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WO2024254190A2 - Médicaments psychoactifs et leur utilisation pour le traitement de pathologies et de troubles psychiatriques et neurologiques - Google Patents

Médicaments psychoactifs et leur utilisation pour le traitement de pathologies et de troubles psychiatriques et neurologiques Download PDF

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Publication number
WO2024254190A2
WO2024254190A2 PCT/US2024/032615 US2024032615W WO2024254190A2 WO 2024254190 A2 WO2024254190 A2 WO 2024254190A2 US 2024032615 W US2024032615 W US 2024032615W WO 2024254190 A2 WO2024254190 A2 WO 2024254190A2
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methylone
subject
disorder
neuropsychiatric illness
dose
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WO2024254190A3 (fr
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Blake MANDELL
Martin Stogniew
Jennifer Louise SCHMIDT
Markus SEELIG
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Transcend Therapeutics Inc
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Transcend Therapeutics Inc
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Priority to US18/784,243 priority Critical patent/US12343326B2/en
Priority to US18/790,708 priority patent/US12295937B2/en
Publication of WO2024254190A2 publication Critical patent/WO2024254190A2/fr
Publication of WO2024254190A3 publication Critical patent/WO2024254190A3/fr
Priority to US19/203,021 priority patent/US20250332139A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin

Definitions

  • MBDB N-methyl-l-(l,3-benzodioxol-5-yl)-2-aminobutane
  • MDMA medicinal chemistry groups synthesized in the 1980s.
  • MBDB is a prototypical member of the “entactogen” class, currently not Schedule I in the United States, which combines two structural features that attenuate binding at monoamine receptors: N- methylation and a-ethylation.
  • MBDB quickly became a recreational drug incorporated as a component of “Ecstasy” pills, along with MDMA and other synthetic cathinones.
  • Synthetic cathinones such as methylone (3,4-methylenedioxy-N-methylcathinone), are psychomotor stimulants that exert their effects by altering the function of plasma membrane transporters for serotonin, dopamine, and norepinephrine. Individual cathinones may vary in their potencies on each of the three monoamine neurotransmitter pathways.
  • Naturally occurring cathinone an alkaloid structurally similar to amphetamine, was originally extracted from the fresh leaves of the Catha edulis or khat plant, chewed in east Africa and the Arabian Peninsula. Synthetic structural modifications of cathinone have led to a number of “designer” derivatives that are commonly sold as “bath salts” through illicit distribution.
  • cathinone derivatives classified chemically as P-ketoamphetamines — include methylone, ethylone, butylone, mephedrone, and 3,4-methylenedioxypyrovalerone (MDPV), and act synergistically at the human dopamine transporter.
  • Cathinones and the other related classes of phenethylamines both behave as Central Nervous System (CNS) stimulants; however, cathinones usually have a lower potency than the corresponding phenethylamine analog, since the P-keto group creates a more polar molecule that is less able to cross the blood-brain barrier.
  • CNS Central Nervous System
  • Methylone s affinity for the vesicular monoamine transporter 2 (VMAT2) is about 13x lower than that of MDMA.
  • VMAT2 vesicular monoamine transporter 2
  • assays for plasmalemmal and vesicular monoamine transporters in a mouse model of locomotor activity found methylone to be a more potent 5-HT and dopamine uptake inhibitor than MDMA. After intraperitoneal administration in rats, methylone peaks in brain and serum concentration in 15-30 minutes, with a half-life of about 1-2 hours.
  • MDMA half-life ranges from 5-7 hours depending on the animal model used and dosing conditions.
  • SSRIs also diminish or prevent the therapeutic effects of MDMA due to substrate competition: side-effects such as increased blood pressure (BP) and hyperthermia are partially due to an interaction of MDMA with the serotonin carrier.
  • BP blood pressure
  • hyperthermia is partially due to an interaction of MDMA with the serotonin carrier.
  • This is another important consideration when thinking about use as a rapid-onset antidepressant or augmentation therapy.
  • Previous research studies have found an association between MDMA use and symptoms of depression or anxiety. The difficulty of assessing the causation or connection between MDMA and depression is increased given that pre-existing psychiatric problems occur in people who choose to use MDMA.
  • a meta-analysis detected an association between MDMA use and selfreported depression symptoms. The range of pharmacogenetic variation in MDMA metabolism also increases risk for depression in a sizable number of patients.
  • Psychiactive treatment is ideally administered by oneself at home or with minimal supervision. Access to MDMA and psilocybin is limited by the amount of time each administration requires, the hours of provider and safety-sitter time, and the training and licensure requirements. In addition to preparation and integration psychotherapy sessions, MDMA and psilocybin have long dosing sessions (up to 8 hours). Likewise, ketamine by IV infusion requires 3-4 hour clinic visits with physicianadministration and supervision, accompanied with intensive psychotherapy.
  • Wellbutrin an atypical triple-reuptake inhibitor (norepinephrine-dopamine reuptake inhibitor, nicotinic receptor antagonist), remains one of the most widely prescribed antidepressants (24 million prescriptions in 2018). Bupropion is often used in adjunct to SSRIs, and it has also been shown to have positive results in treating anxiety associated with depression compared with sertraline and fluoxetine. Bupropion is reported to be used off label in addition to other medications to treat panic disorder.
  • bupropion side effects include > 23% increase in chance of congenital heart defects in children in the first trimester of pregnancy, along with a constellation of neurogenic side effects such as anxiety, abdominal pain, agitation, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance.
  • neurogenic side effects such as anxiety, abdominal pain, agitation, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance.
  • neuropsychiatric pathology includes many difficult-to-treat mood, anxiety and personality disorders such as depression and PTSD, but also: fibromyalgia, suicidal ideation, substance use disorders (SUD), eating disorders, Borderline Personality Disorder (BPD) and other personality disorders, obsessive-compulsive disorder (OCD), palliative care/end-of-life anxiety, existential distress, chronic pain syndromes, body dysmorphia, phobias, social anxiety in autistic adults, and even sleep regulation.
  • fibromyalgia suicidal ideation
  • substance use disorders SUV
  • BPD Borderline Personality Disorder
  • OCD obsessive-compulsive disorder
  • a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof comprising administering a therapeutically effective amount of methylone (3,4- methylenedioxy-N-methylcathinone) or a pharmaceutical composition thereof to the subject.
  • kits for treating and/or preventing a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof comprising administering a therapeutically effective amount of 2C-B (4-Bromo-2,5- dimethoxyphenethylamine) or a pharmaceutical composition thereof to the subject.
  • MBDB N-methyl-l-(l,3- benzodioxol-5-yl)-2-aminobutane
  • methylone (3,4-methylenedioxy-N-methylcathinone) or a pharmaceutical composition thereof to the subject.
  • kits for treating and/or alleviating pain in a subject in need thereof comprising administering a therapeutically effective amount of 2C-B (4-Bromo-2,5-dimethoxyphenethylamine) or a pharmaceutical composition thereof to the subject.
  • methylone (3,4- methylenedioxy-N-methylcathinone) or a pharmaceutical composition thereof to the subject.
  • a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or a prodrug thereof in a therapeutically effective amount that results in a plasma Cmax of methylone of 15 - 3,020 ng/mL in the subject.
  • a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or
  • kits for treating a neuropsychiatric illness, and/or ameliorating a symptom thereof in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or a prodrug thereof in a therapeutically effective amount that results in a plasma Cmax of methylone of 98 - 994 ng/mL in the subject.
  • a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof
  • a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a prodrug thereof, and/or a polymorph thereof.
  • kits for treating and/or preventing a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a serotonin- norepinephrine-dopamine reuptake inhibitor and releaser that lacks agonist or antagonist activity at the 5-HT2A and 5-HT2B receptors.
  • the serotonin- norepinephrine-dopamine reuptake inhibitor and releaser lacks agonist or antagonist activity at the 168 G-protein coupled receptors (GPCRs) set forth in Table 6.
  • the methods comprise: (a) determining whether the compound is a serotonin-norepinephrine- dopamine reuptake inhibitor and releaser; and (b) measuring agonist and antagonist activity of the compound at the 5-HT2A and 5-HT2B receptors, wherein a determination that the compound is a serotonin-norepinephrine-dopamine reuptake inhibitor and releaser and that the compound lacks agonist or antagonist activity at the 5-HT2A and 5-HT2B receptors is indicative that the compound is a potential therapeutic for the neuropsychiatric illness.
  • the methods comprise: (a) determining whether the compound is a serotonin-norepinephrine- dopamine reuptake inhibitor and releaser; and (b) measuring agonist and antagonist activity of the compound at the 168 G-protein coupled receptors (GPCRs) set forth in Table 6, wherein a determination that the compound is a serotonin-norepinephrine-dopamine reuptake inhibitor and releaser and that the compound lacks agonist or antagonist activity at the 168 GPCRs is indicative that the compound is a potential therapeutic for the neuropsychiatric illness.
  • GPCRs G-protein coupled receptors
  • the methods comprise: (a) determining whether the compound is a serotonin-norepinephrine-dopamine reuptake inhibitor and releaser; and (b) measuring agonist and antagonist activity of the compound at the 168 G-protein coupled receptors (GPCRs) set forth in Table 6, wherein a determination that the compound is a serotonin-norepinephrine- dopamine reuptake inhibitor and releaser and that the compound lacks agonist or antagonist activity at the 168 GPCRs is indicative that the compound is a potential therapeutic for pain.
  • GPCRs G-protein coupled receptors
  • oral dosage forms comprising methylone and a diluent/binder, a disintegrant, and a lubricant.
  • the oral dosage form further comprises a surfactant.
  • Figure 1 shows the baseline symptom inventory for symptoms occurring in 2 or more of the 28 patients included in Cohort 2 of Example 4.
  • Figure 2 shows the Baseline Disease Severity in Cohort 2 of Example 4.
  • Figures 3A-3B show the Magnitude of Improvement in Cohort 2 for subjects in the ( Figure 3A) MDD subset and ( Figure 3B) PTSD subset.
  • Figures 4A-4B show the ( Figure 4A) Baseline Disease Severity and ( Figure 4B) Magnitude of Improvement for the patients of Example 5.
  • Figures 8A-8D Methylone has a robust antidepressant-like effect in the Forced Swim Test.
  • Figures 9A-9C Methylone improves fear extinction recall in a PTSD mouse model.
  • Figure 9A Schematic of experimental design. A single CS-US (tone-shock) pairing on day 1 was followed by 6 CS presentations in a novel context (context B). Methylone or saline vehicle was injected 30 min before extinction training on day 2. On day 3, the time spent freezing to the CS was quantified.
  • FIGS 10A-10B MBDB improves fear extinction in a PTSD mouse model.
  • a single CS-US (tone-shock) pairing on day 1 was followed by 6 conditioned stimulus (CS) presentations in a novel context (context B).
  • MBDB or saline vehicle was injected 30 min prior to extinction training on day 2. The time spent freezing to the CS was quantified on day 2.
  • Figure 15 [ 3 H]5HT binding to 5HT2B receptor expressing membranes.
  • Figure 16 2C-B maximally reverses reserpine-induced pain sensitivity in 100% of animals in a rat model of fibromyalgia. 100% of animals given 2C-B showed maximally increased hindpaw thresholds (reduced pain sensitivity) at both doses.
  • Duloxetine brandname: Cymbalta
  • a positive control also increased thresholds but to a lesser extent than 2C-B (i.e., only 44% of animals showed maximum reversal).
  • N 9-10 per group.
  • Figure 17 Methylone is shown docking to PDB structures of 5HT2A, 5HT2B and 5HT2C-
  • Figure 19 MBDB has a rapid-acting and robust anxiolytic effect, increasing time spent in the center of an open field.
  • Figure 20 Schematic for the experimental design of a study (IMPACT- 1) of methylone for PTSD treatment.
  • Figure 21 Methylone produced rapid and durable improvements in Clinician- Administered PTSD Scale for DSM-5 (CAPS-5) scores in an Open-Label Study (IMPACT- 1). Mean (range) at baseline: 47.8 (38 - 59).
  • Figures 22A-22B Figure 22A shows the mean change from baseline in Montgomery - Asberg Depression Rating Scale (MADRS) scores in an Open-Label Study (IMPACT- 1) of methylone to treat PTSD.
  • Figure 22B shows the mean change from baseline in the Anxiety Sub-Scale of MADRS.
  • Figure 23 Response and Remission on CAPS-5 in an Open-Label Study (IMPACT- 1) of methylone for the treatment of PTSD.
  • Figure 24 Pharmacokinetic analysis of plasma in rats following oral (PO), intraperitoneal (IP), intramuscular (IM) or subcutaneous (SC) injection with methylone. Doses are 15 mg/kg unless noted (20 mg/kg).
  • Figures 26A-26C Methylone and MDMA release monoamines.
  • Figures 28A-28G Structural differences between methylone and MDMA support differences in activity at 5HT2A and 5HT2C receptors. Chemical structures of ( Figure 28A) methylone or ( Figure 28B) MDMA are shown. ( Figure 28C) The diagram shows low energy conformations generated in MOE for MDMA (purple) and Methylone (blue) superimposed on the bicyclic ring system. Docking ( Figure 28D) methylone (cyan) or ( Figure 28E) MDMA (grey) to 5HT2A receptors or ( Figures 28F-28G) 5HT2C receptors demonstrates that constraints in methylone’s structure predict less binding to receptors. Orange disks indicate steric clashes. Blue cylinders and dashed lines illustrate hydrogen bonds.
  • Figures 35A-35B Schematic for the experimental design of a study (IMPACT-2) of methylone for the treatment of PTSD.
  • Figures 39A-39B Figure 39A shows the change from baseline in mean Sheehan Disability Scale (SDS) scores over time in an Open-Label Study (IMPACT- 1) of methylone to treat PTSD.
  • Figure 39B is a bar graph of the percent of patients with Mild, Moderate, or Marked Severity by SDS Domain at baseline and at the end of this study.
  • Figure 40 Bar graph showing days per week lost and underproductive at baseline, at the end of the 4-week treatment period and at the end of the Open-Label Study (IMPACT- 1) of methylone to treat PTSD.
  • Figure 41 Bar graph of the percent of patients who were Much or Very Much Improved on the Clinical Global Impression-improvement (CGLI) over time for the Open-Label Study (IMPACT- 1) of methylone to treat PTSD.
  • CGLI Clinical Global Impression-improvement
  • Figures 43A-43B Change from baseline of the Pittsburg Sleep Quality Index (PSQI) Total Score ( Figure 43A) and the PSQI Subscale Scores ( Figure 43B) for the Open-Label Study (IMPACT-1) of methylone to treat PTSD.
  • PSQI Pittsburg Sleep Quality Index
  • Figure 43B PSQI Subscale Scores
  • Figure 44 Methylone induced neuroplasticity in vitro. Graph shows the length of the 20 longest neurites from cultured neurons stimulated by methylone or vehicle.
  • Figure 45 Methylone showed rapid, robust and long-lasting improvement in fear extinction training and recall.
  • Methylone (3,4-methylenedioxy-N-methylcathinone; also known as “Pk-MDMA”) is a synthetic empathogenic cathinone and a close structural analog of MDMA, but with a >50% shorter half-life.
  • Pk-MDMA synthetic empathogenic cathinone and a close structural analog of MDMA, but with a >50% shorter half-life.
  • Methylone and MDMA resemble amphetamines and are agonists of the 5-HT2 family of serotonin receptors.
  • In vitro release assays using rat brain synaptosomes reveal that methylone is a nonselective substrate for plasma membrane monoamine transporters and receptors.
  • Methylone acts as a mixed reuptake inhibitor/releasing agent, and compared to MDMA, has 3x lower affinity for the serotonin transporter, but similar affinity for the norepinephrine and dopamine transporters. This reduced serotonergic pathway predominance is one reason why its efficacy as an antidepressant is not expected.
  • the “comedown” effects from amphetamines, including MDMA or synthetic cathinones like methylone include intense depression and fatigue. Methylone produced a widespread depletion of 5-HT and the serotonin transporter 5-HTT levels in rats that resembles a depressed neurological state. Depression has also been reported in humans using methylone.
  • adverse effects include anxiety, anorexia, derealization/depersonalization, impaired short-term memory, psychosis, hallucinations, suicidal ideations, irritability, motivation suppression, thought deceleration, wakefulness, involuntary tremors, bruxism, jaw clenching, trismus, and unsteadiness of the hands and gait.
  • methylone has mainstream potential as a CNS medication, including as an antidepressant or as a treatment for PTSD, or as an anxiolytic.
  • Methylone has advantages compared to current therapies and others in development: better efficacy to safety ratio, faster-acting effect profile, fewer drug-drug interactions, more effective combination therapy, more frequent adjunct in individual or group psychotherapy.
  • Methylone also causes fewer side effects after longer sessions or chronic usage, unlike symptoms of SSRI tolerance as efficacy wears off for a large proportion of patients.
  • SSRI tolerance symptoms include fatigue, loss of motivation, weariness, sleep disorders, restless leg syndrome, irritability, and depressive moods.
  • the present inventors further identify 2C-B (2,5-dimethoxy-4-bromophenethylamine), as a suitable agent to treat and provide symptom relief in Somatic Symptom Disorders (SSD), Depressive Disorders, PTSD, and other Central Nervous System (CNS) diseases - but especially Fibromyalgia, a syndrome of widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood disorder symptoms. Fibromyalgia treatments, such as the SNRIs duloxetine and milnacipran, are often outweighed by their potential harms, and only a minority of fibromyalgia patients might experience substantial symptom relief without adverse events.
  • SSD Somatic Symptom Disorders
  • PTSD Depressive Disorders
  • CNS Central Nervous System
  • 2C-B is a psychoactive phenethylamine reported to have limited efficacy as a 5-HT2A receptor partial agonist, yet we postulate that it is useful in 5-HT2A implicated pathophysiology. In vitro and in vivo models suggest it acts as a mixed 5-HT2A antagonist, and a 5-HT2B and 5- HT2C partial agonist - receptors which are particularly expressed on apical dendrites of neocortical pyramidal cells in layer V. It is a Schedule 1 drug due to its unfavorable characteristics and potential for abuse, as numerous hospitalizations have been tied to 2C-B ingestion via toxicology studies.
  • Chronic psychiatric disorders often share a common core of intractable symptoms that respond favorably to psychoactive medicines, via complex pharmacological effects that may be further modulated by psychotherapy.
  • Patients experience multiple co-occurring symptoms that are related to each other, have independent or concurrent temporal dimensions or gradings of severity, and may have shared underlying mechanisms.
  • Clusters can also be considered “symptom endophenotypes” which cut across syndromes and disorders via neurobiological correlates of brain circuits and neurotransmitters.
  • SSDs including Fibromyalgia are often diagnoses of exclusion, with chronic somatic symptoms of indeterminate biological or medical cause.
  • the named entities in the DSM-5 under SSD are illness anxiety disorder/hypochondriasis, functional neurological/conversion disorder, pain disorder (under which fibromyalgia is classified), body dysmorphic disorder, and somatoform disorder “not otherwise specified.” They are often comorbid with Mood & Affective disorders, which can include a mood disturbance cluster, and a neuropsychological discomfort cluster. Fibromyalgia patients can be successfully treated with 2C-B at a lower dose range from 1-24 mg, and in combination with other psychoactive medications for CNS disorders.
  • the present inventors further identify MBDB (N -methyl-l-(l,3-benzodioxol-5-yl)-2- aminobutane) as a suitable agent to treat and provide symptom relief in a wide range of anxiety disorders, or as an antidepressant.
  • Animal and human data do not point to a potential medical use for MBDB as a treatment for CNS disorders, or otherwise.
  • MBDB can be used as an anxiolytic, and this treatment effect can be reliably evaluated using measures such as the GAD-7 or the Generalized Anxiety Disorder Severity Scale (GADSS).
  • GAD-7 Generalized Anxiety Disorder Severity Scale
  • methylone 3,4- methylenedioxy-N-methylcathinone
  • a pharmaceutical composition thereof comprising administering a therapeutically effective amount of methylone (3,4- methylenedioxy-N-methylcathinone) or a pharmaceutical composition thereof to the subject.
  • the methylone dose ranges from 0.08-4 mg/kg.
  • the methylone dose ranges from 0.8-5 mg/kg.
  • the methylone dose ranges from 0.8-30 mg/kg.
  • the methylone dose ranges from 5-250 mg.
  • the methylone dose is less than 50 mg.
  • an initial dose of methylone (e.g., 50-500 mg) is administered, which is then boosted 30 minutes-4 hours later by administering a second methylone dose (e.g., an additional 25-250 mg of methylone).
  • a second methylone dose e.g., an additional 25-250 mg of methylone.
  • the methylone is administered, e.g., as a single dose or according to the foregoing dosing schedule, once a week or twice or more times per week (up to daily dosing) or two or three times a day.
  • the methylone is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • the subject is suicidal.
  • the neuropsychiatric illness is treatment-resistant.
  • the methylone is used in combination with an additional therapy for the neuropsychiatric illness.
  • the additional therapy is psychotherapy.
  • the additional therapy comprises administering one or more additional psychoactive agents to the subject.
  • the additional psychoactive agents are selected from the group consisting of selective-serotonin reuptake (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin- norepinephrine-dopamine reuptake inhibitors (SDNRIs), and anxiolytic agents.
  • SSRIs selective-serotonin reuptake
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • SNRIs serotonin-norepinephrine reuptake inhibitors
  • SDNRIs serotonin- norepinephrine-dopamine reuptake inhibitors
  • anxiolytic agents are selected from the group consisting of selective-serotonin reuptake (SSRIs), tricyclic antidepressants
  • the neuropsychiatric illness is a Depressive Disorder.
  • the Depressive Disorder is selected from the group consisting of Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Single and Recurrent Episodes, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication-Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, and combinations thereof.
  • the neuropsychiatric illness is post- traumatic stress disorder (PTSD).
  • the neuropsychiatric illness is acute stress disorder.
  • the neuropsychiatric illness is Fibromyalgia.
  • the neuropsychiatric illness is a mood disorder. In some embodiments, the neuropsychiatric illness is an anxiety disorder. In some embodiments, the neuropsychiatric illness is an eating disorder. In some embodiments, the neuropsychiatric illness is a Personality Disorder (PD). In some embodiments, the Personality Disorder is selected from the group consisting of Borderline Personality Disorder (BPD), Avoidant Personality Disorder (AvPD), Antisocial Personality Disorder (AsPD), Schizotypal Personality Disorder, Other Anxiety and Panic producing Disorders, Specific personality disorders, Impulse disorders, Gender identity disorders, Paraphilias, Other sexual disorders, Other disorders of adult personality and behavior, Unspecified disorder of adult personality and behavior, Personality and behavioral disorders due to known physiological conditions. In some embodiments, the subject with the PD also has a Depressive Disorder. In some embodiments, the neuropsychiatric illness is a substance use disorder (SUD), such as an opioid use disorder (OUD).
  • SDD substance use disorder
  • OPD opioid use disorder
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of methylone.
  • the pharmaceutical composition comprises an enantiomer of methylone.
  • the pharmaceutical composition comprises an isotopologue and/or an isotopomer of methylone.
  • the pharmaceutical composition comprises a solvate (e.g., a hydrate) of methylone.
  • the pharmaceutical composition comprises a prodrug of methylone.
  • the pharmaceutical composition comprises a polymorph of methylone.
  • kits for treating and/or preventing a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof comprising administering a therapeutically effective amount of 2C-B (4-Bromo-2,5- dimethoxyphenethylamine) to the subject.
  • the 2C-B dose ranges from 0.08-4 mg/kg.
  • the 2C-B dose ranges from 0.8-5 mg/kg.
  • the 2C-B dose ranges from 0.8-30 mg/kg.
  • the 2C-B dose ranges from 5-250 mg.
  • the 2C-B dose is less than 50 mg.
  • the 2C-B dose ranges from 5-50 mg. In some embodiments, the 2C-B dose is less than 25 mg. In some embodiments, the 2C-B dose ranges from 5-25 mg. In some embodiments, the 2C-B dose ranges from 50-350 mg. In some embodiments, the 2C-B dose ranges from 50-500 mg. In some embodiments, the 2C-B dose ranges from 50-1,000 mg. In some embodiments, the 2C-B is administered weekly. In some embodiments, the 2C-B is administered more frequently than weekly (e.g., daily). In some embodiments, the 2C-B is administered less frequently than weekly.
  • an initial dose of 2C-B is administered (e.g., 50-500 mg), which is then boosted 30 minutes-4 hours later by administering a second 2C-B dose (e.g., an additional 25-250 mg of 2C-B).
  • the 2C-B is administered, e.g., as a single dose or according to the foregoing dosing schedule, once a week or twice or more per week (up to daily dosing) or two or three times a day.
  • the 2C-B is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • the neuropsychiatric illness is a Somatic Symptom Disorders.
  • the Somatic Symptom Disorder is selected from the group consisting of Illness Anxiety Disorder, Conversion Disorder (Functional Neurological Symptom Disorder), Psychological Factors Affecting Other Medical Conditions, Factitious Disorder, Other Specified Somatic Symptom and Related Disorder, Unspecified Somatic Symptom and Related Disorder, and combinations thereof.
  • the neuropsychiatric illness is Fibromyalgia.
  • the neuropsychiatric illness is a Depressive Disorder.
  • the Depressive Disorder is selected from the group consisting of Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Single and Recurrent Episodes, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication-Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, and combinations thereof.
  • the neuropsychiatric illness is post- traumatic stress disorder (PTSD).
  • the neuropsychiatric illness is acute stress disorder.
  • the neuropsychiatric illness is a mood disorder.
  • the neuropsychiatric illness is an anxiety disorder.
  • the neuropsychiatric illness is an eating disorder. In some embodiments, the subject is suicidal. In some embodiments, the neuropsychiatric illness is treatment-resistant. In some embodiments, the 2C-B is used in combination with an additional therapy for the neuropsychiatric illness. In some embodiments, the additional therapy is psychotherapy. In some embodiments, the additional therapy comprises administering one or more additional psychoactive agents to the subject. In some embodiments, the additional psychoactive agents are selected from the group consisting of SSRIs, TCAs, MAOIs, SNRIs, SDNRIs, and anxiolytics. In some embodiments, the neuropsychiatric illness is a substance use disorder (SUD), such as an opioid use disorder (OUD).
  • SUD substance use disorder
  • ODD opioid use disorder
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of 2C-B.
  • the pharmaceutical composition comprises an enantiomer of 2C-B.
  • the pharmaceutical composition comprises an isotopologue and/or an isotopomer of 2C-B.
  • the pharmaceutical composition comprises a solvate (e.g., a hydrate) of 2C-B.
  • the pharmaceutical composition comprises a prodrug of 2C-B.
  • the pharmaceutical composition comprises a polymorph of 2C-B.
  • MBDB neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof
  • administering a therapeutically effective amount of MBDB (N -methyl-l-(l,3- benzodioxol-5-yl)-2-aminobutane) to the subject.
  • MBDB dose ranges from 0.08-4 mg/kg.
  • the MBDB dose ranges from 0.8-5 mg/kg.
  • the MBDB dose ranges from 0.8-30 mg/kg.
  • the MBDB dose ranges from 5-250 mg.
  • the MBDB dose is less than 50 mg.
  • the MBDB dose ranges from 5-50 mg. In some embodiments, the MBDB dose is less than 25 mg. In some embodiments, the MBDB dose ranges from 5-25 mg. In some embodiments, the MBDB dose ranges from 50-350 mg. In some embodiments, the MBDB dose ranges from 50-500 mg. In some embodiments, the MBDB dose ranges from 50- 1,000 mg. In some embodiments, the MBDB is administered daily. In some embodiments, the MBDB is administered less frequently than daily (e.g., twice a week). In some embodiments, the MBDB is administered weekly. In some embodiments, the MBDB is administered less frequently than weekly.
  • an initial dose of MBDB is administered (e.g., 50-500 mg), which is then boosted 30 minutes-4 hours later by administering a second MBDB dose, e.g., an additional 25-250 mg of MBDB.
  • the MBDB is administered, e.g., as a single dose or according to the foregoing dosing schedule, once a week or twice or more per week (up to daily dosing) or two or three times a day.
  • the MBDB is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • the neuropsychiatric illness is a Depressive Disorder.
  • the Depressive Disorder is selected from the group consisting of Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Single and Recurrent Episodes, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication-Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, and combinations thereof.
  • the neuropsychiatric illness is an Anxiety Disorder.
  • the Anxiety Disorder is selected from the group consisting of Generalized anxiety disorder, Panic disorder, Panic attack, Phobic anxiety disorders, Illness Anxiety Disorder, dissociative, stress-related, somatoform other nonpsychotic mental disorders, acute stress reaction, transient adjustment reaction, neurasthenia, psychophysiologic disorders, Obsessive-compulsive disorder, Reaction to severe stress and adjustment disorders, Separation Anxiety Disorder, episodic paroxysmal anxiety, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Agoraphobia, Substance/Medication-Induced Anxiety Disorder, Anxiety Disorder Due to Another Medical Condition, Anxiety in pregnancy and childbirth, Anxiety in pregnancy antepartum (before childbirth), Anxiety postpartum, Animal type phobia, Arachnophobia, Other animal type phobia, Natural environment type phobia, Fear of thunderstorms, Fear of blood, Fear of injections and transfusions, Fear of other medical care, Fear of injury, Situational type
  • the subject is suicidal.
  • the neuropsychiatric illness is treatment-resistant.
  • the neuropsychiatric illness is post-traumatic stress disorder (PTSD).
  • the neuropsychiatric illness is acute stress disorder.
  • the neuropsychiatric illness is Fibromyalgia.
  • the MBDB is used in combination with an additional therapy for the neuropsychiatric illness.
  • the additional therapy is psychotherapy.
  • the additional therapy comprises administering one or more additional psychoactive agents to the subject.
  • the additional psychoactive agents are selected from the group consisting of SSRIs, TCAs, MAOIs, SNRIs, SDNRIs, and anxiolytics.
  • the neuropsychiatric illness is a substance use disorder (SUD), such as an opioid use disorder (OUD).
  • SUD substance use disorder
  • OOD opioid use disorder
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of MBDB.
  • the pharmaceutical composition comprises an enantiomer of MBDB.
  • the pharmaceutical composition comprises an isotopologue and/or an isotopomer of MBDB.
  • the pharmaceutical composition comprises a solvate (e.g., a hydrate) of MBDB.
  • the pharmaceutical composition comprises a prodrug of MBDB.
  • the pharmaceutical composition comprises a polymorph of MBDB.
  • methylone 3,4-methylenedioxy-N-methylcathinone
  • a pharmaceutical composition thereof comprising administering a therapeutically effective amount of methylone (3,4-methylenedioxy-N-methylcathinone) or a pharmaceutical composition thereof to the subject.
  • the methylone dose ranges from 0.08-4 mg/kg. In some embodiments, the methylone dose ranges from 0.8-5 mg/kg. In some embodiments, the methylone dose ranges from 0.8-30 mg/kg. In some embodiments, the methylone dose ranges from 5-250 mg. In some embodiments, the methylone dose is less than 50 mg. In some embodiments, the methylone dose ranges from 5-50 mg.
  • the methylone dose is less than 25 mg. In some embodiments, the methylone dose ranges from 5-25 mg. In some embodiments, the methylone dose ranges from 50-350 mg. In some embodiments, the methylone dose ranges from 50-500 mg. In some embodiments, the methylone dose ranges from 50-1,000 mg. In some embodiments, the methylone is administered weekly. In some embodiments, the methylone is administered more frequently than weekly (e.g., daily). In some embodiments, the methylone is administered less frequently than weekly.
  • an initial dose of methylone (e.g., 50-500 mg) is administered, which is then boosted 30 minutes-4 hours later by administering a second methylone dose (e.g., an additional 25-250 mg of methylone).
  • a second methylone dose e.g., an additional 25-250 mg of methylone.
  • the methylone is administered, e.g., as a single dose or according to the foregoing dosing schedule, once a week or twice or more times per week (up to daily dosing) or two or three times a day.
  • the methylone is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • the methylone is used in combination with an additional therapy for pain.
  • the subject has acute pain, such as surgical and procedural pain, pain due to trauma/injury, or pain due to acute inflammatory processes.
  • the subject has chronic pain, such as cancer pain, neuropathic pain, fibromyalgia, osteoarthritis pain, or low back pain.
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of methylone.
  • the pharmaceutical composition comprises an enantiomer of methylone.
  • the pharmaceutical composition comprises an isotopologue and/or an isotopomer of methylone.
  • the pharmaceutical composition comprises a solvate (e.g., a hydrate) of methylone. In some embodiments, the pharmaceutical composition comprises a prodrug of methylone. In some embodiments, the pharmaceutical composition comprises a polymorph of methylone.
  • kits for treating and/or alleviating pain in a subject in need thereof comprising administering a therapeutically effective amount of 2C-B (4-Bromo-2,5-dimethoxyphenethylamine) to the subject.
  • the 2C-B dose ranges from 0.08-4 mg/kg.
  • the 2C-B dose ranges from 0.8-5 mg/kg.
  • the 2C-B dose ranges from 0.8-30 mg/kg.
  • the 2C- B dose ranges from 5-250 mg.
  • the 2C-B dose is less than 50 mg.
  • the 2C-B dose ranges from 5-50 mg.
  • the 2C-B dose is less than 25 mg. In some embodiments, the 2C-B dose ranges from 5-25 mg. In some embodiments, the 2C-B dose ranges from 50-350 mg. In some embodiments, the 2C-B dose ranges from 50-500 mg. In some embodiments, the 2C-B dose ranges from 50-1,000 mg. In some embodiments, the 2C-B is administered weekly. In some embodiments, the 2C-B is administered more frequently than weekly (e.g., daily). In some embodiments, the 2C-B is administered less frequently than weekly.
  • an initial dose of 2C-B is administered (e.g., 50-500 mg), which is then boosted 30 minutes-4 hours later by administering a second 2C-B dose (e.g., an additional 25-250 mg of 2C-B).
  • the 2C-B is administered, e.g., as a single dose or according to the foregoing dosing schedule, once a week or twice or more per week (up to daily dosing) or two or three times a day.
  • the 2C-B is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • the pharmaceutical composition comprises a solvate (e.g., a hydrate) of 2C-B. In some embodiments, the pharmaceutical composition comprises a prodrug of 2C-B. In some embodiments, the pharmaceutical composition comprises a polymorph of 2C-B.
  • MBDB N -methyl-l-(l,3-benzodioxol-5-yl)-2-aminobutane
  • the MBDB dose ranges from 0.08-4 mg/kg.
  • the MBDB dose ranges from 0.8-5 mg/kg.
  • the MBDB dose ranges from 0.8-30 mg/kg.
  • the MBDB dose ranges from 5-250 mg.
  • the MBDB dose is less than 50 mg.
  • the MBDB dose ranges from 5-50 mg.
  • the MBDB dose is less than 25 mg. In some embodiments, the MBDB dose ranges from 5-25 mg. In some embodiments, the MBDB dose ranges from 50-350 mg. In some embodiments, the MBDB dose ranges from 50-500 mg. In some embodiments, the MBDB dose ranges from 50-1,000 mg. In some embodiments, the MBDB is administered daily. In some embodiments, the MBDB is administered less frequently than daily (e.g., twice a week). In some embodiments, the MBDB is administered weekly.
  • the MBDB is administered less frequently than weekly.
  • an initial dose of MBDB is administered (e.g., 50-500 mg), which is then boosted 30 minutes-4 hours later by administering a second MBDB dose, e.g., an additional 25-250 mg of MBDB.
  • the MBDB is administered, e.g., as a single dose or according to the foregoing dosing schedule, once a week or twice or more per week (up to daily dosing) or two or three times a day.
  • the MBDB is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • the MBDB is used in combination with an additional therapy for pain.
  • the subject has acute pain, such as surgical and procedural pain, pain due to trauma/injury, or pain due to acute inflammatory processes.
  • the subject has chronic pain, such as cancer pain, neuropathic pain, fibromyalgia, osteoarthritis pain, or low back pain.
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of MBDB.
  • the pharmaceutical composition comprises an enantiomer of MBDB. In some embodiments, the pharmaceutical composition comprises an isotopologue and/or an isotopomer of MBDB. In some embodiments, the pharmaceutical composition comprises a solvate (e.g., a hydrate) of MBDB. In some embodiments, the pharmaceutical composition comprises a prodrug of MBDB. In some embodiments, the pharmaceutical composition comprises a polymorph of MBDB.
  • the methylone dose ranges from 5-25 mg. In some embodiments, the methylone dose ranges from 50-350 mg. In some embodiments, the methylone dose ranges from 50-500 mg. In some embodiments, the methylone dose ranges from 50-1,000 mg. In some embodiments, the methylone is administered weekly. In some embodiments, the methylone is administered more frequently than weekly (e.g., daily). In some embodiments, the methylone is administered less frequently than weekly. In some embodiments, an initial dose of methylone (e.g., 50-500 mg) is administered, which is then boosted 30 minutes-4 hours later by administering a second methylone dose (e.g., an additional 25-250 mg of methylone).
  • a second methylone dose e.g., an additional 25-250 mg of methylone.
  • the methylone is administered, e.g., as a single dose or according to the foregoing dosing schedule, once a week or twice or more times per week (up to daily dosing) or two or three times a day.
  • the methylone is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • the methylone is used in combination with an additional therapy to improve sleep.
  • improvement in sleep comprises an improvement from baseline in the Pittsburg Sleep Quality Index (PSQI) for the subject.
  • PSQI Pittsburg Sleep Quality Index
  • a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or a prodrug thereof in a therapeutically effective amount that results in a plasma Cmax of methylone of 15 - 3,020 ng/mL in the subject.
  • a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or
  • the resulting plasma Cmax of methylone of 153 - 3,020 ng/mL in the subject In some embodiments, the resulting plasma Cmax of methylone of 153 - 755 ng/mL in the subject.
  • methods of treating a neuropsychiatric illness, and/or ameliorating a symptom thereof in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N-methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or a prodrug thereof in a therapeutically effective amount that results in a plasma AUCo-24 of methylone of 104 - 25,350 ng-h/mL in the subject.
  • the Depressive Disorder is selected from the group consisting of Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Single and Recurrent Episodes, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication- Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, and combinations thereof.
  • the neuropsychiatric illness is post-traumatic stress disorder (PTSD).
  • the neuropsychiatric illness is acute stress disorder.
  • the neuropsychiatric illness is Fibromyalgia.
  • the neuropsychiatric illness is a mood disorder.
  • a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or a prodrug thereof in a therapeutically effective amount that results in a plasma Cmax of methylone of 98 - 994 ng/mL in the subject.
  • a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a polymorph thereof and/or
  • the resulting plasma Cmax of methylone of 210 - 882 ng/mL in the subject In some embodiments, the resulting plasma Cmax of methylone of 322 - 770 ng/mL in the subject. In some embodiments, the resulting plasma Cmax of methylone of 434 - 658 ng/mL in the subject. In some embodiments, the resulting plasma Cmax of methylone of about 546 ng/mL in the subject.
  • the neuropsychiatric illness is an anxiety disorder. In some embodiments, the neuropsychiatric illness is an eating disorder. In some embodiments, the neuropsychiatric illness is a Personality Disorder (PD). In some embodiments, the Personality Disorder is selected from the group consisting of Borderline Personality Disorder (BPD), Avoidant Personality Disorder (AvPD), Antisocial Personality Disorder (AsPD), Schizotypal Personality Disorder, Other Anxiety and Panic producing Disorders, Specific personality disorders, Impulse disorders, Gender identity disorders, Paraphilias, Other sexual disorders, Other disorders of adult personality and behavior, Unspecified disorder of adult personality and behavior, Personality and behavioral disorders due to known physiological conditions. In some embodiments, the subject with the PD also has a Depressive Disorder.
  • BPD Borderline Personality Disorder
  • AvPD Avoidant Personality Disorder
  • AsPD Antisocial Personality Disorder
  • Schizotypal Personality Disorder Other Anxiety and Panic producing Disorders, Specific personality disorders, Impulse disorders, Gender identity disorders, Paraphilias,
  • methylone (including stereoisomers, isotopologues and isotopomers thereof) concentrations may be measured and pharmacokinetic parameters may be calculated using any suitable techniques in the art.
  • plasma methylone (including stereoisomers, isotopologues and isotopomers thereof) concentrations may be measured using biological assays or chemical assays.
  • Such techniques include, but are not limited to, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), ultraviolet (UV) detection, fluorescence assays, liquid chromatography coupled with ultraviolet detection (LC-UV), and radio-immunoassays.
  • modulating neuroplasticity in another aspect, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising methylone (3,4-methylenedioxy-N- methylcathinone) or a pharmaceutically acceptable salt thereof, and/or an enantiomer thereof, and/or an isotopologue thereof, and/or an isotopomer thereof, and/or a solvate thereof, and/or a prodrug thereof, and/or a polymorph thereof.
  • modulating neuroplasticity comprises increasing neuroplasticity in the subject.
  • the subject has a neuropsychiatric illness.
  • the neuropsychiatric illness is post-traumatic stress disorder (PTSD). In some embodiments, the neuropsychiatric illness is acute stress disorder. In some embodiments, the neuropsychiatric illness is a Depressive Disorder. In some embodiments, the neuropsychiatric illness is Fibromyalgia. In some embodiments, the neuropsychiatric illness is an anxiety disorder.
  • PTSD post-traumatic stress disorder
  • the neuropsychiatric illness is acute stress disorder.
  • the neuropsychiatric illness is a Depressive Disorder.
  • the neuropsychiatric illness is Fibromyalgia. In some embodiments, the neuropsychiatric illness is an anxiety disorder.
  • kits for treating and/or preventing a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a serotonin- norepinephrine-dopamine reuptake inhibitor and releaser that lacks agonist or antagonist activity at the 5-HT2A and 5-HT2B receptors.
  • the serotonin- norepinephrine-dopamine reuptake inhibitor and releaser lacks agonist or antagonist activity at the 168 G-protein coupled receptors (GPCRs) set forth in Table 6.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser has a Ki for 5-HT2A greater than or equal to 8 pM and a Ki for 5-HT2B greater than or equal to 1 pM.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser has reuptake inhibition (IC50) of less than or equal to 3 pM at the serotonin transporter (SERT), and less than or equal to 1 pM at the norepinephrine transporter (NET), and less than or equal to 4 pM at the dopamine transporter (DAT); and EC50 values for neurotransmitter release of less than or equal to 2 pM at the SERT, and less than or equal to 1 pM at the NET and less than or equal to 6 pM at the DAT.
  • IC50 reuptake inhibition
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser has reuptake inhibition (IC50) of less than or equal to 1 pM at the SERT), and less than or equal to 0.5 pM at the NET, and less than or equal to 3 pM at the DAT; and an EC50 value for neurotransmitter release of greater than or equal to 2 pM at the DAT.
  • IC50 reuptake inhibition
  • agonist or antagonist activity is determined using an in vitro P-arrestin based screen and a concentration of 1 pM of the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser, and and a threshold for agonist activity is less than 30% and a threshold for antagonist activity is less than 50%.
  • agonist or antagonist activity is determined using an in vitro P-arrestin based screen and a concentration of 10
  • the subject is suicidal.
  • the neuropsychiatric illness is treatment-resistant.
  • the neuropsychiatric illness is a Depressive Disorder.
  • the Depressive Disorder is selected from the group consisting of Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Single and Recurrent Episodes, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication- Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, and combinations thereof.
  • the neuropsychiatric illness is post-traumatic stress disorder (PTSD).
  • the neuropsychiatric illness is acute stress disorder.
  • the neuropsychiatric illness is Fibromyalgia.
  • the neuropsychiatric illness is a mood disorder.
  • the neuropsychiatric illness is an anxiety disorder. In some embodiments, the neuropsychiatric illness is an eating disorder. In some embodiments, the neuropsychiatric illness is a Personality Disorder (PD). In some embodiments, the Personality Disorder is selected from the group consisting of Borderline Personality Disorder (BPD), Avoidant Personality Disorder (AvPD), Antisocial Personality Disorder (AsPD), Schizotypal Personality Disorder, Other Anxiety and Panic producing Disorders, Specific personality disorders, Impulse disorders, Gender identity disorders, Paraphilias, Other sexual disorders, Other disorders of adult personality and behavior, Unspecified disorder of adult personality and behavior, Personality and behavioral disorders due to known physiological conditions. In some embodiments, the subject with the PD also has a Depressive Disorder. In some embodiments, the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser is non-hallucinogenic and/or non-psychedelic and/or non-dissociative.
  • BPD Borderline Personality Disorder
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser is an enantiomer of methylone. In some embodiments, the serotonin-norepinephrine- dopamine reuptake inhibitor and releaser is an isotopologue and/or an isotopomer of methylone. In some embodiments, the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser is a prodrug of methylone.
  • the methods comprise: (a) determining whether the compound is a serotonin-norepinephrine- dopamine reuptake inhibitor and releaser; and (b) measuring agonist and antagonist activity of the compound at the 5-HT2A and 5-HT2B receptors, wherein a determination that the compound is a serotonin-norepinephrine-dopamine reuptake inhibitor and releaser and that the compound lacks agonist or antagonist activity at the 5-HT2A and 5-HT2B receptors is indicative that the compound is a potential therapeutic for the neuropsychiatric illness.
  • the methods comprise: (a) determining whether the compound is a serotonin-norepinephrine- dopamine reuptake inhibitor and releaser; and (b) measuring agonist and antagonist activity of the compound at the 168 G-protein coupled receptors (GPCRs) set forth in Table 6, wherein a determination that the compound is a serotonin-norepinephrine-dopamine reuptake inhibitor and releaser and that the compound lacks agonist or antagonist activity at the 168 GPCRs is indicative that the compound is a potential therapeutic for the neuropsychiatric illness.
  • GPCRs G-protein coupled receptors
  • agonist and antagonist activity is measured using an in vitro P- arrestin based screen and a concentration of 1 pM of the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser, and a threshold for agonist activity is less than 30% and a threshold for antagonist activity is less than 50%.
  • agonist and antagonist activity is measured using an in vitro P-arrestin based screen and a concentration of 10 pM of the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser, and a threshold for agonist activity is less than 30% and a threshold for antagonist activity is less than 50%.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser has a Ki for 5-HT2A greater than or equal to 8 pM and a Ki for 5-HT2B greater than or equal to 1 pM.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser has reuptake inhibition (IC50) of less than or equal to 3 pM at the serotonin transporter (SERT), and less than or equal to 1 pM at the norepinephrine transporter (NET), and less than or equal to 4 pM at the dopamine transporter (DAT); and ECso values for neurotransmitter release of less than or equal to 2 pM at the SERT, and less than or equal to 1 pM at the NET and less than or equal to 6 pM at the DAT.
  • IC50 reuptake inhibition
  • the serotonin-norepinephrine- dopamine reuptake inhibitor and releaser has reuptake inhibition (IC50) of less than or equal to 1 pM at the SERT), and less than or equal to 0.5 pM at the NET, and less than or equal to 3 pM at the DAT ; and an EC50 value for neurotransmitter release of greater than or equal to 2 pM at the DAT.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser is non-hallucinogenic and/or non-psychedelic and/or non-dissociative.
  • the neuropsychiatric illness is a Depressive Disorder.
  • the Depressive Disorder is selected from the group consisting of Disruptive Mood Dysregulation Disorder, Major Depressive Disorder, Single and Recurrent Episodes, Persistent Depressive Disorder (Dysthymia), Premenstrual Dysphoric Disorder, Substance/Medication-Induced Depressive Disorder, Depressive Disorder Due to Another Medical Condition, Other Specified Depressive Disorder, Unspecified Depressive Disorder, and combinations thereof.
  • the neuropsychiatric illness is post- traumatic stress disorder (PTSD).
  • the neuropsychiatric illness is acute stress disorder.
  • the neuropsychiatric illness is Fibromyalgia.
  • the neuropsychiatric illness is a mood disorder. In some embodiments, the neuropsychiatric illness is an anxiety disorder. In some embodiments, the neuropsychiatric illness is an eating disorder. In some embodiments, the neuropsychiatric illness is a Personality Disorder (PD). In some embodiments, the Personality Disorder is selected from the group consisting of Borderline Personality Disorder (BPD), Avoidant Personality Disorder (AvPD), Antisocial Personality Disorder (AsPD), Schizotypal Personality Disorder, Other Anxiety and Panic producing Disorders, Specific personality disorders, Impulse disorders, Gender identity disorders, Paraphilias, Other sexual disorders, Other disorders of adult personality and behavior, Unspecified disorder of adult personality and behavior, Personality and behavioral disorders due to known physiological conditions. In some embodiments, the subject with the PD also has a Depressive Disorder.
  • BPD Borderline Personality Disorder
  • AvPD Avoidant Personality Disorder
  • AsPD Antisocial Personality Disorder
  • Schizotypal Personality Disorder Other Anxiety and Panic producing Disorders, Specific
  • the method comprises measuring agonist and antagonist activity of the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser at the 5-HT2A and 5-HT2B receptors, wherein a lack of agonist or antagonist activity at the 5-HT2A and 5-HT2B receptors is indicative of a therapeutic for pain.
  • the methods comprise measuring agonist and antagonist activity of the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser for the 168 G-protein coupled receptors (GPCRs) set forth in Table 6, wherein a lack of agonist or antagonist activity at the 168 GPCRs is indicative of a therapeutic for pain.
  • GPCRs G-protein coupled receptors
  • agonist and antagonist activity is measured using an in vitro P- arrestin based screen and a concentration of 1 pM of the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser, and a threshold for agonist activity is less than 30% and a threshold for antagonist activity is less than 50%.
  • agonist and antagonist activity is measured using an in vitro P-arrestin based screen and a concentration of 10 pM of the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser, and a threshold for agonist activity is less than 30% and a threshold for antagonist activity is less than 50%.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser has a Ki for 5-HT2A greater than or equal to 8 pM and a Ki for 5-HT2B greater than or equal to 1 ,ii M.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser has reuptake inhibition (IC50) of less than or equal to 3 pM at the serotonin transporter (SERT), and less than or equal to 1 pM at the norepinephrine transporter (NET), and less than or equal to 4 pM at the dopamine transporter (DAT); and EC50 values for neurotransmitter release of less than or equal to 2 pM at the SERT, and less than or equal to 1 pM at the NET and less than or equal to 6 pM at the DAT.
  • IC50 reuptake inhibition
  • the serotonin-norepinephrine- dopamine reuptake inhibitor and releaser has reuptake inhibition (IC50) of less than or equal to 1 pM at the SERT), and less than or equal to 0.5 pM at the NET, and less than or equal to 3 pM at the DAT ; and an EC50 value for neurotransmitter release of greater than or equal to 2 pM at the DAT.
  • the serotonin-norepinephrine-dopamine reuptake inhibitor and releaser is non-halucinogenic and/or non-psychedelic and/or non-dissociative.
  • oral dosage forms comprising methylone and a diluent/binder, a disintegrant, and a lubricant.
  • the oral dosage form further comprises a surfactant, for example sodium lauryl sulfate and/or Poloxamer 188.
  • the disintegrant is Croscarmellose Sodium.
  • the lubricant is magnesium stearate and/or sodium stearyl fumarate.
  • the diluent/binder is mannitol.
  • the oral dosage form is a capsule.
  • the methylone is methylone HC1.
  • the oral dosage comprises about 50 mg of methylone.
  • a psychiatric illness, condition, disease or disorder includes, without limitation, the following, and all intermediate ICD- 10 codes in the ranges defined:
  • F10 Alcohol related disorders Fll Opioid related disorders; F12 Cannabis related disorders; F13 Sedative, hypnotic, or anxiolytic related disorders; F14 Cocaine related disorders; F15 Other stimulant related disorders; F16 Hallucinogen related disorders; F17 Nicotine dependence; Fl 8 Inhalant related disorders; F19 Other psychoactive substance related disorders.
  • Caffeine-Related Disorders Caffeine Intoxication Caffeine Withdrawal Other Caffeine-Induced Disorders Substance-Related Disorder Non-Substance-Related Disorders Gambling Disorder Neurocognitive Disorders Delirium Other Specified Delirium Unspecified Delirium Major and Mild Neurocognitive Disorders Major Neurocognitive Disorder Mild Neurocognitive Disorder Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease Major or Mild Frontotemporal Neurocognitive Disorder Major or Mild Neurocognitive Disorder With Lewy Bodies Major or Mild Vascular Neurocognitive Disorder Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury Substance/Medication-Induced Major or Mild Neurocognitive Disorder Major or Mild Neurocognitive Disorder Due to HIV Infection Major or Mild Neurocognitive Disorder Due to Prion Disease Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease Major or Mild Neurocognitive Disorder Due to Huntington’s Disease Major or Mild Neurocognitive Disorder Due to Another
  • F20 Schizophrenia F21 Schizotypal disorder; F22 Delusional disorders; F23 Brief psychotic disorder; F24 Shared psychotic disorder; F25 Schizoaffective disorders; F28 Other psychotic disorder not due to a substance or known physiological condition; F29 Unspecified psychosis not due to a substance or known physiological condition.
  • F40-F48 Anxiety, dissociative, stress-related, somatoform other nonpsychotic mental disorders
  • Anxiety Disorders Separation Anxiety Disorder Selective Mutism Specific Phobia Social Anxiety Disorder (Social Phobia) Panic Disorder Panic Attack (Specifier) Agoraphobia Generalized Anxiety Disorder Substance/Medication-Induced Anxiety Disorder Anxiety Disorder Due to Another Medical Condition Other Specified Anxiety Disorder Obsessive-Compulsive Disorder Body Dysmorphic Disorder Hoarding Disorder Trichotillomania (Hair-Pulling Disorder) Excoriation (Skin-Picking) Disorder Substance/Medication-Induced Obsessive-Compulsive and Related Disorder Obsessive- Compulsive and Related Disorder Due to Another Medical Condition Other Specified Obsessive-Compulsive and Related Disorder Unspecified
  • Trauma- and Stressor-Related Disorders Reactive Attachment Disorder Disinhibited Social Engagement Disorder Posttraumatic Stress Disorder Acute Stress Disorder Adjustment Disorders Other Specified Trauma- and Stressor-Related Disorder Unspecified Trauma- and Stressor-Related Disorder Somatic Symptom and Related Disorders: Somatic Symptom Disorder Illness Anxiety Disorder Conversion Disorder (Functional Neurological Symptom Disorder) Psychological Factors Affecting Other Medical Conditions Factitious Disorder Other Specified Somatic Symptom and Related Disorder Unspecified Somatic Symptom and Related Disorder Feeding and Eating Disorders: Pica Rumination Disorder Avoidant/Restrictive Food Intake Disorder Anorexia Nervosa Bulimia Nervosa Binge-Eating Disorder Other Specified Feeding or Eating Disorder Unspecified Feeding or Eating Disorder
  • Sleep-Wake Disorders Insomnia Disorder Hypersomnolence Disorder Narcolepsy Breathing- Related Sleep Disorders Obstructive Sleep Apnea Hypopnea Central Sleep Apnea Sleep- Related Hypoventilation Circadian Rhythm Sleep- Wake Disorders Parasomnias Non-Rapid Eye Movement Sleep Arousal Disorders Sleepwalking Sleep Terrors Nightmare Disorder Rapid Eye Movement Sleep Behavior Disorder Restless Legs Syndrome Substance/Medication- Induced Sleep Disorder Other Specified Insomnia Disorder Unspecified Insomnia Disorder Other Specified Hypersomnolence Disorder Unspecified Hypersomnolence Disorder Other Specified Sleep- Wake Disorder Unspecified Sleep-Wake Disorder Sexual Dysfunctions: Delayed Ejaculation Erectile Disorder Female Orgasmic Disorder Female sexual Interest/ Arousal Disorder Genito-Pelvic Pain/Penetration Disorder Male Hypoactive Sexual Desire Disorder Premature (Early) Ejaculation Substance/Medication-Induced Sexual Dysfunction Other Specified
  • F50-F59 Behavioral syndromes associated with physiological disturbances and physical factors F50 Eating disorders; F51 Sleep disorders not due to a substance or known physiological condition; F52 sexual dysfunction not due to a substance or known physiological condition; F53 Mental and behavioral disorders associated with the puerperium, not elsewhere classified; F54 Psychological and behavioral factors associated with disorders or diseases classified elsewhere; F55 Abuse of non-psychoactive substances; F59 Unspecified behavioral syndromes associated with physiological disturbances and physical.
  • F60 Specific personality disorders; F63 Impulse disorders; F64 Gender identity disorders; F65 Paraphilias; F66 Other sexual disorders; F68 Other disorders of adult personality and behavior; F69 Unspecified disorder of adult personality and behavior.
  • Disruptive, Impulse-Control, and Conduct Disorders Oppositional Defiant Disorder Intermittent Explosive Disorder Conduct Disorder Antisocial Personality Disorder Pyromania Kleptomania Other Specified Disruptive, Impulse-Control, and Conduct Disorder Unspecified Disruptive, Impulse-Control, and Conduct Disorder
  • Personality Disorders General Personality Disorder Cluster A Personality Disorders Paranoid Personality Disorder Schizoid Personality Disorder Schizotypal Personality Disorder Cluster B Personality Disorders Antisocial Personality Disorder Borderline Personality Disorder Histrionic Personality Disorder Narcissistic Personality Disorder Cluster C Personality Disorders Avoidant Personality Disorder Dependent Personality Disorder Obsessive- Compulsive Personality Disorder Other Personality Disorders Personality Change Due to Another Medical Condition Other Specified Personality Disorder Unspecified Personality Disorder Conditions for Further Study Attenuated Psychosis Syndrome Depressive Episodes With Short-Duration Hypomania Persistent Complex Bereavement Disorder Gaming Disorder Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure Suicidal Behavior Disorder Nonsuicidal Self-Injury
  • a neurologic illness, condition, disease or disorder includes, without limitation, the following, and all intermediate ICD-10 codes in the ranges defined:
  • G20 Parkinson's disease G21 Secondary parkinsonism; G23 Other degenerative diseases of basal ganglia; G24 Dystonia; G25 Other extrapyramidal and movement disorders; G26 Extrapyramidal and movement disorders in diseases classified elsewhere
  • G30 Alzheimer's disease G31 Other degenerative diseases of nervous system, not elsewhere classified; G32 Other degenerative disorders of nervous system in diseases classified elsewhere
  • G35 Multiple sclerosis; G36 Other acute disseminated demyelination; G37 Other demyelinating diseases of central nervous system
  • G40 Epilepsy and recurrent seizures; G43 Migraine; G44 Other headache syndromes; G45 Transient cerebral ischemic attacks and related syndromes; G46 Vascular syndromes of brain in cerebrovascular diseases; G47 Sleep disorders
  • G50 Disorders of trigeminal nerve; G51 Facial nerve disorders; G52 Disorders of other cranial nerves; G53 Cranial nerve disorders in diseases classified elsewhere; G54 Nerve root and plexus disorders; G55 Nerve root and plexus compressions in diseases classified elsewhere; G56 Mononeuropathies of upper limb; G57 Mononeuropathies of lower limb; G58 Other mononeuropathies; G59 Mononeuropathy in diseases classified elsewhere.
  • G60-G65 Polyneuropathies and other disorders of the peripheral nervous system
  • G60 Hereditary and idiopathic neuropathy; G61 Inflammatory polyneuropathy; G62 Other and unspecified polyneuropathies; G63 Polyneuropathy in diseases classified elsewhere; G64 Other disorders of peripheral nervous system; G65 Sequelae of inflammatory and toxic polyneuropathies G70-G73 Diseases of myoneural junction and muscle
  • G70 Myasthenia gravis and other myoneural disorders; G71 Primary disorders of muscles; G72 Other and unspecified myopathies; G73 Disorders of myoneural junction and muscle in diseases classified elsewhere.
  • treatment resistant depression is a shorthand signifier for all related terms, approaches to management, etc., defined here as including but not limited to: non-responder depression, treatment refractory depression, partial response depression, optimization strategy, switching strategy, combination strategy, augmentation strategy, bupropione, mirtazapine, mianserine, lithium, thyroid hormones, second generation antipsychotics (SGA), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, pindolol, sex steroids, and glucocorticoid agents.
  • Management approaches include treatment strategies such as: (1) switching from an ineffective antidepressant to a new antidepressant from a similar or different class; (2) combining a current antidepressant regimen with a second antidepressant from a different class; and (3) augmenting a current antidepressant regimen with a second agent not thought to be an antidepressant itself.
  • the terms “reduce,” “decrease,” “lessen” and similar terms mean a decrease of at least about 10%, about 15%, about 20%, about 25%, about 35%, about 50%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, or more.
  • the terms “improve,” “increase,” “enhance,” and similar terms indicate an increase of at least about 10%, about 15%, about 20%, about 25%, about 50%, about 75%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more.
  • binding refers to compositions having affinity for each other. “Specific binding” is where the binding is selective between two molecules. A particular example of specific binding is that which occurs between an antibody and an antigen. Typically, specific binding can be distinguished from non-specific when the dissociation constant (KD) is less than about IxlO -5 M or less than about IxlO -6 M or IxlO -7 M. Specific binding can be detected, for example, by ELISA, immunoprecipitation, coprecipitation, with or without chemical crosslinking, two-hybrid assays and the like.
  • KD dissociation constant
  • prodrug refers to a precursor or derivative form of a pharmaceutically active substance that can be activated or converted (e.g., enzymatically) into a more active parent form.
  • stereogenic center in their structure.
  • This stereogenic center may be present in an R or an S configuration, the R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976) 45:11.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, solvates, hydrates, tautomers, prodrugs, or mixtures thereof (including all possible stereoisomer mixtures).
  • one or more oxygen atoms may be enriched with 16 O in an amount greater than about 0.24% (e.g., 0.25-0.5%, 0.5-1%, 1-2%, 2-10%, or greater than 10%).
  • deuterated refers to a compound or substituent in which one or more protium ( 1 H) atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s).
  • a variety of other therapeutic agents may find use for administration with the compositions and methods provided herein.
  • the psychoactive compounds provided herein may be used for various therapeutic purposes.
  • the compounds are administered to a subject to treat a neuropsychiatric illness.
  • the compounds are administered to a subject to treat pain.
  • a subject for the purposes of the compositions and methods provided herein includes humans and other animals, preferably mammals and most preferably humans.
  • the compounds provided herein have both human therapy and veterinary applications.
  • the subject is a mammal, and in yet another embodiment the subject is human.
  • condition or “disease” herein are meant a disorder that may be ameliorated by the administration of a pharmaceutical composition comprising the compounds provided herein.
  • Treating” and “treatment” used to refer to treatment of a neuropsychiatric illness in a subject include: preventing, inhibiting or ameliorating the neuropsychiatric illness in the subject, as well as reducing or ameliorating a sign or symptom of the neuropsychiatric illness.
  • Treatment goals may incorporate endpoints such as improvement in DSM-5 severity scales, to measure if resilience and quality of life are enhanced, with engagement of positive cognitive valence systems, and corresponding reduction in negative valence.
  • the psychoactive compositions or compounds used in the methods of treating neuropsychiatric illnesses e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder
  • the psychoactive compositions or compounds used in the methods of treating neuropsychiatric illnesses e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder
  • the psychoactive compositions or compounds used in the methods of treating neuropsychiatric illnesses are non-dissociative.
  • the psychoactive compositions or compounds used in the methods of treating neuropsychiatric illnesses are non-hallucinogenic, non-psychedelic and non-dissociative.
  • the psychoactive compositions or compounds rapidly treat a neuropsychiatric illness (e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder) with the methods provided herein.
  • a rapid treatment comprises a therapeutic effect that is observable or statistically significant less than one month after the first dose or the beginning of a dosing schedule of a psychoactive composition or compound.
  • a rapid treatment comprises a therapeutic effect that is observable or statistically significant less than three weeks after the first dose or the beginning of a dosing schedule of a psychoactive composition or compound.
  • a rapid treatment comprises a therapeutic effect that is observable or statistically significant less than two weeks after the first dose or the beginning of a dosing schedule of a psychoactive composition or compound. In some embodiments, a rapid treatment comprises a therapeutic effect that is observable or statistically significant within ten days of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound. In some embodiments, a rapid treatment comprises a therapeutic effect or statistically significant that is observable within one week of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound.
  • a rapid treatment comprises a therapeutic effect that is observable or statistically significant within six days of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound. In some embodiments, a rapid treatment comprises a therapeutic effect that is observable or statistically significant within five days of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound. In some embodiments, a rapid treatment comprises a therapeutic effect that is observable or statistically significant within four days of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound.
  • a rapid treatment comprises a therapeutic effect that is observable or statistically significant within three days of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound. In some embodiments, a rapid treatment comprises a therapeutic effect that is observable or statistically significant within two days of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound. In some embodiments, a rapid treatment comprises a therapeutic effect that is observable or statistically significant within one day of the first dose or the beginning of a dosing schedule of a psychoactive composition or compound.
  • the psychoactive compositions or compounds durably treat a neuropsychiatric illness (e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder) with the methods provided herein.
  • a durable treatment comprises a therapeutic effect that is observable or statistically significant one week or more after a dose or the conclusion of a dosing schedule of a psychoactive composition or compound.
  • a durable treatment comprises a therapeutic effect that is observable or statistically significant at least two weeks after a dose or the conclusion of a dosing schedule of a psychoactive composition or compound.
  • a durable treatment comprises a therapeutic effect that is observable or statistically significant at least three weeks after a dose or the conclusion of a dosing schedule of a psychoactive composition or compound. In some embodiments, a durable treatment comprises a therapeutic effect that is observable or statistically significant at least one month after a dose or the conclusion of a dosing schedule of a psychoactive composition or compound. In some embodiments, a durable treatment comprises a therapeutic effect that is observable or statistically significant at least six weeks after a dose or the conclusion of a dosing schedule of a psychoactive composition or compound.
  • the psychoactive compositions or compounds robustly treat a neuropsychiatric illness (e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder) with the methods provided herein.
  • a robust treatment is remission of the neuropsychiatric illness.
  • a robust treatment comprises a therapeutic effect that is statistically significant over baseline.
  • the neuropsychiatric illness is PTSD, and robust treatment comprises an improvement from baseline in the Clinician- Administered PTSD Scale for DSM- 5 (CAPS-5) score.
  • the robust treatment comprises an improvement from baseline of at least ten points in the CAPS-5 score. In another embodiment, the robust treatment comprises an improvement from baseline of at least five points in the CAPS-5 score.
  • the neuropsychiatric illness is a depressive disorder, and robust treatment comprises an improvement from baseline of at least ten points in the Montgomery-Asberg Depression Rating Scale (MADRS) score. In one embodiment, the robust treatment comprises an improvement from baseline of at least ten points in the MADRS score. In another embodiment, the robust treatment comprises an improvement from baseline of at least five points in the MADRS score.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • a robust treatment comprises an improvement from baseline of at least one point in Clinical Global Impression-improvement (CGI- 1) score or in Clinical Global Impression- severity (CGI-S) score. In one embodiment, a robust treatment comprises an improvement from baseline of at least two points in CGI-I and/or CGI-S scores.
  • the psychoactive compositions or compounds rapidly and durably treat a neuropsychiatric illness (e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder) with the methods provided herein.
  • a neuropsychiatric illness e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder
  • the psychoactive compositions (e.g., methylone, 2C-B, or MBDB) or compounds rapidly and robustly treat a neuropsychiatric illness (e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder) with the methods provided herein.
  • the psychoactive compositions or compounds improves or reduces functional impairment in a subject having a neuropsychiatric illness (e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder) with the methods provided herein.
  • a neuropsychiatric illness e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder
  • the improvement or reduction in function impairment comprises an improvement from baseline in the Sheehan Disability Scale (SDS) for the subject.
  • the improvement or reduction in function impairment comprises a reduction of the number of underproductive days and/or days lost for the subject.
  • the psychoactive compositions or compounds improves sleep in a subject having a neuropsychiatric illness (e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder) with the methods provided herein.
  • a neuropsychiatric illness e.g., PTSD, acute stress disorder, an anxiety disorder, or a depressive disorder
  • the improvement in sleep comprises an improvement from baseline in the Pittsburg Sleep Quality Index (PSQI) for the subject.
  • the improvement in sleep comprises an improvement from baseline of sleep duration, and/or sleep latency, and/or sleep disturbance, and/or sleep quality.
  • Treatment of pain includes but is not limited to: the treatment of acute pain, (e.g., surgical and procedural pain, pain due to trauma/injury, pain due to acute inflammatory processes) and/or the treatment of chronic pain (e.g., cancer pain, neuropathic pain, fibromyalgia, osteoarthritis pain, low back pain).
  • acute pain e.g., surgical and procedural pain, pain due to trauma/injury, pain due to acute inflammatory processes
  • chronic pain e.g., cancer pain, neuropathic pain, fibromyalgia, osteoarthritis pain, low back pain.
  • methods of treating and/or preventing a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof comprise administering to the subject a therapeutically effective dose of a psychoactive compound provided herein. In some embodiments, methods of treating and/or preventing a neuropsychiatric illness and/or ameliorating a symptom thereof in a subject in need thereof comprise administering to the subject a therapeutically effective dose of a psychoactive compound provided herein in a controlled environment, wherein the subject is provided with psychological support.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviations, per practice in the art.
  • a measurable value such as an amount, a temporal duration, a concentration, and the like, may encompass variations of ⁇ 20% or ⁇ 10%, more preferably ⁇ 5%, even more preferably ⁇ 1% or ⁇ 0.5%, and still more preferably ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • compositions are contemplated for the psychoactive compounds and methods provided herein.
  • Formulations of the compositions and methods provided herein are prepared for storage by mixing said compound having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers, in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as 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); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, his
  • compositions provided herein are in a water-soluble form, such as being present as pharmaceutically acceptable salts, which is meant to include both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Formulations used for in vivo administration are preferably sterile. This is readily accomplished by filtration through sterile filtration membranes or other methods.
  • compositions of psychoactive compounds include, but are not limited to: diluents, e.g., microcrystalline cellulose, starch, mannitol, calcium hydrogen phosphate anhydrous or co-mixtures of silicon dioxide, calcium carbonate, microcrystalline cellulose and talc; disintegrants, e.g., sodium starch glycolate or croscarmellose sodium; binders, e.g., povidone, co-povidone or hydroxyl propyl cellulose; lubricants, e.g., magnesium stearate or sodium stearyl fumurate; glidants, e.g., colloidal silicon dioxide; and film coats, e.g., Opadry II white or PVA based brown Opadry II.
  • diluents e.g., microcrystalline cellulose, starch, mannitol, calcium hydrogen phosphate anhydrous or co-mixtures of silicon dioxide, calcium carbonate, microcrystalline cellulose and talc
  • the psychoactive compounds provided herein may also be entrapped in microcapsules prepared by methods including, but not limited to, coacervation techniques, interfacial polymerization (e.g., using hydroxymethylcellulose or gelatin-microcapsules, or poly- (methylmethacylate) microcapsules), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nano-capsules), and macroemulsions. Sustained-release preparations may be prepared.
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymer, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (for example poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and gamma ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (which are injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid) which is a microsphere-based delivery system composed of the desired bioactive molecule incorporated into a matrix of poly-DL-lactide-co-glycolide (PLG).
  • PLA poly-
  • a pharmaceutical composition comprising a psychoactive compound provided herein, preferably in the form of a sterile aqueous solution, may be done in a variety of ways, including, but not limited to orally, subcutaneously, intravenously, intranasally, intraotically, transdermally, topically (e.g., gels, salves, lotions, creams, etc.), intraperitoneally, intramuscularly, intrapulmonary, vaginally, parenterally, rectally, or intraocularly.
  • pharmaceutical compositions may be formulated accordingly depending upon the manner of introduction.
  • the pharmaceutical formulation is an oral dosage form. In some embodiments, the pharmaceutical formulation is a parenteral dosage form. In some embodiments, the pharmaceutical composition comprises a tablet. In some embodiments, the pharmaceutical composition comprises a capsule. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, more than one dosage form is administered to the subject at substantially the same time. In some embodiments, the subject may be administered the entire therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be split among multiple tablets or capsules.
  • a dose of a psychoactive compound provided herein may be between about 1 mg to about 100 mg.
  • the dose may be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.
  • the dose of a psychoactive compound provided herein is between about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg.
  • the dose of a psychoactive compound provided herein is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, the dose of a psychoactive compound provided herein is between about 0.001 mg to about 1 g. In some embodiments, the dose of a psychoactive compound provided herein is between about 100 mg to about 250 mg. In some embodiments, the dose of a psychoactive compound provided herein is about 25 mg.
  • the psychoactive compound provided herein is administered daily. In some embodiments, the psychoactive compound is administered twice a day. In some embodiments, the psychoactive compound is administered three times a day. In some embodiments, the psychoactive compound is administered every other day. In some embodiments, the psychoactive compound is administered every third day. In some embodiments, the psychoactive compound is administered every fourth day. In some embodiments, the psychoactive compound is administered every fifth day. In some embodiments, the psychoactive compound is administered weekly. In some embodiments, the psychoactive compound is administered every other week. In some embodiments, the psychoactive compound is administered every third week. In some embodiments, the psychoactive compound is administered monthly.
  • about 5 mg of the psychoactive compound is administered daily. In some embodiments, about 5 mg of the psychoactive compound is administered twice a day. In some embodiments, about 5 mg of the psychoactive compound is administered three times a day. In some embodiments, about 5 mg of the psychoactive compound is administered every other day. In some embodiments, about 5 mg of the psychoactive compound is administered every third day. In some embodiments, about 5 mg of the psychoactive compound is administered every fourth day. In some embodiments, about 5 mg of the psychoactive compound is administered every fifth day. In some embodiments, about 5 mg of the psychoactive compound is administered weekly. In some embodiments, about 5 mg of the psychoactive compound is administered every other week. In some embodiments, about 5 mg of the psychoactive compound is administered every third week. In some embodiments, about 5 mg of the psychoactive compound is administered monthly.
  • about 25 mg of the psychoactive compound is administered daily. In some embodiments, about 25 mg of the psychoactive compound is administered twice a day. In some embodiments, about 25 mg of the psychoactive compound is administered three times a day. In some embodiments, about 25 mg of the psychoactive compound is administered every other day. In some embodiments, about 25 mg of the psychoactive compound is administered every third day. In some embodiments, about 25 mg of the psychoactive compound is administered every fourth day. In some embodiments, about 25 mg of the psychoactive compound is administered every fifth day. In some embodiments, about 25 mg of the psychoactive compound is administered weekly. In some embodiments, about 25 mg of the psychoactive compound is administered every other week. In some embodiments, about 25 mg of the psychoactive compound is administered every third week. In some embodiments, about 25 mg of the psychoactive compound is administered monthly.
  • about 50 mg of the psychoactive compound is administered daily. In some embodiments, about 50 mg of the psychoactive compound is administered twice a day. In some embodiments, about 50 mg of the psychoactive compound is administered three times a day. In some embodiments, about 50 mg of the psychoactive compound is administered every other day. In some embodiments, about 50 mg of the psychoactive compound is administered every third day. In some embodiments, about 50 mg of the psychoactive compound is administered every fourth day. In some embodiments, about 50 mg of the psychoactive compound is administered every fifth day. In some embodiments, about 50 mg of the psychoactive compound is administered weekly. In some embodiments, about 50 mg of the psychoactive compound is administered every other week. In some embodiments, about 50 mg of the psychoactive compound is administered every third week. In some embodiments, about 50 mg of the psychoactive compound is administered monthly.
  • about 100 mg of the psychoactive compound is administered daily. In some embodiments, about 100 mg of the psychoactive compound is administered twice a day. In some embodiments, about 100 mg of the psychoactive compound is administered three times a day. In some embodiments, about 100 mg of the psychoactive compound is administered every other day. In some embodiments, about 100 mg of the psychoactive compound is administered every third day. In some embodiments, about 100 mg of the psychoactive compound is administered every fourth day. In some embodiments, about 100 mg of the psychoactive compound is administered every fifth day. In some embodiments, about 100 mg of the psychoactive compound is administered weekly. In some embodiments, about 100 mg of the psychoactive compound is administered every other week. In some embodiments, about 100 mg of the psychoactive compound is administered every third week. In some embodiments, about 100 mg of the psychoactive compound is administered monthly.
  • about 150 mg of the psychoactive compound is administered daily. In some embodiments, about 150 mg of the psychoactive compound is administered twice a day. In some embodiments, about 150 mg of the psychoactive compound is administered three times a day. In some embodiments, about 150 mg of the psychoactive compound is administered every other day. In some embodiments, about 150 mg of the psychoactive compound is administered every third day. In some embodiments, about 150 mg of the psychoactive compound is administered every fourth day. In some embodiments, about 150 mg of the psychoactive compound is administered every fifth day. In some embodiments, about 150 mg of the psychoactive compound is administered weekly. In some embodiments, about 150 mg of the psychoactive compound is administered every other week. In some embodiments, about 150 mg of the psychoactive compound is administered every third week. In some embodiments, about 150 mg of the psychoactive compound is administered monthly.
  • about 200 mg of the psychoactive compound is administered daily. In some embodiments, about 200 mg of the psychoactive compound is administered twice a day. In some embodiments, about 200 mg of the psychoactive compound is administered three times a day. In some embodiments, about 200 mg of the psychoactive compound is administered every other day. In some embodiments, about 200 mg of the psychoactive compound is administered every third day. In some embodiments, about 200 mg of the psychoactive compound is administered every fourth day. In some embodiments, about 200 mg of the psychoactive compound is administered every fifth day. In some embodiments, about 200 mg of the psychoactive compound is administered weekly. In some embodiments, about 200 mg of the psychoactive compound is administered every other week. In some embodiments, about 200 mg of the psychoactive compound is administered every third week. In some embodiments, about 200 mg of the psychoactive compound is administered monthly.
  • about 250 mg of the psychoactive compound is administered daily. In some embodiments, about 250 mg of the psychoactive compound is administered twice a day. In some embodiments, about 250 mg of the psychoactive compound is administered three times a day. In some embodiments, about 250 mg of the psychoactive compound is administered every other day. In some embodiments, about 250 mg of the psychoactive compound is administered every third day. In some embodiments, about 250 mg of the psychoactive compound is administered every fourth day. In some embodiments, about 250 mg of the psychoactive compound is administered every fifth day. In some embodiments, about 250 mg of the psychoactive compound is administered weekly. In some embodiments, about 250 mg of the psychoactive compound is administered every other week. In some embodiments, about 250 mg of the psychoactive compound is administered every third week. In some embodiments, about 250 mg of the psychoactive compound is administered monthly.
  • an initial dose of a psychoactive compound provided herein is administered, which is then boosted 30 minutes-4 hours later by administering a second dose of the psychoactive compound.
  • the boosted dose is administered about 30 min after the initial dose.
  • the boosted dose is administered about 60 min after the initial dose.
  • the boosted dose is administered about 90 min after the initial dose.
  • the boosted dose is administered about 120 min after the initial dose.
  • the boosted dose is administered about 150 min after the initial dose.
  • the boosted dose is administered about 180 min after the initial dose.
  • the boosted dose is administered about 210 min after the initial dose.
  • the boosted dose is administered about 240 min after the initial dose.
  • the boosted dose is 10% to 100% in amount of the initial dose. In some embodiments, the boosted dose is the same amount as the initial dose. In one embodiment, the boosted dose is about half of the amount of the initial dose. In one embodiment, this dosing schedule is performed daily. In one embodiment, this dosing schedule is performed twice a day. In one embodiment, this dosing schedule is performed three times a day. In one embodiment, this dosing schedule is performed every other day. In one embodiment, this dosing schedule is performed every third day. In one embodiment, this dosing schedule is performed every fourth day. In one embodiment this dosing schedule is performed every fifth day. In one embodiment, this dosing schedule is performed weekly. In one embodiment, this dosing schedule is performed every other week. In one embodiment, this dosing schedule is performed every third week. In one embodiment, this dosing schedule is performed monthly.
  • a dose of a psychoactive compound provided herein may be between about 1 mg/kg to about 100 mg/kg.
  • the dose may be about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.
  • the dose of a psychoactive compound provided herein is between about 0.1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 50 mg/kg, or about 5 mg/kg to about 30 mg/kg. In some embodiments, the dose of a psychoactive compound provided herein is about 1 mg/kg, about 10 mg/kg, or about 25 mg/kg. In some embodiments, the dose of a psychoactive compound provided herein is between about 0.001 mg/kg to about 1 g/kg. In some embodiments, the dose of a psychoactive compound provided herein is in the range of about 100 mg/kg to about 250 mg/kg. In some embodiments, the dose of a psychoactive compound provided herein is about 25 mg/kg.
  • the psychoactive compound provided herein is administered, e.g., as a single dose or one or more times per week (up to twice daily or even three times a days). In some embodiments, the psychoactive compound provided herein is administered according to a dosing schedule provided herein. In some embodiments, the psychoactive compound provided herein is administered as an extended release or sustained release formulation, for example, to achieve a dosing regimen disclosed herein and releasing 50 mg to 1 g on a set schedule to patients according to the indication(s) being treated in those patients.
  • subject refers to a mammal, including a human, in need of therapy for, or susceptible to, a condition or its sequelae.
  • the subject may include dogs, cats, pigs, cows, sheep, goats, horses, rats, mice, and humans.
  • subject does not exclude an individual that is normal in all respects.
  • the subject is a male. In some embodiments, the subject is a female. In some embodiments, the female subject is pregnant or post-partum.
  • the subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle- aged subject. In some embodiments, the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age.
  • the subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age.
  • a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements can optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • Example 1 Effects of methylone, 2C-B, and MBDB on fear extinction plasticity and dendritic architecture in mice
  • a key experimental research question is how the short half-life of a compound translates to long-term behavioral changes.
  • One plausible mechanism is neural plasticity.
  • administering psychoactive compounds may drive lasting modifications in neural architecture in the brain by strengthening or increasing the number of synaptic connections.
  • Current evidence supporting this view comes mostly from studies of cultured neurons.
  • Still unknown is the extent to which neural plasticity is induced by psychoactive compounds in the mammalian brain, and whether synaptic remodeling occurs in brain regions implicated in neuropsychiatric disorders.
  • mice It is important to determine the dose range that is behaviorally relevant for mice.
  • head-twitch responses are quantified for a range of doses for the 3 psychoactive compounds (methylone, 2C-B, MBDB) in adult, 6-8 week-old C57BL/6J mice, with 40 mice tested per condition. Briefly, animals are placed in arenas inside a sound- attenuated cubicle. The arenas are illuminated with near-infrared lighting. Movements of the mice within all arenas are captured simultaneously by a ceiling-mounted, high-speed camera. Each animal receives an intraperitoneal injection of 1 of 5 doses of one of the compounds - with a dose range selected based on the literature.
  • mice are assigned randomly to groups. Videos are recorded for ⁇ 10 minutes after administration. In a subset of studies, videos are recorded for up to 2 hours to chart the time course. For analyses, head twitches are counted by an experimenter who is blind to the experimental condition. These experiments are used to inform the dose to be used for further studies.
  • Neural plasticity may promote alterations in emotional learning.
  • Fear extinction is a behavior in which repeated exposure to an associated fear learning stimulus can reduce the intensity of the fear response, and which may be related to the mechanism of action of these compounds in reducing anxiety or fear. It is not known to what extent novel phenethylamines may enhance fear extinction.
  • the rate of fear extinction is determined after administration of drug in 4 conditions (saline, methylone, 2C-B, MBDB) in adult mice, with 10 mice tested per condition. Briefly, each mouse receives tone-shock pairing (day 1) then on a subsequent day they receive a single administration of the compound (at dose informed by prior study) 30 minutes prior to re-exposure to the fear associated stimulus (day 2).
  • fear extinction learning is tested by re-exposing mice again to the associated tone in a fear conditioning apparatus.
  • Fear extinction serves as a model for ameliorating anxiety- and fear-related behaviors in psychiatric disorders and may serve to identify separable behavioral effects from hallucinogenic effects.
  • the circuit mechanisms of potential plasticity enhancement is subsequently addressed in two-photon imaging experiments. Determine long-term effects on dendritic remodeling
  • dendritic spines in the distal apical tuft branches are imaged and are tracked for 7 sessions at -3, -1, 1, 3, 5, 7, and ⁇ 30 days from the day of administration. Imaging the same sets of spines longitudinally allows the determination of the number density of dendritic spines, and also the turnover dynamics including the rates of spine formation and elimination, as well as the fraction of newly formed spines that remain persistent indicating the maturation of a new functional synapse.
  • Example 2 Zebrafish models of neuropsychiatric illnesses
  • zebrafish are ideal for developing valid experimental models of major depression, anxiety, and pain disorders to discover novel therapeutics.
  • Behavioral testing approaches such as approach-avoidance, cognitive, and social paradigms, are available in zebrafish and are useful for identifying depression-like indices in zebrafish in response to physiological, genetic, environmental, and/or psychopharmacological alterations.
  • the high sensitivity of zebrafish to commonly prescribed psychoactive drugs support the use of this model as a tool for pharmacological research and drug screening. Possessing a fully characterized genome, both adult and larval zebrafish are currently widely used for in vivo screening of various psychoactive medicines.
  • reserpine As a specific inhibitor of monoamine transporters, reserpine is known to deplete monoamine neurotransmitters - confirmed with liquid chromatograph-mass spectrometer analysis - and cause decreased swimming distance and average velocity (hypoactivity), and reduced response to both visual and sound stimuli. Reserpine induces depression-like behavior both in adult zebrafish and in larvae; this is used as an assay for drugs affecting these despair- like states, such as methylone, 2C-B and MBDB.
  • a camera algorithm, Histogram of Oriented Gradient (HOG) analyzes the depression and hypoactivity behavior of zebrafish shoaling to achieve accuracy that is not possible for the human observer.
  • Example 3 Rodent models of neuropsychiatric illnesses
  • This Example presents rodent models for several neurological and psychiatric conditions that are used to demonstrate the efficacy of psychoactive compounds described herein. Primate and rodent models have been traditionally used to study cellular mechanisms and neural circuits of hallucinogenic drugs' action.
  • the Forced Swim Test is a classic, and the most used preclinical behavioral assay to screen compounds with antidepressant-like activity and has high predictive and face validity (Porsolt el al. (1977) Nature 266:730; Borsini and Meli (1988) Psychopharmacology 94:147).
  • the premise of the FST is that when rats are placed into a cylinder filled with water, they will initially try to escape, but over time will become immobile. This increased immobility reflects behavioral despair, modeling a depressive-like state.
  • This behavioral assay also widely used as an anxiety paradigm, capitalizes on a rodent’s innate fear of brightly lit open spaces, which are assumed to induce fear or anxiety. Rodents spend more time hugging the walls of the open field during the test, and these effects correlate to underlying brain regions and mechanisms.
  • Method Consecutive beam breaks and/or video-tracking of time spent in the center versus periphery of the open field are measured. Also measured are parameters such as distance traveled and ambulatory activity (horizontal and vertical) for the duration of the test session.
  • Anxiolytics such as diazepam increase time spent (and/or distance traveled) in the center of the open field independent of changes in locomotion, used as positive control to assess an agent’s effect on these parameters.
  • This behavioral assay is based on unconditioned responses of rodents to a potentially dangerous environment: maze height, luminosity, and open space are assumed to induce fear or anxiety, and to correlate to underlying brain regions and mechanisms.
  • Method Video-tracking of time spent in the open arms of the maze to the closed arms, for 5 min starting at the junction.
  • Other ethological parameters include rears, dips, stretched- attend postures.
  • Rats are trained to lever-press for food under a multiple variable interval-fixed ratio (food; food + shock) schedule of reinforcement.
  • This task generally exhibits good predictive validity for anxiolytic-like compounds, such as diazepam, which increase punished responding (i.e., antagonize response suppression in the punished period). It also exhibits selectivity for anxiolytics, with apparently no effects in other classes and can assess MBDB’s anxiolytic effect with a positive control such as Bupropion.
  • Fibromyalgia Reserpine-induced Myalgia Model
  • Reserpine (1 mg/kg/s.c.) is administered for 3 days to mimic chronic widespread pain and complex symptoms.
  • Duloxetine (30 mg/kg, p.o.) is administered 60 min before a vonFrey test, in which filaments of different sizes are touched to the rat hindpaw and the filament size that elicits paw withdrawal is recorded.
  • Results Reserpine significantly reduces the paw withdrawal threshold in the vonFrey test and decreases the amount of 5 -hydroxy tryptamine, dopamine, and norepinephrine in the cerebral cortex. It also increases malondialdehyde and nitric oxide and reduces glutathione contents in brain tissue. Duloxetine reverses reserpine-induced fibromyalgia, as assessed by the measured parameters.
  • Allodynia, hyperalgesia, and other associated fibromyalgia-like symptomologies are rapidly induced via acid injection (pH 4.0). Once induced, animals display a hypersensitivity to mechanical and visceral stimulation. Symptoms last a minimum of 14 days post- induction, allowing for evaluation over time, and comparisons with vehicle and positive control (e.g., buprenorphine).
  • This Example is based on a case series of 32 narratives for methylone administered orally in single or multiple dosing sessions by a clinical psychologist in an outpatient therapy setting.
  • the case series is composed of two datasets (Cohort 1 and Cohort 2):
  • Cohort 1 4 case narratives in a healthy population providing information on safety and tolerability of methylone administered in a single dosing session.
  • Cohort 2 28 case narratives providing efficacy and safety information from consecutive patients with a diagnosis of interest (PTSD or MDD) with baseline assessments. Cohort 2 was evaluated for efficacy post-dosing using the Clinical Global Impression-severity (CGI-S) at baseline and Clinical Global Impressionimprovement (CGI-I), as described in more detail below, compared to baseline CGI-S established prior to first methylone dosing. CGI-S scale was also evaluated in a subset of patients from Cohort 2 post-treatment. Cohort 2 was evaluated for any observed or reported safety events following a single dosing session.
  • CGI-S Clinical Global Impression-severity
  • CGI-I Clinical Global Impressionimprovement
  • CGI Clinical Global Impressions
  • CGI-S Clinical Global Impression-Severity
  • IQR Interquartile range
  • Max Maximum
  • Cohort 1 is composed of 4 healthy adult subjects (3 males and 1 female) ranging in age from 28 to 60 years who were administered methylone in a single administration in either a group setting (3 subjects) or individually (1 subject). Cohort 1 tended to have a higher proportion of male subjects who were younger, and all were Caucasian. Prior experience with methylone was unknown in two subjects and confirmed in the other two subjects (one male and one female).
  • Cohort 2 is composed of 28 patients with PTSD or MDD treated in an outpatient setting. Note that one of the patients included in the MDD population had a primary diagnosis of bipolar disorder type I. Overall, males and females were well represented within Cohort 2 and showed similar proportions within the PTSD and MDD subsets.
  • Baseline disease severity (CGLS) for Cohort 2 is shown in Table 2 and Figure 2. Baseline CGLS ranged from 4 to 7 and 85.7% of patients had baseline CGLS 5 or 6 with similar proportion in both the PTSD and MDD subsets.
  • CGI-S Clinical Global Impression-Severity
  • MDD Major Depressive Disorder
  • PTSD Post Traumatic Stress Disorder
  • Figure 1 shows the baseline symptom inventory for symptoms occurring in 2 or more of the 28 patients included in Cohort 2.
  • the most common symptoms included insomnia (12 patients), anhedonia (10 patients), anger (9 patients) and nightmare/night terrors (7 patients).
  • the 3 males in Cohort 1 were dosed in a group setting during a single session with a total methylone dose of 790 mg administered as a regimen of methylone 280 mg followed by booster doses of 190 mg, 190 mg and 130 mg.
  • the total dose was 870 mg administered as methylone 250 mg followed by booster doses of 220 mg, 200 mg, and 200 mg.
  • methylone dose plus booster dose(s) maximum total dose for each session exceeded 500 mg [methylone dose plus booster dose(s)] in only four sessions in 3 patients.
  • the methylone dose ranged from 100 to 270 mg and the booster dose(s) had a total cumulative dose that ranged from 50 mg to 880 mg but only exceeded 370 mg in two sessions in two patients.
  • Individual methylone booster doses had a minimum range of 50 mg to 240 mg and a maximum range of 80 mg to 250 mg.
  • methylone 150 mg and 150 mg booster highest dose administered when coming down from the medicine. The event was not considered severe and did not require intervention. Previous total doses ranged from 100-250 mg. There was a negative rechallenge (i.e., repeat methylone dosing) with administration of an unknown dose at home.
  • Cohort 1 consisted of healthy volunteers, efficacy is reported for Cohort 2 which consisted of PTSD and MDD patients.
  • CGI-I Clinical Global Impression-Improvement
  • CGI-S post-treatment was only reported in 5 cases as shown in Table 4 including one patient noted to achieve a stable CGI-S 1. One case was noted to sometimes achieve CGI-S 1. In 5 additional case narratives that did not include post-treatment CGI-S scores, it was reported that patients no longer qualified for the diagnosis post-treatment and 5 of these cases achieved CGI-1 1. CONCLUSION
  • Example 5 Clinical Evidence for the Use of Methylone in the Treatment of PTSD: A Case Series with Long-Term follow-up
  • PTSD is a debilitating, and often chronic, psychiatric disorder characterized by a constellation of symptoms including intrusive memories, distressing dreams, dissociative reactions, physiological reactivity to and avoidance of trauma-related stimuli, negative cognition and mood, lassitude, increased arousal, impaired sleep, cognitive dysfunction, irritability, risk-taking behavior, and clinically significant distress and impairment in functioning. It is estimated that 70% of the world population have been exposed to trauma and, though resilience is the norm rather than the exception, approximately 6% of trauma-exposed individuals develop PTSD. The estimated prevalence of PTSD is 20% following interpersonal violence, 25% in combat-exposed military veterans, 50% in rape survivors, and as high as 86% among certain refugee groups. PTSD is a well-established risk factor for suicide, increasing suicide risk 6 to 29-fold above the general population.
  • SSRIs Selective serotonin reuptake inhibitors
  • paroxetine and sertraline are the only FDA-approved medications for treating PTSD.
  • SAADs slow-acting antidepressants
  • Trauma-focused psychotherapy also shows some efficacy in treatment of PTSD and is often the first-line intervention selected, given the known limitations in pharmacotherapy.
  • Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT) are the gold standard treatments, but access to appropriately trained therapists is limited and effective therapy requires a willingness on the part of the patients to expose themselves to trauma-related memories and to experience the attendant distress.
  • the attrition rate among gold-standard psychotherapy outcome studies ranges from 17% to 55.8%, and nonresponse can be as high as 50%.
  • troubling symptoms often persist even in patients classified as treatment responders.
  • the efficacy gap may also be particularly significant among Veterans treated in Veterans Affairs (VA) Medical Center settings, perhaps due, at least in part, to the complexity of these patients, whom often have significant psychiatric and medical comorbidities and repeated chronic trauma exposures.
  • VA Veterans Affairs
  • methylone also known as MDMC, [>k- MDMA, and Ml
  • RAE rapid acting empathogen
  • An observational-naturalistic study compared the acute pharmacological and physiological effects of orally administered methylone and MDMA in healthy participants with a history of prior exposure to both compounds. While the compounds may be mechanistically similar, methylone produced less intense prototypical psychostimulant and empathogenic effects, including lessened euphoria, inebriation, stimulant-like effects, and changes in cognitive and body perception, with increased sociability relative to MDMA.
  • Methylone has significantly lower affinity for 5-HT2A than MDMA and has partial agonist activity at the 5-HTIA receptor, which MDMA does not. Methylone also has weaker antagonistic effects on 5-HT2C relative to MDMA, which has partial agonistic activity. Methylone also inhibits or reverses the monoamine reuptake transporters for dopamine, norepinephrine, and serotonin, which increases extracellular concentrations of these neurotransmitters .
  • This Example presents a more detailed analysis of 21 patients from the previous Example (the 20 patients from the PTSD subset discussed in the previous Example plus one patient from that Example who was mischaracterized and was subsequently determined to have a primary diagnosis of PTSD) with a primary diagnosis of PTSD , with a range of psychiatric comorbidities, who were treated clinically with methylone in an outpatient setting.
  • the patients were not given structured psychotherapy in conjunction with methylone treatment, which differs from recent studies of MDMA that emphasize the importance of a manualized psychedelic-assisted psychotherapy model.
  • Archival clinical data was obtained from 21 patients with a primary diagnosis of PTSD who received at least one oral methylone administration as part of specialty care in an outpatient psychiatric setting. No protected health information was disclosed, and no consent was obtained from patients for use of their archival data. Case narratives were systematically compiled from data collected as part of routine clinical work. Diagnoses were confirmed by an experienced clinician using semi-structured interviews. Baseline symptom severity was evaluated using the Clinical Global Impressions Scale-Severity (CGI-S). Symptom improvement was evaluated using the Clinical Global Impressions Scale-Improvement (CGI-I) following dosing. Patients were evaluated for any observed or reported safety events following their methylone dosing session(s).
  • BPD Borderline personality disorder
  • CBT cognitive behavioral therapy
  • F female
  • GAD generalized anxiety disorder
  • M male
  • MDD major depressive disorder
  • NR not reported
  • PTSD posttraumatic stress disorder
  • SCZ Schizophrenia
  • SSRI selective serotonin reuptake inhibitor
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • SI suicidal ideation
  • UNSP unspecified Results
  • Methylone produced acute and enduring improvements in both PTSD and depression symptoms, without any notable lasting adverse effects.
  • Clinical data are presented in Table 5. Twelve patients (57%) were female; 19 (90%) were White. The mean age was 47.6 years (range: 25 to 78).
  • Baseline CGI-S scores ranged between 4 and 7 for all 21 patients (i.e., moderately to severely ill; see Figure 4).
  • Six patients (28.6%) were on concomitant SSRI or other psychotropic therapy at the time of methylone dosing. This is notable because recent trials of MDMA in PTSD have required that patients be on no other psychotropic medications, as SSRI antidepressants have been shown to attenuate the therapeutic effects of MDMA due to substrate competition.
  • Methylone was administered orally. Other medications were not changed during methylone treatment. In many cases, an additional, booster dose of methylone was administered 1 hour after the initial dose to extend the therapeutic window and optimize clinical response. In several cases, treatment was continued, and, in some cases, the dose was further escalated in later sessions (see Table 5). Booster doses were included for 19 patients in one or more of the sessions. Starting doses were between 100 and 270 mg, and these as well as booster doses were selected based on clinical judgement. [00221] Safety: Methylone was generally well tolerated, and no patients discontinued treatment due to adverse events. A total of four adverse events were noted in three of the 21 patients (two in one patient); none were considered severe, and none required medical intervention.
  • a 70-year- old male administered methylone 690 mg during a single dosing session (200 mg followed by booster doses of 250 mg and 240 mg) did not experience any adverse events during the session but reported sleeplessness and loss of appetite the night following the session. These symptoms had resolved by the following day.
  • Methylone was well-tolerated over a broad dose range (100 to 1,020 mg), with one to ten administrations. A few adverse events were reported in three older patients, age 70 and over; these were mild and required no intervention. No patients discontinued methylone treatment because of adverse events. Notably, none of these adverse events occurred in patients receiving concomitant SSRI therapy.
  • Methylone has not received the same cultural or clinical attention as MDMA, perhaps due to its milder and shorter psychopharmacological effects (e.g., euphoria, empathogenic effects). However, these “softer” effects may be particularly helpful for some patients who are not appropriate for treatment with the more intense acute psychological and physiological effects of MDMA.
  • Example 6 Methylone in the FST: implications for depression, anxiety, and PTSD
  • FST Forced Swim Test
  • rats were placed in a circular plexiglass container filled with water, with no means of escape. Water temperature was maintained at 22- 25° C and changed for every animal. After an acclimation period, rats were timed for inactivity (failure to struggle), activity, swim time and climbing time. Day 1 consisted of a 15 min acclimation trial, and Day 2 (24 h later) consisted of the 5 min test. A time sampling procedure was employed where animals were observed every 5 sec and scored for immobility, swimming, or climbing.
  • Fluoxetine (10 mg/kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle (vehicle 3X group) were administered 23.5, 5, and Ih before testing in the FST.
  • Methylone (5, 10, 15, 20, and 30 mg/kg, IP; Cayman Chemical) or 0.9% saline vehicle (vehicle lx group) were administered 30 min prior to FST testing.
  • rats were administered a single dose of methylone (15 mg/kg) 2 hours before FST testing. The experimenter was blinded to treatment.
  • Radioligand binding was performed using standard protocols using [ 3 H]citalopram, [ 3 H]WIN35428, and [ 3 H] nisoxetine for serotonin (5HT), dopamine (DA), and norepinephrine (NE) transporters, respectively.
  • Radiolabeled 5HT, NE, and DA uptake and release studies in rat brain synaptosomes were conducted using standard protocols.
  • a single dose of methylone produced a robust, dose-dependent and fast-acting antidepressant-like response in the rat FST (Figure 5).
  • 2-3 injections of an SSRI antidepressant are generally required to elicit a behavioral response in the FST, as observed in a fluoxetine control group in the current study that received 3 doses of fluoxetine prior to testing.
  • rats treated with a single dose of methylone 30 minutes before testing in the FST showed highly significant reductions in immobility (Figure 5).
  • a single dose of methylone (5, 10, 15, 20, and 30 mg/kg, IP) administered 30 min prior to testing significantly reduced immobility compared to rats receiving saline vehicle.
  • Mid and high doses of methylone significantly increased swimming. Climbing was only increased at the lowest dose of methylone, reflecting recruitment of noradrenergic receptor activity at this dose level.
  • LSD and psilocybin have been shown to reduce immobility in the FST by 38% and 67%, respectively (Hibicke, 2020).
  • MDMA (5 or 10 mg/kg) has been reported to reduce immobility by 45% and 78% in Sprague Dawley rats, respectively (Majumder el al. (2011) Behav Pharmacol 22:758) but had a more robust effect in Flinders Sensitive Line rats, a genetic model for depression (45% and 93%, respectively, id.).
  • Binding studies confirmed methylone binding at the 5HT, NE, and DA transporters.
  • methylone produced a more robust antidepressant-like response than the SSRI fluoxetine in the FST, a canonical behavioral assay with well-established specificity and selectivity for antidepressant drugs.
  • the magnitude of methylone’s effect in this test also surpassed that of other psychedelics and antidepressants tested in wild-type rats in the literature ( Figure 6).
  • methylone shows distinct effects on monoamine transporter binding, uptake and release.
  • Example 7 2C-B in the FST: implications for depression, anxiety, and PTSD
  • Fluoxetine (10 mg/kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle (vehicle 3X group) were administered 23.5, 5, and Ih before testing in the FST.
  • 2C-B 2.5, 10, or 20 mg/kg, IP, Cayman Chemical
  • 0.9% saline vehicle (vehicle IX group) were administered 30 min prior to FST testing. The experimenter was blinded to treatment.
  • Example 8 Prior Selective Serotonin Reuptake Inhibitor (SSRI) Treatment Does Not Interfere with Efficacy of Methylone in the Rat Forced Swim Test
  • Example 6 shows that Methylone produces a rapid, robust dose-dependent antidepressant-like effect in the Forced Swim Test (FST), greater in magnitude than any other antidepressant tested in this model.
  • Selective serotonin reuptake inhibitors are a first- line treatment for a variety of Central Nervous System (CNS) disorders including post- traumatic stress disorder (PTSD), Major Depressive Disorder (MDD), anxiety disorders, obsessive compulsive disorder (OCD), and fibromyalgia.
  • CNS Central Nervous System
  • PTSD post- traumatic stress disorder
  • MDD Major Depressive Disorder
  • OCD obsessive compulsive disorder
  • fibromyalgia fibromyalgia.
  • MDMA-assisted psychotherapy is in clinical trials for the treatment of PTSD, with the caveat that SSRIs inhibit the efficacy of the MDMA-assisted therapy (Feduccia el al.
  • Example 9 Effects of methylone, 2-CB and MBDB in a mouse model of Post- Traumatic Stress Disorder (PTSD)
  • PTSD Post- Traumatic Stress Disorder
  • Deficient fear extinction memory is a feature of PTSD in patients (Wicking et al. (2016) Neurobiology of Learning and Memory 136:116).
  • SSRI antidepressants similar to the two approved for the treatment of PTSD (i.e., paroxetine and sertraline), prevent fear memory generalization and enhance extinction (Pedraza et al. (2019) Transl Psychiatry 9:53).
  • the enhancement of fear extinction might also underlie the beneficial effect of MDMA as a PTSD treatment (Feduccia & Mithoefer (2016) Progress in Neuro-Psychopharmacology & Biological Psychiatry 84(Part A), 221-228).
  • Effective PTSD treatments facilitate the disassociation between a traumatic memory and the patient’s fear response, making cues for the traumatic memory evoke less of a fear response.
  • This is modeled in the mouse fear extinction paradigm (see Figure 9A) which takes place over 3 days.
  • mice On day 1 (fear conditioning), mice are trained to acquire a “traumatic memory,” namely associating the conditioned stimulus (CS, tone) to the unconditioned stimulus (US, foot shock).
  • day 2 extinction training
  • they are trained to forget the traumatic memory association by presenting the CS 6 times (with no US) in a novel environment.
  • mice On day 3 (extinction recall), the mice are “asked” if that tone (CS) still elicits a fearful response, as measured by the time spent freezing when the tone is presented. Less time freezing means better extinction recall. Drugs that improve extinction recall reduce freezing time on day 3, and, therefore, show potential as a PTSD treatment.
  • the open field test capitalizes on a rodent’ s innate fear of open spaces to assess anxiety-like behavior. More time spent in the center of an open field reflects an anxiolytic (antianxiety) effect.
  • Example 11 Lower doses of methylone given more frequently mimic the antidepressantlike effects of a single larger dose in the rat Forced Swim Test.
  • Methylone HC1 (2.5-15 mg/kg) was formulated in sterile saline vehicle before intraperitoneal administration. Control animals received saline vehicle. The dosing schedule and experimental design are found in Figure 12 A.
  • the FST was performed and scored by an experimenter blind to treatment group according to standard protocols and based on a “modified FST” procedure (Slattery and Cryan (2012) Nat Protoc, 7:1009). Briefly, rats were placed in a circular plexiglass container (29.2 cm diameter, 49.5 cm height) filled with water to a depth of 30 cm so rats could not support themselves by touching the bottom of the tank. Water was maintained at 22-25 °C and was changed for every animal. Day 1 (Training) consisted of a 15 min acclimation trial, and Day 2 (Testing, 24 h later) consisted of the 5 min test.
  • a time sampling procedure was employed where animals were observed every 5 seconds for the duration of the test session (60 counts or 5 minutes) and scored for immobility (defined as the failure to struggle), swimming (defined as a circular movement around the tank), or climbing (defined as an upwards escape behavior). Data are expressed as the percent time spent immobile, swimming or climbing for the 5-minute testing session (e.g., the number of immobility counts divided by 60).
  • Methylone shows no agonist/antagonist activity at 168 different GPCRs in a p-arrestin based screen.
  • PathHunter cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 pL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing.
  • Assay signal was generated through a single addition of 12.5 or 15 pL (50% v/v) of PathHunter Detection reagent cocktail, followed by a one-hour incubation at room temperature. Microplates were read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection.
  • % Activity 100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand - mean RLU of vehicle control).
  • % Inhibition 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of EC80 control - mean RLU of vehicle control)).
  • Activation of a GPCR by a compound acting as an agonist will result in an increase in P-arrestin recruitment to the target GPCR.
  • the activity should be >30%.
  • Inhibition of GPCR activation by a compound acting as an antagonist of a ligand binding will result in a decrease in P-arrestin recruitment to the target GPCR.
  • >50% inhibition should be observed.
  • Table 6 Agonist/Antagonist activity of Methylone (1 or 10
  • FST Forced Swim Test
  • MBDB is the a-ethyl analog of MDMA. This study tested whether MBDB had an antidepressant-like effect in the rat forced swim test (FST).
  • the FST is a classic behavioral test that has been used for over 40 years to screen drugs with antidepressant-like effects. All classes of antidepressants, including serotonergic antidepressants, tricyclic antidepressants and even the more rapidly acting antidepressants like ketamine have been shown to reduce immobility in the FST, consistent with an antidepressant-like effect.
  • drugs that act on the serotonin and norepinephrine system increase swimming and climbing behaviors, respectively, in the FST. Therefore, those behaviors were also measured to glean insight into the underlying mechanism of the antidepressant-like behavioral response.
  • MBDB (0.5-30 mg/kg) was formulated in sterile saline vehicle before intraperitoneal administration. Control animals received saline vehicle.
  • the FST was performed and scored by an experimenter blind to treatment group according to standard protocols and based on a “modified FST” procedure. Briefly, rats were placed in a circular plexiglass container (29.2 cm diameter, 49.5 cm height) filled with water to a depth of 30 cm so rats could not support themselves by touching the bottom of the tank. Water was maintained at 22-25 °C and was changed for every animal. Day 1 (Training) consisted of a 15 min acclimation trial, and Day 2 (Testing, 24 h later) consisted of the 5 min test.
  • a time sampling procedure was employed where animals were observed every 5 seconds for the duration of the test session (60 counts or 5 minutes) and scored for immobility (defined as the failure to struggle), swimming (defined as a circular movement around the tank), or climbing (defined as an upwards escape behavior). Data are expressed as the percent time spent immobile, swimming or climbing for the 5-minute testing session (e.g., the number of immobility counts divided by 60).
  • Methylone is a new and potentially effective treatment option for participants with PTSD.
  • the purpose of this pilot study is to evaluate the safety, tolerability, and efficacy of methylone in adult participants with PTSD.
  • the study is conducted in two parts. Part A is openlabel enrolling up to 15 evaluable participants with PTSD. After completion of Part A, enrollment will begin for Part B, which is double-blind, placebo-controlled and enrolling up to 64 evaluable participants with PTSD.
  • 5D-ASC 5-Dimensional Altered State of Consciousness
  • AE adverse event
  • AESI adverse event of special interest
  • BDI-II Beck Depression Inventory-II
  • DBP diastolic blood pressure
  • CAPS-5 Clinician-Administered PTSD Scale forDSM-5
  • CGI- I Clinician Global Impression of Improvement
  • CGI-S Clinical Global Impression of Severity
  • C-SSRS Columbia Suicide Severity Rating Scale
  • DBP diastolic blood pressure
  • ECG electrocardiogram
  • HR heart rate
  • MADRS Montgomery-Asberg Depression Rating Scale
  • MEQ-30 Mystical Experience Questionnaire - 30 Item
  • PCL-5 PTSD Checklist for DSM-5
  • PGI-C Patient Global Impression of Change
  • PGI-S Patient Global Impression of Severity
  • PSQI Pittsburgh Sleep Quality Index
  • PTGI Post-traumatic Growth Inventory
  • PTSD Post-traumatic stress disorder
  • SDS She
  • Part A is an open-label, non-controlled assessment in up to 15 evaluable participants with PTSD to assess early safety and efficacy and to confirm procedures included in the blinded portion (Part B) of the study.
  • Part B enrollment for Part B will begin in up to 64 participants.
  • Part B is identical to Part A with the exception of the inclusion of a placebo arm in Part B.
  • Part B is a randomized, double-blind, parallel-group, placebo-controlled assessment of methylone for the management of the symptoms of PTSD.
  • Enrollment includes up to 79 evaluable participants (up to 15 in Part A and up to 64 in Part B); in Part B, up to 40 evaluable participants are enrolled initially with an interim analysis to determine if a larger sample size is needed. There are 4 planned dose sessions for each participant. Participants in Part B are randomized 1 : 1 to the two study treatment arms and receive the randomized treatment at each of the weekly dose sessions for the study duration.
  • the two blinded study treatment arms in Part B are:
  • Methylone 150 mg with a booster administration of 100 mg administered 90 ( ⁇ 10) minutes after the initial administration, during each dose session.
  • Screening Period (Day -28 to Day -4): Informed consent, eligibility assessment, and enrolment of eligible participants.
  • Baseline/Preparatory Session (Day -3 to Day -1): Baseline assessments, confirmation of eligibility, and a preparatory psychoeducation session leading to enrolment confirmation.
  • Treatment Period (Day 1 to Day 24): Four weekly dose sessions, with associated remote sessions. The dose sessions last at least 8 hours, or until all effects (physical and psychological) have resolved (whichever is longer). Each dose session is followed by a safety phone call 1 day after dosing and efficacy assessments 2 days after dosing. Each dosing period is video recorded for quality and training purposes. The videos may be reviewed to ensure the Mentor is adhering to the Mentor training.
  • DSM 5 Medically healthy adult participants aged between 18 to 65 years, inclusive. Participants must meet the diagnostic and statistical manual of mental disorders, fifth edition (DSM 5) criteria for current moderate to severe PTSD diagnosis with a symptom duration of at least 6 months at Screening, as assessed by the Mini International Neuropsychiatric Interview (MINI) 7.0.2, CAPS-5, and the Life Events Checklist for DSM-5 (LEC-5) and must have failed at least one treatment for PTSD (either psychotherapy or pharmacological treatment).
  • MINI Mini International Neuropsychiatric Interview
  • CAPS-5 CAPS-5
  • LEC-5 Life Events Checklist for DSM-5
  • participant must not have a primary diagnosis of any other DSM-5 disorder, as assessed by the MINI Version 7.0.2, or have any history, physical or psychological symptoms, medication or other relevant findings that would make a participant unsuitable for the study based on the clinical judgement of study personnel.
  • the treatment duration for both Parts A and B are the same: four weeks as weekly dosing (Day 1, Day 8 [+1 day], Day 15 [+1 day], and Day 22 [+1 day]).
  • the objectives of the Data and Safety Monitoring Board are to review safety data (Parts A and B), review the interim analysis report and provide advice on the advisability of increasing the sample size for Part B.
  • DSMB meetings are scheduled to occur after 8 participants in Part A have completed the Day 29 Follow-Up visit, or EOS if the participant withdraws early (Safety Run-in Phase), and once at the conclusion of enrolment in Part A.
  • DSMB meetings occur at intervals of approximately 20 participants (10 per treatment group). At least two DSMB meetings are scheduled. The first DSMB meeting, after 20 participants have completed the Day 29 Follow-Up visit, or EOS if the participant withdraws early, also includes an interim efficacy report to determine if the sample size is appropriate, have completed the Day 29 Follow-Up visit, or EOS if the participant withdraws early (sample size evaluation). A second DSMB meeting occurs after at least 40 participants have had the opportunity to complete the study, if more than 40 participants are anticipated to be enrolled. Ad hoc DSMB meetings can occur if needed.
  • Efficacy is assessed through several psychometric assessments and scales that assess PTSD symptoms and quality of life.
  • assessments are made of sleep quality, treatment satisfaction and psychedelic effects.
  • a Mixed Model for Repeated Measures is fitted for select efficacy endpoints to analyze the difference between treatments for Part B.
  • the model includes treatment as a fixed effect while visit and treatment by visit are a mixed effect.
  • the baseline value is included (if applicable) as a covariate and participant as a random effect.
  • the analysis uses an alpha of 0.1.
  • Example 15 Methylone binds to the serotonin transporter (SERT) differently than does MDMA.
  • MDMA binds the serotonin transporter (SERT) at its central site (i.e., where serotonin and serotonergic antidepressants bind) as well as at an allosteric site (Islas el al. (2021) Heliyon e07784; Islas & Scior (2022) Molecules 27:2977). Allosteric binding of MDMA to SERT was hypothesized to underlie its supraphysiological increased release and depletion of presynaptic serotonin as well as interference with SSRI antidepressants that has been described in patients and animal models (Feduccia et al. (2021) Psychopharmacology 238:581; Callaway et al. (1990) J Pharmacol Exp Ther, 254:456; Geyer (1994) Neuropsychopharmacology 10:768S).
  • SERT serotonin transporter
  • Example 16 Unlike MDMA, methylone does not bind to 5HT2B receptors, which is a positive differentiator of methylone in terms of cardiovascular safety.
  • Agonists of serotonin 5HT2B receptors are strongly implicated in mediating drug- induced valvular heart disease.
  • 5HT2B agonism is considered a toxicity signal in drug development (Cavero et al. (2014). Journal of Pharmacological and Toxicological Methods 69:150).
  • MDMA has shown to be a non-selective agonist of 5HT2B receptors (Setola et al. (2003) Molecular Pharmacology 63:1223). In this Example, methylone was tested to determine whether it showed any affinity for the 5HT2B receptor by competitive radioligand binding.
  • serotonin receptor subtype activity has been linked to hallucinogenic effects (5HT2A), cardiovascular toxicity (5HT2B) and side effects of SSRI antidepressants (5HT2c) in humans and animal models.
  • Results obtained from a GPCR screen of methylone demonstrate that methylone had no agonist or antagonist activity at 138 different G-protein coupled receptors, including the 5HT2 receptors. Weak/no binding of methylone to 5HT2B receptors has also been shown (Example 16 above).
  • Methylone binds to monoamine transporters and facilitates the release of norepinephrine (NE), serotonin (5HT), and dopamine (DA), but the downstream effects of these changes in key brain areas linked to PTSD and depression have not been investigated. It is these downstream effects (e.g., changes in gene expression) that drive functional changes in the brain that underlie the actions of methylone. Rats were dosed once with methylone (10 mg/kg, IP) or vehicle (saline) and sacrificed 8 hours later. Brains were removed and amygdala, frontal cortex, and hippocampus were dissected and subjected to RNA-sequencing. Results identified differentially expressed genes in these key brain areas linked to PTSD and depression.
  • NE norepinephrine
  • HT serotonin
  • DA dopamine
  • Example 19 MBDB has rapid-acting, robust anxiolytic effect, increasing time spent in the center of an open field
  • MBDB anti-anxiety
  • rats were dosed with MBDB (0.5-30 mg/kg, IP) or vehicle (saline) and 30-minutes later were tested in the open field for 30 minutes.
  • This anxiety test capitalizes on a rodents’ innate fear of wide-open spaces and propensity to hug the walls when placed into the open field. Therefore, a drug that increases the time spent in the center of the open field has anxiolytic activity and predicts utility for treating anxiety in humans.
  • MBDB had a rapid-acting and robust antianxiety effect in the open field, significantly increasing time spent in the center by -40% compared to control animals.
  • Example 20 Methylone for the treatment for PTSD: Initial Results from an Open-Label Study (IMPACT-1)
  • Post-traumatic stress disorder is a serious debilitating disorder impacting approximately 13 million Americans each year. Suicide risk in PTSD is increased by at least 6- fold compared to the general population. Approximately half of people diagnosed with PTSD also have a diagnosis of major depressive disorder (MDD). Approved pharmacotherapies for PTSD treatment (sertraline and paroxetine) have limited effectiveness. Less than 30% of patients treated with first-line pharmacotherapy achieve remission, which often takes many weeks to achieve. Thus, there is an urgent need for rapid-acting, non-hallucinogenic PTSD treatments.
  • Methylone is a rapid-acting neuroplastogen, which rapidly induces neuroplasticity gene expression (e.g., BDNF) in brain areas underlying pathophysiology of PTSD, depression, and anxiety. Well-characterized primary pharmacology. Monoamine transporters are primary site of action. No binding at 5HT2A receptor, not hallucinogenic. Rapid, robust serotonin and norepinephrine release in the frontal cortex.
  • BDNF neuroplasticity gene expression
  • This Example presents initial results from a clinical study for the treatment of PTSD (IMPACT-1).
  • the IMPACT-1 Study has two parts, an open-label study (Part A) and a placebo- controlled study (Part B), the study design is presented in Figure 20.
  • Part A open-label study
  • Part B placebo- controlled study
  • the demographics and baseline characteristics of the open-label study participants are provided in Table 7 below.
  • Methylone was administered once a week for 4 weeks. Each dose was given as an initial dose, followed by a second dose 90 minutes later. During the dosing session, participants were accompanied by a trained Mentor who provided non-directive support. After the 4-week treatment period, participants attended follow-up visits at 1, 2, 3, and 6 weeks following the last dose. Safety was assessed via standard measures including adverse events. PTSD symptoms were assessed via Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), depressive symptoms were assessed via Montgomery-Asberg Depression Rating Scale (MADRS).
  • Antianxiety efficacy was evaluated using the Anxiety Sub-Scale of MADRS, namely, questions (Items 3, 4, 5, 6) that address four anxiety items (inner tension, reduced sleep, reduced appetite, concentration difficulties) Changes from baseline were analyzed using a paired t-test p-values. [00320] Results: Table 8 below presents Treatment- Emergent Adverse Events (TEAE) observed in the Open-Label Study (IMPACT- 1; Part A). The majority of TEAEs were transient and of mild severity. No drug-related SAEs occurred. There was one unrelated SAE that occurred (victim of assault) 20 days after the last dose.
  • TEAE Treatment- Emergent Adverse Events
  • Figure 21 plots mean Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores in the Open-Label Study (IMPACT- 1) over time and shows that methylone produced rapid and durable improvements.
  • CAPS-5 scores decreased by 8.4 points
  • CAPS-5 scores decreased by 23.3 points.
  • CAPS-5 scores decreased by 36.2 points.
  • Figure 22A plots mean change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores over time for the Open-Label Study (IMPACT-1) and shows that methylone also produced rapid, robust, and durable improvements of depressive symptoms.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • IMPACT-1 Open-Label Study
  • Figure 22B plots mean change from Baseline in the Anxiety Sub-Scale of MADRS and shows that methylone also produced rapid, robust, and durable improvements in anxiety in humans.
  • scores were reduced by 20%, 43%, 50%, and 57%, respectively.
  • Days 29, 36, 43, and 64 scores continued to decrease by 56%, 66%, 64%, and 66%, respectively.
  • Figure 23 plots response and remission based on CAPS-5 scores in the Open-Label Study (IMPACT- 1) over time and shows high rates of response and remission occurred after methylone treatment. At Day 10, nearly 40% of participants achieved remission and at the end of the study remission was achieved in 61.5% of participants.
  • Example 21 Methylone was observed to treat chronic pain in a subject with PTSD [00326]
  • the patient reported that his chronic migranne headache was gone with only a throbbing remaining in the temples.
  • Example 22 Evaluating the effect of methylone in a chronic pain model
  • This Example presents a rat model to evaluate the benefit of methylone for fibromyalgia (FMA).
  • FMA fibromyalgia
  • Sprague Dawley rats are tested in a behavioral model of FMA based on the protocol from Nakagura et al. (2009) Pain 146:26.
  • This model uses three daily doses of reserpine (1 mg/kg, SC) or 0.5% acetic acid vehicle to reduce pain thresholds (i.e., increase pain perception) in the Von Frey Test (vFT, procedure outlined below). Animals are tested in the vFT on day -1 (baseline), day 4 (post-reserpine), and then pre-dose, 30, 60, 120, 240 minutes, 24 hours and 72 hours after methylone (test article), duloxetine (positive control/comparator) or vehicle injection (IP).
  • vFT Von Frey Test
  • Static allodynia is measured using Semmes-Weinstein von Frey filaments (Stoelting, Wood Dale, IL). Mechanical allodynia is tested by touching the plantar surface of the animals’ left and right hind paws with von Frey filaments which deliver a calibrated amount of force. Each von Frey filament is presented perpendicularly to the plantar surface for approximately 6 seconds of constant application in either ascending or descending strength in a modified up-and-down method (Chaplan et al. (1994) J Neurosci. Meth. 53:55). Stimulation is presented at intervals of several seconds, allowing for apparent resolution of any behavioral responses to previous stimuli. A positive response is noted if the paw is sharply withdrawn.
  • Methylone has a beneficial effect in this rat fibromyalgia model and restores ‘normal’ pain thresholds in rats with pain sensitivity (Figure 38). Rats were treated with reserpine for 3 days to induce pain sensitivity (+) or vehicle (-) to maintain the ‘normal’ pain threshold. Baseline paw withdrawal thresholds showed significant effect of reserpine vs. vehicle (not shown). On day 4, rats were given vehicle or methylone (15 mg/kg, IP) 30 min before testing in the vonFrey test for pain sensitivity. Methylone significantly increased paw withdrawal thresholds, consistent with a beneficial effect in this model of fibromyalgia.
  • Example 23 Evaluating the effect of 2C-B in a model for fibromyalgia
  • This Example uses a rat model to show the benefit of 2C-B for fibromyalgia (FMA).
  • VonFrey measurements Animals were placed into wire bottom cubicles with opaque Plexiglas walls, allowing access to the underside of their paws. Animals were habituated to this environment for at least 30 minutes before the start of the von Frey filament application. Static allodynia was measured using Semmes-Weinstein von Frey filaments (Stoelting, Wood Dale, IL). Mechanical allodynia (pain sensitivity) was tested by touching the plantar surface of the animals’ left hind paws with von Frey filaments which deliver a calibrated amount of force.
  • Results are shown as means +/- SEM. Statistical analysis was performed using two- way ANOVA and posthoc Dunnett’s multiple comparisons test. Differences were considered statistically significant when p ⁇ 0.05.
  • Results revealed a robust (maximal) and fast-acting effect of 2C-B at both doses (10 and 20 mg/kg) in this model of fibromyalgia (Figure 16).
  • 2C-B significantly and completely reversed reserpine-induced pain sensitivity in 100% of animals tested (9/9)
  • Duloxetine also reversed pain sensitivity, but a maximal effect (i.e., a complete reversal of the increased pain sensitivity) was only observed in 44% of animals (4/9).
  • Example 24 Evaluating the effect of 2C-B in a model for chemotherapy-induced peripheral neuropathy (CIPN)
  • This Example uses a mouse model to show the benefit of 2C-B for chemotherapy- induced peripheral neuropathy (CIPN).
  • CIPN is a painful condition that develops in cancer patients undergoing chemotherapy with platinum-based compounds, taxanes, vinca alkaloids, epothilones, proteasome inhibitors and immunomodulatory drugs.
  • the treatments can damage sensory, motor and autonomic neurons to cause CIPN, which results in significant reduction in function, quality of life, and often in cessation of therapy leading to increased mortality.
  • Cisplatin a platinum-based chemotherapy agent has been used to reduce pain thresholds in a model of CIPN. Effects of acute (single higher dose) or sub-chronic (7 days repeated lower dose) 2C-B on pain thresholds were investigated in cisplatin-treated animals compared with vehicle or cisplatin-treated controls.
  • Static allodynia was measured using Semmes-Weinstein von Frey filaments (Stoelting, Wood Dale, IL). Mechanical allodynia was tested by touching the plantar surface of the animals’ right and left hind paws with von Frey filaments which deliver a calibrated amount of force (0.07, 0.16, 0.4, 0.6. 1.0, 2.0, 4.0, 6.0 g). Each von Frey filament was presented perpendicularly to the plantar surface for approximately 6 seconds of constant application in either ascending or descending strength in a modified up-and-down method (Chaplan el al. (1994) J Neurosci. Meth. 53:55).
  • Stimulation was presented at intervals of several seconds, allowing for apparent resolution of any behavioral responses to previous stimuli. A positive response was noted if the paw was sharply withdrawn. Flinching immediately upon removal of the hair was also considered a positive response. Ambulation is considered an ambiguous response, and, in such cases, the stimulus was repeated. To determine the 50% withdrawal threshold, testing was initiated with the 0.60 g fiber. The withdrawal responses were averaged and compared to the baseline measurement.
  • Figure 24 shows the pharmacokinetic analysis of plasma in rats following oral (PO), intraperitoneal (IP), intramuscular (IM) or subcutaneous (SC) injection with methylone.
  • the pharmacokinetic parameters are presented in Table 9 below: Table 9. Pharmacokinetic parameters for methylone in rats by different administration routes
  • PK pharmacokinetic
  • Noncompartmental analysis was performed within Phoenix WinNonlin (v8.3) to calculate summary PK parameters, including maximum concentration, time to maximum concentration, AUC, and half-life.
  • Population PK modeling was performed within NONMEM (v.7.3). Raw data manipulation, and PK simulations were executed in R (v.4.2.0). Input data for population PK modeling was taken from the dose-escalation study referenced above.
  • the final population PK model was a one-compartment model with absorption lag time and linear clearance from the central compartment. Model parameters were estimated with sufficient precision. Goodness-of-fit plots indicated good agreement between model predictions and observed data with no substantial concentration or time-dependent trends.
  • SD standard deviation
  • excipients in oral solid dosage forms were selected for excipient/ API compatibility.
  • the possible processes (blending, milling and dry granulation ) followed for manufacturing of oral solid dosage forms were considered while shortlisting the excipients.
  • the formulation will require a filler and binder, thus microcrystalline cellulose and mannitol can be used in dry granulation processing.
  • the formulation may also need a disintegrant (croscarmellose sodium and crospovidone xl) irrespective of the manufacturing process followed.
  • Sodium lauryl sulphate and poloxamer 188 may also be required as solubilizers to increase the solubility of the API.
  • Colloidal silicon dioxide may be required in order to aid the flow properties of the blend and magnesium stearate or sodium stearyl fumarate may be used for lubrication.
  • Colorista® capsules are also included to evaluate gelatin and dye in case a capsule dosage form is selected.
  • the ratios of excipients to the API in the compatibility study are driven by possible formulations while taking into account the allowable quantity of each excipient taken from the database of FDA’s inactive ingredient guide (IIG) available at www.accessdata.fda.gov/scripts/cder/iig/index.Cfm.
  • Table 12 lists mixtures of API with varied excipients and a standalone control sample of API alone. Each excipient mixture sample preparation was conducted using a clean spatula to mix the vial ingredients for 30 - 60 seconds. Each vial was properly labeled with the description and storage conditions. One vial was used for testing at
  • Table 15B Table 17A:
  • Table 17B Table 17C:
  • Example 27 Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA
  • Chronic antidepressant treatment increases neuroplasticity genes in the brain, corresponding to the time course of therapeutic benefit. It takes weeks of daily dosing with drugs like fluoxetine (brandname: Prozac) to increase brain expression of neurotrophic factors like brain-derived neurotrophic factor (BDNF) and associated modifications in synapses.
  • drugs like fluoxetine brandname: Prozac
  • BDNF brain-derived neurotrophic factor
  • Radioligand binding was performed in SD rat brain lysates at Gifford Bioscience, Ltd (Birmingham, UK) according to standard protocols. Radioligands used were: [ 3 H]Citalopram (PerkinElmer NET1039250UC); [ 3 H]Nisoxetine (PerkinElmer NET1084250UC); [ 3 H]WIN35428 (PerkinElmer NET1033250UC). Nonspecific compounds used were Citalopram (Tocris Bioscience 1427); JHW007 (Tocris Bioscience 4351); Nomifensine (Abeam abl46004). Test compounds used were methylone (Merck M-140) or MDMA (Merck M-103).
  • Rat brains were dissected and tissue was homogenized in cold lysis buffer, centrifged at lOOxg for 2 min and the supernatant was placed in a fresh tube. Supernatant was centrifuged at 13,000 x g for 10 min at 4 °C to re-pellet the cell lysate. The pellet was resuspended in fresh wash buffer (50 mM Tris-HCl; 5 mM MgCh; 5 mM EDTA) and centrifuged a third time. The pellet was then resuspended in wash buffer containing 10% sucrose as a cryoprotectant, divided into aliquots (0.3 mL) and stored at -80 °C.
  • a sample of the homogenate was analyzed for protein content using the SIGMA® BCA assay.
  • the membrane preparation was thawed, and the pellet resuspended in final assay buffer.
  • Competition binding assays were carried out in 96-well polypropylene plates in a final volume of 250 pL per well. To each well was added 150 pL membranes, 50 pL of non-specific compound or buffer and 50 pL radioligand solution in buffer. The plate was incubated at 30 °C for 90 minutes with gentle agitation.
  • Rat brain synaptosomes were isolated from Sprague Dawley rats (200-250g). Brains were dissected and tissue was added to sucrose buffer (0.32 M), homogenized with a dounce- homogenizer and centrifuged at 100 x g to remove cells and debris. Supernatant was collected and centrifuged 17,000 x g for 10 minutes at 4 °C to pellet the synaptosomes. The pellet was resuspended in fresh assay buffer. Uptake assays were carried out in 96-well plates in a final volume of 250 pL per well. To each well was added 150 pL synaptosomes, 50 pL test or nonspecific compound or buffer alone.
  • the plate was incubated at 30 °C for 30 minutes with gentle agitation.
  • 50 pL radiolabeled neurotransmitter [ 3 H]5-HT (PerkinElmer, NET498001MC); [ 3 H]DA (PerkinElmer, NET673250UC); [ 3 H]NE (PerkinElmer, NET048250UC) in buffer was then added to each well to initiate the uptake.
  • the plate was incubated 30 °C for a further five minutes with gentle agitation. The incubation was stopped by vacuum filtration onto presoaked (0.1% BSA in wash buffer) GF/C filters using a 96-well FILTERMATETM harvester, followed by three washes with ice-cold wash buffer.
  • Drug-evoked release of neurotransmitter was calculated by subtracting the average of the two basal fractions (collected prior to the drug addition), from the four fractions collected in the presence of drug. The drug- evoked release was then expressed as a percentage of the basal release. Potassium-evoked release was calculated by subtracting the average of two fractions collected prior to the addition of high KC1 buffer from that in the two fractions following addition of high KC1 buffer. Potassium-stimulated release was calculated as a percentage of basal release. The drug evoked release as a function of drug concentration plotted and the data fitted. Data was fitted using the non-linear curve fitting routines in PRISM® (Graphpad Software Inc).
  • GPCR Screen Studies were done at Eurofins DiscoverX Corp (Fremont, CA) using the GPCRmax assay according to manufacturer’s protocols. This assay uses enzyme fragment complementation with ⁇ -galactosidase as the functional reporter. When a GPCR is activated, P-galactosidase is recruited, and the reporter is detectable. GPCRmax offers a high-throughput screen of 168 GPCRs for agonist or antagonist activity. Briefly, PathHunter cell lines were propagated, seeded into 384-well microplates and incubated at 37°C.
  • % Inhibition 100% x (1 - (mean RLU of test sample - mean RLU of vehicle control) I (mean RLU of ECso control - mean RLU of vehicle control)).
  • Ligand preparation In cases where there were two stereoisomers of a particular drug/ligand, each stereoisomer was treated separately for preparation and docking. Each ligand was first ionized at pH 7 with MOE’s Wash function to produce the dominant species. This was followed by conformational generation using the stochastic search method to ensure complex ring systems were adequately sampled. All generated conformations were used as input for docking. Docking poses and the likelihood of binding were evaluated by a combination of MOE’s GBVI/WSA dG docking score, ligand conformational strain, and similarity to related experimental structures.
  • RNA Sequencing For RNA-seq, animals were treated with methylone (10 mg/kg, IP), MDMA (10 mg/kg, IP) or saline vehicle 24 h before sacrifice. Frontal cortex, hippocampus, and amygdala were rapidly dissected and frozen on dry ice. RNA extraction, library preparation, sequencing and analysis was done at Azenta Life Sciences (South Plainfield, NJ) as follows: [00365] Extraction-. Total RNA was extracted from fresh frozen tissue samples using RNeasy Plus Universal mini kit following manufacturer’s instructions (Qiagen, Hilden, Germany).
  • RNA samples were quantified using Qubit 2.0 Fluorometer (Life Technologies, Carlsbad, CA, USA) and RNA integrity was checked using Agilent TapeStation 4200 (Agilent Technologies, Palo Alto, CA, USA).
  • RNA sequencing libraries were prepared using the NEBNext Ultra RNA Library Prep Kit for Illumina using manufacturer’s instructions (NEB, Ipswich, MA, USA). Briefly, mRNAs were initially enriched with Oligod(T) beads. Enriched mRNAs were fragmented for 15 minutes at 94 °C. First strand and second strand cDNA were subsequently synthesized.
  • cDNA fragments were end repaired and adenylated at 3 ’ends, and universal adapters were ligated to cDNA fragments, followed by index addition and library enrichment by PCR with limited cycles.
  • the sequencing library was validated on the Agilent TapeStation (Agilent Technologies, Palo Alto, CA, USA), and quantified by using Qubit 2.0 Fluorometer (Invitrogen, Carlsbad, CA) as well as by quantitative PCR (KAPA Biosystems, Wilmington, MA, USA).
  • the sequencing libraries were clustered on 5 lanes of a flowcell. After clustering, the flowcell was loaded on the Illumina instrument (4000 or equivalent) according to manufacturer’s instructions. The samples were sequenced using a 2xl50bp Paired End (PE) configuration.
  • PE 2xl50bp Paired End
  • Pathway Analysis was performed on selected gene lists based on a statistical cutoff (0.32 >log2FC > 0.32, padj ⁇ 0.1) using Metascape gene annotation and analysis resource.
  • Hemisected brains were mounted, sectioned and stained using standard protocols with myelin-basic protein primary antibody (MBP SMI- 99, 1:5000, Biolegend, San Diego, CA) and anti-mouse biotinylated secondary antibody (BA-2001, Vector Laboratories, Newark, CA). Slides were imaged using a Huron Digital Pathology TissueScope LE120 whole slide scanning system. 20x objective was used with a 0.4p m/pixel resolution.
  • MDMA binds to G-protein coupled receptors (GPCRs), including serotonin receptors (e.g., 5HT2A, 5HT2C) and adrenergic receptors (e.g., alA, a2A).
  • GPCRs G-protein coupled receptors
  • serotonin receptors e.g., 5HT2A, 5HT2C
  • adrenergic receptors e.g., alA, a2A.
  • 1M) were screened in the GPCRmax high-throughput screen of 168 GPCRs. Activity greater than 30% typically indicates agonist activity and inhibition greater than 50% indicates antagonist activity.
  • Methylone’s chemical structure differs from MDMA only by a ketone group ( Figures 28A-28B).
  • Figures 28A-28B To determine how differences between methylone and MDMA’s structures may contribute to differences in binding to serotonin receptors, a docking study was performed to predict binding of methylone or MDMA to 5HT2A or 5HT2C receptors. The very similar chemical structures of MDMA and methylone might suggest similar binding characteristics. However, there are several important differences that can lead to major differences in potential binding to a given receptor. First, methylone contains a ketone carbonyl giving it a hydrogen bond acceptor that is not present in MDMA. This gives important physiochemical differences between the two molecules.
  • methylone will have a more polar surface area and it will also change the logP.
  • the carbonyl in methylone causes significant conformational differences compared with MDMA. Specifically, it is a difference in the torsional energy profile for a ketone to aromatic bond compared to a Csp3 to aromatic bond for MDMA.
  • the diagram ( Figure 28C) shows low energy conformations generated for methylone (blue) or MDMA (purple) superimposed on the bicyclic ring system. Since there is better binding if a ligand binds in the low energy conformation, when MDMA fits a receptor, methylone would have to conform to the same shape as MDMA, which would cost energy and be less likely. Each molecule has different shapes with little to no overlap.
  • the amygdala plays a central role in the brain’s response to stress and is affected by CNS disorders like PTSD, MDD and anxiety.
  • RNA-seq was used to determine how methylone or MDMA affected the amygdala, specifically to identify which genes and pathways were regulated within hours after a single dose, in order to shed light on methylone’s mechanism of action.
  • Differential expression (DE) analysis revealed genes significantly regulated by methylone ( Figure 29A) or MDMA (Figure 29B) compared to vehicle-injected controls.
  • Methylone treatment did not significantly upregulate many genes in the amygdala ( Figure 29E), so functional enrichment analysis focused on downregulated genes by methylone ( Figure 31A) or MDMA ( Figure 31B). The most highly significantly enriched term was ‘Ensheathment of neurons’, reflected by the significant downregulation of myelin-associated genes by both methylone and MDMA ( Figure 31C).
  • MBP myelin basic protein
  • the prefrontal cortex shares strong connectivity with the amygdala and has been described as a critical substrate for fear conditioning and PTSD. Therefore, methylone and MDMA effects on gene expression in the frontal cortex was also investigated.
  • Results of differential expression (DE) analysis show genes significantly regulated by methylone ( Figure 33A) or MDMA ( Figure 33B). Consistent with results obtained in the amygdala, MDMA significantly regulated -72% more genes than methylone (825 vs. 480 genes) and 154 of those genes were regulated by both treatments.
  • methylone calcium/Calmodulin-dependent kinase I g (Camklg), selenoprotein N (Selenom), brain-derived neurotrophic factor (BDNF), nuclear factor interleukin 3 related (Nfil3), proline and serine rich coiled-coil 1 (Psrcl), neuronal pentraxin-2 (Nptx2), and Vgf (non-acronymic), all of which are linked to neuroplasticity.
  • BDNF brain-derived neurotrophic factor
  • Nfil3 nuclear factor interleukin 3 related
  • Psrcl proline and serine rich coiled-coil 1
  • Nptx2 neuronal pentraxin-2
  • Vgf non-acronymic
  • the top 10 most significant enrichment terms upregulated by methylone included almost exclusively terms linked to synaptic plasticity, cytogenesis and survival, and neurotrophin signaling (e.g., BDNF signaling pathway) ( Figure 33C).
  • MDMA also regulated neuroplasticity genes ( Figure 33B), but the top 10 enriched terms differed slightly from those of methylone.
  • VEGFA- VEGFR2 signaling, MAPK signaling, protein processing in the endoplasmic reticulum, and protein folding were significantly upregulated (Figure 33D).
  • Orexin receptor pathway and protein folding were also top MDMA enrichment terms in the frontal cortex as observed in the amygdala ( Figure 33D, Figure 31B).
  • Example 28 Methylone shows no hallucinogenic activity in the mouse head-twitch response (HTR) test
  • HTR Head twitch response
  • Mice were ear tagged at least three days after arrival to the animal facility and allowed to rest for at least three days before behavioral testing.
  • Small magnets (SuperMagnetMan -- N45 magnet 3 mm diameter, 0.5 mm thickness) were glued to ear tags (Stoelting - La Pias Aluminum Ear Tags) at least two days before mice were ear tagged.
  • the experimental setup was adapted from Gonzales-Maeso (de la Fuente Revenga et al., 2019) and Kwan (Jefferson et al., 2022; Savalia et al., 2021), including experimental apparatus and MATLAB code for analysis.
  • a small lamp was placed in die back of the larger chamber, and a high-speed camera (Basler - Aca 1920-155 ,u.m) was suspended from the ceiling to record video of the animal s in the plastic boxes. Between each recording, the plastic boxes were cleaned with 70% ethanol.
  • Example 29 Preclinical testing of methylone as a therapeutic for opioid use disorder [00385] This Example presents a mouse model to evaluate the benefit of methylone as a therapeutic for opioid use disorder (OUD).
  • Oxycodone is delivered in sequential doses (1.1, 1.1, 2.2, 4.5, and 9.0 mg/kg IP) every 17 min with respiratory rate being measured continuously with pulse oximetry. Any effects of methylone are repeated at the given dose to confirm and duplicate the result.
  • mice are trained on oxycodone selfadministration until stable intake >3 mg/kg/day for a minimum of two weeks. For testing of intake, the mice are pretreated with doses of methylone (0-30 mg/kg, IP) or vehicle approximately 1 hour prior to the 3-hour self-administration sessions, using a Latin Square Design. If effects are seen at a given dose, the same dose is retested in a new cohort of animals. This determines if methylone modifies ongoing oxycodone intake.
  • a key component to OUD is the development of dependence and the severity of opioid withdrawal. Treating the withdrawal phase of OUD is a critical point in both emergency medicine contexts, as well as the first step toward transitioning to recovery and subsequent treatment. The effects of methylone on both the somatic (physical) signs of withdrawal, as well as on measures of the negative aversive state caused by opioid withdrawal, are assessed.
  • mice do not show signs of physical withdrawal (e.g., jumps), but instead are assessed for a negative state via a conditioned place aversion test. Attenuating this negative state reduces seeking and relapse to drugs of abuse.
  • naloxone is used to produce an aversive state but with minimal somatic signs of withdrawal. This is assessed via conditioned place aversion (CPA) test in a three- chamber box. Two larger chambers, each with different wall colors (white and black) and different floors, are separated by a smaller middle chamber. Mice are first allowed to explore all chambers over 15 min (habituation), and the time spent in each chamber is monitored. Aversive pairing consists of treating each mouse with oxycodone (5 mg/kg, IP) 2 hours before, and either methylone (0-30 mg/kg, IP) or vehicle one hour before placing them in their “aversive side” chamber.
  • oxycodone 5 mg/kg, IP
  • mice Immediately before being placed in the chamber all mice receive naloxone (0.1 mg/kg, IP) to induce moderate withdrawal. Mice are confined to their designated chamber for 30 min. The next day all mice undergo a neutral pairing, consisting of saline treatment 2 hours prior, and vehicle 1 hour prior to placing them in their “neutral side” chamber for 30 min. This sequence of aversion and neutral pairing components are repeated for a total of 3 days of pairing for each condition. On test day, the mice receive no treatment and are allowed to freely move through all three chambers for 15 min. Aversion scores are calculated by subtracting the time spent in the aversive chamber on habituation day from their test day. A negative aversion score in the vehicle group reflects aversion from naloxone pairing.
  • Example 30 Methylone for the Treatment of PTSD: Functional and Global Improvements from the Open- Label Portion of the IMPACT-1 Study
  • Post-traumatic stress disorder is a debilitating psychiatric illness affecting approximately 12 million adults in the US each year. Functional impairment is common with PTSD, often resulting in significant impairments in daily life. Current treatment options for PTSD have limited effectiveness. Non-hallucinogenic compounds with rapid and sustained therapeutic benefits may be clinically useful and more accessible to patients, compared to classical psychedelics. Methylone is a non-hallucinogenic, rapid-acting neuroplastogen and the beta-ketone analog of MDMA. Both methylone and MDMA target monoamine transporters, but differences in affinity and a lack of off-target effects (vs. MDMA) produce distinctive pharmacological and subjective effects.
  • Methylone is well-tolerated in healthy volunteers and shows positive clinical effects in a retrospective case series of patients with PTSD and depression. Methylone also has fast-acting, robust, and long-lasting anxiolytic and antidepressant-like activity in preclinical studies.
  • the IMPACT- 1 study is a multi-center, two-part clinical trial. Part A has completed and was an open-label evaluation involving 14 participants with PTSD. Eligible participants are adults with severe PTSD (CAPS-5 > 35) who had failed at least 1 prior treatment (pharmacotherapy and/or psychotherapy) for PTSD. Participants were treated with 4 doses of methylone given once a week for 4 weeks. Throughout each dosing session, participants were provided non-directive psychological support by a trained mental health practitioner. Following the 4-week treatment period, participants were followed for an additional 6 weeks to evaluate the durability of the therapeutic effect. PTSD symptom improvement was evaluated on the CAPS-5. Functioning was assessed via the 3 domains (school/work, family life, social life) of the Sheehan Disability Scale (SDS). Global improvement was measured by the CGI-I. Safety was assessed by monitoring adverse events, vital signs, and C-SSRS.
  • CGI-I Sheehan Disability Scale
  • the overall SDS is presented as the mean of the 3 domains (Table 19 below).
  • methylone treatment improved the number of days underproductive and days lost (Figure 40). At baseline, the mean number of days underproductive and lost were 4.7 and 2.6, respectively. At the end of the 4-week treatment period, methylone had reduced the number of days underproductive and lost by -3.3 and -2.0, respectively.
  • Example 31 Methylone for the Treatment of PTSD: Improvement in Sleep-Related Outcomes from the Open-Label Portion of the IMPACT- 1 Study
  • Post-traumatic stress disorder is a debilitating psychiatric illness affecting approximately 12 million adults in the US each year. Sleep disturbances with PTSD are common and typically include insomnia and nightmares. Poor sleep can worsen PTSD and result in additional health problems such as heart disease, high blood pressure, obesity, substance abuse, and stroke. Nightmares are often resistant to PTSD treatment and have been linked with a five-fold increase in suicidality; however, nightmares are often overlooked as a secondary symptom of PTSD.
  • Existing medications e.g., prazosin
  • Novel compounds with rapid and sustained therapeutic benefits may be clinically useful and more accessible to patients, compared to classical psychedelics.
  • Methylone is a non-hallucinogenic, rapid-acting neuroplastogen and the beta-ketone analog of MDMA. Both methylone and MDMA target monoamine transporters, but differences in affinity and a lack of off-target effects (vs. MDMA) produce distinctive pharmacological and subjective effects. In preclinical studies, methylone has demonstrated significant benefit in a model of PTSD as well as fastacting, robust, and long-lasting anxiolytic and antidepressant-like activity.
  • the IMPACT- 1 study is a multi-center, two-part clinical trial. Part A was completed and was an open-label evaluation involving 14 participants with PTSD. Eligible participants were adults with severe PTSD (CAPS-5 > 35) who had failed at least 1 prior PTSD treatment.
  • Example 32 An Evaluation of the Safety and Efficacy of Methylone for the Treatment of PTSD (IMPACT-2).
  • This study is designed to evaluate the safety and efficacy of methylone, when given as 3 doses of 150 mg once per week for 3 weeks. This study is intended to complement a study, which is evaluating the safety and efficacy of methylone when given weekly for 4 weeks at a dose of 150 mg, followed by a booster dose of 100 mg after 90 minutes.
  • the rationale for conducting this study is to understand if a less frequent dosing (3 doses vs. 4 doses) without a booster dose will result in similar efficacy. Additionally, the removal of the booster dose allows for the duration of the dosing session to be shortened to 4 hours.
  • Part A the primary objective is to evaluate the preliminary efficacy and safety of three doses of methylone, separated by 1 week, in participants with PTSD.
  • Part B the primary objective is to evaluate the efficacy and safety of three doses of methylone, separated by 1 week, compared to placebo, in participants with PTSD.
  • PSQI Pittsburgh Sleep Quality Index
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • Part A is an open-label assessment in up to 15 participants with PTSD
  • Part B is a randomized (1:1), double-blind, placebo-controlled assessment in up to 64 participants.
  • Figures 35A and 35B are schematics for the experimental design of Part A and Part B, respectively. After completion of Part A, enrolment for Part B will begin.
  • Placebo x 3 doses with each dose separated by 1 week [00416] Participants are adults (age 18 to 70, inclusive) who meet the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for current PTSD, with a symptom duration of at least 6 months at Screening. Eligible participants will have severe PTSD symptoms (based on a Clinician-Administered PTSD Scale for DSM-5 [CAPS-5] total severity score of >35 at Screening). Eligible participants will attend the following study visits:
  • Baseline/Preparatory Session (Day -3 to Day -1): Baseline assessments, confirmation of eligibility, and a preparatory psychoeducation session.
  • Treatment Period (3 weeks; Dav 1 to Dav 17): Each participant will receive a dose of study drug at Day 1, Day 8, and Day 15). For each dose, the participant will remain in clinic, with a qualified Mentor, for at least 4 hours after the dose, or until all effects (physical and psychological) have resolved (whichever is longer).
  • Each dose session is followed by a safety phone call 1 day after dosing and efficacy assessments 2 days after dosing. Each dosing session may be video recorded for quality and training purposes. The videos may be reviewed to ensure the Mentor is adhering to the Mentor training.
  • Planned enrolment includes up to 79 participants (up to 15 in Part A and up to 64 in Part B). Initially in Part B, 40 participants are studied; this may be increased to up to 64 based on an interim analysis that will assess the sample size. In Part B, participants are stratified based on selective serotonin reuptake inhibitor (SSRI) I selective norepinephrine reuptake inhibition (SNRI) use at Screening (e.g., participants undergoing tapering of SSRI/SNRI vs. those not receiving an SSRI/SNRI at Screening). In Part A, attempts are made to enroll ⁇ 50% of participants requiring an SSRI/SNRI washout.
  • SSRI serotonin reuptake inhibitor
  • SNRI selective norepinephrine reuptake inhibition
  • Part A is an open-label evaluation to confirm safety and preliminary efficacy of this methylone dose regimen as a PTSD treatment.
  • Part B is a randomized, doubleblind, placebo-controlled study to evaluate the efficacy and safety of methylone as a PTSD treatment. Double-blinding with use of placebo is included in Part B to permit a true assessment of the safety and tolerability of methylone and to evaluate its benefits and risks.
  • This design also allows for an objective assessment of key safety issues such as suicidality, which can be part of the disease process (PTSD) rather than a side effect of treatment.
  • assessments to evaluate the safety and tolerability such as vital signs, physical examination, 12-lead ECGs, clinical laboratory evaluations and AE collection.
  • the battery of clinical outcome assessments to be performed are those routinely used to assess the severity of PTSD symptoms and functional impairment. These include observer- blinded assessments of PTSD severity and self-administered questionnaires that explore the participant’s experience of life events. These questionnaires and scales are standardly used in clinical trials investigating psychoactive medications in similar patient populations.
  • Participant meets the DSM-5 criteria for severe PTSD diagnosis, with a symptom duration of at least 6 months at Screening, as assessed by the CAPS-5.
  • Participant must have a CAPS-5 score of >35 at Screening.
  • Participant has failed at least one treatment for PTSD (either psychotherapy or pharmacological treatment).
  • WOCBP Women of childbearing potential
  • a participant is excluded from the study if they meet any of the following criteria:
  • Participant has a primary diagnosis of any other DSM-5 disorder, as assessed by the Mini International Neuropsychiatric Interview (MINI).
  • MINI Mini International Neuropsychiatric Interview
  • Participant has a body mass index (BMI) ⁇ 18 kg/m2 or >40 kg/m2.
  • Participant is known to abuse illegal drugs or meets DSM-5 criteria for moderate or severe substance use disorder (mild substance use disorder may be allowed, after consultation with the sponsor, if use of the substance is unlikely to confound the study results) or has a positive urine test for illegal drugs at Screening, Baseline, or prior to dosing on Day 1. The Investigator must confirm the participant is not otherwise impaired prior to dosing on Day 1.
  • Participant smokes an average of >10 cigarettes and/or e-cigarettes per day.
  • LFTs Abnormal liver function tests at Screening defined as: a. AST, ALT or gamma-glutamyl transferase (GGT) >2 x the ULN, OR, b. Total bilirubin levels >1.5 x the ULN (participants with a diagnosis of Gilbert’s syndrome with high unconjugated bilirubin are eligible provided they meet other LFT criteria).
  • Moderate alcohol use disorder in early remission is not exclusionary.
  • Medical or psychiatric condition that is incompatible with establishment of rapport with the Mentor, or safe exposure to study drug. Prior treatment within the 90 days prior to Baseline, with: a. deep brain stimulation, b. vagus nerve stimulation, c. treatment with electroconvulsive therapy, or d. transcranial magnetic stimulation.
  • a psychedelic e.g., lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT], mescaline
  • entactogens such as MDMA
  • Methylone is provided in 50 mg capsules containing 59 mg ( ⁇ 5%) of methylone hydrochloride. Methylone hydrochloride is manufactured and encapsulated by Pisgah Labs, North Carolina. Methylone or placebo capsules are administered orally with water. A hand and mouth check is performed to ensure consumption of the medication. Capsules are administered on each treatment day as follows:
  • Participants should have fasted (water only) for at least 2 hours prior to the dose and at least 2 hours after the dose. Water and clear fluids are encouraged up to a maximum fluid intake of 3 liters during the dosing session. A psychiatrist is available during each dose session for each participant.
  • Part A all participants will receive open-label methylone.
  • Part B participants are randomly assigned, in a 1:1 ratio to receive methylone or placebo. Participants are stratified to treatment based on selective serotonin reuptake inhibitor (SSRI) / selective norepinephrine reuptake inhibition (SNRI) use at Screening (e.g., participants undergoing tapering of SSRI/SNRI vs. those not receiving an SSRI/SNRI at Screening).
  • SSRI serotonin reuptake inhibitor
  • SNRI selective norepinephrine reuptake inhibition
  • Prohibited Medications The following medications are prohibited within 14 days, or 5 half-lives, whichever is longer of Day 1:
  • Serotonin-acting dietary supplements such as 5 hydroxy-tryptophan or St. John’s wort
  • the following are restricted within 24 hours of a dosing session:
  • Participants should abstain from tobacco and nicotine-containing products for 2 hours prior to dosing until at least 8 hours after the administration on each dosing day.
  • Participants should abstain from (methyl) xanthine- and caffeine-containing products for 2 hours before dosing until at least 8 hours after administration on each dosing day.
  • Participants should have fasted (water only) for at least 2 hours prior to dosing and for at least 2 hours after the dose.
  • Participants provide written informed consent before any study-related procedures are initiated, including cessation of prohibited concomitant therapy. If a participant misses a study visit for any reason, the visit should be rescheduled within the visit window specified below.
  • CAPS-5 (Past Month), MINI, PCL-5, LEC-5, SPQ (and SCID-PD if needed).
  • CAPS-5 (Past Month), MINI, and SCID-PD, if needed, are administered via telephone/video by a central rater and recorded for rater fidelity.
  • CAPS-5 (Past Week), MADRS, CGI-S, PCL-5, QIDS, SDS, WEMWBS, PGLS, PTGI, and PSQI.
  • the CAPS-5, MADRS and CGI-S are administered via telephone/video by a central rater and recorded for rater fidelity.
  • the CAPS-5 is performed first followed by MADRS and CGI-S.
  • the participant should complete the self-administered assessments: PCL-5, QIDS, SDS, WEMWBS, PGI-S, PTGI, and PSQI.
  • Preparatory Session Following completion of all baseline assessments. Preparatory sessions should be conducted by a trained Mentor. Mentor will proactively provide the participant with an understanding of the anticipated experience following administration of an entactogen medication, like methylone. If needed, a second preparatory session may occur prior to the first dosing to ensure the participant is adequately prepared for the treatment period.
  • Day 3 visits may be conducted remotely.
  • CAPS-5 (Past Week), MADRS, CGI-S, CGI-I, PCL- 5, QIDS, SDS, WEMWBS (Day 22 and Day 43 only), PGI-S, PGI-C, PTGI (Day 29 only), and PSQI (Day 29 only).
  • the CAPS-5, MADRS, CGI-S and CGI-I are conducted by a central rater via a telephone/video call and recorded for rater fidelity.
  • the CAPS-5 is performed first followed by MADRS, CGI-S and CGI-I.
  • the participant should complete the self-administered assessments: PCL-5, SDS, QIDS, PGLS, PGI-C, WEMWBS (Day 22 and 43 only), PTGI (Day 29 only), and PSQI (Day 29 only).
  • CAPS-5 (Past Week), MADRS, CGI-S, CGI-I, PCL- 5, QIDS, SDS, WEMWBS, PTGI, PSQI, PGI-S, and PGI-C.
  • the CAPS-5, MADRS, CGI-S and CGI-I are conducted by a central rater via a telephone/video call and recorded for rater fidelity.
  • the CAPS-5 is performed first followed by MADRS, CGI-S and CGI-I.
  • the participant should complete the self-administered assessments: PCL-5, QIDS, SDS, WEMWBS, PSQI, PGI-S, PGI-C, and PTGI.
  • CAPS-5 (Past Week), MADRS, CGI-S, CGI-I, PCL- 5, QIDS, SDS, WEMWBS, PTGI, PSQI, PGI-S, and PGI-C.
  • the CAPS-5, MADRS, CGI-S and CGI-I are conducted by a central rater via a telephone/video call and recorded for rater fidelity.
  • the CAPS-5 is performed first followed by MADRS, CGI-S and CGI-I.
  • the participant should complete the self-administered assessments: PCL-5, QIDS, SDS, WEMWBS, PSQI, PGI-S, PGI-C, and PTGI.
  • each participant is in a comfortable, private space so they cannot see or interact with other individuals for the duration of their dose session.
  • the space will have a quiet, calm atmosphere where they are comfortable talking about personal matters.
  • the space will have ambient temperature controls and access to water.
  • the participants are asked to remain in the dosing room for the 4-hour duration of the dose session or until all effects (physical and psychological) have resolved (whichever is longer).
  • Mentors are experienced healthcare providers with professional training and clinical experience in psychotherapy who are able to practice independently.
  • the Mentor will provide the participant psychological support throughout their participation in the study.
  • Each Mentor will undergo formal training prior to working with participants in this study.
  • the same Mentor is present for all sessions with each participant. Their role is to provide unstructured psychological support as the participant explores their response to the medication.
  • the Mentor is present throughout the dose session and a clinical staff member is intermittently available to collect safety assessments (e.g., vital signs); in addition, a trained psychiatrist is immediately available in case of acute psychotic events.
  • the Mentor will not be involved in any medical, nursing, or other research activities.
  • the psychological framework is focused on participant preparation for the dose session, and psychological support/reassurance during the dose session. If needed, the Mentor is available during the Follow-Up visits.
  • the Mentor will provide unstructured psychological guidance. This session will focus on psychoeducation about PTSD, possible physiological and psychological effects of methylone (including possible adverse and challenging effects), building safety for the therapeutic relationship, obtaining the background for the trauma and preparing the participant for dose sessions. Goals and expectations for the dose sessions will also be discussed.
  • the Mentor will provide non-directive support of psychological well-being continuously during each dose session.
  • the Mentor will provide reactive support and engaged listening. The Mentor will provide guidance if the participant falls into a negative pattern.
  • the Mentor will encourage the participant to reflect on their experience and on any strong emotions or thoughts they might have encountered.
  • Drug-related adverse psychological events e.g., psychotic symptoms
  • Drug-related adverse psychological events are not anticipated, but may occur during, or following, the dose sessions.
  • the risk of such events occurring is minimised by the inclusion/exclusion criteria and the Preparatory Session.
  • a psychiatrist is available throughout the dosing day to help support any psychological events.
  • diazepam (5 to 10 mg, orally), lorazepam (1 mg, orally or intramuscularly [IM]) or olanzapine (5 to 10 mg, orally or IM) may be administered, according to the clinical judgement of the responsible physician.
  • Lorazepam and olanzapine should not be given at the same time due to the possibility of excessive sedation and cardiorespiratory depression. The participant should not be discharged from the clinic until the condition has stabilised.
  • Centrally-rated Assessments All clinician-rated efficacy assessments are administered by a central rater via telephone or video call. Remote assessments assure that the assessor who is collecting the primary efficacy outcome measures will not witness dose sessions and the acute effects of methylone, which reduces bias and strengthens the study blind. The central ratings may be recorded to ensure quality ratings and rater fidelity across the central rater pool.
  • CAPS-5 Clinician-Administered PTSD Scale for DSM-5 (CAPS-5):
  • the CAPS-5 is 30-item structured interview.
  • questions target the onset and duration of symptoms, subjective distress, impact of symptoms on social and occupational functioning, improvement in symptoms since a previous CAPS administration, overall response validity, overall PTSD severity and specifications for the dissociative subtype (depersonalization and derealization).
  • the CAPS-5 also rates intrusion symptoms (intrusive thoughts or memories), avoidance, cognitive and mood symptoms, arousal and reactivity symptoms, duration and degree of distress.
  • standardized questions and probes are provided.
  • the ‘past month’ version of the CAPS-5 is performed at Screening to confirm the diagnosis.
  • the ‘past week’ version of the CAPS-5 is performed at each subsequent study visit.
  • Each CAPS-5 is administered by a central rater via telephone or video call.
  • Mini International Neuropsychiatric Interview The MINI is a short, structured diagnostic interview that is compatible with DSM-5 and International Classification of Disease criteria for psychiatric disorders. Each module of the MINI consists of two or three questions where the answer is either ‘Yes’ or ‘No’, and a decision-tree logic is used to determine whether to ask additional questions.
  • the PTSD, suicidality, and antisocial personality disorder modules of the MINI are not required to be administered as these are addressed via other scales.
  • the MINI is administered by a central rater via telephone or video call.
  • SCID-5-PD Structured Clinical Interview for the DSM-5 Personality Disorders
  • the SCID-5-PD is a structured diagnostic interview to assess for DSM-5 personality disorders. In this study, only participants who endorse a positive response for paranoid personality disorder, antisocial personality disorder, or borderline personality on the SPQ is administered the relevant sections of the SCID-5-PD to assess for those personality disorders.
  • the SCID-5-PD is administered by a central rater via telephone or video call.
  • the SIGMA is a standardised version of the MADRS.
  • the SIGMA maintains the original MADRS format, which is a 10-item clinician-rated, diagnostic questionnaire used to measure depression severity, with the exception that the first two items are reversed. Each item is measured on a 7-point scale, from 0 to 6. Higher total MADRS scores indicate more severe depression.
  • the MADRS is administered by a central rater via telephone or video call.
  • CGI-S Clinician Global Impressions Scale - Severity
  • CGI-S Two CGI-S ’s are evaluated, one CGI-S assessing the participants overall clinical status (focusing on their PTSD) and the second CGI-S assessing the participants depressive status.
  • the CGI-S is administered by a central rater via telephone or video call.
  • CGI-I Clinician Global Impressions Scale - Improvement
  • the CGI-I is a 7- point scale that requires the assessor to assess how much the participant’s illness has improved or worsened relative to a baseline state prior to dosing.
  • the CGI-I scale rates improvement with (1) representing a ‘very much improved’ participant to (7) representing a participant who has become ‘very much worse’ due to treatment.
  • the rating (4) represents a participant displaying no change from the treatment.
  • CGI-I Two CGI-I’s are evaluated, one CGI-I assessing the participants overall clinical status (focusing on their PTSD) and the second CGI-I assessing the participants depressive status.
  • the CGI-I is administered by a central rater via telephone or video call.
  • Participant-Completed Assessments Psychometric assessments are administered in a neutral, non-leading manner to minimize the chance for bias.
  • PTSD Checklist for DSM-5 (PCL-5): The PCL-5 is a 20 item self-report measure that assesses the presence and severity of the 20 DSM-5 symptoms of PTSD. Participants are asked to rate each item from 0 (‘not at all’) to 4 (‘extremely’) to indicate the degree to which they have been affected by that particular symptom over the past week; the results are interpreted by a clinician.
  • Life Events Checklist for DSM-5 (LEC-5): The LEC-5 is a brief, 17-item self-report measure designed to screen for potentially traumatic events in a participant’s lifetime, to facilitate the diagnosis of PTSD. It is a companion to the PCL-5 and is used to assess PTSD. The LEC-5 extended version is used.
  • SCID-5 SPQ Structured Clinical Interview for DSM-5 Screening Personality Questionnaire
  • the SCID-5-SPQ is a self-report screening tool to assess for DSM-5 personality disorders. Participants are required to only complete questions specific for assessing personality disorders (paranoid personality disorder, antisocial personality disorder, or borderline personality). Participants who endorse a positive response for paranoid personality disorder, antisocial personality disorder, or borderline personality on the SPQ are administered the SCID-5-PD by the central rater for those personality disorders.
  • Sheehan Disability Scale The SDS is a brief, 5-item self-report tool that assesses functional impairment in work, social life/leisure activities and family life/home responsibilities.
  • the SDS is designed to measure the extent to which the three major domains in a participant’s life are functionally impaired by psychiatric or medical symptoms. Each domain is rated from 0 to 10, with a total score from 0 to 30, where 0 is unimpaired and 30 is highly impaired.
  • PGI-C Patient Global Impression of Change
  • PGI-S Patient Global Impression of Severity
  • WEMWBS Warwick-Edinburgh Mental Wellbeing Scale
  • the WEMWBS is a scale of 14 positively worded items for assessing a population’s mental wellbeing.
  • the items cover both physiological functioning aspects of mental wellbeing (including: optimism, autonomy, agency, curiosity, clarity of thought and positive relationships) and positive effect (feelings, including: confidence, feeling relaxed, cheerful, having the energy to spare).
  • the scale has 5 response categories, summed to provide a single score.
  • QIDS-SR Quick Inventory of Depressive Symptoms - Self Report
  • the QIDS-SR is a 16-item self-report measure a patient-rated scale, is an abbreviated version of the 30- item Inventory of Depressive Symptomatology (IDS) and is designed to assess the severity of depressive symptoms.
  • the QIDS-SR- 16 assesses criterion symptom domains to diagnose a major depressive episode.
  • the QIDS-SR is used to assess the participant’s depressive symptomatology over the past 7 days.
  • PSQI Pittsburgh Sleep Quality Index
  • the PSQI is a measure of self-reported sleep quality and sleep disturbance.
  • the PSQI contains 19 self-rated questions, which are combined to form 7 ‘component’ scores, each of which has a range of 0 to 3 points.
  • the 7 components of the PSQI are: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications and daytime dysfunction.
  • the sleep component scores are summed to yield a total score ranging from 0 to 21, with a higher total score indicating worse sleep quality.
  • Post-Traumatic Growth Inventory measures the extent to which survivors of traumatic e vents perceive personal benefits, including changes in perceptions of self, relationships with others and philosophy of life, accruing from their attempts to cope with trauma and its aftermath.
  • This 21 -item scale includes factors of: new possibilities, relating to others, personal strength, spiritual change and appreciation of life.
  • BIQ Blinding Integrity Questionnaire
  • Safety assessments include the evaluation of treatment emergent adverse events (TEAEs), clinical laboratory tests, ECGs, vital sign measurements, and physical examinations.
  • Electrocardiogram A 12-lead ECG is collected in triplicate, approximately 1 minute apart, within approximately 30 minutes predose and at the end of the dose session. 12-Lead ECGs should be obtained after the participant has rested in the supine position for at least 3 minutes. The ECG machine used should automatically calculate the HR and PR, QRS, QT and QTcF intervals.
  • Supine vital signs including HR, BP, and temperature are collected after the participant has rested in the supine position for at least 3 minutes. Predose vital signs should be collected within 10 minutes predose. Blood pressure and HR are at 30- minute ( ⁇ 15 minute) intervals postdose administration until the end of the dose session.
  • Physical Examination A physical examination, including body weight and height (Screening only), and assessments of the head, eyes, ears, nose, throat, skin, neurological, lungs, cardiovascular system, abdomen, and lymph nodes are conducted.
  • C-SSRS Columbia- Suicide Severity Rating Scale
  • the C-SSRS is used to assess suicide potential or tendency as a study entry criterion and monitored throughout the study.
  • 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.
  • the Investigator must review the participant’s responses in order to (a) at the Screening visit and Baseline/Preparatory session to 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, or appropriateness of further study drug administration in consultation with the Medical Monitor and Sponsor.
  • a significant risk of suicide is defined as a ‘yes’ in answer to:
  • the C-SSRS is completed for the participant’s lifetime history of suicidal ideation and behavior, along with a recent (2 month) recall period. At all other visits, the C-SSRS is completed with a recall period since the last visit.
  • Hematology Hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices (mean cell hemoglobin, mean corpuscular hemoglobin concentration, mean cell volume), platelet count (or estimate), and white blood cell count, including differential.
  • RBC red blood cell
  • RBC indices mean cell hemoglobin, mean corpuscular hemoglobin concentration, mean cell volume
  • platelet count or estimate
  • white blood cell count including differential.
  • Serum Chemistry Albumin total bilirubin, direct bilirubin, total protein, calcium, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma- glutamyl transpeptidase (GGT), blood urea, creatinine, glucose, sodium, potassium, bicarbonate, lactate dehydrogenase, phosphorus, and chloride.
  • Urinalysis pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, nitrite, urobilinogen, and leucocyte esterase Unless otherwise specified, microscopic examination is performed on abnormal findings.
  • Pregnancy Test For all WOCBP. A urine pregnancy test is conducted at all timepoints as specified in the schedule of events. An inconclusive pregnancy test should be confirmed with a serum pregnancy test.
  • Urine Drug Screen A urine drug screen (tests include but are not limited to amphetamines (including MDMA), benzodiazepines, cocaine, opiates,) is performed at screening and prior to dosing.
  • An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have a causal relationship with the product.
  • An AE can therefore be any unfavorable and unintended sign (including a new, clinically important abnormal laboratory finding), symptom, or disease, temporally associated with the product, whether or not related to the product.
  • Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a pre-existing condition is considered an AE.)
  • SAE serious adverse event
  • Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay.
  • An elective hospital admission to treat a condition present before exposure to the study drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or event as an SAE.
  • an overnight stay in the hospital that is only due to transportation, organization, or accommodation problems and without medical background does not need to be considered an SAE.
  • An AE is defined as treatment emergent if the first onset or worsening is after an administration of study drug and not more than 7 days after the last dose. Any AEs that are deemed to be treatment related by the Investigators will always count as TEAEs. The primary safety assessments are based on TEAEs.
  • the clinical severity of an AE is classified as:
  • Severity is a classification of intensity whereas an SAE is an AE that meets serious criteria.
  • Action(s) taken may consist of:
  • Drug withdrawn An indication that a medication schedule was modified through termination of a prescribed regimen of medication.
  • the outcome, including Fatal, at the time of last observation is classified . Only select fatal as an outcome when the AE results in death. If more than 1 AE is possibly related to the participant’s death, the outcome of death should be indicated for each such AE. Although “fatal” is usually an event outcome, events such as sudden death or unexplained death should be reported as SAEs.
  • the investigator will also assess the relationship (if any) between the AE and the study treatment (not related, unlikely, possibly, or probably). The investigator will use the following definitions to classify the relationship of an AE to study medication:
  • This category can generally be considered applicable to those AEs which, after careful medical consideration at the time they are evaluated, are judged to be unrelated to the study drug.
  • An AE may be considered unlikely to be related if or when at least two of the following criteria are fulfilled:
  • This category applies to those AEs which, after careful medical consideration at the time they are evaluated, are felt with a high degree of certainty to be related to the test drug.
  • An AE may be considered probably related if or when least three of the following criteria are fulfilled:
  • Adverse events that occur during the study are treated if necessary by established standards of care. If such treatment constitutes a deviation from the protocol, the participant may continue in the study after consultation with the investigator and medical monitor.
  • the objectives of the DSMB are to review safety data (Part A and Part B), review the interim analysis report and provide advice on the advisability of increasing the sample size (Part B).
  • the safety and tolerability data to be reviewed will include, at a minimum, AEs, 12-lead ECGs, vital signs, clinical laboratory evaluation results, and C-SSRS results, summarised by a non-voting Statistician.
  • the interim analysis will focus on the CAPS-5 data and are used for sample size assessment only. There are no stopping rules for either efficacy or futility.
  • Sample size calculations for Part B assumes a treatment difference of 11 points on the CAPS -5 and a pooled standard deviation (SD) of 12, based upon a previously completed Phase 3 trial of MDMA as a treatment for PTSD. Assuming a treatment effect of 11 points and a pooled SD of 12 in this trial and an N of 20 evaluable participants in each treatment group, the trial should provide 80% power to detect such a difference. Evaluable participants are defined as participants who reach end-of-study assessment or withdrawal with appropriate close-out. [00485] Part B of the study initially recruits up to 40 participants, but this might be increased up to 64 participants based on an interim analysis that assesses the sample size assumptions.
  • mITT Modified Intent-to-treat

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Abstract

L'invention concerne des médicaments psychoactifs comprenant du méthylone, du 2C-B, de la MBDB, leurs sels, métabolites, isomères, énantiomères, solvates, isotopologues et isotopomères, polymorphes, promédicaments et analogues respectifs (série 2C et cathinones) ; leur préparation, leurs formulations, leurs intermédiaires, leurs voies d'administration, leur dosage et leur calendrier destinés à des usages médicaux pour des pathologies et des troubles psychiatriques et neurologiques.
PCT/US2024/032615 2021-08-06 2024-06-05 Médicaments psychoactifs et leur utilisation pour le traitement de pathologies et de troubles psychiatriques et neurologiques Pending WO2024254190A2 (fr)

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US18/784,243 US12343326B2 (en) 2021-08-06 2024-07-25 Psychoactive medicines and their use for treating psychiatric and neurological conditions and disorders
US18/790,708 US12295937B2 (en) 2021-08-06 2024-07-31 Psychoactive medicines and their use for treating psychiatric and neurological conditions and disorders
US19/203,021 US20250332139A1 (en) 2021-08-06 2025-05-08 Psychoactive medicines and their use for treating psychiatric and neurological conditions and disorders

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US202363471412P 2023-06-06 2023-06-06
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US202363605729P 2023-12-04 2023-12-04
US63/605,729 2023-12-04
US202363607702P 2023-12-08 2023-12-08
US63/607,702 2023-12-08
US202463553788P 2024-02-15 2024-02-15
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WO2023081403A1 (fr) * 2021-11-05 2023-05-11 Terran Biosciences Inc. Isotopologues, sels, formes cristallines, stéréoisomères, de méthylone et d'éthylone et leurs procédés d'utilisation
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