Methods of treating neurocognitive disorders and chronic pain and reducing inflammation

Abstract

To provide methods of treating neurocognitive disorders and chronic pain and reducing inflammation.SOLUTION: The disclosure provides methods for treating a subject in need thereof, comprising administering to the subject a therapeutically-effective dose of psilocybin. The methods described herein may be used to treat a variety of diseases, disorders, and conditions. For example, the methods may be used to treat neurocognitive disorders (e.g., Alzheimer's disease, Parkinson's disease), ADHD, epilepsy, autism, sleep-wake disorders, chronic pain, inflammatory disorders, IBD, stroke, ALS, and / or multiple sclerosis.SELECTED DRAWING: Figure 1

Description

[Technical Field]

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

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

[0003] There are several common diseases, disorders, and conditions for which no adequate treatment and / or cure exists, including: Alzheimer's disease (AD) - AD is a neurodegenerative brain disorder characterized by changes in both cognitive and non-cognitive behavior, particularly progressive memory loss, depression, anxiety, dementia, irritability, mood swings, inattention, aggressive and / or apathetic behavior, confusion, gradual physical deterioration, and ultimately death. Parkinson's disease (PD) - PD is the most common type of parkinsonism and is a term that reflects a group of neurological disorders with parkinsonian-like movement disorders such as rigidity, bradykinesia, and tremor. Clinical symptoms of Parkinson's disease include motor and non-motor symptoms. Attention Deficit Hyperactivity Disorder (ADHD) - ADHD is a neurodevelopmental disorder characterized by one or more of the following: inattention, hyperactivity, and impulsivity that is not normally appropriate for a person's age. It is commonly diagnosed in childhood and is one of the most frequent conditions affecting school-age children. Epilepsy - Epilepsy is a neurological disorder characterized by sudden, recurrent episodes of sensory disturbances, loss of consciousness, or seizures related to abnormal electrical activity in the brain. During a seizure, an individual with epilepsy experiences abnormal behaviors, symptoms, and sensations, sometimes including loss of consciousness. Between seizures, there are few symptoms. Autism Spectrum Disorder (ASD) - ASD is a neurodevelopmental syndrome characterized by core deficits in social interaction and communication, the presence of repetitive and restricted patterns of behavior and interests, and / or abnormal reactivity to sensory input. Sleep-wake disorders - Sleep-wake disorders are a class of diseases or disorders that include insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorders (e.g., central sleep apnea), circadian rhythm sleep-wake disorders, disorders of arousal from non-REM sleep, nightmare disorders, REM sleep behavior disorder, restless legs syndrome, and substance / medication-induced sleep disorders. Individuals with these disorders typically present with sleep-wake complaints related to dissatisfaction with the quality, timing, and quantity of sleep, often causing daytime distress. Chronic pain - Pain is the most common symptom of disease and protects against dangerous and noxious stimuli. Chronic pain is pain that lasts longer than the normal course of an acute injury or disease, such as pain that recurs over months or years. Inflammatory disorders - Inflammation underlies the generation and maintenance of some of the leading causes of morbidity and mortality worldwide. Inflammatory disorders are often chronic and can be the result of impaired immune signaling. Inflammatory Bowel Disease (IBD) - IBD is a term used to describe a variety of diseases and disorders, including Crohn's disease and ulcerative colitis, that are characterized by chronic inflammation of the gastrointestinal (GI) tract. Stroke - A stroke is a sudden interruption in the brain's blood supply. Brain cells begin to die within minutes of being deprived of oxygen and nutrients. Amyotrophic lateral sclerosis (ALS) - ALS, also known as motor neuron disease (MND), Lou Gehrig's disease, and Charcot's disease, is a progressive neurodegenerative disease that attacks motor neurons in the brain and spinal cord, resulting in muscle weakness and loss of movement.

[0004] There remains a need in the art for improved compositions and methods for treating these diseases, disorders, and conditions. Summary of the Invention

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

[0006] Provided herein are methods for treating one or more neurocognitive disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0007] Also provided herein is a method for treating Parkinsonism or a symptom thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0008] Also provided herein is a method for treating attention deficit hyperactivity disorder (ADHD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

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

[0010] Also provided herein is a method for treating an autism spectrum disorder (ASD) or a symptom thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0011] Also provided herein are methods for treating one or more sleep-wake disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

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

[0013] Also provided herein are methods for reducing inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0014] Also provided herein is a method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

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

[0016] Also provided herein is a method for treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof, wherein the subject is recovering from a stroke.

[0017] Also provided herein is a method for treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0018] In some embodiments, the psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly pure crystalline psilocybin in the form of Polymorph A, wherein the crystalline psilocybin comprises at least 90% by weight Polymorph A. In some embodiments, the crystalline psilocybin comprises at least 95% by weight Polymorph A. In some embodiments, the crystalline psilocybin has a chemical purity of greater than 97% by high performance liquid chromatography (HPLC) and does not have a single impurity greater than 1%.

[0019] In some embodiments, psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly purified crystalline psilocybin in the form of Polymorph A, the crystalline psilocybin having a chemical purity of greater than 97% by HPLC and not having a single impurity greater than 1%. In some embodiments, psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly purified crystalline psilocybin in the form of Polymorph A, the crystalline psilocybin having a chemical purity of greater than 97% by HPLC and not having a single impurity greater than 1%, and further comprising a mixture of two silicified microcrystalline cellulose variants, the first variant having a particle size of about 45-80 microns and the second variant having a particle size of about 90-150 microns. In some embodiments, not more than about 30% of the microcrystalline cellulose is the first variant having a particle size of about 45-80 microns, and not less than about 70% of the microcrystalline cellulose is the second variant having a particle size of about 90-150 microns. In some embodiments, the psilocybin is administered in an oral dosage form. In some embodiments, the psilocybin is administered in a capsule. In some embodiments, the psilocybin is administered in a tablet.

[0020] In some embodiments, at least one dose of psilocybin is administered to the subject. In some embodiments, the dose of psilocybin is within the range of about 0.1 mg to about 100 mg. In some embodiments, the dose of psilocybin is about 25 mg.

[0021] In some embodiments, the subject participates in at least one psychological support session prior to administration of psilocybin. In some embodiments, the subject participates in at least one psychological support session after administration of psilocybin. In some embodiments, the therapist provides psychological support to the subject for about 4-8 hours after administration of psilocybin. [Brief explanation of the drawings]

[0022] [Figure 1] The numbered structural formula of psilocybin. [Figure 2A] FIG. 1 is an XRPD diffractogram of Polymorph A (GM764B). [Figure 2B] FIG. 1 is an XRPD diffractogram of polymorph A′ (JCCA2160F). [Figure 2C] FIG. 1 is an XRPD diffractogram of polymorph B (JCCA2160-F-TM2). [Figure 2D] FIG. 1 is an XRPD diffractogram of Hydrate A (JCCA2157E). [Figure 2E] FIG. 1 is an XRPD diffractogram of the ethanol solvate (JCCA2158D). [Figure 2F] XRPD diffractograms of the product obtained during the development of the process (CB646-E) (top) compared to polymorph A' (JCCA2160F) (center) and polymorph B (JCCA2160-TM2) (bottom). [Figure 3A] 1 is a DSC and TGA thermograph of polymorph A (GM764B). [Figure 3B] 1 is a DSC and TGA thermograph of polymorph A' (JCCA2160F). [Figure 3C] 1 is a DSC thermograph of polymorph B (GM748A). [Figure 3D] 1 shows DSC and TGA thermographs of Hydrate A (JCCA2157E). [Figure 3E] 1 is a DSC and TGA thermograph of the ethanol solvate (JCCA2158D). [Figure 4] FIG. 1 is a morphology phase diagram showing the interrelationships of morphologies in water-based systems. [Figure 5] This is the 1H NMR (nuclear magnetic resonance) spectrum of psilocybin. [Figure 6] This is the 13C NMR spectrum of psilocybin. [Figure 7] FT-IR spectrum of psilocybin. [Figure 8] Mass spectrum of psilocybin. [Figure 9A] 1 shows a timeline of a Phase 1 exploratory study evaluating psilocybin treatment in healthy volunteer subjects. [Figure 9B]The number of subjects who completed screening (Visit 1), baseline measurements (Visit 2), and drug administration (Visit 3) for the Phase 1 exploratory study is shown. [Figure 9C] Group sizes for dosing sessions of the Phase 1 exploratory study are shown. [Figure 9D] The most frequently reported adverse events from the exploratory phase 1 trials are shown. [Figure 9E] The duration of adverse events in the Phase 1 exploratory study is shown. [Figure 9F] FIG. 1 shows a graph of Paired-Associate Learning Total Errors (Adjustments) (PALTEA) scores over time on the Cambridge Neuropsychological Test Automated Battery (CANTAB) in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9G] 1 shows a graph of the least squares mean difference from placebo in PALTEA scores over time for CANTAB in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9H] 1 shows a graph of spatial working memory between errors over time (SWMBE) scores for CANTAB in psilocybin-treated and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9I] 1 shows a graph of the least squares mean difference from placebo in SWMBE scores over time for CANTAB in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9J] FIG. 1 shows a graph of spatial working memory strategy (SWM strategy) scores over time on CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9K] 1 shows a graph of the least squares mean difference from placebo in SWM strategy scores over time for CANTAB in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9L] FIG. 1 shows a graph of rapid visual processing A-prime (RVPA) scores over time for CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9M]Figure 1 shows a graph of least squares (LS) mean differences for the psilocybin groups (10 mg and 25 mg) compared to the placebo group over time. Psilocybin was administered on day 0. Data were collected remotely on days 7 and 28. A positive score indicates treatment performed better than placebo. A negative score indicates placebo performed better than psilocybin. LS means were calculated using repeated measures analysis of variance and compared with placebo. *p≦0.05. Data are presented as LS means ± SEM. [Figure 9N] FIG. 1 shows a graph of the Emotion Recognition Task Percent Correct (ERTPC) of CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9O] 1 shows graphs of the CANTAB first-choice One Touch Stocking Problem Solved (OTSPSFC) in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9P] FIG. 1 shows a graph of the intra- and extra-dimensional set-shifting total errors (IEDYERT) of the CANTAB in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9Q] FIG. 1 shows a graph of the CANTAB global composite score over time in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9R] 1 shows a graph of the least squares mean difference from placebo over time in the CANTAB global composite score in psilocybin-treated subjects from a Phase 1 exploratory study. [Figure 9S] 1 shows graphs of verbal fluency testing in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9T] FIG. 1 shows a graph of the Digit Span Forward test in psilocybin- and placebo-treated subjects from a Phase 1 exploratory study. [Figure 9U] FIG. 1 shows a graph of 5-Dimensional Altered States of Consciousness (5D-ASC), which measures changes in mood, perception, and experience of self after administration of psilocybin or placebo in a Phase 1 exploratory study. [Figure 9V]The difference in CANTAB composite scores between "psilocybin-naive" (0, left) subjects and subjects with prior psilocybin experience (1, right) is shown. [Figure 10] The effect of psilocin on cell viability, as measured by the percentage of TH (tyrosine hydroxylase)-positive neurons, after 6-OHDA (6-hydroxydopamine) intoxication compared to a 15 μM 6-OHDA-treated group in an in vitro model is shown. One-way ANOVA followed by Fisher's LSD for paired comparisons: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± standard error of mean (SEM). [Figure 11] Figure 1 shows the effect of psilocybin on gait scores in the beam walk test after 6-OHDA intoxication in an in vivo model. One-way ANOVA followed by Fisher's LSD for paired comparisons, *p<0.05, **p<0.01. Data are expressed as mean ± SEM. [Figure 12] Figure 1 shows the effect of psilocybin on the number of segments crossed (crossing score) in the beam-walk test after 6-OHDA intoxication in an in vivo model. One-way ANOVA followed by Fisher's LSD for paired comparisons, *p<0.05, **p<0.01. Data are expressed as mean ± SEM. [Figure 13] Figure 1 shows the effect of psilocybin on ambulation and crossing scores in the beam-walk test after 6-OHDA intoxication in an in vivo model. One-way ANOVA followed by Fisher's LSD for paired comparisons, *p<0.05, **p<0.01. Data are expressed as mean ± SEM. [Figure 14] Figure 1 shows the effect of psilocybin on crossing time in the beam walk test after 6-OHDA intoxication in an in vivo model. One-way ANOVA followed by Fisher's LSD for paired comparisons, *p<0.05, **p<0.01. Data are expressed as mean ± SEM. [Figure 15]Figure 1 shows the effect of psilocybin compared to vehicle / haloperidol treatment 1 hour after administration on the mean descent latency in the haloperidol-induced catalepsy model. One-way ANOVA followed by Fisher's LSD pairwise comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. [Figure 16] Figure 1 shows the effect of psilocybin 1 hour after administration on the kinetics of descent latency in the haloperidol-induced catalepsy model. One-way ANOVA followed by Fisher's LSD pairwise comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. [Figure 17] Figure 1 shows the effect of psilocybin 24 hours after administration on the mean descent latency in the haloperidol-induced catalepsy model. One-way ANOVA followed by Fisher's LSD pairwise comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. [Figure 18] Figure 1 shows the effect of psilocybin 24 hours after administration on the kinetics of descent latency in the haloperidol-induced catalepsy model. One-way ANOVA followed by Fisher's LSD pairwise comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. [Figure 19] Figure 1 shows the effect of psilocybin on the mean descent latency in the haloperidol-induced catalepsy model after one week of administration. One-way ANOVA followed by Fisher's LSD pairwise comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. [Figure 20]Figure 1 shows the effect of psilocybin after one week of administration on the kinetics of descent delay in the haloperidol-induced catalepsy model. One-way ANOVA followed by Fisher's LSD pairwise comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. [Figure 21] Figure 1 shows the number of entries into the open arms and the time spent in the open arms 2 hours after psilocybin administration in a CCK-4 (cholecystokinin-4)-induced anxiety model. One-way ANOVA followed by Fisher's LSD pairwise comparison test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. [Figure 22] Figure 1 shows the number of entries into the open arms and the time spent in the open arms 24 hours after psilocybin administration in the CCK-4-induced anxiety model. One-way ANOVA followed by Fisher's LSD for paired comparisons, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± standard error. [Figure 23] The number of buried marbles 1 hour after psilocybin (PS) treatment is shown. Fluoxetine (Fluox, 30 minutes before treatment) was used as a positive control. Data are presented as mean ± SEM. Statistical significance was determined using an unpaired t-test for vehicle FL and fluoxetine, ***p<0.0001. Statistical significance was determined using one-way ANOVA and Tukey's correction test for vehicle PS and psilocybin, ##p<0.001. FL=fluoxetine; PS=psilocybin. [Figure 24] Figure 1 shows that the PTZ dose required to induce hindlimb tonic seizures is increased in mice treated with psilocybin compared to mice treated with vehicle. One-way ANOVA followed by Dunnett's multiple comparison test, *p<0.05, ***p<0.001. Data are presented as mean ± SEM. [Figure 25]Figure 1 shows the effect of psilocybin on calsyntenin 2 (Clstn2) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 26] Figure 1 shows the effect of psilocybin on fibronectin leucine-rich repeat transmembrane protein 2 (Flrt2) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Two-way ANOVA repeated measures followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 27] Figure 1 shows the effect of psilocybin on Plexin-A4 (Plxna4) expression levels in naive mice compared to vehicle-treated animals in an in vivo model at 1 hour, 24 hours, and 8 days after a single dose of psilocybin. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 28] Figure 1 shows the effect of psilocybin on S100 calcium-binding protein A4 (S100a4) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 29]Figure 1 shows the effect of psilocybin on transforming growth factor alpha (Tgfa) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Two-way ANOVA repeated measures followed by Bonferroni's multiple comparison test, *p<0.05. Data are presented as mean ± SD. [Figure 30] Figure 1 shows the effect of psilocybin on the levels of V-set and immunoglobulin domain-containing 2 (Vsig2) expression levels 1 hour, 24 hours, and 8 days after a single dose of psilocybin in naive mice compared to vehicle-treated animals. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SD. [Figure 31] Figure 1 shows the effect of psilocybin on three-chamber test performance in a valproic acid (VPA) animal model 24 hours after administration. Two-way ANOVA repeated measures followed by Bonferroni's multiple comparison test, *p<0.05. Data are expressed as mean ± SEM. [Figure 32] Figure 1 shows the effect of psilocybin on performance in the social novelty preference test in a valproic acid (VPA) animal model 24 hours after administration (* for within-group comparisons and # for between-group comparisons). Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test, *p<0.05, #p<0.05. Data are expressed as mean ± SEM. [Figure 33] Figure 1 shows the effect of pre-treatment valproic acid (VPA) on repetitive self-grooming behavior compared to wild-type control animals. Unpaired t-test. Data are presented as mean ± SEM. [Figure 34]

[0023] Figure 1 shows the effect of psilocybin on repetitive self-grooming behavior in a valproic acid (VPA) animal model 24 hours after administration. One-way ANOVA test. Data are presented as mean ± SEM. [Figure 35]

[0023] Figure 1 shows the change in Social Connectedness Scale (SCS) scores 2 and 4 weeks after administration of two doses of psilocybin to healthy human volunteers. Two-way repeated measures ANOVA with Bonferroni correction, **p<0.01, #<0.05. Data are expressed as mean ± SEM. [Figure 36]

[0023] Figure 1 shows reaction times of healthy human volunteers in a facial expression recognition task after administration of psilocybin. One-way ANOVA repeated measures, *p<0.05, **p<0.01, ***p<0.001. Data are expressed as mean ± SEM. [Figure 37] Figure 1 shows activation of the left amygdala, represented by the mean Z change in the left amygdala in healthy volunteers after administration of psilocybin. One-way ANOVA repeated measures, *p<0.05, **p<0.01, ***p<0.001. Data are expressed as mean ± SEM. [Figure 38] Graph showing the effect of psilocybin treatment on paw withdrawal threshold in mice undergoing sciatic nerve ligation in a chronic constriction injury (CCI) model compared to vehicle-treated animals. Statistical significance was determined using a two-way repeated measures analysis of variance test followed by Fisher's least significant difference (LSD) for pairwise comparisons. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± SEM. BL = pre-surgery baseline, NeuP = neuropathy (baseline), PTT = post-treatment time point. [Figure 39] A series of graphs showing the change in the amount of wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep over a 24-hour period following psilocybin administration. The black arrow indicates the time of administration. The gray background indicates the dark period (i.e., when the rodent is awake). [Figure 40]

[0023] Figure 1 is a series of graphs showing the amount of wakefulness, NREM sleep, and REM sleep from 1 to 7 hours after psilocybin administration (light phase, i.e., when rodents are asleep). Statistical significance was determined using a one-way repeated measures ANOVA followed by a Dunnett post-hoc test. *p<0.05. Data are expressed as mean ± SEM. [Figure 41]

[0023] Figure 1 is a series of graphs showing the amount of wakefulness, NREM sleep, and REM sleep 11-19 hours (dark phase) after psilocybin administration. Statistical significance was determined using a one-way repeated measures analysis of variance followed by Dunnett's post-hoc test. *p<0.05. Data are expressed as mean ± SEM. [Figure 42]

[0023] Figure 1 is a series of graphs showing changes in absolute and relative waking electroencephalogram (EEG) power frequency and amount of gamma oscillations. Statistical significance was determined using a one-way repeated measures analysis of variance followed by a Dunnett post-hoc test. *p<0.05. Data are presented as mean ± SEM. [Figure 43-1] 1 is a series of graphs showing the variation of absolute and relative wake, NREM and REM sleep EEG power with frequency. [Figure 43-2] 1 is a series of graphs showing the variation of absolute and relative wake, NREM and REM sleep EEG power with frequency. [Figure 44] FIG. 1 is a schematic diagram showing the administration and sample collection protocol described in Example 26. [Figure 45] Graph showing tumor necrosis factor alpha (TNF-α) plasma levels 1 hour after lipopolysaccharide (LPS) administration in rats after pretreatment with various doses (1, 3, and 10 mg / kg) of psilocybin or dexamethasone. Statistical significance was determined using one-way ANOVA followed by Fisher's least significant difference (LSD) for paired comparison tests. DEX = dexamethasone, PS = psilocybin; *p<0.05, **p<0.01, ***p<0.001, ***p<0.0001. Data are presented as mean ± SEM. Significance determined by one-way ANOVA and post hoc LSD vs. control is represented by *. Significance determined by one-way ANOVA and post hoc LSD vs. LPS is represented by #. [Figure 46]Graphs showing interleukin-6 (IL-6) plasma levels in rats 1 hour after treatment with (i) LPS alone, (ii) pretreatment with LPS and dexamethasone, or (iii) pretreatment with various doses of psilocybin (1, 3, and 10 mg / kg). Statistical significance was determined using one-way ANOVA followed by Fisher's least significant difference (LSD) for paired comparison tests. DEX = dexamethasone, PS = psilocybin; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. Significance determined by one-way ANOVA and post hoc LSD vs. control is represented by *. Significance determined by one-way ANOVA and post hoc LSD vs. LPS is represented by #. [Figure 47] 1 is a graph showing interleukin-1β (IL-1β) plasma levels 1 hour after LPS administration in rats after pretreatment with various doses (1, 3, and 10 mg / kg) of psilocybin or dexamethasone. Statistical significance was determined using one-way ANOVA followed by Fisher's least significant difference (LSD) for paired comparison tests. DEX = dexamethasone, PS = psilocybin; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. Significance generated by one-way ANOVA and post hoc LSD vs. control is represented by *. Significance generated by one-way ANOVA and post hoc LSD vs. LPS is represented by #. [Figure 48]1 is a graph showing interleukin-10 (IL-10) plasma levels 1 hour after LPS administration in rats after pretreatment with various doses (1, 3, and 10 mg) of psilocybin. Statistical significance was determined using one-way ANOVA followed by Fisher's least significant difference (LSD) for paired comparison tests. DEX = dexamethasone, PS = psilocybin; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. Significance generated by one-way ANOVA and post hoc LSD vs. control is represented by *. Significance generated by one-way ANOVA and post hoc LSD vs. LPS is represented by #. [Figure 49] Graph showing CXC chemokine ligand 1 (CXCL1) expression levels in naive mice 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals (indicated by *) and compared to other psilocybin doses (indicated by brackets and *). Statistical significance was determined using a two-way repeated measures analysis of variance followed by Bonferroni's multiple comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 50] Graph showing glucagon (Gcg) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Statistical significance was determined using a two-way repeated measures analysis of variance followed by Bonferroni's multiple comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 51]Graph showing receptor tyrosine-protein kinase Erbb4 expression levels in naive mice 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Statistical significance was determined using a two-way repeated measures analysis of variance followed by Bonferroni's multiple comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 52] Graph showing tenascin-R (Tnr) expression levels in naive mice at 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Statistical significance was determined using a two-way repeated measures analysis of variance followed by Bonferroni's multiple comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 53] Graph showing transforming growth factor beta receptor 3 (Tgfbr3) expression levels in naive mice 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Statistical significance was determined using a two-way repeated measures analysis of variance followed by Bonferroni's multiple comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 54] Graph showing activin A receptor, type II-like kinase 1 (Acvrl1) expression levels in naive mice 1 hour, 24 hours, and 8 days after a single dose of psilocybin compared to vehicle-treated animals. Statistical significance was determined using a two-way repeated measures analysis of variance followed by Bonferroni's multiple comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 55]Figure 1 shows repulsive guidance molecule A (Rgma) expression levels at 1 hour, 24 hours, and 8 days after a single dose of psilocybin in naive mice compared to vehicle-treated animals in an in vivo model. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard deviation (SD). [Figure 56] Figure 1 shows tumor necrosis factor superfamily member 6 (Fas) expression levels at 1 hour, 24 hours, and 8 days after a single dose of psilocybin in naive mice compared to vehicle-treated animals in an in vivo model. Two-way repeated measures ANOVA followed by Bonferroni's multiple comparison test; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are expressed as mean ± standard deviation (SD). [Figure 57] Graph showing cell viability after psilocin treatment 10 minutes prior to Abeta 1-40 intoxication compared to the Abeta 1-40 5 μM treatment group. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± standard error of mean (SEM). [Figure 58] Graph showing cell viability after psilocin treatment 48 hours prior to Abeta 1-40 intoxication compared to the Abeta 1-40 5 μM treatment group. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 59A]Graph showing the percent change in total neurite length after psilocin treatment on day 0 compared to the control group in human iPSC (induced pluripotent stem) cells. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 59B] Graph showing the percent change in total neurite length after psilocin treatment on day 3 compared to control in human iPSC (induced pluripotent stem) cells. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 60A] Graph showing the percent change in neurite number per neuron after psilocin treatment on day 0 compared to the control group in human iPSC (induced pluripotent stem) cells. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 60B] Graph showing the percent change in neurite number per neuron after psilocin treatment on day 3 compared to control in human iPSC (induced pluripotent stem) cells. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 61] Graph showing the percent change in spontaneous alternation in mice in the T-maze 1 hour after psilocybin treatment compared to the vehicle / scopolamine group. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 62] Graph showing the percent change in spontaneous alternation in mice in the T-maze 24 hours after psilocybin treatment compared to the vehicle / scopolamine group. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparisons. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 63] Graph showing percent change in spontaneous alternation in aged mice in the T-maze 1 hour after single or chronic psilocybin treatment compared to vehicle / scopolamine treatment. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 64] Graph showing percent change in spontaneous alternation in aged mice in the T-maze 24 hours after single or chronic psilocybin treatment compared to vehicle / scopolamine treatment. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. [Figure 65] Graph showing percent change in spontaneous alternation in aged mice in the T-maze one week after single or chronic psilocybin treatment compared to vehicle / scopolamine treatment. Statistical significance was determined using one-way ANOVA followed by Fisher's LSD pairwise comparison test. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Data are presented as mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION

[0023] 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.

[0024] The singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0025] Additionally, as used herein, the term "about," when referring to a measurable value (dosage, time, temperature, etc.), is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or in some cases ±0.1% of the stated amount.

[0026] The term "and / or," as used herein in the specification and embodiments, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are present conjunctively in some cases and separately in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" elements so conjoined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, which may or may not be related to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0027] As used in this specification and in the embodiments, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., the inclusion of at least one, but also includes more than one element or list of elements, and optionally, further unlisted items. "Only one of" Only terms clearly indicated to the contrary, such as "one of," "exactly one of," or, when used in an embodiment, "consisting of," refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" should be construed only as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in an embodiment, should have its ordinary meaning as used in the field of patent law.

[0028] As used in this specification and in the embodiments, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, which may or may not be related to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally more than one, A, with no B (and optionally including elements other than B); in another embodiment to at least one, optionally more than one, B, with no A (and optionally including elements other than A); in yet another embodiment to at least one, optionally more than one, A, and at least one, optionally more than one, B (and optionally including other elements); etc.

[0029] Unless the context dictates otherwise, it is specifically contemplated that the various features described herein can be used in any combination.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] As used herein, "substantially absent" with respect to an XRPD diffractogram peak means that, compared to a reference peak present in the diffractogram, the peak has a relative intensity of less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the intensity of the reference peak, or the peak is not detectable.

[0034] XRPD diffractograms and XRPD peak positions may be obtained using Cu Kα radiation.

[0035] DSC and TGA thermograms can be obtained using a heating rate of 20°C / min.

[0036] As used herein, the term "diffusion tensor imaging" or "DTI" refers to a technique that detects how water moves along white matter tracts in the brain. In some embodiments, DTI is used to characterize microstructural changes associated with psychiatric disorders (e.g., major depressive disorder) and / or response to treatment in subjects with psychiatric disorders.

[0037] 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.

[0038] As used herein, the terms "subject" and "patient" are used interchangeably.

[0039] As used herein, "treating" and like terms refer to reducing the severity and / or frequency of one or more symptoms, eliminating one or more symptoms and / or the underlying cause of said symptoms, reducing the frequency or likelihood of one or more symptoms and / or their underlying causes, delaying, preventing, and / or slowing the progression of a disease and / or disorder, and ameliorating or correcting damage caused directly or indirectly by a disease and / or disorder.

[0040] As used herein, a "therapeutically effective dose" means a dose sufficient to achieve the intended therapeutic purpose, such as alleviating the signs or symptoms of a disease or disorder in a subject.

[0041] 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.

[0042] As used herein, a subject who is "psilocybin-naive" has not previously been exposed to psilocybin.

[0043] As used herein, the following Medical Dictionary of Clinical Terms (MedDRA) terms are considered to be adverse events that are psychotomimetic in nature: mood changes, altered states of consciousness, self-image hallucinations, delusional perceptions, inhibition, dissociation, dissociative identity disorder, dream state, affective disorder, euphoric mood, abnormal sensations, hallucinations, hyperacusis, hyperesthesia, hypoesthesia, illusions, paranoia, olfactory paraesthesia, photophobia, paresthesia, altered time perception, thought disorder, synesthesia, substance-induced psychotic distress, and somatic hallucinations.

[0044] As used herein, a therapy or therapeutic agent that is administered "concurrently" with another drug is administered within one day of the other drug. In some embodiments, a therapy or therapeutic agent that is administered concurrently with another drug is administered at about the same time, within about 5 minutes, within about 10 minutes, within about 15 minutes, within about 20 minutes, within about 30 minutes, within about 45 minutes, within about 1 hour, within about 2 hours, within about 3 hours, within about 4 hours, within about 5 hours, within about 6 hours, within about 7 hours, within about 8 hours, within about 9 hours, within about 10 hours, within about 11 hours, within about 12 hours, within about 13 hours, within about 14 hours, within about 15 hours, within about 16 hours, within about 17 hours, within about 18 hours, within about 19 hours, within about 20 hours, within about 21 hours, within about 22 hours, within about 23 hours, or within about 24 hours of the administration of the other drug.

[0045] Psilocybin In some embodiments, the method of treatment comprises administering to a subject in need of treatment a therapeutically effective amount of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin, as described herein. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of psilocybin, as described herein. In some embodiments, the method of treatment comprises administering a therapeutically effective amount of psilocin, as described herein. Some embodiments comprise psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin, as described herein, for use in treating an indication. Some embodiments comprise psilocybin for use in treating an indication, as described herein. Some embodiments comprise psilocin for use in treating an indication, as described herein. Some embodiments comprise the use of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin, as described herein, in the manufacture of a medicament for treating an indication.

[0046] The numbered structural formula of psilocybin is shown in Figure 1. Novel polymorphs and hydrates of psilocybin, and their preparation and formulations, are disclosed in U.S. Application No. US2019 / 0119310 A1, which is incorporated herein by reference in its entirety. US2019 / 0119310 discloses several formulations and challenges in formulating psilocybin due to, for example, its hygroscopicity and poor flow properties. US2019 / 0119310 also discloses the importance of a controlled aqueous crystallization process.

[0047] In some embodiments, the psilocybin comprises crystalline psilocybin in the form of polymorph A or polymorph A', as described herein, wherein the crystalline psilocybin exhibits peaks at 11.5, 12.0, and 14.5°2θ±0.1°2θ in an X-ray powder diffraction (XRPD) diffractogram. In some embodiments, the crystalline psilocybin further exhibits at least one peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ in an XRPD diffractogram. Exemplary XRPD diffractograms are provided as Figures 2A and 2B. In some embodiments, the crystalline psilocybin exhibits an endothermic event in a DSC thermogram having a first onset temperature between 145°C and 165°C and a second onset temperature between 205°C and 220°C. Exemplary DSC thermograms are provided as Figures 3A and 3B.

[0048] 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 additional peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ, an XRPD diffractogram substantially as shown in Figure 2a; or An endothermic event in a DSC thermogram having a first onset temperature of 145°C to 165°C and a second onset temperature of 205°C to 220°C, substantially as shown in Figure 3a.

[0049] In some embodiments, the peak at 17.5°2θ±0.1°2θ has a relative intensity that is at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% greater than the peak at 14.5°2θ±0.1°2θ.

[0050] In some embodiments, the present disclosure provides crystalline psilocybin in the form of Polymorph A, which is characterized by one or more of the following: Peaks at 11.5, 12.0, 14.5, and 17.5°2θ±0.2°2θ in the XRPD diffractogram, a peak in an XRPD diffractogram characterized by peaks at 11.5, 12.0, 14.5, and 17.5°2θ±0.2°2θ and at least one further peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.2°2θ, an XRPD diffractogram substantially as shown in Figure 2a; or An endothermic event in a DSC thermogram having a first onset temperature of 145°C to 165°C and a second onset temperature of 205°C to 220°C, substantially as shown in Figure 3a.

[0051] In some embodiments, crystalline psilocybin of Polymorph A exhibits an XRPD diffractogram having at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of the peaks listed in Table 1, or equivalent peaks within about ±0.1 degrees 2θ of the peaks listed in Table 1. In some embodiments, crystalline psilocybin of Polymorph A exhibits an XRPD diffractogram having at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of the peaks listed in Table 1, or equivalent peaks within about ±0.2 degrees 2θ of the peaks listed in Table 1. In some embodiments, Polymorph A exhibits a peak at 17.5 degrees 2θ ±0.1 degrees 2θ that is substantially absent in Polymorph A′. In some embodiments, polymorph A exhibits a peak at 17.5° 2θ±0.2° 2θ that is substantially absent in polymorph A′. [Table 1]

[0052] In some embodiments, crystalline psilocybin polymorph A exhibits XRPD diffractogram peaks at 11.5, 12.0, 14.5, and 17.5 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least one additional peak occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least two additional peaks occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least three additional peaks occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ. In some embodiments, crystalline psilocybin polymorph A exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in Figure 2A.

[0053] In some embodiments, crystalline psilocybin polymorph Form A is characterized by XRPD diffractogram peaks at 14.5 and 17.5°2θ±0.1°2θ, wherein the peak at 17.5°2θ has an intensity that is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% of the intensity of the peak at 14.5°2θ.

[0054] 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.

[0055] In some embodiments, crystalline psilocybin polymorph A is characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 145° C. and 165° C., e.g., between 145° C. and 160° C., or e.g., between 145° C. and 155° C., and a second onset temperature of between 205° C. and 220° C., e.g., between 210° C. and 220° C., e.g., between 210° C. and 218° C., or e.g., between 210° C. and 216° C. In some embodiments, crystalline psilocybin polymorph A exhibits an endothermic event in a DSC thermogram having an onset temperature of about 205° C. to about 220° C., about 210° C. to about 220° C., about 210° C. to about 218° C., or about 210° C. to about 216° C. In some embodiments, crystalline psilocybin polymorph A further exhibits an endothermic event in a DSC thermogram with an onset temperature of about 145° C. to about 165° C., about 145° C. to about 160° C., or about 145° C. to about 155° C. In some embodiments, crystalline psilocybin polymorph A exhibits an endothermic event in a DSC thermogram with an onset temperature of about 205° C. to about 220° C., about 210° C. to about 220° C., about 210° C. to about 218° C., or about 210° C. to about 216° C., and an endothermic event with an onset temperature of about 145° C. to about 165° C., about 145° C. to about 160° C., or about 145° C. to about 155° C. In some embodiments, crystalline psilocybin polymorph A exhibits a DSC thermogram substantially the same as the DSC thermogram of FIG. 3A.

[0056] In some embodiments, crystalline psilocybin polymorph A exhibits a water content of less than 0.5 wt.%, less than <0.4 wt.%, less than 0.3 wt.%, less than 0.2 wt.%, or less than 0.1 wt.%. The water content of a crystalline compound can be determined by known methods, such as Karl Fischer titration. In some embodiments, crystalline psilocybin polymorph A exhibits a weight loss of less than 0.5 wt.%, less than 0.4 wt.%, less than 0.3 wt.%, less than 0.2 wt.%, or less than 0.1 wt.% in a TGA thermogram at ambient temperatures, e.g., about 25°C to 200°C. In some embodiments, 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, e.g., a loss-on-drying test performed at 70°C.

[0057] In some embodiments, the crystalline psilocybin polymorph A is a highly pure crystalline form of polymorph A, e.g., in a loss on drying test, the psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of crystalline psilocybin polymorph A.

[0058] In some embodiments, crystalline psilocybin polymorph A is a white to off-white solid.

[0059] In some embodiments, the crystalline psilocybin polymorph A is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph A contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A does not contain levels of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, the crystalline psilocybin polymorph A has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0060] 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.

[0061] In another embodiment, the disclosure provides a method for the large-scale production of psilocybin, the method comprising subjecting psilocybin to a water crystallization step with controlled drying to produce crystalline psilocybin polymorph A, which exhibits the XRPD diffractogram shown in Figure 2A and the DSC and TGA thermograms shown in Figure 3A. In another embodiment, the disclosure provides a method for the large-scale production of psilocybin, the method comprising subjecting psilocybin to a water crystallization step with controlled drying to produce high-purity crystalline psilocybin polymorph A, which exhibits the XRPD diffractogram shown in Figure 2A and the DSC thermogram shown in Figure 3A.

[0062] In another embodiment of the present disclosure, psilocybin is recrystallized in about 10-20 volumes of water, stirred and heated to a temperature of at least 70°C, polish filtered to a suitable cutoff (typically less than 5 μm), seeded at a temperature of about 70°C, and cooled in a controlled manner to about 5°C over a period of more than two hours.

[0063] In some embodiments, recrystallization of psilocybin involves controlled cooling, decreasing the temperature by about 5°C to 15°C per hour, more preferably about 10°C per hour. In certain embodiments, the polish filtration step is performed through an appropriately sized filter, such as, but not limited to, a 1.2 μm line filter.

[0064] In some embodiments, the stirring is performed by stirring at about 400-500 rpm, typically about 450 rpm.

[0065] In some embodiments, the psilocybin is dissolved in water heated to no more than 90° C. In some embodiments, the psilocybin is dissolved in water heated to no more than 85° C. Without being bound to any particular mechanism, this dissolution step is intended to solubilize the psilocybin while minimizing the formation of hydrolysis products.

[0066] In some embodiments, the psilocybin solution is agitated to speed solubilization and reduce the amount of time the solution is at elevated temperatures, i.e., 80° C. or higher.

[0067] 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.

[0068] In some embodiments, the psilocybin of the crystalline psilocybin is isolated by vacuum filtration.

[0069] In some embodiments, the isolated crystals are vacuum dried at a temperature of at least 30°C, e.g., 30-50°C, or e.g., 40-50°C. In some embodiments, the isolated crystals are vacuum dried for at least 10 hours, e.g., 12-18 hours, or e.g., about 30 hours. In some embodiments, the isolated crystals are vacuum dried at a temperature of at least 30°C, e.g., 30-50°C, or 40-50°C, for at least 10 hours, e.g., 12-18 hours, or e.g., about 30 hours. In some embodiments, the isolated crystals are dried until the isolated crystals lose less than 2% by weight, e.g., less than 0.5% by weight, in a loss-on-drying test.

[0070] In some embodiments, the isolated crystals are washed several times in water and dried under vacuum at about 50° C. for at least 12 hours.

[0071] 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.

[0072] In contrast, crystals obtained without controlled cooling are much smaller in size (typically 5-50 microns) when viewed under a 10x microscope.

[0073] In some embodiments, provided is psilocybin obtained by the crystallization methods described herein.

[0074] In some embodiments, pharmaceutical formulations are provided that include psilocybin polymorph A obtained by the crystallization methods described herein.

[0075] In some embodiments, the pre-crystallization-produced psilocybin may be produced using one of a synthetic or biological method, for example, by fermentation, or may be obtained by extraction from mushrooms. In some embodiments, the pre-crystallization-produced psilocybin is produced according to all or part of the method described in U.S. Application No. 2019 / 0119310 A1, which is incorporated herein by reference in its entirety.

[0076] Polymorph A' The present disclosure provides crystalline psilocybin in the form of Polymorph A′, characterized by one or more of the following: (i) peaks in an XRPD diffractogram at 11.5, 12.0, and 14.5°2θ±0.1°2θ, but with the peak at 17.5°2θ±0.1°2θ absent or substantially absent; (ii) peaks in an XRPD diffractogram at 11.5, 12.0, and 14.5 °2θ ± 0.1 °2θ, but with the peak at 17.5 °2θ ± 0.1 °2θ absent or substantially absent, and further characterized by at least one additional peak at 19.7, 20.4, 22.2, 24.3, or 25.7 °2θ ± 0.1 °2θ; (iii) an XRPD diffractogram substantially as shown in Figure 2B; or (iv) An endothermic event in a DSC thermogram having a first onset temperature between 145°C and 165°C and a second onset temperature between 205°C and 220°C, substantially as shown in Figure 3B.

[0077] In some embodiments, the crystalline psilocybin comprises crystalline psilocybin polymorph A'. Crystalline psilocybin polymorph A' exhibits peaks at 11.5, 12.0, and 14.5°2θ±0.1°2θ in an XRPD diffractogram, with the peak at 17.5°2θ±0.1°2θ being absent or substantially absent. In some embodiments, crystalline psilocybin polymorph A' further exhibits one, two, three, four, or five peaks selected from 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ. An exemplary XRPD diffractogram for Polymorph A' is provided as Figure 2B. An exemplary DSC thermogram for Polymorph A' having an onset temperature of 205-220°C is provided as Figure 3B.

[0078] In some embodiments, psilocybin polymorph A' exhibits an XRPD diffractogram summarized in Table 2. In some embodiments, crystalline psilocybin polymorph A' exhibits at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks listed in Table 2, or equivalent peaks within about ±0.1 degrees 2θ, with the peak at 17.5 degrees 2θ ±0.1 degrees 2θ being absent or substantially absent. [Table 2]

[0079] In some embodiments, crystalline psilocybin polymorph A' exhibits XRPD diffractogram peaks at 11.5, 12.0, and 14.5 degrees 2θ ± 0.1 degrees 2θ, with the peak at 17.5 degrees 2θ ± 0.1 degrees 2θ being substantially absent. In some embodiments, crystalline psilocybin polymorph A' further exhibits at least one additional peak occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 degrees 2θ ± 0.1 degrees 2θ. In some embodiments, crystalline psilocybin polymorph A exhibits at least two additional peaks occurring at 19.7, 20.4, 22.2, 24.3, or 25.7 degrees 2θ ± 0.1 degrees 2θ. In some embodiments, crystalline psilocybin polymorph A' exhibits polymorph A and is distinguished from polymorph A by the presence of a peak occurring at 10.1 degrees 2θ ± 0.1 degrees 2θ. In yet another embodiment, crystalline psilocybin polymorph A' exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in Figure 2B.

[0080] In some embodiments, crystalline psilocybin polymorph A' exhibits XRPD diffractogram peaks at 14.5 and 17.5°2θ±0.1°2θ, wherein the intensity of the peak at 17.5°2θ is less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the intensity of the peak at 14.5°2θ.

[0081] In some embodiments, crystalline psilocybin polymorph Form A' exhibits XRPD diffractogram peaks at 10.1 and 14.5°2θ±0.1°2θ, wherein the intensity of the peak at 10.1°2θ is at least 1%, at least 2%, at least 3%, or at least 4% of the intensity of the peak at 14.5°2θ.

[0082] In some embodiments, crystalline psilocybin polymorph A' is characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 145° C. and 165° C., e.g., between 145° C. and 160° C., or e.g., between 145° C. and 155° C., and a second onset temperature of between 205° C. and 220° C., e.g., between 210° C. and 220° C., e.g., between 210° C. and 218° C., or e.g., between 210° C. and 216° C. In some embodiments, crystalline psilocybin polymorph A' is characterized by an endothermic event in a DSC thermogram having an onset temperature of about 205° C. to about 220° C., about 210° C. to about 220° C., about 210° C. to about 218° C., or about 210° C. to about 216° C. In some embodiments, crystalline psilocybin polymorph A' exhibits an endothermic event in a DSC thermogram with an onset temperature of about 145°C to about 165°C, about 145°C to about 160°C, or about 145°C to about 155°C. In some embodiments, crystalline psilocybin polymorph A' exhibits an endothermic event in a DSC thermogram with an onset temperature of about 205°C to about 220°C, about 210°C to about 220°C, about 210°C to about 218°C, or about 210°C to about 216°C, and an endothermic event with an onset temperature of about 145°C to about 165°C, about 145°C to about 160°C, or about 145°C to about 155°C. In some embodiments, crystalline psilocybin polymorph A' exhibits a DSC thermogram substantially the same as the DSC thermogram in FIG. 3B.

[0083] In some embodiments, crystalline psilocybin polymorph A' exhibits a water content of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight. Methods for determining the water content of crystalline compounds are known, such as Karl Fischer titration. In some embodiments, crystalline psilocybin polymorph A' exhibits a weight loss of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight in a TGA thermogram at ambient temperatures, e.g., between 25°C and 200°C. In some embodiments, crystalline psilocybin polymorph A' loses less than 2%, less than 1%, or less than 0.5% by weight in a loss-on-drying test. In some embodiments, the loss-on-drying test is performed at 70°C.

[0084] In some embodiments, the crystalline psilocybin polymorph A' is a highly purified crystalline form of Polymorph A'. In some embodiments, the crystalline psilocybin comprises at least 90%, 95%, 99%, or 99.5% by weight of Polymorph A'.

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

[0087] In some embodiments, the crystalline psilocybin polymorph A' is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph A' has greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A' has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' does not contain a level of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A' has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin polymorph A' has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0088] 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.

[0089] 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.

[0090] In some embodiments, crystalline psilocybin polymorph A or polymorph A' is a white to off-white solid and / or has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, such as 31 It has no impurity phosphate as measured by P NMR or no impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' does not contain a level of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph A or polymorph A' has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin Polymorph A or Polymorph A' has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0091] Heating of Form A or A' results in an endothermic event with an onset temperature of approximately 150 °C, corresponding to the solid-solid transition of Form A or Form A' to Form B. Continued heating of the resulting solid, Form B, results in a second endothermic event corresponding to the melting point with an onset temperature of 205-220 °C (see Figures 3A and 3B).

[0092] Hydrate A In some embodiments, the disclosure provides a crystalline form of psilocybin hydrate A. In some embodiments, crystalline psilocybin hydrate A exhibits peaks at 8.9, 12.6, and 13.8 °2θ ± 0.1 °2θ in an XRPD diffractogram. In some embodiments, crystalline psilocybin hydrate A further exhibits at least one, two, three, four, or five additional peaks at 6.5, 12.2, 19.4, 20.4, or 20.8 °2θ ± 0.1 °2θ. An exemplary XRPD diffractogram is provided as FIG. 2D. In some embodiments, crystalline psilocybin hydrate A further exhibits endothermic events in a DSC thermogram having a first onset temperature between 90°C and 100°C, a second onset temperature between 100°C and 120°C, and a third onset temperature between 210°C and 220°C. An exemplary DSC thermogram is provided as FIG. 2D.

[0093] In some embodiments, psilocybin hydrate A exhibits an XRPD diffractogram comprising at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks listed in Table 3, or equivalent peaks within about ±0.1° 2θ. [Table 3]

[0094] 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 AA 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 .

[0095] In certain embodiments, crystalline psilocybin hydrate A is characterized by an endothermic event in a DSC thermogram having a first onset temperature between 85° C. and 105° C., e.g., between 90° C. and 100° C., and most preferably about 96° C., a second onset temperature between 100° C. and 120° C., e.g., between 105° C. and 115° C., and most preferably about 109° C., and a third onset temperature between 205° C. and 220° C., e.g., between 210° C. and 220° C., e.g., between 210° C. and 218° C., or between 210° C. and 216° C., or about 216° C. In some embodiments, crystalline psilocybin hydrate A exhibits an endothermic event in a DSC thermogram having an onset temperature between about 205° C. and about 220° C., between about 210° C. and about 220° C., between about 210° C. and about 218° C., or between about 210° C. and about 216° C. In some embodiments, crystalline psilocybin hydrate A exhibits an endothermic event in a DSC thermogram with an onset temperature of about 85° C. to about 105° C., or about 90° C. to about 100° C. In some embodiments, crystalline psilocybin hydrate A exhibits an endothermic event in a DSC thermogram with an onset temperature of about 205 to about 220° C., about 210 to about 220° C., about 210 to about 218° C., or about 210 to about 216° C., and an endothermic event with an onset temperature of about 85 to about 105° C., or about 90 to about 100° C. In some embodiments, crystalline psilocybin hydrate A exhibits a DSC thermogram substantially the same as the DSC thermogram of FIG. 3D.

[0096] In some embodiments, crystalline psilocybin hydrate A exhibits a water content of about 10 to about 18%, about 12 to about 16%, or about 13%. Methods for determining the water content of crystalline compounds are known, such as Karl Fischer titration. In some embodiments, crystalline psilocybin hydrate A exhibits a weight loss of about 10 to about 18%, about 12 to about 16%, or about 13% in a TGA thermogram at ambient temperatures, between about 25°C and 120°C.

[0097] In some embodiments, crystalline psilocybin hydrate A is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, crystalline psilocybin hydrate A contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31 It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin hydrate A has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin hydrate A has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin hydrate A does not contain a level of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin hydrate A has 31 It does not contain phosphoric acid at levels greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin hydrate A has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0098] In some embodiments, the crystalline psilocybin hydrate A is a highly purified crystalline form of hydrate A. In some embodiments, the crystalline psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of hydrate A.

[0099] Polymorph B In some embodiments, the present disclosure provides crystalline psilocybin polymorph B. In some embodiments, crystalline psilocybin polymorph B exhibits peaks at 11.1, 11.8, and 14.3°2θ ± 0.1°2θ in an XRPD diffractogram. In some embodiments, crystalline psilocybin polymorph B exhibits at least one, two, three, four, or five peaks at 14.9, 15.4, 19.3, 20.0, or 20.6°2θ ± 0.1°2θ in an XRPD diffractogram. An exemplary XRPD diffractogram of crystalline psilocybin polymorph B is provided as Figure 2C. In some embodiments, crystalline psilocybin polymorph B exhibits a single endothermic event in a DSC thermogram with an onset temperature of about 205 to about 220°C. An exemplary DSC thermogram of crystalline psilocybin polymorph B is provided as Figure 3C.

[0100] In some embodiments, psilocybin polymorph Form B exhibits an XRPD diffractogram comprising at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks listed in Table 4, or equivalent peaks within about ±0.1 degrees 2θ. [Table 4]

[0101] 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.

[0102] 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.

[0103] In some embodiments, crystalline psilocybin polymorph B exhibits a water content of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight. Methods for determining the water content of crystalline compounds are known, such as Karl Fischer titration. In some embodiments, crystalline psilocybin polymorph B exhibits a weight loss of less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% by weight in a TGA thermogram at ambient temperatures, e.g., 25°C to 200°C. In some embodiments, crystalline psilocybin polymorph A' loses less than 2%, less than 1%, or less than 0.5% by weight in a loss-on-drying test. In some embodiments, the loss-on-drying test is performed at 70°C.

[0104] In some embodiments, the crystalline psilocybin polymorph B is a highly purified crystalline form of polymorph B, e.g., the psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of polymorph B.

[0105] In some embodiments, the crystalline psilocybin polymorph B is chemically pure, e.g., the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, the crystalline psilocybin polymorph B contains greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% of a single impurity, e.g., 31It has no impurity phosphate as measured by P NMR or impurity psilocin as measured by HPLC. In some embodiments, crystalline psilocybin polymorph B has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC. In some embodiments, crystalline psilocybin polymorph B has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph B does not contain levels of psilocin greater than 1 area%, greater than 0.5 area%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by HPLC. In some embodiments, crystalline psilocybin polymorph B has 31 It does not contain levels of phosphate greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% by weight as measured by P NMR. In some embodiments, crystalline psilocybin polymorph B has a chemical assay of at least 95%, at least 96%, or at least 98% by weight.

[0106] In some embodiments, the psilocybin of the present disclosure in the form of Polymorph A or A' has the general properties shown in Table 5. [Table 5]

[0107] In some embodiments, the psilocybin fits the spectrum as shown in Table 6 and illustrated in the spectra of Figures 5-8. [Table 6]

[0108] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0109] 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.

[0110] In some embodiments, the present disclosure provides crystalline psilocybin in the form of Polymorph A or Polymorph A' for use in treating a subject in need thereof. Alternatively, independently, the crystalline psilocybin may be in the form of Hydrate A or Polymorph B.

[0111] In some embodiments, the present disclosure provides crystalline psilocybin polymorph A or polymorph A' for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides crystalline psilocybin polymorph A or polymorph A' for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides crystalline psilocybin polymorph A for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides crystalline psilocybin polymorph A' for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides high-purity crystalline psilocybin polymorph A for use in treating a subject in need of treatment. In some embodiments, the present disclosure provides high-purity crystalline psilocybin polymorph A' for use in treating a subject in need of treatment.

[0112] Pharmaceutical Compositions and Formulations In some embodiments, the present disclosure provides pharmaceutical compositions comprising crystalline psilocybin and one or more pharmaceutically acceptable carriers or excipients.

[0113] In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity psilocybin and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising crystalline psilocybin polymorph A and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising crystalline psilocybin polymorph A' and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity crystalline psilocybin, Polymorph A, or Polymorph A' and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity crystalline psilocybin polymorph A and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising high-purity crystalline psilocybin polymorph A' and one or more pharmaceutically acceptable carriers or excipients.

[0114] 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.

[0115] In some embodiments, the oral dosage form also includes a disintegrant such as, but not limited to, starch glycolate, croscarmellose sodium, and / or mixtures thereof. In some embodiments, the oral dosage form includes 3% or less by weight of disintegrant, less than 3% by weight of disintegrant, and more than 0.001% by weight of disintegrant, about 2.5% or less by weight of disintegrant, 2% or less by weight of disintegrant, 1.5% or less by weight of disintegrant, 1% or less by weight of disintegrant, 0.7% or less by weight of disintegrant, 0.5% or less by weight of disintegrant, or 0.3% or less by weight of disintegrant.

[0116] In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the sodium starch glycolate is present at less than 3% by weight. In other embodiments, the sodium starch glycolate is present at about 2% by weight or less, about 2% by weight, about 1% by weight or less, about 1% by weight or less, about 0.7% by weight or less, about 0.7% by weight, about 0.7% 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.

[0117] In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0118] In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0119] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%-1.0%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0120] In some embodiments, crystalline psilocybin is provided in the form of Polymorph A or Polymorph A' 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.

[0121] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0122] In some embodiments, there is provided crystalline psilocybin, particularly, but not essentially, in the form of Polymorph A or Polymorph A', for use in treating central nervous system disorders.

[0123] Alternatively, independently, the crystalline psilocybin may be in the form of hydrate A or polymorph B.

[0124] In some embodiments, the pharmaceutical formulation is a parenteral dosage form. In some embodiments, the pharmaceutical formulation is an oral dosage form. In some embodiments, the pharmaceutical composition comprises a tablet. In some embodiments, the pharmaceutical composition comprises a capsule. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, two or more dosage forms are administered to a subject substantially simultaneously. In some embodiments, a subject may receive an entire therapeutic dose in one tablet or capsule. In some embodiments, a therapeutic dose may be divided among multiple tablets or capsules. For example, for a 25 mg dose, a subject may receive five tablets or capsules each containing 25 mg of psilocybin. Alternatively, for a 10 mg dose, a subject may receive two tablets or capsules each containing 5 mg of psilocybin.

[0125] 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.

[0126] In some embodiments, the silicided microcrystalline filler may comprise a first filler having a particle size range of about 45-80 microns in an amount of up to 30%, up to 20%, up to 15% or less by weight of the filler, and a second filler having a particle size range of about 90-150 microns in an amount of up to 70%, up to 80%, up to 85% or more by weight of the filler.

[0127] In some embodiments, the oral dosage form may comprise silicified microcrystalline cellulose (SMCC 50) having a particle size of about 45-80 microns, such as Prosolv 50, silicified microcrystalline cellulose (SMCC 90) having a particle size of about 90-150 microns, such as Prosolv 90, or a mixture thereof. In other embodiments, the oral dosage form may comprise a mixture of SMCC 50 and SMCC In other embodiments, the oral dosage form may comprise SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:5 to 1:8 wt%. In still other embodiments, the ratio of SMCC 50 to SMCC 90 is 1:5 to 1:7, 1:6 to 1:7, 1:6 to 1:8, or 1.7 to 1.8. In still other embodiments, the ratio of SMCC 50 to SMCC 90 is 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, or 1:7.

[0128] 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.

[0129] 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.

[0130] In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0131] In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0132] In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 1%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%-1.0%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin, SMCC 50, and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1:6.4, and the sodium starch glycolate is about 0.5%.

[0133] In some embodiments, the oral dosage form comprises 5 mg of crystalline psilocybin in the form of Polymorph A, 12.5 mg of SMCC 50, 79.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate. In some embodiments, the tablet or capsule comprises 5 mg of crystalline psilocybin in the form of Polymorph A, 12.5 mg of SMCC 50, 79.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate.

[0134] In some embodiments, the oral dosage form comprises 1 mg of crystalline psilocybin in the form of Polymorph A, 20.5 mg of SMCC 50, 75.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate. In some embodiments, the tablet or capsule comprises 1 mg of crystalline psilocybin in the form of Polymorph A, 20.5 mg of SMCC 50, 75.5 mg of SMCC 90, 1 mg of sodium starch glycolate, 1 mg of colloidal silicon dioxide, and 1 mg of sodium stearyl fumarate.

[0135] In some embodiments, the tablet or capsule comprises one or more excipients. Non-limiting exemplary excipients include microcrystalline cellulose, including but not limited to silicified microcrystalline cellulose, and starch.

[0136] It should be noted that the formulations may contain psilocybin in any form, not just the polymorphic forms disclosed herein.

[0137] As used herein, oral doses of psilocybin are categorized as "very low doses" (about 0.045 mg / kg or less), "low doses" (about 0.115 to about 0.125 mg / kg), "moderate doses" (about 0.115 to about 0.260 mg / kg), and "high doses" (about 0.315 mg / kg or more). See Studerus et al (2011) J Psychopharmacol 25(11) 1434-1452.

[0138] In some embodiments, the formulated dose of psilocybin comprises from about 0.01 mg / kg to about 1 mg / kg, and in some embodiments, a human dose (for an adult weighing 60-80 kg) comprises from about 0.60 mg to about 80 mg.

[0139] In some embodiments, the formulated dose contains about 2 to about 50 mg of crystalline psilocybin. In some embodiments, the formulated dose contains 2 to 40 mg, 2 to 10 mg, 5 to 30 mg, 5 to 15 mg, or 20 to 30 mg of crystalline psilocybin. In some embodiments, the formulated dose contains about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin.

[0140] In some embodiments, the formulated dose contains about 2 mg to about 50 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof. In some embodiments, the formulated dose contains 2 mg to 40 mg, 2 mg to 10 mg, 5 mg to 30 mg, 5 mg to 15 mg, or 20 mg to 30 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof. In some embodiments, the formulated dose contains about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof. In some embodiments, the formulated dose contains about 5 mg of crystalline psilocybin polymorph A or polymorph A', or a mixture thereof.

[0141] 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 about 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.

[0142] 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'.

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

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

[0145] 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.

[0146] 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.

[0147] In some embodiments, an adult oral dose contains about 1 mg to about 40 mg, about 2 mg to about 30 mg, or about 15 mg to about 30 mg of crystalline psilocybin, e.g., about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin. In some embodiments, an adult oral dose contains about 25 mg of crystalline psilocybin. In some embodiments, the crystalline psilocybin is in the form of Polymorph A.

[0148] In some embodiments, a "microdose" of psilocybin is administered to a subject. A microdose may contain, for example, about 0.05 mg to about 2.5 mg of crystalline psilocybin, such as about 1.0 mg. In the case of microdosing, the regime may include, for example, a regular, continuous regime of daily administration, every other day administration, or weekly administration. Such administration may be without psychological support.

[0149] 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.

[0150] In some embodiments, psilocybin is administered at a therapeutically effective interval. In some embodiments, the therapeutically effective interval may be about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, the therapeutically effective interval may be about 1 month, about 3 months, about 6 months, or about 12 months. In some embodiments, psilocybin is administered once daily. In some embodiments, psilocybin is administered at least once per week or at least twice per week. In some embodiments, psilocybin is administered at least once per month or at least twice per month. In some embodiments, psilocybin is administered at least once every 3 months, at least once every 6 months, or at least once every 12 months.

[0151] In some embodiments, a first dose and a second dose of psilocybin are administered to a subject. In some embodiments, the first dose is about 1 mg and the second dose is about 1 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 1 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 1 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 1 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 1 mg.

[0152] 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.

[0153] Route of administration Exemplary modes for administration of psilocybin include oral, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular [including administration to skeletal muscle, diaphragm muscle, and / or cardiac muscle], intradermal, intrapleural, intracerebral, and intra-articular), topical (e.g., to both cutaneous and mucosal surfaces, including respiratory tract surfaces, and transdermal), inhalation (e.g., via aerosol), rectal (e.g., via suppository), transmucosal, intranasal, buccal (e.g., sublingual), intravaginal, intrathecal, intraocular, transdermal, intrauterine (or intraovo), intralymphatic, and direct tissue or organ injection (e.g., into the liver, skeletal muscle, cardiac muscle, diaphragm muscle, or brain). In some embodiments, psilocybin is administered orally to a subject.

[0154] Treatment method Those skilled in the art will understand that methods of treatment comprising administering psilocybin, a psilocybin prodrug, a psilocybin metabolite, and / or a psilocybin metabolite prodrug for the treatment of one or more of the indications described herein also include the use of psilocybin, a psilocybin prodrug, a psilocybin metabolite, and / or a psilocybin metabolite prodrug in the manufacture of a medicament for the treatment of one or more of the indications described herein, as well as the use of psilocybin, a psilocybin prodrug, a psilocybin metabolite, and / or a psilocybin metabolite prodrug for the treatment of one or more of the indications described herein.

[0155] 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.

[0156] In some embodiments, the method for treating a subject in need thereof comprises at least one of the following: (i) administering to a subject a therapeutically effective amount of psilocybin in a controlled environment, and providing the subject with psychological support; (ii) having the subject participate in one or more pre-administration psychological support session(s); and / or (ii) The subject participates in one or more post-administration psychological support session(s).

[0157] After administration of psilocybin, the subject may not feel the effects of the drug for about 30 minutes to about 90 minutes. In some embodiments, the subject may not feel the effects of the drug for about 60 minutes. This period after administration and before the onset of effects is referred to herein as the early phase of the psilocybin session. The time period characterized by the onset of the drug's effects is referred to herein as the early phase of the psilocybin session.

[0158] In some embodiments, the subject experiences the peak effects of the psilocybin between about 1.5 hours and about 3.5 hours after administration of the psilocybin. The period characterized by the peak psilocybin experience is referred to herein as the peak phase of the psilocybin session.

[0159] In some embodiments, the effects of psilocybin may substantially wear off between about 4 hours and about 6 hours after administration, a period referred to as the late phase of a psilocybin session.

[0160] In some embodiments, non-dual states (e.g., mystical experiences), or feelings of oneness, infinity, ego-annihilation, or transcendence correlate with positive clinical outcomes. Each of these terms can be generally defined as a breakdown of normal relationships between self and others, whereby a subject can feel a sense of oneness and increased connectedness to their surroundings and / or the world at large.

[0161] 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.

[0162] Factors that may influence the subjective experience of psilocybin include, for example, (i) the dose, (ii) the participant's mood before the session, (iii) the setting of the session, (iv) the subject's ability to focus and stay with the experience, and / or (v) the subject's previous experience with psychedelics. These and other factors are described in more detail below, along with methods for maximizing the therapeutic benefit of a psilocybin session.

[0163] Pre-administration psychological support session In some embodiments, the subject participates in at least one psychological support session prior to administration of psilocybin (the "pre-administration psychological support session"). In some embodiments, the pre-administration psychological support session may occur about one month prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about two weeks prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about one week prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about three days prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur about one day prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session may occur on the same day as administration of psilocybin, prior to administration.

[0164] In some embodiments, the subject may participate in one, two, three, four, five, six, seven, or eight pre-administration psychological support sessions. In some embodiments, the subject may participate in at least two pre-administration psychological support sessions. In some embodiments, the subject may participate in at least three pre-administration psychological support sessions. In some embodiments, the subject may participate in a pre-administration psychological support session at least once a week for at least two or three weeks before the psilocybin session. In some embodiments, the subject may participate in an additional pre-administration psychological support session the day before the psilocybin session.

[0165] The pre-administration psychological support session may be an individual session, with the subject meeting one-on-one with a therapist. In some embodiments, the psychological support session may be a group session, with two or more subjects meeting with one therapist or multiple therapists. In some embodiments, one or more of the subject's family or friends may attend the pre-administration psychological support session(s).

[0166] In some embodiments, the purpose of the pre-administration session may include (i) building a therapeutic alliance between the subject and the therapist, (ii) answering the subject's questions and addressing any concerns, and / or (iii) demonstrating and demonstrating self-directed inquiry and experiential processing skills. In some embodiments, the pre-administration psychological support session focuses on discussing possible psilocybin effects and / or preparing the subject for the administration session by implementing relevant therapeutic techniques for reducing avoidance and anxiety, eliciting appropriate treatment goals, building rapport, and / or building a therapeutic alliance. During the psychological support session, self-directed inquiry and experiential processing skills may be demonstrated and / or demonstrated.

[0167] In some embodiments, breathing exercises aimed at promoting calmness and / or relieving anxiety may be demonstrated and / or performed. In some embodiments, the breathing exercises include instructing the subject to focus on whole-body breathing and / or breathing-related sensations. For example, the subject may be instructed to breathe in for a count of four, hold the breath briefly, and then breathe out for a count of eight. In some embodiments, the therapist and subject may discuss the most beneficial ways to assist in case of emotional distress during the psilocybin session. In some embodiments, the subject is given access (e.g., online access) to materials regarding the safety and mechanism of action of psilocybin.

[0168] 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.

[0169] In some embodiments, the therapist is trained to counsel the subject before, during, and / or after the psilocybin session. In some embodiments, the therapist has mental health training. In some embodiments, the therapist is a clinical psychologist, psychiatrist, social worker, physician, or nurse. In some embodiments, the therapist meets the following criteria: ·Demonstrate independent clinical experience in direct subject care in areas requiring counseling and psychotherapeutic skills; · A current unrestricted professional license and / or good professional standing with no history of suspension, professional misconduct, or disciplinary action; and / or ·High level of openness to learning new approaches and receiving feedback.

[0170] Psychological support during psilocybin sessions During the treatment session, the subject may be supervised by one or more trained therapists. The therapist supervising the subject during the psilocybin session may be the same therapist as the subject's pre-administration psychological support session(s), or may be a different therapist. The therapist(s) may provide psychological support to the subject as needed. As used herein, the term "psychological support" refers to any measure(s) taken by the therapist during the subject's psilocybin session to ensure the subject's safety and maximize the clinical effectiveness of the psilocybin session. For example, psychological support may be provided by the therapist to (1) ensure the subject's psychological safety, (2) allow the subject's subjective experience to unfold naturally within the boundaries of the therapeutic intent established in the preparation, (3) maintain attention and awareness of the participant's current experience, thereby allowing the exposure and processing of difficult emotional states and personal memories, and / or (4) generate insights and solutions for the resolution of difficult personal situations, conflicts, and traumatic experiences. In some embodiments, assistance may be in the form of touch therapy, verbal reassurance, guided imagery, and / or relaxation or breathing exercises. In some embodiments, assistance may include reminders, encouragement, or active guidance. Typically, only one technique is applied at a time to allow for minimal intervention and interference with the subject's intrinsic processes.

[0171] In some embodiments, the therapist's primary therapeutic goals during a psilocybin session are (i) minimizing extreme anxiety and (ii) providing appropriate support to enable self-directed inquiry and experiential processing skills and processes. In some embodiments, the therapist demonstrates true presence, patience, curiosity, and / or openness during the psilocybin session. "Presence" refers to being fully available and present with the subject at all stages of the psilocybin session, and always exhibiting calmness. "Curiosity" refers to interest and willingness to understand the subject's experience without preconceptions. "Patience" refers to the therapist facilitating the participant's exploration of the experience, taking the time necessary to do so without suppressing the participant's natural impulse to assist or direct the experience. "Openness" refers to the therapist's ability to maintain a cognitively and experientially open state, including the ability to recognize how the subject's mind will uniquely orchestrate the unfolding content of the session. This includes welcoming all emotions and expressions that may arise.

[0172] In some embodiments, psychological support may include inquisitive questioning, in which brief yet detailed questions are asked of the subject ("How does that make you feel?") to help the subject shift and maintain attention across different levels of cognition and emotion. Because of its applicability across a wide range of mental states and in various settings, the inquisitive questioning technique can typically be used safely and consistently during psilocybin sessions, regardless of the quality or intensity of each subject's experience.

[0173] In some embodiments, the level of psychological support varies during different stages of a subject's psilocybin experience (e.g., initial, early, peak, and late). In some embodiments, the type of psychological support varies during different stages of a subject's psilocybin experience (e.g., initial, early, peak, and late). Because non-dual, ego-annihilating, or "integrative" experiences have been shown to positively correlate with the magnitude and durability of clinical response, in some embodiments, therapists pay particular attention to addressing such states.

[0174] In some embodiments, a subject may experience a compromised sense of self during their psilocybin experience. In some embodiments, this experience is interpreted from a psychoanalytic perspective as a breakdown of ego boundaries, resulting in a blurring of the distinction between self and object representations and preventing the integration of self representations into a coherent whole. In some embodiments, a non-dual, ego-annihilated, or "integrative" experience refers to an altered state of consciousness in which there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a loss of a sense of "self," and instead, only an undivided background awareness, often characterized by a sense of unity or "oneness" that transcends sensory or cognitive comprehension. In some embodiments, a non-dual experience is a state of consciousness in which the subject-object dichotomy of normal waking consciousness is replaced by a non-centered, undivided, integrated background awareness. In some embodiments, an ego-annihilated experience is a spontaneously occurring state of consciousness in which there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a loss of a sense of "self." In some embodiments, an integrative experience is one characterized by a sense of unity or "oneness" that goes beyond sensory or cognitive understanding.

[0175] During the initial and early stages of psilocybin sessions, psychological support may be used to reduce severe and / or prolonged anxiety. Anxiety before or during the onset of psilocybin effects is not uncommon, and therapists can be specially trained to recognize and actively manage the subject through such periods of anxiety until the subject feels comfortable enough to continue on their own. In some embodiments, the therapist validates the subject's feelings of anxiety without providing an interpretation of perceptual disturbances or directing the subject toward specific images or memories, other than encouraging the subject to relax and open up to emergent experiences. For example, in some embodiments, the therapist may use grounding exercises to help alleviate anxiety. In such exercises, the subject may be encouraged to pay attention to surrounding sounds or sensations on the skin when touching the bed / sofa, the ground, or other objects.

[0176] During the initial and early stages of a psilocybin session, the therapist may encourage the subject to lie down, practice relaxation and breathing exercises, and / or listen to calming music. In some embodiments, the therapist may remind the subject of the intent of the treatment session. For example, the therapist may ask the subject, "What does it feel like when you feel better or recovered?" or any number of similar questions. Such reminders provide an implicit orientation to the subjective experience during the psilocybin session, before or during the onset of the psilocybin effect. In some embodiments, the therapist may remind the subject that their primary task during this session is simply to gather new and interesting experiences that can be discussed with the therapist after the session. The therapist may remind the participant of the purpose of psilocybin therapy and the role of experiential processing, i.e., allowing the participant to be open and curious about whatever arises and to encounter thoughts and feelings previously unknown to the participant. In some embodiments, the therapist emphasizes that this process essentially requires a willing passivity to, and no mindfulness of, the psychedelic experience.

[0177] During acute behavioral onset, the subject may experience perceptual changes in visual, auditory, or olfactory modes, as well as a series of unusual physical sensations. These experiences may be anxiety-provoking. In some embodiments, the therapist may perform a reassuring "arm holding," where, at the subject's request, the therapist places a hand on the subject's wrist, arm, hand, or shoulder to help the subject feel at ease during this phase. This training may have been previously conducted in a pre-administration psychological support session.

[0178] 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.

[0179] In some embodiments, the therapist may encourage the subject to wear headphones and listen to music. In some embodiments, the headphones reduce external noise (e.g., "noise-canceling" headphones). In some embodiments, the music is calming music, such as instrumental (e.g., classical) music. In some embodiments, the music includes nature sounds and / or the sounds of moving water (e.g., ocean sounds). In some embodiments, the music includes isochronic sounds. In some embodiments, the music includes periods of silence. In some embodiments, the music is emotionally evocative. In some embodiments, the music includes a playlist that reflects the pharmacodynamics of a typical high-dose psilocybin session: early phase, early stage, peak phase, and late phase. In some embodiments, listening to music helps the subject focus on their internal experience.

[0180] In cases of long-term anxiety or distress, in some embodiments, the therapist may actively guide the participant through such an experience without interpreting or judging the experience or offering advice. Once the participant is comfortable, the therapist can encourage them to reconnect with introspection.

[0181] During the peak and later stages of psilocybin sessions, the therapist can encourage the subject to confront and explore their experiences, including difficult ones. The therapist can guide the subject to engage in self-directed inquiry and experiential processing to develop different perspectives on personal challenges and conflicts and generate unique solutions. Such self-generated insights can provide the subject with self-confidence as well as emotional resolution.

[0182] As used herein, the term "self-directed inquiry" refers to paying attention to internal states. The subject is encouraged to be curious about their moment-to-moment present experience, including foreground and background thoughts, feelings, and physical sensations. During the preparation and integration phases, this inquiry may mean asking specific, detailed questions that help direct attention to internal states. However, during periods of drug behavior, inquiry may simply mean being open to inner experiences.

[0183] As used herein, "experiential processing" refers to a participant's ability to maintain full attention to an experience that is recognized through self-directed inquiry. This includes the willingness and ability to stay with and / or move through uncomfortable or difficult thoughts, feelings, sensations, or emotions until the discomfort is alleviated or resolved.

[0184] In some embodiments, the therapist uses transdiagnostic therapy. In some embodiments, transdiagnostic therapy is Method of Level (MOL) therapy. In yet further embodiments, MOL therapy involves self-directed inquiry and experiential processing. Typically, MOL uses brief, yet detailed, and inquisitive questions to help the subject shift and maintain attention across different levels of cognition and emotion (Carey, 2006; Carey, Mansell, & Tai, 2015). The emphasis within MOL is to identify and address the subject's underlying distress, not just symptoms. Such MOL-related methods and techniques can include the following: (1) Self-Directed Inquiry—Attention to Inner State. Participants are encouraged to be curious about their present-moment experience, including foreground and background thoughts, emotions, and bodily sensations. During the preparation and integration phases, such inquiry can mean asking specific and detailed questions that help direct attention to inner state; however, in some embodiments, during periods of drug effect, inquiry can refer to an attitude of openness to inner experience. (2) Experiential Processing - refers to the ability to sustain a sustained focus on experience and maintain full attention on experiences that participants bring to consciousness through self-directed inquiry. This includes the willingness and ability to stay with and / or move through uncomfortable or difficult thoughts, feelings, sensations, or emotions until the discomfort is reduced or resolved.

[0185] In some embodiments, the psychological support comprises mindfulness-based therapy or cognitive behavioral therapy (CBT). In some embodiments, the psychological support is provided by a functional theory of human behavior called perceived control theory.

[0186] Occasionally, subjects seek distraction while avoiding new experiences or attempting to regain cognitive control over their abnormal state of mind. Such distraction can take different forms. For example, the subject may be premature to engage in conversation or to elaborate on their experiences, perspectives, or insights. When this occurs, the therapist can aim to remain silent as much as possible, thereby allowing the subject and their internal experiences to direct the course of the psilocybin session. In some embodiments, the therapist may use active listening skills paired with prompts to encourage the subject to remain focused on the current experience, especially if the participant engages the therapist in the conversation. In another example, the subject may request to go to the bathroom or get a drink of water. The sudden, urgent nature of such requests may suggest that they are truly trying to avoid the new material. In such cases, the therapist can encourage the subject to linger in the experience by simply redirecting their attention. For example, the therapist might say something like: "Let's take a bathroom break at the end of this music," or "We'll be handing out water shortly. Why don't you put the eye mask back on and relax for a few minutes?" If the subject is trying to avoid a difficult experience, they may listen to the suggestion and relax.

[0187] In some embodiments, spontaneous movement such as rocking, stretching, or dancing while engaging in an experience is acceptable and often encouraged, unless the movement is perceived as a way to distract from the experience. In some embodiments, if the subject is frequently constantly moving, they may be periodically provided with cues to return to a lying position and actively focus inward.

[0188] The therapist need not understand, endorse, or have an opinion about the nature or content of the subject's experiences, but the therapist can validate them and communicate openness to the subject's own perspective on them without denying or pathologizing any experiences based on their abnormal content. These experiences may offer the subject a perspective beyond identification with a personal narrative. In some embodiments, the therapist validates one or more of the subject's experiences. In some embodiments, validating an experience simply means having the courage to be open to the experience and acknowledging the possibility that any experience may serve the intent of the session.

[0189] In some embodiments, the therapist provides psychological support for approximately 4-8 hours immediately after administration of psilocybin. In some embodiments, the therapist uses guided imagery and / or breathing exercises to calm the subject and / or focus the subject's attention. In some embodiments, the therapist touches the subject's hand, arm, or shoulder. In some embodiments, the therapist counsels the subject to do one or more of the following: (1) accept feelings of anxiety, (2) allow the experience to unfold naturally, (3) avoid psychological resistance to the experience, (4) relax, and / or (5) explore the subject's own mental space.

[0190] In some embodiments, the therapist avoids initiating conversation with the subject but responds if the subject initiates a conversation. Typically, active intervention is kept to a minimum during the therapeutic experience. In some embodiments, the subject is encouraged to explore their own mental space, and simple guided imagery may be used to assist relaxation. "Guided imagery" refers to exercises that ask the subject to imagine a scene (e.g., "Picture a scene, perhaps a landscape, and tell me where you are," "Imagine a place where you feel safe").

[0191] Post-administration psychological support session In some embodiments, subjects may be encouraged to participate in a post-administration integration session with their therapist. Integration is a process that involves processing or embodying the psychedelic experience within a therapeutic context. This process begins with the subject verbalizing, reflecting on, and openly discussing with the therapist any experiences from the psilocybin session. Successful integration of the psilocybin experience involves addressing emotional changes and transforming the experience into new insights, perspectives, and new behaviors that can be used to benefit the subject's quality of life thereafter. New perspectives may then influence the participant's current knowledge or values, leading to new ways of relating to cognition, emotions, behavior, and physical experiences.

[0192] In some embodiments, the goals and support methods used by the therapist throughout an integrated session should remain consistent regardless of the intensity or content of the subjective experiences explored by the subject. Nevertheless, the support methods used by the therapist should accommodate all experiences the subject may have encountered.

[0193] The integration process should not be limited to sessions with the therapist and is likely to continue unfolding beyond clinic visits. Therapists may encourage participants to use methods such as spending time in nature, exercise, or creative expression to help further the process. Subjects may also be encouraged to discuss their experiences with friends, family, and / or support networks. The role of the integration session is not to comprehensively address the entire experience, but to empower participants by building their capacity to safely process information experientially. This allows subjects to continue self-directed integration outside of clinical study visits.

[0194] In some embodiments, the subject participates in at least one psychological support session after administration of psilocybin (the "post-administration psychological support session"). In some embodiments, the post-administration psychological support session may occur on the same day as the psilocybin session, after the effects of the psilocybin have substantially worn off. In some embodiments, the post-administration psychological support session may occur the day after the psilocybin session. In some embodiments, the post-administration psychological support session may occur two days after the psilocybin session. In some embodiments, the post-administration psychological support session may occur three days after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about one week after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about two weeks after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about one month after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about three months after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about six months after the psilocybin session. In some embodiments, the post-administration psychological support session may occur about 12 months after the psilocybin session.

[0195] In some embodiments, a subject may participate in 1, 2, 3, 4, 5, 6, 7, or 8 post-administration psychological support sessions, hi some embodiments, a subject may participate in at least 2, or at least 3 post-administration psychological support sessions.

[0196] The post-administration psychological support session may be an individual session, with the subject meeting one-on-one with a therapist. In some embodiments, the psychological support session may be a group session, with two or more subjects meeting with one therapist or multiple therapists. In some embodiments, one or more of the subject's family or friends may attend the post-administration psychological support session(s).

[0197] In some embodiments, post-administration psychological support sessions may focus on integrating the psilocybin experience. Integration may include processing the psychedelic experience in a therapeutic context. Integration may include psychological and somatic processing of the experience and successful assimilation of insights into the subject's life for the purposes of growth, healing, and / or well-being. In integration sessions, subjects may be encouraged to discuss and reflect on their experiences during the psilocybin session. In some embodiments, integration may include external expression of the psilocybin experience, such as word choice, tone of voice, gestures, and / or specific physical activities (e.g., yoga, exercise, bodywork, etc.). In some embodiments, integration includes creatively expressing any insights or experiences gained during the psilocybin experience, for example, through poetry, art, music / singing, dance, writing, or drawing.

[0198] In some embodiments, the subject may be encouraged to reflect on both the thoughts and emotions experienced during the psilocybin session and to express those thoughts and emotions in a tangible form that can serve as a tool for remembering and continuing to integrate those lessons in the future. In some embodiments, the subject may be encouraged to recognize and connect the range of emotional, cognitive, and physical experiences of the psilocybin session and relate them to current experiences in the subject's life situation. This may be achieved, for example, by discussing them initially with the therapist and perhaps later with family, friends, and supportive circles. Integration helps to respond to changes in emotional state as new insights are generated and integrated. When further explored through oscillating attention between foreground and background thoughts and emotions, such insights may lead to natural and effortless changes in perspective or behavior. In some embodiments, the integration process is not limited to the initial integration meeting with the therapist but continues to unfold spontaneously through the participant's own processing and behavior in everyday life.

[0199] In the case of low-intensity experiences, the integration process may focus on mental content that emerged during periods of relaxation and reflection, including reactions to what may have been unremarkable experiences such as disappointment, anger, or relief.

[0200] 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.

[0201] In some embodiments, the pre-administration therapy session is conducted remotely. In some embodiments, the post-administration therapy session (e.g., the integration session) is conducted remotely.

[0202] In some embodiments, psychological support is provided remotely during a subject's psilocybin session. For example, in some embodiments, the subject takes psilocybin at home, and a therapist provides psychological support via voice call, video call, text, email, etc., for at least 4-8 hours after the subject has taken the drug. In some embodiments, the subject takes psilocybin at a dosing facility described herein, and a therapist provides psychological support to the subject, and the therapist provides psychological support via voice call, video call, text, email, etc., for at least 4-8 hours after the subject has taken the drug.

[0203] 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: A digital or electronic system securely connects a subject with one or more therapists or physicians for a “virtual visit.” These virtual visits can be introductory or routine. A digital or electronic system allows subjects to qualify, pre-qualify, or enroll in a psilocybin-based clinical trial or a psilocybin-based psychological support session. The digital or electronic system is configured to help the therapist and / or physician manage and interact with the subject. 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 allow a subject to contact a therapist if the subject is feeling anxious or otherwise needs to urgently speak with a therapist. The digital or electronic system is configured to help the subject prepare for a visit with a therapist and / or physician. For example, the digital or electronic system may include information about psilocybin, treatment protocols, etc. A digital or electronic system is configured to allow a therapist to provide psychological support during a subject's 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.

[0204] In some embodiments, the digital or electronic system is an "app" for use on a mobile phone or computer. In some embodiments, the digital or electronic system is a website. In some embodiments, the digital or electronic system includes a "chat" feature that allows real-time communication between the subject and the therapist. In some embodiments, the website includes a video call feature that allows the therapist to communicate with the subject using video communication. In some embodiments, the digital or electronic system is configured to allow a single therapist to provide psychological support to one or more subjects simultaneously or contemporaneously.

[0205] In some embodiments, psychological support sessions may be pre-recorded (e.g., audio or video recorded) and provided to the subject via a digital or electronic system for use at the subject's convenience.

[0206] Management facilities, "Sets and Settings" As used herein, the term "set and setting" refers to the subject's perspective ("set") and the physical and social environment ("setting") in which a user has a psilocybin session. In some embodiments, psilocybin may be administered in a particular set and setting. In some embodiments, the set and setting are controlled to maximize, to the extent possible, the therapeutic benefit of the psilocybin session.

[0207] In some embodiments, psilocybin is administered by a facility specifically designed for psilocybin administration. Administering psilocybin to a subject in a facility where the subject feels safe and comfortable can help alleviate the subject's anxiety and promote maximum clinical benefit. For example, psilocybin may be administered to a subject in their own home or in a clinical facility.

[0208] In some embodiments, psilocybin is administered to a subject in a facility (e.g., a room) that has a substantially non-clinical appearance. For example, psilocybin can be administered in a room equipped with soft furniture (e.g., plush sofas, chairs, or pillows) and / or plants. In some embodiments, the room can be decorated using subdued colors (e.g., gray, dull, or unsaturated colors). In some embodiments, the light in the room is dimmed and / or the light level is kept relatively low or adjusted. In some embodiments, the room lighting is adjusted for intensity and / or color. In some embodiments, a virtual reality or augmented reality system (e.g., a computer with visual / graphical and auditory output) is used. In some embodiments, the room is equipped with a sound system, e.g., a high-resolution sound system. In some embodiments, the sound system can allow for simultaneous ambient and earphone listening. In some embodiments, the subject can bring a meaningful photo or object into the administration room.

[0209] In some embodiments, the room comprises a couch. In some embodiments, the room comprises a bed. In some embodiments, the room comprises more than one couch or bed, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 couches or beds. In some embodiments, the subject sits or lies on the couch or bed for about 4-8 hours, or a substantial portion thereof, immediately after administration of the psilocybin. In some embodiments, the subject listens to music for about 4-8 hours, or a substantial portion thereof, immediately after administration of the psilocybin. In some embodiments, the subject wears an eye mask for about 4-8 hours, or a substantial portion thereof, immediately after administration of the psilocybin. In some embodiments, the subject is provided with a weighted blanket.

[0210] In some embodiments, each subject is supervised by one therapist during the psilocybin session. In some embodiments, each subject is supervised by more than one therapist during the psilocybin session, such as two therapists, three therapists, four therapists, or five therapists. In some embodiments, one therapist has multiple subjects, and each subject participates in the psilocybin session. For example, one therapist can supervise two, three, four, five, six, seven, eight, nine, or ten subjects.

[0211] Embodiments of the present disclosure include the use of additional tools and / or techniques in conjunction with medication / administration, including various transcranial magnetic stimulation (TMS) methods and protocols, e.g., before or after one or more medication(s), biofeedback devices, etc.

[0212] Some embodiments can be used in conjunction with digital health products or digital solutions. The teachings of the present disclosure include utilizing such digital health products and / or associated digital biomarkers as diagnostic and / or prognostic assessment tools for patient monitoring and management before, during, and / or after treatment. Digital biomarkers may include, by way of non-limiting example, the number and / or duration of phone calls / emails / texts, word length in text communications, gestures used (taps, swipes, or other), gyroscope-derived information such as phone orientation, phone acceleration, keystroke patterns, location-derived information from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media use, sleep patterns, specific words or emojis used or not used, and / or the like. For example, in one embodiment, a digital health product can be utilized to track compliance, determine medication dosage and / or frequency, indications of need for re-dosing, re-dosing amounts, alerts, or warnings.

[0213] In some embodiments, the treatment method can include providing a clearance period for the subject or patient, during which such one or more drugs are absent or substantially removed from the subject's / patient's system. For example, the treatment method can be configured such that, at the time of administration, the subject is not taking other serotonergic agents, such as selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and / or antipsychotics. In some embodiments, the treatment method includes concurrent treatment with one or more drugs, including, but not limited to, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and / or monoamine oxidase inhibitors. In some embodiments, the methods include treatments in which the subject or patient takes concomitant compounds or medications including, but not limited to, benzodiazepines, cannabidiol (CBD) and / or other cannabinoids (e.g., THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabicyclomevarin), CBGM (cannabigerol monomethyl ether), CBE (cannabiertholin), CBT (cannabicitran), and / or the like), magnesium, levomefollic acid, for example, prior to, immediately prior to, and / or concurrently with receiving psilocybin.

[0214] In some embodiments, the methods include treatment in which the subject has not been taking one or more medications, particularly one or more serotonergic medications for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, 3 weeks, or 4 weeks prior to administration of the disclosed psilocybin compounds.

[0215] In some embodiments, the methods and / or treatments can include sub-perceptual dosing (e.g., doses of less than 3 mg, 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, or 0.1 mg) before and / or after administration of a single or multiple relatively large dose (given days to weeks apart), where the single or multiple relatively large dose is one or more of 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg or more, 45 mg or more, 50 mg or more.

[0216] 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.

[0217] In some embodiments, digital biomarkers may be identified from patterns in smartphone use, such as swipes, taps, and other touchscreen activity, and scientifically validated to provide measurements of subjective states, such as cognition and mood, including, by way of non-limiting example, those disclosed in one or more of the following, each of which is expressly incorporated by reference herein for all purposes: US2017 / 0086727, US2017 / 0258382, US2017 / 0258383, US2017 / 0287348, US10 / 148534, US97 / 37759, and / or US10 / 231651.

[0218] Biomarkers that may serve as diagnostic and / or prognostic tools for pre-treatment, during treatment, and / or post-treatment patient management may be identified using one or more of the following: number and / or duration of calls / emails / texts, word length in text communications, gestures used (taps, swipes, or other), information derived from a gyroscope, such as phone orientation, phone acceleration, keystroke patterns, location derived from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media usage, sleep patterns, specific words or emojis used or not used, and / or the like. In some embodiments, health components and / or connected biomonitors and / or smart devices / wearables may be utilized to collect information used in the diagnostic and / or prognostic output. For example, in some embodiments, a heart rate monitor or similar device can collect subject data and heart rate variability (e.g., as disclosed in US10058253, which is incorporated herein by reference in its entirety) can be used to assess / determine metrics related to the subject's current emotional state, relative changes in emotional state, etc., which can be used to determine new or subsequent treatment regimens, adjust treatment regimens, etc.

[0219] According to a further aspect of the present disclosure, there is provided a method of evaluating a subject before, during, and / or after treatment for a central nervous system disorder to determine whether to provide psilocybin treatment or further psilocybin treatment, the method comprising monitoring one or more biomarkers related to executive function, cognitive control, working memory, processing speed, and emotional valence, and determining treatment based on the outcome. The method may further include administering psilocybin for a first time or a subsequent time.

[0220] In some embodiments, biomarkers are identified from patterns in smartphone use, such as swipes, taps, and other touchscreen activity, and scientifically validated to provide measures of cognition and mood. For example, in some instances, patterns are identified using one or more of the following: number and / or duration of calls / emails / texts, word length in text communications, gestures used (taps, swipes, or other), information derived from the gyroscope, such as phone orientation, phone acceleration, keystroke patterns, location derived from GPS, facial expressions and / or micro-expressions, voice or vocal markers, natural language processing, social media use, sleep patterns, specific words or emojis used or not used, and / or the like.

[0221] 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 at a first or subsequent time.

[0222] In some embodiments, the disclosure provides for treating two or more subjects, the method comprising administering a therapeutically effective dose of psilocybin to each subject simultaneously or at substantially the same time (e.g., within minutes of each other, within 5, 10, 15, 20, 25, or 30 minutes of each other), wherein each subject is aware of the other subjects receiving treatment. In some embodiments, the subjects are in the same room. In some embodiments, the subjects are in different rooms.

[0223] In some embodiments, the present disclosure provides a method of treating a subject, the method comprising administering to the subject a therapeutically effective dose of psilocybin and providing a virtual reality / immersive virtual reality digital tool. In some embodiments, the lights in the room are dimmed and / or the light level is kept relatively low or adjusted. In some embodiments, darkened glasses or eye shades are provided. In some embodiments, the room lighting is adjusted for intensity and / or color. In some embodiments, a virtual reality or augmented reality system (e.g., a computer with visual / graphical and audio output) is used.

[0224] subject In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the female subject is pregnant or postpartum. In some embodiments, the subject is attempting to reduce or eliminate the use of a medication, such as an antidepressant or antiepileptic drug. In some embodiments, the subject is attempting to reduce or eliminate the use of a medication before becoming pregnant, undergoing surgery or other medical procedure, or starting the use of a different medication.

[0225] The subject can be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject. In some embodiments, the subject is under about 18 years of age. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10 years of age, about 10-15 years of age, about 15-20 years of age, about 20-25 years of age, about 25-30 years of age, about 30-35 years of age, about 35-40 years of age, about 40-45 years of age, about 45-50 years of age, about 50-55 years of age, about 55-60 years of age, about 60-65 years of age, about 65-70 years of age, about 70-75 years of age, about 75-80 years of age, about 85-90 years of age, about 90-95 years of age, or about 95-100 years of age.

[0226] The subject may have a chronic or terminal illness, hi some embodiments, the subject may have a life-altering disease or condition (such as losing a limb or developing blindness).

[0227] The subject may have recently been diagnosed with disease, disorder or condition.For example, the subject may have been diagnosed within 1 month, 3 months, 6 months or 1 year.In some embodiments, the subject may have been living with disease, disorder or condition for a long period, such as at least 6 months, at least 1 year, at least 3 years, at least 5 years or at least 10 years.

[0228] In some embodiments, the subject may be a cancer patient, such as a stage 4 or terminal cancer patient. In some embodiments, the subject may have been determined to have a limited survival time, such as less than 1 year, less than 6 months, or less than 3 months.

[0229] 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).

[0230] 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.

[0231] 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.

[0232] 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.

[0233] Diseases, disorders, and / or conditions to be treated Provided herein are methods of treating a subject in need thereof, the methods comprising administering to the subject a therapeutically effective dose of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin.

[0234] Neurocognitive disorders (e.g., Alzheimer's disease / Parkinson's disease) In some embodiments, a method for treating one or more neurocognitive disorders in a subject in need thereof comprises administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, the active metabolite is psilocybin.

[0235] In some embodiments, psilocybin treatment results in an improvement as shown in one or more of the following: Mini-Mental State Examination (MMSE), Mini-Cog test, CANTAB test, Cognigram test, Cogniview test, cognitive test, or automated neuropsychological assessment index test.

[0236] In some embodiments, one or more additional therapeutic agents are administered in combination with psilocybin (or its active metabolites). For example, the one or more additional therapeutic agents can be an antidepressant, a cholinesterase inhibitor, an AChE (acetylcholinesterase) inhibitor, a BChE (butyrylcholinesterase) inhibitor, an NMDA (N-methyl-D-aspartate) antagonist, or a combination thereof. A non-limiting list of exemplary types of antidepressants includes SSRIs (selective serotonin reuptake inhibitors), MAOIs (monoamine oxidase inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), and TCAs (tricyclic antidepressants). For example, the antidepressant can be citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine, vilazodone, duloxetine, venlafaxine, desvenlafazine, levomilnacipran, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, mirtazapine, bupropion, trazodone, vortioxetine, or vilazodone.

[0237] Exemplary Neurocognitive Disorders As used herein, the term "neurocognitive disorder" refers to a wide range of disorders that affect the brain and are often associated with a decline or alteration in mental function.

[0238] In some embodiments, the neurocognitive disorder is a major neurocognitive disorder. In some embodiments, the neurocognitive disorder is a mild neurocognitive disorder.

[0239] In some embodiments, the neurocognitive disorder is dementia. In some embodiments, the dementia is selected from the group consisting of late-onset dementia (with or without hallucinations), concurrent hallucinations, and hallucinations due to late-onset dementia, mild dementia, mixed dementia, moderate dementia, organic dementia, presbyophenia, geriatric psychosis, and the like. psychosis), presenile dementia, senile dementia with delirium, presenile dementia with depression, presenile dementia with delusions, primary degenerative dementia, senile dementia, senile dementia with delusions, senile dementia with delirium, depression, paranoia, delusions, or psychosis, or severe dementia.

[0240] In some embodiments, the neurocognitive disorder is caused by bleeding into the brain (intracerebral hemorrhage), bleeding into the space around the brain (subarachnoid hemorrhage), a blood clot within the skull causing pressure on the brain (subdural or epidural hematoma), or a traumatic brain injury such as a concussion.

[0241] In some embodiments, the neurocognitive disorder is caused by a respiratory condition such as low oxygen in the body (hypoxia) or high carbon dioxide levels in the body (hypercarbia).

[0242] In some embodiments, the neurocognitive disorder is caused by a cardiovascular disorder, such as many stroke-related dementias (multi-infarct dementia), cardiac infections (endocarditis, myocarditis), stroke, or transient ischemic attacks (TIAs).

[0243] In some embodiments, the neurocognitive disorder is caused by a degenerative disease such as Alzheimer's disease (also known as senile dementia, Alzheimer's type), Creutzfeldt-Jakob disease, diffuse Lewy body disease, Huntington's disease, multiple sclerosis, normal pressure hydrocephalus, Parkinson's disease, or Pick's disease. In some embodiments, the neurocognitive disorder is due to one or more of Alzheimer's disease, Lewy body dementia, traumatic brain injury, prion disease, HIV infection, Parkinson's disease, or Huntington's disease.

[0244] In some embodiments, the neurocognitive disorder is dementia due to metabolic causes such as kidney disease, liver disease, thyroid disease (hyperthyroidism or hypothyroidism), or vitamin deficiency (B1, B12, or folate).

[0245] In some embodiments, the neurocognitive disorder is caused by a drug or alcohol-related condition, such as alcohol withdrawal, intoxication due to drug or alcohol use, Wernicke-Korsakoff syndrome (a long-term effect of excessive alcohol consumption or malnutrition), or withdrawal from a drug (such as a sedative-hypnotic or corticosteroid).

[0246] In some embodiments, the neurocognitive disorder is caused by an infection, including any sudden-onset (acute) or long-term (chronic) infection. For example, the infection can be blood poisoning (sepsis), brain infection (encephalitis), meningitis (infection of the lining of the brain and spinal cord), prion infection (e.g., mad cow disease), or late syphilis.

[0247] In some embodiments, the neurocognitive impairment is caused by complications from cancer and / or chemotherapy cancer treatment.

[0248] In some embodiments, the neurocognitive disorder is caused by depression, neurosis, or psychosis.

[0249] In some embodiments, the neurocognitive disorder is mild cognitive impairment.

[0250] Neurocognitive impairment and comorbid diseases, disorders, or conditions In some embodiments, the subject has one or more diseases, disorders or conditions that are comorbid with neurocognitive disorders.For example, one or more comorbid conditions can be hypertension, connective tissue disease, depression, diabetes, or chronic lung disease.

[0251] Alzheimer's disease In some embodiments, the neurocognitive disorder results from Alzheimer's disease (AD), such as sporadic Alzheimer's disease or familial Alzheimer's disease.

[0252] Alzheimer's disease (AD) is a neurodegenerative brain disorder characterized by changes in both cognitive and non-cognitive behavior, particularly progressive memory loss, depression, anxiety, dementia, irritability, mood swings, inattention, aggressive and / or apathetic behavior, confusion, gradual physical deterioration, and ultimately death. Alzheimer's disease (AD) is divided into sporadic AD and familial AD, with familial AD accounting for 1-5% of all AD cases.

[0253] At the molecular and cellular levels, pathological manifestations include diffuse and extracellular amyloid plaques, as well as reactive microgliosis, dystrophic neurites, and intracellular neurofibrillary tangles accompanied by neuronal and synaptic loss.

[0254] There are various genetic risk factors for familial AD, the strongest genetic risk factor for familial AD being the epsilon 4 allele of APOE (apolipoprotein E). Individuals with more than one of these risk factors are more likely to progress.

[0255] The pathophysiology of sporadic AD is currently poorly understood but is thought to be multifactorial. Factors that lead to the onset and progression of AD include dysregulation of the cholinergic system, aggregation of amyloid-β (Aβ), propagation of hyperphosphorylated tau protein, and inflammatory processes.

[0256] Amyloid deposition and neurofibrillary degeneration appear 20 and 10 years before the onset of memory decline, respectively. In 2018, a biomarker-based biological classification, the A / T / N (amyloid / tau / neurodegeneration) system, was proposed, in which "A" refers to the presence of Aβ biomarkers detected by amyloid PET (positron emission tomography) or CSF (cerebrospinal fluid) level assays, "T" refers to the value of tau biomarkers measured by CSF phospho-tau assays or tau PET, and "N" refers to the level of [ 18This refers to a biomarker of neurodegeneration or neuronal damage assessed by [F]-fluorodeoxyglucose-PET, structural MRI (magnetic resonance imaging), or measuring total tau in CSF. This allows for the detection of very early stages of AD in patients, thus providing a clinical opportunity to provide patients with early treatment to limit and slow disease progression and delay the emergence of cognitive problems. Although the use of biomarkers is not yet common in clinical practice and there is a need for further development to facilitate their use, they offer a unique opportunity to detect the onset of the disease and act quickly.

[0257] There are currently five medications approved by the U.S. Food and Drug Administration to help manage the symptoms of Alzheimer's disease (Table 7). However, there are currently no pharmacological interventions that slow or prevent disease progression, including the damage and subsequent neuronal death that leads to AD symptoms and makes the disease fatal. [Table 7]

[0258] Cholinesterase inhibitors (e.g., donepezil, rivastigmine, and galantamine) work by increasing levels of acetylcholine, a neurotransmitter messenger involved in memory, judgment, and other thought processes. Certain brain cells release acetylcholine to help transmit messages to other cells. After the message reaches the receiving cell, various other chemicals, including an enzyme called acetylcholinesterase, can break down and regenerate acetylcholine. Alzheimer's disease damages or destroys the cells that produce and use acetylcholine, thereby reducing the amount available to carry messages. Cholinesterase inhibitors slow the breakdown of acetylcholine by blocking the activity of acetylcholinesterase. By maintaining acetylcholine levels, these drugs help compensate for the loss of functional brain cells.

[0259] Memantine appears to work by regulating the activity of glutamate, a neurotransmitter involved in information processing, storage, and retrieval. Glutamate plays an essential role in learning and memory by triggering NMDA receptors to release controlled amounts of calcium into nerve cells. Calcium helps create the chemical environment necessary for information storage. On the other hand, excess glutamate overstimulates NMDA receptors, allowing excessive calcium into nerve cells, which can lead to cell destruction and death. Memantine may protect cells from excess glutamate by partially blocking NMDA receptors.

[0260] The effectiveness of current Alzheimer's disease medications varies from person to person and has a limited duration of effect. Furthermore, none of the current drugs can reverse Alzheimer's disease, meaning they cannot stop the underlying destruction of neurons. Therefore, as brain cell damage progresses, their ability to improve symptoms eventually declines.

[0261] Parkinson's disease Parkinson's disease is the most common type of parkinsonism, a term that reflects a group of neurological disorders with parkinsonian-like movement disorders such as rigidity, bradykinesia, and tremors. Atypical parkinsonism (diseases with parkinsonism and other features) includes multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies.

[0262] Clinical symptoms of Parkinson's disease include motor and non-motor symptoms (see Table 8 below). Motor symptoms consist of tremor, rigidity, slowness, and imbalance in movement and physical tasks and are the primary hallmark of this pathology. Non-motor symptoms are heterogeneous, affecting many organ systems, such as the gastrointestinal and genitourinary systems. Among the non-motor features of Parkinson's disease, cognitive dysfunction is one of the most troublesome problems, as it reduces the quality of life of patients. [Table 8]

[0263] The pathophysiology of Parkinson's disease is characterized by the death of dopaminergic neurons in the substantia nigra. The pathological hallmark of Parkinson's disease is Lewy bodies, neuronal inclusions composed primarily of α-synuclein protein aggregates. The most widely cited model to explain the neuropathological progression of Parkinson's disease is the Braak hypothesis. This model suggests that Parkinson's disease begins in the medulla and olfactory bulb (stages 1 and 2). This early pathology is associated with symptoms that occur before the onset of motor impairment, such as REM sleep behavior disorder and decreased sense of smell. In stages 3 and 4, pathology progresses to the substantia nigra pars compacta and other midbrain and basal forebrain structures. Pathology in these regions is associated with the classic motor symptoms of Parkinson's disease. It is usually diagnosed at this stage. In progressive Parkinson's disease, pathology progresses to the cerebral cortex, with the onset of cognitive impairment and hallucinations.

[0264] Parkinson's disease is associated with progressive neurodegeneration and increasing symptom burden. Parkinson's disease-related mortality increases with age. The causes of death in individuals with Parkinson's disease are similar to those in non-Parkinsonian cohorts, and in many cases, death occurs before the advanced stage of the disease. When individuals die from Parkinson's disease-related symptoms, aspiration pneumonia is the most common cause of death.

[0265] Parkinson's disease is rare in individuals under 50 years of age, increases in prevalence with age, peaking between 85 and 89 years of age, and is more common in men (male to female ratio of 1.4:1). Most cases of Parkinson's disease are idiopathic, but there are known genetic and environmental contributions. Exposure to pesticides, herbicides, and heavy metals has been associated with an increased risk of Parkinson's disease.

[0266] In some embodiments, a method for treating Parkinsonism or a symptom thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof. In some embodiments, the Parkinsonism is Parkinson's disease. In some embodiments, the Parkinsonism is drug-induced.

[0267] In some embodiments, the parkinsonian syndrome is an atypical parkinsonian disorder. In some embodiments, the atypical parkinsonian disorder is multiple system atrophy progressive supranuclear palsy, corticobasal degeneration, or dementia with Lewy bodies.

[0268] In some embodiments, the subject is suffering from motor or non-motor symptoms, or a combination thereof. In some embodiments, the motor symptoms are bradykinesia, rigidity, tremor, resting tremor, postural instability, stiffness, slowness, imbalance, or a combination thereof. In some embodiments, the non-motor symptoms are cognitive dysfunction, loss of smell, sleep dysfunction, autonomic dysfunction, psychiatric disorders, fatigue, soft voice, sialorrhea, difficulty swallowing, or a combination thereof.

[0269] In some embodiments, the subject has one or more diseases, disorders, or conditions comorbid with Parkinsonism. In some embodiments, the comorbid disease is due to a symptom of Parkinsonism. In some embodiments, the comorbid disease is selected from a neuropsychiatric disorder, a sleep disorder, melanoma, neuroorthostatic hypotension, emotional dysregulation, anemia, hypertension, type 2 diabetes, restless legs syndrome, cancer, or a combination thereof. In some embodiments, the comorbid disease is a neuropsychiatric disorder, and the neuropsychiatric disorder is dementia, depression, psychosis, anorexia, anxiety, hallucinations, or a combination thereof. In some embodiments, the comorbid disease is a sleep disorder (e.g., REM sleep behavior disorder), and the sleep disorder is daytime drowsiness and sleepiness, narcolepsy, insomnia, or REM sleep behavior disorder.

[0270] In some embodiments, the method for treating Parkinsonism or a symptom thereof in a subject in need thereof further comprises administering at least one additional therapy to the subject. In some embodiments, the additional therapy is exercise therapy, physical therapy, occupational therapy, or speech therapy. In some embodiments, the additional therapy is a dopamine agonist. In some embodiments, the additional therapeutic agent is carbidopa-levodopa, entacopon, tolcapone, carbidopa, levodopa-entacopon, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, or a combination thereof.

[0271] In some embodiments, the methods of treating Parkinsonism or a symptom thereof described herein improve Parkinsonism or at least one symptom thereof in a subject. In some embodiments, one or more of the following scales are used to assess the effectiveness of treating Parkinson's disease with the methods of the present disclosure: the Hoehn and Yahr Staging Scale, the Unified Parkinson's Disease Rating Scale (UPDRS), the Clinical Impression of Severity Index (CISI-PD), the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Outcome Scale in Parkinson's Disease-motor (SCOPA-Motor), the Schwab & England Activities of Daily Living Scale (SES), the Self-Rating Parkinson's Disease Disability Scale (SPDDS), the Postural Instability and Gait Difficulty Score (PIGD), the Freezing of Gait Questionnaire (FOGQ), the Non-Motor Symptom Questionnaire (NMSQuest), the Non-Motor Symptom Scale (NMSS), the Unified Movement Dysfunction Rating Scale (UDRS), the Wearing-off Questionnaire (WQ), the Pittsburgh Sleep Quality Index self-reported total sleep time, the Beck Depression Rating Scale, the Insomnia Severity Index, or a combination thereof.

[0272] In some embodiments, the Hoehn and Yahr staging scale is used to assess the effectiveness of treating Parkinson's disease with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's stage on the Hoehn and Yahr staging scale is reduced compared to before treatment. In some embodiments, after treatment with the methods of the present disclosure, the subject's stage on the Hoehn and Yahr staging scale is reduced by about 1 stage, about 2 stages, about 3 stages, or about 4 stages compared to before treatment.

[0273] In some embodiments, the Unified Parkinson's Disease Rating Scale (UPDRS) is used to evaluate the effectiveness of treating Parkinson's disease with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's grade on the UPDRS is reduced compared to before treatment. In some embodiments, the reduction is 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%. In some embodiments, the UPDRS score is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%. In some embodiments, the decreased UPDRS score is observed within about 1 week, about 1 month, about 3 months, or about 6 months after psilocybin administration.

[0274] ADHD As used herein, "attention deficit hyperactivity disorder" (ADHD) is a neurodevelopmental psychiatric disorder characterized by one or more of inattention, hyperactivity, and impulsivity that are not naturally appropriate for a person's age. It is commonly diagnosed in childhood and is one of the most frequent conditions affecting school-age children. In children, the core symptoms of inattention, hyperactivity, and impulsivity can lead to disruptive behaviors at home and school, which are typical precursors to clinical referral for diagnosis and treatment. While hyperactivity often decreases in adulthood, inattention, disorganization, and impulsivity typically persist and cause functional challenges for patients on a daily basis.

[0275] There are three subtypes of ADHD: primarily inattentive, primarily hyperactive / impulsive, and combined presentation. These are characterized by the presence of excessive inattention or hyperactive-impulsive symptoms, or by an equal predominance of the two symptom categories. In addition to these core features, several reports have demonstrated the presence of working memory deficits in children with ADHD that persist into adulthood. Speech, language, and visuospatial working memory can all be affected in ADHD patients, and some studies suggest that such deficits may be related to the primary symptoms of the disorder, particularly inattention.

[0276] Individuals with ADHD may also have one or more comorbid diseases, disorders, or conditions. The prevalence of comorbid conditions is higher in adults with ADHD. A non-exhaustive list of comorbid conditions known to occur with ADHD includes oppositional defiant disorder, learning difficulties, depression, anxiety, bipolar disorder, substance use disorders (SUDs) (especially alcohol, nicotine, cannabis, and cocaine in adults), personality disorders, and obsessive-compulsive disorder (OCD). These mental health problems can lead to broader negative outcomes, such as educational underachievement, school exclusion, employment difficulties, difficulty building relationships, and criminal activity.

[0277] Current medications for treating ADHD target the dysregulation of the norepinephrine and dopamine neurotransmitter systems in ADHD. Specifically, ADHD medications increase norepinephrine and dopamine levels in subjects. Current medications target this dysregulation through various mechanisms. Stimulants such as methylphenidate hydrochloride increase extracellular dopamine and block dopamine transporters, which increase the rate of dopamine release. Another stimulant, dextroamphetamine, blocks the catabolism of norepinephrine and dopamine through interaction with the enzyme catechol-o-methyltransferase. Atomoxetine increases extracellular levels of dopamine in the prefrontal cortex, and alpha-adrenergic receptor agonists improve working memory by stimulating postsynaptic alpha-adrenergic receptors. Furthermore, tricyclic antidepressants such as desipramine selectively inhibit norepinephrine reuptake, thereby increasing norepinephrine concentrations. In some embodiments, one or more of the agents listed below are administered in combination with psilocybin or its activated metabolite to a subject in need of treatment for ADHD.

[0278] Stimulants are the most common treatment for ADHD, with 70-80% of patients responding at least partially to these treatments. Stimulants include methylphenidate (e.g., Ritalin) and amphetamines (e.g., Adderall). These have been shown to increase intrasynaptic dopamine and norepinephrine concentrations. Stimulants are approved by the Food and Drug Administration to treat ADHD in children and adolescents and are typically the first pharmacological agent used to treat ADHD. However, many caregivers are reluctant to consider stimulant therapy for their children or adolescents due to the potential for stimulant abuse and addiction, despite some evidence suggesting this is not a common problem.

[0279] Methylphenidate has been shown to improve attention and increase dopamine levels in the ventral striatum, prefrontal cortex, and temporal cortex.Specifically, it can bind to dopamine transporter and block dopamine reuptake from synaptic cleft.The improvement of working memory caused by methylphenidate is related to the normalization of the underactive anterior cingulate network and striatum area.Stimulants have been shown to reduce emotional response to frustration and increase effortful behavior, but they have also been found to promote risky behavior and make people more susceptible to environmental disturbances.

[0280] Amphetamine blocks the action of catechol-o-methyltransferase, an enzyme that breaks down norepinephrine and dopamine, increasing the availability of these neurotransmitters within the synaptic cleft. Dextroamphetamine is a commonly used stimulant drug that comes in three different formulations based on its duration of action: 1. immediate-release dextroamphetamine, 2. sustained-release dextroamphetamine, and 3. sustained-release mixed amphetamine salts (Adderall XR). All formulations are safe and effective in treating ADHD symptoms in children, adolescents, and adults. Mixed amphetamine salts have good cardiovascular tolerability and can be used in patients with mild hypertension. However, common side effects include insomnia, decreased appetite and weight loss, headache, dry mouth, and nervousness.

[0281] Atomoxetine is a selective norepinephrine reuptake inhibitor used to treat ADHD. It can be used alone or in combination with stimulants. It has a slower onset than stimulants and may take several weeks to reach maximum therapeutic benefit. Because it has no abuse potential, it can be used in adults with ADHD who may be at risk for substance abuse. Because atomoxetine is metabolized by the CYP2D6 isoenzyme, it is not suitable for depressed patients taking medications that inhibit CYP2D6, such as fluoxetine or paroxetine. Common side effects include nausea, decreased appetite (in 15-20% of patients), insomnia, fatigue, dizziness, abdominal pain, and slightly increased diastolic blood pressure and heart rate. Weight loss and loss of expected height have been observed in children treated with atomoxetine for 15-18 months, but no significant growth impairment was reported at the end of different studies lasting 5 years. Atomoxetine is not suitable for use in children or adolescents with serious structural heart abnormalities, heart rhythm abnormalities, or cardiomyopathy. It has a similar molecular structure to fluoxetine and has been associated with suicidal thoughts, leading to an FDA "black box" warning in 2005.

[0282] Reboxetine is a selective norepinephrine reuptake inhibitor used as an antidepressant. It increases norepinephrine and dopamine levels in the prefrontal cortex and causes dopamine release in subcortical structures through inhibition of dopamine D1 receptors. It is effective in reducing ADHD symptoms and is generally well tolerated, with the most common side effects including drowsiness, decreased appetite, pallor, headache, dizziness, and sleep disturbances.

[0283] Antihypertensive agents such as guanfacine and clonidine act on presynaptic alpha-2 adrenergic receptors in the prefrontal cortex, inhibiting norepinephrine release and downregulating the noradrenergic system. While immediate-release guanfacine and clonidine are not FDA-approved for children and adolescents with ADHD, they are effective for children with comorbid tic disorders and children with pervasive developmental disorders involving hyperactivity and impulsivity. Extended-release formulations of guanfacine and clonidine are FDA-approved for ADHD in children and adolescents as both once-daily monotherapy and adjunctive therapy to stimulant medications. Side effects include sedation, fatigue, headache, dry mouth, constipation, epigastric pain, irritability, dizziness, bradycardia, orthostatic hypotension, and withdrawal hypertension. Because alpha-2 agonists are antihypertensives, blood pressure and heart rate must be monitored throughout treatment, and cardiac consultation is usually required before initiating treatment.

[0284] Tricyclic antidepressants improve mood and reduce hyperactivity but do not improve cognitive performance or concentration. Desipramine is the most studied tricyclic antidepressant for the treatment of ADHD and has fewer side effects than other tricyclics. It selectively inhibits norepinephrine reuptake at presynaptic transporters, thereby increasing norepinephrine availability. Desipramine is effective in treating ADHD in adults, but is considered less effective than stimulants. Side effects include dry mouth, constipation, sweating, insomnia, tachycardia, elevated blood pressure, electrocardiogram changes, and orthostatic hypotension. These side effects suggest the possibility of cardiotoxic effects, thereby limiting the use of desipramine in patients without underlying cardiovascular disease.

[0285] Bupropion is an antidepressant and dopamine and norepinephrine reuptake inhibitor that has been shown to be effective in improving ADHD symptoms. It is not approved by the FDA as a medication for the treatment of ADHD. Side effects include tachycardia, insomnia, headache, dry mouth, nausea, and weight loss. Serious side effects include the possibility of worsening suicidal thoughts and the risk of seizures.

[0286] Although modafinil is not approved for the treatment of ADHD, its effectiveness has been investigated in children and adolescents. It appears to alter the balance of gamma-aminobutyric acid and glutamate, increasing hypothalamic activation. A 6-week placebo-controlled trial in children aged 7 to 14 with ADHD reported a 78% response rate with modafinil compared to placebo. Side effects include insomnia, headache, and decreased appetite. In 2006, the U.S. Food and Drug Administration (FDA) rejected modafinil for the treatment of ADHD, claiming that the drug was not sufficiently safe for administration to children.

[0287] In some embodiments, a method for treating attention deficit hyperactivity disorder (ADHD) in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof. In some embodiments, the subject is a child. In some embodiments, the subject is an adult. In some embodiments, the subject is an adolescent.

[0288] In some embodiments, the subject in need of treatment has an attention deficit hyperactivity disorder subtype selected from predominantly inattentive, predominantly hyperactive / impulsive, or combined presentation. In some embodiments, the attention deficit hyperactivity disorder subtype is predominantly inattentive. In some embodiments, the attention deficit hyperactivity disorder subtype is predominantly hyperactive / impulsive. In some embodiments, the attention deficit hyperactivity disorder subtype disorder is combined presentation.

[0289] In some embodiments, the subject has at least one disease, disorder, or condition that is comorbid with ADHD. In some embodiments, the comorbid condition is selected from oppositional defiant disorder, learning difficulties, depression, anxiety, bipolar disorder, substance use disorder, autism spectrum disorder, personality disorder, obsessive-compulsive disorder, or a combination thereof. In some embodiments, the comorbid condition is oppositional defiant disorder. In some embodiments, the comorbid condition is anxiety.

[0290] In some embodiments, the subject is administered an additional therapeutic agent in addition to psilocybin (or its active metabolite). In some embodiments, the additional therapeutic agent is a stimulant, a norepinephrine reuptake inhibitor, an α-adrenergic receptor agonist, a tricyclic antidepressant, modafinil, or a combination thereof. In some embodiments, the additional therapeutic agent is a stimulant (e.g., amphetamine or methylphenidate). In some embodiments, the additional therapeutic agent is a norepinephrine reuptake inhibitor (e.g., atomoxetine or reboxetine).

[0291] In some embodiments, administration of psilocybin (or an active metabolite thereof) to a subject alleviates at least one sign or symptom of ADHD.

[0292] In some embodiments, the ADHD Rating Scale-V (ADHD-RS-V) is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the subject's ADHD Rating Scale-V 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%.

[0293] In some embodiments, an adult self-report scale is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, prior to treatment with the methods of the present disclosure, the subject has a score on the adult self-report scale of greater than 24. In some embodiments, prior to treatment with the methods of the present disclosure, the subject has a score on the adult self-report scale of about 17-23. In some embodiments, after treatment with the methods of the present disclosure, the subject's adult self-report scale 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.

[0294] In some embodiments, the Diagnostic Interview for ADHD in Adults is used to diagnose ADHD.

[0295] In some embodiments, the ADHD Investigator Symptom Rating Scale (AISRS) is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the subject experiences an improvement in at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 symptoms of ADHD according to the AISRS. In some embodiments, after treatment with the methods of the present disclosure, the subject's AISRS is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to before the treatment.

[0296] In some embodiments, the Conners Adult Attention-Deficit / Hyperactivity Disorder rating scale is used to assess symptoms of attention deficit disorders, such as attention-deficit / hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the subject experiences an improvement in at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, or at least eight symptoms of ADHD according to the Conners Adult Attention-Deficit / Hyperactivity Disorder rating scale. In some embodiments, after treatment with the methods of the present disclosure, the subject's Conners Adult Attention-Deficit / Hyperactivity Disorder Rating Scale total 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 said treatment.

[0297] In some embodiments, the Test of Variances of Attention (TOVA) score is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, before treatment with the methods of the present disclosure, the subject's TOVA score (reported as a Z-score) is -1.80 or less. In some embodiments, after treatment with the methods of the present disclosure, the subject's TOVA score (reported as a Z-score) improves by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 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%, about 300%, or more.

[0298] In some embodiments, the Brown Attention Deficit Disorder (BADD) scale is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the subject's BADD total 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 said treatment.

[0299] In some embodiments, the National Institute for Children's Health Quality (NICHQ) Vanderbilt Rating Scale is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the NICHQ Vanderbilt Rating Scale 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%.

[0300] In some embodiments, the SNAP-IV Teacher and Parent Rating Scales are used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, SNAP-IV Teacher and Parent Rating Scale scores are reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, prior to treatment, subjects with ADHD Inattentive Type have a Teacher Score of 2.56 or greater or a Parent Score of 1.78 or greater. In some embodiments, prior to treatment, subjects with ADHD Hyperactive-Impulsive Type have a Teacher Score of 1.78 or greater or a Parent Score of 1.44 or greater. In some embodiments, prior to treatment, subjects with ADHD combined have a teacher score of 2.00 or greater, or a parent score of 1.67 or greater.

[0301] In some embodiments, the Connors-Wells Adolescent Self-Report Scale is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the Connors-Wells Adolescent Self-Report Scale 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%.

[0302] In some embodiments, a Child Behavior Checklist is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the Child Behavior Checklist 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%.

[0303] In some embodiments, the Conners Integrated Behavioral Rating Scale is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, after treatment with the methods of the present disclosure, the Conners Integrated Behavioral Rating Scale 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%.

[0304] In some embodiments, the Adult ADHD Quality of Life scale is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, the Adult ADHD Quality of Life scale is used to assess how ADHD symptoms affect a subject's quality of life. In some embodiments, after treatment with a method of the present disclosure, the subject's Adult ADHD Quality of Life score improves by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or more compared to before treatment. , about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, or more.

[0305] In some embodiments, the Clinical Global Impression scale is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, the Clinical Global Impression scale is used to assess how ill or dysfunctional a subject is. In some embodiments, the CGI-Severity (CGI-S) subscale is used to measure the severity of a subject's illness or dysfunction. In some embodiments, the CGI-Improvement (CGI-I) subscale is used to measure improvement in a subject's illness or dysfunction. In some embodiments, the CGI-Efficacy (CGI-E) subscale is used to measure the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the CGI score for a subscore 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.

[0306] In some embodiments, the Global Assessment of Functioning (GAF) is used to assess symptoms of attention deficit disorders, such as attention deficit hyperactivity disorder. In some embodiments, the GAF is used to assess a subject's daily functioning. In some embodiments, after treatment with the methods of the present disclosure, the subject's GAF score increases by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, or more compared to before said treatment.

[0307] In some embodiments, a subject in need of treatment has a reduced ADHD Rating Scale V score following treatment with psilocybin. In some embodiments, the reduced ADHD Rating Scale V score is observed from about 1 hour after psilocybin administration to about 1 year after psilocybin administration. In some embodiments, the ADHD Rating Scale V score is reduced by about 20% to about 100%.

[0308] epilepsy Epilepsy is a neurological disorder characterized by sudden, recurrent episodes of sensory disturbances, loss of consciousness, or seizures associated with abnormal electrical activity in the brain. Epilepsy can result from genetic disorders or acquired brain damage, such as trauma or stroke. During a seizure, individuals with epilepsy experience abnormal behaviors, symptoms, and sensations, sometimes including loss of consciousness. Between seizures, there are few symptoms. Common treatments for epilepsy include various medications (e.g., nerve pain medications, sedatives, and anticonvulsants) and, in some cases, surgery, devices, or dietary changes.

[0309] In some embodiments, a method for treating epilepsy in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof. In some embodiments, the epilepsy is generalized epilepsy, epilepsy with myoclonic absence seizures, focal epilepsy, generalized and focal epilepsy, unknown if generalized and focal epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, childhood absence epilepsy, benign rolandic epilepsy, Doze syndrome, Dravet syndrome, early myoclonic encephalopathy, Jeavons syndrome, epilepsy of infancy with migratory focal seizures, epileptic encephalopathy with continuous spikes and waves during sleep, febrile illness-associated epilepsy syndrome, frontal lobe epilepsy, West syndrome, juvenile absence epilepsy, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, Panayiotopoulos syndrome, progressive myoclonic epilepsy, reflex epilepsy, or temporal lobe epilepsy. In some embodiments, the subject in need of treatment has generalized tonic-clonic seizures, convulsive seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, or atonic seizures.

[0310] In some embodiments, the subject has one or more diseases, disorders, or conditions comorbid with epilepsy. In some embodiments, the comorbid condition is a psychiatric comorbidity, a neurological comorbidity, or a physical condition. In some embodiments, the psychiatric comorbidity is bipolar disorder, ADHD, depression, anxiety, or a combination thereof. In some embodiments, the neurological comorbidity is migraine, cognitive impairment, stroke, cerebrovascular disease, or a combination thereof. In some embodiments, the neurological comorbidity is migraine. In some embodiments, the physical condition is a cardiac, inflammatory, or pulmonary condition. In some embodiments, the cardiac condition is heart disease. In some embodiments, the inflammatory disease is an autoimmune disease, and the autoimmune disease is arthritis, diabetes mellitus, asthma, or a combination thereof. In some embodiments, the pulmonary disease is chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or a combination thereof.

[0311] In some embodiments, the method for treating epilepsy in a subject in need thereof further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a sodium channel blocker, a calcium current inhibitor, a gamma-aminobutyric acid (GABA) enhancer, a glutamate receptor antagonist, a carbonic anhydrase inhibitor, a hormone, an N-methyl-D-aspartate (NMDA) receptor antagonist, a synaptic vesicle glycoprotein 2A (SV2A) ligand, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / kainate receptor antagonist, or a combination thereof. In some embodiments, the additional therapeutic agent is a sodium channel blocker, and the sodium channel blocker is phenytoin, fosphenytoin, carbamazepine, lamotrigine, or valproate. In some embodiments, the additional therapeutic agent is a calcium channel antagonist, and the calcium current inhibitor is ethosuximide or valproate. In some embodiments, the additional therapeutic agent is a GABA enhancer, and the GABA enhancer is a benzodiazepine, a barbiturate, progabide, progesterone, ganaxolone, vigabatrin, tiagabine, gabapentin, or valproate. In some embodiments, the additional therapeutic agent is an NMDA receptor antagonist, and the NMDA receptor antagonist is felbamate or levetiracetam. In some embodiments, the additional therapeutic agent is an AMPA / kainate receptor antagonist, and the AMPA / kainate receptor antagonist is topiramate.

[0312] In some embodiments, the subject experiences about a 15% to about 100% reduction in seizures per month after treatment. In some embodiments, the subject experiences about a 15% to about 100% reduction in seizure duration after treatment.

[0313] In some embodiments, the effectiveness of treating epilepsy with the methods of the present disclosure is assessed using diary assessment, clinician or caregiver assessment, electroencephalogram, or clinical seizure rating scales, non-limiting examples of which include the VA Seizure Frequency and Severity Scale (VA Scale), the Chalfont-National Hospital Seizure Severity Scale, the Liverpool Seizure Severity Scale, the Hague Seizure Severity Scale, or the Occupational Risk Scale.

[0314] In some embodiments, after treating a subject with the methods of the present disclosure, the subject's Chalfont-National Hospital Stroke Severity 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%, compared to before said treatment.

[0315] In some embodiments, after treating a subject with the methods of the present disclosure, the subject's Liverpool Stroke Severity 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%, compared to before said treatment.

[0316] In some embodiments, after treating a subject with a method of the present disclosure, the subject's Hague Stroke Severity Scale score improves 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%, or An increase of 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.

[0317] In some embodiments, after treating a subject with the methods of the present disclosure, the subject's occupational hazard 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%, compared to before the treatment.

[0318] autism Autism spectrum disorder (ASD) is a neurodevelopmental syndrome characterized by core deficits in social interaction and communication, the presence of repetitive and restricted patterns of behavior and interests, and / or abnormal reactivity to sensory input. The DSM-5 redefined autism spectrum disorder to include autistic disorder, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder. Approximately 31% of individuals with ASD have intellectual disability, defined as an intelligence quotient (IQ) below 70, an additional 25% are in the borderline range (IQ, 71-85), and approximately one-third are nonverbal.

[0319] Currently, the etiology and pathophysiology of ASD are largely unknown and are thought to be multifactorial, given the heterogeneity of the population. Recent studies suggest that the causes of ASD are primarily genetic (heritability is approximately 80%), with the relative contribution of environmental factors being smaller than previously thought. Approximately 85% of ASD cases are idiopathic, with no known etiology. In contrast, syndromic autism defines a neurobehavioral phenotype that often includes physical abnormalities and ASD. Examples include fragile X syndrome, RETT syndrome, and tuberous sclerosis complex, and ASD also occurs at a 30–50% rate. These syndromic causes of ASD can be confirmed through genetic testing to identify underlying abnormalities in risk genes, such as FMR1 in fragile X syndrome. Many ASD risk genes are associated with synaptic transmission processes, such as neurite outgrowth, synaptic plasticity, and synaptogenesis, suggesting their involvement in ASD pathophysiology.

[0320] In addition to the core symptoms of ASD described above, another important source of functional impairment and reduced quality of life in this heterogeneous population is associated symptoms and comorbid psychiatric disorders. ASD-related symptoms and challenging behaviors include irritability, aggression, self-injurious behaviors, motor impairments, and cognitive deficits such as cognitive flexibility, sustained attention, working memory, episodic memory, and executive function. Psychiatric disorders are thought to be more prevalent in ASD than in the general population, but reported prevalence and diagnoses of comorbid psychiatric disorders vary considerably. Recent systematic reviews and meta-analyses suggest that attention-deficit hyperactivity disorder (ADHD) and anxiety disorders are the most common comorbid conditions in ASD. Other psychiatric disorders common in ASD include sleep-wake disorders, disruptive disorders, impulse control disorders, and conduct disorders, as well as depressive disorders, obsessive-compulsive disorder (OCD), bipolar disorder, and schizophrenia spectrum disorders. Depression is also more common in individuals with ASD.

[0321] Currently, there are no approved pharmacological treatments for the core symptoms of ASD. The only FDA-approved medications for ASD-related irritability are risperidone and aripiprazole. Risperidone, a second-generation antipsychotic, was the first drug approved by the FDA to treat ASD-related irritability in children aged 5 years and older in 2006, while aripiprazole, a psychotropic medication, was approved by the FDA for the same indication in children aged 6 to 17 years in 2009. Other "off-label" pharmacological interventions used to manage ASD-related symptoms that are not approved for treating core symptoms include, again, typical antipsychotics, haloperidol for agitation and aggression, selective serotonin reuptake inhibitors (SSRIs), sertraline for anxiety disorders, the neuropeptide oxytocin for social deficits, the stimulant methylphenidate, ADHD medications and venlafaxine for hyperactivity and inattention, serotonin and norepinephrine reuptake inhibitors (SNRIs), the SSRIs fluoxetine and citalopram for repetitive behaviors, and N-methyl-D-aspartate (NMDA) receptor antagonists, memantine, and acetylcholinesterase inhibitors, and rivastigmine for cognitive dysfunction. Non-pharmacological treatments for ASD include psychosocial interventions such as applied behavior analysis (ABA), early intensive intervention, social skills training, and cognitive behavioral therapy.

[0322] In some embodiments, a method for treating an autism spectrum disorder (ASD) or a symptom thereof in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof. In some embodiments, the ASD is autistic disorder, Asperger's syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, or a combination thereof. In some embodiments, the signs or symptoms of ASD are irritability, repetitive behavior, restricted behavior, abnormal reactivity to sensory stimuli, social communication deficits, aggression, self-injurious behavior, motor impairments, cognitive deficits, or a combination thereof.

[0323] In some embodiments, the subject is non-verbal.

[0324] In some embodiments, the subject has an intelligence quotient (IQ) of about 71 to about 85. In some embodiments, the subject has an IQ of about 70 or less. In some embodiments, the subject has an IQ in the range of about 70 to about 79. In some embodiments, the subject has an IQ in the range of about 80 to about 89. In some embodiments, the subject has an IQ in the range of about 90 to about 109. In some embodiments, the subject has an IQ in the range of about 110 to about 119. In some embodiments, the subject has an IQ in the range of about 120 to about 129. In some embodiments, the subject has an IQ of about 130 or greater.

[0325] In some embodiments, the subject suffers from a cognitive deficit in cognitive flexibility, sustained attention, working memory, episodic memory, executive function, or a combination thereof.

[0326] In some embodiments, the subject has one or more diseases, disorders, or conditions that are comorbid with ASD. In some embodiments, the comorbid condition is a psychiatric disorder such as attention deficit hyperactivity disorder, anxiety disorder, sleep-wake disorder, impulse control disorder, disruptive behavior, conduct disorder, depressive disorder, obsessive-compulsive and related disorders, bipolar disorder, schizophrenia, or a combination thereof. In some embodiments, the comorbid condition is an inflammatory disorder, gastrointestinal disorder, epilepsy, or a combination thereof.

[0327] In some embodiments, the method for treating ASD or a symptom thereof further comprises administering to the subject an additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is risperidone or aripiprazole. In some embodiments, the at least one additional therapeutic agent is an antidepressant, such as an SSRI (selective serotonin reuptake inhibitor), an MAOI (monoamine oxidase inhibitor), an SNRI (serotonin and norepinephrine reuptake inhibitor), or a TCA (tricyclic antidepressant). For example, the antidepressant can be citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine, vilazodone, duloxetine, venlafaxine, desvenlafazine, levomilnacipran, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, mirtazapine, bupropion, trazodone, vortioxetine, or vilazodone.

[0328] In some embodiments, the Autism Diagnostic Observation Schedule-2 (ADOS-2), Autism Diagnostic Interview-Revised (ADI-R), Childhood Autism Rating Scale-2 (CARS2), Vineland-II Adaptive Behavior Scale (VABS-2), Aberrant Behavior Checklist (ABC), Child Behavior Checklist (CBCL), Autism Behavior Inventory (ABI), Social Responsiveness Scale-2 (SRS-2), Repetitive Behaviors Scale-Revised (RBS-R), Ohio Autism Clinical Impression Scale-Improvement (OACIS-I), Ohio Autism Clinical Impression Scale-Severity (OACIS-S), Gilliam Autism Rating Scale-3 (GARS-3), Social Communication Questionnaire (SCQ), Autism Spectrum Quotient (AQ), Adult Repetitive Behaviors Questionnaire-2 (RBQ-2A), or a combination thereof, is used to assess the effectiveness of treatment with the methods of the present disclosure.

[0329] In some embodiments, the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) is used to diagnose autism spectrum disorder and / or assess the effectiveness of treatment with the methods of the disclosure. In some embodiments, after treatment with the methods of the disclosure, the subject's ADOS-2 composite score is reduced by at least about 5%, e.g., at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or more, compared to before treatment.

[0330] In some embodiments, the Autism Diagnostic Interview-Revised (ADI-R) is used to diagnose autism spectrum disorder and / or assess the effectiveness of treatment according to the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's ADI-R score is reduced by at least about 5%, e.g., at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or more, compared to before treatment. In some embodiments, the Childhood Autism Rating Scale, Second Edition (CARS-2) is used to assess the effectiveness of treatment according to the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's CARS-2 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%, compared to before treatment.

[0331] In some embodiments, the Vineland-II Adaptive Behavior Scale (VABS-2) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's composite score on the VABS-2 is reduced by at least about 5%, e.g., at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or more, compared to before treatment.

[0332] In some embodiments, the Aberrant Behavior Checklist - Second Edition (ABC) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's ABC 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%, compared to the ABC score before treatment.

[0333] In some embodiments, the Child Behavior Checklist (CBCL) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's CBCL percentile 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%, compared to before treatment.

[0334] In some embodiments, the Autism Behavior Inventory (ABI) is used to evaluate the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's ABI score is reduced 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%, compared to before treatment.

[0335] In some embodiments, the Social Responsiveness Scale, Second Edition (SRS-2) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's SRS-2 proxy version t-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%, compared to the pre-treatment score.

[0336] In some embodiments, the Repetitive Behavior Scale-Revised (RBS-R) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's RBS-R 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%, compared to the RBS-R score before treatment.

[0337] In some embodiments, the Ohio Autism Clinical Impression Scale-Improvement / Severity (OACIS-I / S) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's OACIS-I and / or OACIS-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%, compared to before treatment.

[0338] In some embodiments, the Gilliam Autism Rating Scale - Third Edition (GARS-3) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's GARS-3 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%, compared to before treatment.

[0339] In some embodiments, the Autism Spectrum Quotient (AQ) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's AQ 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%, compared to before treatment.

[0340] In some embodiments, the Repetitive Behavior Questionnaire-2 for Adults (RBQ-2A) is used to assess the effectiveness of treatment with the methods of the present disclosure. In some embodiments, after treatment with the methods of the present disclosure, the subject's RBQ-2A 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%, compared to before treatment.

[0341] In some embodiments, the method reduces the subject's Vineland-II Adaptive Behavior Score (VABS-2). In some embodiments, an increased VABS-2 score is observed within one month after psilocybin administration. In some embodiments, the VABS-2 score is reduced by at least about 5%, about 10%, about 15%, or at least about 20%.

[0342] In some embodiments, the method reduces the subject's proxy-version t-score on the Social Responsiveness Scale, Second Edition (SRS-2). In some embodiments, the reduced proxy-version t-score is observed within one month after psilocybin administration. In some embodiments, the proxy-version t-score is reduced by at least about 5%, about 10%, about 15%, or at least about 20%.

[0343] Sleep-wake disorders Sleep-wake disorders are a class of diseases or disorders that include insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorders (such as central sleep apnea), circadian rhythm sleep-wake disorder, non-REM sleep-wake disorder, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, and substance / medication-induced sleep disorders. Individuals with these disorders typically present with sleep-wake complaints about dissatisfaction with the quality, timing, and quantity of sleep, often causing daytime distress.

[0344] As used herein, the term insomnia refers to an individual's sleep disorder. Insomnia is diagnosed using the following criteria: (1) difficulty falling asleep, staying asleep, or difficulty in deep sleep; (2) this difficulty exists despite adequate sleep opportunities and circumstances; (3) this sleep disorder is accompanied by daytime dysfunction or distress; and (4) this sleep difficulty occurs at least three times a week and is a problem for at least one month. Insomnia can be classified as chronic (sleep disorder occurs at least three times a week and has existed for the past three months), short-term (sleep disorder has existed for up to three months), and other (difficulty in initiating or maintaining sleep that does not meet the criteria for chronic insomnia or short-term insomnia). Primary insomnia occurs independently of other factors and may be associated with general psychophysiological polycystic insomnia.

[0345] Hypersomnia disorder is characterized by one of the following three symptoms: 7 hours or more of quality sleep, recurrent sleep duration or delayed sleep within the same day, non-restorative prolonged sleep episodes of more than 9 hours per day, or episodes of significant sleepiness even after sudden awakening with difficulty in fully waking up. This disorder can also be characterized by excessive daytime sleepiness, excessive daytime somnolence, and hypersomnia. The exact cause of hypersomnia is unknown, but risk factors include stress, drug use, a history of head trauma, and a family history of hypersomnia.

[0346] Clinically, narcolepsy manifests with excessive daytime sleepiness, which can result in personal and social impairment. Cataplexy, sleep paralysis, and hypnagogic or waking hallucinations may also be present. There are two types of narcolepsy: type 1 (with cataplexy; transient muscle weakness caused by emotions thought to represent the intrusion of REM sleep during wakefulness) and type 2 (without cataplexy). Narcolepsy type 1, type 2, and idiopathic hypersomnia are subtypes of hypersomnia.

[0347] The term "breathing-related sleep disorder" refers to a spectrum of respiratory abnormalities ranging from chronic or habitual snoring to upper airway resistance syndrome, central sleep apnea, or, in some cases, obesity-hypoventilation syndrome. Central sleep apnea (CSA) is characterized by a lack of drive to breathe during sleep, insufficient or absent ventilation, impaired gas exchange, and a lack of respiratory effort during periods of airflow cessation. The term primary CSA, also known as idiopathic CSA (ICSA), describes a rare type of CSA with unknown etiology. ICSA is characterized by periodic episodes of apnea or hypopnea due to reduced neural input to respiratory motor neurons. Patients with ICSA typically present with complaints of snoring, witnessed apnea, restless sleep, insomnia, and / or excessive daytime sleepiness.

[0348] Sleep-wake disorders may be diagnosed and / or assessed using one or more clinical measures, such as mean sleep latency (MSL), polysomnolence latency test, hypocretin (orexin) levels, sleep-onset REM period (SOREMP) on the Epworth Sleep Scale (ESS), maintenance of wakefulness test (MWT) score, cataplexy and cataplexy-like episodes, objective and subjective sleep latency, total sleep time (TST), polysomnography, Insomnia Severity Index (ISI) questionnaire, Narcolepsy Severity Scale, Pittsburgh Sleep Quality Index score, Epworth Sleep Scale, Groningen Sleep Quality Questionnaire, Apnoea Hypopnea Index, Nightmare Experiences Scale, etc.

[0349] Sleep-wake disorders can occur in association with one or more comorbid conditions. These comorbid conditions can be the cause or consequence of the sleep-wake disorder and therefore can precede, co-occur, or follow the diagnosis. Thus, comorbid conditions and sleep-wake disorders have a bidirectional relationship and can share a common underlying cause.

[0350] The same pathophysiological mechanisms involved in psychiatric disorders such as depression, anxiety, and psychosis can also cause insomnia or hypersomnia. Medications that increase serotonergic activity (e.g., selective serotonin reuptake inhibitors [SSRIs]) can cause insomnia. Increased dopaminergic states, which are involved in the etiology of psychosis, can cause insomnia. This may also be true for drug-induced psychosis—the prototypical example is cocaine-induced psychosis and insomnia.

[0351] Insomnia is found to be highly comorbid with mood and affective disorders such as major depressive disorder (MDD), mania, and anxiety. Insomnia is also common in subjects with substance abuse disorders and autism spectrum disorders.

[0352] Patients with central nervous system hypersomnia may have a spectrum of comorbid medical, neurological, and psychiatric conditions. Hypersomnia is a comorbid condition associated with multiple psychiatric and substance abuse disorders, particularly insomnia, anxiety, and depression, as well as the use of antidepressants and benzodiazepines. Other comorbid conditions may include eating disorders and obesity, diabetes, schizophrenia, fibromyalgia, migraine, cognitive impairment, and psychosocial disorders.

[0353] Narcolepsy can be comorbid with attention deficit hyperactivity disorder (ADHD). Individuals with ADHD are more likely to have sleep problems, obstructive sleep apnea or snoring, rhythmic movement disorders (body rocking and head banging), and parasomnias such as restless legs syndrome / periodic limb movements.

[0354] Narcolepsy also has a high comorbidity with psychiatric disorders. Depressed mood is the most commonly described psychiatric symptom. Many narcoleptic patients also suffer from depression. Anxiety disorders such as panic attacks and social phobia have been reported in many narcoleptic patients. Schizophrenia and narcolepsy also have significant overlap in symptoms, including hallucinations, sleep fragmentation, and psychosis. Comorbid schizophrenia and narcolepsy have been reported, but are considered relatively rare.

[0355] Some narcoleptics report irresistible, persistent cravings for food, especially binge eating accompanied by poor control, and restrictive behaviors to correct the binge eating.

[0356] In some embodiments, a method for treating one or more sleep-wake disorders in a subject in need thereof comprises administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, the sleep-wake disorder is insomnia, hypersomnia, narcolepsy, cataplexy, idiopathic hypersomnia, sleep paralysis, hypnagogic hallucinations, awakening hallucinations, breathing-related sleep disorder, circadian rhythm sleep-wake disorder, non-24-hour sleep-wake disorder, disorder of awakening from non-REM sleep, nightmare disorder, REM sleep behavior disorder, restless legs syndrome, medication-induced sleep disorder, or substance-induced sleep disorder.

[0357] In some embodiments, the sleep-wake disorder is insomnia. In some embodiments, the insomnia is chronic. In some embodiments, the insomnia is short-term.

[0358] In some embodiments, the sleep-wake disorder is hypersomnia, hi some embodiments, the hypersomnia is characterized by one or more of excessive daytime sleepiness, excessive daytime somnolence, and / or hypersomnia.

[0359] In some embodiments, the sleep-wake disorder is narcolepsy, such as type 1 or type 2 narcolepsy.

[0360] In some embodiments, the subject has excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, waking hallucinations, or a combination thereof prior to treatment with psilocybin or its active metabolite, hi some embodiments, the subject experiences improvement in excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, waking hallucinations, or a combination thereof during treatment with psilocybin or its active metabolite.

[0361] In some embodiments, the subject experiences improvement in excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, hypnagogic hallucinations, or a combination thereof after treatment with psilocybin or an active metabolite thereof.

[0362] In some embodiments, the sleep-wake disorder is one or more breathing-related sleep disorders. For example, the breathing-related sleep disorder can be chronic snoring, upper airway resistance syndrome, sleep apnea, or obesity-hypoventilation syndrome. In some embodiments, the breathing-related sleep disorder is sleep apnea, such as central sleep apnea (CSA). In some embodiments, the central sleep apnea can be primary CSA, Cheine-Stokes breathing (CSB), high altitude breathing, CSA due to a medical condition without CSB, drug- or substance-induced central sleep apnea, emergency treatment central apnea, or a combination thereof. In some embodiments, the subject experiences 1 to 30 fewer sleep apnea episodes per hour of sleep after treatment with psilocybin. For example, a subject may experience a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more reduction in sleep apnea per hour.

[0363] In some embodiments, the subject exhibits improvement in one or more of the following after treatment with psilocybin: mean sleep latency (MSL); polysomnography; hypocretin (orexin) levels; sleep-onset REM period (SOREMP) on the Epworth Sleep Scale (ESS); maintenance of wakefulness test (MWT) score; cataplexy and cataplexy-like episodes; objective and subjective sleep latency; total sleep time (TST); polysomnography; Insomnia Severity Index (ISI) questionnaire; Narcolepsy Severity Scale; Pittsburgh Sleep Quality Index score; Epworth Sleep Scale; Groningen Sleep Quality Questionnaire; Apnoea Hypopnea Index; and Nightmare Experiences Scale.

[0364] In some embodiments, the subject exhibits an improvement in MSLT after treatment with psilocybin as described herein, compared to the subject's MSLT score before treatment. In some embodiments, the subject exhibits an improvement in MSLT from 1 to 10 minutes after treatment with psilocybin as described herein, compared to the subject's MSLT score before treatment. In some embodiments, the subject exhibits an improvement in MSLT from 1 to 5 minutes after treatment with psilocybin as described herein, compared to the subject's MSLT score before treatment. In some embodiments, the subject exhibits an improvement in MSLT from 1 to 3 minutes after treatment with psilocybin as described herein, compared to the subject's MSLT score before treatment.

[0365] In some embodiments, the subject has one or more diseases, disorders, or conditions that are comorbid with the sleep-wake disorder. For example, the subject may have one or more of a mood disorder, an affective disorder, a neurodegenerative disease, a neurodevelopmental disorder, an autism spectrum disorder, and a substance abuse disorder. In some embodiments, the subject has major depressive disorder, mania, depression, anxiety, psychosis, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, autism spectrum disorder (ASD), panic attacks, one or more social phobias, one or more eating disorders, and / or schizophrenia.

[0366] In some embodiments, the method for treating one or more sleep-wake disorders in a subject in need thereof further comprises administering to the subject at least one additional therapeutic agent. In some embodiments, the therapeutic agent increases serotonergic activity. In some embodiments, the therapeutic agent is a selective serotonin reuptake inhibitor.

[0367] In some embodiments, the method of treating one or more sleep-wake disorders in a subject in need thereof further comprises administering cognitive behavioral therapy to the subject.

[0368] Pain, including chronic pain Pain is the most common symptom of illness and protects against dangerous and harmful stimuli. It is a sensory and perceptual phenomenon that causes distress and reduces quality of life. Furthermore, pain is a subjective sensation, as its intensity depends on the context and can change in the presence of other physical and mental conditions. Therefore, the same stimulus can be experienced differently by different individuals.

[0369] As used herein, the term "chronic pain" refers to pain that lasts longer than the normal course of an acute injury or disease, such as pain that recurs over months or years. "Nociceptive pain" is high-threshold pain activated by intense stimuli, such as heat, cold, or sharp touch. It minimizes contact with noxious stimuli and requires urgent action and attention. "Neuropathic pain" is chronic pain caused by lesions or diseases of the somatosensory system, which can result in altered transmission of sensory signals to the spinal cord and brain. Conditions associated with neuropathic pain include multiple sclerosis, diabetic neuropathy, retroherpetic neuralgia, brachial plexus injury, allodynia, human immunodeficiency virus (HIV) infection, amputation, nerve injury pain, stroke, cancer-related pain, trigeminal neuralgia, central neuropathic pain, posttraumatic neuropathy, postoperative neuropathy, cervical and lumbar polyneuropathy, leprosy, autoimmune disorders, inflammatory disorders, channelopathies, and metabolic disorders. Additional examples of types of pain include visceral pain and bone pain.

[0370] Amputation causes changes in the peripheral and central nervous systems, resulting in phantom limb sensations, in which the patient feels that the amputated limb is still present. Phantom limb pain is pain that the patient perceives as occurring in a part of the body that is no longer present. Its onset can be immediate or may occur years later. Common sensations described by patients are tingling, throbbing, pricking, pins, and needles.

[0371] Verbal rating scale (pain rating scale), behavioral rating scale (pain intensity based on behavioral effects), physical pain subscale from the SF-36 Health Survey questionnaire, Gracely Box scale (pain intensity and discomfort), colored analog scale, EQ5D 3-point pain subscale (pain and discomfort scale), FACES, facial pain scale, facial affect scale (scale using facial expressions to describe pain), Geriatric Pain Event Inventory (hypothetical painful situations), numerical rating scale (pain rating scale), pain thermometer (verbal descriptors placed with a picture of a thermometer), verbal descriptor scale (pain described using verbal descriptors with or without a numerical scale), Rand There are several self-report tools used in the assessment of pain, such as the Coop Chart (cartoon characteristics of the body), visual analog scale (pain intensity), Brief Pain Inventory (pain intensity, location, impact on mood, impact on daily activities), Pain Measurement in the Elderly (pain intensity, withdrawal due to pain, pain with walking, pain with strenuous activity, and pain with other activities), McCaffery and Pasero's Initial Pain Assessment Tool (pain location, what makes pain better / worsening), McGill Pain Questionnaire (pain quality, location, exacerbation and relief factors), Total Pain Index (pain rating for each body location, frequency, severity, and duration over the past 3 months using a scale of 0 to 10), Pain Behavior Checklist (assessing the patient's pain behavior), West Haven-Yale Multidimensional Pain Inventory (pain severity, interference, mood, activity, sense of control, support, quality of life), Leeds Assessment of Neuropathic Symptoms and Signs (assessing neuropathic pain), Douleur Neuropathique en 4 (indicating neuropathic pain), or Pain DETECT (screening for neuropathic pain).

[0372] Chronic pain is often associated with one or more additional comorbid conditions. For example, chronic pain may be accompanied by depression, anxiety, sleep disorders, fatigue, or substance use disorders. Amputation following trauma can lead to various psychiatric disorders, such as major depressive disorder, post-traumatic stress disorder, suicidal ideation, and anxiety.

[0373] Drugs currently approved by the FDA to treat neuropathic pain syndromes include gabapentin, pregabalin, lamotrigine, carbamazepine, duloxetine, 5% lidocaine patch, opioid analgesics, tramadol hydrochloride, tricyclic antidepressants, fluoxetine, and extended-release tapentadol.

[0374] First-line treatments for neuropathic pain include antidepressants, including tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors. This also includes anticonvulsants that act at calcium channels, such as pregabalin and gabapentin. Topical lidocaine and opioids are often used as second- and third-line treatments for neuropathic pain. Other antiepileptic drugs and topical capsaicin are used as third- and fourth-line treatments in patients who cannot tolerate or do not respond to first- and second-line treatments. A non-limiting list of medications used to treat neuropathic pain includes antidepressants (tricyclic antidepressants (amitriptyline), serotonin-norepinephrine reuptake inhibitors (venlafaxine, duloxetine)), antiepileptic drugs (pregabalin, gabapentin), lidocaine, capsaicin, tramadol, botulinum toxin A, opioid agonists (oxycodone, morphine, fentanyl), cannabinoids, and ketamine.

[0375] A non-limiting list of medications and other therapies used to treat phantom limb pain includes prophylactic analgesia and anesthesia (i.e., during the preoperative period), acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, anticonvulsants, botulinum toxin type B injections, calcitonin, and NMDA receptor antagonists.

[0376] In some embodiments, a method of treating chronic pain in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0377] In some embodiments, the chronic pain is caused by a peripheral neuropathic pain condition. In some embodiments, the peripheral neuropathic pain condition is characterized by allodynia. In some embodiments, the peripheral neuropathic pain condition is characterized by post-herpetic neuralgia.

[0378] In some embodiments, the chronic pain is phantom limb pain.

[0379] In some embodiments, the chronic pain is caused by a central neuropathic pain condition, hi some embodiments, the central neuropathic pain condition is a brachial plexus injury.

[0380] In some embodiments, the chronic pain is caused by cancer or cancer treatment.

[0381] In some embodiments, administration of psilocybin reduces the frequency, duration, or severity of pain in a subject. In some embodiments, the reduction in pain frequency, duration, or severity is measured according to one or more of the following scales: a verbal rating scale, a behavioral rating scale, a bodily pain subscale (SF-36 Health Survey questionnaire), a Gracely Box scale, a colored analog scale, an EQ5D 3-point pain subscale, FACES, Faces Pain Scale, Facial Affects Scale, Geriatric Pain Event Inventory, a numerical rating scale, a pain thermometer, a verbal descriptor scale, a Rand Coop chart, a visual analog scale, a Brief Pain Inventory, Geriatric Pain Measure, McCaffery and Pasero Early Pain Assessment Tool, a McGill Pain Questionnaire, a Total Pain Index, a Pain Behavior Checklist, a West Haven-Yale Multidimensional Pain Inventory, a Leeds Assessment of Neuropathic Symptoms and Signs, a Douleur Neuropathique en 4, or a Pain DETECT.

[0382] In some embodiments, the frequency, duration, or severity of pain in the subject is improved within 24 hours after administration of psilocybin. In some embodiments, the frequency, duration, or severity of pain in the subject is improved within one week after administration of psilocybin. In some embodiments, the frequency, duration, or severity of pain in the subject is improved for at least one month after administration of psilocybin.

[0383] In some embodiments, the subject's pain frequency, duration, or severity is improved for at least 3 months after administration of psilocybin, hi some embodiments, the subject's pain frequency, duration, or severity is improved for at least 12 months after administration of psilocybin.

[0384] In some embodiments, after administration of psilocybin, no other therapy for treating chronic pain is administered.

[0385] In some embodiments, the method for treating a subject in need of treatment further comprises administering at least one additional therapeutic agent to the subject. In some embodiments, the at least one additional therapeutic agent is a tricyclic antidepressant or a serotonin-noradrenaline reuptake inhibitor (SSRI). In some embodiments, the at least one additional therapeutic agent is pregabalin or gabapentin. In some embodiments, the at least one additional therapeutic agent is lidocaine, capsaicin, tramadol, botulinum toxin A, oxycodone, morphine, fentanyl, cannabinoid, ketamine, acetaminophen, a nonsteroidal anti-inflammatory drug, an opioid, calcitonin, or an NMDA receptor antagonist.

[0386] Inflammatory disorders Inflammation is an adaptive response triggered by stimuli recognized as toxic by immune cells, such as tissue injury and infection. These triggers can also be "self" proteins arising from sites of immunological tolerance due to tissue damage, as in autoimmune conditions such as arthritis. Other non-harmful triggers of inflammation include organ transplants in hemolytic disease of the newborn, harmless allergens, and rhesus proteins.

[0387] The five symptoms considered to indicate acute inflammation include redness, heat, swelling, pain, and loss of function, although some inflammation occurs "silently" and does not cause outward symptoms.

[0388] Inflammatory cytokines released by immune cells upon activation by "toxic" stimuli mediate inflammation through signal transduction in target cells and induce the recruitment of further immune cells. Therefore, the concentration of cytokines in the body (e.g., in biological samples such as blood or CSF samples) is considered a marker of inflammation.

[0389] Tumor necrosis factor alpha (TNFα), IL-6, and IL-1b are examples of proinflammatory cytokines produced by activated macrophages (white blood cells that can detect, engulf, and destroy harmful foreign substances and dead cells). IL-6 and TNFα are elevated in most, if not all, inflammatory conditions. Other proinflammatory cytokines include, for example, IL-1 (e.g., IL-1a, IL-1b), IL-2, IL-6, IL-8, IL-12, and further TNFα production. IL-10 can suppress the expression of inflammatory signals.

[0390] Inflammation underlies the generation and maintenance of some of the major causes of morbidity and mortality worldwide. Inflammatory diseases are often chronic and can be the result of impaired immune signaling. Exemplary immune diseases include, but are not limited to, asthma, hepatitis, allergies, arthritis, inflammatory bowel disease, dermatitis, and celiac disease. Examples of chronic inflammatory diseases include stroke, chronic respiratory disease, heart disease, cancer, obesity, and diabetes. Furthermore, cytokine signaling is involved in the initiation and maintenance of pathological pain, such as inflammatory pain and neuropathic pain.

[0391] Inflammatory diseases can be treated with anti-inflammatory therapies aimed at reducing cytokine signaling and subsequent immune activation. Inhibiting the development of acute inflammation can also reduce the prevalence of chronic inflammatory diseases.

[0392] The following exemplary anti-inflammatory therapies may be used to address chronic and acute inflammation: metformin, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, corticosteroids, antibodies, and methotrexate.

[0393] Various clinical measurements can be used to assess the severity of inflammation, such as: Serum biomarker assays: C-reactive protein, erythrocyte sedimentation rate, white blood cell levels, platelet levels, ferritin, haptoglobin, ceruloplasmin, α-1-antitrypsin, plasminogen, complement factors, and fibrinogen, orosomucoid, IL6, sialic acid, serum amyloid A, TNFα, IL1b, IL18, IL12, IL1 receptor antagonist, TGF-beta. Fecal immunochemical assays: fecal calprotectin, lactoferrin, polymorphonuclear elastase, myeloperoxidase, metalloproteinase-9, and neopterin. · Plasma viscosity. ·Disease Activity Score and Clinical Disease Activity Index.

[0394] In some embodiments, a method of reducing inflammation in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0395] In some embodiments, the inflammation is acute. In some embodiments, the inflammation is chronic. In some embodiments, the inflammation is systemic. In some embodiments, the inflammation is localized. In some embodiments, administration of psilocybin reduces the duration of inflammation.

[0396] In some embodiments, administering psilocybin reduces the level of at least one inflammatory biomarker or indicator in a subject's biological sample.In some embodiments, the biological sample is a blood sample, such as a serum sample or a plasma sample.In some embodiments, the biological sample is a cerebrospinal fluid (CSF) sample.

[0397] In some embodiments, the inflammatory biomarker is a pro-inflammatory cytokine. In some embodiments, the pro-inflammatory cytokine is interleukin-1 (IL-1), tumor necrosis factor (TNF), gamma-interferon (IFN-γ), IL-1β, IL-6, IL-10, IL-12, IL-18, granulocyte-macrophage colony-stimulating factor (GMCSF), CXC chemokine ligand 1 (CXCL1), or CXCL9. In some embodiments, the pro-inflammatory cytokine is TNF-α, IL-6, IL-1β, or IL-10. In some embodiments, the pro-inflammatory cytokine is CXCL1 or CXCL9. In some embodiments, the inflammatory biomarker is C-reactive protein (CRP), homocysteine, or hemoglobin A1c (HbA1c). In some embodiments, the inflammatory indicator is plasma viscosity.

[0398] In some embodiments, the level of at least one inflammatory biomarker or indicator is reduced within 24 hours of administering psilocybin, hi some embodiments, the level of at least one inflammatory biomarker or indicator is reduced within one week of administering psilocybin.

[0399] In some embodiments, the level of at least one inflammatory biomarker or indicator is reduced for at least one month following administration of psilocybin.

[0400] In some embodiments, the level of at least one inflammatory biomarker or indicator is reduced for at least 3 months after administration of psilocybin, hi some embodiments, the level of at least one inflammatory biomarker or indicator is reduced for at least 12 months after administration of psilocybin.

[0401] In some embodiments, administration of psilocybin reduces or increases functionality of at least one of fever, pain, skin redness, or swelling in a subject. In some embodiments, fever, pain, skin redness, or swelling is reduced or functionality is increased within 24 hours of administration of psilocybin. In some embodiments, fever, pain, skin redness, or swelling is reduced or functionality is increased within one week of administration of psilocybin. In some embodiments, fever, pain, skin redness, or swelling is reduced or functionality is increased for at least one month after administration of psilocybin.

[0402] In some embodiments, fever, pain, skin redness, or swelling is reduced or functionality is increased for at least 3 months after administration of psilocybin, hi some embodiments, fever, pain, skin redness, or swelling is reduced or functionality is increased for at least 12 months after administration of psilocybin.

[0403] In some embodiments, after administration of psilocybin, no other treatment for reducing inflammation is administered to the subject.

[0404] In some embodiments, the method for reducing inflammation in a subject in need thereof further comprises administering to the subject at least one additional therapeutic agent to reduce inflammation. In some embodiments, the at least one additional therapeutic agent is a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen, aspirin, or naproxen. In some embodiments, the at least one additional therapeutic agent is a corticosteroid such as cortisone, prednisone, or methylprednisolone. In some embodiments, the at least one additional therapeutic agent is metformin, a statin, methotrexate, or an antibody.

[0405] In some embodiments, the subject has asthma, celiac disease, hepatitis, allergies, arthritis, irritable bowel syndrome (IBS), or dermatitis. In some embodiments, the subject has Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or an autism spectrum disorder.

[0406] In some embodiments, administration of psilocybin treats or prevents one or more of allergies, asthma, Alzheimer's disease, diabetes, cardiovascular disease, sepsis, arthritis, joint disease, inflammatory bowel disease, or dermatitis in a subject. In some embodiments, administration of psilocybin treats or prevents one or more of chronic pain, neuropathic pain, and inflammatory pain in a subject. In some embodiments, administration of psilocybin treats or prevents a mood disorder (e.g., depression) in a subject.

[0407] Inflammatory bowel disease (IBD) IBD is a term used to describe a variety of diseases and disorders, including Crohn's disease and ulcerative colitis, that are characterized by chronic inflammation of the gastrointestinal (GI) tract. Prolonged inflammation leads to damage to the GI tract.

[0408] Crohn's disease can affect any part of the GI tract, from the mouth to the anus. Damaged areas appear in patches next to areas of healthy tissue. Typically, Crohn's disease affects most of the small intestine before the large intestine / colon. Crohn's-related inflammation can reach through multiple layers of the GI tract wall.

[0409] Ulcerative colitis occurs in the large intestine (colon) and rectum. The damage is continuous (not patchy) and usually begins in the rectum and spreads further into the colon. Inflammation is only present in the innermost layer of the colon.

[0410] Common symptoms of IBD include persistent diarrhea, abdominal pain, rectal bleeding, bloody stools, weight loss, and fatigue. In IBD, the immune system misresponds to environmental triggers, which causes inflammation in the GI tract. Other symptoms may include mouth sores, skin problems, arthritis, or eye problems that affect vision. IBD symptoms may be worsened by stress. While the exact cause of IBD is unknown, there appears to be a genetic component—individuals with a family history of IBD are more likely to develop the disease.

[0411] In some embodiments, a method for treating inflammatory bowel disease (IBD) in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof. In some embodiments, the IBD is ulcerative colitis. In some embodiments, the IBD is Crohn's disease.

[0412] In some embodiments, at least one sign or symptom of IBD is improved after administration of psilocybin or its active metabolite. In some embodiments, the sign or symptom of IBD is diarrhea, fever, fatigue, abdominal pain and / or cramps, bloody stool, loss of appetite, or unintentional weight loss. In some embodiments, the improvement is verified by endoscopy. In some embodiments, the improvement is verified by biopsy.

[0413] In some embodiments, the subject also has colon cancer, hi some embodiments, the subject is taking a medication to treat colon cancer.

[0414] In some embodiments, administration of psilocybin to a subject results in an improvement in the Mayo score and / or Ulcerative Colitis Activity Index (UCSAI), both of which incorporate scores for stool frequency, rectal bleeding, endoscopic findings, and physician assessment of disease activity.

[0415] In some embodiments, at least one sign or symptom of IBD improves within 24 hours of administering psilocybin, hi some embodiments, at least one sign or symptom of IBD improves within one week of administering psilocybin.

[0416] In some embodiments, at least one sign or symptom of IBD is improved for at least one month after administration of psilocybin. In some embodiments, at least one sign or symptom of IBD is improved for at least three months after administration of psilocybin. In some embodiments, at least one sign or symptom of IBD is improved for at least 12 months after administration of psilocybin.

[0417] In some embodiments, after administration of psilocybin, the subject is not administered any other therapy for treating IBD.

[0418] In some embodiments, the method of treating inflammatory bowel disease (IBD) in a subject in need thereof further comprises administering to the subject at least one additional therapeutic agent in addition to psilocybin to treat IBD. In some embodiments, the at least one additional therapeutic agent is an aminosalicylate, a corticosteroid (e.g., prednisone), an immunomodulator, or a biologic (e.g., a monoclonal antibody). In some embodiments, the subject has surgery before or after administration of psilocybin to the removed damaged portion of the GI tract.

[0419] stroke A stroke is a sudden interruption of the brain's blood supply. Some strokes are caused by a sudden blockage of an artery leading to the brain (ischemic stroke). Other strokes are caused by bleeding into brain tissue when a blood vessel ruptures (hemorrhagic stroke). In a transient ischemic attack (TIA) or mild stroke, stroke symptoms last only a short time (e.g., less than about an hour). Brain cells begin to die within minutes of being deprived of oxygen and nutrients. Early treatment can reduce brain damage and other complications.

[0420] A stroke can cause sudden weakness, loss of sensation, or difficulty speaking, seeing, or walking. Because different parts of the brain control different areas and functions, a stroke usually affects the area that is immediately surrounding it. A person who has a stroke may experience headaches, but a stroke may also be completely painless.

[0421] The effects of a stroke vary depending on which part of the brain is damaged and how severe it is. Strokes can sometimes cause temporary or permanent disability. Complications can include: (i) paralysis or loss of muscle movement (especially on one side of the body), (ii) difficulty speaking or swallowing, (iii) difficulty remembering or thinking, (iv) emotional problems, (v) pain, and (vi) changes in behavior or self-care abilities.

[0422] In some embodiments, psilocybin can be used to treat stroke in a subject in need thereof. In some embodiments, a method of treating stroke in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof. In some embodiments, the stroke is an ischemic stroke. In some embodiments, the stroke is a hemorrhagic stroke.

[0423] In some embodiments, administration of psilocybin ameliorates signs or symptoms of stroke, which can be, for example, paralysis, numbness, or weakness in the arms, face, or legs, difficulty speaking or understanding speech, confusion, slurred speech, vision problems, difficulty walking, loss of balance or coordination, dizziness, or headache.

[0424] In some embodiments, the signs or symptoms of stroke improve within 1 hour of administering psilocybin, hi some embodiments, the signs or symptoms of stroke improve within 12 hours of administering psilocybin.

[0425] In some embodiments, the signs or symptoms of stroke are improved for at least one month after administration of psilocybin. In some embodiments, the signs or symptoms of stroke are improved for at least three months after administration of psilocybin. In some embodiments, the signs or symptoms of stroke are improved for at least 12 months after administration of psilocybin.

[0426] In some embodiments, after administration of psilocybin, no other therapy for treating stroke is administered to the subject.

[0427] In some embodiments, the method for treating stroke in a subject in need thereof further comprises administering to the subject a therapeutically effective amount of at least one additional therapeutic agent in addition to psilocybin, which can be, for example, an antiplatelet agent (e.g., aspirin) or an anticoagulant (e.g., warfarin, dabigatran, rivaroxaban, apizavan, edoxaban).

[0428] In some embodiments, psilocybin can be used to treat a subject recovering from a stroke. In some embodiments, a method for treating a subject in need of treatment comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof, wherein the subject is recovering from a stroke. In some embodiments, the subject is recovering from an ischemic stroke. In some embodiments, the subject is recovering from a hemorrhagic stroke.

[0429] In some embodiments, administration of psilocybin improves conditions caused by a stroke, such as paralysis, cognitive impairment, difficulty understanding speech, difficulty speaking, difficulty controlling or expressing emotions, numbness, pain in the hands or feet, difficulty chewing or swallowing, or problems with bladder or bowel control.

[0430] In some embodiments, the condition caused by the stroke is improved within 24 hours of administering psilocybin, hi some embodiments, the condition caused by the stroke is improved within one week of administering psilocybin.

[0431] In some embodiments, the condition caused by the stroke is improved for at least one month after administration of psilocybin. In some embodiments, the condition caused by the stroke is improved for at least three months after administration of psilocybin. In some embodiments, the condition caused by the stroke is improved for at least 12 months after administration of psilocybin.

[0432] In some embodiments, after administration of psilocybin, the subject is not administered any other therapy to treat the condition caused by the stroke.

[0433] In some embodiments, the method for treating a subject recovering from a stroke further comprises administering to the subject at least one additional therapeutic agent in addition to psilocybin to treat a condition caused by the stroke.

[0434] In some embodiments, the subject has depression. In some embodiments, administration of psilocybin alleviates the depression in the subject.

[0435] Amyotrophic lateral sclerosis (ALS) ALS is a progressive neurodegenerative disease. It is also known as motor neuron disease (MND), Lou Gehrig's disease, and Charcot's disease. ALS attacks motor neurons in the brain and spinal cord, resulting in muscle weakness and loss of movement.

[0436] ALS usually affects people between the ages of 40 and 70. Signs and symptoms of ALS can include muscle spasms, muscle cramps, weakness in the hands, legs, feet, or ankles, and difficulty speaking or swallowing. Senses (hearing, sight, smell, taste, and touch) are not affected by ALS. In most cases, cognitive function is not affected. Most ALS cases are sporadic, with no family history of the disease in the affected individual. A small percentage of ALS cases occur in individuals who inherit a gene mutation from both parents.

[0437] In some embodiments, a method for treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof comprises administering to the subject a therapeutically effective amount of psilocybin or an active metabolite thereof.

[0438] In some embodiments, administration of psilocybin ameliorates a sign or symptom of ALS, ie, muscle twitching, muscle weakness, muscle stiffness, difficulty speaking, difficulty swallowing, difficulty breathing, cognitive impairment, or pain.

[0439] In some embodiments, the signs or symptoms of ALS improve within 24 hours of administering psilocybin, hi some embodiments, the signs or symptoms of ALS improve within one week of administering psilocybin.

[0440] In some embodiments, the signs or symptoms of ALS are improved for at least one month after administration of psilocybin. In some embodiments, the signs or symptoms of ALS are improved for at least three months after administration of psilocybin. In some embodiments, the signs or symptoms of ALS are improved for at least 12 months after administration of psilocybin.

[0441] In some embodiments, after administration of psilocybin, the subject is not administered any other therapy for treating ALS.

[0442] In some embodiments, the method for treating a subject in need of treatment for ALS further comprises administering to the subject at least one additional therapeutic agent, in addition to psilocybin, to treat ALS. In some embodiments, the at least one additional therapeutic agent is riluzole or edaravone.

[0443] In some embodiments, the subject has depression. In some embodiments, administration of psilocybin alleviates the depression in the subject.

[0444] Multiple sclerosis (MS) Multiple sclerosis (MS) is a demyelinating disease in which the insulating covering of nerve cells in the brain and spinal cord is damaged. This damage interferes with the ability of parts of the nervous system to transmit signals, resulting in a variety of signs and symptoms, including physical, mental, and sometimes psychiatric problems.

[0445] In some embodiments, a method for treating multiple sclerosis (MS) in a subject in need thereof comprises administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, the MS is clinically isolated syndrome (CIS). In some embodiments, the MS is relapsing-remitting MS (RRMS).

[0446] In some embodiments, the MS is primary progressive MS (PPMS). In some embodiments, the MS is secondary progressive MS (SPMS).

[0447] In some embodiments, administration of psilocybin improves signs or symptoms of MS. In some embodiments, improved signs or symptoms of MS can include neurological symptoms or signs, such as autonomic, visual, motor, or sensory problems. In some embodiments, improved signs or symptoms of MS can include double vision, blindness in one eye, muscle weakness, sensory problems, coordination problems, loss of sensitivity, sensory changes such as tingling, pins and needles, or numbness, muscle weakness, blurred vision, very noticeable reflexes, muscle spasms, or difficulty moving, coordination and balance difficulties (ataxia), speech or swallowing problems, visual disturbances (nystagmus, optic neuritis, or diplopia), fatigue, acute or chronic pain, and bladder and bowel difficulties (such as neurogenic bladder). In some embodiments, improved signs or symptoms of MS can include difficulty thinking and emotional problems, such as depression or mood instability. In some embodiments, improved signs or symptoms of MS can include a reduction or decrease in Uhthoff phenomenon, a worsening of symptoms due to exposure to higher than normal temperatures, and Lhermitte's sign, which is a sensation of electricity running down the back of the neck when flexing the neck. In some embodiments, after administration of psilocybin, subjects show improvement in their Expanded Disability Status Scale (EDSS) and / or Multiple Sclerosis Functional Composite score.

[0448] In some embodiments, the signs or symptoms of MS improve within 24 hours of administering psilocybin, hi some embodiments, the signs or symptoms of MS improve within one week of administering psilocybin.

[0449] In some embodiments, the signs or symptoms of MS improve for at least one month after administration of psilocybin. In some embodiments, the signs or symptoms of MS improve for at least three months after administration of psilocybin. In some embodiments, the signs or symptoms of MS improve for at least 12 months after administration of psilocybin.

[0450] In some embodiments, after administration of psilocybin, the subject is not administered any other therapy for treating MS.

[0451] In some embodiments, the methods for treating MS in a subject in need thereof further comprise administering to the subject at least one additional therapeutic agent, in addition to psilocybin, to treat MS. In some embodiments, the at least one additional therapeutic agent is interferon beta 1a, interferon beta 1b, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, ocrelizumab, siponimod, cladribine, and ozanimod.

[0452] In some embodiments, the subject has depression. In some embodiments, administration of psilocybin alleviates the depression in the subject.

[0453] Opioid Use Disorder Opioid use disorder (OUD) is a pattern of opioid use that leads to serious impairment or distress. OUD may be characterized by one or more of the following symptoms: (i) taking opioids in larger amounts or for longer periods of time than intended, (ii) persistent desire or unsuccessful efforts to reduce or control opioid use, (iii) spending a significant amount of time acquiring, using, or regaining opioid use, (iv) craving (strong desire or urge) to use opioids, (v) continued use of opioids that causes failure to fulfill major obligations at work, school, or home, (vi) continued use of opioids despite causing recurrent social or personal problems, (vii) a decrease in important social, occupational, or recreational activities due to opioid use, (viii) recurrent opioid use in unsafe situations, (ix) continued use of opioids despite associated physical or psychological problems, (x) tolerance (the need to take higher doses of the drug to feel the same effect or to taper off from the same amount), or (xi) withdrawal (the experience of pain or other unpleasant symptoms in the absence of the drug).

[0454] In some embodiments, a method of treating OUD in a subject in need thereof comprises administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, a method of preventing relapse of OUD in a subject in need thereof comprises administering to the subject an effective amount of psilocybin or an active metabolite thereof.

[0455] In some embodiments, the subject is undergoing one or more opioid substitution therapies (OST) before administering psilocybin. A non-limiting list of exemplary OSTs includes methadone, buprenorphine, or naltrexone. In some embodiments, the subject stops taking OST before administering psilocybin, for example, at least one day, at least one week, or at least two weeks before administering psilocybin. In some embodiments, the subject continues to take OST after administering psilocybin, for example, at least one week, at least one month, at least three months, or at least six months after administering psilocybin. In some embodiments, the subject stops taking OST after administering psilocybin.

[0456] In some embodiments, psilocybin treatment reduces the number of days of opioid use per week in a subject by at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. In some embodiments, psilocybin treatment reduces the number of days of OST use per week in a subject by at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days.

[0457] In some embodiments, treatment with psilocybin prevents or substantially prevents relapse in the subject for at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 1 year, or at least 5 years after administration of psilocybin.

[0458] In some embodiments, treatment with psilocybin improves a subject's score on one or more of the following tests / assessments: C-SSRS, TLFB, OCS, SDS, MADRS, EQ-5D-5L, GAD-7, Severity of Dependence Scale, BIS-11, TIPI, and Pain VAS. These tests / assessments are listed in Table 9 below. In some embodiments, the subject's score increases by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, or more after administration of psilocybin. In some embodiments, the subject's score improves within about 1 day, about 3 days, about 5 days, about 7 days, about 10 days, about 2 weeks, about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months after administration of psilocybin. In some embodiments, the subject's score remains increased for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months after administration of psilocybin. [Table 9-1] [Table 9-2]

[0459] Antisocial personality disorder Antisocial personality disorder, sometimes called antisociopathy, is a mental disorder in which a person consistently disregards right and wrong and the rights and feelings of others. People with antisocial personality disorder tend to antagonize, manipulate, or treat others harshly, or with indifference and coldness. They typically do not show guilt or remorse for their actions.

[0460] Individuals with antisocial personality disorder often break the law and become criminals. They may lie, behave violently or impulsively, and have problems with drug and alcohol use. Because of these characteristics, people with this disorder are usually unable to fulfill responsibilities related to home, work, or school.

[0461] Exemplary signs and symptoms of antisocial personality disorder include: disregard for right and wrong and persistently lying or deceiving in order to exploit others; being callous, sarcastic, and treating others with disrespect; using charm or wit to manipulate others for personal gain or personal pleasure; arrogant, superior-compulsive, and highly opinionated; repeated problems with the law including criminal behavior; repeatedly violating the rights of others through threats and dishonesty; being impulsive or unable to plan ahead; hostility, significant irritability, aggression, aggression, or violence; lack of empathy for others and lack of remorse for hurting others; taking unnecessary risks or engaging in risky behavior without regard for the safety of self or others; poor or abusive relationships; failure to consider the negative consequences of actions or learn from them; being consistently irresponsible and repeatedly failing to meet work or financial obligations.

[0462] In some embodiments, a method for treating antisocial personality disorder in a subject in need thereof comprises administering to the subject an effective amount of psilocybin or an active metabolite thereof. In some embodiments, one or more signs or symptoms of antisocial personality disorder are improved in the subject after administration of psilocybin. In some embodiments, the subject is administered one or more additional therapeutic agents.

[0463] In some embodiments, the subject has one or more comorbid conditions. For example, the comorbid conditions may be conduct disorder, depression, or anxiety. In some embodiments, psilocybin improves at least one sign or symptom of the comorbid condition.

[0464] Prior and concomitant treatments In some embodiments, a treatment method 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 magnesium level is about 1.5 to about 2.5 mEq / L. In some embodiments, if the subject's blood magnesium level is less than about 1.5 to about 2.5 mEq / L, psilocybin is not administered to the subject.

[0465] In some embodiments, a method of treatment comprising administering psilocybin to a subject in need thereof further comprises pretreating the subject with niacin prior to administration of psilocybin. In some cases, niacin is administered daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or at least 6 weeks prior to administration of psilocybin. In some embodiments, the subject is administered about 1 mg to about 5,000 mg of niacin per day, e.g., about 1 mg to about 50 mg, about 10 mg to about 100 mg, about 100 mg to about 200 mg, about 1 mg to about 200 mg, about 100 mg to about 200 mg, about 10 mg to about 50 mg, about 10 mg to about 35 mg, about 100 mg to about 500 mg, or about 1,000 mg to about 3,000 mg. In some embodiments, about 10 mg, about 14 mg, about 15 mg, about 16 mg, about 20 mg, about 30 mg, about 35 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg of niacin is administered to a subject per day (while avoiding any toxic exposure from excess niacin). In some embodiments, niacin is included as an ingredient / component, for example, to reduce risk of abuse and / or improve efficacy. In some embodiments, the niacin is administered to the subject on the same day as the psilocybin. In some embodiments, the niacin is administered to the subject immediately before, simultaneously with, or immediately after the administration of the psilocybin.

[0466] In some embodiments, psilocybin is administered to a subject in combination with one or more additional therapeutic agents. In some embodiments, psilocybin is administered to a subject in combination with one or more antidepressants or anti-anxiety medications, such as an SSRI, a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), or a serotonin norepinephrine reuptake inhibitor (SNRI).

[0467] In some embodiments, the present disclosure provides a method of reducing anxiety in a subject receiving treatment with psilocybin, the method comprising administering to the subject: i) psilocybin or a precursor or derivative thereof, and ii) one or more benzodiazepines.

[0468] In some embodiments, one or more benzodiazepines are administered to a subject simultaneously or nearly simultaneously with psilocybin or a precursor or derivative thereof. In some embodiments, one or more benzodiazepines are administered prior to administration of psilocybin or a precursor or derivative thereof, e.g., about 10, 15, 20, 30, 45, 60, 75, 90, 105, 120, 150, or 180 minutes prior to administration of psilocybin or a precursor or derivative thereof. In some embodiments, the one or more benzodiazepines are administered after administration of psilocybin or a precursor or derivative thereof, for example, to a subject about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after administration of psilocybin or a precursor or derivative thereof.

[0469] In some embodiments, one or more benzodiazepines are administered at a dose lower than that typically used to treat anxiety, such as about 10%, 20%, 25%, 30%, 40%, 50%, or 75% of the typical dose. In some embodiments, one or more benzodiazepines are administered at a dose approximately equal to that typically used to treat anxiety. In some embodiments, one or more benzodiazepines are administered at a dose higher than that typically used to treat anxiety, such as about 125%, 150%, 175%, 200%, 250%, or 300% of the typical dose. In some embodiments, one or more benzodiazepines are administered orally to the subject.

[0470] In some embodiments, the benzodiazepines are adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam , flunitrazepam, flurazepam, flutazolam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, meclonazepam, medazepam, metizolam, mexazolam, midazolam, nifoxipam, nimetazepam, nitemazepam, nitrazepam, nitrazolam, nordiazepam, norflurazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, rilmazefone, temazepam, tetrazepam, and triazolam.

[0471] In certain embodiments, the subject administers psilocybin, or a precursor or derivative thereof, as described herein, to one or more 5-HT 2AIn some embodiments, the subject is administered psilocybin or a precursor or derivative thereof, along with one or more 5-HT specific antagonists and / or inverse agonists. 2A In other embodiments, the subject is administered one or more 5-HT specific antagonists and / or inverse agonists at the same time, such as, but not limited to, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes prior to psilocybin administration. 2A In some embodiments, the subject receives a specific antagonist and / or inverse agonist of one or more 5-HT agonists after psilocybin administration, such as, but not limited to, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after psilocybin administration. 2A Specific antagonists and / or inverse agonists are administered.

[0472] In certain embodiments, one or more 5-HT 2A The specific antagonist and / or inverse agonist is administered at a dose lower than typically used, e.g., about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 75% of the typical dose. 2A In yet another embodiment, the specific antagonist and / or inverse agonist is administered at a dose equivalent to that typically used. 2A The specific antagonist and / or inverse agonist is administered at a higher dose than typically used, for example, about 125%, about 150%, about 175%, about 200%, about 250%, or about 300% of the typical dose.

[0473] 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, etridone, cetoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rauwolscine, phenoxybenzamine, pulvanserin, deramciclane, nerotanserin, rubazodone, mepiprazole, xylamidine, R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinemethanol (M100907), mianserin, AT 1015, DV 7028, eplivanserin, 4F These include, but are not limited to, 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).

[0474] Preferred 5-HT 2A Inverse agonists include, but are not limited to, AC-90179, nerotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and vorinaserin.

[0475] In certain embodiments, 5-HT 2A The antagonist is selected from the compounds in Table 10. [Table 10-1] [Table 10-2]

[0476] In some embodiments, the present disclosure provides methods for reducing negative side effects associated with a traumatic psychedelic experience in a subject receiving treatment with psilocybin, the methods comprising administering to the subject i) psilocybin or a precursor or derivative thereof, and ii) one or more cannabinoids or cannabinoid derivatives.

[0477] 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), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran). In certain embodiments, the cannabinoid is CBD (cannabidiol).

[0478] In some embodiments, at least one symptom of a disease, disorder, or condition described herein is alleviated within 24 hours of administration of psilocybin. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within one week of administration. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within one month of administration. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within six months of administration. In some embodiments, at least one symptom of a disease, disorder, or condition is alleviated within 12 months of administration.

[0479] In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least one month after administration of psilocybin. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least three months after administration. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least six months after administration. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for at least 12 months after administration.

[0480] In some embodiments, prior to administration of psilocybin, the subject is not administered other therapies for treating the disease, disorder, or condition, hi some embodiments, after administration of psilocybin, the subject is not administered other therapies for treating the disease, disorder, or condition.

[0481] Safety and efficacy of psilocybin The present disclosure also relates to the safety and efficacy of using psilocybin as disclosed herein. The following is a non-exhaustive list of tests that can be used to determine the effects of psilocybin, particularly psilocybin formulations, as disclosed herein, administered as disclosed herein.

[0482] In some embodiments, a spatial working memory (SWM) test is utilized to assess the safety and efficacy of psilocybin as disclosed herein. SWM requires the retention and manipulation of visuospatial information. Subjects must find blue tokens in "boxes" on the screen. Boxes are searched by touching them to determine whether they contain a token. Once a token is found, it is "stacked" in a column on the right side of the screen. The subject searches for more tokens until all are located. The remaining tokens are then found only in boxes that have not previously contained a token. Subjects are explicitly informed that this is the case, and revisiting a box in which a token was found constitutes a "between error," the usual key measure of this test. If a subject revisits a box during the same search, it is scored as a "within" error. Many subjects employ a search strategy that systematically searches through the array of boxes. This is also scored by the Cambridge Neuropsychological Test Automated Battery System, resulting in a "Strategy" score. SWM performance is impaired by damage to the prefrontal cortex, particularly the dorsofrontal cortex. Similarly, in neuroimaging studies of healthy volunteers, performance on SWM is associated with activation of the dorsal and ventral prefrontal cortex. The test takes approximately 4 minutes to complete.

[0483] In some embodiments, the efficacy of psilocybin is assessed using a spatial working memory between errors (SWMBE) score. In some embodiments, after treatment with a method of the present disclosure, the subject's SWMBE score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0484] In some embodiments, the efficacy of psilocybin is assessed using a Spatial Working Memory Strategy (SWMS) score. In some embodiments, after treatment with a method of the present disclosure, the subject's SWMS score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to pre-treatment.

[0485] In some embodiments, the Rapid Visual Processing (RVP) test is utilized to assess the safety and efficacy of psilocybin. RVP is a measure of sustained attention that outputs measurements of response accuracy, target sensitivity, and reaction time. In this test, subjects monitor a stream of two to nine digits for a specific sequence (e.g., 3-5-7) and must confirm detection of the sequence by touching an on-screen response button as quickly as possible after the presentation of the third digit. Numbers are presented in a pseudo-like fashion to create the possibility of a "false alarm" response, in which the first two digits of the sequence do not follow the true target. For example, a 3 follows a 5, but not a 7. To successfully complete the task, subjects must maintain continuous attention on a white box displaying the digits. Performance on this task is measured by the speed of response to the presentation of the final target digit, as well as the subject's ability to detect the specific sequence. This test takes approximately 7 minutes to complete. In some embodiments, performance on the Rapid Visual Processing test is reported using the RVP A Prime (RPVA) score. A higher RVPA score indicates better performance. In some embodiments, after treatment with the methods of the present disclosure, the subject's RVPA score is improved by about 5% to about 300%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or more, compared to before treatment. %, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300% or more increase.

[0486] In some embodiments, the paired associative learning (PAL) test is used to assess the safety and / or efficacy of psilocybin. The PAL task is a measure of visuospatial memory, requiring subjects to remember the location of a visual stimulus. Boxes are displayed on the screen and "opened" in random order. One or more of them contain a pattern. The patterns are then displayed one at a time in the center of the screen, and the subject must select the box where the pattern was originally located. If the subject makes an error, the boxes are opened again in sequence to remind the subject of the pattern's location. A higher difficulty level can be used to test high-functioning, healthy individuals. The primary indicator of this test is the number of errors made. The test takes approximately 8 minutes to complete. Success with the PAL test depends on the functional integrity of the temporal lobe, particularly the entorhinal cortex. In some embodiments, the Paired Associate Learning Total Errors (Adjustments) (PALTEA) score is used to assess the efficacy of psilocybin. In some embodiments, after treatment with the methods of the present disclosure, the subject's PALTEA score is reduced by about 5% to about 100%, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% or more, compared to before treatment.

[0487] In some embodiments, the efficacy and / or safety of psilocybin is assessed using a cognitive flexibility panel test.

[0488] In some embodiments, the Emotion Recognition Task (ERT) test is utilized to assess the safety and / or efficacy of psilocybin. The ERT measures the ability to identify six basic emotions in facial expressions along a continuum of different magnitudes. In some embodiments, the ERT is administered according to the following protocol: The subject is presented with computer-generated images on a screen, one at a time, derived from the facial features of real individuals that display a particular emotion. Each face is displayed for 200 milliseconds and then immediately obscured, and the subject must select which face is displayed from six options (happy, sad, anger, fear, surprise, disgust). The subject's correct responses (emotion selections) are assessed as ERT Correct Percentage (ERTPC). A higher score indicates better performance. I...

Claims

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

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