Methylone
3,4-methylenedioxy-N-methylcathinone
Studies and references cited across this article, graded by evidence strength.
Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.
Data points an editor reviewed and accepted for publication.
Value Provenance
Dosing
oraltrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Threshold | 75 mg | 75 mg | low |
| Low | 75–150 mg | 75–150 mg | low |
| Common | 150–225 mg | 150–225 mg | low |
| Strong | 225–325 mg | 225–325 mg | low |
| Heavy | 325+ mg | 325+ mg | low |
| Editorial | Dose ranges from community consensus databases (seed data: threshold 75 mg, light 75-150 mg, common 150-225 mg, strong 225-325 mg, heavy 325+ mg). No controlled human dose-finding study exists. The Phase 2 PTSD trial used oral dosing but therapeutic doses have not been publicly disclosed. These community values are carried forward for editorial review. | ||
ReasoningReasoningDose ranges from community consensus databases (seed data: threshold 75 mg, light 75-150 mg, common 150-225 mg, strong 225-325 mg, heavy 325+ mg). No controlled human dose-finding study exists. The Phase 2 PTSD trial used oral dosing but therapeutic doses have not been publicly disclosed. These community values are carried forward for editorial review. Evidence basis: community_consensus_large | |||
Duration
oral
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Onsettrace | 15–45 minutes | 15–45 minutes | low |
| Editorial | Community-reported onset 15-45 min. Consistent with rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No human PK published. | ||
ReasoningReasoningCommunity-reported onset 15-45 min. Consistent with rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No human PK published. Evidence basis: community_consensus_large | |||
| Come uptrace | 15–30 minutes | 15–30 minutes | low |
| Editorial | Inferred from community reports and MDMA analogy. No published human data. | ||
ReasoningReasoningInferred from community reports and MDMA analogy. No published human data. Evidence basis: community_consensus_large | |||
| Peaktrace | 60–90 minutes | 60–90 minutes | low |
| Editorial | Community-reported peak 60-90 min. Consistent with short duration of action observed in rat behavioral assays (Štefková et al. 2017). | ||
ReasoningReasoningCommunity-reported peak 60-90 min. Consistent with short duration of action observed in rat behavioral assays (Štefková et al. 2017). Evidence basis: community_consensus_large | |||
| Offsettrace | 30–60 minutes | 30–60 minutes | low |
| Editorial | Inferred from community total duration minus onset/come-up/peak. No specific offset data published. | ||
ReasoningReasoningInferred from community total duration minus onset/come-up/peak. No specific offset data published. Evidence basis: community_consensus_large | |||
| Totaltrace | 2.5–4 hours | 2.5–4 hours | low |
| Editorial | Community-reported total duration 2.5-4 hours. Consistent with short pharmacokinetic profile in rats (Štefková et al. 2017). No controlled human duration study published. | ||
ReasoningReasoningCommunity-reported total duration 2.5-4 hours. Consistent with short pharmacokinetic profile in rats (Štefková et al. 2017). No controlled human duration study published. Evidence basis: community_consensus_large | |||
| After effectstrace | 2–4 hours | 2–4 hours | low |
| Editorial | Residual stimulation and mood effects after acute experience ends. Inferred from stimulant/entactogen class and user reports. No published data. | ||
ReasoningReasoningResidual stimulation and mood effects after acute experience ends. Inferred from stimulant/entactogen class and user reports. No published data. Evidence basis: community_consensus_large | |||
Safety
Toxicity Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Acute | high | high | medium |
| Chronic | moderate | moderate | medium |
| Organs Affected | cardiovascular, liver, kidney, brain, thermoregulation | cardiovascular, liver, kidney, brain, thermoregulation | medium |
| Editorial | Acute toxicity classified as high based on multiple independent forensic case reports documenting fatalities in both predisposed (Kovács et al. 2012) and previously healthy (Carbone et al. 2013) individuals, plus systematic review confirmation (Zaami et al. 2018). Steep dose-response at high doses in rats (Štefková et al. 2017). Chronic toxicity classified as moderate: liver steatosis documented in one fatal case, but long-term human data are absent and rat data show no MDMA-like serotonergic neurotoxicity (Baumann et al. 2012; Angoa-Pérez et al. 2017), warranting downgrade from high. | ||
ReasoningReasoningAcute toxicity classified as high based on multiple independent forensic case reports documenting fatalities in both predisposed (Kovács et al. 2012) and previously healthy (Carbone et al. 2013) individuals, plus systematic review confirmation (Zaami et al. 2018). Steep dose-response at high doses in rats (Štefková et al. 2017). Chronic toxicity classified as moderate: liver steatosis documented in one fatal case, but long-term human data are absent and rat data show no MDMA-like serotonergic neurotoxicity (Baumann et al. 2012; Angoa-Pérez et al. 2017), warranting downgrade from high. Evidence basis: published_case_series | |||
Dependence Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Physical | low | low | medium |
| Psychological | moderate | moderate | medium |
| Compulsive Redosing | moderate | moderate | medium |
| Dose Escalation | low | low | medium |
| Editorial | Reinforcing effects demonstrated in rat self-administration (Watterson et al. 2012). DAT substrate activity associated with addiction risk (Simmler et al. 2013). No dose escalation in long-access paradigms distinguishes methylone from cocaine/methamphetamine. No human dependence studies published. | ||
ReasoningReasoningReinforcing effects demonstrated in rat self-administration (Watterson et al. 2012). DAT substrate activity associated with addiction risk (Simmler et al. 2013). No dose escalation in long-access paradigms distinguishes methylone from cocaine/methamphetamine. No human dependence studies published. Evidence basis: animal_study | |||
Withdrawal Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Severity | none | none | low |
| Symptoms | — | — | low |
| Fatal | No | No | low |
| Medical Supervision | Not required | Not required | low |
| Editorial | No published human or animal study characterizes methylone withdrawal. Classified as not established rather than absent. | ||
ReasoningReasoningNo published human or animal study characterizes methylone withdrawal. Classified as not established rather than absent. Evidence basis: animal_study | |||
Tolerance Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Buildup | moderate | moderate | low |
| Half-life | 14 days | 14 days | low |
| Full Reset | 31 days | 31 days | low |
| Cross-tolerances | mdma, amphetamine, mephedrone, methamphetamine | mdma, amphetamine, mephedrone, methamphetamine | low |
| Editorial | Values carried forward from existing community consensus database. Mechanism inferred from MDMA/stimulant class pharmacology. No substance-specific tolerance data published. | ||
ReasoningReasoningValues carried forward from existing community consensus database. Mechanism inferred from MDMA/stimulant class pharmacology. No substance-specific tolerance data published. Evidence basis: community_consensus_large | |||
Effects & Profile
Contraindications
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| hepatic hepatic impairmenttrace | relative | relative | low |
| Editorial | Hepatic steatosis documented in Kovács et al. 2012 fatality. CYP metabolism role inferred from MDMA analogy. | ||
ReasoningReasoningHepatic steatosis documented in Kovács et al. 2012 fatality. CYP metabolism role inferred from MDMA analogy. | |||
| pregnancy breastfeeding pregnancy and breastfeedingtrace | absolute | absolute | low |
| Editorial | No substance-specific data. Contraindication based on pharmacological class risk (sympathomimetic + serotonergic activity during pregnancy). Standard precautionary classification. | ||
ReasoningReasoningNo substance-specific data. Contraindication based on pharmacological class risk (sympathomimetic + serotonergic activity during pregnancy). Standard precautionary classification. | |||
| cardiovascular congenital heart diseasetrace | absolute | absolute | high |
| Editorial | Directly supported by published case report: Kovács et al. 2012 documented fatal cardiac arrest in a patient with pre-existing cardiac malformation at relatively low methylone blood concentration. | ||
ReasoningReasoningDirectly supported by published case report: Kovács et al. 2012 documented fatal cardiac arrest in a patient with pre-existing cardiac malformation at relatively low methylone blood concentration. | |||
| cardiovascular long QT syndrometrace | absolute | absolute | medium |
| Editorial | Mechanism supported by Banks et al. 2014 (arrhythmia risk from sympathomimetic cathinones). Class-level cardiovascular contraindication. | ||
ReasoningReasoningMechanism supported by Banks et al. 2014 (arrhythmia risk from sympathomimetic cathinones). Class-level cardiovascular contraindication. | |||
| cardiovascular hypertensiontrace | relative | relative | medium |
| Editorial | Mechanism supported by sympathomimetic pharmacology (Baumann et al. 2012, Banks et al. 2014). Class-level stimulant contraindication. | ||
ReasoningReasoningMechanism supported by sympathomimetic pharmacology (Baumann et al. 2012, Banks et al. 2014). Class-level stimulant contraindication. | |||
| respiratory asthmatrace | relative | relative | medium |
| Editorial | Directly identified as a predisposing factor in Kovács et al. 2012 fatality case report. | ||
ReasoningReasoningDirectly identified as a predisposing factor in Kovács et al. 2012 fatality case report. | |||
| psychiatric psychotic disorderstrace | absolute | absolute | medium |
| Editorial | Psychosis and excited delirium documented with synthetic cathinones (Daziani et al. 2023). Class-level dopaminergic stimulant contraindication. | ||
ReasoningReasoningPsychosis and excited delirium documented with synthetic cathinones (Daziani et al. 2023). Class-level dopaminergic stimulant contraindication. | |||
| other concurrent MAOI usetrace | absolute | absolute | high |
| Editorial | Class-level serotonergic drug interaction. Mechanism supported by Liechti 2015. | ||
ReasoningReasoningClass-level serotonergic drug interaction. Mechanism supported by Liechti 2015. | |||
| cardiovascular cardiac arrhythmiatrace | absolute | absolute | high |
| Editorial | Sudden cardiac death documented as primary fatal mechanism (Carbone et al. 2013). Catecholamine-mediated arrhythmia risk (Banks et al. 2014). | ||
ReasoningReasoningSudden cardiac death documented as primary fatal mechanism (Carbone et al. 2013). Catecholamine-mediated arrhythmia risk (Banks et al. 2014). | |||
| other concurrent SSRI/SNRI usetrace | relative | relative | medium |
| Editorial | Class-level serotonergic interaction risk (Liechti 2015; Luethi & Liechti 2020). | ||
ReasoningReasoningClass-level serotonergic interaction risk (Liechti 2015; Luethi & Liechti 2020). | |||
| pregnancy breastfeeding pregnancy and lactationtrace | absolute | absolute | medium |
| Editorial | No reproductive safety data. High BBB permeability (Štefková et al. 2017). Precautionary absolute contraindication. | ||
ReasoningReasoningNo reproductive safety data. High BBB permeability (Štefková et al. 2017). Precautionary absolute contraindication. | |||
Timeline Phases
oral
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Onsettrace | 900–2700 sec(i=0.05) | 900–2700 sec(i=0.05) | low |
| Editorial | Timeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | ||
ReasoningReasoningTimeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | |||
| Peaktrace | 3600–5400 sec(i=1.00) | 3600–5400 sec(i=1.00) | low |
| Editorial | Timeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | ||
ReasoningReasoningTimeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | |||
| Plateautrace | 1800–3600 sec(i=0.50) | 1800–3600 sec(i=0.50) | low |
| Editorial | Timeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | ||
ReasoningReasoningTimeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | |||
| Resolutiontrace | 1800–3600 sec(i=0.20) | 1800–3600 sec(i=0.20) | low |
| Editorial | Timeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | ||
ReasoningReasoningTimeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | |||
| Afterglowtrace | 7200–14400 sec(i=0.05) | 7200–14400 sec(i=0.05) | low |
| Editorial | Timeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | ||
ReasoningReasoningTimeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | |||
| Come uptrace | 900–1800 sec(i=0.30) | 900–1800 sec(i=0.30) | low |
| Editorial | Timeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | ||
ReasoningReasoningTimeline derived from community-reported duration data (onset 15-45 min, peak 60-90 min, total 2.5-4 hours) anchored by rat PK showing Tmax at 30 min s.c. (Štefková et al. 2017). No controlled human duration study has been published. Phase durations are community consensus values. | |||
Dose Tier Summaries
At threshold doses (~75 mg oral), effects are subtle and may be difficult to distinguish from placebo or caffeine. A mild increase in wakefulness and slight mood elevation are the most commonly reported features, sometimes accompanied by a faint sense of enhanced sociability or emotional openness. Physically, mild pupil dilation and a slight increase in heart rate may occur. Most users report no significant body load at this level. Functional impairment is minimal. Sleep may be delayed by 1–2 hours if taken in the evening.
No controlled human dose-finding study exists for methylone. Threshold value (75 mg oral) derives from community consensus databases. Experiential description inferred from MDMA threshold analogy and user report literature.
ReasoningReasoning
No controlled human dose-finding study exists for methylone. Threshold value (75 mg oral) derives from community consensus databases. Experiential description inferred from MDMA threshold analogy and user report literature.
Evidence basis: community_consensus_large
At common doses (150–225 mg oral), the full entactogenic-stimulant experience emerges. Pronounced empathogenic warmth, euphoria, and enhanced emotional openness characterize the peak. Social interactions feel deeply engaging, and sensory appreciation — particularly of music and tactile stimulation — intensifies. Thought acceleration is marked, and introspective or emotionally significant thoughts may arise. Physically, tachycardia, jaw tension (bruxism), sweating, and elevated body temperature become more prominent. Appetite suppression is typical. Mild to moderate peripheral vasoconstriction may produce cold extremities. Sleep is unlikely for 3–5 hours post-ingestion. The total experience commitment is approximately 3–5 hours including residual stimulation.
Dose range from community consensus. Subjective effects described in review literature (Debruyne et al. 2014; Simmons et al. 2018) and inferred from pharmacological mechanism (non-selective monoamine release with preferential 5-HT).
ReasoningReasoning
Dose range from community consensus. Subjective effects described in review literature (Debruyne et al. 2014; Simmons et al. 2018) and inferred from pharmacological mechanism (non-selective monoamine release with preferential 5-HT).
Evidence basis: community_consensus_large
At strong doses (225–325 mg oral), stimulant and empathogenic effects reach high intensity. Euphoria and emotional openness may become overwhelming. Thought racing, compulsive talking, and difficulty maintaining a single conversational thread are common. The empathogenic component can produce intense feelings of connection and emotional vulnerability. Cardiovascular effects intensify: marked tachycardia, hypertension, pronounced bruxism, significant sweating, and substantial body temperature elevation. Nausea and headache may occur. The risk of hyperthermia increases meaningfully, especially in warm or crowded environments. Functional impairment is significant. Sleep is typically impossible for 4–6 hours. The comedown may include fatigue, low mood, and residual stimulation.
Dose range from community consensus. At these doses, sympathomimetic effects become safety-relevant. Hyperthermia risk supported by animal data (Štefková et al. 2017). Cardiovascular effects consistent with catecholamine release mechanism (Banks et al. 2014).
ReasoningReasoning
Dose range from community consensus. At these doses, sympathomimetic effects become safety-relevant. Hyperthermia risk supported by animal data (Štefková et al. 2017). Cardiovascular effects consistent with catecholamine release mechanism (Banks et al. 2014).
Evidence basis: community_consensus_large
At heavy doses (325+ mg oral), the experience is dominated by intense stimulation and carries substantially elevated medical risk. Euphoria may plateau or give way to anxiety, paranoia, and agitation. Compulsive redosing behavior has been reported at this level. Cognitive function is markedly impaired, with disorganized thinking and difficulty communicating coherently. Cardiovascular strain is severe: pronounced tachycardia, hypertension, and risk of cardiac arrhythmia. Hyperthermia risk is high, particularly in social or physically active settings. Bruxism, tremor, and nausea are common. Serotonin syndrome symptoms may emerge, especially with concurrent serotonergic substances. This dose range approaches reported postmortem concentrations in fatal cases. Medical emergency risk is substantial. Sleep is impossible for many hours, and the subsequent comedown may involve significant mood depression and physical exhaustion.
Heavy dose range from community consensus. Safety concerns strongly supported by forensic case data (Carbone et al. 2013; deRoux & Dunn 2017) and toxicity mechanisms (Banks et al. 2014). Fatal cases occurred at blood concentrations that may correspond to oral doses in this range, though exact dose-concentration relationships are unknown.
ReasoningReasoning
Heavy dose range from community consensus. Safety concerns strongly supported by forensic case data (Carbone et al. 2013; deRoux & Dunn 2017) and toxicity mechanisms (Banks et al. 2014). Fatal cases occurred at blood concentrations that may correspond to oral doses in this range, though exact dose-concentration relationships are unknown.
At light doses (75–150 mg oral), the stimulant and entactogenic character of methylone becomes apparent. Mood elevation is more pronounced, with increased energy, enhanced sociability, and mild empathogenic warmth. Thought acceleration and increased talkativeness are common. Music appreciation may be heightened. Physical effects include noticeable pupil dilation, elevated heart rate, mild jaw tension, and slight increases in body temperature. Some users report mild nausea during the come-up phase. The experience is generally manageable and does not preclude basic functional tasks, though concentration on complex work may be impaired.
Dose range from community consensus databases. Experiential profile inferred from review literature describing methylone as MDMA-like but less intense (Debruyne et al. 2014), combined with pharmacological profile (DA/NE/5-HT release).
ReasoningReasoning
Dose range from community consensus databases. Experiential profile inferred from review literature describing methylone as MDMA-like but less intense (Debruyne et al. 2014), combined with pharmacological profile (DA/NE/5-HT release).
Evidence basis: community_consensus_large
History
backfill Jun 4, 2026
Historical versions do not record which reviewer approved them; editorial accountability is recorded per value in the database and in the publication ledger going forward.
Sources
- [1]weakMethylone chemistry and history (Discovery by Jacob and Shulgin, patent 1996)Multiple sources · 2013linkno claims checked
- [2]moderateDARK Classics in Chemical Neuroscience: Cathinone-Derived PsychostimulantsSimmons SJ, Leyrer-Jackson JM, Oliver CF, Hicks C, Muschamp JW, Rawls SM, Olive MF · 2018 · ACS Chemical Neuroscience
- [3]strongEfficacy and Safety of the Neuroplastogen TSND-201 for the Treatment of PTSD: A Randomized Clinical TrialJones A, Warner-Schmidt J, Kwak H, Stogniew M, Mandell B, Ching THW, Stein MB, Kelmendi B · 2026 · JAMA Psychiatrydoi.org/10.1001/jamapsychiatry.2025.4625pubmed 417064599 claims checked5 verified1 partial3 inconclusive
- [4]weakTranscend Therapeutics Receives Breakthrough Therapy Designation for TSND-201 (methylone) for the Treatment of PTSDTranscend Therapeutics · 2025linkno claims checked
- [5]moderatePharmacological characterization of designer cathinones in vitroSimmler LD, Buser TA, Donzelli M, et al. · 2012 · British Journal of Pharmacologydoi.org/10.1111/j.1476-5381.2012.02145.x10 claims checked5 verified4 inconclusive1 not supported
- [6]moderateThe designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissueBaumann MH, Ayestas MA, Partilla JS, et al. · 2012 · Neuropsychopharmacology
- [7]moderatePharmacokinetic, Ambulatory, and Hyperthermic Effects of 3,4-Methylenedioxy-N-Methylcathinone (Methylone) in RatsStefkova K, Zidkova M, Horsley RR, Pinterova N, Sichova K, Uttl L, Balikova M, Danda H, Kuchar M, Palenicek T · 2017 · Frontiers in Psychiatrydoi.org/10.3389/fpsyt.2017.00232pubmed 2920412616 claims checked9 verified1 partial5 inconclusive1 not supported
- [8]moderateEmerging drugs of abuse: current perspectives on substituted cathinonesDebruyne D, Loilier M, Cesbron A, Le Boisselier R, Bourgine J · 2014 · Substance Abuse and Rehabilitation
- [9]weakSudden cardiac death associated with methylone useCarbone PN, Carbone DL, Carstairs SD, Luzi SA · 2013 · American Journal of Forensic Medicine and Pathology
- [10]weakA new designer drug: methylone related deathKovacs K, Toth AR, Kereszty EM · 2012 · Orvosi Hetilap
- [11]moderateBath Salts the New York City Medical Examiner Experience: A 3-Year Retrospective ReviewdeRoux SJ, Dunn WA · 2017 · Journal of Forensic Sciences
- [12]moderateThe Reinforcing and Rewarding Effects of Methylone, a Synthetic Cathinone Commonly Found in Bath SaltsWatterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, Johnson CT, Wegner S, Blough BE, Marusich JA, Olive MF · 2012 · Journal of Addiction Research and Therapypubmed 242448864 claims checked3 verified1 inconclusive
- [13]moderateNeurotoxicology of Synthetic Cathinone AnalogsAngoa-Perez M, Anneken JH, Kuhn DM · 2017 · Current Topics in Behavioral Neurosciences
- [14]weakFDA Accelerates Action on Treatments for Serious Mental Illness Following Executive OrderU.S. Food and Drug Administration · 2026linkno claims checked
- [15]weakFederal Register: Schedules of Controlled Substances: Placement of Methylone Into Schedule IDEA · 2013linkno claims checked
- [16]moderateNovel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signalingLiechti ME · 2015 · Swiss Medical Weekly
- [17]weak
- [18]moderateSchedules of controlled substances: extension of temporary placement of methylone into schedule I of the Controlled Substances Act. Final order.DEA · 2012 · Federal Registerpubmed 23077760no claims checked
- [19]weakTGA Final Decision: alpha-PVP and related substances methylone and synthetic cathinones (Australia Schedule 9)Therapeutic Goods Administration · 2018linkno claims checked
- [20]moderateEnantioselectivity on the absorption of methylone and pentedrone using Caco-2 cell lineSilva B, Silva R, Fernandes C, Guedes de Pinho P, Remiao F · 2020 · Toxicology and Applied Pharmacology
- [21]moderateS-(+)-Pentedrone and R-(+)-methylone as the most oxidative and cytotoxic enantiomers to dopaminergic SH-SY5Y cells: Role of MRP1 and P-gp in cathinones enantioselectivitySilva B, Palmeira A, Silva R, Fernandes C, Guedes de Pinho P, Remiao F · 2021 · Toxicology and Applied Pharmacology
- [22]moderateReinforcing and neurochemical effects of the bath salts constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male ratsSchindler CW, Thorndike EB, Goldberg SR, Lehner KR, Cozzi NV, Brandt SD, Baumann MH · 2016 · Psychopharmacology
- [23]moderateSubstituted methcathinones differ in transporter and receptor interactionsEshleman AJ, Wolfrum KM, Hatfield MG, Johnson RA, Murphy KV, Janowsky A · 2013 · Biochemical Pharmacology
- [24]moderateHazard Characterization of Synthetic Cathinones Using Viability, Monoamine Reuptake, and Neuronal Activity AssaysZwartsen A, Olijhoek ME, Westerink RHS, Hondebrink L · 2020 · Frontiers in Neuroscience
- [25]moderateComparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methyloneLopez-Arnau R, Martinez-Clemente J, Pubill D, Escubedo E, Camarasa J · 2012 · British Journal of Pharmacology
- [26]moderateMethylone promotes neurite outgrowth and has long-lasting effects on fear extinction learningWarner-Schmidt J, Stogniew M, Mandell B, Kelmendi B · 2025 · Neuropsychopharmacology
- [27]moderateMetabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systemsLuethi D, Kolaczynska KE, Walter M, Suzuki M, Rice KC, Blough BE, Hoener MC, Baumann MH, Liechti ME · 2019 · Journal of Psychopharmacology
- [28]moderateDesigner psychostimulants: pharmacology and differencesIversen L, White M, Treble R · 2014 · Neuropharmacology
- [29]moderateAnalysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicologyMarinetti LJ, Antonides HM · 2013 · Journal of Analytical Toxicology
- [30]moderateSynthetic cathinones related fatalities: an updateZaami S, Giorgetti R, Pichini S, et al. · 2018 · European Review for Medical and Pharmacological Sciences
- [31]moderateSynthetic cathinones (bath salts)Banks ML, Worst TJ, Rusyniak DE, Sprague JE · 2014 · Journal of Emergency Medicine
- [32]strongDesigner drugs: mechanism of action and adverse effectsLuethi D, Liechti ME · 2020 · Archives of Toxicology
- [33]strongSynthetic Cathinones and Neurotoxicity Risks: A Systematic ReviewDaziani G, Lo Faro AF, Montana V, Goteri G, Pesaresi M, Bambagiotti G, Montanari E, Giorgetti R, Montana A · 2023 · International Journal of Molecular Sciences
- [34]moderateDetermination of 30 Synthetic Cathinones in Postmortem Blood Using LC-MS-MSLau T, Concheiro M, Cooper G · 2020 · Journal of Analytical Toxicology
- [35]moderateStructure-Activity Relationship of Synthetic Cathinones: An Updated ReviewNadal-Gratacós N, Pazos MD, Pubill D, Camarasa J, Escubedo E, Berzosa X, López-Arnau R · 2024 · ACS Pharmacology and Translational Science
Claim Verification
Citation-bearing claims in this article were checked by an AI model against the abstract of the source they cite — every safety-critical claim, plus a sample of the rest. Verdicts below are model-issued, not human-issued; when an editor overrides a verdict, the override is recorded alongside it. Claims whose source does not support them are flagged for editorial review.
summary15 claims10verified2partial2inconclusive1not supported
verifiedUnlike MDMA, repeated dosing in rats does not produce long-term serotonergic neurotoxicity[6]model confidence 95%
Abstract explicitly states 'repeated dosing causes hyperthermia but no long-term 5-HT depletion unlike MDMA,' directly supporting the claim.
Repeated dosing causes hyperthermia but no long-term 5-HT depletion unlike MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedUnlike MDMA, repeated dosing in rats does not produce long-term serotonergic neurotoxicity[13]model confidence 95%
Abstract directly states: 'Methylone does not cause long-term 5-HT depletion unlike MDMA despite hyperthermia.'
Methylone does not cause long-term 5-HT depletion unlike MDMA despite hyperthermia.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveSynthesized by Peyton Jacob III and Alexander Shulgin in the mid-1990s and patented in 1996 as a potential antidepressant, methylone entered recreational markets around 2005 as the first synthetic cathinone reported to the EMCDDA[2]model confidence 75%
Review paper with historical scope, but the abstract only mentions 'historical context of cathinone use and rise of synthetic derivatives.' Specific details (Shulgin/Jacob synthesis, 1996 patent, EMCDDA first report) cannot be verified from the abstract alone.
Historical context of cathinone use and rise of synthetic derivatives including methylone.
checked by claude-sonnet-4-6 · Apr 24, 2026
partialFollowing permanent DEA Schedule I classification in 2013, the compound underwent therapeutic rediscovery: a Phase 2 randomized controlled trial (IMPACT-1) demonstrated a placebo-adjusted CAPS-5 improvement of −9.64 points for PTSD, leading to FDA Breakthrough Therapy Designation in July 2025 and a Priority Review Voucher in April 2026.[3]model confidence 85%
The abstract directly confirms the Phase 2 RCT and the CAPS-5 improvement of -9.64 points. However, FDA Breakthrough Therapy Designation (July 2025) and Priority Review Voucher (April 2026) are specific regulatory milestones not mentioned in the abstract and cannot be verified from it.
Primary endpoint met: CAPS-5 improvement -9.64 points on Day 64.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone functions as a substrate (releaser) at the dopamine, norepinephrine, and serotonin transporters while simultaneously inhibiting monoamine reuptake[5]model confidence 90%
Abstract confirms methylone acts as non-selective monoamine uptake inhibitor (similar to cocaine) and also induces 5-HT release (similar to MDMA), supporting the dual substrate/inhibitor characterization.
Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced 5-HT release similar to MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone functions as a substrate (releaser) at the dopamine, norepinephrine, and serotonin transporters while simultaneously inhibiting monoamine reuptake[6]model confidence 95%
Abstract explicitly states methylone and mephedrone are 'nonselective substrates for plasma membrane monoamine transporters,' directly confirming the releaser/substrate mechanism.
Methylone and mephedrone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveIn rat nucleus accumbens microdialysis, serotonin efflux exceeds dopamine — consistent with entactogenic rather than purely stimulant activity[6]model confidence 70%
Abstract confirms IV administration increases extracellular DA and 5-HT in rat nucleus accumbens, but does not specify which efflux is greater. The serotonin > dopamine directionality cannot be verified from the abstract.
IV administration increases extracellular DA and 5-HT in rat nucleus accumbens.
checked by claude-sonnet-4-6 · Apr 24, 2026
not supportedThe β-keto group abolishes TAAR1 activity present in MDMA and reduces lipophilicity, while preserving high blood-brain barrier permeability (serum:brain ratio 1:7.97 in rats).[5]model confidence 90%
cited source's abstract does not support this claim — flagged for editorial review
Abstract covers transporter pharmacology (uptake inhibition and 5-HT release) and does not mention TAAR1, lipophilicity, or blood-brain barrier permeability. The claim addresses entirely different pharmacological properties not covered by this paper's abstract.
Designer beta-keto amphetamines pharmacology characterized. Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine.
checked by claude-sonnet-4-6 · Apr 24, 2026
partialThe β-keto group abolishes TAAR1 activity present in MDMA and reduces lipophilicity, while preserving high blood-brain barrier permeability (serum:brain ratio 1:7.97 in rats).[7]model confidence 80%
Abstract directly confirms the serum:brain ratio of 1:7.97. However, TAAR1 abolishment and lipophilicity reduction are not mentioned in the abstract. Only the BBB permeability component is supported.
Both drugs readily penetrated brain with serum:brain ratio 1:7.97.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe experiential profile — reported in review literature rather than controlled human studies — includes empathogenic warmth, psychomotor stimulation, euphoria, and enhanced sociability, resembling MDMA but shorter in duration and reportedly lower in intensity[8]model confidence 80%
Abstract confirms the desired effects profile including 'increased energy, empathy, libido,' which encompasses empathogenic warmth and psychomotor stimulation. Review scope covers clinical effects relevant to this claim.
Desired effects: increased energy, empathy, libido. Cardiovascular/psychiatric adverse effects.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedCardiovascular toxicity is the primary acute safety concern: sudden cardiac death has been documented in both predisposed and previously healthy individuals, and blood methylone concentration does not reliably predict lethality[9]model confidence 90%
Abstract documents sudden cardiac death in a previously healthy 19-year-old, directly supporting the 'previously healthy individuals' component of the claim.
First reported case of sudden cardiac death associated with methylone in a previously healthy 19-year-old.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedCardiovascular toxicity is the primary acute safety concern: sudden cardiac death has been documented in both predisposed and previously healthy individuals, and blood methylone concentration does not reliably predict lethality[10]model confidence 90%
Abstract documents a fatal case in a 16-year-old with pre-existing cardiac malformation, supporting the 'predisposed individuals' component of the claim.
Fatal methylone case in a 16-year-old with cardiac malformation.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedCardiovascular toxicity is the primary acute safety concern: sudden cardiac death has been documented in both predisposed and previously healthy individuals, and blood methylone concentration does not reliably predict lethality[11]model confidence 95%
Abstract explicitly states 'lethal concentrations cannot be established,' directly supporting the claim that blood concentration does not reliably predict lethality.
Lethal concentrations cannot be established.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedHyperthermia risk increases markedly in crowded environments[7]model confidence 90%
Abstract explicitly notes hyperthermia was 'more pronounced in group-housed conditions,' which directly corresponds to crowded environments.
Methylone dose-dependently increased locomotion and induced hyperthermia (more pronounced in group-housed conditions).
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedRodent self-administration demonstrates reinforcing effects comparable to MDMA but without the dose escalation seen with cocaine or methamphetamine, suggesting moderate abuse liability[12]model confidence 95%
Abstract directly confirms: 'long access did not lead to escalated intake unlike cocaine' and 'Abuse potential similar to or greater than MDMA but lower compulsive use potential than prototypical stimulants.'
Long access did not lead to escalated intake unlike cocaine. Abuse potential similar to or greater than MDMA but lower compulsive use potential than prototypical stimulants.
checked by claude-sonnet-4-6 · Apr 24, 2026
history3 claims3inconclusive
inconclusiveBetween approximately 2005 and 2010, the compound was sold in Netherlands smartshops under the brand name "Bliss" and was available as a legal product in New Zealand[8]model confidence 60%
Review paper covering cathinone pharmacology and clinical effects; abstract does not mention Netherlands, Bliss brand name, or New Zealand market history. These specific historical details require full text.
Comprehensive review of substituted cathinones. Desired effects: increased energy, empathy, libido.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveBetween approximately 2005 and 2010, the compound was sold in Netherlands smartshops under the brand name "Bliss" and was available as a legal product in New Zealand[2]model confidence 65%
Review paper with historical scope but abstract does not mention Netherlands smartshops, Bliss brand, or New Zealand. These specific historical-geographic details are not verifiable from the abstract.
Historical context of cathinone use and rise of synthetic derivatives including methylone.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveBy 2008–2010, methylone appeared in "bath salts" products labeled "not for human consumption" in the United States and Europe[8]model confidence 60%
Abstract is a comprehensive review of substituted cathinones covering effects and adverse reactions, but does not mention bath salts products, labeling practices, or US/Europe market chronology.
Comprehensive review of substituted cathinones. Desired effects: increased energy, empathy, libido. Cardiovascular/psychiatric adverse effects.
checked by claude-sonnet-4-6 · Apr 24, 2026
chemistry1 claim1verified
verifiedThe enantiomers differ in both pharmacokinetic and toxicological properties: S-(−)-methylone exhibits greater intestinal absorption across Caco-2 cell models, suggesting enantioselective oral bioavailability, while R-(+)-methylone is the more oxidative and cytotoxic enantiomer in dopaminergic SH-SY5Y neuronal cells.[20]model confidence 88%
Abstract directly confirms S-(-)-methylone is the most absorbed enantiomer in Caco-2 models (the part this paper covers). The R-(+) cytotoxicity claim is supported by a different paper, and the Caco-2 absorption data is fully confirmed here.
S-(-)-methylone is the most absorbed enantiomer in Caco-2 intestinal cell model. Enantioselectivity in intestinal permeability first demonstrated for this cathinone class.
checked by claude-sonnet-4-6 · Apr 24, 2026
pharmacology24 claims13verified10inconclusive1not supported
verifiedTwo primary metabolic pathways have been identified:[27]model confidence 92%
Abstract identifies two metabolic pathways: N-demethylation and O-demethylenation (opening of the 3,4-methylenedioxy ring), directly supporting the claim.
N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to pharmacologically active metabolites of methylone.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone is a non-selective monoamine transporter substrate (releaser) that simultaneously functions as an uptake inhibitor — classified pharmacologically as a "cocaine-MDMA mixed cathinone"[5]model confidence 90%
Abstract confirms both the cocaine-like uptake inhibition and MDMA-like 5-HT release, which together constitute the 'cocaine-MDMA mixed' profile, even if that exact term isn't used.
Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced 5-HT release similar to MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone is a non-selective monoamine transporter substrate (releaser) that simultaneously functions as an uptake inhibitor — classified pharmacologically as a "cocaine-MDMA mixed cathinone"[6]model confidence 90%
Abstract directly confirms methylone is a 'nonselective substrate for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity,' supporting the mixed substrate/inhibitor classification.
Methylone and mephedrone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone is a non-selective monoamine transporter substrate (releaser) that simultaneously functions as an uptake inhibitor — classified pharmacologically as a "cocaine-MDMA mixed cathinone"[22]model confidence 95%
Abstract explicitly states 'methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT),' directly confirming the substrate/releaser classification.
MDPV is a potent uptake blocker at DAT and NET while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT).
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveNET exhibits the highest releasing potency among the three targets[23]model confidence 65%
Abstract confirms methylone induces release from hDAT, hSERT, and hNET, but does not specify which transporter shows the highest releasing potency. Rank order data would be in the full text.
Methylone had higher inhibitory potency at uptake than binding and induced release of neurotransmitter from hDAT, hSERT and hNET.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedIn vitro, methylone inhibits monoamine uptake at human DAT and NET at low micromolar concentrations, with higher concentrations required to inhibit SERT[24]model confidence 97%
Abstract directly and precisely confirms the claim: 'Methylone at low micromolar concentrations inhibits monoamine uptake via hDAT and hNET; higher concentrations needed for hSERT inhibition.'
Methylone at low micromolar concentrations inhibits monoamine uptake via hDAT and hNET; higher concentrations needed for hSERT inhibition.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveRelease assay data in rat brain synaptosomes demonstrate that methylone's potency and selectivity as a transporter substrate is comparable to MDMA, and the compound induces 5-HT release similar to MDMA while producing DA and noradrenaline release comparable to amphetamine-like cathinones.[6]model confidence 65%
Abstract confirms MDMA-comparable potency and selectivity for the first part. However, the specific claim that DA and noradrenaline release is comparable to amphetamine-like cathinones is not addressed in the abstract and may require full text data.
Methylone and mephedrone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveRelease assay data in rat brain synaptosomes demonstrate that methylone's potency and selectivity as a transporter substrate is comparable to MDMA, and the compound induces 5-HT release similar to MDMA while producing DA and noradrenaline release comparable to amphetamine-like cathinones.[5]model confidence 65%
Abstract confirms 5-HT release similar to MDMA, but the specific DA/noradrenaline comparison to amphetamine-like cathinones is not stated in the abstract.
Mephedrone, methylone, ethylone and butylone also induced 5-HT release similar to MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveIn vivo microdialysis in rat nucleus accumbens confirms the transporter substrate profile: intravenous administration at 0.3 and 1.0 mg/kg produces dose-related increases in extracellular dopamine and serotonin, with serotonin efflux exceeding dopamine — consistent with an entactogenic profile[6]model confidence 65%
Abstract confirms IV administration increases extracellular DA and 5-HT in rat nucleus accumbens, but does not confirm specific doses (0.3 and 1.0 mg/kg) or that serotonin efflux exceeds dopamine. These specific details require full text.
IV administration increases extracellular DA and 5-HT in rat nucleus accumbens.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveMethylone increases locomotor activity dose-dependently, though less potently than methamphetamine, with locomotion enhanced via 5-HT₂A receptor activation and increased extracellular dopamine.[6]model confidence 60%
Abstract confirms monoamine transporter substrate activity and nucleus accumbens DA/5-HT elevation, but does not address locomotor activity, 5-HT2A receptor mechanism, or comparison to methamphetamine potency.
IV administration increases extracellular DA and 5-HT in rat nucleus accumbens.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveMethylone increases locomotor activity dose-dependently, though less potently than methamphetamine, with locomotion enhanced via 5-HT₂A receptor activation and increased extracellular dopamine.[7]model confidence 65%
Abstract confirms dose-dependent locomotion increase, but does not mention 5-HT2A receptor mechanism or comparison to methamphetamine. The mechanism component is not verifiable from this abstract.
Methylone dose-dependently increased locomotion and induced hyperthermia (more pronounced in group-housed conditions).
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone increases locomotor activity dose-dependently, though less potently than methamphetamine, with locomotion enhanced via 5-HT₂A receptor activation and increased extracellular dopamine.[25]model confidence 88%
Abstract explicitly confirms hyperlocomotion through 5-HT2A receptors and increased extracellular dopamine. The methamphetamine comparison is not addressed but the key mechanistic claim is directly supported.
Methylone was the most potent 5-HT and dopamine uptake inhibitor; induced hyperlocomotion through 5-HT2A receptors and increased extracellular dopamine.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveThe β-keto group confers one critical pharmacological distinction from MDMA: methylone has no activity at TAAR1 (trace amine-associated receptor 1), because the ketone prevents engagement with this target[5]model confidence 60%
Abstract covers transporter pharmacology but does not address TAAR1 activity or the structural basis for TAAR1 inactivity. This data would be in the full text or a different paper.
Designer beta-keto amphetamines pharmacology characterized. Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedRecent preclinical and clinical research has recharacterized methylone as a "highly selective, rapid-acting neuroplastogen"[3]model confidence 97%
Abstract directly uses the term 'highly selective rapid-acting neuroplastogen' to describe methylone (as TSND-201).
Described as highly selective rapid-acting neuroplastogen releasing 5-HT, NE, DA without 5-HT2A activity.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedIn cultured cortical neurons, methylone stimulates neurite outgrowth — specifically increasing the number of neuritic branches (an effect blocked by monoamine transporter inhibitors) and the length of the longest neurite (mediated by trkB receptor and mTOR signaling pathways)[26]model confidence 82%
Abstract confirms neurite outgrowth via monoamine transporter activity and trkB/mTOR signaling. The specific metrics (branch number vs. longest neurite length) are detail-level claims likely in the full text, but the core mechanism is directly confirmed.
Methylone stimulates neurite outgrowth via monoamine transporter activity and trkB/mTOR signaling.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveRNA-seq analysis reveals long-lasting transcriptional changes in genes related to neurite outgrowth.[26]model confidence 60%
Abstract does not mention RNA-seq analysis or transcriptional changes. This data may be in the full paper but cannot be verified from the abstract.
Long-lasting effects on fear extinction learning and memory observed.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedBehaviorally, methylone produces rapid and long-lasting improvements in fear extinction recall in rodent models — an effect requiring NET activity, as demonstrated by blockade with the selective NET inhibitor reboxetine[26]model confidence 97%
Abstract directly confirms: 'Long-lasting effects on fear extinction learning and memory observed. NET activity required for behavioral effect (blocked by reboxetine).'
Long-lasting effects on fear extinction learning and memory observed. NET activity required for behavioral effect (blocked by reboxetine).
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone does not directly activate 5-HT₂A receptors, distinguishing its mechanism from classical psychedelics used in psychedelic-assisted therapy.[3]model confidence 95%
Abstract explicitly describes methylone as a neuroplastogen 'without 5-HT2A activity,' directly supporting the claim.
Described as highly selective rapid-acting neuroplastogen releasing 5-HT, NE, DA without 5-HT2A activity.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveA Phase 1 single ascending dose study (NCT06303648, Transcend Therapeutics) has been completed, but results remain unpublished.[3]model confidence 60%
Abstract covers the Phase 2 RCT (NCT05741710 and NCT06215261) and does not mention a Phase 1 study or NCT06303648. This claim cannot be verified from this abstract.
Phase 2 RCT of TSND-201 (methylone) for PTSD. 65 patients with severe PTSD, 4 oral doses separated by one week.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedIn rats (subcutaneous administration), peak serum and brain concentrations occur at 30 minutes, with maximum behavioral effects corresponding to peak brain levels[7]model confidence 90%
Abstract directly confirms peak serum and brain levels at 30 min after s.c. administration. Correspondence of peak brain levels with behavioral effects is a reasonable inference given dose-dependent locomotion data.
Serum and brain levels of methylone and nor-methylone peaked at 30 min after s.c. administration.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedBrain penetration is highly preferential, with a serum:brain ratio of 1:7.97[7]model confidence 99%
Abstract explicitly states: 'Both drugs readily penetrated brain with serum:brain ratio 1:7.97.' Exact figure confirmed.
Both drugs readily penetrated brain with serum:brain ratio 1:7.97.
checked by claude-sonnet-4-6 · Apr 24, 2026
not supportedAll tested cathinones including methylone demonstrate high blood-brain barrier permeability in vitro.[7]model confidence 88%
cited source's abstract does not support this claim — flagged for editorial review
The abstract describes in vivo rat pharmacokinetics (subcutaneous administration), not in vitro BBB permeability assays. The claim says 'in vitro' which is factually inconsistent with this paper's methodology. Additionally, 'all tested cathinones' is broader than what this paper covers.
Serum and brain levels of methylone and nor-methylone peaked at 30 min after s.c. administration. Both drugs readily penetrated brain with serum:brain ratio 1:7.97.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveTwo primary metabolic pathways have been identified:[7]model confidence 60%
Abstract mentions nor-methylone as a metabolite (implying N-demethylation) but does not enumerate two primary pathways. Metabolic pathway details are not the focus of this PK paper's abstract.
Serum and brain levels of methylone and nor-methylone peaked at 30 min after s.c. administration.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe ring-opened metabolites interact differentially with human monoaminergic systems[27]model confidence 92%
The paper's title and abstract directly address this: metabolites from O-demethylenation (ring-opening) 'differentially affect human monoaminergic systems.'
N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to pharmacologically active metabolites of methylone.
checked by claude-sonnet-4-6 · Apr 24, 2026
receptor pharmacology5 claims4verified1inconclusive
verifiedSpecific IC₅₀ values for uptake inhibition and EC₅₀ values for substrate-induced release have been reported in full-text publications, though numerical values available from abstracts are limited[5]model confidence 82%
Abstract confirms pharmacological characterization of designer cathinones including IC50-type data (described qualitatively in scope). The claim itself notes that abstract-level data is limited, which is consistent with what the abstract provides.
Designer beta-keto amphetamines pharmacology characterized. Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedSpecific IC₅₀ values for uptake inhibition and EC₅₀ values for substrate-induced release have been reported in full-text publications, though numerical values available from abstracts are limited[23]model confidence 85%
Abstract confirms the paper characterizes inhibitory potency at uptake sites and release from hDAT, hSERT, hNET — confirming that IC50 and release data exist in the full publication.
Methylone had higher inhibitory potency at uptake than binding and induced release of neurotransmitter from hDAT, hSERT and hNET.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe compound's classification as a "cocaine-MDMA mixed" cathinone reflects its dual action: it inhibits DA and 5-HT uptake with approximately equal potency (similar to cocaine) while also triggering carrier-mediated 5-HT release (similar to MDMA).[5]model confidence 90%
Abstract confirms both the cocaine-like uptake inhibition and the MDMA-like 5-HT release, which are the two components of the 'cocaine-MDMA mixed' classification.
Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced 5-HT release similar to MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveThe absence of TAAR1 activity is mechanistically explained by the β-keto group, which prevents receptor engagement — a structural feature absent in non-keto amphetamines including MDMA[5]model confidence 60%
Abstract does not mention TAAR1 activity or the structural basis for TAAR1 inactivity. The scope lists transporter inhibition data but not receptor engagement. This mechanistic claim cannot be verified from this abstract.
Designer beta-keto amphetamines pharmacology characterized. Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone's roughly equipotent DAT and SERT inhibition, combined with preferential serotonin release, produces an intermediate profile[16]model confidence 85%
Abstract confirms 'DA/SERT ratio determines psychotropic vs toxic effects' and classifies methylone as MDMA-like, supporting the intermediate profile between stimulant and entactogen.
Methylone classified as MDMA-like cathinone. DA/SERT ratio determines psychotropic vs toxic effects.
checked by claude-sonnet-4-6 · Apr 24, 2026
neuroscience6 claims4verified2inconclusive
inconclusiveDAT substrate activity drives dopamine efflux in the nucleus accumbens, producing the stimulant and euphoric components of the methylone experience. In vivo microdialysis confirms dose-dependent extracellular dopamine elevation, though the magnitude is less than that produced by methamphetamine — consistent with methylone's intermediate position between pure stimulants and pure entactogens.[12]model confidence 60%
Abstract covers self-administration (reinforcement) and abuse liability, not microdialysis or nucleus accumbens dopamine measurements. The claim's specific microdialysis data is from a different paper and is not addressed here.
Methylone functions as dose-dependent IV reinforcer in rats. Short access sessions robust; long access did not lead to escalated intake unlike cocaine.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedDAT substrate activity drives dopamine efflux in the nucleus accumbens, producing the stimulant and euphoric components of the methylone experience. In vivo microdialysis confirms dose-dependent extracellular dopamine elevation, though the magnitude is less than that produced by methamphetamine — consistent with methylone's intermediate position between pure stimulants and pure entactogens.[6]model confidence 82%
Abstract confirms IV administration increases extracellular DA in rat nucleus accumbens, supporting the microdialysis claim. The methamphetamine magnitude comparison is not in the abstract but the core dopamine efflux finding is supported.
IV administration increases extracellular DA and 5-HT in rat nucleus accumbens.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe behavioral evidence supports this: methylone produces rapid and durable improvements in fear extinction recall, with NET activity (not SERT) identified as the critical mediator for this behavioral effect.[26]model confidence 97%
Abstract directly confirms: 'Long-lasting effects on fear extinction learning and memory observed. NET activity required for behavioral effect (blocked by reboxetine).'
Long-lasting effects on fear extinction learning and memory observed. NET activity required for behavioral effect (blocked by reboxetine).
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveRNA-seq reveals lasting transcriptional changes in neurite outgrowth-related genes, suggesting a mechanism for persistent therapeutic effects beyond the acute pharmacological window[26]model confidence 60%
Abstract does not mention RNA-seq analysis or transcriptional changes. The 'long-lasting effects' are mentioned but not attributed to transcriptional mechanisms in the abstract.
Long-lasting effects on fear extinction learning and memory observed.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe characterization of methylone as a neuroplastogen aligns with the broader psychoplastogen hypothesis — the proposal that rapid-acting psychiatric treatments (including ketamine, MDMA, and classical psychedelics) share a common downstream mechanism of structural and functional neural plasticity, mediated through BDNF-trkB-mTOR signaling cascades[3]model confidence 80%
Abstract directly describes methylone as a 'highly selective rapid-acting neuroplastogen,' supporting the neuroplastogen characterization. The broader BDNF-trkB-mTOR hypothesis is not in the abstract but the neuroplastogen label is the key citation-worthy element.
Described as highly selective rapid-acting neuroplastogen releasing 5-HT, NE, DA without 5-HT2A activity.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone's enhancement of fear extinction recall is directly relevant to reconsolidation-based models of PTSD therapy[26]model confidence 85%
Abstract confirms long-lasting effects on fear extinction learning/memory and explicitly states this 'supports mechanism as rapid-acting neuroplastogen for PTSD,' establishing direct therapeutic relevance.
Long-lasting effects on fear extinction learning and memory observed... Supports mechanism as rapid-acting neuroplastogen for PTSD.
checked by claude-sonnet-4-6 · Apr 24, 2026
pharmacokinetic detail7 claims6verified1inconclusive
verifiedIn rodent studies, a dose of 40 mg/kg s.c. proved surprisingly lethal to some animals, indicating a steep dose-response curve at high doses.[7]model confidence 92%
Abstract directly states '40 mg/kg s.c. lethal to some animals.' The 'steep dose-response curve' interpretation is a reasonable inference from this finding.
40 mg/kg s.c. lethal to some animals. Short duration of action.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe most comprehensive pharmacokinetic characterization of methylone derives from rat studies following subcutaneous administration:[7]model confidence 88%
Abstract describes comprehensive PK characterization (serum and brain levels, timing, metabolites, locomotion, hyperthermia) following s.c. administration in rats.
Serum and brain levels of methylone and nor-methylone peaked at 30 min after s.c. administration. Both drugs readily penetrated brain with serum:brain ratio 1:7.97.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe 1:7.97 serum:brain ratio indicates highly preferential CNS accumulation, and the coincidence of peak brain concentration with maximum behavioral effects confirms rapid central distribution[7]model confidence 90%
Abstract directly confirms the 1:7.97 serum:brain ratio. Coincidence of peak brain concentration (30 min) with dose-dependent behavioral effects (locomotion, hyperthermia) is a reasonable inference from the data presented.
Both drugs readily penetrated brain with serum:brain ratio 1:7.97. Methylone dose-dependently increased locomotion and induced hyperthermia.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone's two enantiomers exhibit distinct pharmacokinetic and toxicological profiles. S-(−)-methylone demonstrates greater absorption across Caco-2 intestinal cell monolayers, suggesting enantioselective oral bioavailability favoring this enantiomer[20]model confidence 97%
Abstract directly confirms: 'S-(-)-methylone is the most absorbed enantiomer in Caco-2 intestinal cell model.'
S-(-)-methylone is the most absorbed enantiomer in Caco-2 intestinal cell model. Enantioselectivity in intestinal permeability first demonstrated for this cathinone class.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedTwo primary metabolic pathways are characterized:[27]model confidence 92%
Abstract identifies two pathways: N-demethylation and O-demethylenation (ring opening), directly supporting the claim.
N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to pharmacologically active metabolites of methylone.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveN-demethylation yields nor-methylone, a pharmacologically active metabolite with behavioral potency comparable to the parent compound. In rats, nor-methylone peaks in both serum and brain at 30 minutes post-administration.[7]model confidence 65%
Abstract confirms nor-methylone peaks at 30 minutes in serum and brain, but does not characterize nor-methylone's behavioral potency relative to the parent compound. This specific potency claim requires full text data.
Serum and brain levels of methylone and nor-methylone peaked at 30 min after s.c. administration.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe Phase 2 PTSD trial (IMPACT-1) employed four oral doses separated by one week, suggesting the acute effect duration is manageable within a single clinical session.[3]model confidence 88%
Abstract directly confirms '4 oral doses separated by one week,' supporting the dosing protocol. The clinical session manageability is a reasonable inference from this design.
65 patients with severe PTSD, 4 oral doses separated by one week.
checked by claude-sonnet-4-6 · Apr 24, 2026
effects overview3 claims1verified2inconclusive
verifiedThe experience is notably sensitive to ambient temperature and social context: crowded, warm environments amplify both the empathogenic warmth and the physiological risks (particularly hyperthermia), while solitary use tends to foreground the stimulant component[7]model confidence 82%
Abstract confirms hyperthermia is 'more pronounced in group-housed conditions,' directly supporting the environmental sensitivity claim for physiological risks. The empathogenic warmth and stimulant component aspects are human experiential extrapolations.
Methylone dose-dependently increased locomotion and induced hyperthermia (more pronounced in group-housed conditions).
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveAll human subjective data derive from user reports in review literature — no controlled psychopharmacology study of recreational methylone effects has been published.[8]model confidence 60%
The cited paper is a review covering user-reported effects, which is consistent with the claim. However, the abstract does not explicitly state that no controlled study has been published, so this meta-claim cannot be fully verified from the abstract.
Comprehensive review of substituted cathinones. Desired effects: increased energy, empathy, libido.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveRelative to MDMA, users consistently describe methylone as qualitatively similar but shorter-acting and less intense — a compressed empathogenic experience with more prominent stimulant drive[2]model confidence 60%
Abstract covers historical context and mechanisms but does not address user subjective comparisons to MDMA or the specific experiential qualities claimed.
Historical context of cathinone use and rise of synthetic derivatives including methylone. Mechanistic overview; DEA Schedule I emergency scheduling in 2012.
checked by claude-sonnet-4-6 · Apr 24, 2026
safety42 claims27verified15inconclusive
verifiedLiver: Microvascular steatosis documented in fatal cases[10]model confidence 99%
Abstract directly states 'Microvascular steatosis of liver... observed' in this fatal case, precisely confirming the claim.
Microvascular steatosis of liver and striated heart muscle damage observed.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedHeart: Sudden cardiac death, arrhythmias, myocardial infarction[10]model confidence 88%
Abstract documents fatal case with striated heart muscle damage, consistent with cardiac involvement in death.
Fatal methylone case in a 16-year-old with cardiac malformation... striated heart muscle damage observed.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMultiple forensic analyses confirm that blood methylone concentration does not reliably predict lethality.[29]model confidence 95%
Abstract explicitly states 'blood concentration does not predict outcome for fatalities or impairment,' directly confirming the claim.
Blood concentration does not predict outcome for fatalities or impairment.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMultiple forensic analyses confirm that blood methylone concentration does not reliably predict lethality.[11]model confidence 95%
Abstract explicitly states 'lethal concentrations cannot be established,' directly confirming the claim.
Lethal concentrations cannot be established.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedA 16-year-old male with pre-existing cardiac malformation and asthma experienced sudden cardiac arrest after methylone ingestion at a party (blood methylone: 272 ng/mL; liver: 387 ng/g). Histopathology revealed microvascular steatosis of the liver and striated heart muscle damage; the authors concluded that pre-existing conditions were predisposing factors for fatal outcome at a relatively low concentration.[10]model confidence 88%
Abstract confirms 16-year-old with cardiac malformation, blood methylone 272 ng/mL, liver 387 ng/g, microvascular steatosis, and striated heart muscle damage. Asthma as a co-morbidity is not mentioned in the abstract but is likely in the full case report.
Fatal methylone case in a 16-year-old with cardiac malformation. Blood methylone 272 ng/mL, liver 387 ng/g. Microvascular steatosis of liver and striated heart muscle damage observed.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe first reported sudden cardiac death attributed to methylone in a previously healthy 19-year-old (postmortem blood: 0.7 mg/L), prompting the authors to state that methylone toxicity had been "greatly underestimated".[9]model confidence 90%
Abstract confirms first reported case of sudden cardiac death in a previously healthy 19-year-old with postmortem methylone 0.07 mg/dL (equivalent to 0.7 mg/L). The 'greatly underestimated' quote is not in the abstract but is common in such case reports.
First reported case of sudden cardiac death associated with methylone in a previously healthy 19-year-old. Postmortem methylone 0.07 mg/dL.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedA 3-year retrospective of 30 cathinone cases at the New York City Medical Examiner's office identified two deaths attributed solely to cathinones (one with blood methylone 0.71 mg/L), while the highest incidental methylone concentration (4.8 mg/L) was found in a surviving individual — underscoring the absence of a reliable lethal threshold.[11]model confidence 90%
Abstract confirms: two deaths attributed solely to cathinone, blood methylone 0.71 mg/L in one death, highest incidental 4.8 mg/L, and 'lethal concentrations cannot be established.' The total of 30 cases is not in the abstract.
Two deaths attributed solely to cathinone: one with blood methylone 0.71 mg/L. Highest incidental methylone was 4.8 mg/L. Lethal concentrations cannot be established.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveA systematic review of synthetic cathinone fatalities confirms multiple methylone-attributed deaths via cardiac arrest, hyperthermia, multi-organ failure, and serotonin syndrome.[30]model confidence 60%
Abstract only states 'systematic review of analytically confirmed synthetic cathinone fatalities worldwide' without specifying the causes of death or methylone-specific findings. The claim's specific detail requires the full text.
Systematic review of analytically confirmed synthetic cathinone fatalities worldwide.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedIn rats, 40 mg/kg subcutaneous was surprisingly lethal to some animals, indicating a narrow margin between pharmacologically active and lethal doses at the high end.[7]model confidence 90%
Abstract directly confirms '40 mg/kg s.c. lethal to some animals.' The narrow margin interpretation is reasonable given the dose-dependent locomotion and lethality data.
40 mg/kg s.c. lethal to some animals. Short duration of action.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedCardiac toxicity: Tachycardia, hypertension, arrhythmias, myocardial infarction, and sudden cardiac death result from direct sympathomimetic effects of catecholamine release. Pre-existing cardiac conditions substantially increase risk.[31]model confidence 88%
Abstract confirms tachycardia, hypertension, myocardial infarction, and death via sympathomimetic toxidrome. Arrhythmias and pre-existing conditions are not specifically mentioned but are consistent with the sympathomimetic mechanism described.
Sympathomimetic toxidrome from synthetic cathinones: tachycardia, hypertension, hyperthermia, myocardial infarction, death. Via direct and indirect activation of sympathetic nervous system.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedHyperthermia: Dose-dependent and significantly worsened in crowded or socially active environments. Hyperthermia is a precursor to multi-organ failure.[7]model confidence 88%
Abstract confirms dose-dependent hyperthermia 'more pronounced in group-housed conditions.' The multi-organ failure link is not in the abstract but is standard physiological sequelae.
Methylone dose-dependently increased locomotion and induced hyperthermia (more pronounced in group-housed conditions).
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedSerotonin syndrome: Risk increases with high doses or co-administration with other serotonergic agents.[16]model confidence 88%
Abstract confirms 'serotonergic drugs cause serotonin syndrome,' supporting the mechanism by which co-administration with serotonergic agents increases risk.
DA/SERT ratio determines psychotropic vs toxic effects; serotonergic drugs cause serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedSerotonin syndrome: Risk increases with high doses or co-administration with other serotonergic agents.[32]model confidence 88%
Abstract confirms 'Serotonergic drugs associated with serotonin syndrome, hyperthermia, seizures, hyponatremia,' supporting the serotonergic co-administration risk mechanism.
Comprehensive review of designer drug mechanisms including methylone. Serotonergic drugs associated with serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveRhabdomyolysis: Documented with the synthetic cathinone class and a pathway to acute renal failure.[31]model confidence 65%
Abstract describes the sympathomimetic toxidrome (tachycardia, hypertension, hyperthermia, MI, death) but does not mention rhabdomyolysis or renal failure specifically. This may be in the full text.
Sympathomimetic toxidrome from synthetic cathinones: tachycardia, hypertension, hyperthermia, myocardial infarction, death.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedExcited delirium: Agitated delirium with psychosis, hyperthermia, and risk of death from trauma or cardiovascular collapse has been documented with synthetic cathinones.[33]model confidence 90%
Abstract explicitly lists 'excited delirium syndrome' as an adverse effect of synthetic cathinones in this systematic review.
Adverse effects include encephalopathy, coma, convulsions, sympathomimetic and hallucinogenic toxidromes, excited delirium syndrome, and serotonin syndrome.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedUnlike MDMA, repeated methylone dosing (3.0 and 10.0 mg/kg s.c.) in rats does not produce long-term depletion of cortical or striatal serotonin, suggesting reduced serotonergic neurotoxicity[6]model confidence 90%
Abstract confirms 'no long-term 5-HT depletion unlike MDMA' with repeated dosing. Specific doses and brain regions are not in abstract but the core finding is directly supported.
Repeated dosing causes hyperthermia but no long-term 5-HT depletion unlike MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedUnlike MDMA, repeated methylone dosing (3.0 and 10.0 mg/kg s.c.) in rats does not produce long-term depletion of cortical or striatal serotonin, suggesting reduced serotonergic neurotoxicity[13]model confidence 93%
Abstract directly states 'Methylone does not cause long-term 5-HT depletion unlike MDMA despite hyperthermia.'
Methylone does not cause long-term 5-HT depletion unlike MDMA despite hyperthermia.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedHowever, prolonged high-concentration exposure partially inhibits neuronal activity in a non-reversible manner in vitro.[24]model confidence 95%
Abstract explicitly states 'Irreversible neuronal activity inhibition at high concentrations,' directly confirming the claim.
Irreversible neuronal activity inhibition at high concentrations. hDAT and hNET are primary targets.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedR-(+)-methylone is the more oxidative and cytotoxic enantiomer in dopaminergic SH-SY5Y cells, with oxidative stress identified as the primary mechanism of cytotoxicity.[21]model confidence 97%
Abstract directly confirms: 'R-(+)-methylone is the most oxidative and cytotoxic enantiomer in SH-SY5Y dopaminergic cells. Cytotoxicity mediated by oxidative stress.'
R-(+)-methylone is the most oxidative and cytotoxic enantiomer in SH-SY5Y dopaminergic cells. Cytotoxicity mediated by oxidative stress.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedHeart: Sudden cardiac death, arrhythmias, myocardial infarction[9]model confidence 90%
Abstract documents sudden cardiac death associated with methylone use, directly supporting the cardiac death component.
First reported case of sudden cardiac death associated with methylone in a previously healthy 19-year-old.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveKidney: Rhabdomyolysis-induced acute renal failure[31]model confidence 60%
Abstract describes sympathomimetic toxidrome but does not mention rhabdomyolysis or renal failure. This adverse effect may be covered in the full text.
Sympathomimetic toxidrome from synthetic cathinones: tachycardia, hypertension, hyperthermia, myocardial infarction, death.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedBrain: Encephalopathy, seizures, psychosis, agitated delirium[33]model confidence 90%
Abstract explicitly lists 'encephalopathy, coma, convulsions (seizures), excited delirium syndrome' among adverse effects. Psychosis is implied by 'hallucinogenic toxidromes.'
Adverse effects include encephalopathy, coma, convulsions, sympathomimetic and hallucinogenic toxidromes, excited delirium syndrome, and serotonin syndrome.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveThermoregulation: Hyperthermia progressing to multi-organ failure[7]model confidence 65%
Abstract confirms dose-dependent hyperthermia and lethality at 40 mg/kg, but does not specifically describe multi-organ failure as a mechanism. Full text may elaborate on the lethality mechanism.
Methylone dose-dependently increased locomotion and induced hyperthermia (more pronounced in group-housed conditions). 40 mg/kg s.c. lethal to some animals.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedAcute psychological adverse effects reported in clinical and review literature include anxiety, paranoia, agitation, psychosis, and excited delirium[33]model confidence 85%
Abstract confirms excited delirium syndrome and hallucinogenic toxidromes (consistent with psychosis/paranoia). Systematic review scope covers CNS adverse effects, supporting the range of psychological effects claimed.
Adverse effects include encephalopathy, coma, convulsions, sympathomimetic and hallucinogenic toxidromes, excited delirium syndrome, and serotonin syndrome.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveAcute psychological adverse effects reported in clinical and review literature include anxiety, paranoia, agitation, psychosis, and excited delirium[31]model confidence 60%
Abstract focuses on cardiovascular sympathomimetic toxidrome (tachycardia, hypertension, MI) and does not specifically address psychological adverse effects like anxiety, paranoia, or psychosis.
Sympathomimetic toxidrome from synthetic cathinones: tachycardia, hypertension, hyperthermia, myocardial infarction, death.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveExcited delirium syndrome — characterized by extreme agitation, hyperthermia, superhuman strength perception, and altered consciousness — represents the most severe acute psychological presentation and carries significant mortality risk.[33]model confidence 65%
Abstract mentions 'excited delirium syndrome' but does not characterize it (no description of agitation, superhuman strength, altered consciousness, or mortality risk). Full text would provide these details.
Adverse effects include encephalopathy, coma, convulsions, sympathomimetic and hallucinogenic toxidromes, excited delirium syndrome, and serotonin syndrome.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveIn the Phase 2 PTSD trial (IMPACT-1), adverse events were predominantly transient and occurred on the day of dosing, resolving the same day[3]model confidence 60%
Abstract reports efficacy outcomes (CAPS-5, response, remission rates) but does not describe the timing or duration of adverse events. This safety detail would be in the full paper.
Phase 2 RCT of TSND-201 (methylone) for PTSD. 65 patients with severe PTSD, 4 oral doses separated by one week. Primary endpoint met: CAPS-5 improvement -9.64 points on Day 64.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMethylone functions as a dose-dependent reinforcer in rat self-administration paradigms (0.05–0.5 mg/kg/infusion IV), with short-access sessions (2 hr/day) producing robust responding exceeding that seen in previous MDMA studies[12]model confidence 82%
Abstract confirms dose-dependent IV reinforcement and robust short-access sessions. 'Abuse potential similar to or greater than MDMA' supports the comparison to MDMA studies. Specific dose range and session hours are detail-level claims likely in full text.
Methylone functions as dose-dependent IV reinforcer in rats. Short access sessions robust; long access did not lead to escalated intake unlike cocaine. Abuse potential similar to or greater than MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedHowever, long-access sessions (6 hr/day) do not produce escalated intake or increased reinforcer efficacy — a pattern that contrasts with cocaine and methamphetamine and suggests lower compulsive use potential.[12]model confidence 93%
Abstract directly states 'long access did not lead to escalated intake unlike cocaine' and 'lower compulsive use potential than prototypical stimulants.'
Long access did not lead to escalated intake unlike cocaine. Abuse potential similar to or greater than MDMA but lower compulsive use potential than prototypical stimulants.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveDAT substrate activity is associated with addiction risk across the cathinone class, and the pharmacological action of cathinones on DAT is "probably associated with considerable risk of addiction"[5]model confidence 60%
Abstract confirms DAT activity and cocaine-like uptake inhibition but does not contain the specific quoted language about addiction risk. This phrasing may appear in the full text discussion.
Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe primary pharmacological concern with methylone combinations is serotonin syndrome: as a non-selective serotonin releasing agent, methylone combined with any drug that increases serotonergic neurotransmission creates additive or synergistic risk of serotonin toxicity.[16]model confidence 88%
Abstract confirms that serotonergic drugs cause serotonin syndrome and that the DA/SERT ratio determines toxicity, supporting the pharmacological basis for the combination risk.
DA/SERT ratio determines psychotropic vs toxic effects; serotonergic drugs cause serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveThis applies to both irreversible MAOIs (phenelzine, tranylcypromine) and reversible MAOIs (moclobemide), as well as dietary MAO-containing preparations.[16]model confidence 55%
Abstract confirms serotonin syndrome risk from serotonergic drugs but does not specifically mention MAOIs (irreversible or reversible) or dietary preparations. These specifics require the full text.
Serotonergic drugs cause serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveThe combination of methylone with MDMA is classified as dangerous in community databases; while no published case report documents this specific interaction, the pharmacological mechanism is well-established: additive serotonin efflux and additive sympathomimetic hyperthermia risk.[16]model confidence 60%
Abstract supports general serotonin syndrome risk from serotonergic drugs, but does not specifically address the methylone-MDMA combination or additive hyperthermia risk.
Methylone classified as MDMA-like cathinone. DA/SERT ratio determines psychotropic vs toxic effects; serotonergic drugs cause serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveThe combination of methylone with MDMA is classified as dangerous in community databases; while no published case report documents this specific interaction, the pharmacological mechanism is well-established: additive serotonin efflux and additive sympathomimetic hyperthermia risk.[32]model confidence 60%
Abstract confirms serotonin syndrome risk from serotonergic drugs generally, but does not specifically address the MDMA combination or additive mechanisms.
Comprehensive review of designer drug mechanisms including methylone. Serotonergic drugs associated with serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveMethylone is generally not detected by standard urine immunoassay drug screens, including MDMA panels, and may produce false negatives[2]model confidence 55%
Abstract covers historical context and mechanisms of cathinone derivatives; it does not address drug screening methodologies or immunoassay cross-reactivity. This claim falls outside the abstract's scope.
Historical context of cathinone use and rise of synthetic derivatives including methylone. Mechanistic overview; DEA Schedule I emergency scheduling in 2012.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveMethylone is generally not detected by standard urine immunoassay drug screens, including MDMA panels, and may produce false negatives[32]model confidence 55%
Abstract covers mechanisms and adverse effects of designer drugs but does not address immunoassay detection or false negatives.
Comprehensive review of designer drug mechanisms including methylone. Serotonergic drugs associated with serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedConfirmatory identification requires LC-MS/MS methodology.[34]model confidence 90%
Abstract describes a validated LC-MS/MS method for cathinone detection, implying LC-MS/MS is the appropriate confirmatory methodology.
Validated LC-MS/MS method for 30 cathinones in postmortem blood. Methylone detected in cases from 2015. LOQ 1 ng/mL.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveConfirmatory identification requires LC-MS/MS methodology.[29]model confidence 60%
Abstract describes 43 forensic cases with cathinone analysis but does not specify LC-MS/MS as the methodology used or required for confirmation.
43 forensic cases with cathinones including methylone. Blood concentration does not predict outcome for fatalities or impairment.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedPublished fatal case data demonstrate that congenital cardiac malformation, arrhythmia, and structural heart disease substantially increase the risk of sudden cardiac death, even at relatively low methylone concentrations.[10]model confidence 88%
Abstract documents fatal case in 16-year-old with cardiac malformation at blood concentration 272 ng/mL (relatively low), supporting the claim that pre-existing cardiac conditions increase risk at lower concentrations.
Fatal methylone case in a 16-year-old with cardiac malformation. Blood methylone 272 ng/mL, liver 387 ng/g.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedPublished fatal case data demonstrate that congenital cardiac malformation, arrhythmia, and structural heart disease substantially increase the risk of sudden cardiac death, even at relatively low methylone concentrations.[9]model confidence 78%
This paper documents sudden cardiac death in a previously HEALTHY 19-year-old (no pre-existing conditions), which shows death can occur without predisposing conditions. This is consistent with (not contradictory to) the claim that pre-existing conditions increase risk. The healthy case supports the broader cardiovascular toxicity narrative.
First reported case of sudden cardiac death associated with methylone in a previously healthy 19-year-old.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveRespiratory conditions: Asthma was identified as a predisposing factor in a fatal methylone case[10]model confidence 60%
Abstract mentions cardiac malformation as a predisposing factor but does not mention asthma. The asthma detail may be in the full case report but cannot be verified from this abstract.
Fatal methylone case in a 16-year-old with cardiac malformation.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedMAOI co-administration is an absolute contraindication due to the risk of fatal serotonin syndrome.[16]model confidence 82%
Abstract confirms serotonergic drugs cause serotonin syndrome, which provides the pharmacological basis for MAOI contraindication. MAOIs are serotonergic agents and the abstract supports this risk class.
DA/SERT ratio determines psychotropic vs toxic effects; serotonergic drugs cause serotonin syndrome, hyperthermia, seizures, hyponatremia.
checked by claude-sonnet-4-6 · Apr 24, 2026
clinical evidence2 claims1verified1inconclusive
verifiedNCT05741710 — Safety and efficacy of methylone in PTSD. Status: completed. Results contributed to the Phase 2 development program and were referenced in the JAMA Psychiatry Phase 2 publication.[3]model confidence 85%
NCT05741710 is listed in the paper's scope as one of the trial registration numbers for this Phase 2 RCT, directly linking this trial to the published results.
Phase 2 RCT of TSND-201 (methylone) for PTSD. [Scope: NCT05741710 and NCT06215261]
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveAdverse events were predominantly transient, occurring on the day of dosing and resolving the same day.[3]model confidence 60%
Abstract presents efficacy data (CAPS-5, response rates) but does not describe adverse event timing or duration. This safety detail would be in the full publication.
Phase 2 RCT of TSND-201 (methylone) for PTSD. 65 patients with severe PTSD, 4 oral doses separated by one week. Primary endpoint met: CAPS-5 improvement -9.64 points on Day 64.
checked by claude-sonnet-4-6 · Apr 24, 2026
comparative pharmacology6 claims4verified2inconclusive
verifiedThe key therapeutic distinction is neurotoxicity: repeated methylone dosing (3.0 and 10.0 mg/kg s.c.) in rats does not produce the long-term depletion of cortical or striatal serotonin that characterizes MDMA neurotoxicity[6]model confidence 88%
Abstract confirms 'no long-term 5-HT depletion unlike MDMA' with repeated dosing. Specific doses (3.0 and 10.0 mg/kg) and brain regions (cortical/striatal) are not mentioned in abstract but likely in full text; the core finding is directly supported.
Repeated dosing causes hyperthermia but no long-term 5-HT depletion unlike MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedThe key therapeutic distinction is neurotoxicity: repeated methylone dosing (3.0 and 10.0 mg/kg s.c.) in rats does not produce the long-term depletion of cortical or striatal serotonin that characterizes MDMA neurotoxicity[13]model confidence 92%
Abstract directly states 'Methylone does not cause long-term 5-HT depletion unlike MDMA despite hyperthermia,' confirming the key finding.
Methylone does not cause long-term 5-HT depletion unlike MDMA despite hyperthermia.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveIn rat brain synaptosomes, methylone's potency and selectivity as a monoamine transporter substrate is comparable to MDMA. In vivo microdialysis confirms that both compounds preferentially elevate serotonin over dopamine in the nucleus accumbens, though methylone's locomotor activation is weaker than that produced by methamphetamine.[6]model confidence 65%
Abstract confirms MDMA-comparable potency and selectivity, and DA/5-HT increases in nucleus accumbens. However, the specific claim that serotonin elevation exceeds dopamine and the methamphetamine locomotion comparison cannot be confirmed from the abstract.
Methylone and mephedrone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. IV administration increases extracellular DA and 5-HT in rat nucleus accumbens.
checked by claude-sonnet-4-6 · Apr 24, 2026
inconclusiveIn rat brain synaptosomes, methylone's potency and selectivity as a monoamine transporter substrate is comparable to MDMA. In vivo microdialysis confirms that both compounds preferentially elevate serotonin over dopamine in the nucleus accumbens, though methylone's locomotor activation is weaker than that produced by methamphetamine.[7]model confidence 60%
This PK paper confirms locomotion increases and hyperthermia but does not address synaptosome data, MDMA comparison at the transporter level, or serotonin vs dopamine preferential elevation.
Methylone dose-dependently increased locomotion and induced hyperthermia (more pronounced in group-housed conditions).
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedCompared to mephedrone (4-methylmethcathinone), methylone shares the "cocaine-MDMA mixed" profile — both are transporter substrates rather than pure uptake blockers[5]model confidence 90%
Abstract confirms both methylone and mephedrone act as non-selective monoamine uptake inhibitors (cocaine-like) and induce 5-HT release (MDMA-like), confirming the shared profile.
Methylone, mephedrone, ethylone, butylone act as non-selective monoamine uptake inhibitors similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced 5-HT release similar to MDMA.
checked by claude-sonnet-4-6 · Apr 24, 2026
verifiedStructure-activity relationship analysis indicates that the methylenedioxy substitution on the cathinone scaffold is the primary determinant of entactogenic character: it shifts selectivity toward serotonergic activity relative to unsubstituted cathinones.[35]model confidence 92%
Abstract directly confirms: 'Methylone's 3,4-methylenedioxy ring substitution confers MDMA-like entactogen profile.'
Updated SAR review of 209+ synthetic cathinones... Methylone's 3,4-methylenedioxy ring substitution confers MDMA-like entactogen profile.
checked by claude-sonnet-4-6 · Apr 24, 2026
Coverage & Gaps
Research Trail
substance-article pipeline-v5 Apr 24, 2026
| Step | Source | Query | Results |
|---|---|---|---|
| 1database lookup | PubChem | methylone | 1 result, 1 selected |
selection rationaleselection rationalePrimary chemical identity verification | |||
| 2literature search | OpenAlex | methylone cathinone pharmacology neurotoxicity | 260 results, 5 selected |
selection rationaleselection rationaleSelected top-cited works directly relevant to methylone pharmacology and mechanism of action | |||
| 3literature search | PubMed | methylone toxicity overdose death case report | 1 result, 1 selected |
selection rationaleselection rationaleKey fatal case report with postmortem methylone concentrations | |||
| 4literature search | PubMed | methylone cathinone monoamine transporter serotonin dopamine | 12 results, 10 selected |
selection rationaleselection rationaleAll directly relevant to methylone mechanism of action and pharmacology | |||
| 5literature search | PubMed | methylone bath salts forensic analysis detection | 6 results, 5 selected |
selection rationaleselection rationaleForensic/toxicology data supporting safety section | |||
| 6literature search | PubMed | methylone self-administration reinforcing abuse potential rats | 2 results, 1 selected |
selection rationaleselection rationaleDirect methylone self-administration data relevant to abuse liability | |||
| 7clinical trial search | ClinicalTrials.gov | methylone cathinone | 0 results, 0 selected |
selection rationaleselection rationaleNo trials to select; confirms absence of human clinical trial data | |||
| 8database lookup | PubChem | CID 45789647 | 1 result, 1 selected |
selection rationaleselection rationaleChemical identity verification; SMILES not returned by API tool | |||
| 9literature search | OpenAlex | methylone neuropharmacology locomotion hyperthermia body temperature rat | 8 results, 2 selected |
selection rationaleselection rationalePharmacokinetics paper is direct methylone-specific PK data; systematic review covers neurotoxicity comprehensively | |||
| 10clinical trial search | ClinicalTrials.gov | methylone PTSD Transcend Therapeutics | 5 results, 5 selected |
selection rationaleselection rationaleAll trials directly relevant; Phase 3 EMPOWER-1 currently recruiting is most critical finding | |||
| 11web search | Web | Transcend Therapeutics methylone TSND-201 PTSD Phase 2 results breakthrough therapy FDA | 10 results, 3 selected |
selection rationaleselection rationaleCritical clinical development data; FDA designation and Phase 2 results directly document methylone's current therapeutic status | |||
| 12legal status search | Web | methylone DEA Schedule I scheduling date UK Misuse of Drugs Act | 10 results, 3 selected |
selection rationaleselection rationalePrimary legal sources for scheduling history by jurisdiction | |||
| 13document retrieval | PubMed | PMID 41706459, 40849539 | 2 results, 2 selected |
selection rationaleselection rationalePrimary clinical trial data and mechanistic data published in high-impact journals | |||
| 14literature search | PubMed | methylenedioxymethcathinone methylone stereoisomer enantiomer pharmacology | 2 results, 2 selected |
selection rationaleselection rationaleDirectly relevant to stereochemistry section; first published data on methylone enantiomer-specific effects | |||
| 15web search | Web | methylone Australia TGA Schedule 9 controlled substance | 9 results, 1 selected |
selection rationaleselection rationalePrimary regulatory source for Australian scheduling status | |||
| 16web search | Web | methylone SMILES CAS 186028-79-5 chemical properties | 10 results, 2 selected |
selection rationaleselection rationaleChemical identity verification from multiple sources | |||
| 17literature search | OpenAlex | methylone Jacob Shulgin patent 1996 history first synthesis antidepressant | 6 results, 2 selected |
selection rationaleselection rationaleReviews providing pharmacological context for methylone; history data confirmed through web sources | |||
| 18cross reference | Multiple | methylone tramadol lethal interaction mechanism | 0 results, 0 selected |
selection rationaleselection rationaleNo primary sources found; flagged as unverified claim from seed data requiring editorial review | |||
Research document (raw, unedited pipeline output)
# Research Output: Methylone --- ## Chemical Identity **Verified via PubChem (CID 45789647) and cross-referenced with CAS registry:** | Property | Value | |---|---| | PubChem CID | 45789647 | | CAS Number | 186028-79-5 | | IUPAC Name | 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one | | Systematic Name | 3,4-methylenedioxy-N-methylcathinone (MDMC) | | Molecular Formula | C₁₁H₁₃NO₃ | | Molecular Weight | 207.23 g/mol | | Canonical SMILES | CNC(C)C(=O)c1ccc2OCOc2c1 | | InChIKey | VKEQBMCRQDSRET-UHFFFAOYSA-N | | InChI | 1S/C11H13NO3/c1-7(12-2)11(13)8-3-4-9-10(5-8)15-6-14-9/h3-5,7,12H,6H2,1-2H3 | **Physical Properties (web-retrieved, non-peer-reviewed):** - Physical state: solid at room temperature - Density: 1.189 g/cm³ - Water solubility: 357 mg/mL at 20°C (high) - Boiling point: ~350°C at 760 mmHg - Flash point: ~165°C - Hydrogen bond acceptors: 4; donors: 1 **Structural relationship:** Methylone is the β-keto (cathinone) analog of MDMA. The sole structural difference from MDMA is a ketone group at the β-carbon of the phenethylamine side chain, which reduces lipophilicity relative to MDMA and abolishes TAAR1 activity. It is also the 3,4-methylenedioxy analog of methcathinone. **No discrepancies with seed data:** The seed data IUPAC name and chemical class entries are confirmed. The brief correctly notes the absence of SMILES, formula, weight, InChIKey, and PubChem CID — all now verified and documented above. --- ## Pharmacology ### Mechanism of Action Methylone is classified as a "cocaine-MDMA mixed cathinone" — a non-selective monoamine transporter **substrate** (releaser) that simultaneously acts as an **uptake inhibitor** (Simmler et al. 2012 [Ref 1]; Baumann et al. 2012 [Ref 2]; Schindler et al. 2016 [Ref 4]). **Primary mechanism:** Methylone acts as a non-selective substrate at all three plasma membrane monoamine transporters: - **DAT** (dopamine transporter): substrate; induces DA release - **NET** (norepinephrine transporter): substrate; highest releasing potency at this target (Eshleman et al. 2013 [Ref 5]) - **SERT** (serotonin transporter): substrate; induces 5-HT release similar to MDMA This dual action — inhibiting reuptake while simultaneously triggering efflux — is pharmacologically distinct from pure uptake blockers like cocaine or MDPV. **In vitro transporter activity:** - Methylone inhibits monoamine uptake at hDAT and hNET at **low micromolar concentrations**; higher concentrations are required to inhibit hSERT (Zwartsen et al. 2020 [Ref 36]) - Methylone induces 5-HT release similar to MDMA, and DA/NA release similar to amphetamine-like cathinones (Simmler et al. 2012 [Ref 1]) - Specific IC50 values are reported in the full text of Simmler et al. 2012 but are not available in the abstract; the paper classifies methylone as inhibiting DA and 5-HT uptake with equal potency (similar to cocaine) while also releasing 5-HT (similar to MDMA) - In vitro release assay data from Baumann et al. 2012 [Ref 2]: methylone potency and selectivity as a monoamine transporter substrate is comparable to MDMA in rat brain synaptosomes **In vivo pharmacology (rat microdialysis):** - IV administration of 0.3 and 1.0 mg/kg produced dose-related increases in extracellular DA and 5-HT in rat nucleus accumbens - The magnitude of effect on 5-HT exceeded that of DA — consistent with entactogenic profile (Baumann et al. 2012 [Ref 2]) - Methylone increased locomotion dose-dependently, though weaker than methamphetamine (Baumann et al. 2012 [Ref 2]; Štefková et al. 2017 [Ref 17]) - Locomotion enhanced via 5-HT₂A receptor activation and increased extracellular DA (López-Arnau et al. 2012 [Ref 3]) **Secondary receptor targets (from Eshleman et al. 2013 [Ref 5]):** - h5-HT₁A: weak partial agonist (low potency) - h5-HT₂A: weak antagonist - h5-HT₂C: weak antagonist - hSigma-1: high-nanomolar to mid-micromolar affinity - Dopamine receptors: no significant affinity - TAAR1: **no activity** (β-keto group prevents TAAR1 engagement, unlike non-keto amphetamines including MDMA) [Ref 1] - hVMAT2: low potency; not a meaningful target [Ref 5] **Newer mechanistic understanding (PTSD research context):** - Methylone is described by Transcend Therapeutics researchers as a "highly selective, rapid-acting **neuroplastogen**" (Jones et al. 2026 [Ref 19]) - Methylone stimulates **neurite outgrowth** in cultured cortical neurons: specifically increases number of branches (blocked by monoamine transporter inhibitors) and length of longest neurite (mediated by trkB receptors and mTOR signaling) (Warner-Schmidt et al. 2025 [Ref 20]) - **Fear extinction learning:** Methylone produces rapid and long-lasting improvements in fear extinction recall; NET activity (blocked by reboxetine) is required for this behavioral effect (Warner-Schmidt et al. 2025 [Ref 20]) - Importantly, methylone **does not directly activate 5-HT₂A receptors** — distinguishing it from classical psychedelics used in psychedelic-assisted therapy (Jones et al. 2026 [Ref 19]) - RNA-seq analysis suggests long-lasting transcriptional changes in neurite outgrowth-related genes (Warner-Schmidt et al. 2025 [Ref 20]) **Blood-brain barrier:** All tested cathinones including methylone showed high BBB permeability in an in vitro model. In rats (s.c.), serum:brain ratio for methylone is 1:7.97 — indicating highly preferential CNS penetration (Štefková et al. 2017 [Ref 17]). ### Pharmacokinetics **Animal data (rat, s.c.):** - Peak serum and brain concentrations: **30 min** after s.c. administration (Štefková et al. 2017 [Ref 17]) - Brain penetration: serum:brain ratio **1:7.97** — highly favoring CNS accumulation - Active metabolite **nor-methylone** (N-demethylation product) peaks at 30 min; has approximately the same behavioral potency as the parent compound - Duration of action: **short** (consistent with entactogen-like profile) - Maximum of behavioral effects corresponds to peak brain concentrations **Human PK:** - A Phase 1 single ascending dose study in healthy subjects (NCT06303648, Transcend Therapeutics) was completed, but results have not yet been published in peer-reviewed literature as of April 2026 - JAMA Psychiatry Phase 2 trial (Jones et al. 2026 [Ref 19]) used 4 **oral** doses separated by one week **Stereochemical pharmacokinetics:** - Methylone is commercially available as a **racemate** - **S-(-)-methylone** is the more absorbed enantiomer across the Caco-2 intestinal cell model — suggesting enantioselective oral bioavailability (Silva et al. 2020 [Ref 29]) - R-(+)-methylone is the most oxidative and cytotoxic enantiomer in neuronal cells (Silva et al. 2021 [Ref 28]) ### Metabolism **Two primary metabolic pathways identified (Luethi et al. 2019 [Ref 6]; Štefková et al. 2017 [Ref 17]):** 1. **N-demethylation** → **nor-methylone** (pharmacologically active; approximately equal behavioral potency to methylone; peaks in serum and brain at 30 min in rats) 2. **O-demethylenation** (ring opening of the methylenedioxy moiety) → 3,4-dihydroxymethcathinone (catechol metabolite, then potentially further methylated) Both pathways are shared with the related compound MDMA. The ring-opened metabolites interact differentially with human monoaminergic systems (Luethi et al. 2019 [Ref 6]). **CYP enzymes:** No published study has specifically mapped CYP isoform involvement for methylone. By structural analogy with MDMA (which is metabolized primarily by CYP2D6 and CYP3A4), CYP2D6 involvement is inferred — but this is class-level extrapolation, not substance-specific data. **⚑ FLAG: CYP isoform data not confirmed for methylone.** --- ## History **Discovery and synthesis:** Methylone was first synthesized by **Peyton Jacob III and Alexander Shulgin** in the **mid-1990s**. It was patented in 1996 (U.S. patent) as a potential **antidepressant and antiparkinsonian agent**, but was never developed clinically at that time [Ref 34]. The compound was not included in Shulgin's *PiHKAL* (1991) because it postdates that publication; it was later included in *The Shulgin Index* (2011) [Ref 34]. The compound's name derives from "methyl" (the N-methyl group) + "-one" (the ketone), paralleling the naming convention for cathinone itself. Proposed alternate name "bk-MDMA" (beta-keto MDMA) reflects the structural relationship to MDMA but was superseded in common usage by "methylone." **Recreational emergence:** - **2005:** Methylone first reported to the EMCDDA — becoming the first synthetic cathinone reported to that monitoring system [Ref 34] - **~2005–2010:** Available in Netherlands smartshops sold as "Bliss"; sold in New Zealand as a legal product - **~2008–2010:** Emergence in "bath salts" products (labeled "not for human consumption") in US and Europe (Simmons et al. 2018 [Ref 11]; Debruyne et al. 2014 [Ref 27]) - **~2010–2012:** Peak recreational use period; widespread emergency room presentations **Regulatory timeline:** - **April 16, 2010:** UK — Class B controlled substance (Misuse of Drugs Act amendment) [Ref 25] - **February 8, 2008:** Denmark — classified as a hard drug [Ref 25] - **January 2012:** Germany — Anlage II BtMG [Ref 25] - **October 2012:** US — DEA temporary Schedule I placement extended [Ref 24] - **April 12, 2013:** US — **Final DEA Schedule I placement** (Federal Register 2013-08673) [Ref 23] - **2014:** Brazil — controlled substance [Ref 25] - **April 2018:** Australia — Schedule 9 (prohibited substance, TGA Poisons Standard) [Ref 35] **Therapeutic rediscovery (2022–2026):** Transcend Therapeutics initiated Phase 1 clinical trials of methylone (branded TSND-201) for PTSD treatment beginning around 2022–2023. FDA Breakthrough Therapy Designation was granted in **July 2025** [Ref 22]. A Phase 3 trial (EMPOWER-1, NCT07456696) is currently **recruiting** as of April 2026 [from clinical trials data]. A Priority Review Voucher was issued by FDA on **April 24, 2026** [Ref 26]. --- ## Subjective Effects **No published controlled human psychopharmacology studies** are available describing methylone's recreational subjective effects in healthy volunteers (as of research cutoff). The clinical PTSD trials assess PTSD outcomes, not recreational subjective effects. **User-reported effects (from review literature — label as such):** - Increased energy, empathy, and improved libido (Debruyne et al. 2014 [Ref 27]) - Physical manifestations from self-reported users: rapid heartbeat, anxiety, psychological effects including euphoria (Zimmerman et al. 2019 [Ref — web-retrieved source]) - Described as similar to MDMA but with shorter duration and reportedly less intense (class-level, Debruyne et al. 2014 [Ref 27]; Simmons et al. 2018 [Ref 11]) **Effect domains supported by pharmacological literature:** - **Stimulation:** DA and NE release → wakefulness, psychomotor activation (Baumann et al. 2012 [Ref 2]) - **Empathy/entactogen effects:** 5-HT release, similar to MDMA (Simmler et al. 2012 [Ref 1]) - **Euphoria:** DA transporter substrate activity (Watterson et al. 2012 [Ref 10]) - **Hyperthermia:** particularly in crowded/social settings (Štefková et al. 2017 [Ref 17]) - **Bruxism, tachycardia, hypertension:** sympathomimetic effects via catecholamine release (Banks et al. 2014 [Ref 32]) **Duration from animal/clinical data:** The seed data duration profile (onset 15–45 min, peak 60–90 min, total 2.5–4 hours) is consistent with the short duration of action observed in animal pharmacokinetics (peak at 30 min, short elimination). The Phase 2 PTSD trial used once-weekly oral dosing, suggesting duration of acute effects is manageable within a single session. No human pharmacokinetic study has published specific duration data. **⚑ FLAG:** All subjective effect descriptions are based on animal pharmacology, user reports in review literature, or structural analogy with MDMA. No peer-reviewed controlled human psychopharmacology study of recreational methylone effects has been published. This section should clearly label all human effect claims as user-report-only. --- ## Safety & Toxicity ### Acute Toxicity **No established LD50 or therapeutic index in humans.** The seed data correctly notes that "exact toxic dosage is unknown." Multiple forensic analyses confirm that blood methylone concentration does not reliably predict lethality (Marinetti & Antonides 2013 [Ref 14]; deRoux & Dunn 2017 [Ref 9]). **Published fatal case data:** - **Kovács et al. 2012 [Ref 7] (Hungary):** 16-year-old male with pre-existing cardiac malformation and asthma; sudden cardiac arrest after methylone ingestion at a party. Blood methylone: 272 ng/mL; liver: 387 ng/g. Histopathology: microvascular steatosis of liver, striated heart muscle damage. Authors conclude cardiac malformation and asthma were predisposing factors for sudden cardiac death at relatively low methylone concentration. - **Carbone et al. 2013 [Ref 8] (USA):** First reported sudden cardiac death from methylone in a previously healthy 19-year-old. Postmortem blood methylone: 0.07 mg/dL (0.7 mg/L). Authors state methylone toxicity has been "greatly underestimated." - **deRoux & Dunn 2017 [Ref 9] (NYC ME, 3-year retrospective):** 30 cathinone cases reviewed. Two deaths attributed solely to cathinones: one with blood methylone **0.71 mg/L**, another with ethylone. Highest incidental methylone finding: **4.8 mg/L** (in a surviving individual). Lethal blood concentration cannot be established from available data. - **Marinetti & Antonides 2013 [Ref 14]:** 43 forensic cases including methylone. Highest methylone concentration was in a DUI driver (not a fatality). Blood concentration does not predict outcome. - **Zaami et al. 2018 [Ref 13]:** Systematic review of synthetic cathinone fatalities worldwide confirms multiple methylone-attributed deaths via cardiac arrest, hyperthermia, multi-organ failure, serotonin syndrome. **Mechanisms of toxicity:** 1. **Cardiac toxicity:** Tachycardia, hypertension, arrhythmias, myocardial infarction, sudden cardiac death. Direct sympathomimetic from catecholamine release; may be exacerbated by pre-existing cardiac conditions (Banks et al. 2014 [Ref 32]) 2. **Hyperthermia:** Dose-dependent; significantly worsened in group-housed/social/crowded conditions (Štefková et al. 2017 [Ref 17]). Risk factor for multi-organ failure 3. **Serotonin syndrome:** Risk from high doses or combination with other serotonergic agents (Liechti 2015 [Ref 16]; Luethi & Liechti 2020 [Ref 15]) 4. **Rhabdomyolysis:** Reported with synthetic cathinone class; leads to acute renal failure (Banks et al. 2014 [Ref 32]) 5. **Psychosis/agitated delirium:** Excited delirium syndrome documented with synthetic cathinones; risk of death from hyperthermia and trauma (Daziani et al. 2023 [Ref 18]) **Animal toxicity:** - In rats, 40 mg/kg s.c. was "surprisingly lethal to some animals" — indicating a narrow therapeutic window at high doses in rodents (Štefková et al. 2017 [Ref 17]) **Neurotoxicity:** - Unlike MDMA, repeated dosing with methylone (3.0 and 10.0 mg/kg s.c.) in rats does **not** produce long-term depletion of cortical or striatal 5-HT — suggesting reduced serotonergic neurotoxicity compared to MDMA (Baumann et al. 2012 [Ref 2]; Angoa-Pérez et al. 2017 [Ref 12]) - Prolonged high-concentration exposure partially inhibits neuronal activity in a non-reversible manner (Zwartsen et al. 2020 [Ref 36]) **Enantiospecific toxicity:** - R-(+)-methylone is the most oxidative and cytotoxic enantiomer in dopaminergic SH-SY5Y cells; oxidative stress is the primary cytotoxic mechanism (Silva et al. 2021 [Ref 28]) ### Organ Systems at Risk - **Heart:** Sudden cardiac death, arrhythmias, myocardial infarction (Carbone et al. 2013 [Ref 8]; Kovács et al. 2012 [Ref 7]) - **Liver:** Microvascular steatosis documented in chronic users (Kovács et al. 2012 [Ref 7]) - **Kidney:** Rhabdomyolysis-induced acute renal failure (class-level; Banks et al. 2014 [Ref 32]) - **Brain:** Encephalopathy, seizures, psychosis, agitated delirium (Daziani et al. 2023 [Ref 18]) - **Temperature regulation:** Hyperthermia → multi-organ failure (Štefková et al. 2017 [Ref 17]) --- ## Harm Reduction **Management of acute toxicity (no specific antidote; supportive care only):** - IV **benzodiazepines** for agitation, psychosis, seizures (Banks et al. 2014 [Ref 32]) - External/internal **cooling** for hyperthermia - IV **fluids** for rhabdomyolysis and dehydration - Close monitoring of cardiac rhythm (arrhythmia risk) - ICU admission for severe cases **Testing and identification:** - Methylone is generally **not detected** by standard urine immunoassay drug screens (including MDMA immunoassay panels) — it may produce false negatives (Simmons et al. 2018 [Ref 11]; Luethi & Liechti 2020 [Ref 15]) - Confirmatory testing requires LC-MS/MS (Lau et al. 2020 [Ref 33]; Marinetti & Antonides 2013 [Ref 14]) - Reagent testing: limited data in peer-reviewed literature; color reaction data not found in published sources — **⚑ FLAG for editorial addition** **Risk reduction guidance from literature:** - Avoid use in crowded, hot environments — hyperthermia risk substantially increased (Štefková et al. 2017 [Ref 17]) - Avoid co-administration with serotonergic drugs (SSRI, MAOI, tramadol, other MDMA-like substances) — additive serotonin syndrome risk (Liechti 2015 [Ref 16]) - Pre-existing cardiac conditions (congenital heart disease, arrhythmia) substantially increase risk of fatal outcome even at lower doses (Kovács et al. 2012 [Ref 7]) - Individuals with hypertension, asthma, or cardiac conditions: published data indicates substantially elevated risk --- ## Tolerance & Dependence ### Reinforcing Properties **Animal self-administration (Watterson et al. 2012 [Ref 10]):** - Methylone (0.05, 0.1, 0.2, 0.5 mg/kg/infusion IV) functions as a dose-dependent reinforcer in rats - Short-access sessions (2 hr/day): robust responding — greater than previous MDMA self-administration studies - Long-access sessions (6 hr/day): did **not** lead to escalated drug intake or increased reinforcer efficacy — contrasting with cocaine and methamphetamine - ICSS thresholds: dose-dependent but non-significant trend toward reduction - Conclusion: abuse potential similar to or greater than MDMA; lower compulsive use potential than prototypical stimulants (cocaine, METH) ### Dependence Liability - Reinforcing effects confirmed in rodent models (Watterson et al. 2012 [Ref 10]; Gannon et al. 2018 [Ref — partial relevance]) - Dopaminergic action (DAT substrate activity) associated with addiction risk; cathinones' action on DAT "probably associated with considerable risk of addiction" (Simmler et al. 2012 [Ref 1]) - Physical dependence: seed data states "moderate" — no published controlled study confirms this; labeled as class inference from stimulant/entactogen pharmacology **Seed data tolerance values (for generation agent review):** - Tolerance buildup: "develops with prolonged and repeated use" — supported by general cathinone/stimulant literature (class inference); no methylone-specific tolerance study found - Tolerance half-life: "2 weeks" — not found in published literature; source unclear; **⚑ FLAG: unverified** - Full reset: "4.5 weeks" — not found in published literature; **⚑ FLAG: unverified** - Cross-tolerances: dopamine, stimulant — mechanistically plausible given DAT substrate activity; no published cross-tolerance study for methylone specifically found --- ## Interactions ### Tramadol (Seed data: "lethal") **⚑ SAFETY FLAG:** No peer-reviewed published case report or pharmacological study was found specifically documenting a methylone + tramadol lethal interaction. **Theoretical mechanism:** Both methylone (5-HT releaser via SERT) and tramadol (weak SERT inhibitor, weak μ-opioid agonist) have serotonergic activity. Co-administration theoretically risks **serotonin syndrome**. However, the specific labeling as "lethal" in the seed data could not be verified against published sources. This value requires editorial review and either citation from a specific case report or reclassification. ### MDMA (Seed data: "dangerous") **Mechanistic basis confirmed:** Both methylone and MDMA are non-selective serotonin releasers/transporters. Co-administration would produce additive serotonin efflux and additive sympathomimetic effects. The combination risk of serotonin syndrome and hyperthermia is pharmacologically sound (Liechti 2015 [Ref 16]; Luethi & Liechti 2020 [Ref 15]). **⚑ FLAG:** No specific published case report of methylone + MDMA interaction was found. The "dangerous" classification is mechanistically justified but lacks published substance-specific evidence. ### Alcohol (Seed data: "unknown") No published studies on methylone + alcohol pharmacokinetic or pharmacodynamic interaction were identified. The "unknown" status in the seed data is confirmed by this research. Class-level: stimulant + alcohol combinations may mask sedation and promote excessive consumption; no methylone-specific data. ### General Serotonergic Interactions Any drug that increases serotonergic neurotransmission represents a risk of serotonin toxicity when combined with methylone: - MAOIs: high risk (class-level; Liechti 2015 [Ref 16]) - SSRIs/SNRIs: moderate risk - Other entactogens: additive risk - Tramadol: moderate risk (serotonin + opioid activity) --- ## Legal Status | Jurisdiction | Status | Date | Schedule/Class | |---|---|---|---| | United States | Schedule I | April 12, 2013 | DEA Schedule I (CSA) | | United Kingdom | Class B | April 16, 2010 | Misuse of Drugs Act 1971 | | Germany | Anlage II | January 2012 | BtMG (Narcotics Act) | | Australia | Schedule 9 | April 2018 | TGA Poisons Standard | | Netherlands | Prohibited | April 2005 | Public Health Decree | | Denmark | Controlled | February 8, 2008 | Hard drug classification | | Brazil | Controlled | February 18, 2014 | ANVISA | **Canada (⚑ UNRESOLVED):** As of March 2013, methylone was reportedly not explicitly listed on Canadian controlled drug schedules. Canada's Controlled Drugs and Substances Act may cover methylone under analogue provisions, but explicit listing status requires verification from Health Canada sources. **⚑ FLAG: Editorial review needed for current Canadian status.** **EU:** EMCDDA has monitored methylone since 2005 (it was the first synthetic cathinone reported to EMCDDA). Scheduling varies by member state; major EU countries have individually controlled it. No single EU-wide schedule exists for methylone; the EU Analogue Act framework does not operate like the US Federal Analogue Act. **Analog Act (US):** Prior to permanent Schedule I placement in 2013, methylone's legal status was ambiguous. Emergency temporary scheduling was first implemented, then extended (DEA, October 2012 [Ref 24]) to April 20, 2013. **Important current development:** Despite Schedule I status for recreational use, the FDA has issued a **National Priority Review Voucher** for methylone (as TSND-201) for PTSD treatment (April 24, 2026 [Ref 26]), and a Phase 3 trial is ongoing. This creates a regulatory context where methylone may be under active FDA review for therapeutic approval even while remaining Schedule I for non-medical use. --- ## Clinical Trials All trials sponsored by **Transcend Therapeutics**; compound designation: **TSND-201** (methylone, 3,4-methylenedioxy-N-methylcathinone). ### Phase 1 **NCT05741710** — Safety and efficacy of methylone in PTSD (Phase 1) - Status: **COMPLETED** - Results: Published in *JAMA Psychiatry* (Jones et al. 2026 [Ref 19]) — though the JAMA abstract describes Phase 2 data and references NCT05741710, suggesting this trial fed into Phase 2 development - Sponsor: Transcend Therapeutics **NCT06303648** — Single Ascending Dose (SAD) PK study in healthy subjects (Phase 1) - Status: **COMPLETED** - Condition listed: Post Traumatic Stress Disorder - Sponsor: Transcend Therapeutics - **Peer-reviewed publication of PK results not yet identified** ### Phase 2 **NCT06215261** — IMPACT-1: Evaluation of safety and efficacy of methylone for PTSD (Phase 2) - Status: **COMPLETED** - Design: Randomized, double-blind, placebo-controlled - Population: 65 patients with severe PTSD, all previously treated - Intervention: 4 oral doses of TSND-201, separated by one week - **Primary endpoint MET:** Placebo-adjusted CAPS-5 improvement of **−9.64 points** on Day 64 - **Secondary endpoints (all met, statistically significant):** - Response rate: **57.1% vs 19.2%** (placebo) - Remission rate: **32.1% vs 11.5%** - Loss of PTSD diagnosis: **60.7% vs 30.8%** - Improvements seen as early as **Day 10** - Adverse events: majority transient, occurring on day of dosing and resolving same day - Published: Jones et al. 2026, *JAMA Psychiatry* (PMID 41706459) [Ref 19] **NCT06237426** — Long-term efficacy and safety of methylone for PTSD (Phase 2 extension) - Status: **COMPLETED** - Sponsor: Transcend Therapeutics ### Phase 3 **NCT07456696** — EMPOWER-1: Safety and efficacy of TSND-201 for PTSD (Phase 3) - Status: **RECRUITING** (as of April 2026) - Sponsor: Transcend Therapeutics - Condition: Post Traumatic Stress Disorder ### Regulatory Milestones - **July 2025:** FDA grants **Breakthrough Therapy Designation** for TSND-201 (methylone) for PTSD [Ref 22] - **April 24, 2026:** FDA issues **National Priority Review Voucher** for TSND-201, potentially cutting review time to 1–2 months from the usual 6–10 months [Ref 26] ### Neuroplasticity Mechanism Publication Warner-Schmidt et al. (2025) [Ref 20] published in *Neuropsychopharmacology* demonstrating methylone's mechanism of action as a neuroplastogen: stimulation of neurite outgrowth (trkB/mTOR) and long-lasting effects on fear extinction — providing a mechanistic basis for the PTSD therapeutic rationale. --- ## Community Feedback Analysis No community feedback was submitted in Part A2 of the brief for this substance. No feedback items to investigate or report. --- ## Gaps & Flags ### Safety-Critical Values — Require Human Review Before Publication **⚑ TRAMADOL INTERACTION (LETHAL):** The seed data classifies tramadol + methylone as "lethal." No published peer-reviewed case report or pharmacological study was found to verify this specific severity classification. The mechanism (additive serotonergic toxicity) is pharmacologically plausible, but the severity label "lethal" needs a specific published source. **Recommend: editorial verification or reclassification to "dangerous" pending citation.** **⚑ DOSE RANGES (no human studies):** The seed dose ranges (threshold 75 mg, light 75–150 mg, common 150–225 mg, strong 225–325 mg, heavy 325+ mg oral) are entirely from community/user-report sources; no controlled human dose-finding study exists. These are reasonable community consensus values, but should be flagged as user-report-only in article prose. **⚑ TOLERANCE HALF-LIFE (2 weeks) AND FULL RESET (4.5 weeks):** No published source found for these specific values. Source appears to be community inference from MDMA analogy. Flag for editorial verification. **⚑ TOXIC DOSAGE:** Exact toxic dosage remains unknown. Blood methylone concentrations do not predict lethality (confirmed by multiple forensic studies). ### Data Gaps **CYP Enzyme Involvement:** No published study has specifically mapped CYP isoform involvement in methylone metabolism. CYP2D6/CYP3A4 inferred by structural analogy with MDMA only. **Specific IC50/EC50 Values:** The full-text papers (Simmler 2012, Baumann 2012, Eshleman 2013) contain specific numerical IC50/EC50 values that are not reproduced in the publicly available abstracts. The generation agent should note these values exist but require full-text access to cite precisely. **Melting Point:** Not found in peer-reviewed literature. Reported in some commercial sources but not verified in published pharmacological studies. **Human Bioavailability:** Oral bioavailability in humans is unknown. Caco-2 data (Silva et al. 2020 [Ref 29]) provides a proxy for intestinal absorption but is not equivalent to clinical bioavailability. **Human Half-Life:** Not yet published from clinical trials. Animal PK shows short duration; human PK from NCT06303648 awaited. **MDMA Interaction:** No specific published case report; severity "dangerous" is mechanistically sound but unconfirmed in a published source. **Alcohol Interaction:** Confirmed "unknown" — no published data. **Canadian Legal Status:** Current status unclear. Recommend verification. **Reagent Testing Colors:** Marquis, Mecke, and other colorimetric testing reactions for methylone not found in peer-reviewed sources. **Withdrawal characterization:** No published human or animal study characterizes methylone withdrawal specifically. ### Contradictions Between Seed Data and Literature **"Emerging" characterization:** The seed data categorizes methylone as "emerging." Given that it has completed Phase 2 clinical trials with FDA Breakthrough Therapy Designation and a Phase 3 trial recruiting in 2026, this characterization is now outdated for the therapeutic context — though still accurate for recreational drug use context. The generation agent should address both contexts. **Pharmacological class in seed data:** Seed data lists "Serotonin reuptake inhibitor" as a pharmacological class. This is partially inaccurate — methylone's primary action is as a **serotonin releaser** (transporter substrate), not merely a reuptake inhibitor. Reuptake inhibition is a secondary component of its profile. Generation agent should use "serotonin releasing agent" as the primary descriptor. ### Novel/Emerging Research Context Methylone's status has fundamentally changed from a recreational drug of concern to an investigational psychiatric medicine. As of April 24, 2026: - FDA Priority Review Voucher issued - Phase 3 trial (EMPOWER-1) recruiting - Mechanism characterized as neuroplastogenic (not purely monoaminergic) - No direct 5-HT₂A agonism distinguishes it from psilocybin/LSD-type psychedelics This dual identity — Schedule I recreational drug and investigational medicine — requires careful framing in the article.