Psychoactive pharmaceutical agents and their use for the treatment of psychiatric and neurological conditions and disorders

Abstract

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

[0002] Classical hallucinogens are a class of serotonergic, noradrenergic, and dopaminergic complex modulatory compounds, generally with ethnobotanical provenance. These heterogeneous drugs are psychoactive and can alter cognition, mood, and many other cognitive and physiological processes. Anthropological studies suggest that these drugs were used ritually in societies spanning the ancient Near East, Mediterranean region, and Mesoamerica. After Albert Hoffman's discovery and synthesis of the tryptamine analog lysergic acid-N,N-diethylamide (LSD) in 1943, a period of promising clinical development and therapeutic search followed for several decades. However, the entire class of compounds was subject to restrictions by the mainstream scientific community, for example in the United States under the 1970 Controlled Substances Act, which deemed them "medically useless."

[0003] The incidence of neuropsychiatric disorders such as treatment-resistant depression, fibromyalgia, and post-traumatic stress disorder (PTSD) is increasing, yet there have been no novel treatments that have meaningfully impacted the lives of patients. The dissociative anesthetic ketamine, or its optical isomer esketamine, was first approved in 2019 for major depressive disorder (MDD) and / or suicidality as Spravato. As of May 2021, there are now three FDA breakthrough treatments for hallucinogenic drugs: 3,4-methylenedioxymethamphetamine (MDMA) for PTSD, and psilocybin for both treatment-resistant depression (TRD) and MDD. Coupled with the need for novel psychoactive medicines that do not entail provider-intensive safety and monitoring issues, and that are not contraindicated for patients receiving existing treatments such as selective serotonin reuptake inhibitors (SSRIs) and other drug classes, there is a growing realization that current pharmacological interventions have limited efficacy.

[0004] Phase 3 trials testing MDMA (3,4-methylenedioxy-N-methylamphetamine) in patients with severe PTSD have yielded a convincing efficacy and safety profile. There is recent evidence of the efficacy of psilocybin for major depressive disorder (MDD). Psilocybin is a psychoactive alkaloid produced by over 200 mushroom species, and there is some evidence of fast-acting antidepressant properties. Recent clinical trials with psilocybin have shown that MDD patients have different treatment needs, from single doses to monthly doses, with comparable efficacy and safety. Psilocybin and MDMA offer hope to patients with no other treatment options, but it is estimated that only 5-10% of patients in need will benefit.

[0005] Finding ways to reopen the critical period has been a priority for translational neuroscience. Many neuropsychiatric pathologies are thought to be developmentally related to the end of a "critical period," an early period of survival, when the nervous system would be more susceptible to healthy (or harmful) environmental stimuli necessary for proper circuit organization and learning. Even if optimal conditions are restored, the end of the critical period limits the brain's ability to adapt. Agonists of the 5-hydroxytryptamine (5-HT) serotonin receptor family (including MDMA, DMT, and mescaline) increase the levels of oxytocin; oxytocin is involved in social functions and, according to animal models, suggests that it may initiate a critical period of cortical function; such increased oxytocin levels allow the learning of new behavioral responses. These oxytocin receptors in the nucleus accumbens (NAc) activate 5-HT receptors in medium spiny neurons of the dorsal raphe nucleus. 1B It activates the GABA receptor, but its inhibition 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 peony 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 remain in the traditional neurochemical family, sharing pharmacological commonalities with their classical precursors. A long-standing hypothesis is that these drugs, particularly the phenylalkylamines, activate two of the more than 50 neurotransmitter receptor subclasses: the 5-HT 2A and 5-HT 2C The point is that it is the most selective.

[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 of drugs not currently classified as Schedule 1 in the United States, combining two structural features that weaken its binding to monoamine receptors: N-methylation and alpha-ethylation. MBDB quickly became a recreational drug, along with MDMA and other synthetic cathinones, as a component of "ecstasy" pills. In two retrospective reports of MBDB-related polydrug overdose deaths 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 MDMA overdose deaths, 13 of 77 deaths directly attributable to MDMA toxic effects alone had blood concentrations measured in the range of 0.478–53.9 mg / L, which is comparable to the estimated MBDB toxic levels. In addition, in an animal model, (±)-MBDB·HCl (25 mg / kg) was injected intraperitoneally every 12 hours for 4 days; (±)-MDMA·HCl (20 mg / kg) was also examined for comparison. The multiple-dose regimen used in this study clearly destroyed 55–60% of serotonergic terminals in the cortex and hippocampus based on the loss of 5-HT / 5-HIAA uptake sites, but catecholamines or their metabolites were not significantly altered 2 weeks after treatment. These results indicate that a decline in indicators of serotonergic function occurs after multiple doses of MBDB. The neurotoxic effects were somewhat less than those seen with behaviorally equipotent doses 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), used for chewing in East Africa and the Arabian peninsula. Synthetic structural modifications of cathinones have produced a number of "synthetic" derivatives commonly sold illegally as "bath salts". These cathinone derivatives (chemically classified as β-ketoamphetamines) include methylone, ethylone, butylone, mephedrone, and 3,4-methylenedioxypyrovalerone (MDPV); they act synergistically on the human dopamine transporter. Both cathinones, as well as other phenethylamine-related species, behave as central nervous system (CNS) stimulants, although cathinones are typically less potent than the corresponding phenethylamine analogues because their β-keto group makes them more polar molecules that have difficulty crossing the blood-brain barrier.

[0009] Methylone has an affinity for the vesicular monoamine transporter 2 (VMAT2) approximately 13-fold lower than MDMA. However, there is some mixed evidence; plasma membrane and vesicular monoamine transporter assays in mouse locomotor activity models revealed that methylone is a more potent inhibitor of 5-HT and dopamine uptake than MDMA. Peak brain and serum concentrations of methylone were reached 15–30 min after intraperitoneal administration in rats, with 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 due in part to interactions between MDMA and the serotonin transporter. This is another important consideration when considering its use as a fast-acting antidepressant or augmentation therapy. Previous research trials have found associations between MDMA use and symptoms of depression or anxiety. The difficulty of assessing causation or association between MDMA and depression increases when people who choose to use MDMA already have a psychiatric disorder. A meta-analysis detected an association between MDMA use and self-reported depressive symptoms. The range of pharmacogenetic variation in MDMA metabolism also increases depression risk in a significant number of patients.

[0011] In animal studies investigating the psychological effects of MDMA, a dose of 10 mg / kg was tested in rats for 10 days; measures of anxiety-like behaviors such as open field ambulation showed an enhanced anxiety phenotype after 3 months. Rats administered a 5 mg / kg dose of MDMA four times every 4 hours for two consecutive days reduced responses (active and passive) in the forced swim test and increased immobility up to 12 weeks after MDMA exposure; this likely indicates long-term negative behavioral changes. Treatment with fluoxetine abolished MDMA-induced anxiety in the wake test and immobility duration in the forced swim test, but had no effect on the social interaction test. The study also analyzed postmortem levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and found a decrease in both levels in cortical regions of MDMA-treated rats. Fluoxetine treatment did not significantly affect 5-HT levels in MDMA-pretreated rats, but significantly reduced 5-HIAA levels in all brain regions examined, which may be interpreted as MDMA-induced chronic 5-HT depletion leading to anxiety or depression phenotypes.

[0012] Other mechanisms include acute MDMA-induced release of 5-HT from serotonergic terminals, concomitant with inhibition of 5-HT reuptake, resulting in significant depletion of both 5-HT and 5-HIAA. This has been reported in postmortem human brain tissue, as well as in vivo measurements in cerebrospinal fluid (CSF). Although there is some confusion in the research, this data has been largely ignored after the monoamine theory of depression; this evidence highlights the discrepancy between the acute and chronic pharmacology of MDMA. Acutely, MDMA acts to increase the availability of 5-HT, suggesting rapid antidepressant properties and positive changes to mood; this transient effect is thought to be accompanied by subsequent 5-HT depletion. There is human anecdotal evidence supporting depletion of 5-HT stores at therapeutic doses.

[0013] The reduction in 5-HT and its metabolites in brain tissue and CSF has also been interpreted as indicating that MDMA is neurotoxic in in vivo evaluations. Incidentally, low density of the serotonin transporter (SERT) is also associated with depression. Given the reduction in SERT density shown in the animal literature, the most simplistic interpretation is that repeated MDMA exposure in humans, even at moderate doses, damages the 5-HT neuronal terminals that innervate the cortex. Furthermore, the changes in mood, cognition, and impulse control associated with these changes may contribute to sustained MDMA use.

[0014] These and other inconsistencies in the neurotoxicity data for MDMA remain unresolved; therefore, MDMA is unlikely to be explored as a primary antidepressant, especially when 5-HT neurotransmitter circuits are implicated in both depression pathophysiology and MDMA neurotoxicity. In a recent Phase 2 MDMA trial for PTSD, there were depression / MDD cases with adverse events recorded at the 125mg and 150mg doses, some of which continued to be followed up long term. Anxiety and severe suicidal ideation were also recorded. Before proceeding to Phase 3, the hypothesis that MDMA has potential efficacy as a fast-acting antidepressant is being tested. However, MDMA, psilocybin and the other classical hallucinogens mentioned above have at least the following limitations to their availability to the hundreds of millions of people suffering from treatment-resistant neuropsychiatric disorders:

[0015] (1) Safety Strong serotonergic properties make MDMA a contraindication for patients taking SSRIs and many other psychopharmaceuticals due to the risk of serotonin syndrome, which prevents many, if not most, patients with neuropsychiatric disorders from accessing these medications. Furthermore, sustained use of MDMA can cause various types of arrhythmias and dilated cardiomyopathy, potentially leading to ventricular fibrillation and asystole, and is contraindicated in the presence of existing dysrhythmias or pulmonary disease.

[0016] (2) Concomitant use In patients with treatment-resistant disorders, SSRIs / serotonin-norepinephrine reuptake inhibitors (SNRIs) / tricyclic antidepressants (TCAs) etc. are often tried. It takes a minimum of 6 weeks to taper off SSRIs and other antidepressant treatments in patients. Therefore, developing psychoactive analogs that minimize adverse interactions and have additive therapeutic effects 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.

[0017] (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 amount each administration requires, the provider's time and number of safety escorts, and training and licensing requirements. In addition to preparatory and integrative psychotherapy sessions, MDMA and psilocybin administration sessions are long (up to 8 hours). Similarly, intravenous infusion ketamine requires a 3-4 hour clinic visit with physician administration and supervision along with intensive psychotherapy.

[0018] (4) Desirability from the patient's perspective 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.

[0019] As mentioned above, there is a need for CNS therapeutic agents, including antidepressants and PTSD treatments, that have the highest potential, good safety and efficacy, a more rapid efficacy profile, few drug / drug interactions, and / or are more effective in combination therapy. The prevalence of 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 adverse effects, Wellbutrin (bupropion), an atypical triple reuptake inhibitor (norepinephrine–dopamine reuptake inhibitor, nicotinic receptor antagonist), remains one of the most commonly prescribed antidepressants (24 million prescriptions in 2018). Bupropion is often used adjunctively to SSRIs and has also shown better results in treating anxiety associated with depression compared to sertraline and fluoxetine. Bupropion has been reported for off-label use in addition to other therapeutic agents to treat panic disorder. However, side effects of bupropion include a greater than 23% increased risk of congenital heart defects in children during early pregnancy, 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.

[0020] Thus, there is a need for new psychopharmacological agents that can overcome these and other limitations and / or be used in larger samples of patients with neuropsychiatric pathologies, including many difficult-to-treat mood, anxiety and personality disorders, such as depression and PTSD; but also fibromyalgia, suicidal ideation, substance use disorders (SUD), eating disorders, borderline personality disorder (BPD) and other personality disorders, obsessive-compulsive disorder (OCD), palliative care / end-of-life anxiety, existential distress, chronic pain syndromes, body dysmorphia, phobias, social anxiety in autistic adults, and sleep regulation. Summary of the Invention

[0021] In one aspect, provided herein is a method of treating and / or preventing and / or ameliorating a symptom of a neuropsychiatric disorder 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 0.08-4 mg / kg. 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 5-250 mg. In some embodiments, the methylone dose is less than 50 mg. In some embodiments, the methylone dose is in the range of 5-50 mg. In some embodiments, the methylone dose is less than 25 mg. In some embodiments, the methylone dose is in the range of 5-25 mg. In some embodiments, the methylone dose is in the range of 50-350 mg. In some embodiments, the methylone dose ranges from 50 to 500 mg. In some embodiments, the methylone dose ranges from 50 to 1,000 mg. In some embodiments, an initial dose (e.g., 50 to 500 mg) of methylone is administered, followed by a boost by administering a second methylone dose (e.g., an additional 25 to 250 mg of methylone) 30 minutes to 4 hours later. In some embodiments, methylone is administered, for example, in a single dose or according to the dosing schedule described above, once or more than once per week (up to daily administration), or two or three times per day. In some embodiments, methylone is administered as a sustained or extended release formulation, for example, using 50 mg to 1 g in patients on a set schedule according to the indication being treated in those patients, to achieve the dosing regimen disclosed herein. In some embodiments, the subject is suicidal. In some embodiments, the neuropsychiatric disorder is treatment-resistant. In some embodiments, the methylone is used in combination with an additional therapy for the neuropsychiatric disorder. In some embodiments, the additional therapy is a psychotherapy.In some embodiments, the additional therapy comprises administering one or more additional psychoactive substances to the subject. In some embodiments, the additional psychoactive substances are 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 drugs. 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, unspecified depressive disorder, 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, and personality and behavior disorders due to known physiological conditions. In some embodiments, the subject with PD also has a depressive disorder.

[0022] In another aspect, provided herein is a method of treating and / or preventing and / or ameliorating a symptom of a neuropsychiatric disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 2C-B (4-bromo-2,5-dimethoxyphenethylamine). In some embodiments, the 2C-B dose range is 0.08-4 mg / kg. In some embodiments, the 2C-B dose range is 0.8-5 mg / kg. In some embodiments, the 2C-B dose range is 0.8-30 mg / kg. In some embodiments, the 2C-B dose range is 5-250 mg. In some embodiments, the 2C-B dose is less than 50 mg. In some embodiments, the 2C-B dose range is 5-50 mg. In some embodiments, the 2C-B dose is less than 25 mg. In some embodiments, the 2C-B dose range is 5-25 mg. In some embodiments, the 2C-B dose range is 50-350 mg. In some embodiments, the 2C-B dose range is 50-500 mg. In some embodiments, the 2C-B dose range is 50-1,000 mg. In some embodiments, an initial dose (e.g., 50-500 mg) of 2C-B is administered, followed by boosting 30 minutes to 4 hours later with a second dose of 2C-B (e.g., an additional 25-250 mg of 2C-B). In some embodiments, 2C-B is administered, for example, in a single dose or according to the dosing schedule described above, once or more than once per week (up to daily dosing), or two or three times per day. In some embodiments, 2C-B is administered as a sustained or extended release formulation, for example, using 50 mg to 1 g in patients on one set schedule according to the indication being treated in those patients, to achieve the dosing regimen disclosed herein. In some embodiments, the neuropsychiatric disorder is a 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 disorder and related disorders, unspecified somatic symptom disorder 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, unspecified depressive disorder, 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 combined with an additional therapy for the neuropsychiatric disorder. In some embodiments, the additional therapy is psychotherapy. In some embodiments, the additional therapy comprises administering one or more additional psychoactive substances to the subject. In some embodiments, the additional psychoactive substances are selected from the group consisting of SSRIs, TCAs, MAOIs, SNRIs, SDNRIs, and anxiolytics.

[0023] In another aspect, there is provided a method for 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 0.08-4 mg / kg. 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 5-250 mg. In some embodiments, the MBDB dose is less than 50 mg. In some embodiments, the MBDB dose is in the range of 5-50 mg. In some embodiments, the MBDB dose is less than 25 mg. In some embodiments, the MBDB dose is in the range of 5-25 mg. 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 (e.g., 50-500 mg) of MBDB is administered, followed by boosting 30 minutes to 4 hours later with a second dose (e.g., an additional 25-250 mg of MBDB). In some embodiments, the MBDB is administered, for example, in a single dose or according to the dosing schedule described above, once 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, 50 mg to 1 g in patients on a set schedule according to the indication being treated in those patients, to achieve the dosing regimen disclosed herein. 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, unspecified depressive disorder, and combinations thereof. 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, 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, other disorders, and combinations thereof. The neuropsychiatric disorder is selected from the group consisting of anxiety disorder, anxiety disorder in pregnancy and childbirth, anxiety disorder during pregnancy (prenatal) before childbirth, postpartum anxiety, zoophobia, spider phobia, other zoophobia, natural environment phobia, thunderstorm phobia, blood phobia, injection and blood transfusion phobia, other medical phobia, injury phobia, event 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, in some embodiments, the additional psychoactive substances are selected from the group consisting of SSRIs, TCAs, MAOIs, SNRIs, SDNRIs, and anxiolytics.

[0024] Other features and advantages of the present invention will become apparent from the following detailed description, examples, and figures. However, since various modifications and changes will become apparent to those skilled in the art from this detailed description, it should be understood that the detailed description and specific examples are given solely for the purpose of illustrating preferred embodiments by way of example.

[0025] The following drawings are included as part of the present specification for the purpose of further demonstrating certain aspects of the disclosure; the invention may be more fully 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]

[0026] [Figure 1] 1 shows the baseline symptom list for symptoms present in 2 or more of 28 patients 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 subjects in cohort 2 for the MDD (FIG. 3A) and PTSD (FIG. 3B) subsets is shown. [Figure 4] The baseline disease severity (FIG. 4A) and improvement of the patients in Example 5 (FIG. 4B) are shown. [Diagram 5]Methylone has a stable antidepressant-like effect in the forced swimming test. Quantification of immobility time (F(5, 34) = 59.05, p < 0.0001) (Figure 5A), swimming time (F(5, 34) = 28.72, p < 0.0001) (Figure 5B), or climbing time (F(5, 34) = 3.195, p < 0.05) (Figure 5C) over the course of a 5-min forced swimming test in rats. Rats were allowed to swim for 15 min 24 h before testing. Fluoxetine was administered (10 mg / kg, IP) 1 h, 5 h, and 23.5 h before testing. Methylone was administered (5, 15, 30 mg / kg, IP) 30 min before testing. All data are expressed 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. Quantification of immobility time (F(5, 34) = 17.73, p < 0.0001) (Figure 7A), swimming time (F(5, 34) = 16.49, p < 0.0001) (Figure 7B), or climbing time (F(5, 34) = 4.984, p < 0.001) (Figure 7C) over the course of a 5-minute forced swimming test in rats. Rats were allowed to swim for 15 minutes 24 hours before testing. Fluoxetine was administered (10 mg / kg, IP) 1 hour, 5 hours, and 23.5 hours before testing. 2C-B was administered (2.5, 10, 20 mg / kg, IP) 30 minutes 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 experimental design. Quantification of immobility time (F(4,31)=17.05, p<0.0001) (Figure 8B), climbing time F(4,31)=5.786, p<0.01) (Figure 8C), or swimming time (F(4,31)=6.063, p<0.01) (Figure 8D) over the course of a 5-min forced swimming test in rats. Rats were allowed to swim for 15 min 24 h before the test. Fluoxetine was administered (10 mg / kg, IP) 1 h, 5 h, and 23.5 h before the test. Methylone was administered (5 or 15 mg / kg, IP) 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) pair on day 1 was followed by six CSs in a novel context (context B). On day 2, methylone or saline vehicle was injected 30 min before extinction training. On day 3, the time to freeze to the CS was measured. (Figure 9B) On day 3 (extinction recall), the freezing time during the first cue was significantly shortened in methylone compared to saline (t(26)=2.350, p<0.05). (Figure 9C) No change in locomotor activity was observed on day 3 (t(26)=1.073, p>0.05). Data are expressed 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 CSs in a novel context (context B). On day 2, MBDB or saline vehicle was injected 30 min before extinction training. On day 2, the time to freezing 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) On day 2, MBDB also induced a small but significant increase in locomotor activity (t(24)=2.874, p<0.01). Data are expressed 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. [Figure 12] A schematic diagram shows the experimental design (Figure 12A). Methylone or saline (vehicle) was administered at the indicated time points. Quantification of percentage of time immobile (Figure 12B), climbing (Figure 12C), or swimming (Figure 12D) during a 5 min test session is shown. Data are expressed as mean ± SEM. **p<0.01, ****p<0.0001 vs. vehicle control, ns=not significant (p=0.6) vs. vehicle control; Tukey's post-hoc test; N=6 for methylone group; N=8 for vehicle control group. [Figure 13]In the FST, MBDB or vehicle was administered 30 min prior to testing. Quantification of percentage of time immobile (FIG. 13A), climbing (FIG. 13B), or swimming (FIG. 13C) during a 5 min test session is shown. Data are expressed as mean±SEM. **p<0.01, ****p<0.0001 vs. vehicle control group; Tukey's post-hoc test; N=7 per group. [Figure 14] [3H]5HT uptake in rat brain synaptosomes in the presence or absence of methylone. [Figure 15] [3H]5HT binding to 5HT2B receptor-expressing membranes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present inventors demonstrate that methylone is a suitable drug for the treatment of CNS disorders. Methylone (3,4-methylenedioxy-N-methylcathinone; also known as "βk-MDMA") is a synthetic empathogenic cathinone, a structural analogue very similar to MDMA, but with a half-life that is more than 50% shorter. After being designated Schedule 1 controlled status by the US DEA in 2010, there are no FDA-registered clinical trials for 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 demonstrate that methylone is a nonselective substrate of cell membrane monoamine transporters and receptors.

[0028] Methylone acts as a mixed reuptake inhibitor / releaser, with a threefold 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 it is considered less effective as an antidepressant. Furthermore, the "down" effects of amphetamines, including MDMA or synthetic cathinones such as methylone, include intense depression and fatigue. Methylone caused widespread 5-HT depletion in rats, resulting in serotonin transporter 5-HTT levels that mimic the neurological state of depression. 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.

[0029] Taken together, the above animal and human data do not suggest a potential medical use of methylone for the treatment of CNS disorders, including depression and PTSD. It is unexpected that methylone (the least 5-HT agonist of its class of synthetic cathinones) would be useful for the indications we have identified in patients who are unresponsive, resistant, contraindicated, or controversial to current standard treatments. This includes administration of methylone alone or in combination with SSRIs, TCAs, MAOIs, SNRIs, SDNRIs, or anxiolytics (such as benzodiazepines, beta blockers, alpha blockers, and buspirone).

[0030] The present inventors reveal that methylone has the potential to become mainstream 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, and more often adjunct to individual and group psychotherapy. Methylone also causes few side effects after long 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.

[0031] The present inventors further demonstrate that 2C-B (2,5-dimethoxy-4-bromophenethylamine) is 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 disturbance, and mood disorders). Treatment of fibromyalgia with SNRIs (duloxetine and milnacipran), etc., often has strong potential adverse effects, and only a small proportion of fibromyalgia patients experience substantial symptom relief without adverse events.

[0032] 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 2C-B may be useful in the pathophysiology of 2A It acts as an antagonist and 5-HT 2B and 5-HT 2C(These receptors are specifically expressed on the apical dendrites of neocortical pyramidal cells in layer 5.) Toxicology studies have linked a number of hospitalizations to 2C-B ingestion, and 2C-B is a Schedule 1 drug due to its undesirable properties and potential for abuse.

[0033] Human open-label studies in drug-experienced individuals self-administering 2C-B (doses ranging from 10 to 20 mg) did not reveal any significant adverse effects. At doses higher than 20 mg, 2C-B abusers reported a greater feeling of euphoria, kaleidoscope vision, and distorted perception.

[0034] Chronic psychiatric disorders often share a common core of treatment-resistant symptoms that respond well to psychoactive medications through compound pharmacological effects that may be further modified by psychotherapy. Patients experience multiple interrelated co-occurring symptoms that may have independent or simultaneous time-varying and severity ratings, but may share a common pathogenesis. Clusters may also be considered "symptom endophenotypes" that span syndromes and disorders through neurobiological correlates of brain circuits and neurotransmitters.

[0035] Without wishing to be bound by theory, we hypothesize that 2C-B, with its short-term physical change phenomenon and ongoing psychoactive pharmacological and physiological effect profile, has a compelling neurobiological basis for treating SSD, depression, anxiety, PTSD, and comorbid conditions. SSD, including fibromyalgia, has chronic physical symptoms with unclear biological or medical causes and is often a diagnosis of exclusion. In DSM-5, what we refer to as 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 conditions of mood and affective disorders and may include mood disorder clusters and neuropsychological discomfort clusters. Fibromyalgia patients may be successfully treated with 2C-B in the lower dose range of 1-24 mg in combination with other psychoactive treatments for CNS disorders.

[0036] The inventors further demonstrate that MBDB (N-methyl-1-1,3-benzodioxol-5-yl)-2-aminobutane) is a suitable drug or antidepressant for the treatment of a wide range of anxiety disorders and for alleviating their symptoms. Animal and human data do not suggest a potential medical use of MBDB as a treatment for CNS disorders, but they also do not suggest an absence of medical use. No significant adverse effects were observed in investigational drug users who self-administered MBDB (doses ranging from 100 to 300 mg) under supervision in a controlled environment. In summary, MBDB can be used as an anxiolytic drug, and the therapeutic effect can be reliably assessed using scales such as the GAD-7 or the Generalized Anxiety Disorder Severity Scale (GADSS).

[0037] The diseases, conditions, and disorders listed in the specification are those 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.

[0038] Mental illness, mental condition, mental disease, or mental disorder includes, but is not limited to, the following and all intermediate ICD-10 codes in the ranges defined below: 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 mental 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: Schizophrenia-type 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: Unspecified mood [affect] disorder. Major dysthymic disorder, Persistent depressive disorder (dysthymia), Premenstrual dysphoric disorder, Substance- / medication-induced depressive disorder, Depressive disorder due to other conditions, Other specified depressive disorder, Unspecified depressive disorder, 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; Trauma- and stressor-related disorders not otherwise specified: reactive attachment disorder, disinhibited interpersonal disorder, posttraumatic stress disorder, acute stress disorder; adjustment disorders, other specified trauma- and stressor-related disorders, trauma- and stressor-related disorders not otherwise specified; Somatic symptom and related disorders: somatic symptom disorder, illness anxiety disorder, conversion disorder (functional neurological disorder), psychological factors affecting other medical illnesses, factitious disorder, other specified somatic symptom and related disorders, somatic symptom and related disorders unspecified; Eating disorders and eating disorders: Pica, Rumination, Avoidant / Restrictive Food Intake Disorder, Anorexia Nervosa, Bulimia Nervosa, Binge Eating Disorder, Other Specified Eating Disorder or Eating Disorder, Unspecified Eating Disorder or Eating Disorder; Sleep / wake disorders: insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorders, obstructive sleep apnea-hypopnea, central sleep apnea, sleep-related hypoventilation, circadian rhythm sleep-wake disorders, parasomnia disorders, arousal disorder from NREM 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, unspecified hypersomnia disorder, 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 Libido 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 syndrome associated with physiological disorders and physical factors. F60-F69: Adult personality and behavior disorders F60: Specified 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 / Conduct Disorders: Oppositional Defiant Disorder, Intermittent Explosive Disorder, Conduct Disorder, Antisocial Personality Disorder, Pyrrhonism, Kleptomania, Other Specified Disruptive / Impulse Control / Conduct Disorder, Unspecified Disruptive / Impulse Control / Conduct Disorder, Personality disorders, Personality disorders in general, Cluster A personality disorder, Suspicious personality disorder, Schizoid personality disorder, Schizophrenic 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, Unspecified personality disorder, Conditions for further research, Attenuated psychotic syndrome, Brief depressive episode with 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: Profound intellectual disability, F78: Other intellectual disability, F79: Unspecified intellectual disability. F80-F89: Pervasive and specific developmental disorders F80: Specified developmental disorder of speech and language, F81: Specified developmental disorder of learning ability, F82: Specified developmental disorder of motor function, F84: Pervasive developmental disorder, F88: Other psychological developmental disorder, F89: Unspecified psychological developmental disorder. 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 usually with onset in childhood and adolescence.

[0039] As used herein, a nervous system disease, nervous system condition, neurological disease, or neurological disorder includes, but is not limited to, the following ICD-10 intermediate codes, and all ICD-10 intermediate codes within the scope of the definition: G00-G09: Inflammatory diseases of the central nervous system G00: Bacterial meningitis, not elsewhere classified; G01: Meningitis in bacterial diseases elsewhere classified; G02: Meningitis in other infectious and parasitic diseases elsewhere classified; G03: Meningitis of other and unspecified causes; G04: Encephalitis, myelitis, and encephalomyelitis; G05: Encephalitis, myelitis, and encephalomyelitis in diseases elsewhere classified; G06: Intracranial and intrathecal abscesses and granulomas; G07: Intracranial and intrathecal abscesses and granulomas in diseases elsewhere classified; 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); tumors (C00 to D49); symptoms, signs, and clinical and laboratory abnormalities, not elsewhere classified (R00 to R94). G10-G14: System atrophy that mainly affects the central nervous system G10: Huntington's disease, G11: Hereditary ataxias, G12: Spinal muscular atrophies and related syndromes, G13: System atrophies primarily affecting the CNS in diseases classified elsewhere, G14: Post-polio syndromes. G20-G26: Extrapyramidal and movement disorders G20: Parkinson's disease, G21: Secondary parkinsonism, 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 nerve disorders, 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: Mononeuropathies of upper limbs, G57: Mononeuropathies of lower limbs, G58: Other mononeuropathies, G59: Mononeuropathies 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 disorders of the central nervous system, 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.

[0040] "Treatment-resistant depression" (TRD) herein is a shorthand signifier for all related terms, including management approaches as defined herein, 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 hormone, second generation antipsychotics (SGAs), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, pindolol, sex steroids, and glucocorticoids. Management approaches include the following therapeutic strategies: (1) switching from an ineffective antidepressant to a novel antidepressant of a similar or different class; (2) concomitant use of the current antidepressant regimen with a second antidepressant of a different class; and (3) augmenting a current antidepressant regimen with a second agent that is not itself considered an antidepressant.

[0041] 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.

[0042] 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.

[0043] The term "bind" or "binding" or grammatical equivalents herein refer to compositions that have affinity for one another. "Specific binding" means that the binding is selective between two molecules. Specific examples of specific binding include that which occurs between an antibody and an antigen. Typically, the dissociation constant (KD) is about 1×10 -5 Less than M or about 1×10 -6 Less than M or 1×10 -7 Specific binding can be distinguished from non-specific binding when the binding affinity is less than M. Specific binding can be detected by ELISA, immunoprecipitation, coprecipitation, the presence or absence of chemical cross-linking, two-hybrid assays, etc. Discrimination between "specific" and "non-specific" binding can be made possible by the use of appropriate controls.

[0044] In one embodiment, a variety of other therapeutic agents may be used by administration via the compositions and methods provided herein.

[0045] The psychoactive compounds provided herein can be used for various therapeutic purposes. In one embodiment, the compounds are administered to a subject to treat neuropsychiatric disorders. For the purposes of the compositions and methods provided herein, the "subject" includes humans and other animals, preferably mammals, and more preferably humans. Thus, the compounds described herein have both human therapeutic use 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 administering a pharmaceutical composition comprising the compounds described herein.

[0046] The methods and compositions described herein can be used to prevent neuropsychiatric disorders and improve their signs and / or symptoms.The terms "treat" and "treatment" refer to the treatment of neuropsychiatric disorders in a subject, and include preventing, preventing, or improving the neuropsychiatric disorders in the subject, and reducing or improving the signs or symptoms of neuropsychiatric disorders.Treatment goals can include endpoints such as improvement in DSM-5 severity rating scale to measure positive cognitive valence system and corresponding reduction in negative valence, as well as improvement in resilience and quality of life.

[0047] It will be appreciated by those skilled in the art that methods of treatment and / or prevention, comprising administering a psychoactive compound as described herein for the purpose of treating and / or preventing one or more indications as described herein, also include the use of a psychoactive compound as described herein in the manufacture of a therapeutic medicament for treating and / or preventing one or more indications as described herein; and the use of a psychoactive compound as described herein for treating and / or preventing one or more indications as described herein.

[0048] 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 described 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 described herein in a controlled environment, wherein the subject is provided with psychological support.

[0049] The term "about" or "approximately" refers to an acceptable error range for a particular value as determined by one of ordinary skill in the art, in part depending on the method of measuring or determining the value, i.e., the limitations of the measurement system. For example, "about" can mean within one or more standard deviations per the practice of the art. Alternatively, when referring to a measurable value, such as an amount, time course, concentration, etc., it can 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 particular value (such as variations appropriate in carrying out the disclosed methods).

[0050] The psychoactive compounds and methods provided herein contemplate pharmaceutical compositions.The formulations in the compositions and methods provided herein are prepared for storage by mixing the compounds with desired purity in the form of lyophilized formulations or aqueous solutions 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 examples of such 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 (such as polyvinylpyrrolidone). ); 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; bulking agents (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, and are in the form of a water-soluble pharma- ceutically acceptable salt (meaning to include both acid addition salts and base addition salts). A "pharma-ceutically acceptable acid addition salt" refers to salts that retain the biological effectiveness of the free base, which is not biologically or otherwise undesirable, and that are formed with inorganic and organic acids, such as: Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Formulations to be used for in vivo administration are preferably sterile, which is readily accomplished by filtration through sterile filtration membranes, or other methods.

[0051] 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.

[0052] The psychoactive compounds provided herein may also be encapsulated in microcapsules prepared by the following method: Such microcapsule preparations include, but are 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 also be prepared. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers, where the matrices are in the form of shaped 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).

[0053] Administration of the pharmaceutical composition comprising the psychoactive agent provided herein, preferably in the form of a sterile aqueous solution, can be performed 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, the pharmaceutical composition may be formulated according to the method of introduction.

[0054] 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 the subject substantially simultaneously. In some embodiments, the subject may be administered a total therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be divided into multiple tablets or capsules.

[0055] In some embodiments, the dose of the psychoactive compound described 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 described 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 described herein is about 1 mg, about 10 mg, or about 25 mg. In some embodiments, the dose of the psychoactive compound described herein is in the range of about 0.001 mg to about 1 g. In some embodiments, the dose of a psychoactive compound described herein ranges from about 100 mg to about 250 mg. In some embodiments, the dose of a psychoactive compound described herein is about 25 mg.

[0056] In some embodiments, the psychoactive compound described herein is administered daily. In some embodiments, the psychoactive compound is administered twice a day. In some embodiments, the psychoactive compound is administered three times a day. In some embodiments, the psychoactive compound is administered every two days. In some embodiments, the psychoactive compound is administered every three days. In some embodiments, the psychoactive compound is administered every four days. In some embodiments, the psychoactive compound is administered every five days. In some embodiments, the psychoactive compound is administered once a week. In some embodiments, the psychoactive compound is administered every two weeks. In some embodiments, the psychoactive compound is administered every three weeks. In some embodiments, the psychoactive compound is administered monthly.

[0057] In some embodiments, about 5 mg of the psychoactive compound is administered daily. In some embodiments, about 5 mg of the psychoactive compound is administered twice a day. In some embodiments, about 5 mg of the psychoactive compound is administered three times a day. In some embodiments, about 5 mg of the psychoactive compound is administered every two days. In some embodiments, about 5 mg of the psychoactive compound is administered every three days. In some embodiments, about 5 mg of the psychoactive compound is administered every four days. In some embodiments, about 5 mg of the psychoactive compound is administered every five days. In some embodiments, about 5 mg of the psychoactive compound is administered once a week. In some embodiments, about 5 mg of the psychoactive compound is administered every two weeks. In some embodiments, about 5 mg of the psychoactive compound is administered every three weeks. In some embodiments, about 5 mg of the psychoactive compound is administered monthly.

[0058] In some embodiments, about 25 mg of the psychoactive compound is administered daily. In some embodiments, about 25 mg of the psychoactive compound is administered twice a day. In some embodiments, about 25 mg of the psychoactive compound is administered three times a day. In some embodiments, about 25 mg of the psychoactive compound is administered every two days. In some embodiments, about 25 mg of the psychoactive compound is administered every three days. In some embodiments, about 25 mg of the psychoactive compound is administered every four days. In some embodiments, about 25 mg of the psychoactive compound is administered every five days. In some embodiments, about 25 mg of the psychoactive compound is administered once a week. In some embodiments, about 25 mg of the psychoactive compound is administered every two weeks. In some embodiments, about 25 mg of the psychoactive compound is administered every three weeks. In some embodiments, about 25 mg of the psychoactive compound is administered monthly.

[0059] 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 once a week. 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.

[0060] 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 once a week. 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.

[0061] 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 once a week. 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.

[0062] 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 once a week. 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.

[0063] 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 once a week. 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 the psychoactive compound is administered monthly.

[0064] In some embodiments, a psychoactive compound described herein is administered at an initial dose, which is then enhanced by administering a second dose of the psychoactive compound 30 minutes to 4 hours later. In some embodiments, the enhanced dose is administered about 30 minutes after the initial dose. In some embodiments, the enhanced dose is administered about 60 minutes after the initial dose. In some embodiments, the enhanced dose is administered about 90 minutes after the initial dose. In some embodiments, the enhanced dose is administered about 120 minutes after the initial dose. In some embodiments, the enhanced dose is administered about 150 minutes after the initial dose. In some embodiments, the enhanced dose is administered about 180 minutes after the initial dose. In some embodiments, the enhanced dose is administered about 210 minutes after the initial dose. In some embodiments, the enhanced dose is administered about 240 minutes after the initial dose.

[0065] In some embodiments, the boosted dose is 10% to 100% of the initial dose. In some embodiments, the boosted dose is the same as the initial dose. In some embodiments, the boosted dose is about half the amount of the initial dose. In some embodiments, the administration schedule is performed daily. In some embodiments, the administration schedule is performed twice a day. In some embodiments, the administration schedule is performed three times a day. In some embodiments, the administration schedule is performed every other day. In some embodiments, the administration schedule is performed every third day. In some embodiments, the administration schedule is performed every fourth day. In some embodiments, the administration schedule is performed every fifth day. In some embodiments, the administration schedule is performed once every week. In some embodiments, the administration schedule is performed every two weeks. In some embodiments, the administration schedule is performed every three weeks. In some embodiments, the administration schedule is performed once a month.

[0066] In some embodiments, the dose of the psychoactive compounds described 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 compounds described 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 compounds described herein is about 1 mg / kg, about 10 mg / kg, or about 25 mg / kg. In some embodiments, the dose of the psychoactive compounds described herein is in the range of about 0.001 mg / kg to about 1 g / kg. In some embodiments, the dose of the psychoactive compounds described herein is in the range of about 100 mg / kg to about 250 mg / kg. In some embodiments, the dose of the psychoactive compounds described herein is about 25 mg / kg.

[0067] In some embodiments, the psychoactive compounds described 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 described herein are administered according to a dosing schedule described herein. In some embodiments, for example, the dosing regimen disclosed herein is administered as a sustained release or extended release formulation to release 50 mg to 1 g of the psychoactive compounds described herein on a schedule set for the patient according to the patient's therapeutic indication.

[0068] In one embodiment, the term "subject" refers to a mammal, including a human, in need of treatment for or susceptible to a pathology or its sequelae. The subject 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.

[0069] 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 old. In some embodiments, the subject is at least about 18 years old. 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.

[0070] 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 include a plurality of molecules.

[0071] Reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. In another embodiment, when a range of values ​​is expressed, it includes from one particular value and / or to the other particular value. Moreover, values ​​referred to in a range include every value within that range. All ranges are inclusive and combinable.

[0072] The expression "and / or" herein should be understood to mean "either or both" of the elements it conjoins, i.e., elements that are present together in some cases and disjunctively in other cases. Elements listed with "and / or" should be considered in the same manner, i.e., "one or more" of the elements so conjoined. Other elements than the elements specifically distinguished by the "and / or" expression may optionally be present, whether related or unrelated to the elements specifically distinguished by such expression. Thus, as a non-limiting example, when used with an open-ended expression such as "comprising," the expression "A and / or B" may, in one embodiment, mean only A (optionally including elements other than B); in another embodiment, mean only B (optionally including elements other than A); in yet another embodiment, mean both A and B (optionally including other elements), and so forth.

[0073] It is to be understood that "or" in this specification has the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" is interpreted as inclusive, i.e., including at least one of a plurality of elements or a series of elements, but also including more than one, and optionally including additional non-listed items. In contrast, only terms expressly indicated, 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, when the term "or" in this specification is used after terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of," it is interpreted only as indicating exclusive alternatives (i.e., "one or the other, but not both").

[0074] The phrase "at least one" herein, when referring to one or more listed elements, should be understood to mean at least one element selected from any one or more of the elements of the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, nor does it exclude any combination of the elements of the list of elements. This definition also means that other elements, whether related or unrelated to those specifically identified elements, may optionally be present other than the elements specifically identified in the list of elements to which the phrase "at least one" refers. Thus, as a non-limiting example, "at least one of A and B" (or, similarly, "at least one of A or B," or, similarly, "at least one of A and / or B") can mean, in one embodiment, at least one, optionally including more than one, including A and not including B (and optionally including elements other than B); in another embodiment, it can mean at least one, optionally including more than one, including B and not including A (and optionally including elements other than A); in yet another embodiment, it can mean at least one, optionally including more than one, including A, at least one, optionally including more than one, including B (and optionally including other elements), etc.

[0075] Unless the context indicates otherwise, it is specifically contemplated that the various features described herein may be used in any combination.

[0076] Any patent documents, patent application publications, or scientific publications cited herein are hereby incorporated by reference in their entirety.

[0077] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention, but should not be construed as limiting the broad scope of the invention.

[0078] Working Example Example 1: Effects of methylone, 2C-B, and MBDB on fear extinction plasticity and dendritic structure in mice The main question in experimental research is how to bring about long-term behavioral changes with the short half-life of the compound. One possible mechanism is neuroplasticity. In fact, administration of psychoactive compounds can cause lasting changes in the neuroarchitecture of the brain by strengthening synaptic connections or increasing the number of synaptic connections. However, the current evidence supporting this view is mostly provided by studies of cultured neurons. It remains to be elucidated the extent to which psychoactive compounds induce neuroplasticity in mammalian brains and whether synaptic remodeling occurs in brain regions related to neuropsychiatric disorders.

[0079] This study compares the effects of multiple psychoactive pharmaceuticals 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 antidepressant / anxiolytic), positive controls (e.g., another antidepressant / anxiolytic), and vehicle controls (saline). Dose-response curves for the psychoactive compounds are characterized by measuring mouse head twitch responses. The plasticity-enhancing effects of single dose administration of each compound on fear extinction behavior are also determined. 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) is then used to determine the long-term effects of a single dose of each compound on dendritic spine density and turnover.

[0080] Determine dose-response curves in C57BL / 6J mice It is important to determine behaviorally relevant dose ranges for mice. Forty mice (6-8 week old adult C57BL / 6J mice) per condition are tested to generate dose-response curves across a range of doses of three psychoactive compounds (methylone, 2C-B, MBDB) and quantification of head twitch responses. Briefly, animals are placed in an arena in a soundproof space. The arena is illuminated with near infrared light. Movement of mice within all arenas is captured simultaneously with a ceiling-mounted high-speed camera. Each animal is injected intraperitoneally with one of five doses of one of the compounds at a dose range selected based on the literature. Mice are randomly group-assigned. Video recordings are taken approximately 10 minutes after dosing. In a subset of studies, video recordings are taken for up to 2 hours to chart the time course. For analysis, head twitch responses are counted by an experimenter blinded to the experimental condition. These experiments inform the doses used for further testing.

[0081] 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 the relevant fear-learning stimulus can reduce the intensity of the fear response, and may be related to the mechanism of action of these compounds in reducing anxiety or fear. The extent to which novel phenethylamines promote fear extinction is unknown. Here, we determine the rate of fear extinction after drug administration in adult mice (10 mice per condition tested) in four conditions (saline, methylone, 2C-B, MBDB). Briefly, each mouse receives a tone / shock pairing (day 1); then, the next day, the compound is administered once (at a dose based on previous test information) 30 minutes before reexposure to the fear-related stimulus (day 2). On the third day, fear extinction learning is tested by exposing the mouse to the relevant sound again in a fear conditioning apparatus. Fear extinction is used as a model to improve anxiety-related and fear-related behaviors in psychiatric disorders, and can be used to identify behavioral effects that are separable from hallucinogenic effects. We then investigate the circuit mechanisms underlying potential plasticity enhancement using two-photon imaging experiments.

[0082] Determine long-term effects on neurite remodeling It has become clear that psychoactive compounds can enhance neuroplasticity, but these experiments have examined how different compounds induce different degrees of structural remodeling. Here, we determine dendritic spine turnover in the medial frontal cortex in five conditions (saline, ketamine, methylone, 2C-B, MBDB) in adult mice (five mice per condition tested). Briefly, Thy1-GFP-M transgenic mice are used because a small subset of cortical pyramidal neurons strongly expresses green fluorescent protein, allowing visualization of their dendritic structure. Each mouse is administered a single dose of the compound (at doses determined as above; 10 mg / kg for ketamine). Dendritic spines of the distal apical arbores are imaged and tracked using two-photon microscopy in seven sessions on days -3, -1, 1, 3, 5, 7, and approximately 30 days relative to the day of administration. Longitudinal imaging of the same set of spines allows the measurement of dendritic spine density and turnover kinetics, including the rates of spine formation and disappearance, as well as the proportion of new spines that continue to form, indicating maturation of new functional synapses. These results provide data demonstrating the suitability of several psychoactive compounds for the treatment of neuropsychiatric disorders.

[0083] 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 that 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 their genomes extensively characterized, both adult and juvenile zebrafish are now widely used for in vivo screening of a variety of psychoactive pharmaceutical agents.

[0084] Reserpine-induced depression model in zebrafish Reserpine, a specific inhibitor of monoamine transporters, is known to deplete monoamine neurotransmitters (confirmed by liquid chromatography-mass spectrometry analysis); it also reduces swimming distance and average speed (hypokinesis) and reduces responses to both visual and sound stimuli. Reserpine induces depressive-like behavior in both adult and juvenile zebrafish; it is used to assay those drugs (such as methylone, 2C-B and MBDB) that affect a despair-like state. The camera algorithm, histogram of oriented gradients (HOG), allows the analysis of depressive and hypokinesic behavior in shoaling zebrafish with a high degree of precision not possible with human observers.

[0085] Zebrafish anxiety disorder model Social behaviors such as shoaling and other aggression develop with age, whereas many behaviors including anxiety, fear, and stimulus-dependent learning can be assessed as early as the juvenile stage when the fish can swim about. Multiple types of anxiety tests are performed sequentially or in combination; such tests include the 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, freezing, irregular swimming, or levels of light-area aversion (scotopic preference) in adults and dark aversion in juveniles.

[0086] Example 3: Rodent models of neuropsychiatric disorders This example describes rodent models for several 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 involved in the action of hallucinogenic drugs.

[0087] 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; it also has high predictive reliability (Porsolt et al., (1977) Nature 266:730; Borsini and Meli, (1988) Psychopharmacology 94:147). The premise of the FST is that when rats are placed in a cylinder filled with water, they will initially attempt to escape but over time will become immobile. This increased immobility reflects behavioral despair, i.e., the formation of a depressive state. Various antidepressant treatments have been shown to consistently reduce immobility time, with the observation that increases in swimming or climbing are correlated with serotonergic or noradrenergic activity, respectively (Detke et al., (1995) Psychopharmacology 121:66).

[0088] Anxiety: Open field test (time spent in the center vs. periphery) This behavioral assay is also widely used as an anxiety paradigm, but it exploits rodents' innate fear of brightly lit open spaces that are considered fear- or anxiety-inducing. Rodents spend more time clinging to the walls of the open field over the course of the test, and these effects correlate with the associated brain regions and mechanisms.

[0089] method Time spent in the center and periphery of the open field is measured by continuous beam break and / or video tracking, as well as parameters such as distance traveled and locomotor activity (horizontal and vertical) over the course of the test session.

[0090] result Anxiolytic drugs such as diazepam, used as a positive control for the evaluation of drug effects on these parameters, increase the time spent in the center of the open field (and / or the distance traveled), which is independent of changes in locomotor activity.

[0091] Anxiety: Elevated plus maze This behavioral assay, widely used as an anxiety paradigm, is based on the rodent's unconditioned response to a potentially dangerous environment; the height, brightness, and open space of the maze are considered fear- or anxiety-inducing, and these effects are correlated to the relevant brain regions and mechanisms.

[0092] method Video tracking of time spent in the open arms of the maze starting at the border and leading to the closed arm for 5 min. Other ethological parameters included rearing, head down, and extended body posture.

[0093] result Anxiolytic drugs such as diazepam, used as a positive control for the evaluation of drug effects on these parameters, increase the time spent active in the open arms (time spent and / or entries) without decreasing locomotor activity.

[0094] Modified Geller-Seifter type conflict test Rats are trained to press a lever for food on 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 punishment phase). It also shows anxiolytic selectivity (apparently showing no effect with other drug classes), allowing the anxiolytic effects of MBDB to be evaluated with a positive control such as bupropion.

[0095] Fibromyalgia: Reserpine-induced muscle pain model Reserpine (1 mg / kg / subcutaneously) is administered for three days to mimic widespread chronic pain and symptom complex.

[0096] method Duloxetine (30 mg / kg, orally) is administered 60 min prior to the forced swimming test (FST), and then the rats are exposed to LDI; a single dose of γ-radiation (0.5 Gy) one day prior to the FST.

[0097] result Reserpine significantly increases immobility time in the FST and decreases the levels of 5-hydroxytryptamine, dopamine, and norepinephrine in the cerebral cortex. Reserpine 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 measured parameters.

[0098] Fibromyalgia: The acid-saline model Allodynia, hyperalgesia, and other related fibromyalgia-like symptoms are rapidly induced with acid injection (pH 4.0). Once induced, animals show hypersensitivity to mechanical and visceral stimuli. Symptoms persist for as long as 14 days after induction, allowing for evaluation over time and comparison to vehicle and positive controls (e.g., buprenorphine).

[0099] Example 4: Methylone Case Series This example is based on a series of 32 case records in which clinical psychologists administered oral methylone to outpatients in single or multiple administration sessions. The case series consists of two data sets (Cohort 1 and Cohort 2): Cohort 1: Enrollment of 4 cases from a healthy population to obtain information on the safety and tolerability of methylone administered in a single dosing session. Cohort 2: 28 case enrollments to obtain efficacy and safety information from a consecutive series of patients with a baseline assessment and a diagnosis of the target disorder (PTSD or MDD). Cohort 2 was evaluated for post-treatment efficacy using baseline Clinical Global Severity (CGI-S) and Clinical Global Improvement (CGI-I) and compared to baseline CGI-S obtained before the first methylone dose, as further detailed below. A subset of patients in Cohort 2 also had the CGI-S scale assessed post-treatment. Cohort 2 was evaluated for safety events observed or reported after a single dosing session. Clinical overall improvement The Clinical Global (CGI) scale contains two components: CGI-S ("Severity") and CGI-I ("Improvement"). CGI-S guidelines 1 = Normal - No illness, no symptoms of the disorder in the past 7 days. 2 = Borderline psychiatric disorder - insidious or questionable pathology 3 = Mild illness - clearly noticeable symptoms, if any, with minimal distress or difficulty in social and occupational functioning 4 = Moderate disease - clear symptoms that are easily noticed but cause mild impairment or distress; symptom level may indicate the need for drug treatment 5 = Significant illness - intrusive symptoms that clearly impair social / occupational functioning or cause invasive levels of distress 6 = Severe illness - Severe pathology (symptoms often affect behavior and functioning) may require support from others 7 = Most severely affected 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; shows a substantial and substantial change 2 = Much improved - Much better as symptoms have been significantly reduced; functional level has increased but some symptoms remain 3 = Minimal Improvement - Somewhat better with little or no clinically meaningful symptom relief. Little or no change in underlying clinical status, level of care, or functional ability. 4 = No change - Symptoms essentially unchanged 5 = Minimal deterioration - some deterioration that may not be clinically significant; little change in baseline clinical status or functional ability 6 = Substantial deterioration - clinically significant worsening of symptoms and decline in function 7 = Major deterioration - severe worsening of symptoms and loss of function

[0100] result Baseline Demographics: The demographics of cohorts 1 and 2 are shown in Table 1.

[0101] [Table 1]

[0102] 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 be younger with a higher proportion of male subjects; all were Caucasian. Prior methylone use was unknown for two subjects and confirmed for the other two subjects (one male and one female).

[0103] Cohort 2 consisted of 28 patients with PTSD or MDD treated as outpatients. Note that one patient in the MDD population had a primary diagnosis of bipolar disorder type I. Overall, Cohort 2 had roughly equal numbers of men and women, as well as similar proportions of PTSD and MDD subsets.

[0104] Age distribution was >85% between ages 18 and <65 years overall and in the PTSD and MDD subsets; the full dataset and the PTSD and MDD subsets contained small subsets of older patients (age ≥65 years). The overall age range in Cohort 2 was broad, ranging from 22 to 78 years (mean 45.9 years), with similar age distributions in the PTSD and MDD subsets.

[0105] Characteristics of underlying diseases in cohort 2 Primary diagnosis Overall, the majority of patients included in cohort 2 had a primary diagnosis of PTSD [20 of 28 patients, (71%)], and 29% had a primary diagnosis of MDD or bipolar disorder (7 MDD; 1 bipolar). However, 10 of the 20 PTSD patients (50%) were also found to have a secondary diagnosis of MDD or depression (6 MDD; 4 depression), giving an overall primary or secondary diagnosis of MDD or depression of 64.2%.

[0106] Previous Therapy / Concomitant Therapy In the PTSD subset of Cohort 2, the most common prior / concomitant treatments reported in two or more patients, in descending order, were: These were SSRIs (14 patients), talk therapy (7 patients), breathing exercises (4 patients), cognitive and behavioral therapy, and unspecified antidepressants (4 patients each). The majority of patients had discontinued their respective treatments prior to the initial methylone session. Within the PTSD subset, five patients were treated with combination therapy with an SSRI or other antidepressant class; and four of these patients had a CGI score of 1 or 2. Treatment regimens were as follows: Fluoxetine 20-40mg Fluoxetine (unspecified doses) Fluoxetine and bupropion (unspecified doses) Escitalopram (unspecified dose) Bupropion (unspecified dose) * Lamotrigine (unspecified dose); discontinued after first 6 sessions. * This patient had a quasi-hallucinatory experience, but did not specify which session this was in (further details below).

[0107] In the MDD subset of Cohort 2, the most common prior / concomitant medications reported in two or more patients, in descending order, were: The treatments were SSRIs (3 patients), talk therapy (3 each), psychotherapy (2 patients), and antiepileptic drugs (2 patients). The majority of patients had discontinued their respective treatments before the initial methylone session. Only one patient was on concomitant therapy with unspecified doses of escitalopram, clonazepam, lamotrigine, and propranolol at the time of methylone, which were tapered after the 5th of 10 methylone sessions. The CGI-I score was 2, and there were no reported safety events.

[0108] Underlying disease severity The baseline disease 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; the proportions were similar in both the PTSD and MDD subsets.

[0109] [Table 2]

[0110] Baseline Symptom List Figure 1 shows the baseline symptom profile of symptoms present in ≥2 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).

[0111] Methylone Dosage and Regimen Cohort 1 Three men in cohort 1 received a single-session group treatment; the total methylone dose administered was 790 mg, with a regimen of 280 mg methylone followed by booster doses of 190 mg, 190 mg, and 130 mg. One healthy female volunteer received a total dose of 870 mg; 250 mg methylone followed by booster doses of 220 mg, 200 mg, and 200 mg.

[0112] Cohort 2 Only sessions that included methylone were counted as treatment sessions. For some patients, continued group therapy with methylone was recorded beyond the sessions listed, but improvement ratings on the CGI-I compared to baseline were performed after the methylone treatment sessions listed above.

[0113] MDMA was administered alone on two occasions, once in the first session and once in the second session. In one case involving repeated methylone sessions, 3 grams of mushrooms were administered 30 minutes after methylone administration in the first session.

[0114] Eight of the 28 cases were single-session, but in two of these cases no booster was administered at all. In the remaining cases, multiple sessions were administered, with booster doses used in all or some of the remaining patients (26 case reports); 15 patients had multiple booster doses in some or all of their sessions. The total methylone doses in each session ranged from 100 mg to 690 mg with a minimum range of 180 mg to 1020 mg. Only in four sessions in three patients was the maximum total dose in each session greater than 500 mg [methylone dose + booster dose]. Methylone doses ranged from 100 to 270 mg, and the total cumulative dose of booster doses ranged from 50 mg to 880 mg, but only in two sessions in two patients did it exceed 370 mg. Individual methylone booster doses ranged from 50 mg to 240 mg with a maximum range of 80 mg to 250 mg.

[0115] safety Cohort 1 No adverse effects or sequelae were observed or reported for any of the four subjects in Cohort 1. All three men were able to walk, make tea, and showed no signs of intoxication.

[0116] Cohort 2 In the majority of cases in cohort 2 (25 of 28 cases; 89.3%), methylone administration was well tolerated and no safety events were reported. One case experienced an adverse event of increased anxiety after 117 mg MDMA administration in the first session, which did not contain methylone and which preceded the administration of methylone in subsequent sessions; there was no recurrence of the event even with a total dose of 130 mg (80 mg + 50 mg booster) of methylone. Adverse events reported after methylone administration in three patients (age 65 years or older) were: [I] Case Report A A 75 year old male with a primary diagnosis of PTSD and a medical history of atrial fibrillation and pacemaker experienced dizziness during the fifth session (when withdrawing from the medication) of methylone at 150 mg and a 150 mg booster (highest dose administered). The event was not considered severe and did not require intervention. Total doses received to date ranged from 100 to 250 mg. There were no repeat doses of methylone administered at home (i.e., repeated methylone administration). [II] Case Report B A 70 year old male; primary diagnosis of PTSD and secondary diagnosis of depression; administered 690mg of methylone (200mg followed by booster doses of 250mg and 240mg) in a single session; no adverse events occurred during the course of the session, but adverse events of insomnia and decreased appetite were reported after the session, likely due to the simulant effect of methylone. [III] Case Report C Male, age 78; primary diagnosis was PTSD, secondary diagnosis was anxiety; medical history was of "well-controlled cardiovascular problems"; reported quasi-hallucinatory experiences after methylone administration in the range of 100-300 mg total (100-150 mg methylone, 0-150 mg booster) over five sessions, but doses and further details unknown; no need for intervention.

[0117] Effectiveness Cohort 1 will consist of healthy volunteers, and efficacy will be reported in Cohort 2, consisting of patients with PTSD and MDD.

[0118] Improvement level CGI-I and Time to Initial Improvement All patients showed at least a minimal improvement (CGI-3 or better) after methylone treatment. The maximum improvement observed in the 28 cases included in cohort 2 is shown in Table 3 and Figure 3. 86% of patients [16 / 20 patients (80%) in the PTSD subset and 8 / 8 patients (100%) in the MDD subset] achieved a CGI-I score of 1 or 2; corresponding to "much improved" or "very improved," respectively, compared to the baseline CGI-S. Furthermore, almost 90% of patients (25 of 28 patients) showed their first improvement in the first methylone session. Another two cases showed their first improvement in the second and third sessions, respectively, and one case required 10+ sessions to achieve their first improvement.

[0119] [Table 3]

[0120] Response Durability In the PTSD subset of Cohort 2, 16 case records contained information on durability. One case reported no durable effect, and 15 case records reported a durable effect (12 of the cases for more than 6 months; one for only 3 months; two unspecified). In one of the cases with an unknown duration of durable response, the record stated that after the fourth methylone session, "the subject is no longer said to have the disease."

[0121] In the MDD subset of Cohort 2, six of eight case records contained information on persistence: one reported no sustained effect, and the remaining five reported two patients with sustained effect over two years, one with sustained effect over five years, and two with unknown duration, but one reported as "stable after 13 sessions" and one as "persistent."

[0122] Changes in CGI-S Post-treatment CGI-S was reported in only five cases, as shown in Table 4, including one patient with a stable CGI-S of 1. In one case, it was noted that the CGI-S had sometimes reached 1. An additional five case records that did not include post-treatment CGI-S scores reported that the patient was no longer diagnosed with the disease after treatment, and five of these cases achieved a CGI-I of 1.

[0123] [Table 4]

[0124] conclusion Methylone administered as a single dose or in multiple sessions, including single and / or booster doses, was generally well tolerated. No safety events were reported in healthy volunteers or in adult patients under the age of 18 or 65 years. Three elderly patients reported transient safety events that occurred at higher doses but did not recur on rechallenge. One of these events involved a quasi-hallucinatory experience, occurring approximately 5-6 times per 2,000 methylone doses.

[0125] The majority of patients in the PTSD (90%) and MDD (88%) subsets had baseline CGI-S scores of 5 or higher (i.e., "marked" or "severely ill"), including two PTSD patients with the most severe CGI-S score of 7 (i.e., in the "most severely ill" category). Nevertheless, across cohort 2, 86% of patients [16 / 20 patients (80%) in the PTSD subset and 8 / 8 patients (100%) in the MDD subset] had improvement ratings of 1 or 2; these improvement ratings correspond to "much improved" or "very improved" compared to baseline CGI-S.

[0126] Example 5: Clinical evidence for the use of methylone in the treatment of PTSD: A long-term follow-up case series PTSD is a debilitating and often chronic mental disorder characterized by a range of symptoms, including: Intrusive memories, frightening dreams, dissociative reactions, physiological reactivity and avoidance to trauma-related stimuli, negative cognitions and mood, fatigue, increased arousal, sleep disturbances, cognitive impairment, irritability, risk-taking behavior, and clinically significant distress and impairment in functioning. Although 70% of the world's population is exposed to trauma, resilience is the rule rather than the exception; nevertheless, it is estimated that roughly 6% of people exposed to trauma will develop PTSD. Estimates of the prevalence of PTSD range as high as 20% after interpersonal violence, 25% in combat 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.

[0127] There are only limited pharmacological options available. Selective serotonin reuptake inhibitors (SSRIs) are the best pharmacological treatments, with only paroxetine and sertraline being FDA-approved therapeutic agents for the treatment of PTSD. However, despite their robust efficacy, treatment with these is suboptimal. These are slow-acting slow acting antidepressants (SAADs) that do not show significant benefit in most patients until at least 4 weeks (and up to 8 weeks) of continued treatment. This latency is obviously troublesome, as the risk of suicide and self-harm, as well as other potentially destructive behaviors, increases significantly. Even with optimal delivery, 40% of patients do not respond to SSRIs, and only about 20%-30% achieve remission; furthermore, the degree of difference from placebo ranges from 10%-20%. The rates of non-response or partial response to these therapeutic agents in individuals with chronic and complex PTSD, such as military veterans, are comparable to or worse than those in the civilian patient population. Furthermore, many patients classified as "treatment responders" remain symptomatic and continue to live limited lives.

[0128] Trauma-focused psychotherapy also shows some efficacy in treating PTSD and is often the intervention of choice when pharmacotherapy proves to be limited. Prolonged exposure (PE) and cognitive processing therapy (CPT) are gold-standard treatments, but they can only be administered by appropriately trained therapists, and effective treatments require a willingness on the part of the patient to expose themselves to trauma-related memories and associated distressing experiences. In gold-standard psychotherapy outcome studies, dropout rates range from 17% to 55.8%, and nonresponse can be as high as 50%. Regardless of treatment modality, troublesome symptoms often persist even in patients classified as treatment responders. Efficacy gaps are particularly pronounced in the case of 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 and recurrent, chronic trauma exposures. Thus, there is an urgent need to identify novel, fast-acting strategies for treating PTSD, to explain the mechanisms of treatment efficacy, and to establish baseline markers that can clinically predict treatment response.

[0129] Recent placebo-controlled clinical trials have demonstrated that methylenedioxymethamphetamine (MDMA) produces rapid, beneficial and sustained clinical effects in PTSD after two or three doses in combination with manualized psychotherapy, as assessed by the Clinical Diagnostic Interview for PTSD (CAPS-5) for DSM-5. These robust and sustained clinical effects were replicated in a recent large Phase 3 clinical trial. A second Phase 3 clinical trial is currently underway, and favorable clinical results could move MDMA-assisted psychotherapy smoothly toward FDA approval.

[0130] 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 rapid pharmacological and physiological effects of orally administered methylone and MDMA in healthy participants with previous exposure to both compounds. Although the compounds are likely mechanistically similar, methylone exhibited less of the prototypic psychostimulant and empathic state-inducing effects, including reduced euphoria, intoxication, stimulant-like effects, and altered cognition and body perception, and was associated with increased sociability compared to MDMA. This striking difference in rapid pharmacological effects may be explained in part by their differences in serotonin (5-HT) receptor affinity. Methylone exhibited greater 5-HT receptor activation compared to MDMA. 2A It has significantly lower affinity for 5-HT 1A Methylone also has partial agonist activity at the 5-HT receptor, whereas MDMA lacks this activity. 2C Methylone has weak antagonistic effects on dopamine, whereas MDMA has partial agonist activity. Methylone also inhibits and disables monoamine reuptake transporters for dopamine, norepinephrine, and serotonin, thereby increasing the extracellular concentrations of these neurotransmitters.

[0131] This example describes a more detailed analysis of 21 patients with a range of psychiatric comorbidities (20 patients from the PTSD subset discussed in the previous example + 1 patient from this example who was mischaracterized but subsequently determined to have a primary diagnosis of PTSD) diagnosed with PTSD as a primary diagnosis in the previous example and treated clinically with methylone as an outpatient. These patients did not receive structured psychotherapy in conjunction with methylone treatment, which differs from recent studies of MDMA that highlight the importance of manualized hallucinogen-assisted psychotherapy models. The above properties, together with methylone's short duration of action and less dramatic rapid pharmacological and physiological effects, make methylone an attractive agent for clinical use in the treatment of PTSD.

[0132] Materials and Methods Clinical record data were obtained from 21 patients with a primary diagnosis of PTSD and who received at least one dose of oral methylone as part of specialized medical care in outpatient psychiatric care. No protected health information was disclosed, and no consent was obtained from patients for the use of their record data. Case records were systematically collected from data obtained 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 Severity Scale (CGI-S). Symptom improvement was assessed after administration using the Clinical Global Improvement Scale (CGI-I). Patients were evaluated for safety events observed or reported after the methylone administration session. Because these case records were retrospectively examined from routine clinical care records and not collected in a prospective research trial, more specific validated rating scales for assessing PTSD symptoms were not available. Furthermore, follow-up was different, ranging from 1 week (case 2) to 15 years (case 16).

[0133] [Table 5] TIFF2025510790000007.tif198132TIFF2025510790000008.tif194132TIFF2025510790000009.tif110132

[0134] result Methylone produced rapid and sustained improvements in both PTSD and depression symptoms without significant persistent adverse effects. Clinical data are shown in Table 5. Twelve patients (57%) were female and 19 (90%) were white. Mean age was 47.6 years (range: 25-78 years). All 21 patients had baseline CGI-S scores in the range of 4-7 (i.e., moderate-severe; see Figure 4). 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 by substrate competition. All patients experienced debilitating symptoms despite past and / or ongoing psychological and pharmacological treatments. Prior 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%).

[0135] All 21 patients achieved at least a minimal improvement (CGI-I of 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), of which 8 patients (89%) achieved a CGI-I score of 1 or 2. In patients who received multiple methylone sessions (n ​​= 12), 83% of patients (n = 10) achieved initial improvement after the first session, and one patient experienced improvement after the second session.

[0136] Information on persistence of clinical response was available for 17 of 21 patients. One individual reported no persistence (i.e., symptom severity returned to baseline almost immediately); 16 reported persistence (>6 months in 11 patients), with one patient reporting a 3-month, one patient reporting a 2-month, and one patient reporting a 1-week persistence. In one of the four case records that did not include persistence information, the treatment team determined that the patient was "no longer diagnosed with the disorder (i.e., PTSD)" after the fourth methylone session (10 months after baseline assessment).

[0137] Administration Overview Methylone was administered orally. No other therapeutic agents were changed during the course of methylone treatment. In most cases, an additional booster dose of methylone was administered 1 hour after the first dose in an attempt 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). In 19 patients, one or more of the multiple sessions included a booster dose. Starting doses ranged from 100 to 270 mg, and the starting doses, as well as the booster doses, were selected based on clinical judgment.

[0138] safety Methylone was generally well tolerated, and no patients discontinued treatment due to adverse events. Three of the 21 patients experienced a total of four adverse events (two events in one patient), none of which were considered severe or required medical intervention. A 75-year-old man with stable atrial fibrillation (pacemaker) and a history of Parkinson's disease developed dizziness toward the end of the fifth session with a total dose of 300 mg methylone (150 mg, followed by a booster dose of 150 mg; this was the highest dose given to this patient). The symptoms resolved rapidly; upon discharge, the patient felt well and had no other adverse effects. A 70-year-old man who received 690 mg methylone (200 mg, followed by booster doses of 250 mg and 240 mg) in a single dose session experienced no adverse events over the course of the session, but reported insomnia and decreased appetite the night after the session. These symptoms resolved the next day. A flashback-like experience during one treatment session was reported in a 78-year-old man. The patient participated in five treatment sessions with total methylone doses ranging from 100 to 300 mg per session.

[0139] patient report A 62-year-old male patient with treatment-resistant PTSD (ID = Case 2, Table 5) received methylone in combination with ongoing SSRI treatment; after the first administration session, it was noted that "[his] problems are seemingly disappearing, perhaps even more in his mind than in reality... [and] the methylone treatment seems like a new 'window of hope' that makes suicidal thoughts seem silly and unnecessary." After a single methylone session, following a rapid and sustained reduction in PTSD symptoms, he stated that he was interested in tapering the SSRI and no longer needed it. Another patient, a 52-year-old female patient with treatment-resistant PTSD and comorbid generalized anxiety disorder (ID = Case 7, 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, she empathized with [her]; and [they] were healed of [their PTSD].”

[0140] Consideration Methylone rapidly improved symptoms, as assessed by the CGI-I, in this patient case series with a primary diagnosis of PTSD and a high rate of comorbidity and previous treatment attempts. The majority (90%) had a baseline CGI-S of 5 or higher (significant or severe illness), including three patients in the category of a CGI-S of 7 (i.e., in the category of the most severely ill). 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.

[0141] Methylone was well tolerated over a wide dose range (100-1,020 mg) administered one to ten times. Several adverse events were reported in three elderly patients aged 70 years or older; these events 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.

[0142] 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, certain limitations exist in these data. The participants received clinical treatment; the data in this report were obtained retrospectively by review of clinical records. Treatment and follow-up were inconsistent, and randomization, control, and blinding to treatment conditions were not considered. Furthermore, the sample lacked diversity, and ongoing adjustments to psychotherapy and pharmacological treatments at different follow-up periods may have influenced the clinical course. The strength of this report lies in the complexity of the sample, which supports generalizability. Despite the above limitations, these case series in a complex patient population provide the first clinical evidence of the efficacy of methylone in the treatment of PTSD.

[0143] Methylone has not received as much cultural or clinical attention as MDMA, possibly 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 appropriately treated with MDMA's more intense and acute psychological and physiological effects.

[0144] Example 6: Methylone in the FST: Effects on depression, anxiety, and PTSD In this example, we investigated whether methylone exerts rapid antidepressant-like effects in the rat FST; and the prototypic selective serotonin reuptake inhibitor (SSRI) fluoxetine was used as an antidepressant control.

[0145] method animal Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used in this study (studies were performed at Melior Discovery, Exton, PA). Rats were acclimated in 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 and two rats per cage. Animals had ad libitum access to food and water and were randomly assigned to treatment groups. Animal use and procedures were in accordance with established approved protocols by the IACUC committee, Melior Standard Operating Procedures (SOPs), and Transcend Therapeutics.

[0146] Forced swim test (FST) For the FST test, rats were placed in a circular plexiglass container filled with water without escape mechanisms. 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. A 15-min habituation trial was performed on the first day, and a 5-min test was performed on the second day (24 h later). A time sampling method was used in which animals were observed every 5 seconds 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, 5, 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 min prior to FST testing. The experimenter was blinded to treatment.

[0147] Binding Tests Radioligand binding was measured for the serotonin (5HT), dopamine (DA), and norepinephrine (NE) transporters, respectively [ 3H]citalopram, 3 H]WIN35428, and [ 3 H]nisoxetine was used according to standard protocols. Studies of uptake and release of radiolabeled 5HT, NE, and DA in rat brain synaptosomes were performed using standard protocols.

[0148] 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 ​​less than 0.05 indicating statistical significance.

[0149] Results and Conclusions In the rat FST, a single dose of methylone produced stable dose-dependent and fast-acting antidepressant-like responses (Figure 5). Notably, 2–3 SSRI antidepressant injections are typically required to elicit a behavioral response in the FST, as shown in the fluoxetine control group of 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; this reflects the recruitment of noradrenergic receptor activity at this dose level (FIG. 5C).

[0150] The magnitude of effect of medium and high doses of methylone (99% and 96% reductions) was notably greater than that of fluoxetine (56%, Figure 5A). These data also demonstrate that methylone is superior to other hallucinogenic drugs. Previous reports of ketamine administration have shown reductions in immobility (reviewed in Weston et al., (2021) Frontiers in Psychiatry 12:659052) of 30% (Hibicke et al., (2020) ACS Chem.Neurosci 11:864), 25-55% (Yang et al., (2013) Ups J Med Sci 118:3), or 60% (Tizabi et al., (2012) Neuroscience 213:72). LSD and psilocybin have been shown to improve immobility by 38% and 67%, respectively, in the FST (Hibicke, 2020). MDMA (5 or 10 mg / kg) has been reported to improve immobility by 45% and 78%, respectively, in Sprague Dawley rats (Majumder et al. (2011) Behav Pharmacol 22:758), but more stable effects were obtained in Flinders susceptible rats, a genetic model of depression (45% and 93%, respectively, ibid.). Binding studies confirmed methylone binding to 5HT, NE, and DA transporters.

[0151] In summary, methylone produced more robust antidepressant-like responses in the FST, a standard behavioral assay with robust specificity and selectivity for antidepressants, than the SSRI fluoxetine. The magnitude of effect of methylone in this test 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.

[0152] Taken together, these results demonstrate the utility of methylone in treating depression and other CNS 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.

[0153] Example 7: 2C-B in the FST: Effects on depression, anxiety, and PTSD In this example, we investigated whether 2C-B exerts rapid antidepressant-like effects in the rat forced swim test (FST); and the prototypic selective serotonin reuptake inhibitor (SSRI) fluoxetine was used as an antidepressant control.

[0154] method animal Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used in this study (studies were performed at Melior Discovery, Exton, PA). Rats were acclimated in 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 and two rats per cage. Animals had ad libitum access to food and water and were randomly assigned to treatment groups. Animal use and procedures were in accordance with established approved protocols by the IACUC committee, Melior Standard Operating Procedures (SOPs), and Transcend Therapeutics.

[0155] Forced swimming test For the FST test, rats were placed in a circular plexiglass container filled with water without escape mechanisms. 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. A 15-min habituation trial was performed on the first day, and a 5-min test was performed on the second day (24 h later). A time sampling method was used in which animals were observed every 5 seconds 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, 5, 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 min prior to FST testing. The experimenter was blinded to treatment.

[0156] 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 ​​less than 0.05 indicating statistical significance.

[0157] Results and Conclusions A single injection of 2C-B at either the medium or high dose produced an immediate antidepressant-like response in the rat FST, whereas the lowest dose had no effect (Figure 7). Typically, two to three SSRI antidepressant injections 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 exhibited a statistically significant reduction in immobility (Figure 7A) and a concomitant significant increase in swimming (Figure 7B), consistent with serotonergic activity. The magnitude of the effect of 2C-B at both the medium and high doses (50% and 53%, respectively) was nearly identical to that of the fluoxetine control group (56%). Climbing was significantly reduced only in the group receiving the high dose of 2C-B (Figure 7C), but the interpretation of this result is unclear.

[0158] In summary, 2C-B produced rapid antidepressant-like responses in the FST, a standard behavioral assay with robust specificity and selectivity for antidepressants, comparable to the SSRI fluoxetine. These results demonstrate the utility of 2C-B in treating depression and other CNS disorders for which antidepressants are effective, including but not limited to post-traumatic stress disorder (PTSD), anxiety disorders, obsessive-compulsive disorder (OCD), and fibromyalgia.

[0159] 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), and the effects are more potent than other antidepressants tested in this model. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for a variety of central nervous system (CNS) disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), anxiety disorders, obsessive-compulsive disorder (OCD), and fibromyalgia. MDMA-assisted psychotherapy is in clinical trials for the treatment of PTSD, but it is important to note that SSRIs inhibit the efficacy of MDMA-assisted therapy (Feduccia et al., (2021) Psychopharmacology 238:581). If a patient requires MDMA-assisted therapy, SSRI treatment must be stopped. SSRIs require a tapering and withdrawal period of many weeks, so patients may need a long period of withdrawal from the drug before they can begin MDMA treatment. This poses both treatment delivery and safety risks for individuals with 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.

[0160] method animal Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used in this study (studies were performed at Melior Discovery, Exton, PA). Rats were acclimated in 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 and two rats per cage. Animals had ad libitum access to food and water and were randomly assigned to treatment groups. Animal use and procedures were in accordance with established approved protocols by the IACUC committee, Melior Standard Operating Procedures (SOPs), and Transcend Therapeutics.

[0161] Drug treatment Fluoxetine (10 mg / kg, IP, Sigma Aldrich) or 0.9% sterile saline vehicle was administered 23.5, 5, and 1 h before FST testing. Methylone (5 or 15 mg / kg, IP; Cayman Chemical) or 0.9% saline vehicle was administered 30 min before 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 would yield submaximal responses in the FST, potentially allowing detection of immobility changes that could occur in either direction.

[0162] Forced swimming test In the FST test, rats were placed in a circular Plexiglas container filled with water and had no escape mechanism. The water temperature was maintained at 22-25°C and was changed for each animal. After the habituation period, rats were measured for immobility (stop struggling), activity, swimming time, and climbing time. Experimenters and scorers were blinded to the treatment groups. A 15-min habituation trial was performed on the first day, and a 5-min test was performed on the second day (24 h later). A time sampling method was used, where animals were observed every 5 seconds and scored for immobility, swimming, or climbing.

[0163] 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. Results and Conclusions Three pre-administrations of fluoxetine had no effect on immobility in response to a single dose of methylone (62% immobility improvement 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) improved immobility by 95% (p<0.0001) compared to vehicle, which is consistent with Example 6.

[0164] Methylone significantly enhanced climbing behavior (Figure 8C;F (4,31) = 5.786, p < 0.01); fluoxetine also significantly enhanced swimming behavior (Fig. 8D;F (4,31) = 6.063, p < 0.01); which are consistent with noradrenergic and serotonergic activity, respectively.

[0165] In summary, pretreatment with an SSRI (fluoxetine) was examined and did not affect the behavioral response to methylone in the rat FST. These findings indicate that methylone is distinct from MDMA and suggest that its behavioral efficacy is not subject to interference by SSRIs, as is the case with MDMA. These findings are particularly promising because SSRIs are first-line treatments for many CNS disorders, including PTSD, suggesting that patients could continue to take an SSRI while taking methylone without concern for potential reduced efficacy.

[0166] Example 9: Effects of methylone, 2-CB and MBDB in a mouse model of post-traumatic stress disorder (PTSD) Failure of fear extinction memory in patients is a hallmark of PTSD (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). Facilitating 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).

[0167] Effective PTSD treatments promote the dissociation of the traumatic memory from the patient's fear response, reducing the ability of traumatic memory cues to elicit a fear response. This is modeled in a mouse fear extinction paradigm carried out 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, foot shock). On the second day (extinction training), mice are trained to forget the association to the traumatic memory by presenting the CS six times (without the US) in a novel environment. On the third day (extinction recall), these mice are "tested" to see if the tone (CS) still elicits a fear response, measured as the time spent freezing when the tone is presented. A reduction in the freezing time indicates a good extinction recall. If a drug that improves extinction recall also reduces freezing time on the third day, this would suggest potential for the treatment of PTSD.

[0168] Studies with MDMA have shown that after fear conditioning, extinction recall is enhanced by administration of MDMA (7.5 mg / kg) 30 minutes prior to extinction training, as measured by a 35% reduction in freezing compared to saline-injected controls (Young et al., (2015) Transl Psychiatry 5:e634).

[0169] Using the experimental design shown in Figure 9A, the results show that methylone (30 mg / kg) significantly enhanced (approximately 60%) fear extinction recall compared to saline controls (Figure 9B). It is noteworthy that there were no between-group differences in locomotor activity recorded for the duration of the test session, as effects on locomotor activity could confound the interpretation of these results (Figure 9C).

[0170] 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 in the first trial of extinction training on day 2 (Figure 10 A), and an associated small but significant increase in locomotor activity on day 2 (Figure 10 B).

[0171] Example 10: Pretreatment with selective serotonin reuptake inhibitors (SSRIs) does not inhibit the efficacy of methylone in the rat forced swimming test The open field test (OFT) exploits rodents' innate fear of open spaces to assess anxiety-like behavior: increased time spent in the center of the open field reflects anxiolytic (anti-anxiety) effects.

[0172] A single dose of methylone (5 or 15 mg / kg, IP), administered 30 min before 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. Compared to vehicle controls, a dose of 5 mg / kg methylone had no effect, whereas doses of 15 or 30 mg / kg methylone significantly increased locomotor activity (Figure 11B).

[0173] Example 11: In the rat forced swimming test, two or three low doses of methylone produce a stable antidepressant-like effect comparable to that of a single higher dose. This study investigated whether repeated low doses of methylone have antidepressant-like effects in the forced swimming test (FST) and how these responses compare to single higher doses that have been shown to have maximal effects in the FST. Results showed that a stable antidepressant-like response to methylone was observed in C max or AUC.

[0174] method Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used. Rats were acclimated in 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 and two rats per cage. Animals were fed standard rodent chow and water ad libitum and randomly assigned to treatment groups.

[0175] Methylone hydrochloride (5-15 mg / kg) was formulated in a sterile saline vehicle prior to intraperitoneal administration. Control animals received saline vehicle. A scheme for the dosing schedule and experimental design is shown in Figure 12A.

[0176] The FST was performed and scored according to a standard protocol in a "modified FST" (Slattery and Cryan (2012) Nat Protoc, 7:1009) by an experimenter blinded to treatment groups. Briefly, rats were placed in circular Pyrex glass containers (29.2 cm diameter, 49.5 cm height) filled with water to a depth of 30 cm; this prevented the rats from supporting themselves with their feet on the bottom of the tank. Water was kept at 22-25°C and was changed between animals. A 15-min acclimation trial was conducted on day 1 (training) and a 5-min test was conducted on day 2 (testing, 24 h later). Using a time-sampling method, animals were observed every 5 s over the course of the test session (60 counts or 5 min) and scored for immobility (defined as cessation of struggling), swimming (defined as circular movement around the tank), or climbing (defined as upward escape behavior). Data were expressed as the percentage of time during the 5 min test session during which immobility, swimming, or climbing occurred (eg, number of immobility bouts divided by 60).

[0177] result Consistent with what has been shown above, methylone produced rapid and stable antidepressant-like effects on immobility (F (5,32) =17.67, p<0.0001). (5,32) =17.67, p<0.0001) and swimming (F (5,32) = 17.67, p < 0.0001). Specifically, single doses of 10 and 15 mg / kg methylone produced robust antidepressant-like effects in the FST, significantly shortening immobility time (Figure 12B). In the current experimental design (Figure 12A), the additional stress caused by repeated intraperitoneal injections is likely the primary cause of the overall increased immobility in the 5 and 10 mg / kg groups compared to the previous experiment.

[0178] Notably, two or three doses of 5 mg / kg also significantly reduced immobility. There was no significant difference between the two doses of 5 mg / kg and 10 mg / kg or the three doses of 5 mg / kg and 15 mg / kg, respectively, indicating that the antidepressant-like effect of methylone was due to the AUC but not the C. max This suggests that this is not due to the effects of methylone on the immune system. Using the allometric dose scaling method, a 5 mg / kg dose in rats corresponds to approximately a 50 mg dose in humans, which was the dose with no detectable side effects in a recent clinical trial (Poyatos et al. (2022) Int J Mol Sci, 23:14636). These results support the idea that repeated administration of methylone at lower doses can have beneficial effects, but potentially reduce side effects.

[0179] Example 12: Methylone exhibits no agonist or antagonist activity against 168 different GPCRs in a β-arrestin-based screen DiscoverX GPCR arrestin was used in a screen to test methylone activity against 168 GPCRs to identify potential interactions with a selection of known or orphan GPCR targets. Two concentrations of methylone (1 and 10 micromolar) were used to test for agonist or antagonist activity against the receptors listed below in a β-arrestin-based in vitro screen.

[0180] method Amplification of PathHunter cell lines from frozen stocks was performed according to standard methods. Cells were seeded into white-walled 384-well microplates in a total volume of 20 μL and incubated at 37° C. for the appropriate time before testing.

[0181] For agonist assays, cells were incubated with samples to induce a response. Five samples were prepared by intermediate dilutions of sample stock in assay buffer. 5 μL of sample (5×) was added to cells and incubated at 37°C or room temperature for 90–180 min. Vehicle concentration was 1%.

[0182] To determine whether the antagonist was present, cells were preincubated with the antagonist and then incubated with EC 80 Agonists were added at 6×EC. Sample stocks were intermediately diluted in assay buffer to create 5 samples. 5 μL of sample (5×) was added to cells and incubated at 37° C. or room temperature for 30 minutes. Vehicle concentration was 1%. 6×EC 80 Five microliters of assay buffer containing agonist was added to the cells and incubated at 37°C or room temperature for 90-180 minutes.

[0183] The assay signal was developed by a single addition of 12.5 or 15 μL of PathHunter detection reagent cocktail (50% v / v) followed by a 1 hour incubation at room temperature. After chemiluminescent signal development, the microplate was read on a PerkinElmer Envision™ instrument to detect the signal.

[0184] Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). For agonist mode assays, percent activity was calculated using the following formula: Activity (%)=100%×(mean RLU of test sample−mean RLU of vehicle control) / (mean MAX control ligand−mean RLU of vehicle control).

[0185] For antagonist and negative allosteric assays, the percent inhibition was calculated using the following formula: Inhibition (%)=100%×(1−(mean RLU of test sample−mean RLU of vehicle control) / (mean RLU of EC80 control−mean RLU of vehicle control)).

[0186] Activation of GPCRs by compounds that act as agonists results in increased β-arrestin recruitment to the target GPCR. To determine whether a compound potentially acts as an agonist, activity must be greater than 30%. Inhibition of GPCR activation by compounds that act as ligand binding antagonists results in decreased β-arrestin recruitment to the target GPCR. To determine whether a compound potentially acts as an antagonist that inhibits activation, inhibition must be greater than 50%.

[0187] result At concentrations of 1 and 10 micromolar, methylone did not meet the criteria for either agonist or antagonist activity against any of the 168 GPCRs tested. These data indicate that in a β-arrestin-based screen, methylone activity is highly specific for the monoamine transporters SERT, DAT, and NET, with no interactions observed with select known or orphan GPCR targets.

[0188] Example 13: MBDB exerted rapid and stable antidepressant-like effects in the forced swimming test (FST) MBDB is an alpha-ethyl analog of MDMA. In this study, we investigated whether MBDB exhibits antidepressant-like effects in the rat forced swimming test (FST). The FST is a classic behavioral test that has been used for over 40 years to screen for drugs with antidepressant-like effects. All types of antidepressants, including serotonergic antidepressants, tricyclic antidepressants, and even more rapidly acting antidepressants such as ketamine, have been shown to improve immobility in the FST, which is consistent with an antidepressant-like effect. Furthermore, drugs acting on the serotonin and norepinephrine systems increase swimming and climbing behaviors, respectively, in the FST. Therefore, we examine these behaviors to gain insight into the mechanisms underlying the development of antidepressant-like behavioral responses.

[0189] method Male Sprague Dawley rats (Charles River Laboratories) weighing 180-200 g on arrival were used. Rats were acclimated in 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 and two rats per cage. Animals were fed standard rodent chow and water ad libitum and randomly assigned to treatment groups.

[0190] Prior to intraperitoneal administration, animals were formulated with MBDB (15–45 mg / kg) in sterile saline vehicle. Control animals received saline vehicle.

[0191] The FST was performed and scored according to a "modified FST" method according to standard protocols by an experimenter who was blinded to the treatment groups. Briefly, rats were placed in circular Pyrex glass containers (29.2 cm diameter, 49.5 cm height) filled with water to a depth of 30 cm; therefore, the rats were unable to support themselves with their feet on the bottom of the tank. The water was kept at 22-25°C and was changed for each animal. A 15-min acclimation trial was performed on the first day (training) and a 5-min test was performed on the second day (testing, 24 h later). Using a time-sampling method, animals were observed every 5 seconds over the course of the test session (60 counts or 5 min) and scored for immobility (defined as cessation of struggling), swimming (defined as circular movement around the tank), or climbing (defined as upward escape behavior). Data were expressed as the percentage of time during the 5 min test session during which immobility, swimming, or climbing occurred (eg, number of immobility bouts divided by 60).

[0192] result MBDB significantly improved immobility at all doses tested (15–30 mg / kg) (F (3,24) = 55.0, p < 0.0001) (Figure 13A). Climbing was significantly reduced only at the highest dose (Figure 13B) (F (3,24)= 5.649, p < 0.01); on the other hand, swimming was consistently increased at all doses tested (Figure 13C) (F (3,24) = 42.503, p < 0.001). These results indicate that MBDB has a robust antidepressant-like activity. Furthermore, because the increase in swimming behavior in the FST was associated with an increase in serotonergic activity, the data also suggest that MBDB exerts its antidepressant-like activity primarily through its action on the serotonergic system.

[0193] Example 14: Pilot Study to Evaluate the Use of Methylone in Treating PTSD Methylone is a potentially effective novel treatment option for participants with PTSD. The purpose of this pilot study is to evaluate the safety, tolerability, and efficacy of methylone in adult participants with PTSD. The study will be conducted in two parts. Part A will be an open-label enrollment of up to 15 evaluable participants with PTSD. After completion of Part A, enrollment will open for Part B; which will be double-blind, placebo-controlled, and will enroll up to 64 evaluable participants with PTSD.

[0194] Objectives and Endpoints This is a two-part study with Part A focusing on safety as the primary objective and Part B focusing on efficacy as the primary objective. Therefore, each part of the study has different objectives and endpoints as shown in the table below.

[0195] [Table 6] TIFF2025510790000011.tif175132

[0196] Overall Design Quick Overview This is a two-part study evaluating methylone for PTSD symptom management. Part A is an open-label, uncontrolled evaluation in up to 15 evaluable participants with PTSD to assess initial safety and efficacy, and to validate the methods included in the blinded portion of the study (Part B). After completion of Part A, Part B will open for enrollment with up to 64 participants. Part B is identical to Part A except that Part B will include a placebo group.

[0197] Open-label treatments in Part A are: · 150 mg methylone in each dosing session, with a 100 mg booster dose 90 (± 10) minutes after the first dose.

[0198] Part B is a randomized, double-blind, parallel-group, placebo-controlled evaluation of methylone for the management of PTSD symptoms.

[0199] Enrollment will include up to 79 evaluable participants (up to 15 in Part A and up to 64 in Part B). Part B will initially enroll up to 40 evaluable participants with an interim analysis to determine if a larger sample size is required. Four dosing sessions are planned for each participant. Part B participants will be randomized 1:1 into two study treatment arms and will receive their randomized treatment during each of the weekly dosing sessions during the study.

[0200] The two blinded study arms in Part B are: In each dosing session, 150 mg of methylone will be administered, followed by a 100 mg booster dose 90 (± 10) minutes after the first dose. Each dosing session will have a matching placebo at each time point (initial dose + booster dose).

[0201] For each participant in Parts A and B, the study consisted of: Screening Period (Day -28 to Day -4): Informed consent, eligibility assessment, and enrollment of eligible participants. Baseline / Preliminary Session (Day -3 to Day -1): Baseline assessment, eligibility confirmation, and preparatory psychoeducation session leading to enrollment confirmation. Treatment Period (Days 1-24): 4 weekly dosing sessions with associated remote sessions. The dosing sessions last at least 8 hours or until all effects (physical and psychological) have worn off (whichever is longer). Each dosing session is followed by a safety call the day after dosing and an efficacy assessment 2 days after dosing. Each dosing session is videotaped for quality and training purposes. Videos may be reviewed to ensure mentor adherence to mentor training. Follow-up Period (Days 29-64): Safety and efficacy follow-up visits 1, 2, 3, and 6 weeks after the last dose of study drug. Additionally, Mentor-Led Reflection Sessions will be conducted 1, 2, and 3 weeks after the last dose of study drug. Participants will be contacted by phone on Day 57 (± 2 days) for follow-up. Discontinuation: Participants who discontinue early will have a duplicate 6-week End of Study (EOS) visit but will be asked to return for an additional End of Study (EOS) visit.

[0202] The planned duration of participation for each participant who completes all study visits from screening through the end-of-study visit is up to 16 weeks.

[0203] Study Participants Participants were medically healthy adults aged 18-65 years. Participants must meet criteria for a current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of moderate to severe PTSD with at least 6 months symptom duration at screening, as assessed by the Mini International Neuropsychiatric Interview (MINI) 7.0.2, CAPS-5, and the LEC-5 Event Checklist. Participants must have failed at least one type of PTSD treatment (either psychotherapy or pharmacological treatment).

[0204] Additionally, participants must not have a primary diagnosis of any other DSM-5 disorder as assessed by MINI version 7.0.2, or have any medical history, physical or psychological symptoms, medications, or other relevant findings that would disqualify them from the study based on the clinical judgment of the study personnel.

[0205] Duration of treatment The treatment duration for both parts A and B will be identical, administered once weekly for 4 weeks (days 1, 8 [± 1 day], 15 [± 1 day], and 22 [± 1 day]).

[0206] Data Monitoring The purpose of the Data and Safety Monitoring Board (DSMB) is to review the safety data (Parts A and B), review the interim analysis reports, and provide advice on sample size expansion for Part B.

[0207] One DSMB meeting is planned at the end of enrollment in Part A after the 8 participants in Part A have completed their day 29 follow-up visit or after EOS if a participant is discontinued early (run-in).

[0208] For Part B, DSMB meetings will occur approximately every 20 participants (10 per treatment group). At least two DSMB meetings will be scheduled. The first DSMB meeting will be after 20 participants have completed the Day 29 follow-up visit or after EOS if participants discontinue early, and will include an interim efficacy report to determine whether the sample size is adequate. After the Day 29 follow-up visit or after EOS if participants discontinue early (sample size assessment). If more than 40 participants are expected to be enrolled, a second DSMB meeting will be held after at least 40 participants have completed the study. Ad hoc special DSMB meetings will be conducted as needed.

[0209] The interim analysis focuses on the CAPS-5 data and uses this analysis only for sample size estimation. There are no stopping rules for either efficacy or futility.

[0210] Dose and Route of Administration During each dosing session, participants will fast for 2 hours before dosing and for 2 hours after the first dose. Methylone (or matching placebo in Part B) will be administered orally on days 1, 8 (± 1 day), 15 (± 1 day), and 22 (± 1 day). An initial dose of 150 mg methylone (or matching placebo in Part B) will be boosted 90 (± 10) minutes later with 100 mg methylone (or matching placebo in Part B).

[0211] Evaluation criteria Safety will be assessed by adverse event (AE) reporting, monitoring for AESIs, 12-lead electrocardiograms, vital signs, physical examinations, and laboratory tests. Suicidal ideation and behavior will be assessed using the Columbia Suicide Rating Scale (C-SSRS).

[0212] Efficacy will be assessed through multiple psychological assessments and scales assessing PTSD symptoms and quality of life.

[0213] Additionally, assessments will be conducted regarding sleep quality, treatment outcome, and hallucinogenic effects.

[0214] statistical analysis For Parts A and B, safety parameters will be listed and summarized with descriptive statistics.

[0215] All efficacy endpoint data will be listed for individual participants. All continuous efficacy endpoints will also be summarized using descriptive statistics (n, arithmetic mean, standard deviation [SD], median, minimum, and maximum) for each study part, overall, (for Part B) treatment, and study period. All categorical efficacy endpoints will be summarized using descriptive statistics (n, percentage (%)).

[0216] For Part A, changes from baseline to each time point are expressed as two-tailed t-test p values.

[0217] For the analysis of between-treatment differences in Part B, we fit a repeated measures mixed model to the selected efficacy endpoints. The model includes treatment as a fixed effect, but visit and outpatient treatment are mixed effects. We include baseline values ​​(if available) as covariates and participant as a random effect. We use an alpha of 0.1 for this analysis.

[0218] Example 15: Methylone binds to the serotonin transporter (SERT) in a manner distinct from that bound by MDMA MDMA binds to the central (i.e., site where serotonin and serotonergic antidepressants bind) as well as allosteric sites of the serotonin transporter (SERT) (Islas et al. (2021) Heliyon e07784; Islas and Scior (2022) Molecules 27:2977). Allosteric binding of MDMA to SERT is presumed to be responsible for the supraphysiological increase in serotonin release and presynaptic serotonin depletion, as well as the SSRI antidepressant inhibition reported in patients and animal models (Feduccia et al. (2021) Psychopharmacology 238:581; Callaway et al. (1990) J Pharmacol Exp Ther, 254:456; Geyer (1994) Neuropsychopharmacology 10:768S).

[0219] To clarify whether methylone acts orthosterically or allosterically on SERT, a range of concentrations of 3 Serotonin (5HT) uptake was examined using [H]5HT in the presence or absence of methylone. 3 If [H]5HT counteracts the effect of methylone, this would suggest competitive inhibition (i.e., orthosteric inhibition). d (i.e., increase its value), but B max In the presence of methylone (two different methylone concentrations), 3 Three types of hot saturation curve experiments were performed using [H]5HT.

[0220] The results shown in FIG. 14 show that methylone inhibits K d The right shift of B indicates that the interaction of methylone with SERT is competitive. Furthermore, the inhibition by methylone was negated with increasing 5HT concentration, so B max No decrease occurred.

[0221] The fact that methylone apparently only binds to the core of SERT and not allosterically like MDMA provides a mechanistic explanation for why methylone does not deplete serotonin like MDMA does (Baumann et al. (2012) Neuropsychopharmacology 37:1192), suggesting improved safety. These results may also shed light on why SSRI antidepressants block the action of MDMA (Feduccia et al. (2021) Psychopharmacology 238:581) but not methylone (Warner-Schmidt et al. (January 10, 2023) Frontiers in Psychiatry).

[0222] Example 16: Unlike MDMA, methylone does not bind to the 5HT2B receptor, a positive differentiator for methylone regarding cardiovascular safety Agonists of the serotonin 5HT2B receptor are strongly involved in mediating drug-induced valvular heart disease. Indeed, in drug discovery, 5HT2B agonism is considered a toxic signal (Cavero et al. (2014) Journal of Pharmacological and Toxicological Methods 69:150). MDMA has been shown to be a nonselective agonist of the 5HT2B receptor (Setola et al. (2003) Molecular Pharmacology 63:1223). In this example, methylone was tested by competitive radioligand binding to determine whether it exhibits any affinity for the 5HT2B receptor.

[0223] method Screening of racemic methylone hydrochloride and reference compound SB204741 was performed using human serotonin 5HT2B receptor membrane preparations. Compounds were dissolved in DMSO (10 mM) and stored frozen at -20°C. On the day of the assay, compounds were thawed and diluted in assay buffer to 5x the final maximum assay concentration (e.g., if the final assay concentration was 10 μM, dilute to 50 μM). Human serotonin 5HT2B receptor membranes were dispensed. On the day of the assay, membranes were diluted 1:200 in incubation buffer. Assays were performed in a 96-well plate with a final volume of 250 μL per well. Each well received 150 μL of membrane preparation, 50 μL of test compound, non-specific compound, or buffer alone, and 50 μL of radioligand. Plates were incubated at 35°C for 90 minutes with gentle shaking. Incubation was terminated by vacuum filtration through presoaked GF / C filters using a 96-well FilterMate™ harvester, followed by five washes with ice-cold wash buffer. Filters were then dried using a stream of warm air, sealed in polyethylene, scintillation cocktail was added, and radioactivity was counted using a Wallac® TriLux 1450 MicroBeta counter. Specific binding was obtained by subtracting nonspecific binding from total binding for each drug concentration. Data were fitted using conventional nonlinear curve fitting in Prism® (Graphpad Software Inc) to obtain IC 50 was then determined using the ChengPrusoff equation. i was calculated.

[0224] result As shown in Figure 15, IC 50 = 4285nM and K i = 3749 nM, and methylone showed no affinity for the 5HT2B receptor. In contrast, Ki values ​​of 500 nM and 100 nM have been reported for MDMA and its metabolite MDA, respectively, which is 7.5-37 times higher 5HT2B receptor affinity compared to methylone.

[0225] Taken together, these data strongly suggest improved cardiovascular safety with methylone compared with MDMA.

[0226] 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 is 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. 1. A composition for treating and / or preventing a neuropsychiatric disorder and / or ameliorating a symptom thereof in a subject in need thereof, the composition comprising a therapeutically effective amount of methylone (3,4-methylenedioxy-N-methylcathinone).

2. A composition for treating and / or preventing a neuropsychiatric disorder and / or ameliorating a symptom thereof in a subject in need thereof, the composition comprising a therapeutically effective amount of MBDB (N-methyl-1-(1,3-benzodioxol-5-yl)-2-aminobutane).

3. A composition for treating and / or preventing a neuropsychiatric disorder and / or ameliorating its symptoms in a subject in need thereof, the composition comprising a therapeutically effective amount of 2C-B (4-bromo-2,5-dimethoxyphenethylamine).

4. 4. The composition according to any one of claims 1 to 3, wherein the neuropsychiatric disorder is a depressive disorder or post-traumatic stress disorder (PTSD).

5. 3. The composition of claim 1 or 2, wherein the neuropsychiatric disorder is an anxiety disorder.

6. 4. The composition of claim 1 or 3, wherein the neuropsychiatric disorder is fibromyalgia.

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

8. 4. The composition of claim 3, wherein the neuropsychiatric disorder is somatic symptom disorder.

9. 4. The composition of any one of claims 1 to 3, wherein the methylone, MBDB, or 2C-B is administered at a dose of 5 to 250 mg or at a dose of 0.08 to 4 mg / kg.

10. 4. The composition of any one of claims 1 to 3, wherein the composition comprising methylone, MBDB, or 2C-B is administered once a week or more than once a week, for example, twice a week, three times a week, four times a week, five times a week, or six times a week.

11. The composition of any one of claims 1 to 3, wherein the neuropsychiatric disorder is treatment-resistant.

12. The composition of any one of claims 1 to 3, wherein the subject is suicidal.

13. 4. The composition of any one of claims 1 to 3, wherein the composition comprising methylone, MBDB, or 2C-B is used in combination with an additional therapy for the neuropsychiatric disorder, for example, wherein the additional therapy is psychotherapy, or wherein the additional therapy comprises administering one or more additional psychoactive substances to the subject.

14. 14. The composition of claim 13, wherein the additional psychoactive substance is selected from a selective serotonin reuptake inhibitor (SSRI), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a serotonin-norepinephrine-dopamine reuptake inhibitor (SDNRI), and an anxiolytic, e.g., wherein the additional psychoactive substance is a selective serotonin reuptake inhibitor (SSRI) and wherein the subject is taking, or is taking continuously, the SSRI in combination with the methylone, MBDB, or 2C-B.

15. 4. The composition of any one of claims 1-3, wherein an initial dose of methylone, MBDB, or 2C-B is administered to the subject, followed by augmentation 30 minutes to 4 hours later by administering a second dose of each of methylone, MBDB, or 2C-B in an amount that is about 10% to 100% of the initial dose.

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