Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants.
Isabelle Straumann, Isidora Avedisian, Aaron Klaiber, Nimmy Varghese, Anne Eckert, Deborah Rudin, Dino Luethi, Matthias E. Liechti
Neuropsychopharmacology December 1, 2024 DOI: 10.1038/s41386-024-01972-6 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Qualitative Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Healthy participants |
| Interventions | MDMA S-MDMA R-MDMA |
| Dose | 125 mg, 250 mg |
| Topics | MDMA |
| Keywords | MDMA Research Psychopharmacology Clinical trials Drug metabolism |
| Citations | 20 |
| Registration | NCT05277636 |
| Key findings | S-MDMA produced stronger stimulant-like subjective and physiological effects than R-MDMA or racemic MDMA, while R-MDMA did not produce more psychedelic-like effects. |
Abstract
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.
Comparable studies
Other randomized controlled trials on MDMA, most cited first.
Citations in the library
Cited by 16
- Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants. Neuropsychopharmacology 2026
- Subdiaphragmatic vagotomy reduces hypothalamic oxytocin expression and blood levels after oral MDMA administration in male rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry March 20, 2025
- Stereoselective, sex-dependent 5-HT2A receptor modulation of cortical plasticity by MDMA in mice. Neuropsychopharmacology February 2, 2026
- Pathway-selective signaling of serotonergic psychedelics at 5-HT receptors: Implications for psychoactivity, safety, and therapeutic potential European Neuropsychopharmacology April 10, 2026
- The effect of MDMA on anterior pituitary hormones: a secondary analysis of a randomized placebo-controlled trial. Endocrine connections June 1, 2025
and 11 more in the library
Cites 30
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Psychometric Evaluation of the Altered States of Consciousness Rating Scale (OAV) PLoS One August 31, 2010
- Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Journal of Psychopharmacology October 6, 2015
- MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine October 1, 2023
- MDMA enhances emotional empathy and prosocial behavior Social Cognitive and Affective Neuroscience October 4, 2013
and 25 more in the library