Comparison of acute effects of 3,4-methylenedioxymethamphetamine (MDMA) with and without a supplemental booster dose in healthy participants: a double-blind, randomized, placebo-controlled, crossover study
Mélusine Humbert‐droz, Anna M. Becker, Jan Valenta, Deborah Rudin, Dino Luethi, Ina Vukalović, Anne Eckert, Matthias E. Liechti, Lorenz Mueller
Translational Psychiatry June 4, 2026 Peer reviewed DOI: 10.1038/s41398-026-04148-6 via OpenAlex
Summary
The study found that a booster dose of MDMA (60 mg) given 1.5-2.5 hours after an initial dose (120 mg) prolonged the acute subjective effects from an average of 4.6 hours to 5.6 hours. However, no differences in peak subjective or autonomic effects were noted between the two MDMA conditions. Adverse effects occurred more frequently with both MDMA doses compared to placebo. The clinical implications of using a booster dose for treatment remain uncertain.
Study at a glance
| Design | double-blind, randomized, placebo-controlled, cross-over study |
|---|---|
| Sample size | 25 |
| Population | healthy volunteers |
| Key finding | The booster dose of MDMA prolonged the acute subjective effects compared with the single dose. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AT) is being investigated as a treatment for several psychiatric disorders, particularly posttraumatic stress disorder. Phase 2 and 3 trials typically administered a first dose of MDMA followed by a second "booster" dose 1.5-2.5 h later, to extend the acute effect duration. However, the risks and benefits of the booster dose have not been systematically investigated. In this double-blind, randomized, placebo-controlled, cross-over study, we compared 120 mg MDMA followed by a 60 mg booster dose or placebo after 2 h, and placebo followed by placebo. The primary outcome was the overall duration of any subjective drug effects, measured by a Visual Analog Scale. Secondary outcomes included additional subjective effects, adverse effects, vital signs, and plasma concentrations of MDMA, oxytocin, and neurophysin I. Twenty-five healthy volunteers were included, and twenty-three (12 male, 11 female) completed all dosing sessions. The booster dose of MDMA prolonged the acute subjective effects of MDMA compared with the single dose (mean ± SD, 5.6 ± 1.8 h vs. 4.6 ± 1.2 h, p = 0.001), while no differences in subjective or autonomic peak effects were observed. Acute (0-9 h) and subacute (up to 3 days) adverse effects were more common after both MDMA conditions than placebo. These results indicate that acute MDMA effects can be prolonged by using a booster dose, as intended in clinical trials of MDMA-AT. Whether this translates into clinical benefit remains to be investigated.