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Definitions

• Depression is one of the most common mental illnesses, affecting more than 264 million people worldwide. It is characterized by depressed mood and markedly diminished interest or pleasure in activities. Other symptoms include significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death, suicidal ideation or suicidal attempts.
• Psilocybin may provide numerous clinical benefits, such as benefits in neural plasticity and cognitive function (as measured using e.g., Cambridge Neuropsychological Test Automated Battery (CANTAB) tests) with improvements in, for example, working memory and executive function, sustained attention, and episodic memory. These benefits have implications for psilocybin’s use in the treatment of various diseases, disorders, and conditions, including both psychiatric and neurological aspects thereof.
• the disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering an effective amount of psilocybin or an active metabolite thereof to the subject.
• the subject has a major depressive disorder, atypical depression, bipolar disorder, catatonic depression, a depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder. In some embodiments, the subject has a depressive disorder that is resistant to treatment.
• the methods of the disclosure reduce at least one sign or symptom of depression.
• the sign or symptom of depression is depressed mood, diminished interest in activities, weight loss or gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to concentrate or indecisiveness, or suicidal ideation or behavior.
• the sign or symptom of depression is measured according to a diary assessment, an assessment by clinician or caregiver, a clinical rating scale, or by functional MRI.
• the functional MRI measures the amygdala blood oxygen level- dependent (BOLD) response in the subject.
• the sign or symptom of depression is measured using a clinical depression rating scale
• the clinical depression rating scale is a Quick Inventory of Depressive Symptomatology (QIDS)-16 scale, a QIDS-16 daily scale, a Hamilton Depression Rating scale, a Beck Depression Inventory scale, a Montgomery-Asberg Depression Rating Scale, a Clinical Global Impression Scale, a Zung Self-Rating Depression Scale, a Raskin Depression Rating Scale, and/or a Young Mania Rating Scale.
• the sign or symptom of depression is measured using a Spielberger’s Trait and Anxiety Inventory, a Generalized Anxiety Disorder 7-Item Scale, a Warwick-Edinburgh Mental Wellbeing Scale, a Flourishing Scale, a Snaith Hamilton Anhedonia Pleasure Scale, a Life Orientation Test, a Meaning in Life Questionnaire, a Brief Resilience Scale, a Dysfunctional Attitudes Scale, a 44-item Big Five Inventory, a Peters 21-item Delusional Inventory, an Examination of Anomalous Self- Experience, a Ruminative Responses Scale, a White Bear Suppression Inventory, a Barrett Impulsivity Scale, a Brief Experiential Avoidance Questionnaire, a Modified Tellegen Absorption Questionnaire, a Scale to Assess Therapeutic Relationship, a Credibility/Expectancy Questionnaire, a Connectedness to Nature Scale, a Political Perspective Questionnaire, a Social Connectedness Scale
• At least one sign or symptom of depression is alleviated within 24 hours of administration of the psilocybin. In some embodiments, at least one symptom of depression is alleviated within 1 week of administration of the psilocybin. In some embodiments, at least one symptom of depression is alleviated for a period of at least 1 month after administration of the psilocybin. In some embodiments, at least one symptom of depression is alleviated for a period of at least 3 months after administration of the psilocybin. In some embodiments, at least one symptom of depression is alleviated for a period of at least 12 months after administration of the psilocybin.
• no other treatment is administered to the subject to reduce the sign or symptom of depression after administration of the psilocybin.
• the method of the present disclosure further comprises administering to the subject at least one additional therapeutic to reduce the sign or symptom of depression.
• at least one additional therapeutic is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic antagonist.
• at least one additional therapeutic is administered prior to administration of psilocybin, on the same day as the administration of psilocybin, or after administration of psilocybin.
• the subject with the depressive disorder has an additional comorbidity or disorder.
• the additional comorbidity or disorder is an anxiety disorder, an obsessive-compulsive disorder, alcoholism, a personality disorder, a cardiovascular disease, a neurological disease, or cancer.
• the subject has dementia, Alzheimer’s Disease, or Parkinson’s Disease.
• reducing at least one sign or symptom of depression in the subject using the methods of the present disclosure prevents one or more comorbidities or disorders in the subject.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin or a metabolite thereof, wherein the subject has one or more of the following diseases, disorders, or conditions: Disruptive Mood Dysregulation Disorder, Major Depressive Disorder (MDD), Treatment-Resistant Depression, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication-Induced Depressive Disorder, Post- Partum Depression, Depressive Disorder due to Another Medical Condition, Separation Anxiety Disorder, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Panic Disorder, Panic Attack, Agoraphobia, Generalized Anxiety Disorder, Substance-Medication- Induced Anxiety Disorder, Anxiety Disorder Due to Another Medical Condition, Somatic Symptom Disorder, Illness Anxiety Disorder (hypochondriac), Conversion Disorder (F
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeuticallyeffective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: a Neurocognitive Disorder due to Alzheimer's, Lewy Bodies, Traumatic Brain Injury, Prion Disease, HIV Infection, Parkinson's, Huntington's; concussion; Chronic Traumatic Encephalopathy (CTE); Language Disorder, Speech Sound Disorder (Phonological Disorder); Childhood-Onset Fluency Disorder (Stuttering); Social (Pragmatic) Communication Disorder; Tourette's Disorder; Persistent (Chronic) Motor or Vocal Tic Disorder; Amnestic Disorder Due to Known Physiological Condition (possibly in electroconvulsive therapy (ECT) resistant subjects); Transient Cerebral Ischemic Attack, Cerebral Infarction, Cerebral Bleeding, Progressive Supranuclear Ophthalmoplegia; or Retrograde Amnesi
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Autism Spectrum Disorder, or Antisocial Personality Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Attention-Deficit/Hyperactivity Disorder, Other Specified Attention-Deficit/Hyperactivity Disorder or Unspecified Attention-Deficit/Hyperactivity Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Schizotypal (Personality) Disorder, Delusional Disorder, Schizophrenia, or Schizoaffective Disorder.
• Schizotypal (Personality) Disorder a therapeutically effective dose of psilocybin
• the subject has one or more of the following diseases, disorders, or conditions: Schizotypal (Personality) Disorder, Delusional Disorder, Schizophrenia, or Schizoaffective Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions selected from Insomnia Disorder, Hypersomnolence Disorder, Narcolepsy, or Primary Central Sleep Apnea.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Schizoid Personality Disorder, Schizotypal Personality Disorder, Antisocial Personality Disorder, Borderline Personality Disorder, or Obsessive-Compulsive Personality Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Female sexual Interest/Arousal Disorder, Male Hypoactive Sexual Desire Disorder, or Excessive sexual Drive.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: from Bipolar I Disorder, Bipolar II Disorder, or Cyclothymic Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Age-Related Hearing Loss or Tinnitus.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Multiple Sclerosis, Cranial Nerve Disorder, Neuromyelitis Optica, Bell's Palsy, Guillain Barre Syndrome, Demyelinating Disease of Central Nervous System, or Chronic Inflammatory Demyelinating Polyneuritis.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of psilocybin, wherein the subject suffers from pain, such as phantom pain, chronic pain, or pain associated with another disease or disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has one or more of the following diseases, disorders, or conditions: Myelopathy, Traumatic Brain Injury, Intellectual Disabilities, Mania, Neurodegeneration, Paraphilic disorders (e.g, Pedophilic Disorder), Suicidal Behavior Disorder, Nonsuicidal Self- Injury, Persistent Complex Bereavement Disorder, Gastrointestinal Tract Related Diseases (e.g., Irritable Bowel Syndrome (IBS)), Epilepsy, Sickle Cell Disease, Locked-in Syndrome, Restless Leg Syndrome, Stroke (such as ischemic stroke or hemorrhagic stroke), or Amyotrophic Lateral Sclerosis (ALS).
• myelopathy Traumatic Brain Injury, Intellectual Disabilities, Mania, Neurodegeneration, Paraphilic disorders (e.g, Pedophilic Disorder), Suicidal Behavior Disorder, Nonsuici
• the disclosure provides a method of treating a subject, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein, after administration, the subject exhibits an improvement in cognition.
• the improvement in cognition is an improvement in attention, episodic memory, working memory, spatial memory, social cognition, executive function, and/or cognitive flexibility.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has Treatment-Resistant Depression (TRD).
• TRD Treatment-Resistant Depression
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has Major Depressive Disorder (MDD)
• MDD Major Depressive Disorder
• 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 of Polymorph A. In some embodiments, the crystalline psilocybin comprises at least 95% by weight of Polymorph A. In some embodiments, the crystalline psilocybin has a chemical purity of greater than 97% by high performance liquid chromatography (HPLC), and no single impurity of greater than 1 %.
• HPLC high performance liquid chromatography
• the psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly pure crystalline psilocybin in the form of Polymorph A, wherein the crystalline psilocybin has a chemical purity of greater than 97% by HPLC, and no single impurity of greater than 1 %.
• the psilocybin is administered in a dosage form comprising a therapeutically effective amount of highly pure crystalline psilocybin in the form of Polymorph A, wherein the crystalline psilocybin has a chemical purity of greater than 97% by HPLC, and no single impurity of greater than 1 %, further comprising a mixture of two silicified microcrystalline cellulose variants wherein the first variant has a particle size from about 45 to 80 microns and the second variant has a particle size of about 90 to 150 microns.
• 30% or less of the microcrystalline cellulose is the first variant having a particle size from about 45 to 80 microns and about 70% or more of the microcrystalline cellulose is the second variant having a particle size of about 90 to 150 microns.
• 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.
• At least one dose of psilocybin is administered to the subject.
• the dose of psilocybin is in the range of about 0.1 mg to about 100 mg. In some embodiments, the dose of psilocybin is about 25 mg.
• the subject participates in at least one psychological support session before administration of the psilocybin. In some embodiments, the subject participates in at least one psychological support session after administration of the psilocybin. In some embodiments, a therapist provides psychological support to the subject for approximately 4-8 hours after administration of the psilocybin.
• FIG. 1 is a numbered structural formula of psilocybin.
• FIG. 2a is a XRPD diffractogram of Polymorph A (GM764B).
• FIG. 2b is a XRPD diffractogram of Polymorph A’ (JCCA2160F).
• FIG. 2c is a XRPD diffractogram of Polymorph B (JCCA2160-F-TM2).
• FIG. 2d is a XRPD diffractogram of a Hydrate A (JCCA2157E).
• FIG. 2e is a XRPD diffractogram of an ethanol solvate (JCCA2158D).
• FIG. 2f is a XRPD diffractogram of product obtained during development of the process (CB646- E) (top) - compared to the diffractograms Polymorph A’ (JCCA2160F) (middle) and Polymorph B (JCCA2160-TM2) (bottom).
• FIG. 3a is a DSC and TGA thermograph of Polymorph A (GM764B).
• FIG. 3b is a DSC and TGA thermograph of Polymorph A’ (JCCA2160F).
• FIG. 3c is a DSC thermograph of Polymorph B (GM748A).
• FIG. 3d is a DSC and TGA thermograph of Hydrate A (JCCA2157E).
• FIG. 3e is a DSC and TGA thermograph of ethanol solvate (JCCA2158D).
• FIG. 4 is a form phase diagram showing the inter-relationship of form in water-based systems.
• FIG. 5 is a 1 H NMR (Nuclear Magnetic Resonance) spectrum of psilocybin.
• FIG. 6 is a 13C NMR spectrum of psilocybin.
• FIG. 7 is a FT-IR Spectrum of psilocybin.
• FIG. 8 is a Mass Spectrum of psilocybin.
• Fig. 9A shows a timeline of the Phase 1 exploratory study, which evaluated psilocybin treatment in healthy volunteer subjects.
• Fig. 9B shows the number of subjects that completed screening (Visit 1 ), baseline
• Fig. 9C shows the group sizes of the dosing sessions of the Phase 1 exploratory study.
• Fig. 9D shows the most frequently reported adverse events of the Phase 1 exploratory study.
• Fig. 9E shows the duration of adverse events of the Phase 1 exploratory study.
• Fig. 9F shows a graph of the Paired Associates Learning Total Errors Adjusted (PALTEA) score of the Cambridge Neuropsychological Test Automated Battery (CANTAB) over time for the psilocybin-treated and placebo-treated subjects of the Phase 1 exploratory study.
• PALTEA Paired Associates Learning Total Errors Adjusted
• CANTAB Cambridge Neuropsychological Test Automated Battery
• Fig. 9G shows a graph of the least squares mean difference from placebo for the PALTEA score of the CANTAB over time for the psilocybin-treated subjects of the Phase 1 exploratory study.
• Fig. 9H shows a graph of the spatial working memory between errors (SWMBE) score of the
• Fig. 9I shows a graph of the least squares mean difference from placebo for the SWMBE score of the CANTAB over time for the psilocybin-treated subjects of the Phase 1 exploratory study.
• Fig. 9J shows a graph of the spatial working memory strategy (SWM strategy) score of the
• Fig. 9K shows a graph of the least squares mean difference from placebo for the SWM strategy score of the CANTAB over time for the psilocybin-treated subjects of the Phase 1 exploratory study.
• Fig. 9L shows a graph of the Rapid Visual Information Processing A Prime (RVPA) score of the CANTAB over time for the psilocybin-treated and placebo-treated subjects of the Phase 1 exploratory study.
• RVPA Rapid Visual Information Processing A Prime
• Fig. 9M shows a graph of the least squares (LS) mean difference of psilocybin groups (10 mg and 25 mg) compared to placebo groups over time.
• Psilocybin was administered on Day 0.
• Data on Days 7 and Day 28 were collected remotely. Positive scores indicate psilocybin performed better than placebo. Negative scores indicate placebo performed better than psilocybin.
• LS means were calculated using repated-measures ANOVA and compared with placebo. * p ⁇ 0.05. Data are expressed as LS mean ⁇ sem.
• Fig. 9N shows a graph of the Emotional Recognition Task percent correct (ERTPC) of the
• Fig. 90 shows a graph of the One Touch Stockings Problems Solved on First Choice
• OTSPSFC OTSPSFC
• Fig. 9P shows a graph of the intra-extra dimensional set shift total errors (IEDYERT) of the
• Fig. 9Q shows a graph of the CANTAB global composite score over time for the psilocybin- treated and placebo-treated subjects of the Phase 1 exploratory study.
• Fig. 9R shows a graph of the least squares mean difference from placebo for the CANTAB
• Fig. 9S shows a graph of the verbal fluency test for the psilocybin-treated and placebo-treated subjects of the Phase 1 exploratory study.
• Fig. 9T shows a graph of the digit span forward test for the psilocybin-treated and placebo- treated subjects of the Phase 1 exploratory study.
• Fig. 9U shows a graph of the Five Dimensional - Altered States of Consciousness (5D-ASC), which measures alterations in mood, perception, and experience of self, after administration of psilocybin or placebo in the Phase 1 exploratory study.
• 5D-ASC Five Dimensional - Altered States of Consciousness
• Fig. 9V shows the difference in CANTAB composite score between“psilocybin-naive” (0, left- hand side) subjects and subjects with prior psilocybin experience (1 , right-hand side).
• Fig. 10A shows the study design of the clinical trial examining psilocybin in major depressive disorder.
• Fig. 10B shows the study timeline for examining psilocybin in major depressive disorder.
• Fig. 10C shows a timeline of the first dosing session (Visit 3) in the clinical study.
• Fig. 1 1 shows the study design of the clinical trial examining psilocybin in treatment resistant depression.
• Fig. 12 shows the study design of the clinical trial examining psilocybin in bipolar disorder.
• Fig. 13A is a graph showing the changes in amount of wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep over 24 hours in a rat Wistar- Kyoto model of TRD following psilocybin administration. Black arrow denotes dosing time. Grey background denotes dark period (awake period in rodents).
• Fig. 13E is a graph showing the changes in the absolute and relative wakefulness, NREM and REM sleep EEG power with frequency in a rat Wistar-Kyoto model of TRD.
• Fig. 13B is a graph showing the amount of wakefulness, NREM sleep and REM sleep 1 - 7 hours (light period, sleep period in rodents) post-dosing with psilocybin in a rat Wistar-Kyoto model of treatment-resistant depression.
• Fig. 13C is a graph showing the amount of wakefulness, NREM sleep and REM sleep 1 1 - 19 hours (dark period, awake period in rodents) post-dosing with psilocybin in a rat Wistar-Kyoto model of treatment-resistant depression.
• Fig. 13D is a graph showing the changes in the absolute and relative wakefulness electroencephalogram (EEG) power with frequency, and the amount of gamma oscillations in a rat Wistar-Kyoto model of treatment-resistant depression.
• EEG absolute and relative wakefulness electroencephalogram
• the term“about” as used herein when referring to a measurable value such as a dose, time, temperature, and the like, is meant to encompass variations of ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 1 %, ⁇ 0.5%, or even ⁇ 0.1 % of the specified amount.
• 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.
• “or” should be understood to have the same meaning as“and/or” as defined above.
• “or” or“and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as“only one of’ or“exactly one of,” or, when used in the embodiments,“consisting of,” will refer to the inclusion of exactly one element of a number or list of elements.
• 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 within the list of elements and not excluding any combinations of elements in the list of elements.
• This definition also allows that elements can optionally be present other than the elements specifically identified within the list of elements to which the phrase“at least one” refers, whether related or unrelated to those elements specifically identified.
• “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
• the terms “reduce,”“decrease,” “lessen” and similar terms mean a decrease 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.
• the terms“improve,”“increase,”“enhance,” and similar terms indicate 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.
• references to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise.
• another embodiment includes from the one particular value and/or to the other particular value.
• reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable.
• substantially absent with reference to XRPD diffractogram peak means the peak has a relative intensity compared to a reference peak present in the diffractogram 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 that the peak is not detectable.
• XRPD diffractograms and XRPD peak positions may be acquired using Cu Ka radiation.
• DSC thermograms and TGA thermograms may be acquired using a heating rate of 20°C/min.
• DTI diffusion tensor imaging
• DSM-5 Diagnostic and Statistical Manual of Mental Disorders
• ICD International Classification of Diseases
• 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 cause, delaying, preventing and/or slowing the progression of diseases and/or disorders and improving or remediating damage caused, directly or indirectly, by the diseases and/or disorders.
• “therapeutically-effective dose” means a dose sufficient to achieve the intended therapeutic purpose, such as, to alleviate a sign or symptom of a disease or disorder in a subject.
• a“precursor” and/or“derivative” of psilocybin includes, but is not limited to, prodrugs of psilocybin, prodrugs of an active metabolite of psilocybin, and an active metabolite of psilocybin.
• MedDRA Medical Dictionary for Regulatory Activities
• the methods provided herein are used to treat a subject with a depressive disorder.
• a depressive disorder refers to a group of disorders characterized by low mood that can affect a person’s thoughts, behavior, feelings, and sense of well-being lasting for a period of time.
• the depressive disorder disrupts the physical and psychological functions of a person.
• the depressive disorder causes a physical symptom such as weight loss, aches or pains, headaches, cramps, or digestive problems.
• the depressive disorder causes a psychological symptom such as persistent sadness, anxiety, feelings of hopelessness and irritability, feelings of guilt, worthlessness, or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, remembering, or making decisions.
• the depressive disorder is major depressive disorder, atypical depression, bipolar disorder, catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder.
• major depressive disorder refers to a condition characterized by a time period of low mood that is present across most situations.
• Major depressive disorder is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause.
• major depressive order is characterized by two weeks.
• Major depressive disorder can negatively affect a person’s personal, work, or school life, as well as sleeping, eating habits, and general health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of people who commit suicide had major depressive disorder or another related mood disorder.
• Dysthymia is a subtype of major depressive disorder consisting of the same cognitive and physical problems as major depressive disorder with less severe but longer-lasting symptoms.
• exemplary symptoms of a major depressive disorder include, but are not limited to, feelings of sadness, tearfulness, emptiness or hopelessness, angry outbursts, irritability or frustration, even over small matters, loss of interest or pleasure in most or all normal activities, sleep disturbances, including insomnia or sleeping too much, tiredness and lack of energy, reduced appetite, weight loss or gain, anxiety, agitation or restlessness, slowed thinking, speaking, or body movements, feelings of worthlessness or guilt, fixating on past failures or self-blame, trouble thinking, concentrating, making decisions, and remembering things, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems, such as back pain or headaches.
• the term“atypical depression” refers to a condition wherein an individual shows signs of mood reactivity (i.e. , mood brightens in response to actual or potential positive events), significant weight gain, increase in appetite, hypersomnia, heavy, leaden feelings in arms or legs, and/or long-standing pattern of interpersonal rejection sensitivity that results in significant social or occupational impairment.
• Exemplary symptoms of atypical depression include, but are not limited to, daily sadness or depressed mood, loss of enjoyment in things that were once pleasurable, major changes in weight (gain or loss) or appetite, insomnia or excessive sleep almost every day, a state of physical restlessness or being rundown that is noticeable by others, daily fatigue or loss of energy, feelings of hopelessness, worthlessness, or excessive guilt almost every day, problems with concentration or making decisions almost every day, recurring thoughts of death or suicide, suicide plan, or suicide attempt.
• bipolar disorder refers to a condition that causes an individual to experience unusual shifts in mood, energy, activity levels, and the ability to carry out day-to- day tasks. Individuals with bipolar disorder experience periods of unusually intense emotion, changes in sleep patterns and activity levels, and unusual behaviors. These distinct periods are called“mood episodes.” Mood episodes are drastically different from the moods and behaviors that are typical for the person.
• Exemplary symptoms of mania, excessive behavior include, but are not limited to, abnormally upbeat, jumpy, or wired behavior; increased activity, energy, or agitation, exaggerated sense of well-being and self-confidence, decreased need for sleep, unusual talkativeness, racing thoughts, distractibility, and poor decision-making— for example, going on buying sprees, taking sexual risks, or making sheep investments.
• Exemplary symptoms of depressive episodes or low mood include, but are not limited to, depressed mood, such as feelings of sadness, emptiness, hopelessness, or tearfulness; marked loss of interest or feeling no pleasure in all— or almost all— activities, significant weight loss, weight gain, or decrease or increase in appetite, insomnia or hypersomnia (excessive sleeping or excessive sleepiness), restlessness or slowed behavior, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate, or indecisiveness, and thinking about, planning or attempting suicide.
• depressed mood such as feelings of sadness, emptiness, hopelessness, or tearfulness
• marked loss of interest or feeling no pleasure in all— or almost all— activities significant weight loss, weight gain, or decrease or increase in appetite
• insomnia or hypersomnia excessive sleeping or excessive sleepiness
• restlessness or slowed behavior fatigue or loss of energy
• feelings of worthlessness or excessive or inappropriate guilt decreased ability to think or concentrate, or indecisiveness, and thinking about, planning or attempting suicide.
• Bipolar disorder includes bipolar I disorder, bipolar II disorder, and cyclothymic disorder.
• Bipolar I disorder is defined by manic episodes that last at least 7 days or by severe manic symptoms that require hospitalization. A subject with bipolar I disorder may also experience depressive episodes typically lasting at least 2 weeks. Episodes of depression with mixed features, i.e. depressive and manic symptoms at the same time, are also possible.
• Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but not severe manic episodes typical of bipolar I disorder.
• Cyclothymic disorder also referred to as cyclothymia
• catatonic depression refers to a condition causing an individual to remain speechless and motionless for an extended period.
• exemplary symptoms of catatonic depression include, but are not limited to, feelings of sadness, which can occur daily, a loss of interest in most activities, sudden weight gain or loss, a change in appetite, trouble falling asleep, trouble getting out of bed, feelings of restlessness, irritability, feelings of worthlessness, feelings of guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and/or a suicide attempt.
• the term“depressive disorder due to a medical condition” refers to a condition wherein an individual experiences depressive symptoms caused by another illness.
• medical conditions known to cause a depressive disorder include, but are not limited to, HIV/AIDS, diabetes, arthritis, strokes, brain disorders such as Parkinson’s disease, Huntington’s disease, multiple sclerosis, and Alzheimer’s disease, metabolic conditions (e.g. vitamin B12 deficiency), autoimmune conditions (e.g., lupus and rheumatoid arthritis), viral or other infections (hepatitis, mononucleosis, herpes), back pain, and certain cancers (e.g., pancreatic).
• postpartum depression refers to a condition as the result of childbirth and hormonal changes, psychological adjustment to parenthood, and/or fatigue.
• Postpartum depression is often associated with women, but men can also suffer from postpartum depression as well.
• Exemplary symptoms of postpartum depression include, but are not limited to, feelings of sadness, hopeless, emptiness, or overwhelmed; crying more often than usual or for no apparent reason; worrying or feeling overly anxious; feeling moody, irritable, or restless; oversleeping, or being unable to sleep even when the baby is asleep; having trouble concentrating, remembering details, and making decisions; experiencing anger or rage; losing interest in activities that are usually enjoyable; suffering from physical aches and pains, including frequent headaches, stomach problems, and muscle pain; eating too little or too much; withdrawing from or avoiding friends and family; having trouble bonding or forming an emotional attachment with the baby; persistently doubting his or ability to care for the baby; and thinking about harming themselves or the baby.
• premenstrual dysphoric disorder refers to a condition wherein an individual expresses mood lability, irritability, dysphoria, and anxiety symptoms that occur repeatedly during the premenstrual phase of the cycle and remit around the onset of menses or shortly thereafter.
• Exemplary symptoms of premenstrual dysphoric disorder includes, but are not limited to, lability (e.g., mood swings), irritability or anger, depressed mood, anxiety and tension, decreased interest in usual activities, difficulty in concentration, lethargy and lack of energy, change in appetite (e.g., overeating or specific food cravings), hypersomnia or insomnia, feeling overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, a sensation of ‘bloating’ and weight gain), self-deprecating thoughts, feelings of being keyed up or on edge, decreased interest in usual activities (e.g., work, school, friends, hobbies), subjective difficulty in concentration, and easy fatigability.
• lability e.g., mood swings
• irritability or anger irritability or anger
• depressed mood anxiety and tension
• decreased interest in usual activities e.g., difficulty in concentration, lethargy and lack of energy
• change in appetite e.g., overe
• a depressive disorder refers to a condition wherein an individual experiences mood changes based on the time of the year. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the fall and/or winter season. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the spring and/or summer season. Exemplary symptoms of seasonal affective disorder include, but are not limited to, feeling depressed most of the day or nearly every day, losing interest in activities once found enjoyable, having low energy, having problems with sleeping, experiencing changes in appetite or weight, feeling sluggish or agitated, having difficulty concentrating, feeling hopeless, worthless, or guilty, and having frequent thoughts of death or suicide. In some embodiments, a depressive disorder comprises a medical diagnosis based on the criteria and classification from Diagnostic and Statistical Manual of Medical Disorders, 5th Ed. In some embodiments, a depressive disorder comprises a medical diagnosis based on an independent medical evaluation.
• the methods described herein are provided to a subject with depression that is resistant to treatment.
• the subject has been diagnosed with“treatment-resistant depression”.
• the term“treatment-resistant depression” refers to a kind of depression that does not respond or is resistant to at least one or more treatment attempts of adequate dose and duration.
• the subject with treatment-resistant depression has failed to respond to 1 treatment attempt, 2 treatment attempts, 3 treatment attempts, 4 treatment attempts, or 5 treatment attempts.
• the subject with treatment-resistant depression has been diagnosed with major depressive disorder and has failed to respond to 3 or more treatment attempts.
• the subject with treatment- resistant depression has been diagnosed with bipolar disorder and has failed to respond to 1 treatment attempt.
• the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of major depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of major depressive disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of atypical depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of atypical depression by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of bipolar disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about
• the methods provided herein reduce at least one sign or symptom of bipolar I disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar I disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about
• the methods provided herein reduce at least one sign or symptom of bipolar II disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar II disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of catatonic depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of catatonic depression by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of a depressive disorder due to a medical condition. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder due to a medical condition by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of postpartum depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of postpartum depression by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of premenstrual dysphoric disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of premenstrual dysphoric disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the methods provided herein reduce at least one sign or symptom of seasonal affective disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of seasonal affective disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression is reduced or eliminated in the subject within 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 3 months following administration of psilocybin or an active metabolite thereof.
• the sign or symptom of depression is reduced or eliminated in the subject for a period of 1 day, 3 days, 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, 18 months, 24 months, or 48 months following administration of psilocybin or an active metabolite thereof.
• no other treatment is administered to the subject to reduce the sign or symptom of depression after administration of the psilocybin.
• the method of the present disclosure further comprises administering to the subject at least one additional therapeutic to reduce the sign or symptom of depression.
• at least one additional therapeutic is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic antagonist.
• at least one additional therapeutic is administered prior to administration of psilocybin, on the same day as the administration of psilocybin, or after administration of psilocybin.
• the subject with the depressive disorder has an additional comorbidity or disorder.
• the additional comorbidity or disorder is an anxiety disorder, an obsessive-compulsive disorder, alcoholism, a personality disorder, a cardiovascular disease, a neurological disease, or cancer.
• the subject has dementia, Alzheimer’s Disease, or Parkinson’s Disease.
• reducing at least one sign or symptom of depression in the subject using the methods of the present disclosure prevents one or more comorbidities or disorders in the subject.
• a method of treatment comprises the administration of a therapeutically effective amount of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin to a subject in need thereof as described herein.
• a method of treatment comprises the administration of a therapeutically effective amount of psilocybin as described herein.
• a method of treatment comprises the administration of a therapeutically effective amount of psilocin as described herein.
• Some embodiments comprise psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin for use in the treatment of an indication as described herein. Some embodiments comprise psilocybin for use in the treatment of an indication as described herein. Some embodiments comprise psilocin for use in the treatment of an indication as described herein.
• Some embodiments comprise the use of psilocybin, a prodrug of psilocybin, an active metabolite of psilocybin, or a prodrug of an active metabolite of psilocybin in the manufacture of a medicament for the treatment of an indication as described herein.
• a numbered structural formula of psilocybin is shown in Fig. 1. Novel polymorphs and hydrates of psilocybin, along with the preparation and formulations thereof are disclosed in U.S Application No. US2019/01 19310 A1 , which is incorporated by reference herein in its entirety.
• US2019/01 19310 discloses a number of formulations and the challenges of formulating psilocybin due to e.g. its hygroscopicity and poor flow characteristics. US2019/01 19310 also discloses the importance of a controlled aqueous crystallisation process.
• the psilocybin comprises crystalline psilocybin in the form Polymorph A or Polymorph A’, as described herein, the crystalline psilocybin exhibiting peaks in an X-ray powder diffraction (XRPD) diffractogram at 1 1 .5, 12.0 and 14.5 °2Q ⁇ 0.1 °2Q. In some embodiments, the crystalline psilocybin further exhibits at least one peak in the XRPD diffractogram at 19.7, 20.4, 22.2, 24.3 or 25.7 °2Q ⁇ 0.1 °2Q. Illustrative XRPD diffractograms are provided as FIGs. 2A and 2B.
• the crystalline psilocybin exhibits an endothermic event in a DSC thermogram having a first onset temperature of between 145°C and 165°C and a second onset temperature of between 205°C and 220°C.
• Illustrative DSC thermograms are provided as FIGs. 3A and 3B.
• the present disclosure provides crystalline psilocybin in the form Polymorph A, characterized by one or more of:
• the peak at 17.5 °2Q ⁇ 0.1 °2Q has a relative intensity compared to the peak at 14.5 °2Q ⁇ 0.1 °2Q of at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10%.
• the present disclosure provides crystalline psilocybin in the form Polymorph A, characterized by one or more of:
• DSC thermogram having a first onset temperature of between 145°C and 165°C and a second onset temperature of between 205°C and 220°C substantially as illustrated in FIG. 3a.
• the crystalline psilocybin of Polymorph A exhibits an XRPD diffractogram having at least 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17 of the peaks listed in Table A, or equivalent peaks within about ⁇ 0.1 °20 of the peaks listed in Table A. In some embodiments, the crystalline psilocybin of Polymorph A exhibits an XRPD diffractogram having at least 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17 of the peaks listed in Table A, or equivalent peaks within about ⁇ 0.2°20 of the peaks listed in Table A.
• Polymorph A exhibits a peak at 17.5 °2Q ⁇ 0.1 °2Q that is substantially absent in Polymorph A’. In some embodiments, Polymorph A exhibits a peak at 17.5 °2Q ⁇ 0.2°2Q that is substantially absent in Polymorph A’.
• crystalline psilocybin Polymorph A exhibits XRPD diffractogram peaks at 1 1 .5, 12.0, 14.5, and 17.5°2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph A exhibits at least one additional peak appearing at 19.7, 20.4, 22.2, 24.3 or 25.7°2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph A exhibits at least two additional peaks appearing at 19.7, 20.4, 22.2, 24.3 or 25.7 °2Q ⁇ 0.1 °2Q.
• crystalline psilocybin Polymorph A exhibits at least three additional peaks appearing at 19.7, 20.4, 22.2, 24.3 or 25.7 °2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph A exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in FIG. 2A.
• crystalline psilocybin Polymorph A is characterized by XRPD diffractogram peaks at 14.5 and 17.5°2Q ⁇ 0.1 °2Q with the peak at 17.5°20 having an intensity which 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°20.
• the crystalline psilocybin Polymorph A exhibits no peak at 10.1— that is, the peak at 10.1 is absent or substantially absent.
• 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 such as between 145 and 160°C, or such as between 145 and 155°C and a second onset temperature of between 205 and 220°C, such as between 210 and 220°C, such as between 210 and 218°C, or such as between 210 and 216°C.
• crystalline psilocybin Polymorph A exhibits an endothermic event in a DSC thermogram having an onset temperature of between about 205 and about 220°C, between about 210 and about 220°C, between about 210 and about 218°C, or between about 210 and about 216°C. In some embodiments, crystalline psilocybin Polymorph A further exhibits an endothermic event in the DSC thermogram having an onset temperature of between about 145 and about 165°C, between about 145 and about 160°C, or between about 145 and about 155°C.
• crystalline psilocybin Polymorph A exhibits an endothermic event having an onset temperature of between about 205 and about 220°C, between about 210 and about 220°C, between about 210 and about 218°C, or between about 210 and about 216°C; and an endothermic event having an onset temperature of between about 145 and about 165°C, between about 145 and about 160°C, between about 145 and about 155°C, in a DSC thermogram.
• crystalline psilocybin Polymorph A exhibits a DSC thermogram substantially the same as the DSC thermogram in FIG. 3A.
• crystalline psilocybin Polymorph A exhibits a water content of ⁇ 0.5% w/w, ⁇ 0.4% w/w, ⁇ 0.3% w/w, ⁇ 0.2% w/w, or ⁇ 0.1 % w/w.
• the water content of a crystalline compound can be determined by known methods, for example Karl Fischer Titration.
• crystalline psilocybin Polymorph A exhibits ⁇ 0.5% w/w loss, ⁇ 0.4% w/w, ⁇ 0.3% w/w, ⁇ 0.2% w/w, or ⁇ 0.1 % w/w in the TGA thermogram between ambient temperature, e.g., about 25°C, and 200°C.
• crystalline psilocybin Polymorph A loses less than 2% by weight, less than 1 % by weight, or than 0.5% by weight in a loss on drying test, e.g., a loss on drying test performed at 70°C.
• crystalline psilocybin Polymorph A is a highly pure crystalline form of Polymorph A, for example, the in a loss on drying test psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight crystalline psilocybin of Polymorph A.
• crystalline psilocybin Polymorph A is a white to off-white solid.
• crystalline psilocybin Polymorph A is chemically pure, for example the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC.
• crystalline psilocybin Polymorph A has no single impurity of greater than 1 %, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% e.g., the impurity phosphoric acid as measured by 31 P NMR, or the impurity psilocin measured by HPLC.
• crystalline psilocybin Polymorph A has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC.
• 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 psilocin at a level 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 phosphoric acid at a level greater than 1 weight%, greater than 0.5 weight%, greater than 0.4 weight%, 0.3 weight%, or greater than 0.2 weight%, as measured by 31 P NMR. In some embodiments, crystalline psilocybin Polymorph A has a chemical assay of at least 95 weight%, at least 96 weight%, or at least 98 weight%.
• the disclosure provides a method for large scale manufacture of psilocybin characterized in that the method comprises subjecting psilocybin to a water crystallization step, with controlled drying, to produce crystalline psilocybin Polymorph A.
• the disclosure provides a method for large scale manufacture of psilocybin characterized in that the method comprises subjecting psilocybin to a water crystallization step, with controlled drying, to produced crystalline psilocybin Polymorph A with an XRPD diffractogram as illustrated in Fig 2a and a DSC and TGA thermograph as illustrated in Fig 3a.
• the disclosure provides a method for large-scale manufacture of psilocybin characterized in that the method comprises subjecting psilocybin to a water crystallization step, with controlled drying, to produce a high purity crystalline psilocybin - Polymorph A with an XRPD diffractogram as illustrated in Fig 2a and a DSC thermograph as illustrated in Fig 3a.
• psilocybin is recrystallized in about 10-20 volumes of water, heated with agitation to a temperature of at least 70°C, polish filtered with a suitable cut off (typically, below 5 pm), seeded at a temperature of about 70°C, and cooled in a controlled manner to about 5°C over a period of more than 2 hours.
• psilocybin recrystallization comprises controlled cooling which drops the temperature by about 5 °C -15 °C an hour, more preferably about 10°C an hour.
• the polish filter step is done through an appropriately sized filter such as, but not limited to, a 1.2pm in line filter.
• agitation is by stirring at about 400-500 rpm, typically about 450 rpm.
• 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 by any particular mechanism, this dissolution step is intended to solubilize psilocybin whilst also minimizing the formation of hydrolysis products.
• the psilocybin solution is stirred to speed the solubilization and reduce the time that the solution is at a high temperature, namely one at or around 80°C, or higher.
• the seed is psilocybin Hydrate A. In one embodiment, 0.1 % weight or less of seed is added to the process.
• the psilocybin the crystalline psilocybin is isolated by vacuum filtration.
• the isolated crystals are dried in vacuo at a temperature of at least 30°C, such as between 30 and 50°C, or such as between 40 and 50°C. In some embodiment, the isolated crystals are dried in vacuo for at least 10 hours, such as between 12 and 18 hours, or such as about 30 hours. In some embodiments, the isolated crystals are dried in vacuo at a temperature of at least 30°C, such as between 30 and 50°C, or such as between 40 and 50°C, for at least 10 hours, such as between 12 and 18 hours, or such as about 30 hours. In some embodiments, the isolated crystals are dried until the isolated crystals lose less than 2% weight in a loss on drying test, such as less than 0.5% weight.
• the isolated crystals are washed, several times, in water and dried in vacuo at about 50°C for at least 12 hours.
• the crystals obtained are typically relatively large (range 50 to 200 microns) and uniform when viewed under the microscope x 10.
• crystals obtained without controlled cooling which are much smaller in size (typically 5 to 50microns) when viewed under the microscope x 10.
• Psilocybin obtained by the method of crystallization described herein.
• a pharmaceutical formulation comprising psilocybin polymorph A obtained by the method of crystallization described herein.
• psilocybin manufactured prior to crystallization may be produced using one of the following methods: synthetic or biological, e.g. by fermentation or obtained by extraction from mushrooms. In some embodiments, psilocybin manufactured prior to crystallization is manufactured according to all or some of the methods described in U.S Application No. US2019/01 19310 A1 , which is incorporated by reference herein in its entirety. Polymorph A’
• the present disclosure provides crystalline psilocybin in the form of Polymorph A’, characterized by one or more of:
• the crystalline psilocybin comprises crystalline psilocybin Polymorph A’.
• Crystalline psilocybin Polymorph A’ exhibits peaks in an XRPD diffractogram at 1 1 .5, 12.0 and 14.5 °2Q ⁇ 0.1 °2Q, but absent or substantially absent of a peak at 17.5 °2Q ⁇ 0.1 °2Q.
• crystalline psilocybin Polymorph A’ further exhibits 1 , 2, 3, 4, or 5 peaks selected from 19.7, 20.4, 22.2, 24.3 or 25.7 °2Q ⁇ 0.1 °2Q.
• An illustrative XRPD diffractogram for Polymorph A’ is provided as FIG. 2B.
• An illustrative DSC thermogram having an onset temperature of between 205 and 220°C for Polymorph A’ is provided as FIG. 3B.
• psilocybin Polymorph A’ exhibits an XRPD diffractogram as summarized in Table B.
• crystalline psilocybin Polymorph A’ exhibits at least 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, or 25 peaks listed of Table B or equivalent peaks within about ⁇ 0.1 °20, and absent or substantially absent peak at 17.5 °2Q ⁇ 0.1 °2Q.
• crystalline psilocybin Polymorph A’ exhibits XRPD diffractogram peaks at 1 1 .5, 12.0, and 14.5°2Q ⁇ 0.1 °2Q but substantially absent of a peak at 17.5 °2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph A’ further exhibits at least one additional peak appearing at 19.7, 20.4, 22.2, 24.3, or 25.7 °2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph A’ exhibits at least two additional peaks appearing at 19.7, 20.4, 22.2, 24.3, or 25.7 °2Q ⁇ 0.1 °2Q.
• crystalline psilocybin Polymorph A’ exhibits and is distinguished from Polymorph A by the presence of a peak appearing at 10.1 °2Q ⁇ 0.1 °2Q.
• crystalline psilocybin Polymorph A’ exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in FIG. 2B.
• crystalline psilocybin Polymorph A’ exhibits XRPD diffractogram peaks at 14.5 and 17.5°2Q ⁇ 0.1 °2Q, wherein the intensity of the peak at 17.5°20 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°20.
• crystalline psilocybin Polymorph A’ exhibits XRPD diffractogram peaks at 10.1 and 14.5°2Q ⁇ 0.1 °2Q, wherein the intensity of the peak at 10.1 °20 is at least 1 %, at least 2%, at least 3%, or at least 4% of the intensity of the peak at 14.5°20.
• 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 such as between 145 and 160°C, or such as between 145 and 155°C and a second onset temperature of between 205 and 220°C, such as between 210 and 220°C, such as between 210 and 218°C, or such as between 210 and 216°C.
• crystalline psilocybin Polymorph A’ is characterized by an endothermic event in a DSC thermogram having an onset temperature of between about 205 and about 220°C, between about 210 and about 220°C, between about 210 and about 218°C, or between about 210 and about 216°C. In some embodiments, crystalline psilocybin Polymorph A’ exhibits an endothermic event in the DSC thermogram having an onset temperature of between about 145 and about 165°C, between about 145 and about 160°C, or between about 145 and about 155°C.
• crystalline psilocybin Polymorph A’ exhibits an endothermic event having an onset temperature of between about 205 and about 220°C, between about 210 and about 220°C, between about 210 and about 218°C, or between about 210 and about 216°C, and an endothermic event having an onset temperature of between about 145 and about 165°C, between about 145 and about 160°C, or between about 145 and about 155°C, in a DSC thermogram.
• crystalline psilocybin Polymorph A’ exhibits a DSC thermogram substantially the same as the DSC thermogram in FIG. 3B.
• crystalline psilocybin Polymorph A’ exhibits a water content of ⁇ 0.5% w/w, ⁇ 0.4% w/w, ⁇ 0.3% w/w, ⁇ 0.2% w/w, or ⁇ 0.1 % w/w. Methods to determine the water content of a crystalline compound are known, for example Karl Fischer Titration. In some embodiments, crystalline psilocybin Polymorph A’ exhibits ⁇ 0.5% w/w loss, ⁇ 0.4% w/w, ⁇ 0.3% w/w, ⁇ 0.2% w/w, ⁇ 0.1 % w/w in the TGA thermogram between ambient temperature, e.g., 25°C, and 200°C.
• crystalline psilocybin Polymorph A’ loses less than 2% by weight, less than 1 % by weight, 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.
• crystalline psilocybin Polymorph A’ is a highly pure crystalline form of Polymorph A’. In some embodiments, the crystalline psilocybin comprises at least 90%, 95%, 99%, or 99.5% by weight of Polymorph A’.
• crystalline psilocybin Polymorph A’s is a white to off white solid.
• crystalline psilocybin Polymorph A’ is chemically pure, for example the psilocybin has a chemical purity of greater than 97%, greaterthan 98%, orthan 99% by HPLC. In some embodiments, crystalline psilocybin Polymorph A’ has no single impurity of greater than 1 % or greater than 0.5%, e.g., the impurity phosphoric acid as measured by 31 P NMR or the 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.
• crystalline psilocybin Polymorph A’ has no single impurity greater than 1 area% or greater than 0.5 area%, e.g., as measured by HPLC. In some embodiments, crystalline psilocybin Polymorph A’ does not contain psilocin at a level greater than 1 area% or greater than 0.5 area% as measured by HPLC. In some embodiments, crystalline psilocybin Polymorph A’ does not contain phosphoric acid at a level greater than 1 weight% or greater than 0.5 weight% as measured by 31 P NMR. In some embodiments, crystalline psilocybin Polymorph A’ has a chemical assay of at least 95 weight%, at least 96 weight%, or at least 98 weight%.
• crystalline psilocybin Polymorph A’ is chemically pure, for example the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC.
• crystalline psilocybin Polymorph A’ has no single impurity of greater than 1 %, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% e.g., the impurity phosphoric acid as measured by 31 P NMR, or the impurity psilocin measured by HPLC.
• crystalline psilocybin Polymorph A’ has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC.
• 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 psilocin at a level 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.
• crystalline psilocybin Polymorph A’ does not contain phosphoric acid at a level greater than 1 weight%, greater than 0.5 weight%, greater than 0.4 weight%, 0.3 weight%, or greater than 0.2 weight%, as measured by 31 P NMR. In some embodiments, crystalline psilocybin Polymorph A’ has a chemical assay of at least 95 weight%, at least 96 weight%, or at least 98 weight%.
• Illustrative XRPD diffractograms for high purity crystalline psilocybin, Polymorph A or Polymorph A’ are provided in FIGs. 2A and 2B.
• Illustrative DSC thermographs for high purity crystalline psilocybin, Polymorph A or Polymorph A’ are provided in FIGs. 2A and 2B.
• Polymorph A (including its isostructural variant Polymorph A’) (FIGs. 2A and 2B) differs from Polymorph B (FIG. 2C), the Hydrate A (FIG. 2D) and the ethanol solvate (FIG. 2E: Solvate A), and the relationship between some of the different forms is illustrated in FIG. 4.
• the crystalline psilocybin Polymorph A or Polymorph A’ is a white to off white solid, and/or has a chemical purity of greater than 97%, 98%, or 99% by HPLC. In some embodiments, crystalline psilocybin Polymorph A or Polymorph A’ has no single impurity of greater than 1 %, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% e g., the impurity phosphoric acid as measured by 31 P NMR, or the impurity psilocin measured by HPLC.
• 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 psilocin at a level 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.
• crystalline psilocybin Polymorph A or Polymorph A’ does not contain phosphoric acid at a level greater than 1 weight%, greater than 0.5 weight%, greater than 0.4 weight%, 0.3 weight%, or greater than 0.2 weight%, as measured by 31 P NMR. In some embodiments, crystalline psilocybin Polymorph A or Polymorph A’ has a chemical assay of at least 95 weight%, at least 96 weight%, or at least 98 weight%.
• Polymorph A or A’ results in an endothermic event having an onset temperature of circa 150°C corresponding to solid-solid transition of Polymorph A or Polymorph A’ to Polymorph B.
• Polymorph B results in a second endothermic event corresponding to a melting point having an onset temperature of between 205 and 220°C (see FIGs. 3A and 3B).
• the disclosure provides a crystalline form of psilocybin, Hydrate A.
• crystalline psilocybin Hydrate A exhibits peaks in an XRPD diffractogram at 8.9, 12.6 and 13.8°2Q ⁇ 0.1 °2Q.
• crystalline psilocybin Hydrate A further exhibits at least 1 , 2, 3, 4, or 5 further peaks at 6.5, 12.2, 19.4, 20.4 or 20.8°2Q ⁇ 0.1 °2Q.
• An illustrative XRPD diffractogram is provided as FIG. 2D.
• crystalline psilocybin Hydrate A further exhibits an endothermic event in a DSC thermogram having a first onset temperature of between 90°C and 100°C, a second onset temperature of between 100 3 ⁇ 4 C and 12GX and a third onset temperature of between 21 OX and 220X.
• An illustrative DSC thermogram is provided as FIG. 2D.
• psilocybin Hydrate A exhibits an XRPD diffractogram comprising at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks listed in Table C or equivalent peaks within about ⁇ 0.1 °20.
• crystalline psilocybin Hydrate A exhibits XRPD diffractogram peaks at 8.9, 12.6 and 13.8°2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Hydrate A exhibits at least one peak appearing at 6.5, 12.2, 19.4, 20.4 or 20.8°2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Hydrate A exhibits at least two peaks appearing at 6.5, 12.2, 19.4, 20.4 or 20.8°20 ⁇ 0.1 °20. In some embodiments, crystalline psilocybin Hydrate A exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in FIG. 2D.
• crystalline psilocybin Hydrate A is characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 85°C and 105°C, such as between 90°C and 100°C and most preferably at about 96°C, a second onset temperature of between 100°C and 120°C such as between 105°C and 1 15°C, and most preferably at about 109°C and a third onset temperature of between 205 and 220°C, such as between 210 and 220°C, such as between 210 and 218°C, or such as between 210 and 216°C, or about 216°C.
• crystalline psilocybin Hydrate A exhibits an endothermic event in a DSC thermogram having an onset temperature of between about 205 and about 220°C, between about 210 and about 220°C, between about 210 and about 218°C, or between about 210 and about 216°C. In some embodiments, crystalline psilocybin Hydrate A exhibits an endothermic event in the DSC thermogram having an onset temperature of between about 85 and about 105°C, or between about 90 and about 100°C.
• crystalline psilocybin Hydrate A exhibits an endothermic event having an onset temperature of between about 205 and about 220°C, between about 210 and about 220°C, between about 210 and about 218°C, or between about 210 and about 216°C, and an endothermic event having an onset temperature of between about 85 and about 105°C or between about 90 and about 100°C, in a DSC thermogram.
• crystalline psilocybin Hydrate A exhibits a DSC thermogram substantially the same as the DSC thermogram in FIG. 3D.
• crystalline psilocybin Hydrate A exhibits a water content of between about 10 and about 18%, between about 12 and about 16%, or about 13%. Methods to determine the water content of a crystalline compound are known, for example Karl Fischer Titration. In some embodiments, crystalline psilocybin Hydrate A exhibits a weight loss in the TGA thermogram of between about 10 and about 18%, between about 12 and about 16%, or about 13%, between ambient temperature, about 25°C, and 120°C. In some embodiments, crystalline psilocybin Hydrate A is chemically pure, for example the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC.
• crystalline psilocybin Hydrate A has no single impurity of greater than 1 %, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% e.g., the impurity phosphoric acid as measured by 31 P NMR, or the impurity psilocin measured by HPLC.
• crystalline psilocybin Hydrate A has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC.
• 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.
• crystalline psilocybin Hydrate A does not contain psilocin at a level 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 phosphoric acid at a level greater than 1 weight%, greater than 0.5 weight%, greater than 0.4 weight%, 0.3 weight%, or greater than 0.2 weight%, as measured by 31 P NMR. In some embodiments, crystalline psilocybin Hydrate A has a chemical assay of at least 95 weight%, at least 96 weight%, or at least 98 weight%.
• crystalline psilocybin Hydrate A is a highly pure 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.
• the disclosure provides a crystalline form of psilocybin, Polymorph B.
• crystalline psilocybin Polymorph B exhibits peaks in an XRPD diffractogram at 1 1 .1 , 1 1 .8 and 14.3°2Q ⁇ 0.1 °2Q.
• crystalline psilocybin Polymorph B exhibits at least 1 , 2, 3, 4 or 5 peaks in an XRPD diffractogram at 14.9, 15.4, 19.3, 20.0 or 20.6°20 ⁇ 0.1 °20.
• An illustrative XRPD diffractogram of crystalline psilocybin Polymorph B is provided as FIG. 2C.
• crystalline psilocybin Polymorph B exhibits a single endothermic event in a DSC thermogram having an onset temperature of between about 205 and about 220°C.
• An illustrative DSC thermogram of crystalline psilocybin Polymorph B is provided as FIG. 3C.
• psilocybin Polymorph B exhibits an XRPD diffractogram comprising at least 3, 4, 5, 6, 7, 8, 9, or 10 peaks listed in Table D or equivalent peaks within about ⁇ 0.1 °20.
• Table D XRPD peak positions for Polymorph B
• crystalline psilocybin Polymorph B exhibits XRPD diffractogram peaks at 1 1 .1 , 1 1 .8 and 14.3°2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph B exhibits at least one peak at 14.9, 15.4, 19.3, 20.0 or 20.6°2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph B exhibits at least two peaks appearing at 14.9, 15.4, 19.3, 20.0 or 20.6°2Q ⁇ 0.1 °2Q. In some embodiments, crystalline psilocybin Polymorph B exhibits an XRPD diffractogram substantially the same as the XRPD diffractogram shown in FIG. 2C.
• crystalline psilocybin Polymorph B is characterized by a single endothermic event in a DSC thermogram having an onset temperature of between about 205 and about 220°C, between about 210 and about 220°C, between about 210 and about 218°C, or between about 210 and about 216°C. In some embodiments, crystalline psilocybin Polymorph B exhibits a DSC thermogram substantially the same as the DSC thermogram in FIG. 3C.
• crystalline psilocybin Polymorph B exhibits a water content of ⁇ 0.5% w/w, ⁇ 0.4% w/w, ⁇ 0.3% w/w, ⁇ 0.2% w/w, or ⁇ 0.1 % w/w. Methods to determine the water content of a crystalline compound are known, for example Karl Fischer Titration. In some embodiments, crystalline psilocybin Polymorph B exhibits ⁇ 0.5% w/w, ⁇ 0.4% w/w, ⁇ 0.3% w/w, ⁇ 0.2% w/w, or ⁇ 0.1 % w/w loss in the TGA thermogram between ambient temperature, about 25°C, and 200°C.
• crystalline psilocybin Polymorph B exhibits a loss of less than 2% by weight, less than 1 % by weight, 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.
• crystalline psilocybin Polymorph B is a highly pure crystalline form of Polymorph B, for example, psilocybin comprises at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of Polymorph B.
• crystalline psilocybin Polymorph B is chemically pure, for example the psilocybin has a chemical purity of greater than 97%, 98%, or 99% by HPLC.
• crystalline psilocybin Polymorph B has no single impurity of greater than 1 %, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% e.g., the impurity phosphoric acid as measured by 31 P NMR, or the impurity psilocin measured by HPLC.
• crystalline psilocybin Polymorph B has a chemical purity of greater than 97 area%, greater than 98 area%, or greater than 99 area% by HPLC.
• 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 psilocin at a level 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 phosphoric acid at a level greater than 1 weight%, greater than 0.5 weight%, greater than 0.4 weight%, 0.3 weight%, or greater than 0.2 weight%, as measured by 31 P NMR. In some embodiments, crystalline psilocybin Polymorph B has a chemical assay of at least 95 weight%, at least 96 weight%, or at least 98 weight%.
• the psilocybin of the disclosure in the form Polymorph A or A’ has the general properties illustrated in Table D.
• Table D
• the psilocybin conforms to the spectra as set out in Table E and illustrated in the spectra of FIGs. 5-8.
• the crystalline psilocybin may take the form of Hydrate A or Polymorph B.
• the disclosure provides the crystalline psilocybin in the form 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 a high purity crystalline psilocybin Polymorph A for use in medicine. In some embodiments, the disclosure provides a high purity crystalline psilocybin Polymorph A’ for use in medicine. Alternatively, and independently, the crystalline psilocybin may take the form of Hydrate A or Polymorph B.
• the disclosure provides crystalline psilocybin in the form Polymorph A or Polymorph A’ for use in treating a subject in need thereof.
• the crystalline psilocybin may take the form of Hydrate A or Polymorph B.
• the disclosure provides crystalline psilocybin, Polymorph A or Polymorph A’, for use in treating a subject in need thereof.
• the disclosure provides crystalline psilocybin, Polymorph A or Polymorph A’, for use in treating a subject in need thereof.
• the disclosure provides crystalline psilocybin Polymorph A for use in treating a subject in need thereof.
• the disclosure provides crystalline psilocybin Polymorph A’ for use in treating a subject in need thereof. In some embodiments, the disclosure provides a high purity crystalline psilocybin Polymorph A for use in treating a subject in need thereof. In some embodiments, the disclosure provides a high purity crystalline psilocybin Polymorph A’ for use in treating a subject in need thereof.
• the disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising crystalline psilocybin and one or more pharmaceutically acceptable carriers or excipients.
• the disclosure provides a pharmaceutical formulation comprising high purity psilocybin and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising crystalline psilocybin Polymorph A and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising crystalline psilocybin Polymorph A’ and one or more pharmaceutically carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising high purity crystalline psilocybin, Polymorph A or Polymorph A’, and one or more pharmaceutically acceptable carriers or excipients.
• the disclosure provides a pharmaceutical formulation comprising high purity crystalline psilocybin Polymorph A and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the disclosure provides a pharmaceutical formulation comprising high purity crystalline psilocybin Polymorph A’ and one or more pharmaceutically acceptable carriers or excipients.
• Preferred pharmaceutical excipients for an oral formulation include: diluents, such as microcrystalline cellulose, starch, mannitol, calcium hydrogen phosphate anhydrous or co mixtures of silicon dioxide, calcium carbonate, microcrystalline cellulose and talc; disintegrants, such as sodium starch glycolate or croscarmellose sodium; binders, such as povidone, co povidone or hydroxyl propyl cellulose; lubricants, such as magnesium stearate or sodium stearyl fumurate; glidants, such as colloidal silicon dioxide; and film coats, such as Opadry II white or PVA based brown Opadry II.
• diluents such as microcrystalline cellulose, starch, mannitol, calcium hydrogen phosphate anhydrous or co mixtures of silicon dioxide, calcium carbonate, microcrystalline cellulose and talc
• disintegrants such as sodium starch glycolate or croscarmellose sodium
• binders such as povidone, co povidone or
• the oral dosage form also comprises a disintegrant, such as, but not limited to: starch glycolate, croscarmellose sodium, and/or mixtures thereof.
• a disintegrant such as, but not limited to: starch glycolate, croscarmellose sodium, and/or mixtures thereof.
• the oral dosage form comprises 3% or less by wt disintegrant, less than 3% by wt disintegrant and greater than 0.001 % by wt disintegrant, about 2.5% by wt or less disintegrant; 2% by wt or less disintegrant; 1 .5% by wt or less disintegrant; 1 % by wt or less disintegrant; 0.7% by wt or less disintegrant; 0.5% by wt or less disintegrant, or 0.3% by wt or less disintegrant.
• the disintegrant is sodium starch glycolate.
• the sodium starch glycolate is present at less than 3% wt.
• the sodium starch glycolate is present at about 2% by wt or less, about 2% by wt; about 1 % by wt or less, about 1 % by wt; about 0.7% by wt or less, about 0.7% by wt; about 0.5% by wt or less, or about 0.5% by wt..
• the sodium starch glycolate is present at about 0.5% to 1 % by wt.
• the oral dosage form comprises 5 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 1 %. In some embodiments, the oral dosage form comprises 5 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5% to 1 .0%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5%.
• the oral dosage form comprises 10 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 1 %. In some embodiments, the oral dosage form comprises 10 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5%.
• the oral dosage form comprises 25 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 1 %. In some embodiments, the oral dosage form comprises 25 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5%.
• the crystalline psilocybin in the form Polymorph A or Polymorph A’ for use in medicine.
• crystalline psilocybin Polymorph A for use in medicine.
• crystalline psilocybin Polymorph A for use in medicine.
• a high purity crystalline psilocybin Polymorph A for use in medicine.
• a high purity crystalline psilocybin Polymorph A for use in medicine.
• the crystalline psilocybin may take the form of Hydrate A or Polymorph B.
• crystalline psilocybin particularly but not essentially in the form Polymorph A or Polymorph A’ for use in treating central nervous disorders.
• the crystalline psilocybin may take the form of Hydrate A or Polymorph B.
• 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, more than one dosage form is administered to the subject at substantially the same time. In some embodiments, the subject may be administered the entire therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be split among multiple tablets or capsules. For example, for a dose of 25 mg, the subject may be administered 5 tablets or capsules each comprising 25 mg of psilocybin. Alternatively, for a dose of 10 mg, the subject may be administered 2 tablets or capsules each comprising 5 mg of psilocybin.
• the oral dosage form comprises a functional filler.
• the functional filler may be a silicified filler, such as, but not limited to silicified microcrystalline cellulose (SMCC).
• SMCC silicified microcrystalline cellulose
• the oral dosage form comprises high compactability grades of SMCC with a particle size range of from about 45 to 150 microns. A mixture of two functional fillers having different particle size ranges may be used with the weight percentages of the two favoring the larger sized particles.
• the silicified microcrystalline filler may comprise a first filler, having a particle size range of from about 45 to 80 microns in an amount of up to 30%, up to 20%, up to 15%, or less by weight of filler, and a second filler, having a particle size range of from about 90 to 150 microns, in an amount of up to 70%, up to 80%, up to 85%, or more, by weight of filler.
• the oral dosage form may comprise silicified microcrystalline cellulose with a particle size range of from about 45 to 80 microns (SMCC 50), such as Prosolv 50; silicified microcrystalline cellulose with a particle size range of from about 90 to 150 microns (SMCC 90), such as Prosolv 90; or mixtures thereof.
• SMCC 50 silicified microcrystalline cellulose with a particle size range of from about 45 to 80 microns
• SMCC 90 silicified microcrystalline cellulose with a particle size range of from about 90 to 150 microns
• the oral dosage form may comprise SMCC 50 and SMCC 90.
• 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%.
• the ratio of SMCC 50 to SMCC 90 is 1 :5-1 :7; 1 :6-1 :7; 1 :6-1 :8; or 1 .7- 1.8. In still other embodiments the ratio of SMCC 50 to SMCC 90 is 1 :6; 1 :6.1 ; 1 :6.2; 1 :6.3; 1 :6.4; 1 :6.5; 1 :6.6; 1 .6.7; 1 :6.8; 1.6.9; or 1 :7.
• the formulation may further comprise or consist essentially of a disintegrant, including without limitation sodium starch glycolate; a glidant, including without limitation colloidal silicon dioxide; and a lubricant, including without limitation sodium stearyl fumarate.
• the oral dosage form may comprise a disintegrant such as sodium starch glycolate, at less than 3% (by wt), less than 2%, or 1 % or less.
• a disintegrant such as sodium starch glycolate
• the oral dosage form comprises 5 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 1 %. In some embodiments, the oral dosage form comprises 5 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5% to 1 .0%. In some embodiments, the oral dosage form comprises 5 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5%.
• the oral dosage form comprises 10 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 1 %. In some embodiments, the oral dosage form comprises 10 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 10 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5%.
• the oral dosage form comprises 25 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 1 %. In some embodiments, the oral dosage form comprises 25 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5% to 1.0%. In some embodiments, the oral dosage form comprises 25 mg of psilocybin and SMCC 50 and SMCC 90, wherein the ratio of SMCC 50 to SMCC 90 is 1 :6.4 and sodium starch glycolate at about 0.5%.
• 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 sodium starch glycolate, 1 mg colloidal silicon dioxide and 1 g sodium stearyl fumarate.
• 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 sodium starch glycolate, 1 mg colloidal silicon dioxide and 1 mg sodium stearyl fumarate.
• 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 sodium starch glycolate, 1 mg colloidal silicon dioxide, and 1 mg sodium stearyl fumarate.
• 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 sodium starch glycolate, 1 mg colloidal silicon dioxide, and 1 mg sodium stearyl fumarate.
• the tablet or capsule comprises one or more excipients.
• excipients include microcrystalline cellulose and starch, including without limitation silicified microcrystalline cellulose.
• formulations may comprise psilocybin in any form, not only the polymorphic forms disclosed herein.
• oral doses of psilocybin are classified follows:“very low doses” (about 0.045 mg/kg or less);“low doses” (between about 0.1 15 and about 0.125 mg/kg),“medium doses” (between about 0.1 15 to about 0.260 mg/kg), and“high doses” (about 0.315 mg/kg or more). See Studerus et al (201 1 ) J Psychopharmacol 25(1 1) 1434-1452.
• the formulated dose of psilocybin comprises from about 0.01 mg/kg to about 1 mg/kg. In some embodiments, a human dose (for an adult weighing 60-80kg) comprises between about 0.60 mg and about 80 mg.
• a formulated dose comprises between about 2 and about 50 mg of crystalline psilocybin. In some embodiments, a formulated dose comprises between 2 and 40 mg, between 2 and 10 mg, between 5 and 30 mg, between 5 and 15 mg, or between 20 and 30 mg of crystalline psilocybin. In some embodiments, a formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin.
• a formulated dose comprises between about 2 and about 50 mg of crystalline psilocybin Polymorph A or Polymorph A’ or a mixture thereof. In some embodiments, a formulated dose comprises between 2 and 40 mg, between 2 and 10 mg, between 5 and 30 mg, between 5 and 15 mg, or between 20 and 30 mg of crystalline psilocybin Polymorph A or Polymorph A’ or a mixture thereof. In some embodiments, a formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin Polymorph A or Polymorph A’ or a mixture thereof. In some embodiments, a formulated dose comprises about 5 mg of crystalline psilocybin Polymorph A or Polymorph A’ or a mixture thereof.
• a formulated dose comprises between about 2 and about 50 mg of crystalline psilocybin Polymorph A. In some embodiments, a formulated dose comprises between 2 and 40 mg, between 2 and 10 mg, between 5 and 30 mg, between 5 and 15 mg, or between 20 and 30 mg of crystalline psilocybin Polymorph A. In some embodiments, a formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin Polymorph A.
• a formulated dose comprises between about 2 and about 50 mg of crystalline psilocybin Polymorph A’. In some embodiments, a formulated dose comprises between 2 and 40 mg, between 2 and 10 mg, between 5 and 30 mg, between 5 and 15 mg, or between 20 and 30 mg of crystalline psilocybin Polymorph A’. In some embodiments, a formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin Polymorph A’.
• a formulated dose comprises between about 2 and about 50 mg of crystalline psilocybin Polymorph B. In some embodiments, a formulated dose comprises between 2 and 40 mg, between 2 and 10 mg, between 5 and 30 mg, between 5 and 15 mg, or between 20 and 30 mg of crystalline psilocybin Polymorph B. In some embodiments, a formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin Polymorph B.
• a formulated dose comprises between about 2 and about 50 mg of crystalline psilocybin Hydrate A. In some embodiments, a formulated dose comprises between 2 and 40 mg, between 2 and 10 mg, between 5 and 30 mg, between 5 and 15 mg, or between 20 and 30 mg of crystalline psilocybin Hydrate A. In some embodiments, a formulated dose comprises about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin Hydrate A.
• a therapeutically effective dose of psilocybin is administered to the subject.
• each dose of psilocybin administered to the subject is a therapeutically effective dose.
• a dose of psilocybin may be in the range of about 1 mg to about 100 mg.
• 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 g, or about 100 mg.
• the dose of psilocybin is between about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg.
• 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 rage 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.
• an adult oral dose comprises about 1 mg to about 40 mg, about 2 to about 30 mg, or about 15 to about 30 mg of crystalline psilocybin, for example about 1 mg, about 5 mg, about 10 mg, or about 25 mg of crystalline psilocybin. In some embodiments, an adult oral dose comprises about 25 mg of crystalline psilocybin. In some embodiments, the crystalline psilocybin is in the form of polymorph A.
• a“micro-dose” of psilocybin is administered to a subject.
• a micro dose may comprise, for example, about 0.05 mg to about 2.5 mg of crystalline psilocybin, such as about 1 .0 mg.
• the regime may comprise a regular, continuous regime of, for example, daily administration, every other day administration, or weekly, administration. Such dosing may be absent of psychological support.
• one dose of psilocybin is administered to the subject.
• 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 may be administered to the subject.
• the same dose of psilocybin is administered to a subject during each administration.
• a different dose of psilocybin is administered to a subject during each administration.
• the dose of psilocybin administered to the subject is increased over time.
• the dose of psilocybin administered to the subject is decreased over time.
• the psilocybin is administered at therapeutically effective intervals.
• a 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 1 1 weeks, or about 12 weeks.
• a therapeutically effective interval may be about 1 month, about 3 months, about 6 months, or about 12 months.
• the psilocybin is administered once per day.
• the psilocybin is administered at least once per week or at least twice per week.
• the psilocybin is administered at least once per month or at least twice per month.
• the psilocybin is administered at least once every three months, at least once every six months, or at least once every 12 months.
• a first dose and a second dose of psilocybin are administered to the subject.
• the first dose is about 1 mg and the second dose is about 1 mg.
• the first dose is about 10 mg and the second dose is about 10 mg.
• the first dose is about 25 mg and the second dose is about 25 mg.
• the first dose is about 10 mg and the second dose is about 25 mg.
• the first dose is about 25 mg and the second dose is about 10 mg.
• the first dose is about 1 mg and the second dose is about 10 mg.
• the first dose is about 1 mg and the second dose is about 10 mg.
• the first dose is about 1 mg and the second dose is about 25 mg.
• the first dose is about 10 mg and the second dose is about 1 mg.
• the first dose is about 25 mg and the second dose is about 1 mg.
• a second dose of psilocybin is administered from about one week to about 12 weeks after a first dose. In some embodiments, a second dose of psilocybin is administered about one week after a first dose. In some embodiments, a second dose of psilocybin is administered about two weeks after a first dose. In some embodiments, a second dose of psilocybin is administered about three weeks after a first dose. In some embodiments, a second dose of psilocybin is administered about four weeks after a first dose. In some embodiments, a second dose of psilocybin is administered about five weeks after a first dose. In some embodiments, a second dose of psilocybin is administered about six weeks after a first dose.
• Exemplary modes for administration of psilocybin include oral, parenteral (e.g. , intravenous, subcutaneous, intradermal, intramuscular [including administration to skeletal, diaphragm and/or cardiac muscle], intradermal, intrapleural, intracerebral, and intra-articular), topical (e.g., to both skin and mucosal surfaces, including airway surfaces, and transdermal administration), inhalation (e.g. , via an aerosol), rectal (e.g., via a suppository), transmucosal, intranasal, buccal (e.g.
• parenteral e.g. , intravenous, subcutaneous, intradermal, intramuscular [including administration to skeletal, diaphragm and/or cardiac muscle], intradermal, intrapleural, intracerebral, and intra-articular
• topical e.g., to both skin and mucosal surfaces, including airway surfaces, and transdermal administration
• vaginal intrathecal
• intraocular transdermal
• in utero or in ovo
• intralymphatic and direct tissue or organ injection (e.g., to liver, skeletal muscle, cardiac muscle, diaphragm muscle or brain).
• tissue or organ injection e.g., to liver, skeletal muscle, cardiac muscle, diaphragm muscle or brain.
• psilocybin is administered orally to the subject.
• the methods of treatment comprising administering psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and/or a prodrug of a metabolite of psilocybin for the treatment of one or more indications as described herein also include: the use of psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and/or a prodrug of a metabolite of psilocybin in the manufacture of a medicament for the treatment of one or more indications as described herein; and the use of psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and/or a prodrug of a metabolite of psilocybin for the treatment of one or more indications as
• a method for treating a subject in need thereof comprises administering to the subject a therapeutically effective dose of psilocybin. In some embodiments, a method for treating a subject in need thereof comprises administering to the subject a therapeutically effective dose of psilocybin in a controlled environment, wherein the subject is provided with psychological support.
• a method for treating a subject in need thereof comprises at least one of the following:
• 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 will be referred to herein as the initial stage of the psilocybin session.
• the time marked by the onset of the drug’s effects will be referred to herein as the early stage of the psilocybin session.
• the subject will experience the peak of the psilocybin’s effects at about 1 .5 hours to about 3.5 hours after administration thereof.
• the time period marked by the peak psilocybin experience will be referred to herein as the peak stage of the psilocybin session.
• the effects of the psilocybin may substantially wear off from about 4 hours to about 6 hours after administration. This time period will be referred to as the late stage of the psilocybin session.
• the subject s ability to reach a non-dual state (e.g., a mystical experience), or a sense of unity, boundlessness, ego-dissolution or transcendence correlates with positive clinical outcome.
• a non-dual state e.g., a mystical experience
• a sense of unity, boundlessness, ego-dissolution or transcendence correlates with positive clinical outcome.
• Each of these terms may be commonly defined as the breakdown of the usual relationship between self and other, whereby the subject might feel a oneness and increased sense of connectedness to the surrounding environment and/or the world at large.
• low levels of emotional arousal - which could indicate avoidance, lack of involvement or intellectualization - might, in some embodiments, be correlated with little or no improvement in treatment outcomes.
• Factors that may influence the subjective experience of psilocybin include, for example, (i) dose, (ii) the mindset of the participant prior to the session, (iii) the setting of the session, (iv) the subject’s ability to focus and stay with the experience, and/or (v) the subject’s prior experience with psychedelics. These, and other factors, will be described in more detail below, along with ways to maximize therapeutic benefit of the psilocybin session.
• a pre-administration psychological support session may be held about 1 month prior to the psilocybin administration. In some embodiments, a pre-administration psychological support session may be held about 2 weeks prior to the psilocybin administration. In some embodiments, a pre-administration psychological support session may be held about 1 week prior to the psilocybin administration. In some embodiments, a pre-administration psychological support session may be held about 3 days prior to the psilocybin administration. In some embodiments, a pre-administration psychological support session may be held about 1 day prior to the psilocybin administration. In some embodiments, a pre-administration psychological support session may be held on the same day as and prior to psilocybin administration.
• 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 pre-administration psychological support sessions at least once per week, for at least two or three weeks prior to the psilocybin session. In some embodiments, the subject may additionally participate in a pre administration psychological support session the day before the psilocybin session.
• the pre-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a therapist.
• the psychological support sessions may be group sessions, wherein more than one subject meets with a single therapist, or more than one therapist.
• one or more of the subject’s family members or friends may be present at the pre-administration psychological support session(s).
• the goals of the pre-administration session may include (i) establishing therapeutic alliance between subject and therapist; (ii) answering the subject’s questions and addressing any concerns; and/or (iii) demonstrating and practicing the skills of self- directed inquiry and experiential processing.
• the pre-administration psychological support sessions focus on discussion of possible psilocybin effects, and/or preparing subjects for the dosing session by practicing relevant therapeutic techniques to reduce avoidance and anxiety, eliciting relevant therapeutic goals, building rapport, and/or establishing therapeutic alliance.
• skills of self-directed inquiry and experiential processing may be demonstrated and/or practiced.
• breathing exercises meant to promote calm and/or ease anxiety may be demonstrated and/or practiced.
• the breathing exercise comprise instructing the subject to focus on their breath and/or sensations associated with the breath throughout the body. For example the subject may be instructed to breathe in for a count of four, to hold their breath for a moment, and then to breathe out for a count of eight.
• the therapist and subject may discuss the most helpful ways to support in case of emotional distress during the psilocybin session.
• the subject is given access (e.g., online access) to materials concerning the safety and mechanism of action of psilocybin.
• the pre-administration psychological support sessions will serve to establish a therapeutic goal for the psilocybin session.
• the subject suggests the therapeutic goal for herself or himself.
• the therapist suggests the therapeutic goal to the subject.
• the subject is reminded of the therapeutic goal during the pre-administration psychological support session.
• the therapists are trained to counsel the subject before, during, and/or after the psilocybin sessions.
• the therapist will have mental health training.
• the therapist will be a clinical psychologist, a psychiatrist, a social worker, a doctor or a nurse.
• the therapist will meet the following criteria: • Demonstrate independent clinical experience with direct subject care in areas that require counseling and psychotherapeutic skills;
• 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 from 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 necessary.
• the term“psychological support” refers to any measure(s) taken by the therapist during the subject’s psilocybin session to ensure the safety of the subject and maximize the clinical effectiveness of the psilocybin session.
• the psychological support may be anything done by the therapist to (1 ) to ensure psychological safety of the subject; (2) to allow the subject’s subjective experience to unfold naturally within the boundaries of the therapeutic intention set at the preparation; (3) to maintain participant’s attention and awareness on the experience of the present moment thus allowing exposure and processing of the challenging emotional states and personal memories; and/or (4) to generate insights and solutions forthe resolution of challenging personal situations, conflicts and traumatic experiences.
• support can be in the form of therapeutic touch, verbal reassurance, guided imagery and/or relaxation or breathing exercises.
• the support may comprise reminders, encouragement, or active guiding. Typically, only one technique is applied at a time to allow for minimal intervention and interference with the subject’s unique process.
• the main therapeutic goals of the therapist during the psilocybin session are to (i) minimize extreme anxiety, and (ii) provide appropriate support that enables the skills and processes of self-directed inquiry and experiential processing.
• the therapist demonstrates genuine presence, patience, curiosity, and/or openness during the psilocybin session.“Presence” refers to being totally available and present with the subject during all stages of the psilocybin session, and exuding calmness at all times.“Curiosity” refers to interest and willingness to understand the subject’s experience, without making assumptions.“Patience” means that the therapist facilitates the participant taking as much time as needed to explore their experiences without controlling the natural urge to help or direct the experience.“Openness” is the ability of the therapist to remain cognitively and experientially open, including a capacity to be curious about how the subject’s mind may uniquely choreograph the unfolding content of a session. This includes welcoming all emotions and expressions that might occur.
• the psychological support may comprise curious questioning.
• questioning of subjects is used to help the subjects shift and sustain their attention towards different levels of cognition and emotions (“How does that make you feel?”) Due to the applicability across a range of mental states and within various settings, the technique of curious questioning can typically be used safely and consistently during the psilocybin session, regardless of the quality or intensity of the experience of each subject.
• the level of psychological support will vary during the various stages of the subject’s psilocybin experience (e.g., the initial stage, the early stage, the peak stage, and the late stage).
• the type of psychological support will vary during the various stages of the subject’s psilocybin experience (e.g., the initial stage, the early stage, the peak stage, and the late stage). Because non-dual, ego-dissolution or“unitive” experiences have been shown to positively correlate with the magnitude and durability of the clinical response, the therapist will, in some embodiments, attend to such states with particular care.
• a subject may experience of a compromised sense of self during the subject’s psilocybin experience. In some embodiments, this is interpreted from a psychoanalytic perspective as a disruption of ego-boundaries, which results in a blurring of the distinction between self-representation and object-representation, and precludes the synthesis of self-representations into a coherent whole.
• non-dual, ego-dissolution or “unitive” experiences refer 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 compromised sense of “self’ and instead only a undivided background awareness, often characterised by a sense of unity or“oneness” that exceeds sensory or cognitive apprehension.
• a non-dual experience is state of consciousness in which the subject- object dichotomy in normal waking consciousness is substituted for a unified background awareness that is centreless and undivided.
• an ego dissolution experience is a spontaneously occurring state of consciousness where there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a compromised sense of“self’.
• a unitive experience is an experience characterised by a sense of unity or“oneness” that exceeds sensory or cognitive apprehension.
• psychological support may be used to reduce severe and/or prolonged anxiety.
• Anxiety prior to or during the onset of psilocybin effects is not uncommon, and the therapists may be specially trained to recognize and actively manage subjects through such periods of anxiety until the subject is comfortable enough to continue on their own.
• therapists validate the subject’s feelings of anxiety without providing interpretations of perceptual disturbances or guiding subjects towards a particular image or memory, other than encouraging them to stay relaxed and open to the emergent experiences.
• the therapist may help alleviate anxiety using a grounding exercise. In such an exercise, the subject may be encouraged to pay attention to the sounds around them or to sensations on their skin when touching the bed/couch, ground, or other objects.
• the therapist may encourage the subject to lie down, practice relaxation and breathing exercises, and/or listen to calming music.
• the therapist may remind the subject of the intention for the treatment session. For example, the therapist may ask the subject“What does feeling better or recovery feel like?” or any number of similar questions. Such reminders prior to the onset of or at the onset of psilocybin effects provide an implicit direction for the subjective experience during the psilocybin session.
• the therapist may remind the subject that their primary task during this session is to simply collect new and interesting experiences which can then be discussed with the therapist after the session.
• the therapist may remind the participant of the purpose of the psilocybin therapy and the role of experiential processing, namely allowing the participant to be open and curious to whatever arises and encountering thoughts and feelings previously unknown to them.
• the therapist emphasizes that this process inherently requires letting go and a willing passivity to the psychedelic experience.
• the subject might experience perceptual changes in visual, auditory or olfactory modes, and a range of unusual physical sensations. These experiences could be anxiety-provoking.
• the therapist may practice reassuring“arm holding”. This is where, upon the subject’s request, a therapist will place his or her hand on the subject’s wrist, arm, hand, or shoulder, as a way of helping the subject feel secure during this phase. This exercise may have been previously practiced during the pre-administration psychological support session.
• the therapist may encourage the subject to put on an eye mask, such as a Mindfold eyeshade. In some embodiments, the therapist encourages the subject to put on the eye mask before, during, or after the onset of the psilocybin’s effects.
• the therapist may encourage the subject to put on headphones and listen to music.
• the headphones reduce outside noise (e.g.,“noise cancelling” headphones).
• the music is calming music such as instrumental ( e.g ., classical) music.
• the music comprises nature sounds and/or the sound of moving water (e.g., ocean sounds).
• the music comprises isochronic tones.
• the music comprises moments of silence.
• the music is emotionally evocative.
• the music comprises a playlist which mirrors the pharmacodynamics of a typical high-dose psilocybin session: the initial stage, the early stage, the peak stage, and the late stage.
• listening to music helps the subject to focus on their internal experience.
• therapists may, in some embodiments, actively guide participants through such experiences without interpreting or judging the experiences or giving advice. Once participants are comfortable, the therapist may encourage them to again engage in introspection.
• the therapist may encourage subjects to face and explore their experience, including the challenging ones.
• Therapists may direct subjects to participate self-directed inquiry and experiential processing to develop a different perspective on their personal challenges and conflicts, and to generate their own solutions.
• Such self-generated insights are not only therapeutic because of the emotional resolution, but also empowering to subjects.
• the term“self-directed inquiry” refers to directing attention to internal states. Subjects are encouraged to be curious about experiences in the present moment, including foreground and background thoughts, emotions, and physical sensations. During the preparation and integration stages, this inquiry might mean asking specific and detailed questions to help direct attention to internal states. However, during the period of drug action, inquiry might simply mean an attitude of openness to inner experiences.
• experiential processing refers to a participant’s ability to maintain full attention on the experiences that come into awareness through self-directed enquiry. This includes a willingness and ability to be with and/or move‘in and through’ even uncomfortable or challenging thoughts, feelings, sensations or emotions, until discomfort is diminished or resolved.
• the therapist will employ a transdiagnostic therapy.
• the transdiagnostic therapy is a Method of Levels (MOL) therapy.
• the MOL therapy comprises Self-Directed Enquiry and Experiential Processing.
• MOL uses brief, but detailed, curious questioning to help subjects shift and sustain their attention towards different levels of cognition and emotions (Carey, 2006; Carey, Mansell & Tai, 2015).
• the emphasis within MOL is on identifying and working with a subject’s underlying distress as opposed to just their symptoms.
• Such MOL related methods and techniques can include: (1 ) Self-directed enquiry - directing attention to internal states.
• enquiry can mean asking specific and detailed questions to help direct attention to internal states, although for some embodiments, during the period of drug action, enquiry can refer to an attitude of openness to inner experiences; and (2) Experiential processing - sustained focus on the experience; refers to a participant’s ability to maintain full attention on the experiences that come into awareness through self-directed enquiry. This includes a willingness and ability to be with and/or move‘in and through’ even uncomfortable or challenging thoughts, feelings, sensations or emotions, until discomfort is diminished or resolved.
• the psychological support comprises mindfulness-based therapy or CBT cognitive behavioral therapy (CBT).
• CBT CBT cognitive behavioral therapy
• the psychological support is informed by a functional theory of human behavior called Perceptual Control Theory.
• the subject will try to avoid emerging experiences or distract him/herself while trying to regain cognitive control over the unusual state of their mind.
• Such distractions may take different forms.
• the subject might want to engage in a conversation or prematurely describe in detail their experience, visions or insights.
• the therapist may aim to remain as silent as possible, thereby enabling the subject and his/her inner experience to direct the course of the psilocybin session.
• the therapist may use active listening skills paired with prompts to encourage the subject to continue focusing attention on present experiences, particularly if the participant engages the therapist in conversation.
• a subject might ask to go to the bathroom or have a drink of water.
• the sudden and urgent character of such requests might suggest that they are really trying to avoid emerging material.
• the therapist may encourage the subject to stay with the experience by simply redirecting their attention. For example, the therapist may say something like,“We will take a bathroom break at the end of this piece of music” or“I will get you water in a little while. Why don’t you put the eye shades back on and relax for a few minutes?” If the subject is trying to avoid a difficult experience, they might listen to the suggestion and relax.
• spontaneous movement such as shaking, stretching or dancing while engaging with the experience is accepted and often encouraged, unless the movement seems to be a way to distract oneself from the experience.
• reminders to periodically return to a lying down position and to actively focus inwards may be provided.
• the therapist is not required to understand, support or even have an opinion about the nature or content of the subject’s experiences, but the therapist may validate them and convey openness toward the subject’s own view of them without dismissing or pathologizing any experience based on its unusual content. These experiences may provide the subject with a perspective that goes beyond identification with their personal narrative.
• the therapist will validate one or more of the subject’s experiences.
• validation of the experiences simply means acknowledging the courage of opening up to the experience and the possibility that any experience will serve the intention of the session.
• a therapist provides psychological support for approximately 4-8 hours immediately after administration of the psilocybin.
• the therapist uses guided imagery and/or breathing exercises to calm the subject and/or focus the subject’s attention.
• the therapist holds the hand, arm, or shoulder of the subject.
• the therapist counsels the subject to do one or more of the following: (1 ) to accept feelings of anxiety, (2) to allow the experience to unfold naturally, (3) to avoid psychologically resisting the experience, (4) to relax, and/or (5) to explore the subject’s own mental space.
• the therapist avoids initiating conversation with the subject, but responds if the subject initiates conversation.
• active intervention is kept to a minimum during the treatment experience.
• the subject is encouraged to explore their own mental space, and simple guided imagery may be used to assist relaxation.“Guided imagery” refers to an exercise wherein the subject is asked to imagine a scene (e.g.,“Invite a scene, perhaps a landscape, and tell me where you find yourself’;“Imagine a place that feels safe to you.”)
• subjects may be encouraged to engage in post-administration integration sessions with their therapist.
• Integration is a process that involves processing, or embodying, a psychedelic experience within a therapeutic context. The process initially begins by the subject verbalising and reflecting upon any experience from the psilocybin session, and discussing it openly with their therapist.
• Successful integration of a psilocybin experience accommodates for emotional changes and comprises of translating experiences into new insights, perspectives, and subsequently new behaviors that can be used to benefit the subject’s quality of life. New perspectives might in turn influence the participant’s current knowledge or values and lead to new ways of relating to cognitions, emotions, behaviors and physical experiences.
• the goals and supportive methods used by the therapist throughout integration sessions should remain consistent, regardless of the intensity or content of the subjective experience explored by the subject. That said, the methods of support used by the therapist should accommodate for the full range of experiences a subject might have faced.
• the integration process is not one that should be limited to the sessions with the therapist, and is a process that will likely continue to unfold beyond the visits in clinic.
• the therapist might encourage the participant to use methods such as spending time in nature, exercise, or creative expression to help facilitate the process further.
• the subject might also be encouraged to discuss experiences with their friends, family, and/or support network.
• the role of the integration sessions is not to cover and work on every experience, but to empower the participant by building their capacity to experientially process information safely. This enables the patient to continue self- directed integration, even outside of study visits.
• the subject participates in at least one psychological support session after administration of the psilocybin (“post-administration psychological support session”).
• a post-administration psychological support session may be held on the same day as the psilocybin session, after the effects of the psilocybin have substantially worn off.
• a post-administration psychological support session may be held the day after the psilocybin session.
• a post administration psychological support session may be held two days after the psilocybin session.
• a post-administration psychological support session may be held three days after the psilocybin session.
• a post-administration psychological support session may be held about one week after the psilocybin session. In some embodiments, a post-administration psychological support session may be held about two weeks after the psilocybin session. In some embodiments, a post-administration psychological support session may be held about one month after the psilocybin session. In some embodiments, a post administration psychological support session may be held about three months after the psilocybin session. In some embodiments, a post-administration psychological support session may be held about six months after the psilocybin session. In some embodiments, a post-administration psychological support session may be held about twelve months after the psilocybin session.
• the subject may participate in one, two, three, four, five, six, seven, or eight post-administration psychological support sessions. In some embodiments, the subject may participate in at least two, or at least three post-administration psychological support sessions.
• the post-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a therapist. In some embodiments, the psychological support sessions may be group sessions, wherein more than one subject meets with a single therapist, or more than one therapist. In some embodiments, one or more of the subject’s family members or friends may be present at the post-administration psychological support session(s).
• the post-administration psychological support session may focus on integration of the psilocybin experience. Integration may involve processing a psychedelic experience in a therapeutic context. Integration may comprise psychological and somatic processing of the experience and a successful assimilation of insights into the subject’s life for the purpose of growth, healing and/or well-being. During an integration session, a subject may be encouraged to talk about and reflect upon their experiences during the psilocybin session.
• integration may comprise an external expression of the psilocybin experience, such as choice of words, tone of voice, gestures, and/or particular physical activities (yoga, exercise, bodywork, etc.)
• integration comprises creatively expressing any insights or experiences gained during a psilocybin experience, for example through poetry, art, music/singing, dance, writing or drawing.
• the subject may be encouraged to reflect on both the thoughts and the feelings that he or she underwent during the psilocybin session, as well as to express those ideas and emotions into a concrete form that can serve as a tool for continuing to remember and integrate those lessons into the future.
• the subject may be encouraged to acknowledge and connect with the range of the emotional cognitive and physical experiences of the psilocybin session, and relate them to current experiences in their life situation. This may be accomplished, for example, by discussing them initially with their therapist, and perhaps later with their family, friends, and support circle. Integration helps accommodate changes in emotional states as new insights are generated and integrated.
• the integration process is not limited to initial integration meetings with the therapist, but continues to unfold spontaneously through a participant’s own processing and actions in everyday life.
• the integration process might focus on the mental content that emerged during the hours of relaxation and introspection. This might also include reactions to what might have been an unremarkable experience, such as feeling of disappointment, anger, relief etc.
• psychological support may be provided remotely to a subject.
• a therapist providing psychological support may not be in the same room, the same building, or in the same facility as a subject.
• Remote psychological support may be provided, for example by telephone (i.e., by voice call), by video call or video conference, by text, or by email.
• a pre-administration therapy session is conducted remotely.
• a post-administration therapy session e.g., an integration session is conducted remotely.
• psychological support is provided remotely during the subject’s psilocybin session.
• the subject takes the psilocybin in his or her own home, and a therapist provides psychological support by voice call, video call, text, email, etc., for at least 4-8 hours after the subject has taken the drug.
• the subject takes the psilocybin in an administration facility as described herein, and the therapist provides psychological support to the subject a therapist provides psychological support by voice call, video call, text, email, etc., for at least 4-8 hours after the subject has taken the drug
• remote psychological support is provided to the subject using a digital or electronic system.
• the digital or electronic system may comprise one or more of the following features:
• the digital or electronic system securely connects patients with one or more therapists or physicians for“virtual visits.” These virtual visits may be introductory or routine.
• the digital or electronic system allows a subject to qualify, prequalify, or register for a psilocybin-based clinical trial, or a psilocybin-based psychological support session.
• the digital or electronic system is configured to help therapists and/or physicians manage and interact with patients.
• the electronic system may allow the therapist to share documents with subjects, keep notes about sessions, or schedule future sessions.
• the digital or electronic system is configured to provide alerts for crisis intervention.
• the digital or electronic system may allow the subject to contact the therapist if they are feeling anxiety or otherwise urgently need to talk to the therapist.
• the digital or electronic system is configured to help prepare the subject for a visit with their therapist and/or physician.
• the digital or electronic system may contain information regarding psilocybin, the therapeutic protocol, etc.
• the digital or electronic system is configured to allow the therapist to provide psychological support during the subject’s psilocybin session.
• the system may comprise a video calling or chat feature.
• the digital or electronic system is configured to allow the therapist to provide psychological support during a post-administration session (e.g., an integration session).
• the digital or electronic system is configured to track the subject’s adherence to the treatment regimen or goals.
• the digital or electronic system is configured to assess one or more clinical endpoints in the subject.
• the system may comprise one or more questionnaires or exercises for the subject to complete. Results may be made available to the subject’s physician and/or therapist.
• the digital or electronic system is an“app” for use on a mobile phone or a computer.
• the digital or electronic system is a website.
• the digital or electronic system comprises a“chat” feature which allows communication between the subject and the therapist in real time.
• the website comprises a video calling feature, which allows for the therapist to communicate with the subject using video communication.
• the digital or electronic system is configured to allow a single therapist to provide psychological support to one or more subjects at or around the same time.
• psychological support sessions may be pre-recorded (e.g., audio or video recording) and provided to the subject for use at the subject’s convenience via the digital or electronic system.
• the term“set and setting” refers to the subject’s mindset (“set”) and the physical and social environment (“setting”) in which the user has the psilocybin session.
• the psilocybin may be administered in a particular set and setting.
• the set and setting is controlled, to the extent possible, to maximize therapeutic benefit of the psilocybin session.
• the psilocybin is administered by in a facility specifically designed for psilocybin administration.
• Administration of the psilocybin to the subject in a facility where the subject feels safe and comfortable may help ease anxiety in the subject, and may facilitate maximum clinical benefit.
• Psilocybin may be administered to a subject, for example, in the subject’s home or at a clinical facility.
• the psilocybin is administered to the subject in a facility (e.g., a room) with a substantially non-clinical appearance.
• a facility e.g., a room
• the psilocybin can be administered in a room that comprises soft furniture (e.g., plush couches, chairs, or pillows) and/or plants.
• the room may be decorated using muted colors (e.g., greyed, dulled, or desaturated colors).
• the light in the room is dimmed and/or light levels are kept or adjust to be relatively low.
• the room lighting is adjusted for intensity and/or color.
• a virtual reality or augmented reality system e.g., computer with visual/graphical and auditory outputs
• the room comprises a sound system, for example a high-resolution sound system.
• the sound system can allow for simultaneous ambient and earphone listening.
• the subject may bring meaningful photographs or objects into the administration room.
• 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.
• the subject sits on or lies in the couch or bed for approximately 4-8 hours, or a substantial fraction thereof, immediately after administration of the psilocybin. In some embodiments, the subject listens to music for approximately 4-8 hours, or a substantial fraction thereof, immediately after administration of the psilocybin. In some embodiments, the subject wears an eye mask for approximately 4-8 hours, or a substantial fraction thereof, immediately after administration of the psilocybin. In some embodiments, the subject is provided with a weighted blanket.
• 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 multiple subjects, wherein each subject is participating in a psilocybin session. For example, one therapist may supervise two, three, four, five, six, seven, eight, nine, or ten subjects.
• Embodiments of the disclosure include use of additional tools and/or technique(s) with dosage/administration, including various transcranial magnetic stimulation (TMS) methods and protocols, for example, prior or subsequent to one or more dosing(s), biofeedback devices, etc.
• TMS transcranial magnetic stimulation
• Some embodiments can be used with a digital health product or digital solution.
• Teachings of the disclosure include utilization of such digital health products and/or related digital biomarkers as diagnostic and/or prognostic tools for patient monitoring and management pre-treatment, during treatment, and/or post treatment.
• Digital biomarkers can include, by way of non-limiting example: Number of and / or time of phone calls/e-mails/texts; word length in text communication; Gestures used (taps, swipes, or other); Gyroscope derived information e.g.
• a digital health product can be utilized to determine dosing amount and/or dosing frequency, indicator of a need for re-dosing, re-dosing amount, a warning or alert, as tracking of compliance, etc.
• methods of treatment can include providing a clearance time for a subject or patient, such one or more medications is not present or substantially cleared from the system of the subject/patient.
• methods of treatment can be configured such that, upon administration, the subject is not taking other serotonergic medications such as: selective- serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors and/or antipsychotics.
• the method of treatment include treatment concurrently with one or more medications, including but not limited to selective-serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and/or monoamine oxidase inhibitors.
• one or more medications including but not limited to selective-serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and/or monoamine oxidase inhibitors.
• the method include treatment such that subjects or patients take concomitant compounds or medications, including but not limited to benzodiazepines, cannabidiol (CBD) and/or other cannabinoids (e.g., THC (tetrahydrocannabinol); THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); CBT (cannabicitran); and/or the like) magnesium, Levomefolic acid, e.
• THC
• the method includes treatment such that a subject has not taken one or more medications, particularly has not taken one or more serotonergic medications for at least 2 days, at least, 3 days, at least 4 days, at least 5 days, at least six days, at least 1 week, at least 2, 3, or 4 weeks before administration of the disclosed psilocybin compound.
• the method and/or treatment can comprise subperceptual-dosing (e.g., a dose of less than 3mg, 2.5mg, 2mg, 1.5mg, 1 mg, 0.9mg, 0.8mg, 0.7mg, 0.6mg, 0.5mg, 0.4mg, 0.3mg, 0.2mg, or 0.1 mg) prior to and/or following the administration of a relatively larger single dose or multiple doses (given a few days to a few weeks apart), where the relatively larger single dose or multiple doses is one or more of 5mg or more, 10mg or more, 15mg or more, 20mg or more, 25mg or more, 30mg or more, 35mg or more, 40mg or more, 45mg or more, 50mg or more.
• subperceptual-dosing e.g., a dose of less than 3mg, 2.5mg, 2mg, 1.5mg, 1 mg, 0.9mg, 0.8mg,
• Embodiments of the disclosure include method utilizing a digital biomarker, for example, as a diagnostic and/or prognostic tool for patient management pre-, during and/ or post treatment with psilocybin wherein the digital biomarker is one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and/or emotional valence.
• a digital biomarker for example, as a diagnostic and/or prognostic tool for patient management pre-, during and/ or post treatment with psilocybin
• the digital biomarker is one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and/or emotional valence.
• the digital biomarker is identified from patterns in smartphone use such as swipes, taps, and other touchscreen activities, andean be scientifically validated to provide measurements of subject status, such as cognition and mood, including, by way of non limiting example, as disclosed in one or more of the following, each of which is herein expressly incorporated by reference for all purposes: US20170086727, US20170258382, US20170258383, US20170287348, US10148534, US9737759, and/or US10231651 .
• Biomarkers which may serve as a diagnostic and / or prognostic tool for patient management pre, during and/ or post treatment may be identified using one or more of: Number of and / or time of phone calls/e-mails/texts; word length in text communication; Gestures used (taps, swipes, or other); Gyroscope derived information e.g. orientation of the phone; Acceleration of the phone; Keystroke patterns; Location derived information from GPS; facial expressions and/or microexpressions; voice or vocal markers; natural language processing; social media use; sleep patterns; specific words or emojis used or not used; and/or the like.
• health components and/or connected biomonitors and/or smart devices/wearables can be utilized to collect information to be used in diagnostic and /or prognostic outputs.
• a heart rate monitor or similar device can collect a subject’s data and heart rate variability (for example only, as disclosed in US10058253, the entirety of which is herein incorporated by reference) can be used to assess/determine a metric relating to the subject’s current emotional state, relative change in emotional state, etc., which can be used in determining a new or follow-on treatment plan, adjusting a treatment plan, etc.
• a method of assessing a subject pre, during and/ or post treatment of a central nervous system disorder to determine whether to provide a psilocybin treatment or a further psilocybin treatment comprising monitoring one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and emotional valence, and determining the treatment based on an outcome.
• the method can further comprise the step of administering psilocybin for a first or a subsequent time.
• the biomarker is identified from patterns in smartphone use such as swipes, taps, and other touchscreen activities, and are scientifically validated to provide measurements of cognition and mood.
• the pattern is identified using one or more of: Number of and / or time of phone calls/e-mails/texts; word length in text communication; Gestures used (taps, swipes, or other); Gyroscope derived information e.g. orientation of the phone; Acceleration of the phone; Keystroke patterns; Location derived information from GPS; facial expressions and/or microexpressions; voice or vocal markers; natural language processing; social media use; sleep patterns; specific words or emojis used or not used; and/or the like.
• Embodiments include a method of assessing a subject pre, during and/ or post treatment of a central nervous system disorder to determine whether to provide a psilocybin treatment or a further psilocybin treatment comprising monitoring one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and emotional valence, and determining the treatment based on an outcome; the method can further comprise administering psilocybin for a first or a subsequent time.
• the disclosure provides for treating 2 or more subjects, the method comprising administering to each subject a therapeutically-effective dose of psilocybin at the same time or substantially the same time (e.g., dosed within several minutes of each other, within 5, 10, 15, 20, 25, or 30 min of each other), wherein each subject is aware of the other subject also receiving treatment.
• the subjects are in the same room. In some embodiments, the subjects are in different rooms.
• the 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 reality digital tool.
• the light in the room is dimmed and/or light levels are kept or adjusted to be relatively low.
• darkened glasses or eye shades are provided.
• the room lighting is adjusted for intensity and/or color.
• a virtual reality or augmented reality system e.g., computer with visual/graphical and auditory outputs
• the subject is a male. In some embodiments, the subject is a female. In some embodiments, the female subject is pregnant or post-partum. In some embodiments, the subject is attempting to reduce or eliminate their use of a pharmaceutical agent, such as an anti-depressant or an anti-epileptic drug. In some embodiments, the subject is attempting to reduce or eliminate their use of the pharmaceutical agent before becoming pregnant, having surgery or other medical procedure, or starting to use different pharmaceutical agent.
• a pharmaceutical agent such as an anti-depressant or an anti-epileptic drug.
• the subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle aged subject. In some embodiments, the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age.
• the subject may have a chronic disease or a terminal disease.
• the subject may have a life-altering disease or condition (such as the loss of a limb or onset of blindness).
• the subject may have recently been diagnosed with a disease, disorder, or condition. For example, the subject may have been diagnosed within 1 month, within 3 months, within 6 months, or within 1 year. In some embodiments, the subject may have been living with a disease, disorder, or condition for an extended period time, such as at least 6 months, at least 1 year, at least 3 years, at least 5 years, or at least 10 years.
• the subject may be a cancer patient, such as a Stage 4 or terminal cancer patient.
• the subject may have been determined to have a limited time to live, such as less than 1 year, less than 6 months, or less than 3 months.
• the subject may have previously taken a psychedelic drug, or may have never previously taken a psychedelic drug.
• the subject may or may not have previously taken psilocybin, a psilocybin mushroom (“magic mushroom”), LSD (lysergic acid diethylamide or acid), mescaline, or DMT (N,N-Dimethyltryptamine).
• the subject may have previously taken one or more serotonergic antidepressants (e.g., selective serotonin reuptake inhibitors (SSRIs)). In some embodiments, the subject has never 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. In some embodiments, the subject may have previously received electroconvulsive therapy (ECT). In some embodiments, the subject has not received any ECT for at least 2 weeks, at least 4 weeks, or at least 6 weeks prior to receiving psilocybin.
• ECT electroconvulsive therapy
• the subject may have a medical condition that prevents the subject from receiving a particular medical therapy (such as an SSRI or ECT).
• a particular medical therapy such as an SSRI or ECT
• the subject may have previously had an adverse reaction to a particular medical therapy (such as an SSRI or ECT).
• a prior medical therapy (such as an SSRI or ECT) was not effective in treating a disease, disorder, or condition in the subject.
• kits 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, or conditions including particular psychiatric and neurological aspects of the diseases, disorders, or conditions.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin or a metabolite thereof, wherein the subject has at least one or more of the following diseases, disorders, or conditions: Disruptive Mood Dysregulation Disorder, Major Depressive Disorder (MDD), Treatment Resistant Depression, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication-Induced Depressive Disorder, Post- Partum Depression, Depressive Disorder due to Another Medical Condition, Separation Anxiety Disorder, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Panic Disorder, Panic Attack, Agoraphobia, Generalized Anxiety Disorder, Substance-Medication- Induced Anxiety Disorder, Anxiety Disorder Due to Another Medical Condition, Somatic Symptom Disorder, Illness Anxiety Disorder (hypochondriac), Conversion Disorder (MDD), Treatment
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: a Neurocognitive Disorder due to Alzheimer's, Lewy Bodies, Traumatic Brain Injury, Prion Disease, Human Immunodeficiency Virus (HIV) Infection, Parkinson's, Huntington's; concussion; Chronic Traumatic Encephalopathy (CTE); Language Disorder, Speech Sound Disorder (Phonological Disorder); Childhood-Onset Fluency Disorder (Stuttering); Social (Pragmatic) Communication Disorder; Tourette's Disorder; Persistent (Chronic) Motor or Vocal Tic Disorder; Amnestic Disorder Due to Known Physiological Condition (possibly in ECT shock-resistant subjects); Transient Cerebral Ischemic Attack, Cerebral Infarction, Cerebral Bleeding, Progressive Supranuclear Ophthalmoplegi
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Autism, Autism Spectrum-Disorder, or Antisocial Personality Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Attention-Deficit/Hyperactivity Disorder, Other Specified Attention-Deficit/Hyperactivity Disorder or Unspecified Attention-Deficit/Hyperactivity Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Schizotypal (Personality) Disorder, Delusional Disorder, Schizophrenia, or Schizoaffective Disorder.
• Schizotypal (Personality) Disorder a therapeutically-effective dose of psilocybin
• the subject has at least one of the following diseases, disorders, or conditions: Schizotypal (Personality) Disorder, Delusional Disorder, Schizophrenia, or Schizoaffective Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Insomnia Disorder, Hypersomnolence Disorder, Narcolepsy, or Primary Central Sleep Apnea.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Schizoid Personality Disorder, Schizotypal Personality Disorder, Antisocial Personality Disorder, Borderline Personality Disorder, or Obsessive-Compulsive Personality Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Female sexual Interest/Arousal Disorder, Male Hypoactive Sexual Desire Disorder, and Excessive sexual Drive.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Bipolar I Disorder, Bipolar II Disorder, or Cyclothymic Disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Age-Related Hearing Loss or Tinnitus.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the has at least one of the following diseases, disorders, or conditions: Multiple Sclerosis, Cranial Nerve Disorder, Neuromyelitis Optica, Bell's Palsy, Guillain Barre Syndrome, Demyelinating Disease of Central Nervous System, or Chronic Inflammatory Demyelinating Polyneuritis.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject suffers from pain, such as phantom pain, chronic pain, or pain associated with another disease or disorder.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Myelopathy, Traumatic Brain Injury, Intellectual Disabilities, Mania, Neurodegeneration, Paraphilic disorders (e.g., Pedophilic Disorder), Suicidal Behavior Disorder, Nonsuicidal Self- Injury, Persistent Complex Bereavement Disorder, Gl Tract Related Diseases (e.g., IBS), Epilepsy, Sickle Cell Disease, locked-in syndrome, restless leg syndrome, stroke (such as ischemic stroke or hemorrhagic stroke), or Amyotrophic Lateral Sclerosis (ALS).
• Myelopathy Traumatic Brain Injury, Intellectual Disabilities, Mania, Neurodegeneration, Paraphilic disorders (e.g., Pedophilic Disorder), Suicidal Behavior Disorder, Nonsuicidal Self- Injury, Persistent Complex Bereave
• the disclosure provides a method of treating a subject, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein after administration the subject exhibits an improvement in cognition.
• the improvement in cognition is an improvement in attention, episodic memory, working memory, spatial memory, social cognition, executive function, and/or cognitive flexibility.
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has Treatment Resistant Depression (TRD).
• TRD Treatment Resistant Depression
• the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has Major Depressive Disorder (MDD).
• MDD Major Depressive Disorder
• the methods of treatment comprising administering psilocybin to a subject in need thereof further comprise pretreating the subject with magnesium before administration of the psilocybin.
• magnesium is administered daily for a 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 before administration of the psilocybin.
• about 10 mg to about 500 mg of magnesium are administered to the subject per day.
• 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 are administered to the subject per day.
• the magnesium is administered to the subject on the same day as the psilocybin.
• the magnesium is administered to the subject immediately before, concurrently with, or immediately after administration of the psilocybin.
• magnesium supplements are administered to the subject until the subject’s blood level for magnesium is about 1 .5 to about 2.5 mEq/L.
• psilocybin is not administered to the subject if the subject’s blood level of magnesium is less than about 1.5 to about 2.5 mEq/L.
• the methods of treatment comprising administering psilocybin to a subject in need thereof further comprise pretreating the subject with niacin before administration of the psilocybin.
• niacin is administered daily for a 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 before administration of the psilocybin.
• about 1 mg to about 5,000 mg of niacin are administered to the subject per day, for example about 1 mg to about 50 mg, about 10 mg to about 100 mg, about 100 mg to about 200 mg, about 1 mg to about 200 mg, about 100 mg to about 200 mg, about 10 mg to about 50 mg, about 10 to about 35 mg, about 100 mg to about 500 mg, or about 1 ,000 mg to about 3,000 mg.
• niacin is included as an ingredient / component, for example, to reduce risk of abuse and/or to improve efficacy.
• the niacin is administered to the subject on the same day as the psilocybin.
• the niacin is administered to the subject immediately before, concurrently with, or immediately after administration of the psilocybin.
• psilocybin is administered to the subject in combination with one or more additional therapies.
• psilocybin is administered to the subject in combination with one or more anti-depressant or anti-anxiety drugs, such as SSRIs, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or serotonin norepinephrine reuptake inhibitors (SNRIs).
• SSRIs tricyclic antidepressants
• TCAs tricyclic antidepressants
• MAOIs monoamine oxidase inhibitors
• SNRIs serotonin norepinephrine reuptake inhibitors
• the disclosure provides a method of reducing anxiety in a subject undergoing treatment with psilocybin, the method comprising administering to the subject: i) psilocybin or a precursor or derivative thereof, and ii) one or more benzodiazepines.
• the one or more benzodiazepines are administered to the subject at or around the same time as the psilocybin or precursor or derivative thereof. In some embodiments, the one or more benzodiazepines are administered to the subject prior to administration of the psilocybin or precursor or derivative thereof, such as 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 before administration of the psilocybin or precursor or derivative thereof.
• the one or more benzodiazepines are administered to the subject after the psilocybin or precursor or derivative thereof, such as about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, or about 180 minutes after administration of the psilocybin or precursor or derivative thereof.
• the one or more benzodiazepines are administered at a dose that is lower than doses typically used to treat anxiety, such as about 10%, 20%, 25%, 30%, 40%, 50%, or 75% of a typical dose. In some embodiments, the one or more benzodiazepines are administered at a dose that is approximately equivalent to doses typically used to treat anxiety. In some embodiments, the one or more benzodiazepines are administered at a dose that is higher than doses typically used to treat anxiety, such as about 125%, 150%, 175%, 200%, 250%, or 300% of a typical dose. In some embodiments, the one or more benzodiazepine is administered orally to the subject.
• the benzodiazepine is selected from the group consisting of adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam, flunitrazolam, flurazepam, flutazolam, flu
• a patient is administered psilocybin or a precursor or derivative thereof as described herein along with one or more 5-HT 2A specific antagonists and/or inverse agonists.
• the patient is administered psilocybin or a precursor or derivative thereof and the one or more 5-HT 2A specific antagonists and/or inverse agonists at the same time.
• the patient is administered one or more 5-HT 2A specific antagonists and/or inverse agonists prior to 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 before psilocybin administration.
• 5-HT 2A specific antagonists and/or inverse agonists prior to 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 before psilocybin administration.
• the patient is administered one or more 5-HT 2A specific antagonists and/or inverse 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.
• 5-HT 2A specific antagonists and/or inverse 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.
• the one or more 5-HT 2A specific antagonists and/or inverse agonists are administered at doses that are lower than doses typically used, e.g., about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 75% of a typical dose.
• the one or more 5-HT 2A specific antagonists and/or inverse agonists are administered at doses that are equivalent to doses typically used.
• the one or more 5-HT 2A specific antagonists and/or inverse agonists are administered at doses that are higher than doses typically used, e.g., about 125%, about 150%, about 175%, about 200%, about 250%, or about 300% of a typical dose.
• Suitable 5-HT 2A antagonists include but are not limited to, trazodone, mirtazapine, metergoline, ketanserin, ritanserin, nefazodone, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro- pyrimido-azepine, 9-aminomethyl-9,10-dihydroanthracene (AMDA), haloperidol, chlorpromazine, hydroxyzine (atarax), 5-MeO-NBpBrT, niaprazine, altanserin, aripiprazole, etoperidone, setoperone, chlorprothixene, cinaserin, adatanserin, medifoxamine, rau
• Suitable 5-HT 2A reverse agonists include but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and volinaserin.
• the 5-HT 2A antagonist is selected from the compounds of Table I .
• the disclosure provides a method of reducing the negative side effects associated with a traumatic psychedelic experience in a patient undergoing treatment with psilocybin, the method comprising administering to the patient: i) psilocybin or a precursor or derivative thereof, and ii) one or more cannabinoids or cannabinoid derivatives.
• the cannabinoid is selected from the group consisting of THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); and CBT (cannabicitran).
• THC tetrahydrocannabinol
• THCA tetrahydrocannabinolic acid
• CBD canannabidiol
• CBDA canannabidiolic acid
• CBN cannannabinol
• the cannabinoid is CBD (cannabidiol).
• at least one symptom of a disease, disorder, or condition described herein is alleviated within 24 hours of administering psilocybin.
• at least one symptom of the disease, disorder, or condition is alleviated within 1 week of the administering.
• at least one symptom of the disease, disorder, or condition is alleviated within 1 month of the administering.
• at least one symptom of the disease, disorder, or condition is alleviated within 6 months of the administering.
• at least one symptom of the disease, disorder, or condition is alleviated within 12 months of the administering.
• At least one symptom of the disease, disorder, or condition is alleviated for a period of at least 1 month after administering psilocybin. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for a period of at least 3 months after the administering. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for a period of at least 6 months after the administering. In some embodiments, at least one symptom of the disease, disorder, or condition is alleviated for a period of at least 12 months after the administering.
• no other treatment is administered to the subject to treat the disease, disorder, or condition before administration of the psilocybin. In some embodiments, no other treatment is administered to the subject to treat the disease, disorder, or condition after administration of the psilocybin.
• the present disclosure also relates to the safety and efficacy of the use of psilocybin as disclosed herein.
• the following is a non-exhaustive list of tests that can be used to determine the effects of psilocybin, and in particularthe psilocybin formulations as disclosed herein administered as disclosed herein.
• the Spatial Working Memory (SWM) test is utilized to evaluate the safety and efficacy of psilocybin as disclosed herein.
• SWM requires retention and manipulation of visuospatial information. Study subjects are required to find the blue tokens in the on-screen ‘boxes’. Boxes are searched by touching them to determine whether they contain a token. Once a token has been located it is‘stacked’ in a column on the right of the screen. Study subjects then search for further tokens until they have all been located. The remaining tokens will thereafter only be found in boxes that have not so far yielded a token.
• the efficacy of psilocybin is evaluated using the spatial working memory between errors (SWMBE) score.
• SWMBE score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the efficacy of psilocybin is evaluated using the spatial working memory strategy (SWMS) score.
• SWMS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the Rapid Visual Information Processing (RVP) test is utilized to evaluate the safety and efficacy of psilocybin.
• the RVP is a measure of sustained attention outputting measures of response accuracy, target sensitivity and reaction times.
• the study subject is required to monitor a stream of digits from 2 to 9 for specific sequences (e.g., 3- 5-7) and to acknowledge detection of the sequence by touching the on-screen response button as quickly as possible after presentation of the third digit. Digits are presented pseudorandomly to create the possibility of‘false alarm’ responses in which the first 2 digits of a sequence are not followed by a true target, e.g., when 3 is followed by a 5, but not then by a 7.
• Performance on this task is measured by the speed of response to the presentation of the final digit of a target, as well as the study subject’s ability to detect specified sequences. This test takes approximately 7 min to complete.
• performance on the Rapid Visual Information Processing test is reported using a RVP A Prime (RPVA) score. Higher scores on the RVPA indicated better performance.
• a subject’s RVPA score increases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 1 10 %, 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,
• the Paired Associates Learning (PAL) test is utilized to evaluate safety and/or efficacy of psilocybin.
• the PAL task is a measure of visuo-spatial memory in which study subjects are required to remember locations at which visual stimuli are located. Boxes are displayed on the screen and are“opened” in a randomized order. One or more of them will contain a pattern. The patterns are then displayed in the middle of the screen, one at a time and the subject must select the box in which the pattern was originally located. If the subject makes an error, the boxes are opened in sequence again to remind the subject of the locations of the patterns. Increased difficulty levels can be used to test high-functioning, healthy individuals. The primary metric for this test is the number of errors made.
• PALTEA Paired Associates Learning total errors adjusted
• a subject’s PALTEA score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the efficacy and/or safety of psilocybin is evaluated using the cognitive flexibility panel test.
• the Emotion Recognition Task (ERT) test is utilized to evaluate the safety and/or efficacy of psilocybin.
• the ERT measures the ability to identify 6 basic emotions in facial expressions along a continuum of expression magnitude.
• the ERT is performed according to the following protocol: Subjects are shown computer morphed images derived from the facial features of real individuals each showing a specific emotion, on a screen, one at a time. Each face is displayed for 200 ms and then immediately covered up, and the subject must select which emotion the face displayed from the six options (happy, sad, anger, fear, surprise, disgust). The ERT percent correct (ERTPC) of correct responses (emotion selection) the subject made is assessed. A higher score indicates better performance.
• ERTPC after treating according to the methods of the disclosure, increases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 1 10 %, 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,
• the Intra-Extra Dimensional Set Shift (IED) test is used to evaluate the safety and/or efficacy of psilocybin.
• the IED consists of four 7-item subscales, each of which taps a separate aspect of the global concept "empathy.”
• the Intra-Extra Dimensional Set Shift total errors (IEDYERT) score is used to assess the efficacy of psilocybin.
• a subject’s IEDYERT score decreases 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
• the One Touch Stockings (OTS) of Cambridge test is used to evaluate the safety and/or efficacy of psilocybin.
• the OTS is a test of executive function, based upon the Tower of Hanoi test. It assesses both the spatial planning and the working memory subdomains. This test takes approximately 10 min to perform.
• the OTS test reports an one touch stockings of Cambridge problems solved on first choice (OTSPSFC) score. A higher OTSPSFC score is associated with better executive function.
• a subject’s OTSPSFC score increases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about
• verbal fluency is used to evaluate the safety and/or efficacy of psilocybin.
• the study subject is asked to name as many different category exemplars (e.g.,‘animals’) as they can in 1 min, subject to certain scoring rules, such as repetition.
• Successful performance on this test is reliant on the integrity of a number of cognitive abilities and especially those traditionally viewed as executive functions, such as planning and working memory.
• the primary metric for this test is the total number of acceptable words generated.
• a subject’s verbal fluency category score improves by about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 1 10 %, 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, as compared to prior to treatment.
• the Digit Span Forward (DSF) test is used to evaluate the safety and/or efficacy of psilocybin.
• DSF is used to measure number storage capacity. Subjects hear a sequence of digits and are tasked to recall the sequence correctly, with increasingly longer sequences being tested in each trial. The subject’s span is the longest number of sequential digits that can accurately be remembered. Digit span tasks can be given forwards or backwards, meaning that once the sequence is presented, the subject is asked to either recall the sequence in normal or reverse order. For this study, subjects will be asked to recall the sequence in the order presented, i.e., Digit Span Forward. The primary metric for this test is the number of digit sequences successfully recalled.
• a subject’s Digit Span Forward score improves by about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 1 10 %, 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, as compared to prior to treatment.
• the Five Dimension Altered States of Consciousness questionnaire is utilized to evaluate the safety and/or efficacy of psilocybin.
• the 5D-ASC measures the acute drug effects using 5 primary dimensions and 1 1 lower-order scales to assess alterations in mood, perception and experience of self in relation to environment and thought disorder.
• the 5 dimensions include oceanic boundlessness, anxious ego dissolution, visionary restructuralization, auditory alterations and reduction of vigilance.
• a subject experiences an increase on a dimension or a subscale compared to prior to treatment.
• the lower-order scales include “experience of unity,”“spiritual experience,”“blissful state,”“insightfulness,”“disembodiment,” “impaired control of cognition,”“anxiety,”“complex imagery,”“elementary imagery,”“audio-visual synesthesia,” and“changed meaning of percepts.”
• the increase is about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 1 10 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %,
• the Positive and Negative Affect Schedule (PANAS) is used to evaluate the safety and/or efficacy of psilocybin.
• the PANAS measures the acute emotional drug effects and comprises 2 mood scales that measure positive and negative affect.
• Positive affect refers to the propensity to experience positive emotions and interact with others positively.
• Negative affect involves experiencing the world in a more negative way.
• Subjects respond to 10 questions associated with negative affect and 10 questions associated with positive affect. The questions are scaled using a 5-point scale that ranges from“slightly or not at all (1 )” to“extremely (5)”. A total higher score on the positive affect questions indicates more of a positive effect while a lower score on the negative affect questions indicates less of a negative affect.
• a subject experiences a decrease in negative affect score of the PANAS, between about 5 % and 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 prior to treatment.
• a subject experiences an increase in positive affect score of the PANAS, between about 5 % and 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 %, about 1 10 %, 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 %
• the NEO-Five Factor Inventory (NEO-FFI) test is used to evaluate the safety and/or efficacy of psilocybin.
• the NEO-FFI evaluates 5 broad domains of personality - Neuroticism, Extroversion, Openness, Agreeableness and Conscientiousness.
• the Symptom Checklist-90 item (SCL-90) questionnaire is used to evaluate the safety and/or efficacy of psilocybin.
• the SCL-90 is a relatively brief self-report psychometric instrument designed to evaluate a broad range of psychological problems and symptoms of psychopathology.
• the SCL-90 is used to assess somatization, obsessive-compulsive behaviors, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism of a subject treated according to the methods of the disclosure.
• the 90 items in the questionnaire are scored on a 5-point Likert scale, indicating the rate of occurrence of the symptom during the time reference.
• a subject’s SCL-90 score decreases by about 5 % to about 100 %, for example, 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 %.
• the Life Changes Inventory (LCI) questionnaire is utilized to evaluate the safety and/or efficacy of psilocybin.
• the LCI is designed as a questionnaire to investigate those variables present in the day-to-day experience of adults that might relate either to stability or decline of intellectual ability.
• Social Cognition Panel scales are utilized to evaluate the safety and/or efficacy of psilocybin.
• the social cognition panel scales comprise the pictorial empathy test (PET), reading the mind in the eyes test (RMET), social value orientation (SVO) test, the Toronto Empathy Questionnaire (TEQ), and the scale of social responsibility (SSR).
• the Pictorial Empathy Test is utilized to evaluate the effect of psilocybin on affective empathy.
• Reading the Mind in the Eyes Test is utilized to evaluate the safety and/or efficacy of psilocybin.
• the RMET has 36 items, in which subjects are presented with a photograph of the eyes region of the face and must choose 1 of 4 adjectives or phrases to describe the mental state of the person pictured. A definition handout is provided at the beginning of the task and a practice item precedes the first trial.
• the Social Value Orientation (SVO) test is utilized to evaluate the safety and/or efficacy of psilocybin.
• the SVO Slider Measure has 6 primary items with 9 secondary (and optional) items. All of the items have the same general form. Each item is a resource allocation choice over a well-defined continuum of joint payoffs.
• one or more of the subject’s Social Cognition Panel Scales Score improves by about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, about 1 10 %, 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 %
• the Toronto Empathy Questionnaire (TEQ) is utilized to evaluate the safety and/or efficacy of psilocybin.
• the TEQ represents empathy as a primarily emotional process.
• the TEQ has exhibited good internal consistency and high test-retest reliability.
• the TEQ is a brief, reliable and valid instrument for the assessment of empathy.
• TEQ score increases by about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, about 1 10 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment.
• the Scale of Social Responsibility is utilized to evaluate the safety and/or efficacy of psilocybin.
• the SSR measures perceptions regarding the importance of ethics and social responsibility.
• the Sheehan Suicidality Tracking Scale (SSTS) is utilized to evaluate the safety and/or efficacy of psilocybin.
• the SSTS is a 16-item scale that assesses the seriousness of suicidality phenomena on a Likert-type scale (0-4) ranging from“not at all” (0) to “extremely”.
• the SSTS assesses the frequency of key phenomena and the overall time spent in suicidality.
• the Mini International Neuropsychiatric Interview (MINI) (version 7.0.2) is utilized to evaluate the safety and efficacy of psilocybin.
• the MINI is a brief structured interview for the major Axis I psychiatric disorders in DSM-5 and International Classification of Diseases-10.
• the MINI is used to diagnose a subject with a disorder.
• the McLean Screening Instrument for Borderline Personality Disorder is utilized for evaluating the safety and/or efficacy of psilocybin.
• the MSIBPD is a useful screening tool for identifying the presence of DMS-IV borderline personality disorder.
• the Tellegen Absorption Scale is utilized for evaluating the safety and/or efficacy of psilocybin.
• the Tellegen Absorption Scale is a 34-item multidimensional measure that assesses imaginative involvement and the tendency to become mentally absorbed in everyday activities.
• the safety and/or efficacy of psilocybin is evaluated by physical examination.
• a physical examination includes, but is not limited to, an examination of the subject’s general appearance, including an examination of the skin, neck, eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities and musculoskeletal system.
• body weight and height of a subject are assessed.
• body mass index is used to assess the safety and/or efficacy of psilocybin.
• an electrocardiogram is utilized to evaluate the safety and/or efficacy of psilocybin.
• ECG electrocardiogram
• a Standard 12-lead ECG is obtained.
• vital signs of a subject are used to evaluate safety and/or efficacy of psilocybin.
• Vital signs include, but are not limited to, blood pressure (BP), respiratory rate, oral body temperature and pulse.
• blood pressure is taken after a subject has been sitting down for at least three minutes.
• clinical laboratory tests are utilized to evaluate the safety and/or efficacy of psilocybin.
• the clinical laboratory tests include blood samples and/or urine samples.
• hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count (with differential) and platelet count are measured to evaluate safety and/or efficacy of psilocybin.
• albumin alkaline phosphatase, alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect and total), calcium, chloride, creatine kinase, creatinine, y- glutamyl transferase, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, protein-total, sodium, blood urea nitrogen and/or uric acid are measured to evaluate the safety and/or efficacy of psilocybin.
• urine is tested for pregnancy and/or illicit drugs.
• the safety and/or efficacy of psilocybin are evaluated by measuring adverse events.
• Adverse events are classified as mild, moderate, or severe.
• a mild adverse event does not interfere in a significant mannerwith the subject’s normal level of functioning.
• a moderate adverse event produces some impairment of functioning, but is not hazardous to the subject’s health.
• a serious adverse event produces significant impairment of functioning or incapacitation and is a definite hazard to the subject’s health.
• Adverse events may include, for example, euphoric mood, dissociative disorder, hallucination, psychotic disorder, cognitive disorder, disturbances in attention, mood alterations, psychomotor skill impairments, inappropriate affects, overdoses, and intentional product misuse.
• serious adverse events include death, life- threatening adverse events, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, and congenital anomaly/birth defect in the offspring of a subject who received psilocybin.
• serious adverse events include intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
• the sign or symptom of depression is measured in a subject before, during, or after treatment with the methods described herein. In some embodiments, the sign or symptom of depression is measured according to a diary assessment, an assessment by clinician or caregiver, a clinical rating scale, an imaging test, or a blood of CSF test.
• the sign or symptom of depression in a subject is measured using a neuropsychological assessment or clinical rating scale.
• the neuropsychological assessment or clinical rating scale is the Hamilton Depression Rating Scale, the Clinical Global Impression (CGI) Scale, the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, the Inventory of Depressive Symptomatology (IDS), the Quick Inventory of Depressive Symptomatology (QIDS), the Columbia-Suicide Severity Rating Scale, or the Suicidal Ideation Attributes Scale.
• CGI Clinical Global Impression
• MADRS Montgomery-Asberg Depression Rating Scale
• BDI Beck Depression Inventory
• BDI Zung Self-Rating Depression Scale
• Raskin Depression Rating Scale the Inventory of Depressive Symptomatology
• IDS Inventory of Depressive Symptomatology
• QIDS Quick Inventory of Depressive Symptomatology
• Columbia-Suicide Severity Rating Scale
• the sign or symptom of depression in a subject is measured using the Hamilton Depression Rating (HAM-D) scale.
• the subject’s HAM-D score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Clinical Global Impression (CGI) scale.
• CGI scale is a 3-item scale that measures illness severity, global improvement or change, and therapeutic response.
• the CGI is rated on a 7-point scale, with the severity of illness measured using a range of responses from 1 (normal) through 7 (amongst the most severely ill subjects).
• the subject’s CGI score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Montgomery-Asberg Depression Rating Scale (MADRS).
• the subject’s MADRS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Beck Depression Inventory (BDI).
• BDI Beck Depression Inventory
• the subject’s BDI score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Zung Self-Rating Depression Scale.
• the Zung Self-Rating Depression Scale is a 20-item self- report questionnaire that measures the psychological and somatic symptoms associated with depression. The questionnaire takes about 10 minutes to complete, and items are framed in terms of positive and negative statements. Each item is scored on a Likert scale ranging from 1 to 4. A total score is derived by summing the individual item scores, and ranges from 20 to 80. Most people with depression score between 50 and 69, while a score of 70 and above indicates severe depression.
• the subject’s Zung Self-Rating Depression score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Raskin Depression Rating Scale.
• the subject after treatment with the methods described herein, decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Inventory of Depressive Symptomatology (IDS).
• IDS Inventory of Depressive Symptomatology
• the subject’s IDS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Quick Inventory of Depressive Symptomatology (QIDS).
• QIDS Quick Inventory of Depressive Symptomatology
• the subject’s QIDS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Young Mania Rating Scale (YMRS).
• YMRS Young Mania Rating Scale
• the YMRS is an 1 1 -item inventory that measures manic signs and symptoms.
• a total score is derived by summing the individual item scores; scores between 9-15 indicate mild mania, scores between 16-25 indicate moderate mania, and scores 26 or greater indicate severe mania.
• the subject’s YMRS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Columbia-Suicide Severity Rating Scale (C-SSRS).
• C-SSRS measures the severity of suicidal ideation and behavior.
• a subject is considered to have suicidal ideation and/or behavior if they answer“yes” to any of the 10 questions.
• the subject’s C-SSRS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using the Suicidal Ideation Attributes Scale (SIDAS).
• SIDAS measures the presence and severity of suicidal thoughts.
• the subject’s SIDAS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom in subjects with depression is measured using a Spielberger’s Trait and Anxiety Inventory, a Generalized Anxiety Disorder 7-Item Scale, a Warwick-Edinburgh Mental Wellbeing Scale, a Flourishing Scale, a Snaith Hamilton Anhedonia Pleasure Scale, a Life Orientation Test, a Meaning in Life Questionnaire, a Brief Resilience Scale, a Dysfunctional Attitudes Scale, a 44-item Big Five Inventory, a Peters 21-item Delusional Inventory, an Examination of Anomalous Self- Experience, a Ruminative Responses Scale, a White Bear Suppression Inventory, a Barrett Impulsivity Scale, a Brief Experiential Avoidance Questionnaire, a Modified Tellegen Absoprtion Questionnaire, a Scale to Assess Therapeutic Relationship, Credibility/Expectancy Questionnaire, a Connectedness to Nature Scale, a Political Perspective Questionnaire, a Social Connected
• the sign or symptom of depression measured using any of the assessments listed above decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression in a subject is measured using an imaging test before, during, or after treatment with the methods described herein.
• the imaging test is a CT scan.
• the imaging test is a functional MRI scan.
• the functional MRI scan measures the blood oxygen level-dependent (BOLD) response as an indicator of brain activity and/or functional connectivity.
• the BOLD response is measured in the subject at resting state, in response to emotional faces, or in response to music.
• the BOLD response in a region of the brain increases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the BOLD response in the amygdala increases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the BOLD response in a region of the brain decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the BOLD response in the amygdala decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
• the sign or symptom of depression is measured using a marker for depression in the blood or cerebral spinal fluid.
• the marker for depression is measured in the subject before, during, or after treatment with the methods or compositions described herein.
• the marker for depression is red blood cell folate, serum folate, vitamin B12, plasma homocysteine, serum methylfolate, and/or testing for one or more of brain-derived neurotrophic factor (BDNF) Val66Met, bone morphogenetic protein rs41271330, and/or 5-HTTLPR polymorphisms.
• BDNF brain-derived neurotrophic factor
• the marker for depression decreases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 1 10 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment.
• the marker for depression increases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 1 10 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Disruptive Mood Dysregulation Disorder, Major Depressive Disorder (MDD), Treatment-Resistant Depression, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication-Induced Depressive Disorder, Post-Partum depression, or Depressive Disorder due to Another Medical Condition, Separation Anxiety Disorder, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Panic Disorder, Panic Attack, Agoraphobia, Generalized Anxiety Disorder, Substance- Medication-Induced Anxiety Disorder, Anxiety Disorder Due to Another Medical Condition, Somatic Symptom Disorder, Illness Anxiety Disorder (hypochondriac), Conversion Disorder (Functional Neurological Symptom Disorder), Factitious Disorder,
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Neurocognitive Disorders due to Alzheimer's, Lewy Bodies, Traumatic Brain Injury, Prion Disease, HIV Infection, Parkinson's, or Huntington's; concussion; chronic traumatic encephalopathy (CTE); Language Disorder, Speech Sound Disorder (Phonological Disorder); Childhood-Onset Fluency Disorder (Stuttering); Social (Pragmatic) Communication Disorder; Tourette's Disorder; Persistent (Chronic) Motor or Vocal Tic Disorder; Amnestic Disorder Due to Known Physiological Condition; Transient Cerebral Ischemic Attack, Cerebral Infarction, Cerebral Bleeding, Progressive Supranuclear Ophthalmoplegia, or Retrograde Amnesia.
• diseases, disorders, or conditions wherein the subject has at least one of the following diseases, disorders, or
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions:Autism Spectrum Disorder, or Antisocial Personality Disorder.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the followings diseases, disorders, or conditions: Attention-Deficit/Hyperactivity Disorder, Other Specified Attention-Deficit/Hyperactivity Disorder; or Unspecified Attention-Deficit/Hyperactivity Disorder.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Schizotypal (Personality) Disorder, Delusional Disorder, Schizophrenia, or Schizoaffective Disorder
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Female sexual Interest/Arousal Disorder, Male Hypoactive Sexual Desire Disorder, or Excessive sexual Drive.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Bipolar I Disorder, Bipolar II Disorder, or Cyclothymic Disorder.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Insomnia Disorder, Hypersomnolence Disorder, Narcolepsy, or Primary Central Sleep Apnea.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Schizoid Personality Disorder, Schizotypal Personality Disorder, Antisocial Personality Disorder, Borderline Personality Disorder, or Obsessive-Compulsive Personality Disorder.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: age-related hearing loss or tinnitus.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Multiple Sclerosis, Cranial Nerve Disorder, Neuromyelitis Optica, Bell's Palsy, Guillain Barre Syndrome, Demyelinating Disease of Central Nervous System, or Chronic Inflammatory Demyelinating Polyneuritis.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject suffers from pain.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has at least one of the following diseases, disorders, or conditions: Myelopathy, Traumatic Brain Injury, Intellectual Disabilities, Mania, Neurodegeneration, Paraphilic disorders (e.g. Pedophilic Disorder), Suicidal Behavior Disorder, Nonsuicidal Self-Injury, Persistent Complex Bereavement Disorder, Gastrointestinal Tract Related Diseases, Epilepsy, Sickle Cell Disease, locked-in syndrome, restless leg syndrome, stroke, or Amyotrophic Lateral Sclerosis (ALS).
• diseases, disorders, or conditions including Myelopathy, Traumatic Brain Injury, Intellectual Disabilities, Mania, Neurodegeneration, Paraphilic disorders (e.g. Pedophilic Disorder), Suicidal Behavior Disorder, Nonsuicidal Self-Injury, Persistent Complex Bereavement Disorder, Gastrointestinal Tract Related Diseases, Epilepsy, Si
• a method of treating a subject comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein after administration the subject exhibits an improvement in cognition.
• the method of embodiment 14 wherein the improvement in cognition is an improvement in attention, episodic memory, working memory, spatial memory, social cognition, executive function, and/or cognitive flexibility.
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has Treatment Resistant Depression (TRD).
• TRD Treatment Resistant Depression
• a method of treating a subject in need thereof comprising administering to the subject a therapeutically-effective dose of psilocybin, wherein the subject has Major Depressive Disorder (MDD).
• MDD Major Depressive Disorder
• the dosage form comprises 5 mg of crystalline psilocybin in the form of Polymorph A, 12.5 mg of SMCC 50, 79.5 mg of SMCC 90, 1 mg sodium starch glycolate, 1 mg colloidal silicon dioxide and 1 mg sodium stearyl fumarate.
• the dosage form comprises 1 mg of crystalline psilocybin in the form of Polymorph A, 20.5 mg of SMCC 50, 75.5 mg of SMCC 90, 1 mg sodium starch glycolate, 1 mg colloidal silicon dioxide, and 1 mg sodium stearyl fumarate.
• a method of treating depression in a subject in need thereof comprising administering an effective amount of psilocybin or an active metabolite thereof to the subject.
• the clinical depression rating scale is a Quick Inventory of Depressive Symptomatology (QIDS)-16 scale, a QIDS-16 daily scale, a Hamilton Depression Rating scale, a Beck Depression Inventory scale, a Mongomery-Asberg Depression Rating Scale, a Clinical Global Impression Scale, a Zung Self-Rating Depression Scale, a Raskin Depression Rating Scale, and/or Young Mania Rating Scale.
• QIDS Quick Inventory of Depressive Symptomatology
• the at least one additional therapeutic is selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic antagonist.
• microcrystalline cellulose is the first variant having a particle size from about 45 to 80 microns and about 70% or more of the microcrystalline cellulose is the second variant having a particle size of about 90 to 150 microns.
• the dosage form comprises 5 mg of crystalline psilocybin in the form of Polymorph A, 12.5 mg of SMCC 50, 79.5 mg of SMCC 90, 1 mg sodium starch glycolate, 1 mg colloidal silicon dioxide and 1 mg sodium stearyl fumarate.
• the dosage form comprises 1 mg of crystalline psilocybin in the form of Polymorph A, 20.5 mg of SMCC 50, 75.5 mg of SMCC 90, 1 mg sodium starch glycolate, 1 mg colloidal silicon dioxide, and 1 mg sodium stearyl fumarate.
• each dose of psilocybin administered is in the range of about 0.1 mg to about 100 mg.
• a method of reducing anxiety in a subject undergoing treatment with psilocybin comprising administering to the subject:
• MDD Disruptive Mood Dysregulation Disorder
• benzodiazepine is selected from the group consisting of adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam .camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam, flunitrazolam, fluraz
• kits for treating a subject in need thereof comprising:
• a first pharmaceutical composition comprising psilocybin, or a precursor or derivative thereof, and
• a second pharmaceutical composition comprising one or more benzodiazepines.
• kit comprising instructions for administering the first and the second pharmaceutical composition to the subject.
• a method of reducing the negative side effects associated with a traumatic psychedelic experience in a subject undergoing treatment with psilocybin comprising administering to the subject:
• MDD Disruptive Mood Dysregulation Disorder
• the 5-HT 2A specific antagonist is trazodone, mirtazapine, metergoline, ketanserin, ritanserin, nefazodone, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl- 4-aryl-tetrahydro-pyrimido-azepine, 9-aminomethyl-9, 10-dihydroanthracene (AMDA), haloperidol, chlorpromazine, hydroxyzine (atarax), 5-MeO-NBpBrT, niaprazine, altanserin, aripiprazole, etoperidone, setoperone, chlorprothixene, cinaserin, adatanserin, medi
• kits for treating a subject in need thereof comprising:
• a first pharmaceutical composition comprising psilocybin, or a precursor or derivative thereof, and
• a second pharmaceutical composition comprising one or more 5-HT 2A specific antagonists and/or inverse agonists.
• kit of embodiment 37, wherein the kit further comprises instructions for administering the first and the second pharmaceutical composition to the subject.
• a method of reducing the negative side effects associated with a traumatic psychedelic experience in a subject undergoing treatment with psilocybin comprising administering to the subject:
• Crystalline psilocybin Polymorph A or Polymorph A’ characterised by one or more of: a) peaks in an XRPD diffractogram at 1 1.5, 12.0 and 14.5 °2Q ⁇ 0.1 °2Q; and/ or b) an endothermic event in a DSC thermogram having a first onset temperature of between 145°C and 155°C and a second onset temperature of between 210°C and 220°C for use in the treatment of: Alzheimer’s, Autism spectrum disorder, Attention deficit hyperactivity disorder (ADHD), Downs, Epilepsy (though not seizures), Multiple Sclerosis, Parkinson’s disease, Schizophrenia, Huntington’s, Stroke and other cerebrovascular conditions, Traumatic brain injury, Major depressive disorder, chronic cluster headaches, antisocial personality disorder and psychopathy.
• a method for the treatment of Alzheimer’s, Autism spectrum disorder, Attention deficit hyperactivity disorder (ADHD), Downs, Epilepsy (though not seizures), Multiple Sclerosis, Parkinson’s disease, Schizophrenia, Huntington’s, Stroke and other cerebrovascular conditions, Traumatic brain injury, Major depressive disorder, chronic cluster headaches, antisocial personality disorder and psychopathy comprising administering to a subject in need thereof an effective amount of crystalline psilocybin Polymorph A or Polymorph A’, characterised by one or more of
• Crystalline psilocybin Polymorph A or Polymorph A characterised by one or more of:
• MOL Method of Levels
• MOL Method of Levels
• transdiagnostic therapy is a Method of Levels (MOL) therapy.
• Method of Levels (MOL) therapy comprises Self-directed enquiry and Experiential processing.
• a digital biomarker as a diagnostic and / or prognostic tool for patient management pre, during and/ or post treatment of a central nervous system disorder with psilocybin wherein the digital biomarker is one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and emotional valence.
• Gestures used tapes, swipes, or other
• Gyroscope derived information e.g. orientation of the phone; Acceleration of the phone;
• a method of assessing a subject pre, during and/ or post treatment of a central nervous system disorder to determine whether to provide a psilocybin treatment or a further psilocybin treatment comprising monitoring one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and emotional valence, and determining the treatment based on an outcome.
• a method as claimed in claim 12 further comprising administering psilocybin for a first or a subsequent time.
• a pharmaceutic formulation comprising psilocybin, one or more fillers, and one or more disintegrants.
• composition of embodiment 3 comprising silicified microcrystalline cellulose with a particle size range of from about 45 to 80 microns (SMCC 50), silicified microcrystalline cellulose with a particle size range of from about 90 to 150 microns (SMCC 90), or mixtures thereof.
• SMCC 50 silicified microcrystalline cellulose with a particle size range of from about 45 to 80 microns
• SMCC 90 silicified microcrystalline cellulose with a particle size range of from about 90 to 150 microns
• composition of embodiment 17 comprising about 1 mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, or 50mg psilocybin.
• Ex. 1 D was used as a base formulation for the optimization of an exemplary higher dose tablet (5 mg). Tablets tested for dissolution from all five examples were found be unaffected by change in the fillers ratio and quantity of glidant. Hence, it was decided to study the level of disintegrate in the final formulation. Two batches of Psilocybin tablet 5 mg were manufactured using high (3% w/w) and low (1 % w/w) levels of a disintegrant in the formulation composition. The additional studies were conducted to justify the amount of disintegrant in the formulation. These studies were performed on the higher strength product (5 mg).
• Psilocybin tablet formulations comprising 1 mg and 5 mg of API are presented in Table 1 C.
• a subject is counseled as to the expected effects of psilocybin by a professional who is trained to administer psilocybin therapy.
• One or more tablets or capsules comprising psilocybin are administered to the subject, in an environment where the subject is made to feel safe and comfortable.
• the total dose of psilocybin administered to the subject is between about 1 mg to about 25 mg.
• the subject is supervised by the professional during administration of the psilocybin, and for a period of time thereafter (e.g. , from about 4 hours to about 12 hours) until the psychoactive effects of the psilocybin have worn off.
• the subject may receive psychological support during administration of the psilocybin, and for a period of time thereafter (e.g. , from about 4 hours to about 12 hours).
• Each subject was assigned 1 treatment bottle containing 5 capsules packaged in a double blind fashion, depending on the randomized treatment arm, the bottle contained one of the following:
• Psilocybin 10 mg 2 c 5-mg oral psilocybin capsules plus 3 c placebo capsules
• Psilocybin 25 mg 5 c 5-mg oral psilocybin capsules
• Each 5-mg oral psilocybin capsules comprised 5 mg crystalline psilocybin in the form or Polymorph A, 12.5 mg of SMCC 50, 79.5 mg of SMCC 90, 1 mg sodium starch glycolate, 1 mg colloidal silicon dioxide, and 1 mg sodium stearyl fumarate
• the dose was swallowed with at least a full glass of water.
• SWM Spatial Working Memory
• RVP Rapid Visual Information Processing
• PAL Paired Associates Learning
• IED Intra-Extra Dimensional Set Shift
• OTS Touch Stockings
• NEO-Five Factor Inventory (NEO-FFI) (performed at Visit 2, Visit 5, and Visit 7).
• SCL-90 Symptom Checklist-90 item (SCL-90) (performed at Visit 2, Visit 5, and Visit 7).
• LCI Life Changes Inventory
• PTT Pictorial Empathy Test
• RMET Reading the Mind in the Eyes Test
• SSR Scale of Social Responsibility
• MINI Mini International Neuropsychiatric Interview
• Electrocardiogram (performed at Visit 1 , Visit 2, Visit 3 and Visit 4).
• hemoglobin hematocrit
• red blood cell count mean corpuscular hemoglobin
• mean corpuscular volume mean corpuscular hemoglobin concentration
• white blood cell count with differential
• Urine samples were obtained at Screening (Visit 1 ) and Baseline (Visit 2) for the following: i. Urine Drug Screen: for illicit drugs or drugs of abuse at Screening (Visit 1 ) and Baseline (Visit 2). Results of a positive drug screen will be reviewed by the study clinician for pattern of use.
• Urine Pregnancy Test a dipstick test in females of childbearing potential at Screening (Visit 1) and Baseline (Visit 2).
• i. Mild The AE does not interfere in a significant manner with the subject’s normal level of functioning.
• ii. Moderate The AE produces some impairment of functioning, but is not hazardous to the subject’s health.
• (b) Life-threatening An AE is life-threatening if the subject was at immediate risk of death from the event as it occurred; i.e., it did not include a reaction that if it had occurred in a more serious form might have caused death. For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life threatening even though drug- induced hepatitis can be fatal.
• Visit 1 Eligibility Screening (Days -56 to Day -2): All subjects were screened for eligibility in the 8 weeks (i.e., Day -56 to Day -2) prior to Baseline: including medical and psychiatric history, the Mini International Neuropsychiatric Interview (MINI, English version, 7.0.2), McLean Screening Instrument for Borderline Personality Disorder (MSIBPD), SSTS, physical examination, vital signs, body weight, height, body mass index (BMI), 12-lead electrocardiogram (ECG), clinical laboratory tests, urine drug screen, urine pregnancy test, documentation of contraceptive method, review of prior and concomitant medications and recording of AEs.
• MINI Mini International Neuropsychiatric Interview
• MSIBPD McLean Screening Instrument for Borderline Personality Disorder
• SSTS Supplemental Component Intercardiogram
• ECG electrocardiogram
• Visit 2 Baseline Assessments (Day -1): Subjects completed the Baseline assessments (Day -1 [V2]) 1 day prior to study drug administration including: Tellegen Absorption Scale (TAS), NEO-FFI, SCL-90, PANAS, PET, RMET, SVO, TEQ, SSR, SWM, RVP, SSTS, Paired Associates Learning (PAL), vital signs, urine drug screen, review of prior and concomitant medications and recording of AEs.
• TAS Tellegen Absorption Scale
• NEO-FFI NEO-FFI
• SCL-90 Baseline assessments
• PANAS PET
• RMET SVO
• TEQ TEQ
• SSR SWM
• RVP RVP
• SSTS Paired Associates Learning
• vital signs vital signs
• urine drug screen review of prior and concomitant medications and recording of AEs.
• Visit 3 Drug Administration (Day 0): The subject was asked to eat a light breakfast at least two hours prior to coming to the clinic for study drug administration. On Day 0 (V3), the subject underwent the SSTS, had vital signs obtained, medications reviewed, AEs recorded and eligibility reviewed prior to being randomized to study drug. The study drug was administered to up to six subjects simultaneously in individual beds separated by a curtain. The subject was invited to put on eyeshades and headphones, lie down and listen to calming music for the rest of the session (six hours). The subject was supported 1 : 1 with a chaperone and supervised by the study psychiatrist and lead therapist.
• the effects of psilocybin usually started about 20 to 30 min after administration, becoming most intense in the first 90 to 120 min and gradually subsiding in about 5 to 6 hours.
• the subjects were asked to remain in the room for the duration of the session regardless of the intensity of the effects, preferably lying down and mostly silent unless they have a concern or need to communicate a discomfort or seek reassurance from the therapist, or use the restroom.
• a light meal and fruit was available for the subject after the session.
• PANAS and 5D-ASC All subjects were assessed for safety and asked to complete the following assessments: PANAS and 5D-ASC. Medications used, if any, during study drug administration session, and adverse events were recorded.
• the subjects also discussed their psilocybin experience with their therapist.
• the subject was discharged 6 to 8 hours post dose when, in the opinion of the investigator, the acute effects of psilocybin were resolved. After the acute effects of study drug administration subsided, subjects returned home accompanied by a family member, friend, or chaperone. The therapists checked with the subjects by phone at the end of the day to ensure that the subject arrived home safely.
• Visit 4 Safety Assessments (Day 1 ): Subjects returned to the clinic the next morning (Day 1 [V4]) for safety assessments, including but not limited to: SSTS, vital signs, clinical laboratory tests, review of concomitant medications and AEs and a one-on-one discussion about the subject’s experience with the subject’s assigned therapist.
• Visit 5 (V5): Follow up visit (Day 7 or at Early Termination): Psychometric assessments were completed remotely on Day 7 (V5) or at Early Termination (ET): NEO-FFI, SCL-90, LCI, PET, RMET, SVO, TEQ, SSR, SSTS, SWM, RVP, PAL, review of concomitant medication and recording of AEs. Additionally, at Day 7 (V5) the ERT, IED, OTS, Verbal Fluency and Digit Span Forward tests were conducted.
• Visit 6 Follow up visit (Day 28): The SSTS, SWM, RVP, PAL, review of concomitant medication and recording of AEs were obtained at Day 28 (V6).
• Visit 7 Follow up Visit (Day 84): The NEO-FFI, SCL-90, LCI, PET, RMET, SVO, TEQ and SSR was obtained remotely at Day 84 (V7). If the subject discontinued the study early, this visit was performed early.
• Table 2A summarizes the assessments and procedures that were performed at each visit.
• This session may be done remotely by telephone or in the clinic.
• a preparatory session will be conducted in a group session at Baseline (Day -1 , V2) and prior to dosing on Day 0 (V3).
• An individual session will also be conducted at Baseline (Day -1 , V2).
• Haematology haemoglobin, haematocrit, red blood cell count, mean corpuscular haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, white blood cell count (with differential) and platelet count.

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