Pharmacological effects of methylone and MDMA in humans

Design and participants: The investigation was a randomised, double-blind, placebo-controlled, crossover trial. Eighteen healthy volunteers were recruited and 17 (14 males, 3 females) completed all sessions. Eligible participants reported prior recreational use of psychostimulants (at least twice in the past year and six times lifetime) and were screened by medical history, ECG and blood/urine tests. Exclusion criteria included recent organic illness, major surgery, or current/recent mental disorders including substance use disorder (except nicotine). Interventions and dosing: Each participant attended three experimental sessions separated by a one-week washout and received in random order oral placebo, 200 mg methylone or 100 mg MDMA. Doses were chosen after pilot dose-finding work in which methylone doses of 50–200 mg were evaluated; 200 mg methylone was selected to approximate the subjective effects of 100 mg MDMA. Study drugs (methylone hydrochloride and MDMA hydrochloride) and placebo were encapsulated in identical gelatin capsules by the hospital pharmacy. Procedures and measures: Sessions began in the morning after overnight fasting; participants remained under observation for about 11 h and were required to abstain from illicit drugs, alcohol and caffeine prior to sessions and to test negative on a urine drug screen at arrival. Physiological monitoring included repeated measures of systolic and diastolic blood pressure, heart rate, oral temperature and pupil diameter at baseline and multiple post-dose time points up to 24 h; continuous ECG monitoring was used for safety. Blood and oral fluid for drug/metabolite assays were collected at baseline and several post-dose times (including 15, 30, 60 minutes and later up to 24 h) and urine was collected over 24 h. Subjective effects were assessed using visual analogue scales (31-item VAS), the 49-item short form of the Addiction Research Center Inventory (ARCI), the VESSPA-SSE questionnaire for stimulant effects, the Sensitivity to Drug Reinforcement Questionnaire (SDRQ; drug liking and wanting), and a pharmacological class identification question. Psychomotor function was measured using a psychomotor vigilance task (PVT) and Maddox wing assessment of heterophoria. Pharmacokinetics and safety: Although detailed pharmacokinetic results from the main trial are not presented in full in the extracted text, pilot pharmacokinetic data for methylone (50–200 mg) are referenced. Safety monitoring included repeated psychiatric assessment with the Young Mania Rating Scale and continuous ECG. Statistical analysis: Baseline-adjusted outcomes were derived; the primary derived metrics included Emax (maximum change from baseline) and Tmax (time to maximum effect) and AUC0–6h calculated by the trapezoidal rule. One-way repeated measures ANOVA tested differences in Emax and AUC across treatments with Tukey post hoc comparisons when appropriate. Tmax values used non-parametric tests (Friedman, Wilcoxon with Bonferroni adjustment). Time-course analyses used two-way repeated measures ANOVA (treatment × time) with post hoc tests. The sample size was calculated to detect cardiovascular differences based on bioequivalence methodology and was increased to 17 to improve power; statistical significance was set at p < 0.05.

Participants and safety: Seventeen participants completed the study (mean age 23 years, mean weight 70.8 kg, mean BMI 23.2 kg/m2). All reported prior use of MDMA and a range of other recreational drugs. One participant was excluded after two sessions due to anxiety and uneasiness attributed to an active treatment (unblinding showed placebo then MDMA); no further therapeutic intervention was required. Aside from that case, no serious adverse events, psychotic episodes or hallucinations were reported. Physiological effects: Both 200 mg methylone and 100 mg MDMA produced significant increases in systolic and diastolic blood pressure, heart rate and pupil diameter compared with placebo. Maximum cardiovascular and pupil responses for the two active drugs differed from placebo but not significantly from one another. Some temporal distinctions were noted: methylone tended to reach higher and earlier maximum effects on systolic blood pressure and heart rate than MDMA, although these differences did not reach statistical significance for Emax; methylone showed a lower AUC and earlier Tmax for pupil diameter than MDMA. Methylone produced a sustained increase in heart rate that remained significantly elevated relative to placebo until 10 h post-dose and returned to baseline by 24 h. No consistent differences in oral temperature between active treatments were observed except at one time point (2 h). Subjective effects: Both active drugs elicited robust subjective effects on VAS and questionnaire measures versus placebo. The most affected domains were stimulation and wellbeing (VAS items such as “stimulation”, “high”, “good effects”, “liking”), altered perception (changes in distances, lights, body feeling, surroundings) and empathy/social measures (“open”, “trust”, “feeling close to others”, “I want to be with other people”, “I want to hug someone”). Methylone’s subjective effects typically appeared earlier (around 0.5 h) and returned toward baseline by 2.5–3 h, whereas MDMA effects emerged later (about 0.75 h) and normalised by 4 h. For stimulation, wellbeing and empathy, methylone reached Tmax at a median 0.75 h versus 1 h for MDMA; time-course analyses showed higher early effects for methylone (0.5–0.75 h) and later peaks for MDMA (2–2.5 h). Participants reported more dizziness after MDMA than methylone. On ARCI subscales both drugs changed all subscales, notably MBG (euphoria) and A (amphetamine effects); methylone produced higher maximum scores on MBG, BG (intellectual efficiency) and A, whereas MDMA produced higher PCAG (sedation) and LSD (dysphoria) scores, but only PCAG and BG differed significantly between active treatments. VESSPA results showed both drugs increased anxiety (ANX), pleasure/sociability (SOC) and activity/energy (ACT); methylone had higher maxima for ANX, SOC and ACT, while MDMA scored higher for sedation (S), changes in perception (CP) and psychotic symptoms (PS); VESSPA CP was the only subscale with significant differences in both maximum effect and AUC between methylone and MDMA. On the SDRQ, methylone scored higher for “how pleasant” and “wanting” but differences versus MDMA did not reach statistical significance. In the pharmacological identification task, 94.1% of participants identified methylone as a designer drug (same as MDMA identification rates). Psychomotor performance: Methylone significantly improved reaction time on the PVT (reduced mean reaction time), with significant reductions versus MDMA and placebo at 1 and 2 h post-dose. MDMA did not significantly affect reaction time compared with placebo. Both active drugs induced inward ocular deviation (esophoria) on the Maddox wing; MDMA produced numerically greater esophoria but differences were not statistically significant. Methylone’s esophoria appeared earlier than MDMA’s, with significant differences between active treatments at 2 and 3 h. Pharmacokinetics (pilot data referenced): In pilot studies cited by the investigators, 200 mg methylone produced a plasma Cmax of 604 ng/mL at a Tmax of 2 h and an elimination half-life of 6.4 h. The methylone metabolite HMMC had a plasma Cmax of 42.1 ng/mL, Tmax of 1.5 h and t1/2 of 6.3 h. The authors note methylone’s pharmacokinetics appear faster than MDMA’s (MDMA Tmax 2–2.5 h, t1/2 7.7–12 h) and slower than mephedrone’s (Tmax ~1.25 h, t1/2 ~2.15 h).

[Poyatos] and colleagues interpret their findings as demonstrating that a single oral dose of 200 mg methylone produces clear cardiovascular stimulation and desirable subjective effects such as stimulation, euphoria, increased sociability and altered perception, yielding an overall profile comparable to MDMA. A salient distinction was methylone’s faster onset and earlier offset of subjective effects relative to MDMA, a pattern that the investigators suggest reflects faster pharmacokinetics and a shorter elimination half-life. The sustained heart rate elevation observed after methylone—lasting up to 10 h despite normalisation of blood pressure—was highlighted as a noteworthy pharmacodynamic difference. The authors situate their results alongside earlier work: their controlled findings align with a prior naturalistic observational study that reported methylone’s stimulant and empathogenic properties, although subjective effects in the present trial were generally larger and peaked earlier, which the investigators attribute to differences in participant experience and study setting. Comparisons with mephedrone are drawn: methylone and mephedrone share many subjective and cardiovascular characteristics, including early onset and MDMA-like effects, although methylone produced improved psychomotor reaction times in this study whereas mephedrone did not consistently do so in prior work. Pharmacokinetic observations are used to explain temporal dissociation between plasma concentrations and peak subjective effects; the authors note that maximum effects often precede Cmax for methylone and related cathinones. Limitations are acknowledged: the sample size limited statistical power to detect differences between active drugs, the small number of female participants precluded sex-based analyses, and only a single methylone dose was tested so no dose–response relationship can be inferred. The authors also note the short-lived subjective effects of methylone and the high scores on wanting measures at 1 h post-dose, which may favour a redosing pattern in recreational use and could increase risk. Overall, the investigators conclude that methylone’s pharmacological and subjective profile implies an abuse potential comparable to MDMA, with the faster kinetics and shorter subjective duration possibly promoting repeated dosing behaviour.

This controlled human study provides the first experimental evidence that oral methylone (200 mg) produces cardiovascular activation and MDMA-like subjective effects including stimulation, euphoria, sociability and altered perception. Compared with 100 mg MDMA, methylone had a faster onset and earlier offset of subjective effects and produced a sustained increase in heart rate; psychomotor reaction time improved after methylone but not after MDMA. The investigators conclude that methylone’s abuse potential in humans appears similar to MDMA’s, while its shorter-lived subjective effects may promote redosing and attendant risks.