Comparative Acute Effects of R-MDMA and S-MDMA in Healthy Participants (R-S-)

This randomised, triple-blind, placebo-controlled Phase I crossover trial (n=24) will compare the acute effects of two enantiomers of MDMA—R-MDMA (300mg) and S-MDMA (100mg)—in healthy adult participants.

The study, led by University Hospital Basel in Switzerland, aims to clarify the distinct pharmacological and subjective effects of each enantiomer of MDMA, which are mirror-image molecules of the same compound. R-MDMA is thought to act more directly on serotonin 5-HT2A receptors and promote prosocial effects with fewer stimulant properties, while S-MDMA is believed to be more associated with stimulant effects through the release of dopamine, norepinephrine, serotonin, and oxytocin.

Participants will undergo three separate dosing sessions (R-MDMA, S-MDMA, and placebo) in a triple-blind crossover design. Outcomes will include subjective experiences (measured repeatedly each session using Visual Analogue Scales), vital signs, hormone levels (including oxytocin and prolactin), and personality traits. The researchers hope this study will inform future therapeutic applications of MDMA by understanding how each enantiomer contributes to the full drug experience and its safety profile. The trial is expected to run from May 2025 to November 2026.

Trial Details

MDMA is a racemic substance containing equal amounts of the enantiomers S(+)- and R(-)-MDMA. Preclinical research indicates that S-MDMA mainly releases dopamine (DA), norepinephrine (NE), serotonin (5-HT), and oxytocin while R-MDMA may act more directly on 5-HT2A receptors and release prolactin (PRL). Animal studies also indicate that the two enantiomers act synergistically to produce the subjective effects of MDMA and that S-MDMA is mainly responsible for psychostimulation while R-MDMA may have fewer adverse effects and have greater prosocial effects. A human study conducted between 10/2022 and 01/2024 by our team compared the effects of R-MDMA, S-MDMA, and racemic MDMA revealing that both enantiomers have generally similar effects. However, the study did not administer equivalent doses of R- and S-MDMA. In the present study a single dose of R-MDMA and a single dose of S-MDMA, now adjusted and presumed to be equivalent, will be compared.

Trial Number NCT06905652

Data attribution

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