Treatment of depression and other various disorders with psilocybin

Abstract

This disclosure provides a method for treating an individual in need of therapy, comprising administering a therapeutically effective dose of serocepin to the individual. The method described herein can be used to treat a variety of diseases, disorders, and conditions. For example, this method can be used to treat depression, neurocognitive disorders, autism spectrum disorders, and / or attention deficit / hyperactivity disorder.

Description

[Technical Field] This invention relates to the treatment of depression and other various disorders with psilocybin. Related Applications: This application claims all of the following U.S. application numbers filed on April 17, 2019: 62 / 835,449; 62 / 835,450; 62 / 835,458; 62 / 835,460; 62 / 835,464; 62 / 835,465; 62 / 835,472; 62 / 835,474; 62 / 835,476; 62 / 835,477; 62 / 835,478; 62 / 835,479; 62 / 835,479. Priority claims to U.S. Application No. 5,480; 62 / 835,481; 62 / 835,482; 62 / 835,484; and 62 / 835,485, U.S. Application No. 62 / 893,110 filed August 28, 2019, U.S. Application No. 62 / 893,611 filed August 29, 2019, and U.S. Application No. 62 / 946,159 filed December 10, 2019, each of which is incorporated herein by reference in its entirety. [Previous Technology] Depression is one of the most common mental illnesses, affecting more than 264 million people worldwide. It is characterized by depressed mood, a significant decrease in interest in activities, and a marked reduction in feelings of joy. Other symptoms include significant weight loss or gain, significant decrease or increase in appetite, insomnia or somnolence, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, impaired or indecisive thinking or concentration, recurrent thoughts of death, suicidal ideation, or suicide attempts. Current treatment for depression typically consists of psychotherapy combined with one or more daily medications that regulate neurotransmitters such as dopamine, serotonin, and norepinephrine. These medications often take weeks to months to achieve their full effect, and during this time, individuals continue to suffer from their symptoms, are at risk of self-harm, and experience impairment in their personal and professional lives. There remains a need for effective treatments for depression that provide a rapid onset of antidepressant effects within hours or days and have a long-lasting effect. [Summary of the Invention] Psilocybin offers numerous clinical benefits, such as benefits to neuroplasticity and cognitive function (measured using, for example, the Cambridge Neuropsychological Test Automated Battery (CANTAB) test), and improves, for example, working memory and executive function, sustained attention, and episodic memory. These benefits influence the use of psilocybin in the treatment of various disorders, dysregulations, or conditions (both psychiatric and neurological). In some embodiments, this disclosure provides a method for treating depression in an individual in need of treatment, comprising administering an effective amount of psilocybin or its active metabolite to the individual. In some embodiments, the individual suffers from major depressive disorder, atypical depression, bipolar disorder, catatonic depression, medically induced depression, postpartum depression, premenstrual mood disorder, or seasonal affective disorder. In some embodiments, the individual suffers from treatment-resistant depression. In some embodiments, the method of this disclosure alleviates at least one sign or symptom of depression. In some implementation scenarios, signs or symptoms of depression include depressed mood, decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or somnolence, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, impaired or indecisive concentration, and suicidal ideation or behavior. In some implementation scenarios, signs or symptoms of depression are measured based on diary assessments, assessments by clinicians or caregivers, clinical rating scales, or functional MRI. In some implementation scenarios, functional MRI can measure the individual's blood oxygen level-dependent (BOLD) response. In some implementation scenarios, the symptoms or signs of depression are measured using clinical depression rating scales, including the Quick Inventory of Depressive Symptoms (QIDS)-16, the QIDS-16 Daily Rating Scale, the Hamilton Depression Rating Scale, the Beck Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression Scale, and the Zung Self-Rating Depression Scale.The scales used include the Depression Scale, the Raskin Depression Rating Scale, and / or the Young Mania Rating Scale. In some implementations, symptoms or signs of depression are measured using the following measures: Spielberger's Trait and Anxiety Inventory, Generalized Anxiety Disorder 7-Item Scale, Warwick-Edinburgh Mental Well-being Scale, Flourishing Scale, Snaith Hamilton Anhedonia Pleasure Scale, Life Orientation Test, Meaning in Life Questionnaire, Brief Resilience Scale, Dysfunctional Attitudes Scale, 44-item Big Five Inventory, Peters 21-item Delusional Inventory, and Examination of Anomalous Self-Experiences. Self-Experience Scale, Ruminative Responses Scale, White Bear Suppression Inventory, Barrett Impulsivity Scale, Brief Experiential Avoidance Questionnaire, Modified Tellegen Absorption Questionnaire, Therapeutic Relevance Assessment Scale, Credibility / Expectancy Questionnaire, Connectedness to Nature Scale, Political Perspective Questionnaire, Social Connectedness ScaleScales including: Bech-Rafaelsen Mania Scale, Revised Santa Clara Brief Compassion Scale, Gratitude Questionnaire, Short Suggestibility Scale, Rosenberg Self-Esteem Scale, Universality Subscale of the Spiritual Transcendence Scale, Oxford Questionnaire on the Emotional Side-effects of Antidepressants, Lauks Emotional Intensity Scale, Sexual Dysfunction Questionnaire, Brief Index of Sexual Functioning for Women, Sexual Perception Questionnaire, Barnes Akathisia Rating Scale, Work Productivity and Activity Impairment Questionnaire, Work and Social Adaptation Scale, Connectedness Questionnaire. Questionnaire, Standard Assessment of Personality, Positive and Negative Syndrome Scale, Mastery Insight Scale, Self-Reflection and Insight Scale, Psychological Insight Scale, Metaphysical Beliefs Questionnaire, Spiritual Bypassing Scale, Adverse Childhood Experience Questionnaire, Therapeutic Music Experience Questionnaire, Setting Questionnaire, Absorption in Music Scale, Psychedelic Predictor Scale.The following scales are used: Predictor Scale, Surrender Scale, EuroQOL-5 Dimension-3 Level Scale, Columbia-Suicide Severity Rating Scale, Suicidal Ideation Attributes Scale, or any combination thereof. In some implementation scenarios, at least one symptom of depression was relieved within 24 hours of serozebin administration. In some implementation scenarios, at least one symptom of depression was relieved within one week of serozebin administration. In some implementation scenarios, at least one symptom of depression was relieved for at least one month after serozebin administration. In some implementation scenarios, at least one symptom of depression was relieved for at least three months after serozebin administration. In some implementation scenarios, at least one symptom of depression was relieved for at least 12 months after serozebin administration. In some implementation scenarios, no other treatment to reduce the symptom of depression was given to the individual after serozebin administration. In some embodiments, the method disclosed herein further includes administering at least one additional therapeutic agent to the individual to alleviate symptoms or signs of depression. In some embodiments, the at least one additional therapeutic agent is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a norepinephrine antagonist. In some embodiments, the at least one additional therapeutic agent is administered before, on the same day as, or after serozidine administration. In some embodiments, the individual with depression has additional comorbidities or disorders. In some embodiments, these additional comorbidities or disorders are anxiety disorders, obsessive-compulsive disorder, alcoholism, personality disorders, cardiovascular disease, neurological disorders, or cancer. In some implementation scenarios, the individual suffers from dementia, Alzheimer's disease, or Parkinson's disease. In some implementation scenarios, using the methods disclosed herein to alleviate at least one symptom or sign of depression in an individual may prevent one or more comorbidities or disorders. In some implementation scenarios, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of seroconvertin or its metabolites to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: Disruptive Mood Dysregulation.Disorders, major depressive disorder (MDD), treatment-resistant depression, persistent depression (mild depression), premenstrual mood disorder, substance / drug-induced depression, postpartum depression, or depression due to other medical conditions, separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance- and drug-induced anxiety disorder, anxiety disorder due to other medical conditions, somatic symptom disorder, illness anxiety disorder (hypochondriac), conversion disorder (functional neurotic symptom disorder), human error disorder, post-traumatic stress disorder (PTSD), adjustment disorder, acute distress disorder. Disorders, including obsessive-compulsive disorder, body eccentricity, hoarding disorder, trichotillomania (hair pulling disorder), skin picking disorder (skin scratching disorder), substance / drug-induced obsessive-compulsive disorder and related disorders, obsessive-compulsive disorder and related disorders caused by other medical conditions, substance-related disorders, alcohol-related disorders, cannabis-related disorders, psychedelic-related disorders, inhaler-related disorders, cocaine-related disorders, opioid-related disorders, sedative-, hypnotic-, or anxiety-related disorders, stimulant-related disorders, tobacco-related disorders, non-substance-related disorders (gambling or gaming disorders), migraines, cluster headaches (including chronic cluster headaches), periodic vomiting, tension-type headaches, dysphasia, pica, anorexia nervosa, bulimia nervosa, bulimia, oppositional defiance disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathology, arsonism, or kleptomania. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of seroxiben to the individual, wherein the individual suffers from at least one of the following diseases, disorders, or conditions: Alzheimer's disease, Lewy body syndrome, traumatic brain injury, Prion's disease, HIV infection, Parkinson's disease, or neurocognitive impairment due to Huntington's disease; concussion; chronic traumatic encephalopathy (CTE); language disorder; speech-related speech disorders (phonological disorders), childhood-onset fluency disorders.Disorders include stuttering, social (practical) communication impairment; Tourette syndrome; persistent (chronic) motor or vocal tic disorders; amnesia due to a known physiological condition (possibly in individuals receiving antielectroconvulsive therapy (ECT); transient ischemic attack, cerebral infarction, cerebral hemorrhage, progressive supranuclear ophthalmoplegia, or retrograde amnesia. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of seroprepine to the individual, wherein the individual suffers from at least one of the following disorders, anxieties, or conditions: autism spectrum disorder, or antisocial personality disorder. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serocillin to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: attention deficit hyperactivity disorder (ADHD), other specific ADHD, or nonspecific ADHD. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serocillin to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: schizophrenia (personality) disorder, paranoia, schizophrenia, or affective schizophrenia. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serocillin to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: insomnia, hypersomnia, narcolepsy, or primary central sleep apnea. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serozepine to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: social personality disorder, schizophrenia, antisocial personality disorder, borderline personality disorder, or obsessive-compulsive personality disorder. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serozepine to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: female sexual interest / excitement disorder, male hypoactive sexual desire disorder, or hyperactive sexual desire disorder. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serozepine to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: bipolar I, bipolar II, or cyclothymic mood disorder.In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serocillin to the individual, wherein the individual suffers from at least one of the following diseases, disorders, or conditions: age-related hearing loss or tinnitus. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serocillin to the individual, wherein the individual suffers from at least one of the following diseases, disorders, or conditions: multiple sclerosis, cranial nerve disorders, neuromyelitis optica, Bell's palsy, Guillain-Barré syndrome, demyelination of the central nervous system, or chronic inflammatory demyelination polyneuritis. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serocepin to the individual, wherein the individual suffers from pain, such as phantom limb pain, chronic pain, or pain associated with other diseases or conditions. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serocillin to the individual, wherein the individual suffers from at least one of the following disorders, disorders, or conditions: myelopathy, traumatic brain injury, intellectual disability, mania, neurodegenerative disease, paraphilia (e.g., pedophilia), suicidal behavior disorder, non-suicidal self-harm, persistent complex bereavement disorder, gastrointestinal-related disorder (e.g., irritable bowel syndrome (IBS)), epilepsy, sickle cell anemia, locked-in syndrome, restless leg syndrome, stroke (such as ischemic or hemorrhagic stroke), or amyotrophic lateral sclerosis (ALS). In some embodiments, this disclosure provides a method for treating an individual, comprising administering a therapeutically effective dose of serocillin to the individual, wherein, after administration, the individual exhibits cognitive improvement. In some embodiments, cognitive improvements include improvements in attention, episodic memory, working memory, spatial memory, social cognition, executive function, and / or cognitive resilience. In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serozepine to the individual, wherein the individual suffers from treatment-resistant depression (TRD). In some embodiments, this disclosure provides a method for treating an individual in need, comprising administering a therapeutically effective dose of serozepine to the individual, wherein the individual suffers from major depressive disorder (MDD).In some embodiments, cilostazine is administered as a dosage form of high-purity crystalline cilostazine containing a therapeutically effective amount of polymorph A, wherein the crystalline cilostazine contains at least 90% by weight of polymorph A. In some embodiments, the crystalline cilostazine contains at least 95% by weight of polymorph A. In some embodiments, the crystalline cilostazine has a chemical purity greater than 97% as measured by high-performance liquid chromatography (HPLC) and is free of more than 1% of single impurities. In some embodiments, cilostazine is administered as a dosage form of high-purity crystalline cilostazine containing a therapeutically effective amount of polymorph A, wherein the crystalline cilostazine has a chemical purity greater than 97% as measured by HPLC and is free of more than 1% of single impurities. In some embodiments, cilostabene is administered as a dosage form containing a therapeutically effective amount of high-purity crystalline cilostabene in the form of polymorph A, wherein the crystalline cilostabene has a chemical purity greater than 97% as measured by HPLC and is free of single impurities greater than 1%, and further comprises a mixture of two silicated microcrystalline cellulose variants, wherein the first variant has a particle size of about 45 to 80 micrometers and the second variant has a particle size of about 90 to 150 micrometers. In some embodiments, 30% or less of the microcrystalline cellulose is the first variant with a particle size of about 45 to 80 micrometers, and about 70% or more of the microcrystalline cellulose is the second variant with a particle size of about 90 to 150 micrometers. In some embodiments, cilostabene is administered in an oral dosage form. In some embodiments, cilostabene is administered in capsule form. In some embodiments, cilostabene is administered in tablet form. In some implementation scenarios, at least one dose of selozepine is administered to the individual. In some implementation scenarios, the dose of selozepine ranges from about 0.1 mg to about 100 mg. In some implementation scenarios, the dose of selozepine is about 25 mg. In some implementation scenarios, the individual attends at least one supportive therapy session before the administration of selozepine. In some implementation scenarios, the individual attends at least one supportive therapy session after the administration of selozepine. In some implementation scenarios, the therapist provides psychological support to the individual for approximately 4 to 8 hours after the administration of selozepine.

Implementation Method

Claims

1. The use of a crystalline psilocybin for the manufacture of a medicament for treating depression in individuals in need, wherein the crystalline psilocybin is characterized by XRPD peaks at 11.5±0.1, 12.0±0.1, 14.5±0.1, 17.5±0.1 and 19.7±0.1 °2θ, wherein the crystalline psilocybin has a chemical purity greater than 97% as measured by HPLC.

2. As requested in item 1, wherein the individual suffers from major depressive disorder, atypical depression, bipolar disorder, catatonic depression, medically induced depression, postpartum depression, premenstrual mood disorder, or seasonal affective disorder.

3. As requested in item 2, in which the individual suffers from major depressive disorder.

4. As requested in item 2, in which the individual suffers from bipolar disorder.

5. As requested in item 4, in which the individual suffers from bipolar disorder type I.

6. As requested in item 4, in which the individual suffers from bipolar disorder type II.

7. As requested in item 1, the depression is intractable.

8. For the purposes of claim 1, at least one symptom or symptom of depression is alleviated.

9. As requested in item 8, wherein the symptoms or signs of depression include depressed mood, decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or somnolence, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, impaired or indecisive ability to concentrate, suicidal ideation or behavior.

10. As requested in item 9, wherein the symptoms or signs of depression are measured according to a clinical depression rating scale, such clinical depression rating scale being the Quick Inventory of Depressive Symptoms (QIDS)-16, QIDS-16 Daily Rating Scale, Hamilton Depression Rating Scale, Beck Depression Rating Scale, Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression Scale, Zung Self-Rating Depression Scale, Raskin Depression Rating Scale, and / or Young Mania Rating Scale.

11. As requested in item 9, the symptoms or signs of depression are measured using the following measures: Spielberger's Trait and Anxiety Inventory, Generalized Anxiety Disorder 7-Item Scale, Warwick-Edinburgh Mental Wellbeing Scale, Flourishing Scale, Snaith Hamilton Anhedonia Pleasure Scale, Life Orientation Test, Meaning in Life Questionnaire, Brief Resilience Scale, Dysfunctional Attitudes Scale, 44-item Big Five Inventory, Peters 21-item Delusional Inventory, Examination of Anomalous Self-Experience. The following scales are listed: Self-Experience, Ruminative Responses Scale, White Bear Suppression Inventory, Barrett Impulsivity Scale, Brief Experiential Avoidance Questionnaire, Modified Tellegen Absorption Questionnaire, Therapeutic Relevance Assessment Scale, Credibility / Expectancy Questionnaire, Connectedness to Nature Scale, Political Perspective Questionnaire, Social Connectedness Scale, Bech-Rafaelsen Mania Scale, and Revised Santa Clara Brief Compassion Scale.The following questionnaires are available: Gratitude Questionnaire, Short Suggestibility Scale, Rosenberg Self-Esteem Scale, Universality Subscale of the Spiritual Transcendence Scale, Oxford Questionnaire on the Emotional Side-effects of Antidepressants, Lauks Emotional Intensity Scale, Sexual Dysfunction Questionnaire, Brief Index of Sexual Functioning for Women, Sexual Perception Questionnaire, Barnes Akathisia Rating Scale, Work Productivity and Activity Impairment Questionnaire, Work and Social Adaptation Scale, Connectedness Questionnaire, Standard Assessment of Personality, Positive and Negative Syndrome Scale, and Mastery Insight Scale. Scales including: Self-Reflection and Insight Power Scale, Psychological Insight Power Scale, Metaphysical Beliefs Questionnaire, Spiritual Bypassing Scale, Adverse Childhood Experience Questionnaire, Therapeutic Music Experience Questionnaire, Setting Questionnaire, Absorption in Music Scale, Psychedelic Predictor Scale, Surrender Scale, and EuroQOL-5 Dimension-3 Level Scale.The Columbia Suicide Severity Rating Scale, the Suicidal Ideation Attributes Scale, or any combination thereof.

12. As requested in item 9, wherein the symptoms or signs of depression are measured by functional MRI, which measures the blood oxygen level-dependent (BOLD) response of the amygdala.

13. As requested in claim 12, wherein the BOLD response is measured in a static state to reflect emotional facial expressions and / or music as a pleasurable stimulus.

14. For any of the uses described in claims 1 to 13, at least one of the symptoms or signs of depression is relieved within 24 hours after administration of the crystalline serocepin.

15. For the purposes of any of claims 1 to 13, at least one symptom of depression is relieved within one week after administration of the crystalline serocepin.

16. For the purposes of any of claims 1 to 13, at least one symptom of depression is relieved for at least one month after administration of the crystalline serocepin.

17. For the purposes of any of claims 1 to 13, at least one symptom of depression is relieved for at least 3 months after administration of the crystalline serocepin.

18. For the purposes of any of claims 1 to 13, at least one symptom of depression is relieved for at least 12 months after administration of the crystalline serocepin.

19. As requested in claim 1, wherein the crystalline serocepin has no single impurity greater than 1%.

20. As claimed in claim 1, wherein the crystalline serocepin is administered in an oral dosage form.

21. As claimed in claim 20, wherein the oral dosage form is a capsule.

22. As claimed in claim 20, wherein the oral dosage form is a tablet.

23. As claimed in claim 1, wherein the amount of the crystalline serocepin is in the range of 0.1 mg to 100 mg.

24. As claimed in claim 23, wherein the amount of the crystalline serocepin is 1 mg.

25. As claimed in claim 23, wherein the amount of the crystalline serocepin is 10 mg.

26. As claimed in claim 23, wherein the amount of the crystalline serocepin is 25 mg.

27. As claimed in claim 1, wherein the crystalline selosine is administered by one of the following routes: oral, intravenous, intramuscular, parenteral, local, inhalation, rectal, transmucosal, intranasal, buccal, vaginal, intrathecal, intraocular, transdermal, intrauterine, intralymphatic, or by direct tissue or organ injection.

28. As claimed in claim 27, wherein the crystalline serocepin is administered orally.

29. As requested in item 1, wherein the individual attends at least one psychological support session prior to receiving the crystallized seroside.

30. As requested in item 1, wherein the individual participates in at least one psychological support session after the crystallized seroside is administered.

31. As claimed in claim 1, wherein another characteristic of the crystalline seroxipin is at least one peak selected from the group consisting of 20.4±0.1, 22.2±0.1, 24.3±0.1 and 25.7±0.1 °2θ.

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