Psychoactive medicinal products and their use for the treatment of psychiatric and neurological conditions and disorders - Patents.com

Abstract

The present invention relates to psychoactive pharmaceutical agents including methylone, 2C-B, MBDB, their respective metabolites, isomers, enantiomers, polymorphs, and analogues (2C series and cathinones); their preparation, formulations, intermediates, routes of administration, dosing and schedules for medical use for psychiatric and neurological conditions and disorders.

Description

[Technical field]

[0001] The present invention relates to psychoactive pharmaceutical agents including methylone, 2C-B, MBDB, their respective metabolites, isomers, enantiomers, polymorphs, and analogues (2C series and cathinones); their preparation, formulations, intermediates, routes of administration, dosing and schedules for medical use and for the treatment of psychiatric and neurological conditions and disorders. [Background technology]

[0002] Classical hallucinogens are a class of mixed serotonergic, noradrenergic, and dopaminergic modulatory compounds, generally of ethnobotanical provenance. These heterogeneous agents are psychoactive and can alter cognition, mood, and many other cognitive and physiological processes. Anthropological studies suggest their ritual use in societies spanning the ancient Near East, Mediterranean basin, and Mesoamerica. The discovery and synthesis of the tryptamine analog lysergic acid-N,N-diethylamide (LSD) by Albert Hoffman in 1943 was followed by decades of promising clinical development and the search for therapeutic agents. However, the entire species of compound was restricted from the mainstream scientific community and characterized as having "no medical use" in the United States, for example, by the 1970 "Controlled Substances Act."

[0003] The incidence of neuropsychiatric disorders such as treatment-resistant depression, fibromyalgia, and post-traumatic stress disorder (PTSD) is increasing, resulting in a lack of new treatments that meaningfully impact patients' lives. The dissociative anesthetic ketamine, i.e., its optical isomer esketamine, was first approved in 2019 as Spravato for major depressive disorder (MDD) and / or suicidality. As of May 2021, there are three FDA breakthrough therapy designations for psychedelic drugs: 3,4-methylenedioxymethamphetamine (MDMA) for PTSD, and psilocybin for both treatment-resistant depression (TRD) and MDD. There is growing recognition of the limited efficacy of current pharmacological interventions, with the need for novel psychoactive medications without provider-intensive safety and monitoring issues, or contraindicated in patients receiving existing therapeutic agents such as selective serotonin reuptake inhibitors (SSRIs) and other drug classes.

[0004] A phase 3 trial investigating MDMA (3,4-methylenedioxy N-methylamphetamine) in patients with severe PTSD revealed acceptable efficacy and safety profiles. There is recent evidence for the efficacy of psilocybin in major depressive disorder (MDD). Psilocybin is a psychoactive alkaloid produced by over 200 mushroom species, with some evidence of fast-acting antidepressant properties. In a recent clinical trial with psilocybin, MDD patients differed in their need for treatment from single doses to monthly doses, but had similar efficacy and safety. Psilocybin and MDMA offer hope to patients with no other treatment options, but it is estimated that they will only benefit 5-10% of patients in need.

[0005] Identification of manipulations that reopen the critical period has been a priority for translational neuroscience. Many neuropsychiatric pathologies are thought to be developmentally related to the closure of the "critical period," an early period of survival when the nervous system is more susceptible to healthy (or harmful) environmental stimuli required for proper circuit organization and learning. The closure of the critical period limits the brain's ability to adapt even when optimal conditions are restored. Agonists of the 5-hydroxytryptamine (5-HT) serotonin receptor family, including MDMA, DMT, and mescaline, increase levels of oxytocin - which is involved in social function and animal models suggest it may extend the critical period in cortical function - allowing the learning of new behavioral responses. These oxytocin receptors in the nucleus accumbens (NAc) bind to 5-HT in medium spiny neurons of the dorsal raphe nucleus. 1B It is activated through a receptor, the inhibition of which prevents social reward learning.

[0006] Mescaline (3,4,5-trimethoxyphenethylamine), an ancient precursor of the modern synthetic phenethylamine 2-CB (2,5-dimethoxy-4-bromophenethylamine), is derived from the crown buds of the peyote cactus, native to Mexico and southwest Texas. After one methylation step, mescaline is highly similar to the catecholamine signaling molecules dopamine and noradrenaline; its psychoactive properties are thought to derive from this structural similarity. Most novel psychoactive compounds still fall into the traditional neurochemical family, with pharmacology that overlaps with their classical precursors. A long-standing hypothesis is that these drugs, particularly the phenylalkylamines, activate two types of receptors out of more than 50 neurotransmitter receptor subclasses: 5-HT 2A and 5-HT 2C The point is that it is the most selective for

[0007] MBDB (N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane) is an alpha-ethyl analog of MDMA that was synthesized by several medicinal chemistry research groups in the 1980s. MBDB is the prototypical member of the "entactogen" class, currently not Schedule 1 in the United States, which combines two structural features that weaken binding at monoamine receptors: N-methylation and alpha-ethylation. MBDB quickly became a recreational drug, incorporated as a component of "ecstasy" pills along with MDMA and other synthetic cathinones. In two retrospective reports of polydrug overdose deaths associated with MBDB, in which alcohol and cannabis levels were also measured, blood concentrations of 0.435 and 1.2 mg / L were measured. In a meta-analysis of deaths from MDMA overdoses, 13 of 77 deaths directly attributable to the toxic effects of MDMA alone had blood concentrations measured in the range of 0.478–53.9 mg / L, which is comparable to the estimated toxicity levels of MBDB. Furthermore, in animal models, (±)-MBDB·HCl (25 mg / kg) was injected intraperitoneally every 12 h for 4 days, with (±)-MDMA·HCl (20 mg / kg) for comparison. Based on the disappearance of 5-HT / 5-HIAA uptake sites, the multiple-dose regimen used in this study apparently destroyed 55–60% of serotonergic terminals in the cortex and hippocampus without significantly altering catecholamines or their metabolites 2 weeks after treatment. These results indicate that a decline in indicators of serotonergic function occurred after multiple doses of MBDB. This neurotoxic effect was somewhat lower than that observed with a behaviorally equivalently potent dose of MDMA.

[0008] Synthetic cathinones, such as methylone (3,4-methylenedioxy N-methylcathinone), are psychomotor stimulants that exert their effects by altering the function of cell membrane transporters for serotonin, dopamine, and norepinephrine. Individual cathinones may differ in their potency on each of the three monoamine neurotransmitter pathways. Natural cathinones, alkaloids structurally similar to amphetamine, were first extracted from the fresh leaves of the khat plant (Catha edulis), which is chewed in East Africa and the Arabian Peninsula. Synthetic structural modifications of cathinone have led to a large number of "designer" derivatives commonly sold illegally as "bath salts". These cathinone derivatives (chemically classified as β-ketoamphetamines), which include methylone, ethylone, butylone, phedrone, and 3,4-methylenedioxypyrovalerone (MDPV), act synergistically at the human dopamine transporter. Both cathinones, as well as phenethylamines and other related species, behave as central nervous system (CNS) stimulants, although cathinones are typically less potent than the corresponding phenethylamine analogues because the β-keto group creates a more polar molecule that is less able to cross the blood-brain barrier.

[0009] Methylone's affinity for the vesicular monoamine transporter 2 (VMAT2) is approximately 13-fold lower than that of MDMA. However, there is some mixed evidence: plasma membrane and vesicular monoamine transporter assays in mouse models of locomotor activity found methylone to be a more potent inhibitor of 5-HT and dopamine uptake than MDMA. After intraperitoneal administration in rats, methylone peaked in brain and serum concentrations in 15-30 min and had a half-life of approximately 1-2 h. In contrast, the half-life of MDMA ranges from 5-7 h depending on the animal model and administration conditions used.

[0010] In humans, SSRIs also weaken or prevent the therapeutic effects of MDMA through substrate competition; side effects such as elevated blood pressure (BP) and hyperthermia are in part due to MDMA's interaction with the serotonin transporter. This is another important consideration when considering its use as a fast acting antidepressant or augmentation therapy. Previous research studies have found associations between MDMA use and symptoms of depression or anxiety. The difficulty of assessing causation or association between MDMA and depression is compounded when considering that pre-existing psychiatric disorders may manifest in people who choose to use MDMA. Meta-analyses have detected associations between MDMA use and self-reported depressive symptoms. A range of pharmacogenetic variations in MDMA metabolism also increases the risk of depression in a significant number of patients.

[0011] Animal studies examining the psychological effects of MDMA tested a dose of 10 mg / kg for 10 days in rats; measures of anxiety-like behaviors such as open-field ambulation showed an increased anxiety phenotype after 3 months. A dose of 5 mg / kg of MDMA administered to rats four times over 4 h on two consecutive days reduced responding (active and passive) in the forced swim test and increased immobility for up to 12 weeks after MDMA exposure - possibly indicating long-term negative behavioral changes. Fluoxetine treatment reversed MDMA-induced anxiety in the wake test and immobility duration in the forced swim test, but had no effect in the social interaction test. The study also analyzed postmortem levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), both of which were reduced in cortical regions of rats treated with MDMA. Fluoxetine treatment did not significantly affect 5-HT levels in MDMA-pretreated rats, but significantly reduced 5-HIAA levels in all brain sites examined. This could be interpreted as MDMA-induced chronic 5-HT depletion resulting in an anxiety or depression phenotype.

[0012] Other mechanisms include acute MDMA-induced 5-HT release from serotonergic terminals, together with inhibition of 5-HT reuptake, which results in significant depletion of both 5-HT and 5-HIAA. This has been reported in human postmortem brain tissue, as well as in vivo from cerebrospinal fluid (CSF) measurements. Although the studies are somewhat confusing, following the monoamine theory of depression, the data are discouraging; the evidence highlights the discrepancy between the acute and chronic pharmacology of MDMA. On the one hand, acutely, MDMA acts to enhance 5-HT availability, suggesting immediate antidepressant properties and positive changes to mood, and this transient effect may be accompanied by subsequent 5-HT depletion. There is human anecdotal evidence supporting depleted 5-HT stores at therapeutically used doses.

[0013] The reduced levels of 5-HT and its metabolites in brain tissue and CSF have also been interpreted as indicating that MDMA is neurotoxic, as assessed in vivo. Coincidentally, low SERT density is also associated with depression. Given the reduced SERT density in the animal literature, the simplest interpretation is that repeated exposure to MDMA in humans, even at low doses, results in damage to 5-HT neuronal terminals that innervate the cortex. Furthermore, changes in mood, cognition, and impulse control associated with these changes may contribute to sustaining MDMA use.

[0014] These and other inconsistencies in MDMA neurotoxicity data remain unresolved, making MDMA unlikely to be explored as a mainstream antidepressant, especially if 5-HT neurotransmitter circuits are involved in both depression pathophysiology and MDMA neurotoxicity. In a recent PTSD Phase 2 MDMA trial, there were cases of depression / MDD recorded as adverse events at the 125mg and 150mg doses, some of which continued during long-term follow-up. Anxiety and severe suicidal ideation were also recorded. And before proceeding to Phase 3, the hypothesis that MDMA has potential efficacy as a fast-acting antidepressant is being investigated. However, MDMA, psilocybin and the other classical hallucinogens mentioned have at least the following limitations to reach the hundreds of millions of people suffering from treatment-resistant neuropsychiatric disorders: (1) Safety Given their strong serotonergic properties, they are contraindicated in patients taking SSRIs and many other psychotherapeutic drugs due to the risk of serotonin syndrome. This prevents many, if not most, patients suffering from neuropsychiatric disorders from accessing these drugs. Furthermore, MDMA can cause arrhythmias and various forms of dilated cardiomyopathy with prolonged use, potentially resulting in ventricular fibrillation and asystole, and is contraindicated in pre-existing dysrhythmias or pulmonary disease. (2) Combination Patients whose disorder is treatment-resistant often try SSRIs / Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) / Tricyclic Antidepressants (TCAs), etc. It takes a minimum of 6 weeks to wean patients off SSRIs and other antidepressant treatments. Therefore, developing psychoactive analogs that minimize adverse interactions and add therapeutic benefit would be of great benefit to patients in need. It would be a shame if those who would benefit most from psychoactive treatments were hindered by their past or current treatment regimens. (3) Ease of provision / access to medical care Psychoactive treatments are ideally self-administered at home or with minimal supervision. Access to MDMA and psilocybin is limited by the time each administration requires, the provider's time and the number of safety chaperones, and training and licensing requirements. In addition to preparatory and integrative psychotherapy sessions, MDMA and psilocybin have long administration sessions (up to 8 hours). Similarly, ketamine by intravenous infusion requires a 3-4 hour clinic visit with intensive psychotherapy, administered and supervised by a physician. (4) Patient desirability Many patients are reluctant to undergo treatment with classical hallucinogens and entactogens such as psilocybin and MDMA, where clinical outcomes would depend on deep subjective experiences that are often difficult, unpleasant, or frightening.

[0015] Thus, there is a need for CNS therapeutic agents, including antidepressants and PTSD treatments, with mainstream potential, better safety and efficacy, a more rapid effect profile, fewer drug / drug interactions, and / or more effective in combination therapy. The prevalence of having any mental illness (AMI) in U.S. adults is over 50 million, more than 20% of the population. The gap between disease burden and effective treatment is widening. Despite its adverse effects, Wellbutrin (bupropion), 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 to sertraline and fluoxetine. Bupropion has been reported to be used off-label in addition to other therapeutic agents to treat panic disorder. However, side effects of bupropion include a greater than 23% increase in the likelihood of congenital heart defects in children during the first trimester, along with a range of neurological side effects such as anxiety, abdominal pain, shaking, insomnia, headache / migraine, nausea / vomiting, constipation, tremors, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and hearing loss.

[0016] Thus, there is a need for novel psychopharmacological agents that can overcome these and other limitations and / or reach a larger cross-section of patients with neuropsychiatric conditions, including many difficult-to-treat mood, anxiety and personality disorders, such as depression and PTSD; 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. Summary of the Invention

[0017] In one aspect, provided herein is a method of treating and / or preventing a neuropsychiatric disorder and / or ameliorating a symptom thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of methylone (3,4-methylenedioxy N-methylcathinone). In some embodiments, the methylone dose is in the range of 0.8-5 mg / kg. In some embodiments, the methylone dose is in the range of 0.8-30 mg / kg. In some embodiments, the methylone dose is in the range of 50-350 mg. In some embodiments, the methylone dose is in the range of 50-500 mg. In some embodiments, the methylone dose is in the range of 50-1,000 mg. In some embodiments, an initial dose (e.g., 50-500 mg) of methylone is administered, which is then boosted 30 minutes to 4 hours later by administering a second methylone dose (e.g., an additional 25-250 mg of methylone). In some embodiments, methylone is administered once a week, or more than once a week (up to daily administration), or two or three times a day, e.g., as a single dose, or according to the administration schedules described above. In some embodiments, methylone is administered as a sustained or extended release formulation, e.g., to achieve the administration regimen disclosed herein, releasing 50 mg to 1 g on a set schedule to the patient according to the indication being treated in those patients. In some embodiments, the subject is suicidal. In some embodiments, the neuropsychiatric disorder is treatment-resistant. In some embodiments, methylone is used in combination with an additional therapy for the neuropsychiatric disorder. In some embodiments, the additional therapy is psychotherapy. In some embodiments, the additional therapy includes administering one or more additional psychoactive substances to the subject.In some embodiments, the additional psychoactive substance is selected from the group consisting of selective serotonin reuptake (SSRI), tricyclic antidepressant (TCA), monoamine oxidase inhibitor (MAOI), serotonin-norepinephrine reuptake inhibitor (SNRI), serotonin-norepinephrine-dopamine reuptake inhibitor (SDNRI), and anxiolytic. In some embodiments, the neuropsychiatric disorder is a depressive disorder. In some embodiments, the depressive disorder is selected from the group consisting of major dysthymia, major depressive disorder, single and recurrent episodes, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other conditions, other specified depressive disorder, depressive disorder not otherwise specified, and combinations thereof. In some embodiments, the neuropsychiatric disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neuropsychiatric disorder is acute stress disorder. In some embodiments, the neuropsychiatric disorder is fibromyalgia. In some embodiments, the neuropsychiatric disorder is a mood disorder. In some embodiments, the neuropsychiatric disorder is an anxiety disorder. In some embodiments, the neuropsychiatric disorder is an eating disorder. In some embodiments, the neuropsychiatric disorder 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), schizophrenic personality disorder, other anxiety and panic disorders, specified personality disorders, impulsive disorders, gender identity disorder, disorders of sexual preference, other sexual disorders, other disorders of adult personality and behavior, unspecified disorders of adult personality and behavior, personality and behavior disorders due to known physiological conditions. In some embodiments, the subject with PD also has a depressive disorder.

[0018] In another aspect, provided herein is a method of treating and / or preventing a neuropsychiatric disorder and / or ameliorating a symptom thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 2C-B (4-bromo-2,5-dimethoxyphenethylamine). In some embodiments, the 2C-B dose is in the range of 0.8-5 mg / kg. In some embodiments, the 2C-B dose is in the range of 0.8-30 mg / kg. In some embodiments, the 2C-B dose is in the range of 50-350 mg. In some embodiments, the 2C-B dose is in the range of 50-500 mg. In some embodiments, the 2C-B dose is in the range of 50-1,000 mg. In some embodiments, an initial dose (e.g., 50-500 mg) of 2C-B is administered, which is then boosted 30 minutes to 4 hours later by administering a second 2C-B dose (e.g., an additional 25-250 mg of 2C-B). In some embodiments, 2C-B is administered once a week, or more than once a week (up to daily administration), or two or three times a day, e.g., as a single dose or according to the dosing schedules described above. In some embodiments, 2C-B is administered as a sustained or extended release formulation, e.g., to achieve the dosing regimens disclosed herein, releasing 50 mg to 1 g on a set schedule to patients according to the indication being treated in those patients. In some embodiments, the neuropsychiatric disorder is somatic symptom disorder. In some embodiments, the somatic symptom disorder is selected from the group consisting of illness anxiety disorder, conversion disorder (functional neurological disorder), psychological factors affecting other medical disorders, factitious disorder, other specified somatic symptom disorders and related disorders, unspecified somatic symptom disorders and related disorders, and combinations thereof. In some embodiments, the neuropsychiatric disorder is fibromyalgia. In some embodiments, the neuropsychiatric disorder is a depressive disorder.In some embodiments, the depressive disorder is selected from the group consisting of major dysthymia, major depressive disorder, single and recurrent episodes, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other conditions, other specified depressive disorder, depressive disorder not otherwise specified, and combinations thereof. In some embodiments, the neuropsychiatric disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neuropsychiatric disorder is acute stress disorder. In some embodiments, the neuropsychiatric disorder is a mood disorder. In some embodiments, the neuropsychiatric disorder is an anxiety disorder. In some embodiments, the neuropsychiatric disorder is an eating disorder. In some embodiments, the subject is suicidal. In some embodiments, the neuropsychiatric disorder is treatment-resistant. In some embodiments, 2C-B is used in combination with an additional therapy for the neuropsychiatric disorder. In some embodiments, the additional therapy is psychotherapy. In some embodiments, the additional therapy comprises administering to the subject one or more additional psychoactive substances. In some embodiments, the additional psychoactive substance is selected from the group consisting of an SSRI, a TCA, an MAOI, an SNRI, an SDNRI, and an anxiolytic.

[0019] In another aspect, provided herein is a method of treating and / or preventing a neuropsychiatric disorder and / or ameliorating a symptom thereof in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of MBDB (N-methyl-1-1,3-benzodioxol-5-yl)-2-aminobutane). In some embodiments, the MBDB dose is in the range of 0.8-5 mg / kg. In some embodiments, the MBDB dose is in the range of 0.8-30 mg / kg. In some embodiments, the MBDB dose is in the range of 50-350 mg. In some embodiments, the MBDB dose is in the range of 50-500 mg. In some embodiments, the MBDB dose is in the range of 50-1,000 mg. In some embodiments, an initial dose of MBDB (e.g., 50-500 mg) is administered, which is then boosted 30 minutes to 4 hours later by administering a second MBDB dose (e.g., an additional 25-250 mg of methylone). In some embodiments, the MBDB is administered as a single dose or according to the dosing schedules described above, for example, once per week, or more than once per week (up to daily administration), or two or three times per day. In some embodiments, the MBDB is administered as a sustained or extended release formulation, for example, to achieve the dosing regimens disclosed herein, releasing 50 mg to 1 g on a set schedule to patients according to the indication being treated in those patients. In some embodiments, the neuropsychiatric disorder is an anxiety disorder.In some embodiments, the anxiety disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, panic attacks, phobic anxiety disorder, illness anxiety disorder, dissociative, stress-related, somatoform, and other non-psychotic mental disorders, acute stress reaction, transient adaptation reaction disorder, neurasthenia, psychophysiological disorders, obsessive-compulsive disorder, disorders of response and adaptation to severe stress, separation anxiety disorder, episodic paroxysmal anxiety, selective mutism, specific phobias, social anxiety disorder (social phobia), agoraphobia, substance / medication-induced anxiety disorder, and other disorders. The subject may be selected from the group consisting of anxiety disorder, anxiety disorder in pregnancy and childbirth, anxiety disorder during pregnancy (prenatal) before birth, postpartum anxiety, animal-type phobia, spider phobia, other animal-type phobia, natural environment phobia, thunderstorm phobia, blood phobia, injection and transfusion phobia, other medical phobia, injury phobia, incident phobia, claustrophobia, height phobia, other unspecified anxiety disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), skin picking disorder (skin picking disorder), and combinations thereof. In some embodiments, the subject is suicidal. In some embodiments, the neuropsychiatric disorder is treatment resistant. In some embodiments, the neuropsychiatric disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neuropsychiatric disorder is acute stress disorder. In some embodiments, the neuropsychiatric disorder is fibromyalgia. In some embodiments, the MBDB is used in combination with an additional therapy for the neuropsychiatric disorder. In some embodiments, the additional therapy is psychotherapy. In some embodiments, the additional therapy comprises administering to the subject one or more additional psychoactive substances, hi some embodiments, the additional psychoactive substances are selected from the group consisting of SSRIs, TCAs, MAOIs, SNRIs, SDNRIs, and anti-anxiety drugs.

[0020] Other features and advantages of the present invention will become apparent from the following detailed description, examples, and drawings. It should be understood, however, that the detailed description and specific examples are given by way of illustration only, while indicating preferred embodiments, since various modifications and changes will become apparent to those skilled in the art from this detailed description.

[0021] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [Brief description of the drawings]

[0022] [Figure 1] 1 shows the baseline symptom list for symptoms occurring in 2 or more of the 28 patients included in Cohort 2 of Example 4. [Diagram 2] 1 shows the severity of underlying disease in cohort 2 of Example 4. [Diagram 3] Improvement in Cohort 2 for subjects in (FIG. 3A) the MDD subset and (FIG. 3B) the PTSD subset is shown. [Figure 4] (FIG. 4A) Baseline disease severity and (FIG. 4B) improvement for the patients in Example 5 are shown. [Diagram 5] Methylone has a stable antidepressant-like effect in the forced swimming test. Measurements of time spent immobile (FIG. 5A) (F(5, 34)=59.05, p<0.0001), swimming (FIG. 5B) (F(5, 34)=28.72, p<0.0001), or climbing (FIG. 5C) (F(5, 34)=3.195, p<0.05) over the course of a 5-min forced swimming test in rats. Rats were subjected to a 15-min swim 24 h before testing. Fluoxetine (10 mg / kg, IP) was administered 1, 5, and 23.5 h before testing. Methylone (5, 15, 30 mg / kg, IP) was administered 30 min before testing. All data are presented as mean ± SEM. One-way ANOVA and Tukey's post-hoc test. *p<0.05 vs. vehicle 1X group ****p<0.0001 vs. vehicle 1X group; ++++p<0.0001 vs. vehicle 3X group; N=6-8 per group. [Figure 6] Methylone is superior to other antidepressants in the forced swimming test. [Figure 7]2C-B has an immediate antidepressant-like effect in the forced swimming test. Measurements of time spent immobile (FIG. 7A) (F(5, 34)=17.73, p<0.0001), swimming (FIG. 7B) (F(5, 34)=16.49, p<0.0001), or climbing (FIG. 7C) (F(5, 34)=4.984, p<0.001) during the course of a 5-min forced swimming test in rats. Rats were subjected to a 15-min swim 24 h before testing. Fluoxetine was administered (10 mg / kg, IP) 1, 5, and 23.5 h before testing. 2C-B (2.5, 10, 20 mg / kg, IP) was administered 30 min before testing. All data are expressed as mean ± standard error. One-way ANOVA and Tukey's post-hoc test. **p<0.01 vs. Vehicle 1X group; ****p<0.0001 vs. Vehicle 1X group; ++++p<0.0001 vs. Vehicle 3X group; +++p<0.001 vs. Vehicle 3X group; N=6-8 per group. [Figure 8] Methylone has a stable antidepressant-like effect in the forced swimming test. (Figure 8A) Scheme of the experimental design. Measurement of the time spent immobile (Figure 8B) (F(4,31)=17.05, p<0.0001), climbing (Figure 8C) (F(4,31)=5.786, p<0.01), or swimming (D) (F(4,31)=6.063, p<0.01) during the course of a 5-min rat forced swimming test. Rats were subjected to a 15-min swim 24 h before the test. Fluoxetine (10 mg / kg, IP) was administered 1, 5, and 23.5 h before the test. Methylone (5 or 15 mg / kg, IP) was administered 30 min before the test. All data are expressed as mean ± standard error. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. vehicle control group; +p<0.05, ++p<0.01 vs. fluoxetine-treated group; ap=0.06 vs. fluoxetine-treated group; bp=0.08 vs. vehicle control group; N=6-8 per group. [Figure 9]Methylone improves fear extinction recall in a PTSD mouse model. (Figure 9A) Scheme of experimental design. A single CS-US (tone-shock) pairing on day 1 was followed by six 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 measured. (Figure 9B) The time spent freezing during the first cue (extinction recall) on day 3 was significantly shortened by methylone compared to saline (t(26)=2.350, p<0.05). (Figure 9C) No changes in locomotor activity were observed on day 3 (t(26)=1.073, p>0.05). Data are presented as mean ± SEM. N=12 for methylone group (30 mg / kg, IP); and N=16 for saline control group. *p<0.05. [Figure 10] MBDB improves fear extinction in a PTSD mouse model. A single CS-US (tone-shock) pairing on day 1 was followed by six CS presentations in a novel context (context B). MBDB or saline vehicle was injected 30 min before extinction training on day 2. On day 3, the freezing time to the CS was measured. (Figure 10A) The freezing time during the first extinction training trial on day 2 was significantly shortened by MBDB compared to saline control (t(24)=3.095, p<0.01). (Figure 10B) A small but significant increase in locomotor activity was also induced by MBDB on day 2 (t(24)=2.874, p<0.01). Data are presented as mean ± SEM. N=10 for MBDB group (5 mg / kg, IP); and N=16 for saline control group. **p<0.01 vs. vehicle control group. [Figure 11]Methylone reduces anxiety and increases locomotor activity in the open field test. Rats received a single injection of methylone 30 min before a 30 min test in the open field. (Figure 11A) Time spent in the center revealed an anxiolytic effect of methylone compared to vehicle-treated controls (F(3,20)=7.139, p<0.01). (Figure 11B) Total distance traveled showed increased locomotor activity after medium and high doses of methylone (F(3,20)=6.209, p<0.01). Data are expressed as mean ± SEM. N=6 per group. *p<0.05; **p<0.01 vs. vehicle control group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present inventors identify methylone as a suitable agent for the treatment of CNS disorders. Methylone (3,4-methylenedioxy N-methylcathinone; also known as "βk-MDMA") is a synthetic empathogenic cathinone, a close structural analogue of MDMA, but with a half-life that is >50% shorter. After being designated Schedule 1 controlled status by the US DEA in 2010, there have been no FDA-registered clinical trials of its efficacy or safety profile. Methylone and MDMA are similar to 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 cell membrane monoamine transporters and receptors.

[0024] Methylone acts as a mixed reuptake inhibitor / release agent, with a three-fold lower affinity for the serotonin transporter compared to MDMA, but similar affinity for the norepinephrine and dopamine transporters. This reduced dominance of the serotonergic pathway is why its efficacy as an antidepressant is not expected. Furthermore, the "down" effects from amphetamines, including synthetic cathinones such as MDMA or methylone, include intense depression and fatigue. Methylone produced widespread depletion of 5-HT and serotonin transporter 5-HTT levels in rats, resembling a depressed neurological state. Depression has also been reported in humans with methylone. Other adverse effects include anxiety, anorexia, derealization / depersonalization, short-term memory impairment, psychosis, hallucinations, suicidal ideation, irritability, motivational depression, bradymonas, wakefulness, involuntary tremors, teeth grinding, jaw clenching, trismus, and unsteadiness of the upper limbs and gait.

[0025] Taken together, the animal and human data do not suggest a potential medical use of methylone as a treatment for CNS disorders, including depression and PTSD. It is unexpected that methylone (which has the lowest 5-HT agonism in its class of synthetic cathinones) would be useful for the indications identified by the inventors in patients who are unresponsive, resistant, contraindicated, or controversial to current standard treatments. This may include administration of methylone either alone or in combination with SSRIs, TCAs, MAOIs, SNRIs, SDNRIs, or anxiolytics (such as benzodiazepines, beta blockers, alpha blockers, and buspirone).

[0026] The inventors find that methylone has mainstream potential as a CNS therapeutic agent (including as an antidepressant, or as a PTSD treatment, or as an anxiolytic). Compared to other treatments, methylone has advantages over current and developing treatments: better efficacy:safety ratio, more rapid efficacy profile, fewer drug / drug interactions, more effective combination therapy, more frequent adjunct in individual group psychotherapy. Methylone also produces fewer side effects after longer sessions or chronic use, unlike symptoms of SSRI resistance, which gradually decrease in efficacy in the majority of patients. Symptoms of SSRI resistance include fatigue, loss of motivation, fatigue, sleep disorders, restless legs syndrome, irritability, and depressed mood.

[0027] The inventors further identify 2C-B (2,5-dimethoxy-4-bromophenethylamine) as a suitable drug for the treatment and symptom relief of somatic symptom disorder (SSD), depressive disorder, PTSD, and other central nervous system (CNS) disorders (particularly fibromyalgia, a widespread musculoskeletal pain syndrome with symptoms of fatigue, sleep disturbance, memory impairment, and mood disorders). Treatments for fibromyalgia, such as SNRIs (duloxetine and milnacipran), are often outweighed by their potential harms, and only a small proportion of fibromyalgia patients experience substantial symptom relief without adverse events.

[0028] 2C-B is 5-HT 2A Although psychoactive phenethylamines have been reported to have limited efficacy as partial agonists of the 5-HT 2A We hypothesize that it will be useful in pathophysiology involving mixed 5-HT. 2A Antagonists, and 5-HT 2B and 5-HT 2C (These receptors are specifically expressed in the apical dendrites of neocortical pyramidal cells in layer 5.) It is a Schedule 1 drug due to its undesirable properties and potential abuse potential, as many hospitalizations have been linked to 2C-B ingestion by toxicology studies.

[0029] Human open-label studies in experienced drug users who self-administered 2C-B (at various doses between 10 and 20 mg) found no significant adverse effects. At doses higher than 20 mg, 2C-B users reported greater euphoria, kaleidoscope vision, and distorted perception.

[0030] Chronic psychiatric disorders often share a common core of treatment-resistant symptoms that respond well to psychoactive medications, with complex pharmacological effects that can be further modulated by psychotherapy. Patients experience multiple co-occurring symptoms that are related to each other, have independent or simultaneous time-varying and severity ratings, and may have common underlying mechanisms. Clusters may also be considered "symptom endophenotypes," spanning multiple syndromes and disorders with neurobiological correlates of brain circuits and neurotransmitters.

[0031] Without wishing to be bound by theory, we hypothesize that 2C-B has a compelling neurobiological basis for treating SSD, depression, anxiety, PTSD, and comorbid conditions due to its acute, somatic alteration phenomenology and persistent psychoactive pharmacological and physiological effect profile. SSD, including fibromyalgia, is often a diagnosis of exclusion due to chronic somatic symptoms with unclear biological or medical causes. DSM-5 specific entities included in SSD are illness anxiety disorder / hypochondriasis "not otherwise specified," functional neurological / conversion disorder, pain disorder (in which fibromyalgia is classified), body dysmorphic disorder, and somatoform disorder. These are often comorbid with mood and affective disorders, which may include mood disorder clusters and neuropsychological discomfort clusters. Fibromyalgia patients may be successfully treated with 2C-B at lower dose ranges of 1-24 mg and in combination with other psychoactive treatments for CNS disorders.

[0032] The inventors further identify MBDB (N-methyl-1-1,3-benzodioxol-5-yl)-2-aminobutane) as a suitable drug to treat and provide symptomatic relief for a wide range of anxiety disorders, or as an antidepressant. Animal and human data do not suggest potential medical uses of MBDB as a treatment for CNS disorders, or otherwise. Investigational drug users who self-administered MBDB under supervision in a controlled environment at doses ranging from 100 to 300 mg did not experience any significant adverse effects. In summary, MBDB can be utilized as an anxiolytic drug, and this therapeutic effect can be reliably assessed using scales such as the GAD-7 or the Generalized Anxiety Disorder Severity Scale (GADSS).

[0033] The diseases, conditions, and disorders listed herein are described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association, or the International Classification of Diseases (ICD) published by the World Health Organization.

[0034] Mental illness, mental condition, mental disease, or mental disorder includes, without limitation, the following and all intermediate ICD-10 codes within the defined scope: F01-F09: Psychiatric disorders due to known physiological conditions. F01: Vascular dementia, F02: Dementia of other diseases classified elsewhere, F03: Dementia unspecified, F04: Organic amnesic syndromes due to known physiological conditions, F05: Delirium due to known physiological conditions, F06: Other psychiatric disorders due to known physiological conditions, F07: Personality and behavior disorders due to known physiological conditions, F09: Mental disorders unspecified due to known physiological conditions. F10-F19: Mental and behavioral disorders due to the use of psychoactive substances F10: Alcohol-related disorders, F11: 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, F18: Inhalant-related disorders, F19: Other psychoactive substance-related disorders. caffeine-related disorder, caffeine addiction, caffeine withdrawal, other caffeine-induced disorder, substance-related disorder, non-substance-related disorder, gambling disorder, neurocognitive disorder, delirium, delirium other specified, delirium unspecified, severe and mild neurocognitive disorder, severe neurocognitive disorder, mild neurocognitive disorder, severe or mild neurocognitive disorder due to Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder associated with Lewy body disease, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder due to traumatic brain injury, severe or mild substance / medication induced neurocognitive disorder, severe or mild neurocognitive disorder due to HIV infection, severe or mild neurocognitive disorder due to prion disease, severe or mild neurocognitive disorder due to Parkinson's disease, severe or mild neurocognitive disorder due to Huntington's disease, severe or mild neurocognitive disorder due to other medical illness, severe or mild neurocognitive disorder of multiple etiology, neurocognitive disorder unspecified. F20-F29: Schizophrenia, schizophreniform disorder, delusional disorder, and other non-mood psychotic disorders F20: Schizophrenia, F21: Schizophreniform disorder, F22: Delusional disorder, F23: Transient psychotic disorder, F24: Sensitive delusional disorder, F25: Schizoaffective disorder, 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. F30-F39: Mood [emotional] disorders F30: Manic episode, F31: Bipolar disorder, F32: Major depressive disorder, single episode, F33: Major depressive disorder, recurrent, F34: Persistent mood [affect] disorder, F39: Mood [affect] disorder not otherwise specified. Major dysthymia, Persistent depressive disorder (dysthymia), Premenstrual dysphoric disorder, Substance- / medication-induced depressive disorder, Depressive disorder due to other conditions, Other specified depressive disorder, Depressive disorder not otherwise specified, Treatment-resistant depression. F40-F48: Anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders F40: Phobic anxiety disorders, F41: Other anxiety disorders, F42: Obsessive-compulsive disorder, F43: Disorders of response and adaptation to severe stress, F44: Dissociative and conversion disorders, F45: Somatoform disorders, F48 Other non-psychotic mental disorders. Anxiety Disorders: separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks (specific term), agoraphobia, generalized anxiety disorder, substance / medication induced anxiety disorder, anxiety disorder due to other conditions, other specified anxiety disorders, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, skin picking disorder, substance / medication induced obsessive-compulsive disorder and related disorders, obsessive-compulsive disorder and related disorders due to other medical conditions, other specified obsessive-compulsive disorder and related disorders, adjustment disorder, other specified trauma- and stress-related disorders; Trauma- and stressor-related disorders not otherwise specified: reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder, acute stress disorder; Somatic symptom and related disorders: somatic symptom disorder, illness anxiety disorder, conversion disorder (functional neurological disorder), psychological factors affecting other medical illness, factitious disorder, other specified somatic symptom and related disorders, somatic symptom and related disorders not specified; Eating and eating disorders: Pica, Rumination, Avoidant / Restrictive Food Intake Disorder, Anorexia Nervosa, Bulimia Nervosa, Binge Eating Disorder, Other Specified Eating and Eating Disorders, Unspecified Eating and Eating Disorders; Sleep / Wake Disorders: Insomnia Disorder, Hypersomnia Disorder, Narcolepsy, Breathing-Related Sleep Disorder, Obstructive Sleep Apnea Hypopnea, Central Sleep Apnea, Sleep-Related Hypoventilation, Circadian Rhythm Sleep-Wake Disorder, Parasomnia Disorder, Awakening from Non-REM Sleep, Sleepwalking, Sleep Startle Disorder, Nightmare Disorder, REM Sleep Behavior Disorder, Restless Legs Syndrome, Substance / Medication-Induced Sleep Disorder, Other Specified Insomnia Disorder, Insomnia Disorder Unspecified, Other Specified Hypersomnia Disorder, Hypersomnia Disorder Unspecified, Other Specified Sleep-Wake Disorder, Unspecified Sleep-Wake Disorder; Sexual Dysfunctions: delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genito-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, substance / medication induced sexual dysfunction, other specified sexual dysfunction, unspecified sexual dysfunction, gender dysphoria, gender dysphoria, other specified gender dysphoria, unspecified gender dysphoria. F50-F59: Behavioral syndromes associated with physiological disorders and physical factors F50: Eating disorders, F51: Nonorganic sleep disorders not due to substances or known physiological conditions, F52: Sexual dysfunction not due to substances or known physiological conditions, F53: Mental and behavioural disorders associated with the puerperium, not elsewhere classified, F54: Psychological or behavioural factors associated with a disorder or disease classified elsewhere, F55: Abuse of nonpsychoactive substances, F59: Unspecified behavioural syndromes associated with physiological disorders and physical factors. F60-F69: Adult personality and behavior disorders F60: Specific personality disorders, F63: Impulsive disorders, F64: Gender identity disorder, F65: Sexual preference disorders, F66: Other sexual disorders, F68: Other disorders of adult personality and behaviour, F69: Unspecified disorders of adult personality and behaviour. 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 disorders, unspecified disruptive, impulse control, and conduct disorders, Personality disorders, Personality disorders in general, Cluster A personality disorder, Suspicious personality disorder, Schizoid personality disorder, Schizotypal personality disorder, Cluster B personality disorder, Antisocial personality disorder, Borderline personality disorder, Histrionic personality disorder, Narcissistic personality disorder, Cluster C personality disorder, Avoidant personality disorder, Dependent personality disorder, Obsessive-compulsive personality disorder, Other personality disorder, Personality change due to other medical illness, Other specified personality disorder, Personality disorder not specified, Conditions for further study, Attenuated psychotic syndrome, Depressive episode with brief hypomania, Persistent complex bereavement disorder, Gaming disorder, Neurobehavioral disorders associated with prenatal alcohol exposure, Suicidal behavior disorder, Nonsuicidal self-harm. F70~F79: Intellectual disability F70: Mild intellectual disability, F71: Moderate intellectual disability, F72: Severe intellectual disability, F73: Very profound intellectual disability, F78: Other intellectual disability, F79: Unspecified intellectual disability. F80-F89: Pervasive and specific developmental disorders F80: Specific developmental disorders of speech and language, F81: Specific developmental disorders of learning abilities, F82: Specific developmental disorders of motor skills, F84: Pervasive developmental disorders, F88: Other psychological developmental disorders, F89: Unspecified psychological developmental disorders. Neurodevelopmental disorders, Intellectual disability, Intellectual disability (intellectual developmental disorder), Global developmental delay, Intellectual disability not otherwise specified (intellectual developmental disorder not otherwise specified), Communication disorders, Speech disorders (formerly phonological disorders), Childhood-onset fluency disorder (stuttering), Social (pragmatic) communication disorder, Communication disorder not otherwise specified, Autism spectrum disorder, Autism spectrum disorder, Attention-deficit / hyperactivity disorder, Attention-deficit / hyperactivity disorder, Other specified attention-deficit / hyperactivity disorder, Attention-deficit / hyperactivity disorder not otherwise specified, Specific learning disorder, Specific learning disorder, Movement disorders, Developmental coordination disorder, Stereotypic movement disorder, Tic disorders, Tourette's disorder, Persistent (chronic) motor or vocal tic disorder, Provisional tic disorder, Other specified tic disorder, Tic disorder not otherwise specified, Other neurodevelopmental disorders, Other specified neurodevelopmental disorders, Neurodevelopmental disorders not otherwise specified. F90-F98: Behavioral and emotional disorders usually occurring during childhood and adolescence F90: Hyperactivity disorder, F91: Conduct disorder, F93: Emotional disorders specifically with onset in childhood, F94: Disorders of social functioning specifically with onset in childhood and adolescence, F95: Tic disorders, F98: Other behavioral and emotional disorders specifically with onset in childhood and adolescence.

[0035] As used herein, a nervous system disease, nervous system condition, neurological disease, or neurological disorder includes, without limitation, the following and all intermediate ICD-10 codes in the defined range: G00-G09: Inflammatory diseases of the central nervous system G00: Bacterial meningitis, not elsewhere classified; G01: Meningitis in bacterial diseases classified elsewhere; G02: Meningitis in other infectious and parasitic diseases classified elsewhere; G03: Meningitis of other and unspecified causes; G04: Encephalitis, myelitis, and encephalomyelitis; G05: Encephalitis, myelitis, and encephalomyelitis in diseases classified elsewhere; G06: Intracranial and intrathecal abscesses and granulomas; G07: Intracranial and intrathecal abscesses and granulomas in diseases classified elsewhere; G08: Intracranial and intrathecal phlebitis and thrombophlebitis; G09: Sequelae of inflammatory diseases of the central nervous system. With the following exceptions: Certain conditions of perinatal origin (P04 to P96); certain infectious and parasitic diseases (A00 to B99); complications of pregnancy, childbirth, and the puerperium (O00 to O9A); congenital malformations, congenital malformations, and chromosomal abnormalities (Q00 to Q99); endocrine, nutritional, and metabolic disorders (E00 to E88); certain other consequences of injury, poisoning, and external causes (S00 to T88); tumours (C00 to D49); symptoms, signs, and clinical and laboratory abnormalities, not elsewhere classified (R00 to R94). G10-G14: System atrophy affecting primarily the central nervous system G10: Huntington's disease, G11: hereditary ataxias, G12: spinal muscular atrophies and related syndromes, G13: system atrophies affecting primarily the central nervous system in diseases classified elsewhere, G14: post-polio syndromes. G20-G26: Extrapyramidal and movement disorders G20: Parkinson's disease, G21: Secondary parkinsonisms, G23: Other degenerative diseases of the basal ganglia, G24: Ataxias, G25: Other extrapyramidal disorders and movement disorders, G26: Extrapyramidal disorders and movement disorders in diseases classified elsewhere. G30-G32: Other degenerative neurological diseases G30: Alzheimer's disease, G31: Other degenerative diseases of the nervous system not elsewhere classified, G32: Other degenerative disorders of the nervous system in diseases classified elsewhere. G35-G37: Demyelinating diseases of the central nervous system G35: multiple sclerosis, G36: other acute disseminated demyelinating diseases, G37: other demyelinating diseases of the central nervous system. G40-G47: Episodic and paroxysmal disorders G40: Epilepsy and recurrent seizures, G43: Migraine, G44: Other headache syndromes, G45: Transient ischemic attacks and related syndromes, G46: Cerebrovascular syndromes in cerebrovascular disease, G47: Sleep disorders. G50-G59: Disorders of nerves, nerve roots and plexuses G50: Trigeminal neuropathy, G51: Facial nerve disorders, G52: Other cranial nerve disorders, G53: Cranial nerve disorders in diseases classified elsewhere, G54: Disorders of nerve roots and plexuses, G55: Compression of nerve roots and plexuses in diseases classified elsewhere, G56: Mononeuropathy of upper limbs, G57: Mononeuropathy of lower limbs, G58: Other mononeuropathy, G59: Mononeuropathy in diseases classified elsewhere. With the following exceptions: Current traumatic disorders of nerves, nerve roots, and plexuses, nerves in body areas, neuralgia NOS (M79.2); neuritis NOS (M79.2); peripheral neuritis in pregnancy (O26.82); radiculitis NOS (M54.1). G60-G65: Polyneuropathy and other disorders of the peripheral nervous system G60: Hereditary and idiopathic neuropathies, G61: Inflammatory polyneuropathy, G62: Other and unspecified polyneuropathy, G63: Polyneuropathy in diseases classified elsewhere, G64: Other disorders of the peripheral nervous system, G65: Sequelae of inflammatory and toxic polyneuropathy. G70-G73: Disorders of the neuromuscular junction and muscles G70: Myasthenia gravis and other neuromuscular disorders, G71: Primary myopathies, G72: Other and unspecified myopathies, G73: Disorders of the neuromuscular junction and muscles in diseases classified elsewhere. G80-G83: Cerebral palsy and other paralytic syndromes G80: Cerebral palsy, G81: Hemiplegia and hemiparesis, G82: Paraplegia (paraparesis) and quadriplegia (tetraparesis), G83: Other paralytic syndromes. G89-G99: Other disorders of the nervous system G89: Pain, not elsewhere classified, G90: Disorders of the autonomic nervous system, G91: Hydrocephalus; G92: Toxic encephalopathy, G93: Other brain disorders, G94: Other brain disorders in diseases classified elsewhere, G95: Other and unspecified spinal cord diseases, G96: Other central nervous system disorders, G97: Complications and disorders during and after procedures of the nervous system, not elsewhere classified, G98: Other disorders of the nervous system, not elsewhere classified, G99: Other disorders of the nervous system in diseases classified elsewhere.

[0036] As used herein, "treatment-resistant depression" (TRD) is a shorthand signifier for all relevant terms such as approaches for management, which are defined herein as including, but not limited to, non-responder depression, refractory depression, partially responsive depression, optimization strategies, switching strategies, combination strategies, augmentation strategies, bupropion, mirtazapine, mianserin, lithium, thyroid hormones, second generation antipsychotics (SGAs), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, pindolol, sex steroids, and glucocorticoids. Approaches to management include treatment strategies such as (1) switching from an ineffective antidepressant to a novel antidepressant from a similar or different class; (2) combining the current antidepressant regimen with a second antidepressant from a different class; and (3) augmenting the current antidepressant regimen with a second agent that is not considered an antidepressant in its own right.

[0037] As used herein, the terms "reduce," "reduce," "diminish" and similar terms refer to a reduction of at least about 10%, about 15%, about 20%, about 25%, about 35%, about 50%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, or more.

[0038] As used herein, the terms "improve," "increase," "enhance," and similar terms refer to an increase of at least about 10%, about 15%, about 20%, about 25%, about 50%, about 75%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more.

[0039] As used herein, the term "bind" or "binding" or grammatical equivalents refer to compositions that have affinity for one another. "Specific binding" is binding that is selective between two types of molecules. A specific example of specific binding is that which occurs between an antibody and an antigen. Typically, specific binding has a dissociation constant (KD) of about 1×10 -5 Less than M or about 1×10 -6 Less than M or 1×10 -7 If the binding is less than M, it can be distinguished from non-specific binding. Specific binding can be detected by ELISA, immunoprecipitation, co-precipitation, two-hybrid assays with or without chemical cross-linking, etc. Using appropriate controls, "specific" binding can be distinguished from "non-specific" binding.

[0040] In one embodiment, a variety of other therapeutic agents are available for administration by the compositions and methods provided herein.

[0041] The psychoactive compounds provided herein can be utilized for various therapeutic purposes. In one embodiment, the compounds are administered to a subject to treat neuropsychiatric disorders. "Subject" for the compositions and methods provided herein includes humans and other animals, preferably mammals, and most preferably humans. Thus, the compounds provided herein have both human therapeutic and veterinary applications. In another embodiment, the subject is a mammal, and in yet another embodiment, the subject is a human. As used herein, "pathology" or "disease" refers to a disorder that can be ameliorated by administration of a pharmaceutical composition comprising the compounds provided herein.

[0042] The methods and compositions described herein can be used to prevent neuropsychiatric disease and improve its signs and / or symptoms.The terms "treat" and "treatment" used to refer to the treatment of neuropsychiatric disease in a subject include preventing, preventing or improving neuropsychiatric disease in a subject, and reducing or improving signs or symptoms of neuropsychiatric disease.Treatment goals can incorporate endpoints such as improvement in DSM-5 severity rating scale to measure whether resilience and quality of life are improved, along with the involvement of positive cognitive valence system and corresponding reduction in negative valence.

[0043] One of skill in the art will appreciate that the methods of treatment and / or prevention comprising administering a psychoactive compound provided herein for the treatment and / or prevention of one or more indications as described herein also include the use of a psychoactive compound provided herein in the manufacture of a therapeutic medicament for the treatment and / or prevention of one or more indications as described herein; and the use of a psychoactive compound provided herein for the treatment and / or prevention of one or more indications as described herein.

[0044] In some embodiments, the method of treating and / or preventing a neuropsychiatric disorder and / or ameliorating a symptom thereof in a subject in need thereof comprises administering to the subject a therapeutically effective dose of a psychoactive compound provided herein. In some embodiments, the method of treating and / or preventing a neuropsychiatric disorder and / or ameliorating a symptom thereof in a subject in need thereof comprises 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.

[0045] The term "about" or "approximately" means within an acceptable error range for a 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 deviation, as is customary in the art. Alternatively, when referring to a measurable value, such as an amount, time course, concentration, etc., it may include a variation of ±20% or ±10%, more preferably ±5%, even more preferably ±1% or ±0.5%, and even more preferably ±0.1% from the specified value, such that the variation is appropriate for carrying out the disclosed method.

[0046] Pharmaceutical 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 the compounds with the desired degree of purity, in the form of a lyophilized formulation or aqueous solution, with optional pharma- ceutically acceptable carriers, additives, or stabilizers. Acceptable carriers, additives, or stabilizers are non-toxic to recipients at the dosages and concentrations used, and include: buffers (such as phosphate, citric acid, acetic acid, and other organic acids); antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium 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 (fewer than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers (polyvinylpyrrolidone, and the like); amino acids (such as glycine, glutamine, asparagine, histidine, arginine, or lysine); monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents (such as EDTA); sugars (such as sucrose, mannitol, trehalose, or sorbitol); sweeteners and other flavoring agents; fillers (such as microcrystalline cellulose, lactose, corn starch, and other starches); binders; additives; colorants; salt-forming counterions (such as sodium); metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants or polyethylene glycol (PEG). In another embodiment, the pharmaceutical compositions provided herein are in a water-soluble form, such as present as pharma- ceutically acceptable salts, which is meant to include both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness of the free base and which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, and organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, 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). The formulations used for in vivo administration are preferably sterile. This is easily accomplished by filtration through a sterile filter or other methods.

[0047] Pharmaceutically acceptable excipients for formulation of the psychoactive compounds provided herein include, but are not limited to, the following: diluents such as microcrystalline cellulose, starch, mannitol, anhydrous calcium hydrogen phosphate or a co-mixture of silicon dioxide, calcium carbonate, microcrystalline cellulose and talc; disintegrants such as sodium starch glycolate or croscarmellose sodium; binders such as povidone, copovidone or hydroxyl propyl cellulose; lubricants such as magnesium stearate or sodium stearyl fumarate; glidants such as colloidal silicon dioxide; and film coating agents such as Opadry II white or PVA-based Opadry II brown.

[0048] The psychoactive compounds provided herein may also be encapsulated in microcapsules prepared by methods including, but not limited to, droplet formation techniques, interfacial polymerization (e.g., using hydroxymethylcellulose, or gelatin-microcapsules, or poly(methyl methacrylate) microcapsules), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), and macroemulsions. Sustained release preparations may be prepared. Suitable examples of sustained release preparations include solid hydrophobic polymer semipermeable matrices, where the matrices are in the form of molded articles (e.g., films, or microcapsules). Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylic acid), or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyrate, a microsphere-based delivery system composed of the desired bioactive molecule incorporated into a matrix of poly(D,L-lactide-co-glycolide) (PLG).

[0049] Administration of pharmaceutical compositions comprising psychoactive agents provided herein, preferably in the form of a sterile aqueous solution, can be accomplished in a variety of ways, including, but not limited to, orally, subcutaneously, intravenously, intranasally, intraotically, transdermally, topically (e.g., gels, ointments, lotions, creams, etc.), intraperitoneally, intramuscularly, intrapulmonary, intravaginally, parenterally, rectally, or intraocularly. As is known in the art, pharmaceutical compositions may be formulated appropriately for the method of introduction.

[0050] In some embodiments, the pharmaceutical formulation is an oral dosage form. In some embodiments, the pharmaceutical formulation is a parenteral dosage form. In some embodiments, the pharmaceutical formulation comprises a tablet. In some embodiments, the pharmaceutical formulation comprises a capsule. In some embodiments, the pharmaceutical formulation comprises a dry powder. In some embodiments, the pharmaceutical formulation comprises a solution. In some embodiments, two or more dosage forms are administered to a subject substantially simultaneously. In some embodiments, a subject may receive a total therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be divided among multiple tablets or capsules.

[0051] In some embodiments, the dose of the psychoactive compound provided herein may range from about 1 mg to about 100 mg. For example, the dose may be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some embodiments, the dose of the psychoactive compound provided herein is about 0.1 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 30 mg. In some embodiments, the dose of the psychoactive compound provided herein is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, the dose of the psychoactive compound provided herein is in the range of about 0.001 mg to about 1 g. In some embodiments, the dose of the psychoactive compounds provided herein ranges from about 100 mg to about 250 mg. In some embodiments, the dose of the psychoactive compounds provided herein is about 25 mg.

[0052] In some embodiments, the psychoactive compounds provided herein are administered daily. In some embodiments, the psychoactive compounds provided herein are administered twice a day. In some embodiments, the psychoactive compounds are administered three times a day. In some embodiments, the psychoactive compounds are administered every two days. In some embodiments, the psychoactive compounds are administered every three days. In some embodiments, the psychoactive compounds are administered every four days. In some embodiments, the psychoactive compounds are administered every five days. In some embodiments, the psychoactive compounds are administered weekly. In some embodiments, the psychoactive compounds are administered every two weeks. In some embodiments, the psychoactive compounds are administered every three weeks. In some embodiments, the psychoactive compounds are administered monthly.

[0053] In some embodiments, 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 two days. In some embodiments, about 50 mg of the psychoactive compound is administered every three days. In some embodiments, about 50 mg of the psychoactive compound is administered every four days. In some embodiments, about 50 mg of the psychoactive compound is administered every five days. 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 two weeks. In some embodiments, about 50 mg of the psychoactive compound is administered every three weeks. In some embodiments, about 50 mg of the psychoactive compound is administered monthly.

[0054] In some embodiments, 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 two days. In some embodiments, about 100 mg of the psychoactive compound is administered every three days. In some embodiments, about 100 mg of the psychoactive compound is administered every four days. In some embodiments, about 100 mg of the psychoactive compound is administered every five days. 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 two weeks. In some embodiments, about 100 mg of the psychoactive compound is administered every three weeks. In some embodiments, about 100 mg of the psychoactive compound is administered monthly.

[0055] In some embodiments, 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 two days. In some embodiments, about 150 mg of the psychoactive compound is administered every three days. In some embodiments, about 150 mg of the psychoactive compound is administered every four days. In some embodiments, about 150 mg of the psychoactive compound is administered every five days. 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 two weeks. In some embodiments, about 150 mg of the psychoactive compound is administered every three weeks. In some embodiments, about 150 mg of the psychoactive compound is administered monthly.

[0056] In some embodiments, 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 two days. In some embodiments, about 200 mg of the psychoactive compound is administered every three days. In some embodiments, about 200 mg of the psychoactive compound is administered every four days. In some embodiments, about 200 mg of the psychoactive compound is administered every five days. 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 two weeks. In some embodiments, about 200 mg of the psychoactive compound is administered every three weeks. In some embodiments, about 200 mg of the psychoactive compound is administered monthly.

[0057] In some embodiments, 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 two days. In some embodiments, about 250 mg of the psychoactive compound is administered every three days. In some embodiments, about 250 mg of the psychoactive compound is administered every four days. In some embodiments, about 250 mg of the psychoactive compound is administered every five days. In some embodiments, about 250 mg of the psychoactive compound is administered daily. 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 two weeks. In some embodiments, about 250 mg of the psychoactive compound is administered every three weeks. In some embodiments, about 250 mg of psychoactive compound is administered monthly.

[0058] In some embodiments, an initial dose of a psychoactive compound provided herein is administered, which is then boosted 30 minutes to 4 hours later by administering a second dose of the psychoactive compound. In some embodiments, the boosted dose is administered about 30 minutes after the initial dose. In some embodiments, the boosted dose is administered about 60 minutes after the initial dose. In some embodiments, the boosted dose is administered about 90 minutes after the initial dose. In some embodiments, the boosted dose is administered about 120 minutes after the initial dose. In some embodiments, the boosted dose is administered about 150 minutes after the initial dose. In some embodiments, the boosted dose is administered about 180 minutes after the initial dose. In some embodiments, the boosted dose is administered about 210 minutes after the initial dose. In some embodiments, the boosted dose is administered about 240 minutes after the initial dose.

[0059] In some embodiments, the boosted dose is 10% to 100% of the amount of the initial dose. In some embodiments, the boosted dose is the same amount as the initial dose. In some embodiments, the boosted dose is about half the amount of the initial dose. In some embodiments, the dosing schedule is performed daily. In some embodiments, the dosing schedule is performed twice a day. In some embodiments, the dosing schedule is performed three times a day. In some embodiments, the dosing schedule is performed every other day. In some embodiments, the dosing schedule is performed every third day. In some embodiments, the dosing schedule is performed every fourth day. In some embodiments, the dosing schedule is performed every fifth day. In some embodiments, the dosing schedule is performed weekly. In some embodiments, the dosing schedule is performed every two weeks. In some embodiments, the dosing schedule is performed every three weeks. In some embodiments, the dosing schedule is performed monthly.

[0060] In some embodiments, the dose of the psychoactive compound provided herein may range from about 1 mg / kg to about 100 mg / kg. For example, 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. In some embodiments, the dose of the psychoactive compound provided herein is 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 the psychoactive compound provided herein is about 1 mg / kg, about 10 mg / kg, or about 25 mg / kg. In some embodiments, the dose of the psychoactive compound provided herein is in the range of about 0.001 mg / kg to about 1 g / kg. In some embodiments, the dose of the psychoactive compound provided herein is in the range of about 100 mg / kg to about 250 mg / kg. In some embodiments, the dose of the psychoactive compound provided herein is about 25 mg / kg.

[0061] In some embodiments, the psychoactive compounds provided herein are administered, for example, as a single dose or one or more times per week (up to twice daily or three times daily). In some embodiments, the psychoactive compounds provided herein are administered according to the dosing schedules provided herein. In some embodiments, the psychoactive compounds provided herein are administered as sustained or extended release formulations, for example, to achieve the dosing regimens disclosed herein and release 50 mg to 1 g on a schedule set for the patient depending on the indication being treated in the patient.

[0062] The term "subject" refers to a mammal, including a human, in one embodiment, in need of treatment for or susceptible to a condition or its sequelae. Subjects may include dogs, cats, pigs, cows, sheep, goats, horses, rats, and mice, as well as humans. The term "subject" does not exclude individuals who are normal in all respects.

[0063] In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the female subject is pregnant or postpartum. The subject may be an elderly subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject. In some embodiments, the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10 years old, about 10-15 years old, about 15-20 years old, about 20-25 years old, about 25-30 years old, about 30-35 years old, about 35-40 years old, about 40-45 years old, about 45-50 years old, about 50-55 years old, about 55-60 years old, about 60-65 years old, about 65-70 years old, about 70-75 years old, about 75-80 years old, about 85-90 years old, about 90-95 years old, or about 95-100 years old.

[0064] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. For example, the term "a molecule" can also include a plurality of molecules.

[0065] Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values ​​is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, reference to values ​​stated in a range includes all values ​​within that range. All ranges are inclusive and combinable.

[0066] The phrase "and / or" as used herein should be understood to mean "either or both" of the elements it conjoins, i.e., elements that are present in some cases together and in other cases disjunctively. Multiple elements listed with "and / or" should be considered in the same manner, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present in addition to the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B", when used with an open-ended expression such as "comprising", may refer in one embodiment to only A (optionally including elements other than B); in another embodiment to only B (optionally including elements other than A); in yet another embodiment to both A and B (which may optionally include other elements), and so forth.

[0067] As used herein, "or" should be understood to have the same meaning as "and / or" defined above. For example, when separating items in a list, "or" or "and / or" is interpreted as inclusive, i.e., the inclusion of at least one of a plurality of elements or a series of elements, including two or more, and optionally including further unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of", or "consisting of" when used in an embodiment, refer to the inclusion of exactly one element of a plurality or series of elements. In general, the term "or" as used herein is only interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either", "one of", "only one of", or "exactly one of".

[0068] As used herein, 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 list of elements, but may not necessarily include at least one of every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for elements to optionally be present other than the specifically identified elements in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer, in one embodiment, to at least one, optionally including more than one, A, and no B (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, and no A (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.

[0069] Unless the context indicates otherwise, it is specifically contemplated that the various features described herein may be used in any combination.

[0070] Any patent documents, patent application publications, or scientific publications cited herein are hereby incorporated by reference in their entirety.

[0071] The following examples are presented to more fully illustrate the preferred embodiments of the invention and should not be construed as limiting the broad scope of the invention.

[0072] Working Example Example 1: Effects of methylone, 2C-B, and MBDB on fear extinction plasticity and dendritic structure in mice A major question in experimental studies is how the short half-life of a compound can lead to long-term behavioral changes. One possible mechanism is neuroplasticity. Indeed, administration of psychoactive compounds can produce lasting changes in the neuroarchitecture of the brain by strengthening synaptic connections or by increasing the number of synaptic connections. However, current evidence supporting this view comes mostly from studies of cultured neurons. What remains unclear is the degree to which neuroplasticity is induced by psychoactive compounds in the mammalian brain and whether synaptic remodeling occurs in brain regions associated with neuropsychiatric disorders.

[0073] In this study, the effects of multiple psychoactive pharmaceuticals are compared in a rodent in vivo model. Multiple conditions are tested, including three psychoactive compounds of interest (methylone, 2C-B, and MBDB) in both sustained exposure versus treatment-naive groups (e.g., imipramine, or other antidepressants / anxiolytics), positive controls (e.g., another antidepressant / anxiolytic), and vehicle controls (saline). Dose-response curves of the psychoactive compounds are characterized by measuring head-twitch responses in mice. The plasticity-enhancing effects of single dose administration of each compound on fear extinction behavior are also determined. The long-lasting effects of a single dose of each compound on dendritic spine density and turnover are then determined using two-photon imaging microscopy (Shao LX et al., Neuron. 2021 Jun 25:S0896-6273(21)00423-2. doi:10.1016 / j.neuron.2021.06.008).

[0074] Determine dose-response curves in C57BL / 6J mice It is important to determine a dose range that is behaviorally relevant for the mice. To generate dose-response curves, head-twitch responses are tested with 40 mice per condition to quantitate a dose range for three psychoactive compounds (methylone, 2C-B, MBDB) in 6-8 week old adult C57BL / 6J mice. Briefly, animals are placed in arenas in a soundproof space. The arenas are illuminated with near infrared light. The movements of the mice in all arenas are captured simultaneously by a high-speed camera mounted on the ceiling. Each animal receives one intraperitoneal injection of one of five doses of the compound, with a dose range selected based on the literature. Mice are randomly assigned to groups. Video is recorded for approximately 10 minutes after administration. In a subset of trials, videos are recorded for up to 2 hours to chart the time course. For analysis, head twitches are counted by an experimenter blinded to the experimental conditions. These experiments are used to inform the doses used in further studies.

[0075] Determine the effects of methylone, MBDB, and 2C-B on fear extinction plasticity Neuroplasticity may promote changes in emotional learning. Fear extinction is a behavior in which repeated exposure to relevant fear-learning stimuli can reduce the strength of the fear response, which may be related to the mechanism of action of these compounds in reducing anxiety or fear. It is unknown to what extent the novel phenethylamines promote fear extinction. Here, the rate of fear extinction is determined after drug administration in adult mice in four conditions (saline, methylone, 2C-B, MBDB), with 10 mice per condition tested. Briefly, each mouse receives a tone / shock pairing (day 1); then the next day, it receives a single dose of compound (at a dose informed by the previous test) 30 minutes before reexposure to the fear-associated stimulus (day 2). On the third day, fear extinction learning is tested by reexposing the mouse again to the relevant tone in a fear conditioning apparatus. Fear extinction serves as a model for improving anxiety- and fear-related behaviors in psychiatric disorders and helps to identify behavioral effects that are separable from hallucinatory effects. The circuit mechanisms of potential plasticity enhancement are then investigated by two-photon imaging experiments.

[0076] Determine long-term effects on neurite remodeling Although it has been shown that psychoactive compounds can enhance neuroplasticity, these experiments examine how different compounds induce different degrees of structural remodeling. Here, dendritic spine turnover in the medial frontal cortex is determined for five conditions (saline, ketamine, methylone, 2C-B, MBDB) in adult mice, with five mice per condition tested. Briefly, Thy1-GFP-M transgenic mice are used because a small subset of cortical pyramidal neurons expresses enhanced green fluorescent protein, allowing visualization of their dendritic structures. Each mouse receives a single dose of compound (at doses determined as above; for ketamine, 10 mg / kg). Using two-photon microscopy, dendritic spines at the distal apical arborescence are imaged and followed for seven sessions at days -3, -1, 1, 3, 5, 7, and approximately 30 days from the day of administration. Imaging the same set of spines over time allows the determination of the density of dendritic spine numbers and also the turnover kinetics, including the rates of spine formation and disappearance, as well as the proportion of newly formed spines that still persist (indicating maturation of new functional synapses). These results provide data for multiple psychoactive compounds to demonstrate their suitability for treating neuropsychiatric disorders.

[0077] Example 2: Zebrafish models of neuropsychiatric disorders Due to their physiological (neuroanatomical, neuroendocrine, neurochemical) and genetic similarities to mammals, stable phenotypes, and utility in high-throughput genetic and chemogenetic screens, zebrafish are ideal for the development of appropriate 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 indicators in zebrafish that respond to physiological, genetic, environmental, and / or psychopharmacological changes. Furthermore, the high sensitivity of zebrafish to commonly prescribed psychoactive drugs supports the use of this model as a tool for pharmacological research and drug screening. With a fully characterized genome, both adult and juvenile zebrafish are now widely used for in vivo screening of a variety of psychoactive pharmaceutical agents.

[0078] Reserpine-induced depression model in zebrafish As a specific inhibitor of monoamine transporters, reserpine is known to deplete monoamine neurotransmitters (as confirmed by liquid chromatography-mass spectrometry analysis) and to decrease swimming distance and average speed (hypokinetic), and to reduce responses to both visual and acoustic stimuli. Reserpine induces depression-like behavior in both adult and larval zebrafish; it is used as an assay for drugs that affect these despair-like states, such as methylone, 2C-B, and MBDB. A camera algorithm, histogram of oriented gradients (HOG), analyzes the depression and hypokinetic behavior of shoaling zebrafish, achieving a precision not possible with human observers.

[0079] Zebrafish models of anxiety disorders Many behaviors, including anxiety, fear, and stimulus-dependent learning, can be assessed as early as the free-swimming juvenile stage, while social behaviors such as shoaling and directional aggression develop with age. Multiple types of anxiety tests are performed, either sequentially or in combination, including elevated plus maze, novelty tank, light-dark box, and open field tests. Known anxiolytic drugs, such as benzodiazepines, are used as positive controls to evaluate the effects of drugs on diving and exploration behavior, thigmotaxis, hyperactive swimming, erratic swimming, freezing, or levels of light-area aversion (scotopic preference) in adults and dark aversion in juveniles.

[0080] Example 3: Rodent models of neuropsychiatric disorders This example presents rodent models for multiple neurological and psychiatric conditions that are used to demonstrate the efficacy of the psychoactive compounds described herein. Primate and rodent models are traditionally used to study the cellular mechanisms and neural circuits of action of hallucinogenic drugs.

[0081] Depression: The Forced Swimming Test (FST) The forced swimming test (FST) is the classic and most commonly used preclinical behavioral assay for screening compounds with antidepressant-like activity, and has high predictive and face validity (Porsolt et al., (1977) Nature 266:730-732; Borsini and Meli, (1988) Psychopharmacology 94:147-160). The premise of the FST is that when rats are placed in a cylinder filled with water, they initially attempt to escape but over time become immobile. This increased immobility reflects behavioral despair and forms a depression-like state. A variety of antidepressant treatments have been shown to concordantly reduce immobility time, with the observation that increases in swimming or climbing correlate with serotonergic or noradrenergic activity, respectively (Detke et al., (1995) Psychopharmacology 121:66-72).

[0082] Anxiety: Open field test (time spent in the center vs. periphery) This behavioral assay is also widely used as an anxiety paradigm and exploits rodents' innate fear of brightly lit open spaces, which are considered to be fear- or anxiety-inducing. Rodents spend more time clinging to the walls of the open field during testing, and these effects correlate with underlying brain regions and mechanisms.

[0083] Methods: Continuous beam break and / or video tracking measures the time spent in the center versus periphery of the open field. Also measured are parameters such as distance traveled and locomotor activity (horizontal and vertical) during the test session.

[0084] Results: Anxiolytics such as diazepam, used as a positive control to assess drug effects on these parameters, increased the time spent in the center of the open field (and / or the distance traveled) independent of changes in locomotion.

[0085] Anxiety: Elevated plus maze This behavioral assay is widely used as an anxiety paradigm and is based on the unconditioned response of rodents to a potentially dangerous environment; the height, brightness, and open space of the maze are considered to elicit fear or anxiety and correlate to the underlying brain regions and mechanisms.

[0086] Methods: Video tracking of time spent in the open arms of the maze starting at the border and progressing to the closed arms for 5 min. Other ethological parameters included rearing, head down, and body extension postures.

[0087] Results: Anxiolytics such as diazepam, used as a positive control to assess drug effects on these parameters, increase the time spent (duration and / or entries) in the open arm activity without decreasing locomotion.

[0088] Modified Geller-Seifter type conflict test Rats are trained to press a lever for food under a multiple variable interval fixed ratio (food; food + shock) schedule of reinforcement. This task generally shows good predictive reliability for anxiolytic-like compounds such as diazepam that potentiate punished responding (i.e., antagonize response inhibition during the punished period). It also shows selectivity for anxiolytics, with no apparent effect for other drug classes, allowing the anxiolytic effects of MBDB to be evaluated with a positive control such as bupropion.

[0089] Fibromyalgia: Reserpine-induced muscle pain model Reserpine (1 mg / kg / subcutaneously) is administered for 3 days to mimic widespread chronic pain and symptom complex.

[0090] Methods: Duloxetine (30 mg / kg, orally) is administered 60 min prior to the forced swimming test (FST), and rats are then exposed to LDI: a single dose of γ-radiation (0.5 Gy) 1 day prior to the FST.

[0091] Results: Reserpine significantly increases immobility time in the FST and decreases the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in the cerebral cortex. It also increases malondialdehyde and nitric oxide and decreases glutathione content in brain tissue. LDI alone or in combination with duloxetine completely antagonizes reserpine-induced fibromyalgia as assessed by the parameters measured.

[0092] Fibromyalgia: The acid-saline model Allodynia, hyperalgesia, and other related fibromyalgia-like symptoms are rapidly induced by acid injection (pH 4.0). Once induced, animals show hypersensitivity to mechanical and visceral stimuli. Symptoms continue for a minimum of 14 days from induction, allowing for time-course evaluation and comparison to vehicle and positive controls (e.g., buprenorphine).

[0093] Example 4: Methylone Case Series This example is based on a case series of 32 discourses on methylone administered orally in single or multiple administration sessions by a clinical psychologist in an outpatient treatment setting. This case series consists of two data sets (Cohort 1 and Cohort 2): Cohort 1: Four case narratives in a healthy population providing information on the safety and tolerability of methylone administered in a single dosing session. Cohort 2: 28 case narratives providing efficacy and safety information from a series of patients with a baseline assessment and a diagnosis of the disorder of interest (PTSD or MDD). Cohort 2 was assessed for efficacy after dosing using the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) at baseline, as further detailed below, compared to the baseline CGI-S established before the first methylone dose. The CGI-S scale was also assessed in a subset of patients from Cohort 2 after treatment. Cohort 2 was assessed for any observed or reported safety events after a single dosing session.

[0094] Clinical Global Improvement Scale The Clinical Global Impression (CGI) scale includes two components: CGI-S ("Severity") and CGI-I ("Improvement"). CGI-S guidelines 1 = Normal - Not ill at all, no symptoms of the disorder in the past 7 days. 2 = Borderline psychiatric disorder - insidious or questionable pathology 3 = Mild illness - clearly established symptoms, with minimal, if any, distress or difficulty in social and occupational functioning 4 = Moderate disease - clear symptoms that are easily noticed but cause minor impairment or distress; symptom level may justify medical treatment 5 = Significant illness - intrusive symptoms that clearly impair social / occupational functioning or cause invasive levels of distress 6 = Severe illness - disruptive pathology, behavior and functioning are frequently affected by symptoms and may require support from others 7 = Very severely ill patients - pathology significantly impairs many life functions; may require hospitalization CGI-I guidelines 1 = Much improved - Almost everything is good; good level of functioning; minimal symptoms; very substantial change 2 = Much improved - Much better with a significant reduction in symptoms; increased level of functioning but some symptoms remain 3 = Minimally Improved - slightly better with little or no clinically meaningful reduction in symptoms; little change in baseline clinical status, level of care, or functional ability 4 = No Change - Symptoms remain essentially unchanged 5 = Minimal deterioration - slight deterioration that may not be clinically significant; little change in baseline clinical status or functional ability 6 = Much worse - clinically significant worsening of symptoms and functional decline 7 = Greatly worsened - severe worsening of symptoms and loss of function

[0095] result Baseline Demographics: The demographics of cohorts 1 and 2 are shown in Table 1.

[0096] [Table 1]

[0097] Cohort 1 consisted of four healthy adult subjects (three males and one female) ranging in age from 28 to 60 years who received a single dose of methylone either in a group (three subjects) or individually (one subject). Cohort 1 tended to have a higher proportion of younger male subjects and all were Caucasian. Prior methylone use was unknown for two subjects and confirmed for the other two subjects (one male and one female).

[0098] Cohort 2 consisted of 28 patients with PTSD or MDD treated in an outpatient setting. Note that one patient included in the MDD population had a primary diagnosis of bipolar disorder type I. Overall, men and women were well-equipped within Cohort 2, and showed similar proportions within the PTSD and MDD subsets.

[0099] Age cohorts were over 85% aged 18 to <65 years overall and in the PTSD and MDD subsets, with a small subset of older patients (age 65 years and older) in the full dataset as well as in the PTSD and MDD subsets. The overall age range in Cohort 2 was broad, ranging from 22 to 78 years (mean 45.9 years), with a similar distribution in the PTSD and MDD subsets.

[0100] Characteristics of underlying diseases in cohort 2 Primary diagnosis Overall, the majority of patients included in cohort 2 [20 of 28 patients, (71%)] had a primary diagnosis of PTSD, and 29% had a primary diagnosis of one MDD or bipolar disorder (7 MDD; 1 bipolar). However, 10 of the 20 PTSD patients (50%) also had a secondary diagnosis of MDD or depression (6 MDD; 4 depression), and overall 64.2% had both a primary and secondary diagnosis of MDD or depression.

[0101] Previous Therapy / Concomitant Therapy In the PTSD subset of Cohort 2, the most common prior / concomitant treatments reported for two or more patients were, in descending order, SSRIs (14 patients), talk therapy (7 patients), breathing techniques (4 patients), cognitive and behavioral therapy, and unspecified antidepressants (4 patients each). The majority of patients discontinued their respective treatments before the initial methylone administration session. Within the PTSD subset, five patients had concomitant therapy with an SSRI or other antidepressant class, and four of these patients had a CGI improvement score of 1 or 2. Treatment regimens were as follows: Fluoxetine 20-40mg Fluoxetine (unspecified dose) Fluoxetine and bupropion (unspecified doses) Escitalopram (unspecified dose) Bupropion (unspecified dose) * Lamotrigine (dose unspecified); discontinued after first 6 sessions. * The patient had a quasi-hallucinatory experience, as described in more detail below, but it was not specified in which session this occurred.

[0102] In the MDD subset of cohort 2, the most common prior / concomitant treatments reported for two or more patients were, in descending order, SSRIs (3 patients), talk therapy (3 patients each), psychotherapy (2 patients), and antiepileptic drugs (2 patients). The majority of patients discontinued their respective treatments before the initial methylone session. Only one patient had concomitant therapy with unspecified doses of escitalopram, clonazepam, lamotrigine, and propranolol at the time of methylone administration, which were tapered after the 5th of 10 methylone sessions. The degree of improvement was CGI-I 2, and no safety events were reported.

[0103] Underlying disease severity The baseline illness severity index (CGI-S) for cohort 2 is shown in Table 2 and Figure 2. Baseline CGI-S ranged from 4 to 7, with 85.7% of patients having a baseline CGI-S of 5 or 6, with similar proportions in both the PTSD and MDD subsets.

[0104] [Table 2]

[0105] Baseline Symptom List Figure 1 shows the baseline symptom inventory for symptoms occurring in two 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 nightmares / night terrors (7 patients).

[0106] Methylone Dosage and Regimen Cohort 1 Three men in cohort 1 were group dosed during a single session; a total methylone dose of 790 mg was administered as a regimen of 280 mg methylone followed by booster doses of 190 mg, 190 mg, and 130 mg. For one healthy female volunteer, a total dose of 870 mg was administered as 250 mg methylone followed by booster doses of 220 mg, 200 mg, and 200 mg.

[0107] Cohort 2 Only sessions that included methylone were counted as treatment sessions. Although some patients were noted to continue group therapy with methylone beyond the sessions listed, improvement on the CGI-I compared to baseline was assessed after the methylone treatment session.

[0108] In two cases, one as the first session and one as the second session, MDMA was administered as a single agent. One case of repeated methylone administration sessions, the first session, included co-administration of 3 grams of mushrooms 30 minutes after methylone administration.

[0109] A single session was performed in 8 of the 28 cases, and in 2 of these cases no booster was given. In the remaining cases, multiple sessions were performed, and booster doses were used in all or part of the remaining patients (26 case reports), with 15 patients using multiple booster doses in some or all of the sessions. The total methylone dose in each session had a minimum range of 100 mg to 690 mg and a maximum range of 180 mg to 1020 mg. The maximum total dose in each session exceeded 500 mg [methylone dose + booster dose] only in 4 sessions in 3 patients. Methylone doses ranged from 100 to 270 mg, and booster doses ranged from 50 mg to 880 mg, but the total cumulative dose exceeded 370 mg in only 2 sessions in 2 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.

[0110] safety Cohort 1 No adverse effects or sequelae were observed or reported for all four subjects in Cohort 1. All three men were found to be able to walk, make tea, and show no signs of intoxication.

[0111] Cohort 2 In the majority of cases included in cohort 2 (25 of 28 cases; 89.3%), methylone administration was well tolerated and no safety events were reported. One case report involved an adverse event of increased anxiety after 117 mg of MDMA administered in the first session, which did not contain methylone and did not recur when methylone was administered at a total dose of 130 mg (80 mg + 50 mg booster) prior to administration of methylone in a subsequent session. In three patients (all age 65 years or older), adverse events were reported after methylone administration as follows: [I] Case Report A A 75 year old male; primary diagnosis PTSD, history of atrial fibrillation and pacemaker; experienced dizziness resulting from medication during the fifth session with methylone 150 mg and 150 mg booster (highest dose administered). The event was not considered severe and did not require intervention. Total doses administered to date ranged from 100-250 mg. There were no negative remedications (i.e., repeated methylone administration) due to administration of unknown doses at home. [II] Case Report B A 70 year old male; primary diagnosis was PTSD and secondary diagnosis was depression; received 690mg of methylone (200mg followed by booster doses of 250mg and 240mg) during a single session and did not experience any adverse events during the session, but reported adverse events of insomnia and decreased appetite after the session, likely due to the mimetic effect of methylone. [III] Case Report C A man aged 78 years; with a primary diagnosis of PTSD and a secondary diagnosis of anxiety; with a history of "well-controlled cardiovascular problems" who had been administered methylone over five sessions at total doses ranging from 100-300 mg in each session (100-150 mg methylone, 0-150 mg booster) reported quasi-hallucinatory experiences, but doses and further details unknown. No intervention was required.

[0112] Effectiveness As cohort 1 consisted of healthy volunteers, efficacy is reported for cohort 2, which consisted of patients with PTSD and MDD.

[0113] Degree of improvement CGI-I and time to first improvement All patients achieved at least a minimal improvement (CGI-3 or better) after treatment with methylone. The maximum improvement observed for the 28 cases included in cohort 2 is shown in Table 3 and Figure 3. CGI-I 1 or 2 was achieved in 86% of patients [16 / 20 patients (80%) for the PTSD subset and 8 / 8 patients (100%) for the MDD subset]; this corresponds to "much improved" or "very improved" compared to the baseline CGI-S. Furthermore, initial improvement was noted at the first methylone session in almost 90% of patients (25 of 28 patients). Two further cases experienced initial improvement after the second and third sessions, respectively, and one case required 10+ sessions for initial improvement.

[0114] [Table 3]

[0115] Response Durability Within the PTSD subset of Cohort 2, 16 case narratives included information about persistence. One case reported no persistence and 15 case narratives reported persistence (>6 months in 12 cases; limited to 3 months in 1 case; unknown in 2 cases). In one case where the duration of persistence response was unknown, the narrative stated that "the subject can no longer be said to have the disease" after the fourth methylone administration session.

[0116] Within the MDD subset of Cohort 2, six of the eight case narratives included information about persistence: one case reported no persistent effect, and the remaining five reported persistent effects that were acknowledged as being "stable after 13 sessions" in one patient, "sustained" in another, and "sustained" in two patients.

[0117] Changes in CGI-S Post-treatment CGI-S was reported in only five cases as shown in Table 4, including one patient who was noted to have achieved a stable CGI-S of 1. One case was noted to occasionally achieve a CGI-S of 1. In five additional case discourses that did not include post-treatment CGI-S scores, the patients were reported to have no longer been diagnosed with the disease after treatment, and five of these cases achieved a CGI-I of 1.

[0118] [Table 4]

[0119] conclusion Overall, methylone was well tolerated when administered as a single dose and / or in single or multiple sessions with booster doses. No safety events were reported in healthy volunteers or adult patients under the age of 18 or 65 years. Transient safety events were reported in three elderly patients, which occurred at higher doses or did not recur on re-dosing. One of these events involved a quasi-hallucinatory experience, occurring approximately 5-6 times per 2,000 methylone doses.

[0120] The majority of patients in the PTSD (90%) and MDD (88%) subsets had a baseline CGI-S of 5 or higher (significant or severe illness), including two PTSD patients in the most severe category of CGI-S 7 (i.e., the "most severely ill" category). Nevertheless, cohort 2 had an improvement rating of 1 or 2 in 86% of patients overall [16 / 20 patients (80%) for the PTSD subset and 8 / 8 patients (100%) for the MDD subset]; these improvement ratings correspond to "much improved" or "very improved" compared to baseline CGI-S.

[0121] 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, often chronic, mental disorder characterized by a constellation of symptoms including: intrusive memories, frightening dreams, dissociative reactions, physiological reactivity and aversion to trauma-related stimuli, negative cognitions and mood, fatigue, increased arousal, sleep disturbances, cognitive impairment, irritability, risk-taking behavior, and clinically significant distress or impairment in functioning. It is estimated that 70% of the world's population has been exposed to trauma, and roughly 6% of people exposed to trauma develop PTSD, although resilience is the rule rather than the exception. Estimates of the prevalence of PTSD range as high as 20% after interpersonal violence, 25% in combat-exposed veterans, 50% in victims of sexual assault, and 86% in certain refugee groups. PTSD is a known risk factor for suicide, increasing the risk of suicide by 6 to 29 times over the general population.

[0122] Available pharmacotherapy options are limited. Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatments, with paroxetine and sertraline being the only FDA-approved agents for the treatment of PTSD. However, despite their established efficacy, these treatments are suboptimal. These are slow-acting antidepressants (SAADs) with a slow onset of action, and most patients do not see a noticeable effect until at least 4 weeks (and up to 8 weeks) of continued treatment. This latency is obviously troublesome, as it significantly increases the risk of suicide and self-harm, as well as other potentially destructive behaviors. Even when optimally delivered, 40% of patients do not respond to SSRIs, and only about 20%-30% go into remission, with the degree of difference from placebo ranging from 10%-20%. Rates of non-response or partial response to these therapeutic agents among individuals with chronic and complex PTSD, such as military veterans, are comparable to or worse than those in civilian patient populations. Furthermore, many patients classified as "treatment responders" remain symptomatic and continue to live limited lives.

[0123] Trauma-focused psychotherapy has also shown some efficacy in treating PTSD, and is often the best intervention of choice given known limitations in pharmacotherapy. Prolonged exposure (PE) and cognitive processing therapy (CPT) are gold-standard treatments, but access to appropriately trained therapists is limited, and effective treatments require a willingness on the part of the patient to expose themselves to trauma-related memories and to experience the associated distress. Attrition rates in gold-standard psychotherapy outcome studies range from 17% to 55.8%, and nonresponse can be as high as 50%. Regardless of treatment modality, troubling symptoms often persist even in patients classified as treatment responders. Efficacy gaps are also particularly pronounced among veterans treated at Veterans Affairs (VA) medical centers, likely due, at least in part, to the complexity of these patients, who often have significant psychiatric and medical comorbidities as well as repeated and chronic trauma exposures. Thus, there is an urgent need to identify novel, fast-acting strategies to treat PTSD, to explain the mechanisms underlying treatment efficacy, and to establish baseline markers that can clinically predict treatment response.

[0124] Recently, multiple placebo-controlled clinical trials have demonstrated acute and durable beneficial clinical effects in PTSD, as assessed by the Clinical Diagnostic Interview for PTSD Scale (CAPS-5) for DSM-5, after two to three doses of methylenedioxymethamphetamine (MDMA) in conjunction with manualized psychotherapy. These stable and sustained clinical effects were recently replicated in a large Phase 3 clinical trial. A second Phase 3 clinical trial is currently underway, and favorable clinical results could advance MDMA-assisted psychotherapy to FDA approval.

[0125] 3,4-Methylenedioxy N-methylcathinone (methylone; also known as MDMC, βk-MDMA, and M1) is a rapid-acting empathogen (RAE) structurally related to MDMA. A recent observational naturalistic study compared the acute pharmacological and physiological effects of both orally administered compounds in healthy participants with a history of previous exposure to both methylone and MDMA. While the compounds are likely mechanistically similar, methylone produced less prototypic psychostimulant and empathy-inducing effects, including reduced euphoria, intoxication, stimulant-like effects, and altered cognition and body perception, and was associated with increased sociability compared to MDMA. The striking differences in acute pharmacological effects may be explained in part by their differences in serotonin (5-HT) receptor affinity. Methylone has a greater affinity for 5-HT than MDMA. 2A has a significantly lower affinity for 5-HT 1A Methylone also has partial agonist activity at the 5-HT receptor, which MDMA does not have. 2C Methylone has weaker antagonistic effects on dopamine, whereas MDMA has partial agonist activity. Methylone also inhibits or reverses monoamine reuptake transporters for dopamine, norepinephrine, and serotonin, which increases the extracellular concentrations of these neurotransmitters.

[0126] This example presents a more detailed analysis of 21 patients from the previous example (20 patients from the PTSD subset discussed in the previous example + 1 patient from that example who was mischaracterized and subsequently determined to have a primary diagnosis of PTSD) with a primary diagnosis of PTSD and various psychiatric comorbidities who were clinically treated with methylone in an outpatient setting. The patients did not receive structured psychotherapy in conjunction with methylone treatment, which differs from recent studies of MDMA that highlight the importance of a manualized hallucinogen-assisted psychotherapy model. These properties, along with methylone's short duration of action and less dramatic acute pharmacological and physiological effects, make methylone an attractive agent for clinical use in the treatment of PTSD.

[0127] Materials and Methods Clinical record data were obtained from 21 patients with a primary diagnosis of PTSD who received one or more doses of oral methylone as part of specialized medical care in an outpatient psychiatric setting. Protected health information was not disclosed and consent was not obtained from patients for the use of their record data. Case narratives were systematically compiled from data collected as part of routine clinical work. Diagnosis was confirmed by an experienced clinician using a semi-structured interview. Baseline symptom severity was assessed using the Clinical Global Impression-Severity (CGI-S). Symptom improvement was assessed after administration using the Clinical Global Improvement (CGI-I). Patients were evaluated for observed or reported safety events after their methylone administration session. Because these case narratives were examined retrospectively from routine clinical care records and not collected prospectively in a research trial, more specific validated rating scales for assessing PTSD symptoms were not available. Furthermore, follow-up was variable, with duration of follow-up ranging from 1 week (case 2) to 15 years (case 16).

[0128] [Table 5] JPEG2024530007000007.jpg194158JPEG2024530007000008.jpg197158JPEG2024530007000009.jpg140158

[0129] result Methylone produced acute and durable improvements in both PTSD and depression symptoms without significant lasting adverse effects. Clinical data are shown in Table 5. Twelve patients (57%) were female and 19 (90%) were Caucasian. Mean age was 47.6 years (range: 25-78 years). Baseline CGI-S scores ranged from 4 to 7 (i.e., moderate-severe; see Figure 4) for all 21 patients. Six patients (28.6%) were using concomitant SSRIs or other psychotropic therapies at the time of methylone administration. This is noteworthy because recent clinical trials of MDMA in PTSD have required that patients not use other psychotropic therapeutic agents, as SSRI antidepressants have been shown to attenuate the therapeutic effects of MDMA through substrate competition. All patients were experiencing debilitating symptoms despite past and / or ongoing psychological and pharmacological treatments. Previous treatments included SSRIs / SNRIs (n=14; 66.7%), supportive unstructured therapy (n=8; 38%), structured cognitive and behavioral therapy (n=4; 19%), and unspecified antidepressant therapy (n=3; 14.3%).

[0130] All 21 patients achieved at least a minimal improvement (CGI-I 1, 2, or 3) after methylone treatment, with 17 achieving a CGI-I of 1 (very improved; 9 patients) or 2 (much improved; 8 patients; see Figure 4). This trend was also observed in patients who received only a single dose of methylone (n=9), with 8 patients (89%) achieving a CGI-I score of 1 or 2. In patients who received multiple methylone sessions (n=12), initial improvement was noted after the first session in 83% of patients (n=10), with one other patient experiencing improvement after the second session.

[0131] Information on persistence of clinical effect was available for 17 of 21 patients. One individual reported no persistent effect (i.e., symptom severity returned to baseline almost immediately), and 16 reported persistent effect (greater than 6 months in 11 patients), with one patient each reporting persistent effect of 3 months, 2 months, and 1 week, respectively. In one of the four case narratives that did not include persistence information, the patient was "no longer diagnosed with the disorder (i.e., PTSD)" after the fourth methylone administration session (10 months after baseline assessment), as determined by the treatment team.

[0132] Administration Overview Methylone was administered orally. Other therapeutic agents were not changed during methylone treatment. In many cases, an additional booster dose of methylone was administered 1 hour after the first dose to expand the therapeutic window and optimize the clinical response. In several cases, treatment was continued and in some cases the dose was further escalated in subsequent sessions (see Table 5). Booster doses were included in 19 patients in one or more of the multiple sessions. Starting doses ranged from 100 to 270 mg, and these starting doses as well as the booster doses were selected based on clinical judgment.

[0133] safety Methylone was generally well tolerated, and no patients discontinued treatment due to adverse events. A total of four adverse events were noted in 3 of 21 patients (2 events in 1 patient), none of which were considered severe or required medical intervention. A 75-year-old male with stable atrial fibrillation (pacemaker in place) and a history of Parkinson's disease became dizzy toward the end of the 5th session with methylone at a total dose of 300 mg (150 mg, followed by a 150 mg booster dose; this was the highest dose given to this patient). The symptoms resolved rapidly, and the patient felt well upon discharge, with no other adverse effects. A 70-year-old male who received 690 mg of methylone (200 mg, followed by 250 mg and 240 mg booster doses) during a single-dose session did not experience any adverse events during the session, but reported insomnia and decreased appetite the night after the session. These symptoms resolved by the next day. A 78-year-old man reported a flashback-like experience during one treatment session. This patient participated in five treatment sessions with total methylone doses ranging from 100 to 300 mg per session.

[0134] Patient reports A 62-year-old male patient with treatment-resistant PTSD (ID = Case 2 in Table 5) who received methylone in combination with ongoing SSRI treatment noted after the first administration session that "[his] problems are seemingly disappearing, maybe more in his head than in reality.... [and] the methylone treatment seems like a new 'window of hope' that makes the suicidal thoughts seem silly and unnecessary." After a rapid and sustained reduction in PTSD symptoms after a single methylone session, he expressed interest in tapering off the SSRI since it was no longer necessary. Another patient, a 52-year-old female patient with treatment-resistant PTSD and comorbid generalized anxiety disorder (ID = Case 7 in Table 5), described one session as "healing the inner girl." She described the realization that "PTSD would no longer dominate [her] life; [she] was there for that inner child and she was empathizing with [her]; and [they were cured of [their PTSD]."

[0135] Consideration In this case series of patients with a primary diagnosis of PTSD and a high rate of comorbidities and previous treatment attempts, methylone produced rapid symptomatic improvement as assessed by the CGI-I. The majority (90%) had a baseline CGI-S of 5 or higher ("marked" or "severely ill"), including three patients in the category of a CGI-S of 7 (i.e., falling into the category of "most severely ill" patients). The majority of patients (81%) achieved CGI-I scores corresponding to "much improved" or "very improved" (Figure 4). These effects are similar to those observed in a recent controlled clinical trial of MDMA in combination with manualized PTSD psychotherapy, where rapid and stable improvements were observed in severe, complex, and treatment-resistant patients.

[0136] Methylone was well tolerated over a wide dose range (100-1,020 mg) with 1-10 administrations. Several adverse events were reported in three elderly patients aged 70 years or older; these were minor and did not require intervention. No patient discontinued methylone treatment due to adverse events. Of note, none of these adverse events occurred in patients receiving concomitant SSRI therapy.

[0137] Advantages and limitations This is the first report of methylone administration in patients with PTSD. This case series provides evidence that methylone has utility in the pharmacological treatment of PTSD. However, these data have certain limitations. The participants were treated clinically; data for this report were collected retrospectively from review of clinical records. Administration and follow-up varied, and there was no randomization, control, or blinding to treatment condition. Furthermore, the sample lacked diversity, and ongoing psychotherapy and pharmacological treatment adjustments at various follow-up periods may have influenced the clinical course. A strength of this report is the complexity of the sample, which aids generalizability. Despite these limitations, these case narratives in a complex patient population constitute the first clinical evidence of the efficacy of methylone for the treatment of PTSD.

[0138] Methylone has not received the same cultural and clinical attention as MDMA, likely due to its milder and shorter psychopharmacological effects (e.g., euphoria, empathic state-inducing effects), but these "milder" effects may be particularly useful for some patients who are not amenable to treatment with MDMA's more intense and acute psychological and physiological effects.

[0139] Example 6: Methylone in the FST: Effects on depression, anxiety, and PTSD In this example, we investigated whether methylone produces rapid antidepressant-like effects in the rat FST, and used the prototypic selective serotonin reuptake inhibitor (SSRI) fluoxetine as an antidepressant control.

[0140] method animal Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used in this study, which was performed at Melior Discovery (Exton, PA). Rats were acclimated to their home cages for at least 1 week prior to testing and maintained in a controlled environment with no more than two rats per cage and a 12-h light / dark cycle. Animals received food and water ad libitum and were randomly assigned to treatment groups. Animal use and procedures followed established protocols approved by the IACUC committee, Melior Standard Operating Procedures (SOP), and Transcend Therapeutics.

[0141] Forced swim test (FST) For the FST test, rats were placed in a circular plexiglass container filled with water without an escape mechanism. Water temperature was maintained at 22-25°C and changed for each animal. After the habituation period, rats were measured for immobility (stop struggling), activity, swimming time, and climbing time. Day 1 consisted of a 15-min habituation trial, and day 2 (after 24 h) consisted of a 5-min test. Using a time sampling method, animals were observed every 5 s and scored for immobility, swimming, or climbing. Fluoxetine (10 mg / kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle (vehicle 3X group) was administered 23.5 h, 5 h, and 1 h before the FST test. Methylone (5, 15, or 30 mg / kg, IP; Cayman Chemical) or 0.9% saline vehicle (Vehicle 1X group) was administered 30 minutes prior to FST testing. Experimenters were blinded to treatment.

[0142] Binding Tests Radioligand binding was measured for the serotonin (5HT), dopamine (DA), and norepinephrine (NE) transporters, respectively, using [ 3 H]citalopram, 3 H]WIN35428, and [ 3 H]nisoxetine was used in experiments using standard protocols. Radiolabeled 5HT, NE, and DA uptake and release studies in rat brain synaptosomes were performed using standard protocols.

[0143] statistical analysis Data for each parameter of the test (immobility, swimming, or climbing) are expressed as mean ± SEM. Differences between groups were determined by one-way ANOVA and Tukey's post-hoc test, with p-values ​​of <0.05 indicating statistical significance.

[0144] Results and Conclusions A single dose of methylone produced a stable, dose-dependent, and fast-acting antidepressant-like response in the rat FST (Figure 5). Notably, 2–3 injections of SSRI antidepressants are typically required to elicit a behavioral response in the FST, as shown by the fluoxetine control group in this study that received three doses of fluoxetine prior to testing (Figure 5). However, rats treated with a single dose of methylone 30 min prior to testing in the FST showed highly significant reductions in immobility (Figure 5A). Notably, a single dose of methylone (5, 15, or 30 mg / kg, IP) administered 30 min prior to testing reduced immobility by 54%, 99%, or 96%, respectively, compared to rats receiving saline vehicle (p<0.0001). Medium and high doses of methylone significantly increased swimming (Figure 5B). Climbing was increased only at the lowest dose of methylone, reflecting the recruitment of noradrenergic receptor activity at this dose level (FIG. 5C).

[0145] The magnitude of effect of medium and high doses of methylone (99% and 96% reduction) was notably greater than that of fluoxetine (56%, Figure 5A). These data also demonstrate that methylone is superior to other hallucinogenic drugs. Previous studies of ketamine administration show a 30% (Hibicke et al., (2020) ACS Chem. Neurosci 11:864-871), 25-55% (Yang et al., (2013) Ups J Med Sci 118:3-8), or 60% (Tizabi et al., (2012) Neuroscience 213:72-80) reduction in immobility (reviewed by Weston et al., (2021) Frontiers in Psychiatry 12:659-52). LSD and psilocybin have been shown to reduce immobility in the FST by 38% and 67%, respectively (Hibicke et al., 2020). MDMA (5 or 10 mg / kg) has been reported to reduce immobility by 45% and 78%, respectively, in Sprague Dawley rats (Majumder et al., (2011) Behav Pharmacol 22:758-65), but had a more stable effect in Flinders susceptible strain rats, a genetic model of depression (45% and 93%, respectively, ibid.). Binding studies confirmed methylone binding at 5HT, NE, and DA transporters.

[0146] In summary, methylone produced a more robust antidepressant-like response in the FST, a standard behavioral assay with well-established specificity and selectivity for antidepressants, than the SSRI fluoxetine. The magnitude of methylone's effect in this test also exceeded that of other hallucinogens and antidepressants tested in wild-type rats in the literature (Figure 6). Despite its structural similarity to MDMA, methylone exhibits distinct effects on monoamine transporter binding, uptake, and release.

[0147] Taken together, these results demonstrate the utility of methylone in treating depression and other central nervous system disorders for which antidepressants are effective, including, but not limited to, post-traumatic stress disorder (PTSD), mood disorders, anxiety disorders, obsessive-compulsive disorder (OCD), and fibromyalgia.

[0148] Example 7: 2C-B in the FST: Effects on depression, anxiety, and PTSD In this example, we investigated whether 2C-B produces rapid antidepressant-like effects in the rat forced swimming test (FST), and used the prototypic selective serotonin reuptake inhibitor (SSRI) fluoxetine as an antidepressant control.

[0149] method animal Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used in this study, which was performed at Melior Discovery (Exton, PA). Rats were acclimated to their home cages for at least 1 week prior to testing and were maintained in a controlled environment with a 12-h light / dark cycle, with no more than two rats per cage. Animals received food and water ad libitum and were randomly assigned to treatment groups. Animal use and procedures followed established protocols approved by the IACUC committee, Melior Standard Operating Procedures (SOPs), and Transcend Therapeutics.

[0150] Forced swimming test For the FST test, rats were placed in a circular plexiglass container filled with water and without an escape mechanism. Water temperature was maintained at 22-25°C and changed for each animal. After the habituation period, rats were measured for immobility (stop struggling), activity, swimming time, and climbing time. Day 1 consisted of a 15-min habituation trial, and day 2 (after 24 h) consisted of a 5-min test. Using a time sampling method, animals were observed every 5 s and scored for immobility, swimming, or climbing. Fluoxetine (10 mg / kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle (vehicle 3X group) was administered 23.5 h, 5 h, and 1 h before the FST test. 2C-B (2.5, 10, or 20 mg / kg, IP, Cayman Chemical) or 0.9% saline vehicle (Vehicle 1X group) was administered 30 minutes prior to FST testing. Experimenters were blinded to treatment.

[0151] statistical analysis Data for each parameter of the test (immobility, swimming, or climbing) are expressed as mean ± SEM. Differences between groups were determined by one-way ANOVA and Tukey's post-hoc test, with p-values ​​of <0.05 indicating statistical significance.

[0152] Results and Conclusions A single injection of medium or high doses of 2C-B produced an immediate antidepressant-like response in the rat FST, while the lowest dose had no effect (Figure 7). Typically, 2-3 injections of SSRI antidepressants are required to elicit a behavioral response in the FST, as shown by the fluoxetine control group in this study, which received three doses of fluoxetine prior to testing (Figure 7). Particularly notable is that rats receiving a single dose of 2C-B 30 min prior to testing in the FST showed a statistically significant reduction in immobility (Figure 7A), accompanied by a significant increase in swimming (Figure 7B), consistent with serotonergic activity. The magnitude of the effect of both medium and high doses of 2C-B (50% and 53%, respectively) was nearly identical to the fluoxetine control group (56%). Climbing was significantly reduced only in the group receiving high dose 2C-B (Figure 7C), although the interpretation of this result is unclear.

[0153] In summary, 2C-B produced rapid antidepressant-like responses in the FST, a standard behavioral assay with well-established specificity and selectivity for antidepressants, that were comparable to the SSRI fluoxetine. These results demonstrate the utility of 2C-B in treating depression and other central nervous system disorders for which antidepressants are effective, including but not limited to post-traumatic stress disorder (PTSD), anxiety disorders, obsessive-compulsive disorder (OCD), and fibromyalgia.

[0154] Example 8: Selective serotonin reuptake inhibitor (SSRI) pretreatment does not inhibit the efficacy of methylone in the rat forced swimming test Example 6 shows that methylone produces rapid, stable, dose-dependent antidepressant-like effects in the forced swim test (FST) that are greater in magnitude than any other antidepressant tested in this model. Selective serotonin reuptake inhibitors (SSRIs) are first-line treatments 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. MDMA-assisted psychotherapy is in clinical trials for the treatment of PTSD, and it should be noted that SSRIs inhibit the efficacy of MDMA-assisted therapy (Feduccia et al., (2021) Psychopharmacology 238:581-588). If a patient requires MDMA-assisted therapy, SSRI treatment must be stopped. Because SSRIs require a period of tapering discontinuation lasting many weeks, it may take a long period of withdrawal from the drug before the patient can begin MDMA treatment. This poses both treatment delivery and safety risks for individuals suffering from severe PTSD. Because SSRIs interfere with the clinical effectiveness of MDMA-assisted psychotherapy, this example examined whether pretreatment with the prototypic SSRI fluoxetine influenced behavioral responses to methylone in the FST.

[0155] method animal Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used in this study, which was performed at Melior Discovery (Exton, PA). Rats were acclimated to their home cages for at least 1 week prior to testing and maintained in a controlled environment with a 12-h light / dark cycle, with no more than two rats per cage. Animals received food and water ad libitum and were randomly assigned to treatment groups. Animal use and procedures followed established protocols approved by the IACUC committee, Melior Standard Operating Procedures (SOPs), and Transcend Therapeutics.

[0156] Drug treatment Fluoxetine (10 mg / kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle was administered 23.5, 5, and 1 h prior to FST testing. Methylone (5 or 15 mg / kg, IP; Cayman Chemical) or 0.9% saline vehicle was administered 30 min prior to FST testing (Figure 8A). Control animals received fluoxetine alone, methylone alone, or saline vehicle. We focused on the lower dose of methylone (5 mg / kg) because it produced submaximal responses in the FST, thus allowing potential detection of changes in immobility that may occur in either direction.

[0157] Forced swimming test For the FST test, rats were placed in a circular plexiglass container filled with water and without an escape mechanism. Water temperature was maintained at 22-25°C and changed for each animal. After an acclimation period, rats were measured for immobility (stop struggling), activity, swimming time, and climbing time. Experimenters and scorers were blinded to treatment groups. Day 1 consisted of a 15-min acclimation trial, and day 2 (24 h later) consisted of a 5-min test. Using a time sampling method, animals were observed every 5 seconds and scored for immobility, swimming, or climbing.

[0158] statistical analysis Data for each parameter of the test (immobility, swimming, or climbing) are expressed as mean ± SEM. Differences between groups were determined by one-way ANOVA and Tukey's post-hoc test, with p-values ​​of <0.05 indicating statistical significance.

[0159] Results and Conclusions Three pre-administrations of fluoxetine reduced immobility in response to a single dose of methylone (62% reduced immobility vs. vehicle; Fig. 8B; F (4,31)=17.05, p<0.0001). Consistent with the results of Example 6, both fluoxetine and methylone (5 mg / kg) reduced immobility by 60% (p<0.001) and 71% (p<0.0001), respectively, compared to vehicle. Notably, combined treatment with a higher dose of methylone (15 mg / kg) reduced immobility by 95% (p<0.0001) compared to vehicle, which was consistent with Example 6.

[0160] Methylone significantly enhanced climbing behavior (Figure 8C;F (4,31) = 5.786, p < 0.01), and fluoxetine significantly enhanced swimming behavior (Figure 8D; F (4,31) = 6.063, p < 0.01), consistent with noradrenergic and serotonergic activity, respectively.

[0161] In summary, we examine pretreatment with an SSRI (fluoxetine) that does not affect behavioral responses to methylone in the rat FST. These findings differentiate methylone from MDMA and suggest that, unlike MDMA, SSRIs do not interfere with the behavioral efficacy of methylone. Because SSRIs are first-line treatments for many central nervous system disorders, including PTSD, these findings are particularly promising because they suggest that patients could continue to take an SSRI while also taking methylone, presumably without concern for reduced efficacy.

[0162] Example 9: Effects of methylone, 2-CB and MBDB in a mouse model of post-traumatic stress disorder (PTSD) Dysfunction in fear extinction memory is a hallmark of PTSD in patients (Wicking et al. (2016) Neurobiology of Learning and Memory 136:116). SSRI antidepressants, similar to two approved for PTSD treatment (i.e., paroxetine and sertraline), prevent fear memory generalization and promote extinction (Pedraza et al. (2019) Transl Psychiatry 9:53). Enhanced fear extinction may also underlie the beneficial effects of MDMA as a PTSD treatment (Feduccia & Mithoefer (2018) Progress in Neuro-Psychopharmacology & Biological Psychiatry 84(Part A), 221-228).

[0163] An effective PTSD treatment would promote dissociation between the traumatic memory and the patient's fear response, such that traumatic memory cues evoke less fear responses. This is modeled in a mouse fear extinction paradigm conducted over three days (see Figure 9A). On the first day (fear conditioning), mice are trained to acquire the "traumatic memory"; that is, to associate a conditioned stimulus (CS, tone) with an unconditioned stimulus (US, footshock). On the second day (extinction training), mice are trained to forget the traumatic memory association by six presentations of the CS (without the US) in a novel environment. On the third day (extinction recall), mice are "asked" whether the tone (CS) still evokes a fear response, as measured by the time they spend freezing when the tone is presented. Less freezing time means better extinction recall. Agents that improve extinction recall would reduce freezing time on the third day, thus showing potential as PTSD treatments.

[0164] Studies with MDMA show that after fear conditioning, administration of MDMA (7.5 mg / kg) 30 minutes prior to extinction training enhances extinction recall, measured as a 35% reduced freezing compared to saline-injected controls (Young et al. (2015) Transl Psychiatry 5:e634).

[0165] Using the experimental design shown in Figure 9A, the results show that methylone (30 mg / kg) significantly enhanced fear extinction recall by nearly 60% compared to saline controls (Figure 9B). It should be noted that there were no between-group differences in locomotor activity recorded during the test session, as effects on locomotor activity could confound the interpretation of these results (Figure 9C).

[0166] MBDB was also tested in the fear extinction model of PTSD, using an experimental design similar to that outlined in Figure 9 A. Mice injected with a single dose of MBDB (5 mg / kg, IP) showed improved extinction acquisition on the first trial of extinction training on day 2 (Figure 10 A), and a concomitant small but significant increase in locomotor activity on day 2 (Figure 10 B).

[0167] Example 10: Pretreatment with selective serotonin reuptake inhibitors (SSRIs) does not interfere with the efficacy of methylone in the rat forced swim test The open field test (OFT) exploits rodents' innate fear of open spaces to assess anxiety-like behavior: more time spent in the center of the open field reflects an anxiety-reducing (anxiolytic) effect.

[0168] A single methylone dose (5 or 15 mg / kg, IP) administered 30 min prior to testing significantly increased the time spent in the center of the open field compared to vehicle-treated controls (Figure 11A). Locomotor activity was also measured in the OFT. There was no effect of the 5 mg / kg methylone dose compared to vehicle controls, but there was a significant increase in locomotor activity with 15 or 30 mg / kg methylone doses (Figure 11B).

[0169] Those skilled in the art will appreciate that changes may be made to the above-described embodiments without departing from the broad inventive concept of the present invention. It will be understood therefore that the invention is not limited to the particular embodiments disclosed, but is intended to cover modifications which are within the spirit and scope of the invention as defined in the appended claims.

Claims

1. A composition comprising a therapeutically effective amount of methylone (3,4-methylenedioxy-N-methylcathinone) for use in a method for treating and / or preventing and / or ameliorating the symptoms of a neuropsychiatric disorder in a subject in need thereof.

2. The composition described in claim 1, wherein the neuropsychiatric disorder is post-traumatic stress disorder (PTSD), and optionally the PTSD is treatment-resistant.

3. 3. The composition of claim 1 or 2, wherein methylone is administered at a dose of 50 to 1,000 mg or 0.8 to 30 mg / kg.

4. The composition described in claim 1 or 2, wherein the subject has suicidal tendencies.

5. The methylone is used in combination with an additional therapy for a neuropsychiatric disorder, the additional therapy is a psychotherapy, or 3. The composition of claim 1 or 2, wherein the additional therapy comprises administering to the subject one or more additional psychoactive substances.

6. The composition of claim 5, wherein the additional psychoactive substance is selected from selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin-norepinephrine-dopamine reuptake inhibitors (SDNRIs), and anti-anxiety drugs.

7. The additional psychoactive substance is a selective serotonin reuptake inhibitor (SSRI), and 7. The composition of claim 6, wherein the subject is taking or continues to take an SSRI concurrently with methylone.

8. The composition described in claim 1 or 2, wherein the methylone is administered weekly.

9. 3. The composition of claim 1 or 2, wherein the administering step comprises administering an initial dose of methylone, which is then boosted 30 minutes to 4 hours later by administering a second dose of methylone in an amount that is about 10% to 100% of the initial dose.

10. The composition of claim 1, wherein the neuropsychiatric disorder is acute stress disorder, depressive disorder, personality disorder (PD), anxiety disorder, mood disorder, fibromyalgia, or eating disorder.

11. The depressive disorder is selected from major dysthymia, major depressive disorder, single and recurrent episodes, persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other conditions, other specified depressive disorder, depressive disorder not otherwise specified, and combinations thereof; or The composition of claim 10, wherein the depressive disorder is treatment-resistant.

12. The personality disorder is selected from the group consisting of borderline personality disorder (BPD), avoidant personality disorder (AvPD), antisocial personality disorder (AsPD), schizophrenic personality disorder, other anxiety and panic disorders, specific personality disorders, impulsive disorders, gender identity disorder, sexual preference disorders, other sexual disorders, other disorders of personality and behavior in adults, unspecified disorders of personality and behavior in adults, personality and behavior disorders due to known physiological conditions, or the subject has a depressive disorder, or The composition of claim 10 , wherein the PD is treatment-resistant.

13. The anxiety disorder is generalized anxiety disorder, panic disorder, panic attack, phobic anxiety disorder, illness anxiety disorder, dissociative, stress-related, somatoform, other non-psychotic mental disorders, acute stress reaction, transient adaptation reaction disorder, neurasthenia, psychophysiological disorders, obsessive-compulsive disorder, disorders of response and adaptation to severe stress, 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 other conditions, 11. The composition of claim 10, wherein the phobia is selected from pregnancy and childbirth anxiety, prenatal anxiety during pregnancy (prenatal), postpartum anxiety, animal-type phobias, spider-phobia, other animal-type phobias, natural environment-type phobias, thunderstorm-phobia, blood-phobia, fear of injections and blood transfusions, other medical phobias, injury-phobia, event-phobia, claustrophobia, height-phobia, other unspecified anxiety disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), skin picking disorder (dermatillomania), and combinations thereof.

Images