Human pharmacology of mephedrone in comparison with MDMA

Mephedrone (4-methylmethcathinone, 4-MMC) is a synthetic cathinone and a novel psychoactive substance that emerged in the recreational drug market because users report stimulant, empathogenic, and sensory-enhancing effects comparable to cocaine, amphetamine and MDMA. Its recreational popularity, association with sympathomimetic toxicity (eg, tachycardia, hypertension, agitation, mydriasis), reports of fatalities, and varied routes of administration (oral, nasal, intravenous) have raised public health concerns. Preclinical work indicates mephedrone acts as a monoamine releaser and uptake inhibitor, increasing dopamine and serotonin, and supporting self-administration in animals at rates higher than MDMA; pharmacokinetic data in humans were limited and the role of metabolic polymorphisms such as CYP2D6 remained unclear. Papaseit and colleagues set out to characterise, under controlled experimental conditions, the clinical pharmacology, subjective/psychomotor effects, and pharmacokinetics of oral mephedrone and to compare its abuse liability with that of MDMA. The study used a placebo-controlled, double-blind, randomised, crossover design in healthy recreational drug users and measured physiological, psychomotor, subjective, and plasma concentration outcomes following single oral doses of mephedrone 200 mg and MDMA 100 mg.

The investigators conducted a randomised, double-blind, placebo-controlled, crossover study with a minimum 1-week washout between sessions. Twelve healthy male recreational drug users participated (mean age 31 years, range 21–39; mean weight 75.2 kg). Inclusion required prior use (≥6 lifetime exposures) of substances such as MDMA, amphetamines and cocaine without a history of dependence (except nicotine) and phenotypic CYP2D6 extensive metabolism (assessed by urinary dextromethorphan) to reduce risk of atypical metabolism. Ethical approval and clinical trial registration were obtained. Each participant attended three 12-hour experimental sessions after an overnight fast and received, in random order, oral mephedrone 200 mg, MDMA 100 mg, or placebo in identical capsules. The selected mephedrone dose derived from pilot testing. Participants were monitored in a calm laboratory setting; urine drug screens were performed before each session and meals were provided at 4, 6, and 10 hours post-dosing. Psychiatric evaluation and adverse-event assessments were performed during and the day after sessions. Physiological measures included noninvasive systolic and diastolic blood pressure, heart rate, oral temperature and pupillary function (PD MAX and PD MIN) recorded repeatedly from baseline to 24 h; continuous ECG was recorded for 12 h. Psychomotor testing comprised the digit symbol substitution test (correct responses in 90 s) and the Maddox-wing device (horizontal exophoria in transformed diopters). Subjective effects were assessed with 23 visual analogue scales (VAS), the Addiction Research Center Inventory (ARCI) short form, the VESSPA-SEE questionnaire, and a pharmacological class identification question at specified time points up to 24 h. Pharmacokinetic blood sampling occurred at multiple points from predose to 24 h; plasma mephedrone and MDMA concentrations were measured by GC/MS and mephedrone quantitation used an internal standard and derivatisation. Pharmacokinetic parameters (Cmax, Tmax, AUCs, t1/2, Ke) were calculated using a pharmacokinetic Excel tool. For pharmacodynamics, outcomes were transformed to change from baseline; Emax (peak change in first 4 h), 4-h AUCs, and time courses (0–4 h) were analysed. Statistical analyses used repeated-measures ANOVA (one-way for Emax/AUC; two-way for time course), Tukey post hoc tests, Friedman test for Tmax with Wilcoxon signed-rank post hoc comparisons (adjusted p), and significance set at p<0.05.

Twelve male participants completed all sessions with no serious adverse events reported. Global analyses indicated statistically significant differences from placebo for multiple physiological, psychomotor and subjective measures for both active drugs; key differences between mephedrone and MDMA were primarily in time course and duration rather than peak magnitude. Physiological effects: Both mephedrone 200 mg and MDMA 100 mg increased systolic and diastolic blood pressure, heart rate, oral temperature and pupil diameter (PD MAX and PD MIN) relative to placebo when considering peak effects and/or AUCs. Mephedrone induced earlier peaks: median Tmax values for physiological variables ranged ~0.75–1 h for mephedrone versus 1–3 h for MDMA. Pupil changes differed between active drugs: mephedrone PD MAX 0.87 ± 1.07 mm and PD MIN 0.37 ± 1.20 mm peaked at 0.75 h, whereas MDMA PD MAX 1.76 ± 0.52 mm and PD MIN 1.38 ± 0.60 mm peaked at 1.5 h. Temperature peak effects also differed between the two actives at some time points. Psychomotor performance: Both active drugs increased correct responses on the digit symbol substitution test versus placebo (considering peak effects and AUC), with no significant differences between mephedrone and MDMA. On the Maddox-wing measure both produced exophoria versus placebo; mean peak changes were −1.24 transformed diopters for mephedrone (peak ~0.38 h) and −1.17 for MDMA (peak ~1.25 h), without significant differences in AUC, peak effects or time-course points between the two. Subjective effects: Mephedrone and MDMA each produced robust increases versus placebo on VAS measures of stimulant-like effects and euphoria (eg, 'stimulated', 'high', 'good effects', 'liking') and on measures of perceptual change. Time-course analyses showed mephedrone subjective effects onset at 0.25 h, peaking around 0.75 h, returning to half-maximum at 1.5–2 h and near baseline by 2–3 h. MDMA effects appeared later (~0.75 h), peaked at ~1–1.5 h, persisted to 2–3 h and returned toward baseline by ~4 h. On the ARCI, both drugs increased MBG (euphoria), BG (stimulant/energy) and A (amphetamine-like) subscales; MDMA produced greater increases in LSD (dysphoria/somatic) scores than mephedrone, with statistical differences in peak effects, AUC and time-course (1–4 h). VESSPA-SEE subscales increased for both drugs versus placebo; direct peak/AUC differences between actives were largely nonsignificant except for AUC of the sedation subscale. In the pharmacological class identification task, 10/12 participants (83.3%) identified mephedrone as a designer drug (mostly 'ecstasy'); 8/12 identified MDMA as a designer drug. Pharmacokinetics: Mephedrone was rapidly absorbed and eliminated with notable interindividual variability. Mean Cmax for mephedrone was 134.6 ng/ml (range 51.7–218.3 ng/ml) with median Tmax 1.25 h (range 0.5–4 h) and mean t1/2 2.15 h; plasma concentrations declined to ~6.1 ng/ml at 12 h and were generally undetectable at 24 h. For MDMA, mean Cmax was 202.8 ng/ml (range 160.1–262.4 ng/ml), median Tmax 2.00 h (range 1.5–4 h) and mean t1/2 7.89 h. These pharmacokinetic differences paralleled the shorter onset and duration of mephedrone’s pharmacodynamic effects.

Papaseit and colleagues interpret their findings as demonstrating that oral mephedrone 200 mg produces stimulant-like, euphoric and mild perceptual effects that are qualitatively similar in magnitude to those produced by MDMA 100 mg but have an earlier onset and substantially shorter duration. The shorter time to peak concentration (median ~1.25 h) and a brief elimination half-life (mean 2.15 h) for mephedrone likely explain the more transient physiological and subjective effects compared with MDMA (Tmax ~2 h; t1/2 ~7.9 h). The investigators note that this pharmacokinetic–pharmacodynamic correspondence occurred despite considerable interindividual variability in plasma levels. The authors relate their human data to preclinical findings indicating monoamine-releasing actions of mephedrone and animal self-administration studies suggesting high abuse liability. They suggest the rapid onset and short duration could promote compulsive redosing in real-world use and thereby increase toxicity risk, especially given common patterns of multiple dosing or alternative routes (nasal insufflation, injection). Mephedrone produced marked but transient cardiovascular activation and mydriasis; pupil effects were present but somewhat less pronounced than with MDMA. Limitations acknowledged by the investigators include the small sample size, restricting statistical power for direct comparisons between active drugs, and the use of a single mephedrone dose, which prevents assessment of dose–response relationships or extrapolation to higher doses. They also note that inclusion was limited to phenotypic CYP2D6 extensive metabolizers, so the study cannot address how CYP2D6 polymorphisms might modulate mephedrone toxicity. Finally, the authors highlight that no serious adverse events occurred under controlled conditions, but caution that real-world patterns of redosing and polydrug use could alter risk.