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

Racemic 3,4-methylenedioxymethamphetamine (MDMA) acutely increases mood, feelings of empathy, trust, and closeness to others and is investigated to assist psychotherapy. Preclinical research indicates that S-MDMA releases monoamines and oxytocin more potently than R-MDMA, whereas R-MDMA more potently stimulates serotonin 5-hydroxytryptamine-2A receptors. S-MDMA may have more stimulant properties, and R-MDMA may be more psychedelic-like. However, acute effects of S- and R-MDMA have not been examined in a controlled human study. We used a double-blind, randomized, placebo-controlled, crossover design to compare acute effects of MDMA (125 mg), S-MDMA (125 mg), R-MDMA (125 mg and 250 mg), and placebo in 24 healthy participants. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics, and plasma oxytocin, prolactin, and cortisol concentrations. S-MDMA (125 mg) induced greater subjective effects ("stimulation," "drug high," "happy," "open") and higher increases in blood pressure than R-MDMA (both 125 and 250 mg) and MDMA (125 mg). Unexpectedly, R-MDMA did not produce more psychedelic-like effects than S-MDMA. S-MDMA increased plasma prolactin more than MDMA, and S-MDMA increased plasma cortisol and oxytocin more than MDMA and R-MDMA. The plasma elimination half-life of S-MDMA was 4.1 h after administration. The half-life of R-MDMA was 12 and 14 h after the administration of 125 and 250 mg, respectively. Half-lives for S-MDMA and R-MDMA were 5.1 h and 11 h, respectively, after racemic MDMA administration. Concentrations of the CYP2D6-formed MDMA-metabolite 4-hydroxy-3-methoxymethamphetamine were lower after R-MDMA administration compared with S-MDMA administration. The pharmacokinetic findings are consistent with the R-MDMA-mediated inhibition of CYP2D6. Stronger stimulant-like effects of S-MDMA in the present study may reflect the higher potency of S-MDMA rather than qualitative differences between S-MDMA and R-MDMA. Equivalent acute effects of S-MDMA, MDMA, and R-MDMA can be expected at doses of 100, 125, and 300 mg, respectively, and need to be investigated.Trial registration: ClinicalTrials.gov identifier: NCT05277636.