safety of psilocybin is evaluated using the Cognitive Flexibility Panel Test.

[0305] In some embodiments, the Emotion Recognition Task (ERT) test is utilized to evaluate 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 of facial expression. In some embodiments, the ERT is administered according to the following protocol: The subject is shown, one at a time, on a screen, computer-generated images derived from the facial features of real individuals that show a certain emotion. Each face is displayed for 200 milliseconds, then immediately obscured, and the subject must choose which face is displayed from six options (happy, sad, angry, fear, surprise, disgust). The ERT Percentage Correct (ERTPC) of correct responses (emotion selections) made by the subject is evaluated. 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 about 100% higher than 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.

[0306] In some embodiments, the Inner-Outer Dimension Set-Shifting (IED) test is used to assess the safety and / or efficacy of psilocybin. The IED is composed of four 7-item subscales, each tapping a separate aspect of the global concept "empathy". In some embodiments, the Inner-Outer Dimension Set-Shifting Total Errors (IEDYERT) score is used to assess the efficacy of psilocybin. In some embodiments, after treatment with the methods of the present disclosure, the 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 before treatment.

[0307] In some embodiments, the Cambridge Test One Touch Stocking (OTS) is used to evaluate 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. The test takes about 10 minutes to perform. The OTS test reports a One Touch Stocking of First Choice Solved Cambridge Problems (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 is improved by about 5% to about 300%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 100%, about 15 ... 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.

[0308] In some embodiments, verbal fluency is used to evaluate the safety and / or efficacy of psilocybin. In the verbal fluency test, subjects are asked to name as many examples of different categories (e.g., "animals") as possible in one minute, following certain 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 indicator of this test is the total number of acceptable words produced. In some embodiments, after treatment with psilocybin, subjects' verbal fluency category scores are improved 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 10 ... 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.

[0309] 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 that can be correctly remembered. The digit span task can be given 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 measure of this test is the number of digit sequences that are successfully recalled. In some embodiments, after treatment with psilocybin, the subject's digit span forward score is improved 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.

[0310] 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 uses five main dimensions and eleven lower-order scales to measure acute drug effects and evaluate changes in mood, perception, and experience of self related to the environment and thought disorders. The five dimensions include oceanic infinity, anxiety ego annihilation, visual restructuring, auditory changes, and reduced vigilance. In some embodiments, after treatment with the methods of the present disclosure, subjects experience an increase in a dimension or subscale compared to before treatment. The lower-order scales include "unity experience," "spiritual experience," "euphoric state," "insight," "inability to carry out," "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.

[0311] In some embodiments, the Positive and Negative Affect Schedule (PANAS) is used to evaluate 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 "very much (5)." A higher overall score on the questions giving positive affect indicates the presence of positive affect, and a lower score on the questions giving negative affect 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 has an improvement in PANAS positive 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%, about 100%, about 100%, 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 10 ... %, 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.

[0312] 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.

[0313] In some embodiments, the Symptom Checklist-90 item (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 time. 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%.

[0314] In some embodiments, the Life Change Inventory (LCI) questionnaire is utilized to assess the safety and / or efficacy of psilocybin. The LCI is designed as a questionnaire to explore variables present in the everyday experience of adults that may be associated with either stability or decline in intellectual ability.

[0315] In some embodiments, social cognition panel scales are utilized to assess the safety and / or efficacy of psilocybin, including the Pictorial Empathy Test (PET), Reading the Mind in the Eyes Test (RMET), Social Value Orientation (SVO) Test, Toronto Empathy Questionnaire (TEQ), and the Social Responsibility Scale (SSR).

[0316] In some embodiments, the Pictorial Empathy Test (PET) is utilized to assess the effects of psilocybin on emotional empathy.

[0317] 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 picture 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 picture. A definition handout is provided at the beginning of the task and practice items are provided prior to the first trial.

[0318] 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.

[0319] 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 87%, 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 102%, 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 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 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 150%, about 151%, about 152%, about 153%, about 15 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.

[0320] In some embodiments, the Toronto Empathy Questionnaire (TEQ) is utilized to assess the safety and / or efficacy of psilocybin. The TEQ represents empathy as a primarily emotional process. The TEQ exhibits good internal consistency and high test-retest reliability. The TEQ is a brief, reliable, and valid tool for the assessment of empathy. In some embodiments, after treatment with a method of the present disclosure, a subject's TEQ score is increased 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.

[0321] In some embodiments, the Social Responsibility Scale (SSR) is utilized to assess the safety and / or efficacy of psilocybin. The SSR measures perceptions regarding the importance of ethics and social responsibility.

[0322] 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 scale that assesses the severity of suicidality phenomena on a Likert-type scale (0-4) ranging from "not at all" (0) to "extremely." The SSTS assesses the frequency of major phenomena and the total treatment time spent on suicidality.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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 examination of the skin, neck, eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and musculoskeletal system.

[0327] In some embodiments, the subject's weight and height are assessed, hi some embodiments, body mass index is used to assess the safety and / or efficacy of psilocybin.

[0328] 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.

[0329] 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.

[0330] In some embodiments, laboratory tests are utilized to assess the safety and / or efficacy of psilocybin. In some embodiments, the laboratory tests include blood and / or urine samples. In some embodiments, hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count (with differential), and platelet count are measured to assess the safety and / or efficacy of psilocybin. In some embodiments, albumin, alkaline phosphatase, alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect, and total), calcium, chloride, creatine kinase, creatinine, gamma-glutamyltransferase, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, total protein, sodium, blood urea nitrogen, and / or uric acid are measured to assess the safety and / or efficacy of psilocybin.

[0331] In some embodiments, urine is tested for pregnancy and / or illicit drugs.

[0332] In some embodiments, the safety and / or efficacy of psilocybin is evaluated 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 impairment in function but are not dangerous to the subject's health. Severe adverse events cause significant 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, altered mood, impaired psychomotor skills, 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 / 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, blood disorders or seizures not requiring inpatient hospital care, or the development of drug addiction or abuse.

[0333] Depression assessment In some embodiments, the signs or symptoms of depression are measured in subjects before, during or after treatment with the methods described herein.In some embodiments, the signs or symptoms of depression are measured according to diary assessment, clinician or caregiver assessment, clinical rating scale, imaging test, blood or CSF test.

[0334] 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, Inventory of Depressive Symptoms (IDS), Brief Inventory of Depressive Symptoms (QIDS), Columbia Suicide Severity Rating Scale, or Suicidal Ideation Attribution Scale.

[0335] In some embodiments, the signs or symptoms of depression in the 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 usually takes 15-20 minutes to complete the interview and score the results. Eight items are scored on a 5-point scale from 0=not present to 4=severe. Nine items are scored on a 3-point scale from 0=not present 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.

[0336] 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 seven-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.

[0337] In some embodiments, the signs or symptoms of depression in a subject are measured using the Clinical Global Impression Scale-Severity (CGI-S). In some embodiments, after treatment with the methods described herein, the subject's CGI-S 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.

[0338] In some embodiments, the signs or symptoms of depression in a subject are measured using the Clinical Global Impression Scale-Improvement (CGI-I). In some embodiments, after treatment with the methods described herein, the subject's CGI-I 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.

[0339] 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 major 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 abnormality and 6 = severe abnormality. 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.

[0340] In some embodiments, after treatment with the methods described herein, the subject's MADRS score is reduced by at least about 50% compared to before treatment. In some embodiments, after treatment with the methods described herein, the subject's MADRS score is reduced by 5 to about 20 points compared to before treatment, e.g., about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, about 10 points, about 11 points, about 12 points, about 13 points, about 14 points, about 15 points, about 16 points, about 17 points, about 18 points, about 19 points, and about 20 points. In some embodiments, after treatment with the methods described herein, the subject's MADRS score is 10 points or less (i.e., the treated subject is in MADRS remission). In some embodiments, following treatment with the methods described herein, the subject's MADRS score is 10 or less for at least about 3 weeks to about 12 weeks, e.g., 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, and about 12 weeks.

[0341] 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. The items are rated on a continuum ranging from 0 to 3, with 0=no abnormality and 3=severe abnormality. 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.

[0342] In some embodiments, the 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 the psychological and physical symptoms associated with depression. The questionnaire takes approximately 10 minutes to complete, and the items contain both positive and negative statements. Each item is scored on a Likert scale of 1 to 4. A total score is obtained by summing 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-Rated 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.

[0343] In some embodiments, the 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 summing the individual item scores, with a score of 9 or greater 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.

[0344] In some embodiments, the signs or symptoms of depression in a subject are measured using the 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 26-38 indicating mild depression, a score of 39-48 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.

[0345] In some embodiments, signs or symptoms of depression in a subject are measured using the Quick Inventory for 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 0-3, 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 11-15 indicating moderate depression, a score of 16-20 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.

[0346] 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. There are four items scored on a scale of 0-8, ranging from 0=not present to 8=severe. The remaining seven items are scored on a scale of 0-4, ranging from 0=not present to 4=severe. A total score is obtained by summing the scores of 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.

[0347] 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 thoughts and behaviors. The scale includes 10 dichotomous questions (no=0 points, yes=1 point), each of which corresponds to a different component of the severity of the subject's suicidal thoughts and behaviors. A subject is considered to have suicidal thoughts and / or behaviors 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.

[0348] In some embodiments, signs or symptoms of depression in a subject are measured using the Suicide 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 greater 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.

[0349] 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 Examination of Aberrant Self-Experiences, the Preoccupied Response 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 Clara Inventory, the Political Perspective Questionnaire, the Social Connectedness Scale, the Bech-Rafaelsen Mania Rating Scale, the ... Clara Brief Compassion Scale, Gratitude Questionnaire, Short Recommendation Scale, Rosenberg Self-Esteem Scale, Universality Subscale of 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 Levels 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.

[0350] 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 is increased 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 increased 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 other 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.

[0351] In some embodiments, signs or symptoms of depression are measured using markers of depression in blood or cerebrospinal fluid.In some embodiments, markers of depression are measured in subjects before, during, or after treatment with the methods or compositions described herein.In some embodiments, markers of depression are 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%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 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 15 ... 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. EXAMPLES

[0352] The following examples are included herein for illustrative purposes only and are not intended to be limiting.

[0353] Example 1 - Formulation Development Table 1 shows capsule formulations of psilocybin developed for clinical use that have been optimized to improve flowability, blend uniformity, content uniformity and dissolution as described in WIPO Patent Application Publication No. 2022 / 207746, the contents of which are incorporated herein by reference in their entirety. [Table 8]

[0354] Example 2 - Clinical Trial Examining Psilocybin as an Adjunctive Therapy in Participants with Treatment-Resistant Depression We explored the efficacy of 25mg COMP360 as an adjunctive therapy in participants with TRD.

[0355] The study was a phase IIb, international, multicenter, fixed-dose, open-label study. The study population included adult men and women aged 18 years or older with TRD. Participants with TRD were defined as those who met Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) diagnostic criteria for a single or recurrent episode of major depressive disorder (MDD) without psychotic features and who had failed two, three, or four pharmacological treatments of adequate doses and durations for the current episode. The duration of the current episode must be at least 3 months but not more than 2 years.

[0356] Participants will be outpatients and will be recruited primarily by referral from general practitioners and specialist psychiatric services.

[0357] Subjects will be assessed for eligibility using the Mini-International Structured Interview for Mental Illnesses version 7.0.2 (MINI 7.0.2), the Hamilton Depression Rating Scale (17 items; HAM-D-17), the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (MGH-ATRQ), the C-SSRS, and the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD). At the first screening visit (V1), participants will also be assessed with the Brief Depressive Symptoms Scale-Self-Report-16 item (QIDS-SR-16). In addition, medical history, ECG, blood tests, and vital signs will be obtained.

[0358] All subjects will undergo safety assessments at clinic visits weekly for at least 3 weeks prior to psilocybin administration. At these visits, the C-SSRS and any changes in medication since the previous visit will be obtained in addition to other assessments, at the discretion of the study clinician.

[0359] Subjects will meet with a therapist for at least three visits during the screening period. These will be called safety sessions and will cover what to expect during a psilocybin session. The therapist and subject will review the psychoeducational materials provided at the time of enrollment.

[0360] The day before the psilocybin session, subjects undergo a baseline assessment (3–6 weeks after initial screening [Visit 1]) consisting of the HAM-D-17, MADRS, CGI-S and CGI-I, QIDS-SR-16, C-SSRS, GAD-7, EQ-5D-3L (administered to both subject and caregiver [the latter is not required]), WSAS, vital signs, urinalysis, urine drug screen, and urine pregnancy test (for women of childbearing potential only). After baseline data are entered into the EDC, the CAT team completes a final review to confirm the subject's continued eligibility. Until this approval is obtained, subjects cannot proceed to Visit 3.

[0361] The psilocybin administration session (V3, day 1) lasts approximately 6 hours and is assisted by a trained therapist. Study medication is administered simultaneously to up to six participants. Blood pressure is continuously monitored during the session. COMP360 administration sessions may be videotaped for training and adherence monitoring. After the acute effects of psilocybin have ended, participants are assessed for safety and accompanied home. On day 2 (V4), the day after psilocybin administration, participants meet in person for safety checks, assessments for suicidality, and clinical and self-report assessments, as well as to discuss experiences during the psilocybin administration session. All sessions between therapist and participant may be audio recorded for adherence monitoring and quality assurance.

[0362] Subjects will meet in the clinic for Screening (and 3 safety visits), Baseline (Day -1), Day 1 (medication), Day 2, Week 1, Week 2, and Week 3. AEs, serious adverse events (SAEs), and concomitant medications and therapies will be recorded at all clinic visits. The MADRS will be administered by telephone.

[0363] Clinicians are encouraged to continue participants' baseline selective serotonin reuptake inhibitor (SSRI) (fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, vilazodone, vortioxetine, or escitalopram) prescriptions, ideally at the same dose, over the follow-up period.

[0364] The study schematic is shown in Figure 9 and the evaluation schedule is provided below in Table 2A: [Table 9] [Table 10-1] [Table 10-2]

[0365] Test Purpose The primary objective of this study is to evaluate the efficacy of 25 mg of psilocybin as an adjunct to serotonergic antidepressants in participants with TRD as assessed by change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Baseline is defined as the rating score obtained on day -1. The primary evaluation time point is week 3.

[0366] Additional objectives of this study are to evaluate the effectiveness of psilocybin compared to 1 mg of psilocybin on: (a) Proportion of subjects with a response, defined as ≥50% reduction in MADRS total score from baseline to Week 3. (b) Proportion of subjects with remission (defined as a MADRS total score ≦10) 3 weeks after psilocybin administration. (c) Change from baseline Clinical Global Impression Scale-Severity (CGI-S) 3 weeks after psilocybin administration.

[0367] Another objective is to evaluate the safety and tolerability of psilocybin in subjects with TRD based on AEs, changes in vital signs, and suicidal ideation / behavior (measured using the Columbia-Suicide Severity Rating Scale [C-SSRS]) scores across all visits.

[0368] Other objectives are to evaluate the effects of psilocybin on quality of life and health, function and related disorders, cognitive function, and anxiety. Study endpoints are listed in Table 2B below. [Table 11]

[0369] Test procedure by evaluation period

[0370] The study timeline included seven visits over three weeks to evaluate the effects of psilocybin as an adjunctive treatment for TRD. Screening assessments for each visit are listed in Table 2A.

[0371] Visit 1: Screening Period Subjects will be screened to assess suitability for the study. All subjects will be seen in clinic weekly for a minimum of 3 weeks prior to Baseline (Visit 2) to ensure safe discontinuation of current antidepressant therapy as required by the protocol and to conduct psychoeducation.

[0372] At the screening visit, several assessments will be performed and recorded, as shown in Table 2A.

[0373] If the subject is deemed eligible, they may proceed to the next visit (Visit 1a). Subjects cannot begin psychoeducation until they attend the clinic for the screening visit (Visit 1a).

[0374] At subsequent screening visits (V1a, V1b, etc.), medication intake and changes in medications since the previous visit and the C-SSRS will be obtained.

[0375] Visit 2: Baseline Visit - Day 1 At the baseline visit, subject eligibility will be confirmed by reviewing inclusion / exclusion criteria and updating medical history. The baseline visit should occur the day before the anticipated psilocybin session. The following assessments performed at the baseline visit are listed in Table 2A:

[0376] If the subject continues to meet the eligibility criteria, arrange for the participant to return to the study site for investigational product (IP) administration the following day. The study team will complete a final review to confirm the subject's continued eligibility. Until this approval is received, the subject will not be able to proceed to Visit 3.

[0377] Visit 3: Psilocybin session – Day 0 The psilocybin session (Visit 3) should occur the day after the baseline visit (Visit 2). In exceptional circumstances, subjects may visit the clinic 7 days or less after the baseline visit (Visit 2). Even if the psilocybin session is not performed the day after baseline (Visit 2), a preparation session with a therapist will always be conducted the day before the psilocybin session. If a subject is outside of the 7-day or less window, all baseline assessments should be repeated, except for randomization. Assessments provided at the psilocybin session are listed in Table 2A.

[0378] Visit 4: Day 1 after administration The day after treatment, subjects returned to the study site for a safety review and to discuss their experiences during the psilocybin administration session. Assessments provided at the post-administration session are listed in Table 2A.

[0379] Visit 5: 1 week after administration Subjects will return to the clinic one week (7 days ± 1 day) after psilocybin administration. Assessments obtained during Visit 5 are shown in Table 2A.

[0380] Visit 6: 2 weeks after administration Subjects will return to the clinic 2 weeks (14 days ± 1 day) after psilocybin administration. Assessments obtained during Visit 6 are shown in Table 2A.

[0381] Visit 7: 3 weeks after administration Subjects will return to the clinic 3 weeks (21 days ± 1 day) after psilocybin administration. Assessments obtained during Visit 7 are shown in Table 2A.

[0382] Test procedure explanation Efficacy, safety, and other types of assessments that will be performed during the study are listed below in Tables 2C-2E. All measurements below will be taken electronically.

[0383] [Table 12-1] [Table 12-2] [Table 13-1] [Table 13-2] [Table 14-1] [Table 14-2]

[0384] Subject recruitment A total of 20 subjects with concurrent study drug administration to up to 6 participants.

[0385] Subjects who meet all of the following inclusion criteria, shown in Table 2F below, should be considered for study entry. [Table 15]

[0386] Subjects who meet any of the psychiatric or general medical exclusion criteria shown in Tables 2G and 2H below will not be enrolled in the study. No deviations from the exclusion criteria will be permitted. [Table 16] [Table 17]

[0387] Psilocybin Dosage and Administration

[0388] The study drug will be administered simultaneously to up to six participants. Each participant will receive 1 x 25 mg treatment bottle containing 5 x 5 mg capsules.

[0389] Two hours prior to dosing, under the observation of the investigator, after a light breakfast, the five capsule dose will be swallowed with a full glass of water. Depending on the number of capsules in the dose, additional water may be required to swallow the dose. The investigator will ensure that all five capsule doses are swallowed.

[0390] To prepare for the drug experience, subjects take an appropriate dose of psilocybin and lie down on a couch in a room with dim lights and a standard playlist of relaxing music playing softly. A trained therapist is with the subject at all times.

[0391] The effects of psilocybin usually begin about 20-30 minutes after administration, are strongest in the first 90-120 minutes, and gradually weaken over 5-6 hours. Subjects are asked to remain in the room, preferably lying down, and mostly silent for the duration of the session, regardless of the intensity of the effects, unless they have concerns, communicate discomfort, seek reassurance from the therapist, or need to use the restroom. Therapists "check in" with subjects (i.e., ask how they are doing) at 30-60 minute intervals after administration. Subjects are provided with snacks and fruit.

[0392] Approximately 5-6 hours after dosing, a trained therapist will discuss the subject's experience with psilocybin. Subjects will be discharged 6-8 hours after dosing, when, in the investigator's opinion, the acute effects of psilocybin have subsided. Subjects will be escorted home. The facility will be notified that the subject has safely returned home, and if no phone number is available, facility staff will contact the subject directly.

[0393] Combination therapy: All prescription and nonprescription medications (e.g., over-the-counter medications and herbal supplements) that subjects report taking during the 30 days prior to Screening (Visit 1) will be assessed and recorded at that visit. For each medication, documentation should include the trade or generic name, total daily dose including units (or dose, units, planned and actual times taken if not taken daily), route of administration, and reason for use.

[0394] Concomitant medications refer to all medications and treatments used from the time the informed consent form was signed until the end of study participation.

[0395] Medications changes, additions, or discontinuations will be assessed and recorded during each study visit. All as-needed prescription medications will need to be converted to reflect the actual number of pills or doses per day.

[0396] Acceptable Medications Participants must have been receiving treatment with an appropriate dose of SSRI (fluoxetine, fluvoxamine, sertraline, paroxetine, vilazadone, vortioxetine, citalopram or escitalopram) in accordance with local recommendations for at least 6 weeks prior to screening (V1) and baseline (V2, day -1). Dose modifications within appropriate limits are acceptable. We recommend that participants continue their SSRI, ideally at the same dose, throughout the follow-up period of the study.

[0397] Medications for management of co-occurring anxiety and insomnia, or non-psychiatric medications with potential psychotropic effects, are permitted within the following restrictions: From the first screening visit (V1) through the final study visit (V7, EOS), participants will be permitted to use benzodiazepines (up to 2 mg lorazepam equivalent per day) for insomnia and anxiety, provided they are not taken within 12 hours of psilocybin administration. Prescription and non-prescription medications with psychoactive properties used as needed for non-psychiatric conditions (e.g., pseudoephedrine for allergy or cold symptoms, zopiclone for sleep disorders) should not be used more than twice a week and should not be used within 12 hours of study assessment. Documentation of the use of adjunctive anxiolytics, hypnotics, or medications with potential psychotropic properties (including OTC prescriptions) will be obtained at each clinic visit.

[0398] Therapy deemed necessary for the subject's welfare may be administered at the discretion of the study clinician.

[0399] Adverse events During the study, all adverse events (AEs) will be monitored and recorded, including a description of the AE, start and end dates, severity, actions taken, and relationship to treatment. If an AE occurs, the first concern will be the safety of the study subject.

[0400] An AE is any untoward medical occurrence in a subject administered a medicinal product, which does not necessarily have a causal relationship to this treatment. Thus, an AE can be any untoward, unintended sign (including, for example, abnormal laboratory findings), symptom, or disease temporarily associated with the use of a medicinal product, whether or not it is considered related to the medicinal product.

[0401] Medical interventions such as surgery, diagnostic procedures, and therapeutic procedures are steps taken to treat a medical condition, not an AE. These should be recorded as treatments for an AE.

[0402] Efficacy and endpoints: Efficacy and outcome measures included MADRS, CGI-S, CGI-I, EQ-5D-3L (subject and caregiver), QIDS-SR-16, GAD-7, PANAS, 5D-ASC, and C-SSRS.

[0403] Safety Analysis: A safety analysis will be performed using data from the safety population. Safety will be assessed based on AEs, vital signs, clinical laboratory assessments, and ECG findings.

[0404] Columbia-Suicide Severity Rating Scale (C-SSRS)

[0405] Item scores from the C-SSRS, across all visits by randomized treatment, item scores from the version assessing suicidality since the last visit, and across all post-baseline visits by treatment (including Visits 3 through 7) will be tabulated. Summary statistics for suicidal ideation and behavior following psilocybin administration will be presented by randomized treatment.

[0406] Adverse events AEs will be coded by Preferred Term (PT) using the Medical Dictionary for Clinical Practice (MedDRA) classification. All reported AEs that occurred or worsened after study drug administration will be included in the analysis. Incidence of AEs will be summarized by treatment group, severity, and relationship to psilocybin. Serious AEs and AEs leading to withdrawal from study will be tabulated.

[0407] A TEAE is defined as any AE that occurs during or after administration of psilocybin, or any pre-existing condition that worsens during or after administration of psilocybin.

[0408] The incidence of TEAEs and treatment-related AEs will also be summarized by MedDRA major system organ and PT for greatest severity and most relevant relationship to psilocybin. This summary will include the total number and percentage of subjects who reported events. When counting the number of events reported, consecutive events, i.e., events reported multiple times and not discontinued, will be counted only once; non-sequential AEs reported multiple times by the same subject will be counted as multiple events.

[0409] Electrocardiogram Data ECG data will be summarized descriptively based on measurements of change in each ECG parameter from Visit 1 to post-treatment (Visit 4). A frequency summary of abnormal conditions will be provided. ECG variables to be analyzed include heart rate, PR interval, QRS interval, QT interval, and QT interval corrected using the following correction methods: QT corrected according to Bazett's formula, and QT corrected according to Fridericia's formula.

[0410] Inspection Data Laboratory data (hematology and blood chemistry parameters) for each treatment group are presented using descriptive statistics, including means and mean changes from baseline at each scheduled time point. Shift tables display the number of subjects with normal / abnormal values ​​at baseline and after treatment. The frequency of laboratory abnormalities is tabulated. Subject-specific data listings display laboratory values ​​outside normal reference ranges or notable abnormal findings.

[0411] Vital signs Changes from baseline in vital signs blood pressure (systolic and diastolic), temperature, pulse rate, and respiratory rate will be summarized for each treatment group using descriptive statistics. The last measurements obtained before treatment administration will serve as the baseline. The percentage of subjects with values ​​outside clinically important limits will be summarized. A listing of weight and height at Visit 1 will be provided.

[0412] Demographic and baseline characteristics Treatment groups were compared with respect to subject demographic characteristics, baseline characteristics were summarized using descriptive statistics, and no formal statistical analysis tests were performed. Table 3 shows subject demographic data, and Table 4 shows subject baseline depression. [Table 18] [Table 19]

[0413] result:

[0414] In the trial, 19 patients were given a single 25 mg dose of psilocybin as an adjunct to SSRI therapy, along with psychiatric support from a professionally trained therapist.

[0415] Figure 10 shows patient disposition from the clinical trial. Figure 11 shows the SSRIs participants were taking on the days they were administered psilocybin.

[0416] Effectiveness

[0417] 12A-12B show the mean change from baseline in MADRS total score and the mean MADRS total score by visit, respectively. Participants had an average decrease in MADRS total score from baseline of 14.9 at week 3. Patients receiving the combination of psilocybin and an SSRI exhibited a greater decrease in MADRS score compared to patients receiving psilocybin alone. Rapid onset of action. No participants started new treatment for depression during the 3-week follow-up. Table 5 shows a summary of the MADRS total scores by visit. [Table 20]

[0418] Figure 13 shows the percentage of MADRS responders by visit (responder: ≥50% decrease from baseline in MADRS total score). Rapid responses were observed beginning on day 2, with approximately 42% of participants being MADRS responders by week 3. Table 6 shows the number of MADRS responders at day 2, week 1, week 2, and week 3. [Table 21]

[0419] Figure 14 shows the percentage of MADRS remitters by visit during the study. Rapid remission was observed beginning on day 2, with approximately 42% of participants in MADRS remission by week 3. Table 7 shows the number of MADRS remitters at day 2, week 1, week 2, and week 3. [Table 22]

[0420] Figure 15A shows the mean change from baseline in Clinical Global Impression Scale-Severity (CGI-S) total scores observed at each visit. Figure 15B shows the mean CGI-S total scores observed at each visit. There was a clear and rapid reduction in depression severity according to clinical judgment. On average, participants had a CGI-S score of 4, "moderately ill," at baseline, which reduced to a score of 3, "mildly ill," at week 3. Figure 16 shows the percentage of CGI-S responders by visit. Rapid responses were observed beginning on Day 2, with 52.6% of participants responding by Week 3. Table 8 shows the number of CGI-S responders at Day 2, Week 1, Week 2, and Week 3. [Table 23]

[0421] Figure 17A shows the mean change from baseline in the Generalized Anxiety Disorder 7-item scale (GAD-7) total score by visit. Figure 17B shows the mean GAD-7 total score observed by visit. There was a clear reduction in anxiety symptoms.

[0422] Figure 18A shows the mean change from baseline in the Positive and Negative Affect Schedule (PANAS) negative affect total score by visit, as well as the mean PANAS negative affect total score. Figure 18B shows the mean change from baseline in the PANAS positive affect total score by visit, as well as the mean PANAS positive affect total score. On day 2, there was a higher change from baseline in positive affect and a lower change from baseline in negative affect.

[0423] FIG. 19 shows a summary of the Five-Dimensional Altered State of Consciousness Scale (5D-ASC) scores on Day 1 observed during the clinical trial described in Example 2.

[0424] Figure 20A shows the mean change from baseline in the 16-item Brief Inventory of Depressive Symptoms-Self-Report (QIDS-SR-16) total score by visit. Findings were consistent with the pharmacological profile of psilocybin in previous studies, as expected, across all major dimensions. Figure 20B shows the mean QIDS-SR-16 total score by visit. The QIDS-SR-16 shows a similar pattern to the MADRS data, with a rapid reduction in self-reported depressive symptoms from day 2 onwards.

[0425] Figure 21A shows the mean change from baseline in the EuroQol-5 Dimension-3 Level Scale (EQ-5D-3L) total score observed during the clinical trial described in Example 2. Figure 21B shows the mean EQ-5D-3L total score by visit.

[0426] Figure 22A shows the mean change from baseline in Euro QoL visual analog scale (EQ-VAS) total score by visit. Figure 22B shows the mean EQ-VAS total score by visit. At week 3, participants reported having better overall health.

[0427] Figure 23 shows the percentage of Clinical Global Impression Scale-Improvement (CGI-I) responders by visit. At week 3, participants reported having better overall health. Table 9 shows the number of CGI-I responders at day 2, week 1, week 2, and week 3. [Table 24]

[0428] safety COMP360 was generally well tolerated. In the study, 11 participants (58%) reported at least one treatment-emergent adverse event (TEAE). The most common TEAE was headache (6 participants with 6 events), which occurred on the day of dosing or the day after, and all cases resolved within 1 or 2 days. Table 10 shows treatment-emergent adverse events by group. [Table 25]

[0429] There were no TEAEs classified as serious (TESAEs) in the study, and no TEAEs related to suicidal thoughts or behavior, or intentional self-harm. ******

[0430] All documents, patents, patent applications, publications, product descriptions, and protocols cited herein are incorporated by reference in their entirety for all purposes.

[0431] The embodiments illustrated and discussed herein are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. The above-described embodiments of the invention may be modified or changed as understood by those skilled in the art in light of the above teachings without departing from the invention. It is therefore understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

[0432] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The present invention is defined by the following claims, including equivalents of the claims contained therein.

Claims

1. 1. A method of treating treatment-resistant depression in a subject in need of treatment, comprising administering to the subject an effective amount of psilocybin, or an active metabolite thereof, as an adjunct to selective serotonin reuptake inhibitor (SSRI) therapy.

2. 2. The method of claim 1, wherein the SSRI is selected from the group consisting of escitalopram, sertraline, fluoxetine, vilazodone, vortioxetine, paroxetine, or citalopram.

3. 3. The method of any one of claims 1-2, wherein the SSRI is administered prior to administration of psilocybin.

4. 3. The method of any one of claims 1-2, wherein the SSRI is administered following administration of psilocybin.

5. 5. The method of any one of claims 1 to 4, wherein the SSRI is administered on the same day as the psilocybin.

6. 6. The method of any one of claims 1 to 5, wherein the subject is administered about 25 mg of psilocybin or an active metabolite thereof.

7. 7. The method of any one of claims 1-6, wherein said administration of psilocybin reduces at least one sign or symptom of depression.

8. 8. The method of claim 7, wherein the 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 loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased concentration or indecisiveness, or suicidal thoughts or behaviors.

9. 8. The method of claim 7, wherein the 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.

10. 10. The method of claim 9, wherein the clinical rating scale is the Quick Inventory for 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 (MADRS), the Clinical Global Impression scale, the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, and / or the Young Mania Rating Scale.

11. 10. The method of claim 9, wherein the clinical rating scale is the MADRS.

12. 12. The method of claim 11, wherein said administration of psilocybin results in about a 50% decrease in the patient's MADRS total score compared to before treatment with psilocybin.

13. 13. The method of any of claims 11-12, wherein said administration of psilocybin results in a reduction in said patient's MADRS total score to 10 or less.

14. 10. The method of claim 9, wherein the clinical rating scale is the Clinical Global Impression Scale-Severity (CGI-S).

15. 15. The method of claim 14, wherein said administration of psilocybin results in a reduction in said patient's CGI-S score to 2 or less.

16. 10. The method of claim 9, wherein the clinical assessment scale is the Clinical Global Impression-Improvement (CGI-I).

17. 17. The method of claim 16, wherein said administration of psilocybin results in a reduction in said patient's CGI-I score reported as "very improved" or "much improved" compared to before treatment with psilocybin.

18. 18. The method of any one of claims 1-17, wherein said administration of psilocybin results in a reduction in anxiety in said patient compared to before treatment with psilocybin.

19. 19. The method of claim 18, wherein said administration of psilocybin results in a decrease in said patient's Generalized Anxiety Disorder 7-item scale (GAD-7) total score compared to before treatment with psilocybin.

20. 20. The method of any one of claims 1-19, wherein at least one sign or symptom of depression is alleviated within 24 hours of administration of the psilocybin.

21. 20. The method of any one of claims 1-19, wherein at least one symptom of depression is alleviated within one week of administration of the psilocybin.

22. 22. The method of any one of claims 1-21, wherein at least one symptom of depression is alleviated for at least one month following administration of the psilocybin.

23. 22. The method of any one of claims 1-21, wherein at least one symptom of the depression is alleviated for at least three months following administration of the psilocybin.

24. 22. The method of any one of claims 1-21, wherein at least one symptom of the depression is alleviated for at least 12 months following administration of the psilocybin.

25. 25. The method of any one of claims 1 to 24, wherein at least two doses of psilocybin are administered to the subject.

26. 25. The method of any one of claims 1 to 24, wherein the psilocybin is administered once daily.

27. 27. The method of any one of claims 25-26, wherein the psilocybin is administered at least once a week.

28. 27. The method of any one of claims 25-26, wherein the psilocybin is administered at least twice a week.

29. 27. The method of any one of claims 25-26, wherein the psilocybin is administered at least once a month.

30. 27. The method of any one of claims 25-26, wherein the psilocybin is administered at least twice a month.

31. 27. The method of any one of claims 25-26, wherein the psilocybin is administered at least once every three months.

32. 27. The method of any one of claims 25-26, wherein the psilocybin is administered at least once every six months.

33. 27. The method of any one of claims 25-26, wherein the psilocybin is administered at least once every 12 months.

34. 34. The method of any one of claims 25-33, wherein each dose of psilocybin administered is about 25 mg.

35. 35. The method of any one of claims 1-34, wherein the psilocybin is administered by one of the following routes: oral, intravenous, intramuscular, parenteral, topical, inhalation, rectal, transmucosal, intranasal, buccal, vaginal, intrathecal, intraocular, transdermal, intrauterine, intralymphatic, or by direct tissue or organ injection.

36. 36. The method of claim 35, wherein the psilocybin is administered orally.

37. 37. The method of any one of claims 1 to 36, wherein the psilocybin comprises a crystalline polymorph of psilocybin.

38. 38. The method of claim 37, wherein the crystalline polymorph of psilocybin comprises polymorph A.

39. 39. The method of claim 38, wherein the crystalline polymorph A of psilocybin is characterized by XRPD peaks at 11.5±0.1, 12.0±0.1, 14.5±0.1, 17.5±0.1, and 19.7±0.1 degrees 2θ.

40. 40. The method of claim 39, wherein said polymorph A is further characterized by at least one peak selected from the group consisting of 20.4±0.1, 22.2±0.1, 24.3±0.1, and 25.7±0.1 degrees 2θ.

41. 38. The method of claim 37, wherein the crystalline psilocybin comprises Hydrate A.

42. 42. The method of claim 41, wherein said Hydrate A is characterized by X-ray powder diffraction (XRPD) peaks at 8.9±0.1, 13.8±0.1, 19.4±0.1, 23.1±0.1, and 23.5±0.1 degrees 2θ.

43. 43. The method of claim 42, wherein said Hydrate A is further characterized by at least one peak selected from the group consisting of 6.5±0.1, 12.2±0.1, 12.6±0.1, 16.2±0.1, 20.4±0.1, 20.8±0.1, and 21.5±0.1 degrees 2θ.

44. 44. The method of any one of claims 1-43, wherein the psilocybin has no impurities greater than 1% as determined by HPLC analysis.

45. 45. The method of any one of claims 1-44, wherein the psilocybin has a chemical purity of greater than 97% as determined by HPLC analysis.

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