Pharmaceutical compositions of psilocin and uses thereof

Abstract

The invention features methods for utilizing psilocin in the treatment of a wide array of clinical applications, including psychiatric conditions, pain disorders, and neurological conditions. Provided are specific therapeutically effective doses of psilocin which are well tolerated by patients, sufficient to induce mystical experiences and which are short lasting.

Description

[0001] PHARMACEUTICAL COMPOSITIONS OF PSILOCIN AND USES THEREOF

[0002] BACKGROUND

[0003] Significant interest in the therapeutic application of psilocin has developed, based upon evidence of possible therapeutic effects in a wide array of clinical applications, including psychiatric conditions, pain disorders, and neurological conditions. However, there remains a need in the art for the provision of specific therapeutically effective doses of psilocin which are well tolerated by patients, sufficient to induce mystical experiences and which are short lasting.

[0004] SUMMARY OF THE INVENTION

[0005] The invention features a method of treating a disease or condition in a subject in need thereof, the method including administering to the subject a pharmaceutical composition including: (i) about 4 mg of psilocin, or about 4 mg psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, and (ii) one or more pharmaceutically acceptable carriers or excipients, wherein the disease or condition is selected from one or more of: major depressive disorder (MDD), moderate to severe MDD, treatmentresistant MDD, major depression, melancholic depression, atypical depression, dysthymia, anxiety, treatment-resistant anxiety, end of life anxiety, generalised anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, social phobia, substance abuse, alcoholism, tobacco abuse, drug abuse, anorexia nervosa, bulimia nervosa, binge eating disorder, primary impulse-control disorders, and obsessive-compulsive disorder.

[0006] In some embodiments, the pharmaceutical composition is suitable for intravenous administration.

[0007] In particular embodiments, the method includes the intravenous infusion of the pharmaceutical composition, to the subject, over about 10 minutes, optionally, to induce a complete mystical experience in the subject. In some embodiments, the administration of the pharmaceutical composition to the subject induces a complete mystical experience as identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-claim revised Mystical Experience Questionnaire (MEQ30) and / or through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire. In particular embodiments, the complete mystical experience is induced within about 5, 10, 15, 20, 25 or 30 minutes of administration of the pharmaceutical composition. In some embodiments, the complete mystical experience is induced within about 5, 10, 15, 20, 25 or 30 minutes of initiation of administration of the pharmaceutical composition. In particular embodiments, the complete mystical experience is resolved within about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 minutes of administration of the pharmaceutical composition.

[0008] In some embodiments, the pharmaceutical composition is for use in a method of rapidly treating moderate to severe major depressive disorder wherein a clinically significant reduction in MADRS score is present within about 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition.

[0009] In some embodiments, the pharmaceutical composition is for use in a method of rapidly treating moderate to severe major depressive disorder wherein a clinically significant reduction in MADRS score is present within about 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and wherein the clinically significant reduction in MADRS score is a reduction from baseline of at least about 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 points.

[0010] In some embodiments, the pharmaceutical composition is for use in a method of rapidly treating moderate to severe major depressive disorder wherein a clinically significant reduction in MADRS score is present within about 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and the reduction is sustained following administration. In particular embodiments, the reduction is sustained for about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks.

[0011] In particular embodiments, the subject is ready for discharge within about 90, 100, 110, 120, 130, 140, 150 or 160 minutes following administration. In some embodiments, the subject is ready for discharge within about 140 minutes following administration. In particular embodiments, the subject is ready for discharge within about 90, 100, 110, 120, 130, 140, 150 or 160 minutes following initiation of administration. In some embodiments, the subject is ready for discharge within about 140 minutes following initiation of administration.

[0012] In particular embodiments, the pharmaceutical composition is for use in a method of treatment without concomitant treatment with one or more further active agents, optionally without concomitant treatment with one or more further active agents selected from: a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA) or any other antidepressant compound; optionally wherein the subject discontinues treatment with the one or more further active agents prior to undergoing treatment with the pharmaceutical composition (e.g., a washout period of 1 -3 weeks prior to initiating psilocin treatment).

[0013] In particular embodiments, the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents selected from: a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA) or any other antidepressant compound. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents selected from: Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen / Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4) and / or Triiodothyronine (T3).

[0014] In particular embodiments, the pharmaceutical composition is for use in a method of treatment alongside one or more SSRIs. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents selected from: citalopram, escitalopram, sertraline, fluoxetine, paroxetine or vilazodone. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30 or 40 mg once daily of citalopram. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside 10 or 20 mg once daily of escitalopram. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside 50, 100, 150 or 200 mg once daily of sertraline. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30, 40, 50 or 60 mg once daily of fluoxetine. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30 or 40 mg once daily of paroxetine. In some embodiments, the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30 or 40 mg once daily of vilazodone.

[0015] In particular embodiments, the method of treatment includes the provision of psychological support to the subject. In some embodiments, the method of treatment includes the provision of psychological support to the subject prior to administration of the pharmaceutical composition. In some embodiments, the method of treatment includes the provision of psychological support to the subject following administration of the pharmaceutical composition.

[0016] In particular embodiments, the method of treatment is a method of treatment of a subject without a history of Hallucinogen Persisting Perceptual Disorder (HPPD). In some embodiments, the method of treatment is a method of treatment of a subject without a history of diagnosis of Hallucinogen Persisting Perceptual Disorder (HPPD). In some embodiments, the method of treatment is a method of treatment of a subject without current, or a history within 6 months prior to administration of, alcohol or substance use disorder, such as but not limited to, cannabis, cocaine, ketamine, opiates, MDMA, psilocybin and LSD, but excluding nicotine and caffeine use, as assessed by a structured clinical interview, such as MINI Version 7.0.2, conducted prior to administration, or determined by a self-report or a positive urine drugs of abuse test and / or alcohol breath test prior to administration.

[0017] In particular embodiments, the method of treatment is a method of treatment of a subject without current, or a history within 6 months prior to administration of, use of pharmacological compounds for psychiatric or neurological conditions acting on the central nervous system, excluding SSRIs.

[0018] In particular embodiments, the method of treatment is a method of treatment of a subject without current or clinically relevant history of schizophrenia, psychosis, bipolar disorder, delusional disorder, paranoid personality disorder, schizoaffective disorder, borderline personality disorder or panic disorder, as assessed by a structured clinical interview, such as MINI Version 7.0.2, prior to administration.

[0019] In particular embodiments, the method of treatment is a method of treatment of a subject without, in first-degree relatives, a history of schizophrenia, psychosis, bipolar disorder, delusional disorder, paranoid personality disorder or schizoaffective disorder. In some embodiments, the method of treatment is a method of treating a subject without a history of schizophrenia, psychosis, bipolar disorder, delusional disorder, paranoid personality disorder or schizoaffective disorder in their parents, siblings, or offspring.

[0020] In particular embodiments, the method of treatment is a method of treatment of a subject without significant suicide risk. In some embodiments, the method of treatment is a method of treatment of a subject without significant suicide risk.

[0021] In particular embodiments, the method of treatment is a method of treating a subject without one or more of:

[0022] • Suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within 1 year prior to administration;

[0023] • Suicidal behaviours within 1 year prior to administration; or

[0024] • Clinical assessment of significant suicidal risk prior to administration.

[0025] In particular embodiments, the method of treatment is a method of treatment of a subject without a known sensitivity to psilocybin or psilocin.

[0026] In particular embodiments, the method of treatment is a method of treatment of a subject without a known sensitivity to any tryptamine alkaloid.

[0027] In particular embodiments, the method of treatment is a method of treatment of a subject without any clinically relevant abnormal laboratory results. In some embodiments, the method of treatment is a method of treatment of a subject without current or previous medical history of any significant cardiovascular conditions, such as myocardial infarction or ischaemia, symptomatic arrhythmias, cerebral vascular accident or transient ischaemic attack.

[0028] In particular embodiments, the method of treatment is a method of treatment of a subject without a history or evidence of valvulopathy or pulmonary hypertension.

[0029] In particular embodiments, the method of treatment is a method of treatment of a subject without aspartate transaminase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) or total bilirubin levels >1 x upper limit of normal (ULN) prior to administration.

[0030] In particular embodiments, the method of treatment is a method of treatment of a subject without a QT corrected for heart rate (QTcF) >450 msec prior to administration, optionally as determined by triplicate electrocardiogram (ECG) readings.

[0031] In particular embodiments, the method of treatment is a method of treatment of a subject without clinically significant ECG abnormalities.

[0032] In particular embodiments, the method of treatment is a method of treatment of a subject without a presence or relevant history of any of the following medical conditions: organic brain disorders, such as epilepsy, seizure, intracranial hypertension, intracranial bleed and aneurysmal disease, brain tumour or other medical conditions associated with seizures or convulsions.

[0033] In particular embodiments, the method of treatment is a method of treatment of a subject who is not a woman of childbearing potential (WOCBP) who is pregnant, breastfeeding or planning to conceive.

[0034] In particular embodiments, the method of treatment is a method of treatment of a subject who does not test positive for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody (anti-HCV) or human immunodeficiency virus I and II (anti-HIV l / ll). In particular embodiments, the method of treatment is a method of treatment of a subject who does not have renal condition resulting in estimated Glomerular Filtration Rate (eGFR) <60 mL / min / 1 ,73m2.

[0035] In particular embodiments, the method of treatment is a method of treatment of a subject who has not used any classical psychedelic compound, such as mescaline, LSD, psilocybin or DMT, within 3 months of administration of the pharmaceutical composition.

[0036] In particular embodiments, the method of treatment is a method of treatment of a subject who does not consume >2 cigarettes / day, or >3 mg of e-cigarettes / day.

[0037] In particular embodiments, the method of treatment is a method of treatment of a subject who has not taken 5-hydroxytryptophan or St John’s Wort within 28 days prior to administration.

[0038] In particular embodiments, the method of treatment is a method of treatment of a subject who has not taken any drugs known to inhibit monoamine oxidase within 28 days prior to administration.

[0039] In particular embodiments, the method of treatment is a method of treatment of a subject who has not donated or received any blood or blood products within 3 months prior to administration.

[0040] In particular embodiments, the method of treatment is a method of treatment of a subject who abstains from sperm donation for 4 months following the last administration of the pharmaceutical composition.

[0041] In particular embodiments, the method of treatment is a method of treatment of a subject who has veins suitable for venepuncture and / or cannulation.

[0042] In particular embodiments, the method of treatment is a method of treatment of a subject who refrains from alcohol intake for 48 hours prior to each administration.

[0043] In particular embodiments, the method of treatment is a method of treatment of a subject who refrains from consuming poppy seeds 48 hours prior to each administration.

[0044] In particular embodiments, the method of treatment is a method of treatment of a subject who is diagnosed with major depressive disorder, or moderate to severe major depressive disorder (MDD), by a licensed professional in accordance with accepted medical practice.

[0045] In particular embodiments, the method of treatment is a method of treating a subject who has concentration difficulties, wherein administration of the pharmaceutical composition results in improved concentration of the subject. In particular embodiments, the method of treatment is a method of treating one or more sleep disturbances, wherein administration of the pharmaceutical composition improves sleep quality. In particular embodiments, the method of treatment is a method of treating a lack of, or reduced, appetite, wherein administration of the pharmaceutical composition improves appetite. In particular embodiments, the method of treatment is a method of reducing inner tension, wherein administration of the pharmaceutical composition reduces inner tension. In particular embodiments, the method of treatment is a method of treating an inability to feel, wherein administration of the pharmaceutical composition leads to an increase in a subject's ability to feel.

[0046] In particular embodiments, the pharmaceutical composition includes 4mg freebase equivalent of a pharmaceutically acceptable salt of psilocin wherein the salt anion is selected from: acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, hexanoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iodide, isethionate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfate, tartrate, teoclate, tosylate, and triethiodide. In some embodiments, the salt is crystalline. In some embodiments, the salt is psilocin benzoate. In some embodiments, the salt is psilocin benzoate and the pharmaceutical composition includes about 6.4 mg psilocin benzoate. In some embodiments, the salt is psilocin benzoate and the pharmaceutical composition includes about 6.39 mg psilocin benzoate.

[0047] In an embodiment, the pharmaceutical composition comprises about 3.5, 3.75, 4, 4.25 or 4.75 mg of psilocin or about 3.5, 3.75, 4, 4.25 or 4.75 mg psilocin freebase equivalent of a pharmaceutically acceptable salt thereof.

[0048] In an embodiment, the pharmaceutical composition is for use in a method of inducing a complete mystical experience in a subject in need thereof.

[0049] In an embodiment, the pharmaceutical composition is for use in a method of treatment of one or more conditions as described herein in a subject in need thereof.

[0050] Substance abuse disorders frequently co-occur with major depressive disorder and substance abuse disorders frequently lead to infectious diseases such as HIV and hepatitis. In an embodiment, there is therefore provided a pharmaceutical composition for use in a method of preventing a substance use disorder subject from contracting an infectious disease, said pharmaceutical composition being as disclosed herein.

[0051] In an embodiment, the pharmaceutical composition for use comprises a pharmaceutically acceptable salt of psilocin, wherein the pharmaceutically acceptable salt is a 1 :1 benzoate salt.

[0052] In another embodiment, the pharmaceutical composition for use comprises a pharmaceutically acceptable salt of psilocin, wherein the pharmaceutically acceptable salt is a 1 :1 tartrate salt.

[0053] In a further embodiment, the pharmaceutical composition for use comprises a pharmaceutically acceptable salt of psilocin, wherein the pharmaceutically acceptable salt is a 2:1 succinate salt.

[0054] In another embodiment, the pharmaceutical composition for use comprises a pharmaceutically acceptable salt of psilocin, wherein the pharmaceutically acceptable salt is a 2:1 salt of 1 ,5- naphthalenedisulfonic acid, a 1 :1 salt of 1 ,5-naphthalenedisulfonic acid, or a mixture thereof. In some embodiments, the crystalline psilocin 1 ,5-naphthalenedisulfonate is characterized by one or more peaks at diffraction angle 20 (°) as provided in FIG. 4 or FIG. 5 (NAP Pattern 1 ) as measured using an x-ray wavelength of 1 .5406 A.

[0055] In a related embodiment, the pharmaceutical composition for use comprises a pharmaceutical composition including a psilocin salt of the invention and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient can be any pharmaceutically acceptable excipient described herein.

[0056] In another embodiment, the pharmaceutical composition for use comprises (i) an aqueous solution having a pH of between about 3 and about 9 (e.g., 3±1 , 4±1 , 5±1 , 6±1 , 7±1 , 8±1 , and 9±1 ) and (ii) between about 0.1 mg / mL and about 50 mg / mL (e.g., 0.1 ±0.1 mg / mL, 0.2±0.1 mg / mL, 0.3± 0.1 mg / mL, 0.4± 0.1 mg / mL, 0.5±0.5 mg / mL, 1 ±0.5 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11 ±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, 15±1 mg / mL, 16±1 mg / mL, 17±1 mg / mL, 18±1 mg / mL, 19±1 mg / mL, 25±5 mg / mL, 30±5 mg / mL, 35±5 mg / mL, 40±5 mg / mL, 45±5 mg / mL, and 50±5 mg / mL) of any one of pharmaceutically acceptable salts of psilocin described herein. The aqueous pharmaceutical composition can be suitable for infusion into a subject for treating a disease or condition described herein.

[0057] In some embodiments, the aqueous solution has between about 1 mg / mL and about 15 mg / mL (e.g., 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 1 1 ±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, and 15±1 mg / mL) of any one of pharmaceutically acceptable salts of psilocin described herein.

[0058] In a related embodiment, the pharmaceutical composition for use comprises a crystal form of a 1 :1 tartrate salt of psilocin having at least four, five, six, or seven peaks at diffraction angle 20 (°) selected from 6.7±0.5, 12.6±0.5, 13.4±0.5, 14.7±0.5, 15.8±0.5, 16.2±0.5, 17.2±0.5, 18.8±0.5, 19.9±0.5, 20.8±0.5, 21 ,8±0.5, 22.5±0.5, 23.4±0.5, 23.7±0.5, 24.7±0.5, 25.5±0.5, 26.5±0.5, 27.0±0.5, 28.5±0.5, and 29.4±0.5 (TAR Pattern 1 ) as measured by X-ray powder diffractometry.

[0059] In a further embodiment, the pharmaceutical composition for use comprises a crystal form of a 2:1 succinate salt of psilocin having at least four, five, six, or seven peaks at diffraction angle 20 (°) selected from 9.7±0.5, 1 1 ,2±0.5, 12.3±0.5, 13.8±0.5, 15.9±0.5, 16.4±0.5, 19.4±0.5, 20.0±0.5, 21 ,3±0.5, 22.6±0.5, 23.3±0.5, 23.5±0.5, 23.8±0.5, 24.5±0.5, 24.7±0.5, 25.0±0.5, 28.0±0.5, 28.3±0.5, 29.0±0.5, and 29.4±0.5 (SUC Pattern 3) as measured by X-ray powder diffractometry.

[0060] In a related embodiment, the pharmaceutical composition for use comprises a crystal form of a 1 :1 benzoate salt of psilocin having at least four, five, six, or seven peaks at diffraction angle 20 (°) 9.4±0.5, 10.9±0.5, 12.3±0.5, 13.3±0.5, 14.5±0.5, 15.3±0.5, 16.3±0.5, 16.4±0.5, 18.2±0.5, 18.9±0.5, 19.3±0.5, 19.7±0.5, 20.0±0.5, 20.8±0.5, 21 ,3±0.5, 21 ,9±0.5, 22.6±0.5, 22.9±0.5, 23.8±0.5, 24.1 ±0.5, 24.9±0.5, 25.6±0.5, 26.0±0.5, 26.3±0.5, 26.5±0.5, 26.9±0.5, 27.5±0.5, and 28.5±0.5 (BEN Pattern 1 ) as measured by X-ray powder diffractometry.

[0061] In a related embodiment, the pharmaceutical composition for use comprises a crystal form of a psilocin salt and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient can be any pharmaceutically acceptable excipient described herein. In some embodiments, any one of the pharmaceutical compositions described herein is stored in a container that shields the pharmaceutical composition from exposure to light, such as an amber glass bottle, or an ambient light impermeable container.

[0062] In a related embodiment, the pharmaceutical composition for use is for use in a method of treating a disease or condition in a subject in need thereof, the method including administering to the subject a psilocin salt of the invention in an amount sufficient to treat the disease or condition. The disease or condition can be a neurological injury, neurodegenerative disease, an inflammatory condition, chronic pain, or a psychological condition. In certain embodiments, the disease or condition is an inflammatory condition (e.g., lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and / or septicemia). In particular embodiments, the inflammatory condition is chronic obstructive pulmonary disease (COPD), or Alzheimer’s disease. In certain embodiments, the disease or condition is a neurological injury (e.g., a stroke, a traumatic brain injury, or a spinal cord injury). In some embodiments, the disease or condition is chronic pain (e.g., pain resulting from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica). In particular embodiments, the chronic pain condition results from trigeminal autonomic cephalalgia (e.g., episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)). In some embodiments, the trigeminal autonomic cephalalgia is episodic or chronic CH. In certain embodiments, the condition is a psychological condition (e.g., depression, anxiety, addiction, post-traumatic stress disorder, an eating disorder, or compulsive behavior). In particular embodiments, the psychological condition is depression or anxiety.

[0063] In an embodiment, the disclosure provides a pharmaceutical composition including (i) an aqueous solution having a pH of between about 3.5 and about 6.5 (e.g., 3.5±0.5, 4.0±0.5, 4.5±0.5, 5.0±0.5, 5.5±0.5, 6.0±0.5, and 6.5±0.5), (ii) between about 0.0053 mg / mL and about 4.0 mg / mL (e.g., 0.006±0.001 mg / mL, 0.0075±0.0025 mg / mL, 0.01 ±0.005 mg / mL, 0.05±0.025 mg / mL, 0.075±0.025 mg / mL, 0.1 ±0.05 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.1 mg / mL, 0.6±0.1 mg / mL, 0.7±0.1 mg / mL, 0.8±0.1 mg / mL , 0.9±0.1 mg / mL, 1 ±0.5 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL) of psilocin benzoate, and (iii) an antioxidant, wherein the pharmaceutical composition is suitable for infusion. In some embodiments, the aqueous solution includes a citrate buffer, an acetate buffer, or a phosphate buffer, and has a pH of between about 4.0 and about 6.0 (e.g., 4.0±0.5, 4.5±0.5, 5.0±0.5, 5.5±0.5, and 6.0±0.5).

[0064] In another embodiment, the invention provides a pharmaceutical composition including (i) a citrate buffered aqueous solution having a pH of between about 4.0 and about 5.0 (e.g., 4.0±0.5, 4.5±0.5, and 5.0±0.5), and (ii) between about 0.0053 mg / mL and about 4.0 mg / mL (e.g., 0.006±0.001 mg / mL, 0.0075±0.0025 mg / mL, 0.01 ±0.005 mg / mL, 0.05±0.025 mg / mL, 0.075±0.025 mg / mL, 0.1 ±0.05 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.1 mg / mL, 0.6±0.1 mg / mL, 0.7±0.1 mg / mL, 0.8±0.1 mg / mL , 0.9±0.1 mg / mL, 1 ±0.5 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL) of psilocin benzoate, wherein the pharmaceutical composition is suitable for infusion.

[0065] In certain embodiments, the aqueous solution includes between about 0.001 % (w / v) to 2% (w / v) of an antioxidant (e.g., 0.004±0.002 (w / v), 0.006±0.002% (w / v), 0.008±0.002% (w / v), 0.01 ±0.005% (w / v), 0.015±0.05% (w / v), 0.02±0.01 % (w / v), 0.03±0.01 % (w / v), 0.04±0.01 % (w / v), 0.05±0.01 % (w / v), 0.06±0.01 % (w / v), 0.07±0.01 % (w / v), 0.08±0.01 % (w / v), 0.09±0.01 % (w / v), 0.1 ±0.05% (w / v), 0.15±0.05% (w / v), 0.2±0.1 % (w / v), 0.3±0.1 % (w / v), 0.4±0.2% (w / v), 0.6±0.2% (w / v), 0.8±0.2% (w / v), 1 ±0.5% (w / v), 1 .5±0.5% (w / v), and 2±0.5% (w / v) of an antioxidant). For example, the antioxidant may be in an amount of between 0.01 % (w / v) and 2% (w / v) (e.g., 0.01 ±0.01 % (w / v), 0.02±0.01 % (w / v), 0.03±0.01 % (w / v), 0.04±0.01 % (w / v), 0.05±0.01 % (w / v), 0.06±0.01 % (w / v), 0.07±0.01 % (w / v), 0.08±0.01 % (w / v), 0.09±0.01 % (w / v), 0.1 ±0.1 % (w / v), 0.2±0.1 % (w / v), 0.3±0.1 % (w / v), 0.4±0.1 % (w / v), 0.5±0.1 % (w / v), 0.6±0.1 % (w / v), 0.7±0.1 % (w / v), 0.8±0.1 % (w / v), 0.9±0.1 % (w / v), 1 ±0.1 % (w / v), 1 .1 ±0.1 % (w / v), 1 ,2±0.1 % (w / v), 1 ,3±0.1 % (w / v), 1 ,4±0.1 % (w / v), 1 ,5±0.1 % (w / v), 1 ,6±0.1 % (w / v), 1 ,7±0.1 % (w / v), 1 ,8±0.1 % (w / v), 1 .9±0.1 % (w / v), and 2±0.1 % (w / v)).

[0066] In some embodiments, the antioxidant is vitamin C, thioglycerol, sodium bisulfite, or sodium sulfite. In particular embodiments, the aqueous solution includes about 0.01 ±0.005% sodium bisulfite. The pharmaceutical composition may further include one or more pharmaceutically acceptable excipients selected from a preservative, or a tonicity agent. In some embodiments, the pharmaceutical composition further includes from 0.1 % (w / v) to 1 % (w / v) (e.g., 0.2±0.1 % (w / v), 0.3±0.1 % (w / v), 0.4±0.1 % (w / v), 0.5±0.1 % (w / v), 0.6±0.1 % (w / v), 0.7±0.1 % (w / v), 0.8±0.1 % (w / v), 0.9±0.1 % (w / v) and 1 ±0.1 % (w / v)) sodium chloride as a tonicity agent.

[0067] In particular embodiments, the pharmaceutical composition includes: (i) a citrate buffered aqueous solution having a pH of between 4.0 and 5.0 (e.g., 4.0±0.5, 4.5±0.5, and 5.0±0.5), (ii) between about 0.0053 mg / mL and about 0.7 mg / mL (e.g., 0.006±0.001 mg / mL, 0.0075±0.0025 mg / mL, 0.01 ±0.005 mg / mL, 0.05±0.025 mg / mL, 0.075±0.025 mg / mL, 0.1 ±0.05 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.05 mg / mL, 0.45±0.05 mg / mL, 0.5±0.05 mg / mL, 0.55±0.05 mg / mL, 0.6±0.05 mg / mL, 0.65±0.05 mg / mL, and 0.7±0.05 mg / mL) of psilocin benzoate, and (iii) 0.01 to 0.075% (w / v) sodium bisulfite (e.g., 0.02±0.01 % (w / v), 0.03±0.01 % (w / v), 0.4±0.01 % (w / v), 0.05±0.01 % (w / v), 0.06±0.01 % (w / v), and 0.07±0.01 % (w / v) sodium bisulfite). In some embodiments, the pharmaceutical composition includes: (i) a citrate buffered aqueous solution having a pH of between 4.0 and 5.0, (ii) between about 0.0053 mg / mL and about 0.7 mg / mL of psilocin benzoate, and (iii) 0.01 to 0.075% (w / v) sodium bisulfite.

[0068] In particular embodiments, the pharmaceutical composition includes an aqueous solution containing 75 mM citrate buffer, 0.4% w / v sodium chloride, 0.01 % w / v sodium bisulfite, wherein the volume of the solution is 15 to 30mL and the pH is 4.5.

[0069] In some embodiments, the pharmaceutical composition includes from about 50 to about 200 mM citrate buffer (e.g., 50±10 mM, 60±10 mM, 70±10 mM, 80±10 mM, 90±10 mM, 100±10 mM, 1 10±10 mM, 120±10 mM, 130±10 mM, 140±10 mM, 150±10 mM, 160±10 mM, 170±10 mM, 180±10 mM, 190±10 mM, and 200±10 mM).

[0070] In another embodiment, the disclosure provides a reconstitutable powder including psilocin benzoate, an antioxidant, and a buffer, wherein reconstitution of the reconstitutable powder in from 5 mL to 50 mL (e.g., 5±1 mL, 6±1 mL, 7±1 mL, 8±1 mL, 9±1 mL, 10±5 mL, 15±5 mL, 20±5 mL, 25±5 mL, 30±5 mL, 35±5 mL, 40±5 mL, 45±5 mL, and 50±5 mL) of an aqueous solution produces any one of the pharmaceutical compositions described herein. In certain embodiments, the powder includes between about 0.01 % (w / w) and 2% (w / w) of psilocin benzoate (e.g., 0.01 ±0.01 % (w / w), 0.02±0.01 % (w / w), 0.03±0.01 % (w / w), 0.04±0.01 % (w / w), 0.05±0.01 % (w / w), 0.06±0.01 % (w / w), 0.07±0.01 % (w / w), 0.08±0.01 % (w / w), 0.09±0.01 % (w / w), 0.1 ±0.1 % (w / w), 0.2±0.1 % (w / w), 0.3±0.1 % (w / w), 0.4±0.1 % (w / w), 0.5±0.1 % (w / w), 0.6±0.1 % (w / w), 0.7±0.1 % (w / w), 0.8±0.1 % (w / w), 0.9±0.1 % (w / w), 1 ±0.1 % (w / w), 1 .1 ±0.1 % (w / w), 1 ,2±0.1 % (w / w), 1 ,3±0.1 % (w / w), 1 ,4±0.1 % (w / w), 1 ,5±0.1 % (w / w), 1 ,6±0.1 % (w / w), 1 ,7±0.1 % (w / w), 1 ,8±0.1 % (w / w), 1 ,9±0.1 % (w / w), and 2±0.1 % (w / w)).

[0071] In another embodiment, the disclosure provides a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject any one of the pharmaceutical compositions described herein in an amount sufficient to treat the disease or condition. In some embodiments, the method includes intravenously administering to the subject any one of the pharmaceutical compositions described herein over a period of between 1 minute and 60 minutes (e.g., between 1 minute and 10 minutes, 10 minutes and 60 minutes, 20 minutes and 60 minutes, 30 minutes and 60 minutes, 40 minutes and 60 minutes, 50 minute and 60 minutes, 1 minute and 10 minutes, 1 minute and 20 minutes, 1 minute and 30 minutes, 1 minutes and 40 minutes, and 1 minute and 50 minutes). For example, the pharmaceutical composition may be administered to the subject over a period of 20 to 60 minutes (e.g., 20 minutes to 50 minutes, 20 minutes to 40 minutes, 20 minutes to 30 minutes, 30 minutes to 60 minutes, 40 minutes to 60 minutes, and 50 minutes and 60 minutes. In some embodiments, the administration may be self-administration. In some embodiments, the administration is performed by a medical professional.

[0072] In some embodiments, the disease or condition is a neurological injury, a neurodegenerative disease, an inflammatory condition, chronic pain, or a psychological condition. In particular embodiments, the disease or condition is an inflammatory condition. In certain embodiments, the inflammatory condition is lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and / or septicemia. In some embodiments, the inflammatory condition is chronic obstructive pulmonary disease (COPD), or Alzheimer’s disease. In certain embodiments, the disease or condition is a neurological injury. In particular embodiments, the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury.

[0073] In some embodiments, the disease or condition is chronic pain. The chronic pain may result from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica. In particular embodiments, the chronic pain condition results from trigeminal autonomic cephalalgia. The trigeminal autonomic cephalalgia may be selected from the group consisting of episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). In particular embodiments, the trigeminal autonomic cephalalgia is episodic or chronic CH.

[0074] In some embodiments, the condition is a psychological condition. The psychological condition may be depression, anxiety, addiction, post-traumatic stress disorder, an eating disorder, or compulsive behavior. For example, the psychological condition may be depression. In particular embodiments, the psychological condition is anxiety.

[0075] In certain embodiments the disease or condition is a neurodegenerative disease selected from Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease.

[0076] In certain embodiments, the method includes further administering to the subject a pharmacologically effective amount of an antiemetic agent. The antiemetic agent may include a non- selective 5-HT antagonist, 5-HT3 receptor antagonist, 5-HT4 receptor agonist, CB1 agonist, D2 receptor antagonist, D3 receptor antagonist, GABA receptor agonist, H1 receptor antagonist, muscarinic acetylcholine receptor antagonist, NK1 receptor antagonist, or a combination thereof. In particular embodiments, the antiemetic ondansetron is intravenously infused.

[0077] In some embodiments, the intravenous infusion includes a pharmacologically effective amount of a benzodiazepine. The benzodiazepine may be a 1 ,4-benzodiazepine, 1 ,5-benzodiazepine, 2,3- benzodiazepine, triazolobenzodiazepine, imidazobenzodiazepine, oxazolobenzodiazepine, thienodiazepine, thienotriazolodiazepine, thienobenzodiazepine,pyridodiazepine, pyridotriazolodiazepine, pyrralodiazepine, tetrahydroisoquinobenzodiazepine, a benzodiazepine prodrug, or a combination thereof. In particular embodiments, the benzodiazepine is lorazepam or diazepam. In some embodiments, the benzodiazepine is administered in a dosage between 2 mg and 10 mg (e.g., 2±1 mg, 3±1 mg, 4±1 mg, 5±1 mg, 6±1 mg, 7±1 mg, 8±1 mg, 9±1 mg, and 10±1 mg). In some embodiments, the intravenous infusion includes a pharmacologically effective amount of an anesthetic, a sedative, an antiemetic, an anticonvulsant, an antidepressant, an antimigraine, an antipsychotic, an anxiolytic, and / or an antiparkinson agent.

[0078] In some embodiments, the method further includes administering to the subject a preparation including a pharmacologically effective amount of an anti-inflammatory agent. In certain embodiments, the administration of the preparation is an intravenous infusion of ketorolac or pharmaceutically acceptable salt thereof. In certain embodiments, the administration of the preparation is an intramuscular infusion of a pharmacologically effective amount of a triptan or a pharmaceutically acceptable salt thereof. In particular embodiments, the preparation includes sumatriptan or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the intravenous infusion including a pharmacologically effective amount of psilocin benzoate is administered at least twice over the course of a month (e.g., at least two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, or more over the course of a month). In some embodiments, the intravenous infusion including a pharmacologically effective amount of psilocin benzoate is administered between 2 and 10 times over the course of a year (e.g., 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times over the course of a year).

[0080] In some embodiments, the method of treatment is a method of treating a subject. In some embodiments, the subject is a mammal. In particular embodiments, the subject is human.

[0081] In some embodiments, the pharmaceutical composition is administered to the subject once every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 15 days every 16 days, every 17 days, every 18 days, every 19 days, every 20 days, every 21 days, every 22 days, every 23 days, every 24 days, every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 14 days.

[0082] In some embodiments, the pharmaceutical composition is administered to the subject once every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, or every 14 weeks. In some embodiments, the pharmaceutical composition is administered to the subject between once about every 5 weeks and once about every 13 weeks (e.g. once every 5±1 weeks, every 6±1 weeks, every 7±weeks, every 8±1 weeks, every 9±1 weeks, every 10±1 weeks, every 11 ±1 weeks, every 12±1 weeks, or every 13±1 weeks).

[0083] In some embodiments, the disease or condition is major depressive disorder in a subject.

[0084] In some embodiments, the subject has a MADRS score of less than 9 (e.g., less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, or less than 1 ) after administration of the pharmaceutical composition. In some embodiments, the subject has a MADRS score of less than 9 (e.g., less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, or less than 1 ) two days after administration of the pharmaceutical composition to the subject.

[0085] In some embodiments of any of the above, the subject experiences remission following the administration. In some embodiments, the subject has concentration difficulties. In some embodiments, the subject experiences improved concentration after the administration.

[0086] In some embodiments, the subject has experienced at least one sleep disturbance. In some embodiments, the subject experiences an improvement in sleep quality after the administration.

[0087] In some embodiments, the method of treatment is a method of treating a subject having a reduced appetite. In some embodiments, the subject experiences an increase in appetite after the administration.

[0088] In some embodiments, the subject has inner tension. In some embodiments, the subject experiences a reduction in inner tension after the administration.

[0089] In some embodiments, the method of treatment is a method of treating a subject having an inability to feel. In some embodiments, the subject experiences an increase in the ability to feel after the administration.

[0090] In an embodiment, the disclosure provides a lyophilized solid comprising (i) amorphous psilocin, or a pharmaceutically acceptable salt thereof; (ii) citrate buffer as a buffering agent; (iii) mannitol as a bulking agent; and (iv) less than 2% (w / w) water.

[0091] In some embodiments, the pharmaceutically acceptable salt thereof of psilocin may be the benzoate, succinate, tartrate, 1 ,5-naphthalenedisulfonate, stearate, lactate, acetate, aspartate, benzenesulfonate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, hexanoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, sulfate, teoclate, tosylate, and triethiodide.

[0092] In an embodiment, the disclosure provides a lyophilized solid comprising (i) amorphous psilocin benzoate; (ii) citrate buffer as a buffering agent; (iii) mannitol as a bulking agent; and (iv) less than 2% (w / w) water.

[0093] In an embodiment, the disclosure provides a lyophilized solid comprising (i) an amorphous acid addition salt of psilocin benzoate; (ii) a buffering agent; and (iii) less than 2% (w / w) water.

[0094] For example, the freebase of psilocin when reacted with benzoic acid would give an acid addition salt of psilocin benzoate. In an embodiment, there is provided a lyophilized solid comprising an amorphous acid addition salt of psilocin, wherein the acid addition salt is psilocin benzoate. In an embodiment, there is provided a lyophilized solid comprising (i) an amorphous acid addition salt of psilocin, wherein the acid addition salt is psilocin benzoate; (ii) a buffering agent; and (iii) less than 2% (w / w) water.

[0095] In another embodiment, the disclosure provides a lyophilized solid comprising (i) an amorphous acid addition salt of psilocin benzoate; (ii) a buffering agent; and (iii) less than 3% (w / w) water. In some embodiments, the psilocin benzoate has a concentration of between 0.01% (w / w) and 10% (w / w) (e.g., between 0.01 % (w / w) and 9% (w / w), 0.01% (w / w) and 8% (w / w), 0.01% (w / w) and 7% (w / w), 0.01% (w / w) and 6% (w / w), 0.01% (w / w) and 5% (w / w), 0.01% (w / w) and 4% (w / w), 0.01% (w / w) and 3% (w / w), 0.01 % (w / w), 0.01% (w / w) and 1% (w / w), 0.01% (w / w) and 0.5% (w / w), 0.01% (w / w) and 0.05% (w / w), 0.05% and 10% (w / w), 0.5% (w / w) and 10% (w / w), 1 % (w / w) and 10% (w / w), 2% (w / w) and 10% (w / w), 3% (w / w) and 10% (w / w), 4% (w / w) and 10% (w / w), 5% (w / w) and 10% (w / w), 6% (w / w) and 10% (w / w), 7% (w / w) and 10% (w / w), 8% (w / w) and 10% (w / w), or 9% (w / w) and 10% (w / w)).

[0096] The solid may comprises less than 80% (w / w) (e.g., less than 70% (w / w), less than 60% (w / w), less than 50% (w / w), less than 40% (w / w), less than 30% (w / w), less than 20% (w / w), or less than 10% (w / w)) of a buffering agent. In some embodiments, the solid comprises between 10% (w / w) and 95% (w / w) (e.g., between 10% (w / w) and 90% (w / w), 10% (w / w) and 80% (w / w), 10% (w / w) and 70% (w / w), 10% (w / w) and 60% (w / w), 10% (w / w) and 50% (w / w), 10% (w / w) and 40% (w / w), 10% (w / w) and 30 % (w / w), 10% (w / w) and 20 % (w / w), 20% (w / w) and 95% (w / w), 30% (w / w) and 95% (w / w), 40% (w / w) and 95% (w / w), 50% (w / w) and 95% (w / w), 60% (w / w) and 95% (w / w), 70% (w / w) and 95% (w / w), or 80% (w / w) and 95% (w / w)) buffering agent. For example, the solid may include between 10% (w / w) and 30% (w / w) (e.g., 10% (w / w)± 2% (w / w), 12% (w / w)± 2% (w / w), 14% (w / w)± 2% (w / w), 16% (w / w)± 2% (w / w), 18% (w / w)± 2% (w / w), 20% (w / w)± 2% (w / w), 22% (w / w)± 2% (w / w), 24% (w / w)± 2% (w / w), 26% (w / w)± 2% (w / w), 28% (w / w)± 2% (w / w), or 30% (w / w)± 2% (w / w)) buffering agent.

[0097] The buffering agent may be a citrate buffer.

[0098] In some embodiments, the solid further comprises a bulking agent. The bulking agent may have a concentration of between 65% (w / w) and 95% (w / w) (e.g., between 65% (w / w) and 90% (w / w), 65% (w / w) and 85% (w / w), 65% (w / w) and 80% (w / w), 65% (w / w) and 75% (w / w), 65% (w / w) and 70% (w / w), 70% (w / w) and 95% (w / w), 75% (w / w) and 95% (w / w), 80% (w / w) and 95% (w / w), 85% (w / w) and 95% (w / w), or 90% (w / w) and 95% (w / w)). For example, the bulking agent has a concentration of between 70% (w / w) and 90% (w / w) (e.g., 70% (w / w)± 2% (w / w), 72% (w / w)± 2% (w / w), 74% (w / w)± 2% (w / w), 76% (w / w)± 2% (w / w), 78% (w / w)± 2% (w / w), 80% (w / w)± 2% (w / w), 82% (w / w)± 2% (w / w), 84% (w / w)± 2% (w / w), 86% (w / w)± 2% (w / w), 88% (w / w)± 2% (w / w) or 90% (w / w)± 2% (w / w)). In certain embodiments, the bulking agent is mannitol.

[0099] In another embodiment, the disclosure provides a lyophilized solid comprising (i) an amorphous psilocin benzoate in an amount of between 0.01 % (w / w) and 10% (w / w) (e.g., between 0.01 % (w / w) and 8% (w / w), 0.01 % (w / w) and 6% (w / w), 0.01 % (w / w) and 4% (w / w), 0.01 % (w / w) and 2% (w / w), 0.01 % (w / w) and 1 % (w / w), 1 % (w / w) and 10% (w / w), 2% (w / w) and 10% (w / w), 3% (w / w) and 10% (w / w), 4% (w / w) and 10% (w / w), 5% (w / w) and 10% (w / w), 6% (w / w) and 10% (w / w), 7% (w / w) and 10% (w / w), 8% (w / w) and 10% (w / w), or 9% (w / w) and 10% (w / w)), (ii) a buffering agent in an amount of between 10% (w / w) and 30% (w / w) (e.g., 10% (w / w)± 2% (w / w), 12% (w / w)± 2% (w / w), 14% (w / w)± 2% (w / w), 16% (w / w)± 2% (w / w), 18% (w / w)± 2% (w / w), 20% (w / w)± 2% (w / w), 22% (w / w)± 2% (w / w), 24% (w / w)± 2% (w / w), 26% (w / w)± 2% (w / w), 28% (w / w)± 2% (w / w), or 30% (w / w)± 2% (w / w)); (iii) a bulking agent in an amount of between 70% (w / w) and 95% (w / w) (e.g., 70% (w / w)± 2% (w / w), 72% (w / w)± 2% (w / w), 74% (w / w)± 2% (w / w), 76% (w / w)± 2% (w / w), 78% (w / w)± 2% (w / w), 80% (w / w)± 2% (w / w), 82% (w / w)± 2% (w / w), 84% (w / w)± 2% (w / w), 86% (w / w)± 2% (w / w), 88% (w / w)± 2% (w / w), 90% (w / w)± 2% (w / w), 92% (w / w)± 2% (w / w), 94% (w / w)± 2% (w / w), or 95% (w / w)± 2% (w / w)); and (iii) less than 3% (w / w) water (e.g., less than 2.5% (w / w), 2% (w / w), 1 .5% (w / w), 1 % (w / w), 0.5% (w / w), 0.05% (w / w)).

[0100] In some embodiments, the buffer is a citrate buffer. In certain embodiments, the bulking agent comprises mannitol. In some embodiments, the solid comprises less than 1 % (w / w) (e.g., less than 0.9% (w / w), less than 0.8% (w / w), less than 0.7% (w / w), less than 0.6% (w / w), less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1 % (w / w), less than 0.05% (w / w)) water.

[0101] The lyophilized solid may have a pH of between 3.5 and 5 (e.g., pH of between 3.5 and 5, 4 and 5, 4.5 and 5, 3.5 and 4.5, or 4 and 4.5) when dissolved in between 10 mL and 50 mL (e.g., between 10 mL and 40 mL, 10 mL and 30 mL, 10 mL and 20 mL, 20 mL and 50 mL, 30 mL and 50 mL, or 40 mL and 50 mL) of unbuffered water or saline for injection.

[0102] In some embodiments, the solid further comprises less than 1 % (w / w) of an antioxidant. The antioxidant may be sodium bisulfite. In certain embodiments, the solid is free of any antioxidant.

[0103] The solid may comprise less than 20% (w / w) by weight of sodium chloride. In some embodiments, the solid is free of sodium chloride. In some embodiments, the lyophilized solid does not comprise mannitol hemihydrate. In some embodiments, the lyophilized solid is substantially free of mannitol hemihydrate. In some embodiments, the lyophilized solid is substantially free of mannitol hemihydrate and wherein the lyophilized solid is characterized by an X-ray powder diffractogram (XRPD) which does not comprise a peak at the 20 values of 17.9±0.1 °, 17.9±0.2° or 17.9±0.3° as measured using an X-ray wavelength of 1 .5406 A.

[0104] In another embodiment, the disclosure provides a method of preparing a lyophilized solid comprising (i) an amorphous acid addition salt of psilocin benzoate; (ii) a buffering agent; and (iii) less than 3% (w / w) water, wherein the solid described herein is dissolved in between 5 mL to 50 mL (e.g., between 5 mL and 40 mL, 5 mL and 30 mL, 5 mL and 20 mL, 5 mL and 10 mL, 10 mL and 50 mL, 20 mL and 50 mL, 30 mL and 50 mL, or 40 mL and 50 mL) of an aqueous solution and undergoes a thermal treatment step, followed by a drying step. In some embodiments, the thermal treatment step is performed for between 30 hours and 70 hours (e.g., between 30 hours and 60 hours, 30 hours and 50 hours, 30 hours and 40 hours, 40 hours and 70 hours, 50 hours and 70 hours, or 60 hours and 70 hours) at a temperature of between -50 °C and 10 °C (e.g., between -50 °C and 0 °C, -50 °C and -10 °C, -50 °C and - 20 °C, -50 °C and -30 °C, -50 °C and -40 °C, -40 °C and 10 °C, -30 °C and 10 °C, -20 °C and 10 °C, -10 °C and 10 °C, or 0 °C and 10 °C). In some embodiments, the thermal treatment step comprises between 3 and 8 steps (e.g., 3, 4, 5, 6, 7, or 8 steps).

[0105] The thermal treatment step may include (i) a first step, wherein the first step is performed at about 5 °C for about 10 minutes; (ii) a second step, wherein the second step is performed at about -40 °C for about 45 minutes; (iii) a third step, wherein the third step is performed at about -40 °C for about 120 minutes; (iv) a fourth step, wherein the fourth step is performed at about -9 °C for about 31 minutes; (v) a fifth step, wherein the fifth step is performed at about -9 °C for about 300 minutes; (vi) a sixth step, wherein the sixth step is performed at about -40 °C for about 31 minutes; and (vii) a seventh step, wherein the seventh step is performed at about -40 °C for about 120 minutes.

[0106] In certain embodiments, the drying step comprises a primary drying step and a secondary drying step. In some embodiments, the primary drying step is performed for between 5 hours and 10 hours (e.g., between 5 hours and 8 hours, 5 hours and 6 hours, 6 hours and 10 hours, or 8 hours and 10 hours) at a temperature of between -50 °C and 0 °C (e.g., between -50 °C and -10 °C, -50 °C and -20 °C, -50 °C and -30 °C, -50 °C and -40 °C, -40 °C and 0 °C, -30 °C and 0 °C, -20 °C and 0 °C, or -10 °C and 0 °C), and a pressure of between 20 pBar and 300 pBar (e.g., between 20 pBar and 100 pBar, 20 pBar and 200 pBar, 20 pBar and 300 pBar, 100 pBar and 300 pBar, 100 pBar and 200 pBar, or 50 pBar and 200 pBar). The primary drying step may comprises a first step, a second step, and a third step, wherein the first step is performed at about -40 °C for about 60 minutes with a pressure of about 50 pBar, wherein the second step is performed at about -9 °C for about 31 minutes with a pressure of about 200 pBar, and wherein the third step is performed at -9 °C for about 2566 minutes with a pressure of about 200 pBar. The secondary dry step may comprises a first step and second step, wherein the first step is performed at 25 °C for about 78 minutes at a pressure of about 50 pB Tar and wherein the second step is performed at 25 °C for about 480 minutes at a pressure of about 50 pBar.

[0107] In another embodiment, the disclosure provides a method of treating a disease or condition in a subject in need thereof including intravenously administering to the subject any one of the lyophilized solids described herein dissolved in from 5 mL to 50 mL (e.g., between 5 mL and 40 mL, 5 mL and 30 mL, 5 mL and 20 mL, 5 mL and 10 mL, 10 mL and 50 mL, 20 mL and 50 mL, 30 mL and 50 mL, or 40 mL and 50 mL) of an aqueous solution in an amount sufficient to treat the disease or condition.

[0108] In a related aspect, the invention features a pharmaceutical composition as described herein, as a composition of matter. In some embodiments, the pharmaceutical composition includes: (i) 4 mg of psilocin, or 4 mg of psilocin freebase equivalent of a pharmaceutically acceptable salt thereof; and (ii) one or more pharmaceutically acceptable carriers or excipients.

[0109] In another related aspect, the invention features a kit including a pharmaceutical composition as described herein and instructions for use according to any method described herein.

[0110] In another related aspect, the invention features an IV infusion device including a pharmaceutical composition as described herein, optionally with instructions for use according to any method described herein.

[0111] The invention further features a pharmaceutical composition including a reconstitutable powder including (i) 4 mg of psilocin, or 4 mg psilocin freebase equivalent of a pharmaceutically acceptable salt thereof; and (ii) one or more pharmaceutically acceptable carriers or excipients, wherein the pharmaceutical composition is for use in a method of treatment of one or more of: major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression, dysthymia, anxiety, treatment-resistant anxiety, end of life anxiety, generalised anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, social phobia, substance abuse, alcoholism, tobacco abuse, drug abuse, anorexia nervosa, bulimia nervosa, binge eating disorder, primary impulse-control disorders or obsessive-compulsive disorder, in a subject in need thereof, wherein, optionally, administration of the pharmaceutical composition induces a complete mystical experience in the subject.

[0112] The person skilled in the art will appreciate that embodiments which refer to a pharmaceutical composition for use are a disclosure of the pharmaceutical composition perse and said pharmaceutical composition for one or more particular uses.

[0113] Definitions

[0114] To facilitate the understanding of this invention, a number of terms are defined below and throughout the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims.

[0115] Terms such as “a”, “an,” and “the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration.

[0116] As used herein, the term “about” refers to a value that is within 10% above or below the value being described.

[0117] As used herein, the terms “acute stress disorder” and “ASD” refer to a condition that arises as a response to a stressful event or situation of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime). Like PTSD, acute stress disorder is an anxiety disorder that involves a very specific reaction following exposure to a traumatic event or stressor. However, the duration of acute stress disorder is shorter than that for PTSD, such that the symptoms are present for at least one, two, or three days, but no more than four, five, or six weeks. For individuals exhibiting symptoms persisting for a longer period of time, a diagnosis of PTSD may be warranted.

[0118] The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a subject. The compound or pharmaceutical composition may be administered by the subject, a medical professional, or another person to the subject.

[0119] As used herein, the term “concentration difficulties” refers to the subjective feeling of a subject experiencing challenges coalescing thoughts gathering their thoughts into coherent ideas. A subject experiencing difficulties concentrating may have a reduced ability to read or converse. Concentration difficulties in a subject may be self-assessed by the subject or by a clinical professional.

[0120] As used herein, the term “C-SSRS” refers to the Columbia Suicide Severity Rating Scale, a six- item questionnaire utilized for assessment of suicidal ideation or behavior. The items of the questionnaire are as follows:

[0121] 1 . Have you wished you were dead or wished you could go to sleep and not wake up?

[0122] 2. Have you had any thoughts about killing yourself?

[0123] 3. Have you been thinking about how you might do this?

[0124] 4. Have you had these thoughts and had some intention of acting on them?

[0125] 5. Have you started to work out or worked out the details of how to kill yourself? Did you intend to carry out this plan?

[0126] 6. Have you done anything, started to do anything, or prepared to do anything to end your life?

[0127] (If yes, was this within the past 3 months?)

[0128] By “dysthymia” or “dysthymic disorder” is meant a chronically depressed mood that occurs for most of the day, more days than not, for at least two years. In children and adolescents, the mood may be irritable rather than depressed, and the required minimum duration is one year. During the two-year period (one year for children or adolescents), any symptom-free intervals last no longer than 2 months. During periods of depressed mood, at least two of the following additional symptoms are present: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration, or difficulty making decisions, and feelings of hopelessness. The symptoms cause clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning. The diagnosis of dysthymia is not made if: the individual has ever had a manic episode, a mixed episode, a hypomanic episode; has ever met the criteria for a cyclothymic disorder; the depressive symptoms occur exclusively during the course of a chronic psychotic disorder (e.g., schizophrenia); or if the disturbance is due to the direct physiological effects of a substance or a general medical condition. After the initial two-years of dysthymic disorder, major depressive episodes may be superimposed on the dysthymic disorder (“double depression”). Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, I 994. Diagnostic guidance for psychological disorders can be found, for example, in the ICD-10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and the DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).

[0129] As used herein, the term “first-degree relative” refers to a relative to a subject or patient having substantially similar genetic material and / or are directly blood-related. Examples of first-degree relatives include parents, siblings, or offspring.

[0130] By “free base equivalent” is meant an amount corresponding to a free base equivalent in a mass of psilocin benzoate. For example, a free base equivalent of 1 mg of psilocin is equal to 1 mg of psilocin in its free base form and equal to 1 .60 mg of psilocin in its benzoate salt form (e.g., 1 ,0x(326.39 / 204.27) to account for the mass contribution of the benzoic acid).

[0131] As used herein, the term “inability to feel” refers to a subjective experience by a subject wherein they show reduced interest in activities that previously brought joy, happiness or pleasure. An inability to feel may be diagnosed as anhedonia in a subject. The feeling of disinterest may apply to the surroundings, and a subject may lack observation thereof. The inability to feel also manifests in a subject by causing a reduced ability to show emotion or a reduced ability to empathize. Symptoms associated with loss of ability to feel may be loss of joy associated with a subjects’ interests, loss of feeling for friends or acquaintances, or emotional paralysis. Emotional paralysis is indicated by the inability of a subject to experience anger, grief, pleasure, fear, or other emotions, or lacking the ability to empathize with friends and / or family.

[0132] As used herein, the term “inner tension” refers to feelings of general discomfort, the feeling of being “on-edge” or edginess, jumpiness, inner turmoil, dread, anguish, panic, lack of trust in other individuals, difficulty making decisions, or feeling unsure in a subject. Inner tension in a subject may be assessed by any of the evaluations described herein, by assessment of a clinical professional, or by selfevaluation by the subject.

[0133] As used herein, the term “psychological support” may refer to one or more of the following: therapy, psychotherapy, talk therapy, cognitive behavioral therapy (CBT), counseling, guided self-help and / or group therapy.

[0134] As used herein, the term “generalized anxiety disorder” refers to a condition characterized by excessive anxiety and worry (i.e. , apprehensive expectation). Typically, the excessive anxiety and worry occur on more days than not for a period of time (e.g., one, two, three, or four months or more). The anxiety and worry can be associated with (i) restlessness, feeling keyed up, or on edge; and / or (ii) muscle tension. The anxiety and worry can be associated with (a) a marked avoidance of situations in which a negative outcome could occur; (b) a marked time and effort preparing for situations in which a negative outcome could occur; (c) a marked procrastination in behavior or decision-making due to worries; and (d) repeatedly seeking reassurance due to worries. The anxiety, worry, or physical symptoms can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in many, but not necessarily all individuals with GAD.

[0135] As used herein, the term “MADRS” refers to the Montgomery-Asberg Depression Rating Scale, a ten-item questionnaire used by clinical professionals for assessing the severity of depression in a subject. The items of the assessment are divided by category to which the questions gauge symptoms, and are as follows:

[0136] 1 . apparent sadness

[0137] 2. reported sadness

[0138] 3. inner tension

[0139] 4. reduced sleep

[0140] 5. reduced appetite

[0141] 6. concentration difficulties

[0142] 7. lassitude

[0143] 8. inability to feel

[0144] 9. pessimistic thoughts

[0145] 10. suicidal thoughts

[0146] A subject may be evaluated in each item on a scale of 1 to 6 in the MADRS assessment, yielding an overall score totaling from 0 to 60. Higher scores indicate more severe depressive symptoms in a subject. For the purposes of the invention, subjects with an elevated MADRS score that becomes reduced to less than 9, following any of the methods of treatment disclosed herein, is considered to be in remission. A clinically significant reduction in MADRS score is a lowering by 6 or more points on the assessment scale. In some embodiments of the invention, the MADRS assessment is used to identify subjects in need of the methods of treatment disclosed herein. It is contemplated that the methods of treatment disclosed herein may be used as methods of treating a subject experiencing symptoms as described by some of the MADRS assessment items — subjects receiving the methods of treatment are expected to experience an alleviation of symptoms. Alleviation of symptoms in a subject may characterised, but not limited to, an improvement in mood or happiness (i.e. , a reduction in sadness), a reduction of inner tension, an increase in the amount of quality of sleep, an improvement or increase in appetite, an improvement in concentration, a renewed interest in surroundings, or an increase in the enjoyment of life. Assessment of a subject by other evaluation tools as described above are expected, and symptoms are expected to be improved following treatment regardless of the evaluation tool utilized by the subject or medical professional. The symptoms are determined to be “reduced” or “increased” in a subject by comparing a baseline evaluation and subsequent evaluations of a subject. The skilled artisan recognizes the subjective nature of the symptoms as reported by the subject or evaluated by a medical practitioner.

[0147] As used herein, the terms “obsessive compulsive disorder,” “OCD,” and “anxiety and obsessive- compulsive spectrum disorders” refer to a condition characterized by obsessions and / or compulsions. Obsessions are recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that usually cause marked anxiety or distress in which the obsessed individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e., by performing a compulsion). Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly. The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent, or are clearly excessive. Typically the obsessions or compulsions are time consuming (for example, take more than 1 hour a day), or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0148] As used herein, the term “panic disorder” refers to a condition characterized by recurrent and unexpected panic attacks. Panic disorder includes both panic disorder with agoraphobia and panic disorder without agoraphobia. Subjects with this condition can exhibit one or both of the following: (i) a persistent concern or worry about additional panic attacks or their consequences (e.g., losing control, having a heart attack, going crazy); and / or (ii) significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks), which may include agoraphobic avoidance.

[0149] As used herein, the term “patient” refers to a subject undergoing any of the methods of treatment disclosed herein or being administered any of the pharmaceutical compositions described herein. The terms “patient” and “subject” are considered to be interchangeable with respect to the methods of treatment herein described.

[0150] As used herein, the terms “pharmacologically effective amount,” “therapeutically effective amount,” and the like, when used in reference to a therapeutic composition, refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, such as clinical results. For example, in the context of treating depression, described herein, these terms refer to an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition. The quantity of a given composition described herein that will correspond to such an amount may vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like. An “effective amount,” “pharmacologically effective amount,” or the like, of a composition of the present disclosure, also include an amount that results in a beneficial or desired result in a subject as compared to a control (e.g., a decrease in the score on the Montgomery-Asberg Depression Rating Scale).

[0151] As used herein, the terms “post traumatic stress disorder” and “PTSD” refer to a condition that arises as a delayed and / or protracted response to a stressful event or situation (either short- or long- lasting) of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime). Predisposing factors such as personality traits (e.g., compulsive, asthenic) or previous history of neurotic illness may lower the threshold for the development of the condition or aggravate its course, but they are neither necessary nor sufficient to explain its occurrence. PTSD is a less frequent and more enduring consequence of psychological trauma than the more frequently seen acute stress response. PTSD has been recognized in the past as railway spine, stress syndrome, shell shock, battle fatigue, traumatic war neurosis, and post-traumatic stress syndrome. Diagnostic symptoms include re-experiencing original trauma(s), by means of flashbacks or nightmares; avoidance of stimuli associated with the trauma; and increased arousal, such as difficulty falling or staying asleep, anger, and hypervigilance. Formal diagnostic criteria (DSM-V, DSM-IV, and / or ICD-9) require that the symptoms last more than one month and cause significant impairment in social, occupational, or other important areas of functioning (e.g., problems with work and / or relationships). Formal diagnostic criteria can include: (i) intrusion symptoms that are associated with the traumatic event (e.g., (a) spontaneous or cued recurrent, involuntary, and intrusive distressing memories of the traumatic event; (b) recurrent distressing dreams in which the content and / or affect of the dream is related to the event; (c) dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event were recurring (such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings; (d) intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an embodiment of the traumatic event; and / or (e) marked physiological reactions to reminders of the traumatic event); (ii) persistent avoidance of stimuli associated with the traumatic event (e.g., (a) thoughts, feelings, or physical sensations that arouse recollections of the traumatic event; (b) activities, places, physical reminders, or times (e.g., anniversary reactions) that arouse recollections of the traumatic event; and / or (c) people, conversations, or interpersonal situations that arouse recollections of the traumatic event); (iii) negative alterations in cognitions and mood that are associated with the traumatic event (e.g., (a) inability to remember an important embodiment of the traumatic event (typically dissociative amnesia); (b) persistent and exaggerated negative expectations about one’s self, others, or the world; (c) persistent distorted blame of self or others about the cause or consequences of the traumatic event; (d) pervasive negative emotional state (e.g., fear, horror, anger, guilt, or shame); (e) markedly diminished interest or participation in significant activities; (f) feeling of detachment or estrangement from others; and / or (g) persistent inability to experience positive emotions (e.g., unable to have loving feelings, psychic numbing); and (iv) alterations in arousal (i.e., hyperarousal) and reactivity that are associated with the traumatic event (e.g., (a) irritable, angry, or aggressive behavior; (b) reckless or self-destructive behavior; (c) hypervigilance; (d) exaggerated startle response; (e) problems with concentration; and / or (f) sleep disturbance (e.g., difficulty falling or staying asleep, or restless sleep)). Formal diagnostic criteria can further include that the duration of disturbance is more than a certain period of time (e.g., one month, three months, or six months) and that the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. In a small proportion of patients the condition may show a chronic course over many years and a transition to an enduring personality change. The three main symptoms associated with PTSD are (1 ) “reliving” the traumatic event, such as flashbacks, nightmares, intrusive thoughts and recollections, (2) avoidance behaviors and emotional numbing, and (3) hypersensitivity such as an inability to sleep, anxious feelings, overactive startle response, hyperarousal, hypervigilance, irritability, and outbursts of anger.

[0152] As used herein, the term “preservative” refers to the class of pharmaceutically acceptable excipients that are useful in improving the shelf life of a composition by inhibiting undesirable chemical transformations and / or the growth of microbes. Non-limiting examples of preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol.

[0153] As used herein, the terms “psychological disorder” and “psychological condition” refer to a condition characterized by a disturbance in one’s emotional or behavioral regulation that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental function. Psychological disorders include, but are not limited to depressive disorders (major depression, treatment resistant depression, melancholic depression, atypical depression, or dysthymia), anxiety disorders (end of life anxiety, generalized anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, or social phobia), addictions (e.g., substance abuse, e.g., alcoholism, tobacco abuse, or drug abuse)), eating disorders (e.g., anorexia nervosa, bulimia nervosa, and binge eating disorder) and compulsive behavior disorders (e.g., primary impulse-control disorders or obsessive-compulsive disorder). Psychological disorders can be any psychological condition associated with one or more symptoms, e.g., somatic symptoms (e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause), or psychosomatic symptoms (e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome). Psychological disorders also include repetitive body-focused behaviors, such as tic disorders (e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder). In some cases, development of a psychological disorder is associated with or characterized by a prodromal symptom, such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying / brooding, decreased self-esteem, irritability, dependency, self-pity, somatic complaints, decreased effectiveness, helplessness, and decreased initiation of voluntary responses.

[0154] As used herein, the term “reduced appetite” refers to a reduced desire to consume food in a subject relative to a previous baseline appetite of the subject. The subject may be experiencing a loss of appetite associated with any of the diseases, disorders, or conditions described herein. In some cases, the subject experiences a reduction in sense of taste or identifies food as tasteless. In other examples, a reduced appetite in a subject is indicated by the need of persuasion or coercion of the subject to facilitate consumption of food.

[0155] As used herein, the term “reduced sleep” refers to a reduction in the amount or quality of sleep as compared to a baseline level of sleep the subject experienced in the subject’s past. A subject experiencing any of the disorders, diseases, or conditions described herein may have symptoms that restrict the ability to sleep a normal amount of time or compromise the quality of sleep that they achieve, such that the subject then feels unrested. Reduced sleep is characterized by an inability to sleep for full durations, insomnia leading to an inability to fall asleep, repetitive waking from sleep, and feeling unrested despite having slept a normal duration. Sleep disturbances are contemplated to fall within the scope of experiences leading to reduced sleep and are indicated by a subject experiencing any of the above disordered sleep patterns. “Sleep disturbances” may be further characterised by, but not limited to, a reduction in amount of sleep, repetitive waking from sleep, inability to fall asleep e.g. insomnia, excessive sleep e.g. hypersomnia, non-restorative sleep, sleep apnea, experiencing nightmares, circadian rhythm sleep-wake disorders, restless leg syndrome, narcolepsy, or sleep-related hypoventilation.

[0156] As used herein, the term “sensitivity” refers to a subject being prone to having an adverse reaction or experiencing an adverse event as a result of exposure to a compound to which the subject has the sensitivity. Examples of the adverse reactions or adverse events the subject may experience as a result of the sensitivity include but are not limited to panic, panic attacks, anxiety, confusion, agitation, disorientation, accidental self-injury, suicidal ideation, attempted suicide, violent behavior, psychosis, derealization or a disconnection from reality, mania, depersonalization, or convulsions in a subject.

[0157] As used herein, the term “significant suicide risk” in a subject is refers to suicidal ideation as endorsed under items 4 and 5 on the C-SSRS within the previous 12 months, or suicidal behaviors present within the previous 12 months, or a clinical assessment according to any evaluation that indicates risk of suicide by a subject. For example, a subject may be considered to have a significant suicide risk if the subject is determined to be in significant mental distress, has mentioned thoughts of suicide to a friend of family member, or has made statements indicating that the subject is considering or has considered suicide.

[0158] As used herein, the terms “social phobia” and “social anxiety disorder” refer to a condition characterized by fear or anxiety associated with one or more social situations. Subjects with this condition typically exhibit a marked fear or anxiety about one or more social situations in which the person is exposed to possible scrutiny by others. Examples include social interactions (e.g., having a conversation), being observed (e.g., eating or drinking), or performance in front of others (e.g., giving a speech). Typically, an individual with this condition (i) fears that he or she will act in a way, or show anxiety symptoms that will be negatively evaluated (i.e., be humiliating, embarrassing, lead to rejection, or offend others); (ii) the social situations almost invariably provoke immediate fear or anxiety; (iii) the social situations are avoided or endured with intense fear or anxiety; and (iv) the fear or anxiety is out of proportion to the danger posed by the social situation. In children, the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking or refusal to speak in social situations. The fear, anxiety, and avoidance can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0159] As used herein, the term “tonicity agent” refers to a class of pharmaceutically acceptable excipients that are used to control osmolarity of pharmaceutical compositions. Non-limiting examples of a tonicity agent include substantially neutral buffering agents (e.g., phosphate buffered saline, tris buffer, or artificial perilymph), dextrose, mannitol, glycerin, potassium chloride, and sodium chloride (e.g., as a hypertonic, isotonic, or hypotonic saline).

[0160] As used herein, the terms “treat,” “treating,” or “treatment” refer to administration of a compound or pharmaceutical composition for a therapeutic purpose. To “treat a disorder” or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease to ameliorate the disease or one or more symptoms thereof to improve the patient’s condition (e.g., by reducing one or more symptoms of inflammation). The term “therapeutic” includes the effect of mitigating deleterious clinical effects of certain inflammatory processes (i.e., consequences of the inflammation, rather than the symptoms of inflammation). The methods of the invention can be used as a primary prevention measure, i.e. , to prevent a condition or to reduce the risk of developing a condition. Prevention refers to prophylactic treatment of a patient who may not have fully developed a condition or disorder, but who is susceptible to, or otherwise at risk of, the condition. Thus, in the claims and embodiments, the methods of the invention can be used either for therapeutic or prophylactic purposes.

[0161] By “major depressive disorder” is meant a clinical course that is characterized by one or more major depressive episodes in an individual without a history of manic, mixed, or hypomanic episodes. The diagnosis of unipolar depression is not made if: manic, mixed, or hypomanic episodes develop during the course of depression; if the depression is due to the direct physiological effects of a substance; if the depression is due to the direct physiological effects of a general medical condition; if the depression is due to a bereavement or other significant loss (“reactive depression”); or if the episodes are better accounted for by schizoaffective disorder and are not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder. If manic, mixed, or hypomanic episodes develop, then the diagnosis is changed to a bipolar disorder. Depression may be associated with chronic general medical conditions (e.g., diabetes, myocardial infarction, carcinoma, and stroke). Generally, unipolar depression is more severe than dysthymia. The essential feature of a major depressive episode is a period of at least two to 15 weeks during which there is either depressed mood or loss of interest or pleasure in nearly all activities. In children and adolescents, the mood may be irritable rather than sad. The episode may be a single episode or may be recurrent. The individual also experiences at least four additional symptoms drawn from a list that includes changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. Each symptom must be newly present or must have clearly worsened compared with the person's preepisode status. The symptoms must persist for most of the day, nearly every day, for at least two consecutive weeks, and the episode must be accompanied by clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, 1994). Diagnostic guidance for psychological disorders can be found, for example, in the ICD-10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and the DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).

[0162] Other features and advantages of the invention will be apparent from the following Detailed Description, Examples, Figure, and Claims.

[0163] BRIEF DESCRIPTION OF THE DRAWINGS

[0164] The following drawings form part of the present specification and are included to further demonstrate certain embodiments of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0165] FIG. 1 shows the mean plasma concentration for a range of psilocin benzoate dosages. FIG. 2 shows the subjective drug intensity (SDI) scores for a range of psilocin benzoate dosages.

[0166] FIG. 3 shows the 30-claim revised Mystical Experience Questionnaire (MEQ30) scores for a range of psilocin benzoate dosages.

[0167] FIG. 4 shows the XRPD pattern of NAP Pattern 1 from psilocin 1 ,5-naphthalenedisulfonate (bottom scan).

[0168] FIG. 5 shows the XRPD of the NAP Pattern 1 from the crystalline solid remaining after dissolution in saline solution.

[0169] FIG. 6 shows the change from baseline in MADRS score over time from a Phase Ila clinical trial of ELE-101 (psilocin benzoate).

[0170] FIG. 7 shows the mean change from baseline in MADRS scores over time from a Phase Ila clinical trial of ELE-101 .

[0171] DETAILED DESCRIPTION OF THE INVENTION

[0172] Psilocin has the structure:

[0173] Psilocybin is a phosphate prodrug for psilocin, and when administered to a subject, psilocybin is metabolized to form psilocin. Psilocybin undergoes an enzymatic dephosphorylation reaction resulting in a loss of the phosphate group revealing psilocin’s hydroxy group. Psilocybin exists as a zwitterion in which the phosphate and amine ionize each other. The existence of a zwitterion limits the solubility of psilocybin and also curtails its ability to make a salt with an alternate acid that could exist under physiologically tolerated conditions. Removing the phosphate group allows the formation of alternate acid salt forms of psilocin’s dimethylamine that are not possible to be prepared with psilocybin. Being able to exist in a non-ionized form, Psilocin is much more lipid soluble in comparison to psilocybin, and therefore is capable of crossing the blood brain barrier more effectively to elicit a response. Psilocin has a high affinity for and is able to activate the 5-HT2A receptor, which plays a key role in regulating mood, sexual behavior, aggression, impulsivity, cognitive function, appetite, pain, sleep, and memory along with other behaviors. As result, psilocin has effects at 5-HT2A receptor that mimic the action of the endogenous neurotransmitter serotonin. This disclosure provides therapeutically effective doses of psilocin, and compositions thereof, that are useful in therapy, such as in the treatment of a patient having a psychological condition or a neurological injury.

[0174] T eatment Methods

[0175] The disclosure provides psilocin salt forms useful for treating psychological conditions, neurological injuries, pain, cephalic pain (e.g., headache), inflammatory conditions, and anxiety. Psychological Conditions

[0176] The pharmaceutical compositions comprising psilocin, or a psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, of the invention can be used to treat psychological conditions. The psychological condition may be any psychological condition described herein. In some embodiments the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder (PTSD), an eating disorder, or compulsive behavior. In some embodiments, the psychological condition may be depression. The psychological condition may also be anxiety. The anxiety may be experienced by a subject who is receiving palliative care or is enrolled in a hospice program. In certain embodiments, the subject who is experiencing anxiety has symptoms such as hypervigilance, fatigue, racing thoughts, irritability, excessive worry, and / or fear. In certain embodiments, the subject may be experiencing symptoms such as difficulty concentrating (i.e., concentration difficulties), sleep disturbances, reduced sleep quality, reduction or loss of appetite, inner tension, or an inability or reduced ability to feel. In some embodiments, the subject experiences an improvement or reduction of symptoms following the administration.

[0177] The subject diagnosed with a psychological condition may be diagnosed by evaluation of the subject’s symptoms by a physician, clinician, or therapist based on a physical examination. For example, a blood test may be used to evaluate blood concentration levels of certain biomarkers such as hormones, calcium, vitamin D, electrolytes, and iron in diagnosing depression. Additionally, or alternatively, for patients with a possible depression condition a depression screening test may be performed by the physician, clinician, or therapist to aid in the diagnosis of depression. In some embodiments, the methods described herein may be used to treat psychosomatic pain conditions. In some embodiments, the psychosomatic pain condition may be fibromyalgia, chronic fatigue, migraines, or back pain.

[0178] The pharmaceutical compositions of the invention may be for use in the treatment of a subject in need thereof having a disease or condition selected from one or more of: major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression, dysthymia, anxiety, treatment-resistant anxiety, end of life anxiety, generalised anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, social phobia, substance abuse, alcoholism, tobacco abuse, drug abuse, anorexia nervosa, bulimia nervosa, binge eating disorder, primary impulse-control disorders, and obsessive-compulsive disorder. A subject experiencing symptoms associated with these diseases, disorders, or conditions may be evaluated by a physician or medical professional to determine the severity of the condition, establish a clinical history of the condition, or to determine a course of treatment.

[0179] In some embodiments, the evaluation by a physician or medical professional may be through a structured clinical interview. In some embodiments, the evaluation may be through a diagnostic questionnaire. In some embodiments, the questionnaire may be self-administered. The evaluation may be performed using one or more of the following assessments: the Columbia Suicide Severity Rating Scale (C-SSRS), the clinical global impression (CGI) rating scale, the Structure Clinical Interview for DSM-IV or DSM-V (SCID or SCID-5 / SCID-V), the Mini-International Neuropsychiatric Interview (MINI), the World Health Organization Composite International Diagnostic Review (Cl DI), the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), the Diagnostic Interview for Genetic Studies (DIGS), the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression Scale (CES-D), the EQ-5D or EQ-5D-Y, the Hamilton Rating Scale for Depression (abbreviated by any of HDRS, HRSD, or HAM-D), the Montgomery- Asberg Depression Rating Scale (MADRS), the Social Problem-Solving Inventory- Revised (SPSI-RTM) assessment in either long form (52 questions) or short form (25 questions), the Beck Hopelessness Scale, the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), the Patient Health Questionnaire (PHQ, usually version 9: PHQ-9), the Reminiscence Functions Scale (RFS), the Short Form Health Survey (SF-36), the Social Adjustment Scale-Self Report (SAS-SR), the Social Functioning Questionnaire (SFQ), the Geriatric Depression Scale (GDS), the Life Satisfaction Index (also known as the Life Satisfaction Ratings, LSR), the Alcohol Use Disorders Identification Test, or the Anorectic Behavior Observation Scale. It is contemplated that alternative or unlisted assessments utilized for analogous purposes (e.g. clinical assessment or evaluation) to those listed above may be utilized for the methods of treatment disclosed herein. In other embodiments, modified versions of any of the above assessments may be used. For example, the MINI may be administered as the MINI, or it may be administered as the MINI-Screen, the MINI-Tracking, or MINI-KID variants of the assessment. Another example of an alternative assessment includes the self-rating version of the MADRS, the MADRS-S. In some embodiments, the results of the assessments are collected by a medical professional. In other embodiments, the results of the assessments are reported by the subject (i.e. self-reported). It is contemplated that the collection of responses to any of the above evaluations falls within the scope of “clinical assessment” for a subject for determining the need of utilizing the methods of treatment described herein.

[0180] The subject may experience an improvement of one or more symptoms of the disease or condition after administration of the pharmaceutical composition. The improvement may be measured by a clinical assessment, such as by a survey or evaluation performed by a medical professional. The improvement in the one or more symptoms may be self-reported by the subject based on the subject’s assessment of his or her symptoms. For example, the subject may report an increase in their ability to concentrate, increase in appetite, reduction in sleep disturbances, increase in sleep quality, reduction in suicidal thought, reduction in inner tension, or increase in the ability to feel after administration of the pharmaceutical composition. In some embodiments, the improvement to the one or more symptoms is assessed by a clinical professional using one or more methods known in the art. The improvement to the one or more symptoms may occur within 1 day, 2 days, 3 days, 4 days, or 5 days of administration of the pharmaceutical composition to the subject. In some embodiments, the improvement to the one or more symptoms occurs within 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or 3 years of administration of the pharmaceutical composition to the subject.

[0181] Neurological Injuries

[0182] The pharmaceutical compositions comprising psilocin, or a psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, of the invention can be used to treat a neurological injury. The neurological injury may be any neurological injury. In some embodiments, the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury. The methods of treating a neurological injury described herein may reduce acute inflammation. In certain embodiments, hippocampal hyperactivity is reduced. In particular embodiments, the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury, by administering the pharmaceutical compositions comprising psilocin, or a psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, as needed to pain, inflammation, and / or other symptoms associated with the neurological injury.

[0183] Neurodegenerative Conditions

[0184] The pharmaceutical compositions comprising psilocin, or a psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, of the invention can be used to treat neurodegenerative conditions. The neurodegenerative condition to be treated can be Alzheimer’s disease, Huntington’s disease, or Parkinson’s disease, among others.

[0185] Inflammatory Conditions

[0186] The pharmaceutical compositions comprising psilocin, or a psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, of the invention can be used to treat inflammatory conditions. The inflammatory condition to be treated can be a lung inflammation (e.g., chronic obstructive pulmonary disease (COPD)), neuroinflammation (e.g., inflammation associated with Alzheimer’s disease), chronic inflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, and / or septicemia.

[0187] Chronic Pain

[0188] The pharmaceutical compositions comprising psilocin, or a psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, of the invention can be used to treat conditions associated with chronic pain. The chronic pain may result from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, or sciatica. The chronic pain may arise from an operation. The chronic pain may also be pain associated with a particular disease or condition such as nephropathy, multiple sclerosis, shingles, or complex regional pain syndrome. As used herein, a disorder or condition associated with cephalic pain is a disorder or condition which has as one of its symptoms cephalic / head pain (e.g., headache). Examples of such disorders or conditions include trigeminal autonomic cephalalgias such as episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). Other examples of disorders or conditions which can be treated according to the present invention include vascular headaches (e.g., migraine headaches), tension headaches, headaches associated with the use of a substance (e.g., triptans such as sumatriptan, benzodiazepines such as alprazolam, analgesics such as ibuprofen, ergots such as ergotamine, opioids such as morphine, recreational drugs such as caffeine, nicotine, alcohol, and hormone replacement therapy containing, for example, estrogen) or its withdrawal. Yet additional examples of disorders or conditions associated with cephalic pain include miscellaneous headache unassociated with a structural lesion, headache associated with a nonvascular intracranial disorder, headache associated with a non-cephalic infection, headache associated with a metabolic disorder, headache associated with a disorder of the cranium, neck, eyes, nose, sinuses, teeth, mouth, or other facial or cranial structure, nerve trunk pain and deafferentation pain. Compositions

[0189] The invention features pharmaceutical compositions including a psilocin salt form of the invention and a pharmaceutically acceptable excipient. Examples of a pharmaceutically acceptable excipients include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form. Examples of other excipients include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.

[0190] The pharmaceutical compositions of the invention can include one or more solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, tonicity agents, solid binders, and lubricants, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Eighteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1990) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional excipient medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoyl lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, diastearoyl phosphatidylethanolamine (DSPE) and its pegylated esters, such as DSPE-PEG750 and, DSPE-PEG2000, phosphatidic acid, phosphatidyl glycerol and phosphatidyl serine; and hydroxypropyl- beta-cyclodextrin and sulfonic acid substituted cyclodextrin (e.g., CAPTISOL™). Commercial grades of lecithin which are preferred include those which are available under the trade name Phosal® or Phospholipon® and include Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90 NG; soy-phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; 5% dextrose solution and combinations with the foregoing aqueous solutions; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0191] The above-described compositions, in any of the forms described above, can be used for treating a disease or condition described herein. An effective amount refers to the amount of an active compound / agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment. A pharmaceutical composition of this invention can be administered parenterally, orally, nasally, rectally, topically, or buccally. The term “parenteral” as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.

[0192] For use in the methods and compositions of the invention, the pharmaceutically acceptable psilocin salt, may be contained in any appropriate amount in any suitable carrier substance formulated for intravenous infusion and is generally present in an amount of 0.01 -95% by weight of the total weight of the composition. In particular embodiments, the pharmaceutically acceptable psilocin salt is present in an amount of 0.01 -5% by weight of the of the total weight of the composition. In some embodiments, an aqueous solution suitable for intravenous infusion including the pharmaceutically acceptable psilocin salt may be formulated in a saline solution. The formulation of infusions is well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy (23rded.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). Compositions for infusion use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added. The solution of the pharmaceutically acceptable psilocin salt suitable for intravenous infusion may have a pH of about 3 and about 9 (e.g., 3±1 , 4±1 , 5±1 , 6±1 , 7±1 , 8±1 , and 9±1 ). Furthermore, the solution of the pharmaceutically acceptable psilocin salt suitable for intravenous infusion may include a concentration of the pharmaceutically acceptable psilocin salt between about 0.1 mg / mL and about 50 mg / mL (e.g., 0.1 ±0.1 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.5 mg / mL, 1 ±0.5 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11 ±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, 15±1 mg / mL, 16±1 mg / mL, 17±1 mg / mL, 18±1 mg / mL, 19±1 mg / mL, 25±5 mg / mL, 30±5 mg / mL, 35±5 mg / mL, 40±5 mg / mL, 45±5 mg / mL, and 50±5 mg / mL). In some embodiments, the aqueous solution has between about 1 mg / mL and about 15 mg / mL (e.g., 1 ±1 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 1 1 ±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, and 15±1 mg / mL) of any one of pharmaceutically acceptable salts of psilocin described herein. In particular embodiments, the aqueous solution has between about 0.1 mg / mL and about 1 mg / mL (e.g., 0.1 ±0.1 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.1 mg / mL, 0.6±0.1 mg / mL, 0.7±0.1 mg / mL, 0.8±0.1 mg / mL, 0.9±0.1 mg / mL, and 1 ±0.1 mg / mL) of any one of pharmaceutically acceptable salts of psilocin described herein.

[0193] A sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Such solutions include, but are not limited to, 1 ,3-butanediol, mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acids, such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, or polyoxyethylated versions thereof. These oil solutions or suspensions also can contain a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents. Other commonly used surfactants, such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms also can be used for the purpose of formulation.

[0194] A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used excipients include, but are not limited to, lactose and corn starch. Lubricating agents, such as, but not limited to, magnesium stearate, also are typically added. For oral administration in a capsule form, useful diluents include, but are not limited to, lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

[0195] Other routes of administration may also be considered for administering the pharmaceutical compositions described herein to a subject in an appropriate amount. Nonlimiting examples of the routes of administration considered within the scope of the invention include, but are not limited to, oral, intravenous, subcutaneous, transdermal, topical, intranasal, or transmucosal. In some embodiments, the pharmaceutical compositions are self-administered. In other embodiments, the pharmaceutical compositions may be administered by a medical practitioner. Automated devices capable of delivering controlled doses of the pharmaceutical compositions over time to the subject are also contemplated to be within the scope of the present invention. In some cases, administration of the pharmaceutical composition may be facilitated by a kit the provides the composition and a device for administration. In preferred embodiments, the kit contains a device that enables intravenous infusion of the pharmaceutical composition. In other embodiments, the kit contains instructions for use of the pharmaceutical composition.

[0196] Administration of the pharmaceutical compositions to a subject may be co-administered or administered at substantially different times than another drug substance or medicament which the subject is concurrently receiving. In some embodiments, the methods of treating a subject may be in a subject undergoing treatment with a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA) or any other antidepressant compound for more than 6 weeks or more prior to the first administration of the pharmaceutical composition disclosed herein. In other embodiments, the subject has discontinued treatment for at least 3 weeks prior to a first administration of the pharmaceutical composition. In some cases, administration of the pharmaceutical compositions may be substantially at the same time as (e.g. <30 minutes between) administration of a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA) or any other antidepressant compound. In other examples, administration of the pharmaceutical compositions disclosed herein may occur at substantially different times, e.g. >30 minutes apart, from administration of an antidepressant compound. In some embodiments, the method of treatment also includes administering to the subject Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibria), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen / Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4) and / or Triiodothyronine (T3) alongside the pharmaceutical compositions and at any of the time periods listed above.

[0197] The dosing schedule and frequency of administration corresponding to the methods of treatment disclosed herein may vary depending on considerations by a medical practitioner, as the skilled artisan recognizes. For example, the administration of the pharmaceutical composition may occur between once every day and once every 31 days, between once every 7 days and once every 21 days, or about once every 14 days. In some embodiments, the administration occurs once every week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the administration may occur more than once during any given administration period.

[0198] The pharmaceutical composition may be administered to the subject once every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 14 days, every 15 days every 16 days, every 17 days, every 18 days, every 19 days, every 20 days, every 21 days, every 22 days, every 23 days, every 24 days, every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 14 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 35 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 40 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 50 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 60 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 70 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 80 days. In some embodiments, the pharmaceutical composition is administered to the subject once every about 90 days. In some embodiments, the pharmaceutical composition is administered to the subject once between about every 35 days and about every 90 days. The pharmaceutical composition may be administered to the subject once every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 1 1 weeks, every 12 weeks, every 13 weeks, or every 14 weeks. In some embodiments, the pharmaceutical composition is administered to the subject once between about every 5 weeks and about every 13 weeks (e.g. once every 4±1 weeks, every 5±1 weeks, every 6±1 weeks, every 7±weeks, every 8±1 weeks, every 9±1 weeks, every 10±1 weeks, every 1 1 ±1 weeks, every 12±1 weeks, every 13±1 weeks, or every 14±1 weeks).

[0199] The above-described compositions, in any of the forms described above, may be stored in a light impenetrable container. For example, the compositions described herein may be contained in an amber bottle.

[0200] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

[0201] EXAMPLES

[0202] Example 1. A Phase I, Randomised, Double-Blind, Placebo-Controlled Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Intravenous Doses of ELE-101 (psilocin benzoate) in Healthy Adult Participants

[0203] A phase 1 clinical trial has been performed investigating the safety and tolerability of single intravenous (IV) administrations of a range of doses (0.25, 0.75, 2, 3 and 4 mg) of ELE-101 in healthy participants. Further objectives of the clinical trial were:

[0204] • To evaluate the plasma pharmacokinetics (PK) of psilocin and its putative metabolites following IV administration.

[0205] • To evaluate the subjective drug intensity (SDI) of single dose IV administrations of a range of doses of ELE-101 .

[0206] • To determine time from the start of infusion to Readiness for Discharge.

[0207] The plasma PK of psilocin can be seen in Figure 1 . Peak plasma concentration of psilocin was reached in <10 minutes and the doses tested showed a consistent and predictable PK profile, a desirable property for a pharmaceutical. The plasma psilocin levels reached thresholds previously shown to correlate with maximal receptor occupancy.

[0208] The SDI of single dose IV administrations of a range of doses of ELE-101 can be seen in Figure 2. Subjective effects began within 2 minutes of start of the infusion with ratings of 9 or 10 achieved with the 4 mg dose in 4 / 6 subjects. The mean time to discharge was 105 minutes with the 3 mg dose and 141 minutes with the 4 mg dose.

[0209] The mean total 30-item Mystical Experience Questionnaire (MEQ30) scores can be seen in Figure 3. Subjects were able to reach >3 on all factors with the 4 mg dose, a complete mystical experience. The MEQ30 is a self-report measure that has been used to measure mystical-type experiences in studies of psychedelics. It is known that the occurrence of a mystical experience, following treatment with a psychedelic, is a primary predictor of therapeutic outcomes in patients. Typically, a complete mystical experience is defined as scoring 60% or more on all four factors of the MEQ30. The four factors of the MEQ30 are: mystical, positive mood, transcendence of time and space, and ineffability.

[0210] All events were reported as mild with the exception of 1 moderate headache.

[0211] Previous work with psilocybin, the prodrug of psilocin, has shown that there is substantial variability in the ability of psilocybin to induce such an experience in study populations (see, e.g., Becker et al., Clin Pharmacol Ther. 2022 Apr;111 (4):886-895; and Davis et al., JAMA Psychiatry. 2021 May 1 ;78(5):481 -489). In contrast, the present studies surprisingly demonstrate that about 4 mg of psilocin was sufficient to induce a complete mystical experience across a variety of subjects. In addition, psilocybin experiences are reported to be significantly longer (i.e., 6-8 hours compared with a mean time to discharge of 141 minutes for 4 mg psilocin) requiring much higher healthcare resource utilization (and associated cost of treatment).

[0212] Example 2. A Phase Ila, Open-Label Study to Evaluate a Range of Pharmacodynamic Effects of a Single Intravenous Dose of ELE-101 (psilocin benzoate) in Patients with Major Depressive Disorder

[0213] A phase Ila clinical trial is underway to evaluate the SDI of a single IV infusion of ELE-101 in patients with major depressive disorder (MDD). Further objectives of the clinical trial will be:

[0214] • To evaluate the antidepressant effect of a single IV dose of ELE-101 in MDD patients.

[0215] • To evaluate the safety and tolerability of a single IV dose of ELE-101 in MDD patients.

[0216] • To evaluate the plasma PK of psilocin and its putative metabolites following IV administration.

[0217] • To evaluate the efficacy of a single IV dose of ELE-101 in MDD patients.

[0218] • To determine time from the start of infusion to Readiness for Discharge.

[0219] The purpose of this open-label study is to evaluate a range of PD effects of a single 10 minute 4mg IV infusion of ELE-101 (4mg free base equivalent psilocin benzoate) in patients with MDD (with a MADRS score of >26 and CGI-S score of >4 at Screening and Baseline).

[0220] Patients will receive a single IV injection of ELE-101 on Day 1 . Following dosing, patients will be closely monitored by trained Attendants. A physician will also be present in the clinic for monitoring and support until at least 2 hours post dose or longer where clinically indicated. Psychiatric support will be available from a qualified psychiatrist.

[0221] Patients may either not have taken any antidepressants for at least 3 months prior to Day -1 , or may be receiving a chronic stable dose of a single permitted SSRI (citalopram, escitalopram, sertraline, fluoxetine, paroxetine or vilazodone) for at least 6 weeks prior to Day -1 until the end of the study. Each participant will be in a separate space so they cannot see or interact with other participants for the duration of their drug administration and safety assessment. They will be provided with eye shades and noise cancelling headphones and will be encouraged to allow themselves to focus inwards on their internal experience.

[0222] Inclusion criteria Participants meeting the following criteria will be included in the study: Male or female participants aged 18 to 65 years, inclusive.

[0223] Participants have a body mass index (BMI) of 18 to 35 kg / m2, inclusive.

[0224] Participant is >50 kg.

[0225] Healthy (except for a diagnosis of MDD) as determined by the Investigator, based on no clinically significant findings from medical evaluation including medical history, physical examination, concomitant medication, vital signs, 12-lead ECG, clinical laboratory evaluations (including haematology, biochemistry, urinalysis and serology [Screening visit only]) at the Screening visit and admission.

[0226] Male participants must use a condom during the trial and for 3 months after dosing, if their partner is a woman of childbearing potential. In addition, their female partner of childbearing potential must use an additional method of highly effective contraception prior to dosing until 3 months after dosing.

[0227] Female participants; of childbearing potential must be established on a highly effective method of contraception in combination with male partner’s use of a condom prior to dosing until 3 months after dosing. Participants must have a negative pregnancy test at Screening and Day -1 . of nonchildbearing potential (i.e. , postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy and bilateral oophorectomy). Postmenopausal is defined as spontaneous amenorrhea for at least 12 months, and a serum follicle stimulating hormone (FSH) level within the menopausal range, unless the participant is taking hormone replacement therapy or is using hormonal contraception.

[0228] Participants are able and willing to give written informed consent, adhere to the compliance terms during participation in the study, undergo the examinations and testing set forth in the study Protocol and clearly and reliably communicate their subjective symptoms to the Investigator.

[0229] Patient has a diagnosis of MDD as diagnosed by a structured clinical interview (Mini International Neuropsychiatric Interview [MINI], Version 7.0.2) conducted at Screening. The patient must have a MADRS score >26 at Screening and Day -1 .

[0230] The patient must have a CGI-S scale score >4 at Screening and Day -1 .

[0231] Concomitant depression therapy:

[0232] Patients must either not have taken any antidepressants for at least 3 months prior to Day -1 , or the patient has been on a stable, chronic dose of a single permitted SSRI medication (citalopram, escitalopram, sertraline, fluoxetine, paroxetine or vilazodone) for at least 6 weeks prior to Day -1 and must remain on this dose until the end of the study.

[0233] Patients receiving any form of psychotherapy or counselling must have been receiving therapy on a regular schedule for at least 2 months prior to Day -1 and must be willing to continue their therapy until the end of the study. Patients must be willing to avoid starting any new antidepressant medications, new treatments for depression or any new psychoactive medications until the end of the study.

[0234] Exclusion criteria

[0235] Participants with any of the following will be excluded from study participation:

[0236] Current, or history (within the last 6 months) of, alcohol or substance use disorder, such as but not limited to, cannabis, cocaine, ketamine, opiates, MDMA, psilocybin and LSD (excluding nicotine and caffeine) as assessed by a structured clinical interview (MINI, Version 7.0.2) conducted at Screening, or determined by a self-report or a positive urine drugs of abuse test and / or alcohol breath test at Screening or Day -1 . Repeat tests may be considered by the Investigator with justification. For clarity, prior use of psilocybin recreationally or in a previous medical trial is not by definition exclusionary.

[0237] Use of pharmacological compounds for psychiatric or neurological conditions acting on the central nervous system within 30 days or 5 half-lives (whichever is longer) prior to Screening, with the exception of the permitted SSRIs.

[0238] Current or clinically relevant history of schizophrenia, psychosis, bipolar disorder, delusional disorder, paranoid personality disorder, schizoaffective disorder, borderline personality disorder or panic disorder, as assessed by a structured clinical interview (MINI, Version 7.0.2) at Screening.

[0239] In first-degree relatives, a history of schizophrenia, psychosis, bipolar disorder, delusional disorder, paranoid personality disorder or schizoaffective disorder.

[0240] History of a diagnosis of Hallucinogen Persistent Perceptual Disorder (HPPD).

[0241] Significant suicide risk as defined by:

[0242] Suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within 1 year prior to Screening or on Day 1 , or

[0243] Suicidal behaviours within 1 year prior to Screening, or

[0244] Clinical assessment of significant suicidal risk during Participant interview.

[0245] Other personal circumstances and behaviour that is incompatible with establishment of rapport or safe exposure to psilocin, as judged by the Investigator.

[0246] History or evidence of clinically relevant physical or mental health (except a diagnosis of MDD) interfering with the study as determined by medical history and physical examinations obtained during Screening as judged by the Investigator (including, but not limited to: psychiatric, respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders or any other medically relevant condition as judged by the Investigator). Clinically relevant abnormal laboratory results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), 12-lead ECG and vital signs, echocardiogram, or physical findings at Screening and / or Day -1 as judged by the Investigator, that in the Investigator’s opinion may constitute a risk for an individual who is exposed to psilocin. In case of uncertain or questionable results, tests performed during Screening may be repeated to confirm eligibility or judged to be clinically irrelevant for healthy participants.

[0247] Any other concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study.

[0248] Current or previous medical history of any significant cardiovascular conditions, such as myocardial infarction or ischaemia, symptomatic arrhythmias, cerebral vascular accident or transient ischaemic attack. History or evidence of valvulopathy or pulmonary hypertension. Participants with abnormal vital signs which are clinically significant and out of range at Screening or Day 1 , following triplicate readings.

[0249] AST, ALT, gamma-glutamyl transferase (GGT) or total bilirubin levels >1 x ULN at Screening or Day -1 . These laboratory evaluations may be repeated once at the discretion of the Investigator. If the repeat test is within the reference range of 1 x ULN, the participant may be included only if the Investigator considers that the previous finding will not introduce additional risk factors and will not interfere with interpretation of safety data.

[0250] QTcF >450 msec at Screening or predose on Day 1 , following triplicate ECG readings.

[0251] Presence of clinically significant ECG abnormalities at the Screening visit, as defined by medical judgement.

[0252] Participants have a presence or relevant history of any of the following medical conditions: organic brain disorders (e.g., epilepsy, seizure, intracranial hypertension, intracranial bleed and aneurysmal disease, brain tumour or other medical conditions associated with seizures or convulsions).

[0253] Participants have a known sensitivity to psilocybin, psilocin and / or any excipients present in the formulation.

[0254] Women of childbearing potential (WOCBP) who are pregnant, breastfeeding or planning to conceive.

[0255] Positive test for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody (anti-HCV) or human immunodeficiency virus I and II (anti-HIV l / ll) at Screening.

[0256] Inclusion in a previous group / cohort for this clinical study.

[0257] Participants have a renal condition resulting in estimated Glomerular Filtration Rate (eGFR) <60 mL / min / 1 .73m2 at Screening.

[0258] Use of any classical psychedelics (mescaline, LSD, psilocybin and DMT) within 3 months prior to Screening.

[0259] Participants consume >2 cigarettes / day, or >3 mg of e-cigarettes / day.

[0260] Intake of >21 units of alcohol weekly, and the inability to refrain from alcohol use from 48 hours prior to each visit during the study. One unit is defined as 10 millilitres (10 grams) of pure alcohol. This is equivalent to a 285 mL glass (half a pint) of 3% beer or 1 (25 mL) measure of 40% spirits or 1 small glass (125 mL) of 9% wine.

[0261] Treatment with an investigational drug or device within 30 days or 5 half-lives (whichever is longer) prior to Screening. Use of any prescription or non-prescription medications, including herbal and nutritional supplements, or OTC medications within 7 days prior to dosing until the end of the study, with the exception of paracetamol (<2 g per day) and the permitted SSRIs. The Investigator and study team may review medication on a case-by-case basis to determine if its use would compromise participant safety or interfere with study procedures or data interpretation.

[0262] Participants are taking or have taken OTC doses of 5-hydroxytryptophan or St John’s Wort within 28 days prior to dosing.

[0263] Participants are taking or have taken any drugs known to inhibit monoamine oxidase within 28 days prior to dosing.

[0264] Participants have donated or received any blood or blood products within 3 months prior to dosing.

[0265] Male participants who will not abstain from sperm donation between dosing and 4 months after dosing.

[0266] Participants have veins unsuitable for venepuncture and / or cannulation.

[0267] Participants are unlikely to cooperate with the requirements of the study, in the opinion of the Investigator or designee.

[0268] Participants are receiving chronic administration of any psychoactive medication, with the exception of the permitted SSRIs. The SSRI dose must have been stable for at least 6 weeks prior to Day -1 and must remain the same until the end of the study. Other excluded psychoactive medications include, but are not limited to, typical or atypical antipsychotics, antidepressants, anxiolytics or anticonvulsants, such as tricyclic antidepressants or lithium, haloperidol, SNRIs or monoamine oxidase inhibitors, within 6 weeks prior to Screening.

[0269] Lifestyle restrictions

[0270] Participants should abstain from strenuous exercise for 48 hours prior to each visit.

[0271] Participants will be advised to limit their daily ultraviolet (UV) exposure during the study, and for 7 hours after dosing. Sun protection measures which should be taken include:

[0272] Avoiding the use of sunbeds or prolonged sunbathing.

[0273] Avoid direct exposure to sunlight.

[0274] Use of protective clothing, e.g., sunglasses, hats, etc.

[0275] The participants are required to adhere to the following restrictions:

[0276] Participants should refrain from alcohol intake for 48 hours prior to each visit. Participants may not drink >21 units of alcohol per week for the duration of the study. For example, 1 unit of alcohol is 1 small glass of 9% wine, half a pint of low strength beer (3%), or 25 mL of spirits. Participants must not smoke >2 cigarettes per day, or >3 mg e-cigarettes per day, for the duration of the study.

[0277] Participants should refrain from consuming poppy seeds 48 hours prior to Screening and Day -1 to avoid a positive result on the drugs of abuse screen.

[0278] Columbia-Suicide Severity Rating Scale The C-SSRS will be used to assess suicide potential or tendency as a study entry criterion and monitored throughout the study.

[0279] The C-SSRS is a semi-structured interview designed to assess the severity and intensity of suicidal ideation, suicidal behaviour and non-suicidal self-injurious behaviour over a specified time period. The measurement of suicidal ideation is based on five ‘yes’ or ‘no’ questions with accompanying descriptions arranged in order of increasing severity. If the participant answers ‘yes’ to either questions 1 or 2, the intensity of ideation is assessed in five additional questions related to frequency, duration, controllability, deterrents and reasons for the most severe suicidal ideation. Suicidal behaviour is assessed by asking questions categorising behaviours into actual, aborted and interrupted attempts; preparatory behaviour, and non-suicidal self-injurious behaviour.

[0280] If any item(s) on the C-SSRS are answered ‘yes’, the Investigator must review the participant’s responses in order to (a) at the Screening visit, determine the participant’s study eligibility and potential need for referral to a mental health professional, and (b) during the study evaluate the participant’s need for appropriate medical management such as a referral to a mental health professional.

[0281] A significant risk of suicide is defined as a ‘yes’ in answer to (a) questions 4 or 5 on the suicidal ideation section; or (b) any questions on any item in the suicidal behaviour section. This must be reported as an AE or SAE as appropriate and followed up accordingly. Additionally, if a participant responds ‘yes’ to any of the suicidal ideation questions 1 through 3, the Investigator should apply clinical judgement to determine the need for reporting this as an AE or SAE and the need for any appropriate referral.

[0282] For any participant who responds ‘yes’ to relevant questions postcode, their GP will be notified.

[0283] Mini Mental State Exam

[0284] The Mini Mental State Exam (MMSE) is a widely used test of cognitive function and delirium. The MMSE consists of 30-points, including tests of orientation, attention, memory, language and visual-spatial skills. The MMSE will be used at various time points.

[0285] Subjective Drug Intensity Visual Analogue Scale

[0286] A Likert scale, ranging from 0 to 10 will be used to determine the intensity of the psychedelic experience at various time points, until the effects of ELE-101 have waned. Participants will be asked to verbally indicate their current experience, where ‘0 = Not at all’ and ‘10 = Extremely’. The SDI will be performed at all PK sampling timepoints, as well as during the ‘Readiness for Discharge’ process.

[0287] Participant Dischargeability

[0288] Participants will be evaluated for dischargeability once their SDI score drops to <2 (i.e., 0, 1 or 2). This would be considered as the participant returning to baseline after their psychedelic experience. The dischargeability evaluations will include the C-SSRS and Positive Scale of the PANSS. If any item(s) on the C-SSRS relating to current suicidal ideation or reported any suicidal intent or behaviour are answered ‘yes’, the Investigator must review the participant’s responses to evaluate the participant’s need for appropriate medical management, such as referral to a mental health professional, prior to discharge from the site. Each of these discharge assessments is intended to inform the Investigator’s decision regarding dischargeability. Clinical judgement should be used to determine the appropriate time for dischargeability.

[0289] If the participant is deemed not ready for discharge, the ‘Readiness for Discharge’ process will be repeated after 10 (±2) minutes as needed.

[0290] Positive and Negative Syndrome Scale - Positive Scale

[0291] The PANSS - Positive Scale is a scale used to measure (or assess) the severity of symptoms in schizophrenia and is commonly used in clinical trials of antipsychotic agents. The Positive Scale comprises of 7 domains (delusions, conceptual disorganisation, hallucinatory behaviour, excitement, grandiosity, suspiciousness / persecution and hostility) which are rated using a 7-point scale, from ‘1 = Absent’ to ‘7 = Extreme’, with a higher total average score indicating more severe symptoms. The PANSS - Positive Scale will be performed at various time points. If a participant scores >2 to any of the questions in this assessment, the Investigator must review the participant’s responses to evaluate the participant’s need for appropriate medical management, such as referral to a mental health professional, prior to discharge from the site.

[0292] Mystical Experiences Questionnaire

[0293] The MEQ30 is a 30-item questionnaire which assesses four factors of the psychedelic experience: mystical, positive mood, transcendence of time and space, and ineffability. Participants will be asked to rate the degree to which at any time during the dosing session they experienced psychedelic effects, on a scale from 0 to 5, where ‘0 = None; not at all’ and ‘5 = Extreme (more than any other time in my life)’. The MEQ30 will be performed at various time points.

[0294] Challenging Experience Questionnaire

[0295] The CEQ is a 26-item self-report measure that will be used to assess the intensity of unpleasant reactions, or ‘challenging experiences’ to administration of ELE-101 at various time points. The CEQ assesses 7 separate factors: fear, grief, physical distress, insanity, isolation, death and paranoia. Scoring of each factor is associated with difficulty, meaningfulness, spiritual significance and change in well-being attributed to the challenging experiences. Participants will be asked to rate the intensity of each item from 0 to 5, where ‘0 = None; not at all’ and ‘5 = Extreme (more than any other time in my life)’.

[0296] Montgomery-Asberg Depression Rating Scale

[0297] The MADRS is a 10-item clinician-rated, diagnostic questionnaire used to measure depression severity. Each item is measured on a 7-point scale, from 0 to 6. Higher total MADRS scores indicate more severe depression. The MADRS will be performed at various time points.

[0298] Clinician Global Impressions Scale - Severity

[0299] The CGI-S is designed to acquaint the patient’s severity of symptoms with those of other people experiencing the same mental ailment. The CGI-S rates this severity on a 7-point scale, with (1 ) representing normal symptoms, meaning the patient is not ill, and (7) representing patient among the most severely ill. The rating (4) represents a patient that is defined as moderately ill. The CGI-S will be performed at various time points.

[0300] Results

[0301] 6 patients have so far been treated with 4 mg free base equivalent of psilocin benzoate (ELE-

[0302] 101 ) and the MADRS scores at baseline, and at various follow-up timepoints, are shown below:

[0303] The mean change at Day 2 was a reduction in MADRS score (compared with baseline) of about 25.7.

[0304] The mean change at Day 4 was a reduction in MADRS score of about 28.0. The mean change at Day 8 was a reduction in MADRS score of about 26.2. The mean change at Day 15 was a reduction in MADRS score of about 25. The mean change at Day 29 was a reduction in MADRS score of about 21 .2.

[0305] A clinically significant reduction in MADRS score is a reduction of 6 or more. A patient is considered to be in remission if they have a MADRS score of 9 or less.

[0306] It is immediately apparent from the results herein disclosed that 4 mg free base equivalent of psilocin benzoate provides a rapid and sustained antidepressant response in patients suffering with MDD.

[0307] At day 8, on average, patients remained in remission following a single administration of ELE-101 . At day 15, on average, patients remained in remission following a single administration of ELE-101.

[0308] ELE-101 was well-tolerated with mostly mild, transient adverse events and no serious or severe adverse events reported. ELE-101 also demonstrated a short treatment duration, with acute effects resolving and patients deemed ready to be discharged by Investigators within a mean time of approximately 2 hours.

[0309] In an embodiment, there is therefore provided a method of treatment of major depressive disorder, wherein the method comprises the administration of ELE-101 once every about 14 days to a patient in need thereof, wherein the administration leads to remission from major depressive disorder in a patient in need thereof.

[0310] Example 3. Further results from a Phase Ila, Open-Label Study to Evaluate a Range of Pharmacodynamic Effects of a Single Intravenous Dose of ELE-101 (psilocin benzoate) in Patients with Major Depressive Disorder

[0311] 4 of the 6 patients described in Example 2 were followed out to Day 90 (89 days from the day of dosing, which is Day 1 ) and the MADRS scores (from baseline to Day 90) are shown in Figure 6. Only 2 patients (5 and 6) completed follow-up on Day 60.

[0312] The mean MADRS total score can be seen in Figure 7.

[0313] The mean results shown in Example 2 seemed to indicate that there was an initial large response to treatment (decrease in reported MADRS) followed by a small trend back in the direction of baseline.

[0314] Surprisingly, the results disclosed herein show that such a trend was transient, with the mean reported MADRS score at both Day 60 and Day 90 being lower than that at all previous timepoints. Please see below:

[0315] The mean change at Day 60 (for those patients who completed follow-up) was a reduction in MADRS score (compared with baseline) of about 30.2. The mean change at Day 90 was a reduction in MADRS score of about 29.7.

[0316] At day 60, on average, patients remained in remission following a single administration of ELE-101 . At day 90, on average, patients remained in remission following a single administration of ELE-101 .

[0317] There is therefore provided herein a method of treatment comprising the administration of a pharmaceutical composition as described herein: between about once every 35 and about once every 90 days; between about once every 40 and about once every 90 days; between about once every 50 and about once every 90 days; between about once every 60 and about once every 90 days; between about once every 70 and about once every 90 days; or between about once every 80 and about once every 90 days.

[0318] In an embodiment, there is provided a method of treatment comprising the administration of a pharmaceutical composition as described herein about once every 90 days. In an embodiment, the pharmaceutical composition is administered about once every 80 days. In an embodiment, the pharmaceutical composition is administered about once every 70 days. In an embodiment, the pharmaceutical composition is administered about once every 60 days. In an embodiment, the pharmaceutical composition is administered about once every 50 days. In an embodiment, the pharmaceutical composition is administered about once every 40 days. In an embodiment, the pharmaceutical composition is administered about once every 35 days.

[0319] In an embodiment, there is provided a method of treatment comprising the administration of a pharmaceutical composition as described herein not more often than about once every 90 days. In an embodiment, the pharmaceutical composition is administered not more often than about once every 80 days. In an embodiment, the pharmaceutical composition is administered not more often than about once every 70 days. In an embodiment, the pharmaceutical composition is administered not more often than about once every 60 days. In an embodiment, the pharmaceutical composition is administered not more often than about once every 50 days. In an embodiment, the pharmaceutical composition is administered not more often than about once every 40 days. In an embodiment, the pharmaceutical composition is administered not more often than about once every 35 days.

[0320] In an embodiment, there is therefore provided a method of treatment of major depressive disorder, wherein the method comprises the administration of ELE-101 once every about 35, 40, 55, 60, 65, 70, 75, 80, 85 or 90 days to a patient in need thereof, wherein the administration leads to remission from major depressive disorder in a patient in need thereof.

[0321] In an embodiment, there is provided a method of treatment comprising the administration of a pharmaceutical composition as described herein: between about once every 5 and about once every 13 weeks; between about once every 6 and about once every 13 weeks; between about once every 7 and about once every 13 weeks; between about once every 8 and about once every 13 weeks; between about once every 9 and about once every 13 weeks; between about once every 10 and about once every 13 weeks; between about once every 11 and about once every 13 weeks; or between about once every 12 and about once every 13 weeks.

[0322] In an embodiment, there is provided a method of treatment comprising the administration of a pharmaceutical composition as described herein about once every 13 weeks. In an embodiment, the pharmaceutical composition is administered about once every 12 weeks. In an embodiment, the pharmaceutical composition is administered about once every 11 weeks. In an embodiment, the pharmaceutical composition is administered about once every 10 weeks. In an embodiment, the pharmaceutical composition is administered about once every 9 weeks. In an embodiment, the pharmaceutical composition is administered about once every 8 weeks. In an embodiment, the pharmaceutical composition is administered about once every 7 weeks. In an embodiment, the pharmaceutical composition is administered about once every 6 weeks. In an embodiment, the pharmaceutical composition is administered about once every 5 weeks.

[0323] In an embodiment, there is provided a method of treatment comprising the administration of a pharmaceutical composition as described herein not more often than about once every 13 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 12 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 11 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 10 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 9 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 8 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 7 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 6 weeks. In an embodiment, the pharmaceutical composition is administered not more often than about once every 5 weeks.

[0324] In an embodiment, there is therefore provided a method of treatment of major depressive disorder, wherein the method comprises the administration of ELE-101 once every about 5, 6, 7, 8, 9, 10, 11 , 12, or 13 weeks to a patient in need thereof, wherein the administration leads to remission from major depressive disorder in a patient in need thereof.

[0325] Example 4. Psilocin Salts

[0326] To identify psilocin salts with improved properties, a salt screen was performed with 24 different counterions and 3 different solvent systems. Crystalline material with a novel XRPD pattern was isolated from experiments with 13 of the counterions and their properties assessed. Following identification of preferred salts with optimal properties, polymorph screening of these salts was conducted.

[0327] The results are disclosed in US11312684 and US20240124398A1 , the content of each of which is incorporated herein by reference in their entirety.

[0328] In an embodiment, the pharmaceutical composition comprises a psilocin salt wherein the salt anion is selected from: acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, hexanoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iodide, isethionate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfate, tartrate, teoclate, tosylate, and triethiodide.

[0329] In an embodiment, the pharmaceutical composition comprises a crystalline psilocin salt as characterized by one or more peaks in the Table below:

[0330] It will be appreciated that different salts of psilocin will have different formula weights and any reference herein to a specific mass (mg) of a psilocin salt refers to the mass of that specific psilocin salt required to provide that specific mass (mg) of psilocin freebase when administered. For example, psilocin freebase has a weight of 204.27 g / mol, whilst psilocin benzoate has a weight of 326.38 g / mol. A pharmaceutical composition comprising about 4 mg of psilocin benzoate should be understood to refer to a pharmaceutical composition comprising about 6.39 mg psilocin benzoate, the amount of psilocin benzoate equivalent to 4 mg psilocin freebase.

[0331] Example 5. ELE-101 (psilocin benzoate) in Patients with Major Depressive Disorder Following Discontinuation of Other Antidepressant Drugs.

[0332] A subject suffering from major depressive disorder and undergoing treatment with an active agent selected from a selective serotonin reuptake inhibitor (SSR I), a serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA) or any other antidepressant compound ceases treatment with the active agent. The subject undertakes a washout period of 7-28 days. Following the washout period, the subject is dosed with a single 10 minute IV infusion containing about 4 mg of psilocin, or about 4 mg psilocin freebase equivalent of a pharmaceutically acceptable salt thereof. A reduction in depression symptoms is observed in the subject in the weeks subsequent to the dosing.

[0333] OTHER EMBODIMENTS

[0334] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

[0335] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0336] Other embodiments are within the claims.

Claims

CLAIMSWhat is claimed is:1 . A method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising: (i) about 4 mg of psilocin, or about 4 mg psilocin freebase equivalent of a pharmaceutically acceptable salt thereof, and (ii) one or more pharmaceutically acceptable carriers or excipients, wherein the disease or condition is selected from one or more of: major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression, dysthymia, anxiety, treatment-resistant anxiety, end of life anxiety, generalised anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, social phobia, substance abuse, alcoholism, tobacco abuse, drug abuse, anorexia nervosa, bulimia nervosa, binge eating disorder, primary impulse-control disorders, and obsessive-compulsive disorder.

2. The method of claim 1 , wherein the pharmaceutical composition is suitable for intravenous administration.

3. The method of claim 2, wherein the method comprises the intravenous infusion of the pharmaceutical composition, to the subject, over about 10 minutes, optionally, to induce a complete mystical experience in the subject.

4. The method of claim 3, wherein administration of the pharmaceutical composition to the subject induces a complete mystical experience as identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-claim revised Mystical Experience Questionnaire (MEQ30) and / or through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire.

5. The method of claim 3 or claim 4, wherein the complete mystical experience is induced within about 5, 10, 15, 20, 25 or 30 minutes of administration of the pharmaceutical composition.

6. The method of claim 3 or claim 4, wherein the complete mystical experience is induced within about 5, 10, 15, 20, 25 or 30 minutes of initiation of administration of the pharmaceutical composition.

7. The method of any one preceding claim, wherein the complete mystical experience is resolved within about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125,130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 minutes of administration of the pharmaceutical composition.

8. The method of any one of claims 1 -7, wherein the pharmaceutical composition is for use in a method of rapidly treating moderate to severe major depressive disorder in a subject, wherein a clinicallysignificant reduction in MADRS score is present within about 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition.

9. The method of any one of claims 1 -8, wherein the pharmaceutical composition is for use in a method of rapidly treating moderate to severe major depressive disorder in a subject, wherein a clinically significant reduction in MADRS score is present within about 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and wherein the clinically significant reduction in MADRS score is a reduction from baseline of at least about 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 points.

10. The method of any one of claims 1 -9, wherein the pharmaceutical composition is for use in a method of rapidly treating moderate to severe major depressive disorder in a subject, wherein a clinically significant reduction in MADRS score is present within about 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and said reduction is sustained following administration.11 . The method of claim 10, wherein the reduction in MADRS score is sustained for about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks.

12. The method of any one of claims 1 -11 , wherein the subject is ready for discharge within about 90, 100, 110, 120, 130, 140, 150 or 160 minutes following administration.

13. The method of any one of claims 1 -12, wherein the subject is ready for discharge within about 90, 100, 110, 120, 130, 140, 150 or 160 minutes following initiation of administration.

14. The method of any one of claims 1 -13, wherein the subject is ready for discharge within about 140 minutes following initiation of administration.

15. The method of any one of claims 1 -14, wherein the pharmaceutical composition is for use in a method of treatment without concomitant treatment with one or more further active agents, optionally without concomitant treatment with one or more further active agents selected from: a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA) or any other antidepressant compound; optionally wherein the subject discontinues treatment with the one or more further active agents prior to undergoing treatment with the pharmaceutical composition.

16. The method of any one of claims 1 -14, wherein the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents.

17. The method of claim 16, wherein the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents selected from: a selective serotonin reuptake inhibitor (SSRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA) or any other antidepressant compound.

18. The method of claim 16 or claim 17, wherein the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents selected from: Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen / Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4) and / or Triiodothyronine (T3).

19. The method of claim 16, wherein the pharmaceutical composition is for use in a method of treatment alongside one or more SSRIs.

20. The method of claim 19, wherein the pharmaceutical composition is for use in a method of treatment alongside one or more further active agents selected from: citalopram, escitalopram, sertraline, fluoxetine, paroxetine or vilazodone.21 . The method of claim 20, wherein the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30 or 40 mg once daily of citalopram.

22. The method of claim 20, wherein the pharmaceutical composition is for use in a method of treatment alongside 10 or 20 mg once daily of escitalopram.

23. The method of claim 20, wherein the pharmaceutical composition is for use in a method of treatment alongside 50, 100, 150 or 200 mg once daily of sertraline.

24. The method of claim 20, wherein the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30, 40, 50 or 60 mg once daily of fluoxetine.

25. The method of claim 20, wherein the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30 or 40 mg once daily of paroxetine.

26. The method of claim 20, wherein the pharmaceutical composition is for use in a method of treatment alongside 10, 20, 30 or 40 mg once daily of vilazodone.

27. The method of any one of claims 1 -26, wherein the method of treatment further comprises the provision of psychological support to the subject.

28. The method of any one of claims 1 -27, wherein the method of treatment further comprises the provision of psychological support to the subject prior to administration of the pharmaceutical composition.

29. The method of any one of claims 1 -28, wherein the method of treatment further comprises the provision of psychological support to the subject following administration of the pharmaceutical composition.

30. The method of any one of claims 1 -29, wherein the method of treatment is a method of treatment of a subject without a history of Hallucinogen Persisting Perceptual Disorder (HPPD).31 . The method of any one of claims 1 -30, wherein the method of treatment is a method of treatment of a subject without a history of diagnosis of Hallucinogen Persisting Perceptual Disorder (HPPD).

32. The method of any one of claims 1 -31 , wherein the method of treatment is a method of treatment of a subject without current, or a history within 6 months prior to administration of the pharmaceutical composition, of alcohol or substance use disorder, such as but not limited to, cannabis, cocaine, ketamine, opiates, MDMA, psilocybin and LSD, but excluding nicotine and caffeine use, as assessed by a structured clinical interview, such as MINI Version 7.0.2, conducted prior to administration, or determined by a self-report or a positive urine drugs of abuse test and / or alcohol breath test prior to administration.

33. The method of any one of claims 1 -32, wherein the method of treatment is a method of treatment of a subject without current, or a history within 6 months prior to administration of, use of pharmacological compounds for psychiatric or neurological conditions acting on the central nervous system, excluding SSRIs.

34. The method of any one of claims 1 -33, wherein the method of treatment is a method of treatment of a subject without current or clinically relevant history of schizophrenia, psychosis, bipolar disorder, delusional disorder, paranoid personality disorder, schizoaffective disorder, borderline personality disorder or panic disorder, as assessed by a structured clinical interview, such as MINI Version 7.0.2, prior to administration.

35. The method of any one of claims 1 -34, wherein the method of treatment is a method of treatment of a subject without, in first-degree relatives, a history of schizophrenia, psychosis, bipolar disorder, delusional disorder, paranoid personality disorder or schizoaffective disorder.

36. The method of any one of claims 1 -35, wherein the method of treatment is a method of treatment of a subject without significant suicide risk.

37. The method of claim 36, wherein the method of treatment is a method of treatment of a subject without: a) Suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within 1 year prior to administration; b) Suicidal behaviours within 1 year prior to administration; or c) Clinical assessment of significant suicidal risk prior to administration.

38. The method of any one of claims 1 -37, wherein the method of treatment is a method of treatment of a subject without a known sensitivity to psilocybin or psilocin.

39. The method of any one of claims 1 -38, wherein the method of treatment is a method of treatment of a subject without a known sensitivity to any tryptamine alkaloid.

40. The method of any one of claims 1 -39, wherein the method of treatment is a method of treatment of a subject without current or previous medical history of any significant cardiovascular conditions, such as myocardial infarction or ischaemia, symptomatic arrhythmias, cerebral vascular accident or transient ischaemic attack.41 . The method of any one of claims 1 -40, wherein the method of treatment is a method of treatment of a subject without a history or evidence of valvulopathy or pulmonary hypertension.

42. The method of any one of claims 1 -41 , wherein the method of treatment is a method of treatment of a subject without aspartate transaminase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) or total bilirubin levels >1 x upper limit of normal (ULN) prior to administration.

43. The method of any one of claims 1 -42, wherein the method of treatment is a method of treatment of a subject without a QT corrected for heart rate (QTcF) >450 msec prior to administration, optionally as determined by triplicate electrocardiogram (ECG) readings.

44. The method of any one of claims 1 -43, wherein the method of treatment is a method of treatment of a subject without clinically significant ECG abnormalities.

45. The method of any one of claims 1 -44, wherein the method of treatment is a method of treatment of a subject without a presence or relevant history of any of the following medical conditions: organic brain disorders, such as epilepsy, seizure, intracranial hypertension, intracranial bleed and aneurysmal disease, brain tumour or other medical conditions associated with seizures or convulsions.

46. The method of any one of claims 1 -45, wherein the method of treatment is a method of treatment of a subject who is not a woman of childbearing potential (WOCBP) who is pregnant, breastfeeding or planning to conceive.

47. The method of any one of claims 1 -46, wherein the method of treatment is a method of treatment of a subject who does not test positive for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody (anti-HCV) or human immunodeficiency virus I and II (anti-HIV l / ll).

48. The method of any one of claims 1 -47, wherein the method of treatment is a method of treatment of a subject having an estimated Glomerular Filtration Rate (eGFR) of at least 60 mL / min / 1 ,73m2.

49. The method of any one of claims 1 -48, wherein the subject has not used any classical psychedelic compound, such as mescaline, LSD, psilocybin or DMT, within 3 months of administration of the pharmaceutical composition.

50. The method of any one of claims 1 -49, wherein the subject consumes less than 2 cigarettes per day and less than 3 mg of e-cigarettes per day.51 . The method of any one of claims 1 -50, wherein the subject has not been administered 5- hydroxytryptophan or St John’s Wort within 28 days prior to administration.

52. The method of any one of claims 1 -51 , wherein the subject has not been administered a monoamine oxidase inhibitor within 28 days prior to administration.

53. The method of any one of claims 1 -52, wherein the subject has not donated or received any blood or blood products within 3 months prior to administration.

54. The method of any one of claims 1 -53, wherein the subject abstains from sperm donation for 4 months following the last administration of the pharmaceutical composition.

55. The method of any one of claims 1 -54, wherein the subject has veins suitable for venepuncture and / or cannulation.

56. The method of any one of claims 1 -55, wherein the subject refrains from alcohol intake for 48 hours prior to each administration.

57. The method of any one of claims 1 -56, wherein the subject refrains from consuming poppy seeds 48 hours prior to each administration.

58. The method of any one of claims 1 -57, wherein the subject is diagnosed with major depressive disorder, or moderate to severe major depressive disorder (MDD), by a licensed professional in accordance with accepted medical practice.

59. The method of any one of claims 1 -58, wherein the pharmaceutical composition comprises 4 mg freebase equivalent of a pharmaceutically acceptable salt of psilocin wherein the salt anion is selected from: acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, hexanoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iodide, isethionate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfate, tartrate, teoclate, tosylate, and triethiodide.

60. The method of claim 59, wherein the salt is crystalline.61 . The method of claim 59 or claim 60, wherein the salt is psilocin benzoate.

62. The method of claim 59 or claim 60, wherein the salt is psilocin benzoate and the pharmaceutical composition comprises about 6.4 mg psilocin benzoate.

63. The method of claim 59 or claim 60, wherein the salt is psilocin benzoate and the pharmaceutical composition comprises about 6.39 mg psilocin benzoate.

64. The method of any one of claims 60-63, wherein the crystalline psilocin benzoate is characterised by one or more peaks at diffraction angle 20(°) 9.4±0.5, 10.9±0.5, 12.3±0.5, 13.3±0.5, 14.5±0.5, 15.3±0.5, 16.3±0.5, 16.4±0.5, 18.2±0.5, 18.9±0.5, 19.3±0.5, 19.7±0.5, 20.0±0.5, 20.8±0.5, 21 ,3±0.5, 21 ,9±0.5, 22.6±0.5, 22.9±0.5, 23.8±0.5, 24.1 ±0.5, 24.9±0.5, 25.6±0.5, 26.0±0.5, 26.3±0.5, 26.5±0.5, 26.9±0.5, 27.5±0.5, and 28.5±0.5 (BEN Pattern 1 ) as measured using an x-ray wavelength of 1.5406 A.

65. The method of claim 59 or claim 60, wherein the salt is psilocin tartrate.

66. The method of claim 65, wherein the crystalline psilocin tartrate is characterised by one or more peaks at diffraction angle 20 (°) selected from 6.7±0.5, 12.6±0.5, 13.4±0.5, 14.7±0.5, 15.8±0.5, 16.2±0.5, 17.2±0.5, 18.8±0.5, 19.9±0.5, 20.8±0.5, 21.8±0.5, 22.5±0.5, 23.4±0.5, 23.7±0.5, 24.7±0.5, 25.5±0.5, 26.5±0.5, 27.0±0.5, 28.5±0.5, and 29.4±0.5 (TAR Pattern 1 ) as measured using an x-ray wavelength of1 .5406 A.

67. The method of claim 59 or claim 60, wherein the salt is psilocin succinate.

68. The method of claim 67, wherein the crystalline psilocin succinate is characterised by one or more peaks at diffraction angle 20 (°) selected from 9.7±0.5, 11 .2±0.5, 12.3±0.5, 13.8±0.5, 15.9±0.5, 16.4±0.5, 19.4±0.5, 20.0±0.5, 21.3±0.5, 22.6±0.5, 23.3±0.5, 23.5±0.5, 23.8±0.5, 24.5±0.5, 24.7±0.5, 25.0±0.5, 28.0±0.5, 28.3±0.5, 29.0±0.5, and 29.4±0.5 (SUC Pattern 3) as measured using an x-ray wavelength of 1 .5406 A.

69. The method of claim 59 or claim 60, wherein the salt is psilocin 1 ,5-naphthalenedisulfonate.

70. The method of claim 69, wherein the crystalline psilocin 1 ,5-naphthalenedisulfonate is characterised by one or more peaks at diffraction angle 20 (°) as provided in FIG. 4 or FIG. 5 (NAP Pattern 1 ) as measured using an x-ray wavelength of 1 .5406 A.71 . The method of any one of claims 1 -70, wherein the pharmaceutical composition is an aqueous solution having a pH of between about 3.5 and about 6.5.

72. The method of claim 71 , wherein the pharmaceutical composition is an aqueous solution having a pH of about 4.5.

73. The method of claim 71 or claim 72, wherein the pharmaceutical composition is an aqueous solution comprising a citrate buffer, an acetate buffer, or a phosphate buffer.

74. The method of claim 73, wherein the pharmaceutical composition is an aqueous solution comprising 75 mM citrate buffer.

75. The method of any one of claims 71 -74, wherein the aqueous solution comprises between about 0.001% (w / v) to 2% (w / v) of an antioxidant.

76. The method of claim 75, wherein the antioxidant is vitamin C, thioglycerol, sodium bisulfite, or sodium sulfite.

77. The method of claim 76, wherein the aqueous solution comprises about 0.01 ±0.005% (w / v) sodium bisulfite.

78. The method of any one of claims 71 -77, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients selected from a preservative, or a tonicity agent.

79. The method of claim 78, wherein the pharmaceutical composition further comprises from 0.1% (w / v) to 1% (w / v) sodium chloride as a tonicity agent.

80. The method of any one of claims 71 -79, wherein the pharmaceutical composition comprises: (i) a citrate buffered aqueous solution having a pH of between 4.0 and 5.0, (ii) between about 0.0053 mg / mL and about 0.7 mg / mL of psilocin benzoate, and (iii) 0.01 to 0.075% (w / v) sodium bisulfite.81 . The method of claim 80, wherein the pharmaceutical comprises from about 50 to about 200 mM citrate buffer.

82. The method of any one of claims 1 -81 , wherein the pharmaceutical composition comprises an aqueous solution containing 75 mM citrate buffer, 0.4% w / v sodium chloride, 0.01 % w / v sodium bisulfite, wherein the volume of the solution is 15 to 30mL and the pH is 4.5.

83. The method of any one of claims 1 -82, wherein the subject is human.

84. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 14 days.

85. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 35 days.

86. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 40 days.

87. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 50 days.

88. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 60 days.

89. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 70 days.

90. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 80 days.91 . The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 90 days.

92. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject between once about every 35 days and once about every 90 days.

93. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 5 weeks.

94. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 6 weeks.

95. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 7 weeks.

96. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 8 weeks.

97. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 9 weeks.

98. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 10 weeks.

99. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 11 weeks.

100. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 12 weeks.101 . The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject once every about 13 weeks.

102. The method of any one of claims 1 -83, wherein the pharmaceutical composition is administered to the subject between once about every 5 weeks and once about every 13 weeks.

103. The method of any one of claims 84-102, wherein the disease or condition is major depressive disorder in a subject.

104. The method of any one of claims 84-102, wherein the subject has a MADRS score of <9 two days after the administration of the pharmaceutical composition.

105. The method of claims 103 or 104, wherein the subject experiences remission following the administration of the pharmaceutical composition.

106. The method of any one of claims 1 -105, wherein the subject has concentration difficulties.

107. The method of claim 106, wherein the subject experiences improved concentration after the administration.

108. The method of any one of claims 1 -107, wherein the subject has experienced at least one sleep disturbance.

109. The method of claim 108, wherein the subject experiences an improvement in sleep quality after the administration.

110. The method of any one of claims 1 -109, wherein the method of treatment is a method of treating a subject having a reduced appetite.

111. The method of claim 110, wherein the subject experiences an increase in appetite after the administration.

112. The method of any one of claims 1 -111 , wherein the subject has inner tension.

113. The method of claim 112, wherein the subject experiences a reduction in inner tension after the administration.

114. The method of any one of claims 1 -113, wherein the method of treatment is a method of treating a subject having an inability to feel.

115. The method of claim 114, wherein the subject experiences an increase in the ability to feel after the administration.

116. A pharmaceutical composition as claimed in any one of claims 1 -115.

117. A pharmaceutical composition as claimed in any one of claims 1 -116, as a composition of matter.

118. A pharmaceutical composition comprising: (i) 4 mg of psilocin, or 4 mg of psilocin freebase equivalent of a pharmaceutically acceptable salt thereof; and (ii) one or more pharmaceutically acceptable carriers or excipients.

119. A kit comprising a pharmaceutical composition as claimed in any one of claims 1 -118 and instructions for use.

120. A kit comprising a pharmaceutical composition as claimed in any one of claims 1 -118 and instructions for use, for the use of any one preceding claim.121 . An intravenous (IV) infusion device comprising a pharmaceutical composition as claimed in any one of claims 1 -120.

122. The IV infusion device of claim 103, for the use of any one of claims 1 -120.

123. A pharmaceutical composition comprising a reconstitutable powder comprising (i) 4 mg of psilocin, or 4 mg psilocin freebase equivalent of a pharmaceutically acceptable salt thereof; and (ii) one or more pharmaceutically acceptable carriers or excipients, wherein the pharmaceutical composition is for use in a method of treatment of one or more of: major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression, dysthymia, anxiety, treatment-resistant anxiety, end of life anxiety, generalised anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, social phobia, substance abuse, alcoholism, tobacco abuse, drug abuse, anorexia nervosa, bulimia nervosa, binge eating disorder, primary impulse-control disorders or obsessive-compulsive disorder, in a subject in need thereof, wherein, optionally, administration of the pharmaceutical composition induces a complete mystical experience in the subject.

Images