Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants

MDMA (3,4-methylenedioxymethamphetamine) is a racemic compound known to release serotonin, norepinephrine, dopamine and oxytocin and to produce acute effects such as increased well-being, empathy and social connectedness that are being investigated to assist psychotherapy for post-traumatic stress disorder. Preclinical work indicates that the enantiomers differ pharmacologically: S(+)-MDMA more potently releases monoamines and oxytocin and shows more stimulant-like properties, whereas R(-)-MDMA appears relatively more active at 5-HT2A receptors and has been characterised as potentially more psychedelic-like and less neurotoxic in animals. These divergent profiles have led to the suggestion that one enantiomer might offer safety or efficacy advantages over racemic MDMA, but controlled human data directly comparing the enantiomers are lacking. Straumann and colleagues therefore designed a double-blind, placebo-controlled, crossover study to compare the acute subjective, autonomic, endocrine and pharmacokinetic effects of racemic MDMA, S-MDMA, R-MDMA and placebo in healthy volunteers. The primary hypotheses were that S-MDMA would produce greater subjective stimulation on a visual analogue scale (VAS) than R-MDMA, and that R-MDMA would evoke more psychedelic-like effects as measured by the 5-Dimensions of Altered States of Consciousness (5D-ASC) scale than S-MDMA. The study aimed to characterise both pharmacodynamic and pharmacokinetic differences between the enantiomers and the racemate in humans.

The investigators employed a double-blind, placebo-controlled, within-subject crossover design with five test sessions per participant: placebo; 125 mg racemic MDMA; 125 mg S-MDMA; 125 mg R-MDMA; and 250 mg R-MDMA. Block randomisation produced counterbalanced treatment orders and washout intervals were at least 10 days. Sessions took place in a calm hospital room with a single participant and one investigator present; each session lasted 10 hours with follow-up measures 24 hours after dosing. Twenty-four healthy adults (12 men, 12 women; mean age 29 ± 9 years, range 18–47) were enrolled. Exclusion criteria included pregnancy, personal or first-degree family history of major psychiatric disorders, use of medications that could interact with study drugs, significant medical illness or abnormal screening labs/ECG, heavy tobacco smoking (>10 cigarettes/day), high lifetime illicit drug use (>20 instances) or recent use (<2 months, except THC), and illicit drug use during the study. Participants were asked to limit alcohol intake before sessions. All provided written informed consent; the study was approved by local ethics authorities and registered on ClinicalTrials.gov. Study drugs were manufactured to Good Manufacturing Practice standards as 25 mg hydrochloride capsules. Ten capsules were administered per session to achieve the target doses: placebo (10 placebo capsules), 125 mg racemate (five 25 mg MDMA + five placebo), 125 mg S-MDMA (five S-MDMA + five placebo), 125 mg R-MDMA (five R-MDMA + five placebo), and 250 mg R-MDMA (ten R-MDMA). Participants guessed treatment at session end to evaluate blinding. Primary and secondary outcome assessments included repeated subjective ratings on multiple VAS items (including the VAS item labelled "simulated" as the primary measure of stimulation) up to 24 hours, the Adjective Mood Rating Scale (AMRS), the 5D-ASC and 3D-ASC (administered at 9 hours to retrospectively rate peak effects), and the Psychedelic Experience Scale (PES/MEQ30) for mystical-type experiences. Autonomic measures (blood pressure, heart rate, tympanic temperature) were recorded repeatedly. Endocrine assays measured plasma oxytocin (baseline, 2, 3, 6 h), cortisol and prolactin (baseline, 2, 3 h). Plasma concentrations of MDMA enantiomers and metabolites (MDA, HMMA) were sampled at multiple time points up to 24 h and analysed with achiral and enantioselective LC–MS/MS methods. Pharmacokinetic parameters were estimated non-compartmentally using Phoenix WinNonlin. Peak or peak-change values from repeated measures were analysed with repeated-measures ANOVA (drug as within-subjects factor) followed by Tukey post hoc tests; significance was set at p < 0.05.

All 24 participants completed the study. Subjective VAS responses showed that 125 mg S-MDMA produced overall stronger subjective effects than 125 mg racemic MDMA and both R-MDMA doses at the doses tested. Specifically, S-MDMA induced significantly greater ratings on VAS items including "bad drug effects," "alteration of vision," "audio-visual synesthesia," and measures of stimulation and drug high compared with R-MDMA and, for some items, compared with racemic MDMA. Both 125 mg and 250 mg R-MDMA produced lower peak effects than MDMA and S-MDMA on items such as "drug high," "happy," "content," "talkative," "open," "trust," and "I feel close to others." Female participants showed larger responses than males, which the authors attribute to body-weight differences; prior MDMA experience did not significantly alter responses. Mean effect durations (based on the VAS any-effect plots and a 10% onset/offset threshold) were 3.5 h for 125 mg R-MDMA, 4.2 h for 125 mg MDMA, 4.7 h for 125 mg S-MDMA, and 5.2 h for 250 mg R-MDMA. Measures of psychedelic-type experience (5D-ASC, 3D-ASC total score and PES/MEQ) indicated that 125 mg MDMA, 125 mg S-MDMA and 250 mg R-MDMA produced comparable alterations of mind and mystical-type experiences at the doses used; R- and S-MDMA produced similar 3D-ASC total scores. On the AMRS, 250 mg R-MDMA increased "introversion" relative to MDMA, while S-MDMA produced more "emotional excitation" than R-MDMA. All active substances increased VAS ratings of social items ("talkative," "open," "trust," "I feel close to others") versus placebo, but S-MDMA produced higher ratings than R-MDMA on these items. Autonomic data showed that S-MDMA induced greater increases in blood pressure than MDMA and R-MDMA. Heart rate and tympanic body temperature increased to a similar extent after MDMA, S-MDMA and 250 mg R-MDMA. Adverse-event profiles on the List of Complaints were similar across active substances and included fatigue, headache, decreased appetite, feeling dull, concentration problems and dry mouth. All substances produced nominal increases in self-rated depressive symptoms on the Beck Depression Inventory 1–3 days post-dose; only S-MDMA reached a statistically higher score than placebo. No severe adverse events occurred. Endocrine assays demonstrated that all active substances elevated plasma prolactin and cortisol relative to placebo. S-MDMA increased prolactin more than MDMA, and S-MDMA produced larger increases in cortisol and oxytocin than MDMA and R-MDMA. Pharmacokinetics revealed differences between the enantiomers. When racemic MDMA was given, elimination half-lives were approximately 5.1 h for S-MDMA and 11 h for R-MDMA. When administered alone, S-MDMA had a half-life of 4.1 h, while R-MDMA half-lives were 12 h and 14 h after 125 mg and 250 mg doses, respectively, indicating dose-related prolongation. Formation of HMMA was lower after R-MDMA administration compared with S-MDMA, and increasing the R-MDMA dose did not proportionally increase HMMA concentrations. The authors report these findings as consistent with dose-dependent CYP2D6 inhibition by R-MDMA. Blinding was generally successful for active substances (participants could not distinguish active enantiomers from racemate), whereas placebo was correctly identified by 83% of participants after sessions. Correlational analyses between plasma concentrations and responses were reported in supplementary figures.

Straumann and colleagues interpret their findings as showing broadly similar qualitative acute effects across racemic MDMA, S-MDMA and R-MDMA at the doses tested, with some quantitative differences that largely align with enantiomer potency rather than starkly different effect profiles. As hypothesised, S-MDMA produced greater stimulant-like subjective effects than R-MDMA; however, contrary to the hypothesis, R-MDMA did not evoke stronger psychedelic-like effects than S-MDMA on retrospective scales (5D-ASC, PES/MEQ) at the doses used. The authors suggest that the generally stronger effects of S-MDMA compared with racemic MDMA and R-MDMA likely reflect a roughly 25% higher potency of S-MDMA rather than a qualitatively distinct phenomenology. Supporting measures included greater blood pressure responses and larger increases in cortisol, prolactin and oxytocin after S-MDMA, consistent with stronger serotonergic and noradrenergic stimulation. Pharmacokinetic data are discussed as indicating that R-MDMA produces greater plasma exposure and a longer elimination half-life than S-MDMA, and that R-MDMA inhibits CYP2D6 in a dose-dependent manner, reducing formation of HMMA and prolonging its own elimination. The authors therefore infer that when administered as the racemate, R-MDMA contributes to slower elimination of S-MDMA via CYP2D6 inhibition. From the observed differences at the tested doses, the investigators propose approximate dose equivalences: 125 mg racemic MDMA ≈ 100 mg S-MDMA ≈ 300 mg R-MDMA, though they note these equivalences would need direct testing. Strengths highlighted include the within-subject, double-blind design, balanced sex distribution, close pharmacokinetic sampling with chiral analysis, and inclusion of two R-MDMA doses. Key limitations acknowledged are the restricted dose range (only one S-MDMA dose and two R-MDMA doses), non-equivalent dosing across substances which limits causal attribution of qualitative differences, the healthy volunteer hospital setting that may not generalise to patients or other environments, and the possibility that the instruments used may not capture subtle experiential differences between enantiomers. The authors caution that some observed differences could be dose-dependent rather than inherently enantiomer-specific. Finally, they conclude that the present data do not support a clear therapeutic advantage of either enantiomer over racemic MDMA for substance-assisted psychotherapy based on acute effects.

The authors conclude that racemic MDMA, S-MDMA and R-MDMA produce overall similar acute subjective and adverse-effect profiles when administered at the doses tested, though S-MDMA shows slightly greater stimulant-like properties. Pharmacokinetic findings indicate that R-MDMA dose-dependently inhibits CYP2D6, prolonging its own elimination and affecting HMMA formation. Based on the present data there is no evidence that either enantiomer offers a relevant advantage over racemic MDMA for substance-assisted therapy, and suggested dose-equivalence estimates (125 mg MDMA ≈ 100 mg S-MDMA ≈ 300 mg R-MDMA) require further investigation.