Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants.

Isabelle Straumann; Patrick Vizeli; Isidora Avedisian; Livio Erne; Diana Noorshams; Ina Vukalović; Anne Eckert; Dino Luethi; Deborah Rudin; Matthias E. Liechti

doi:10.1038/s41386-025-02248-3

Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants.

Isabelle Straumann, Patrick Vizeli, Isidora Avedisian, Livio Erne, Diana Noorshams, Ina Vukalović, Anne Eckert, Dino Luethi, Deborah Rudin, Matthias E. Liechti

Neuropsychopharmacology 2026 DOI: 10.1038/s41386-025-02248-3 (opens in new tab)

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AI-extracted from the abstract

Characteristics	Randomized controlled trial Placebo-controlled Double-blind Peer reviewed
Sample size	23
Population	Healthy participants (12 women, 11 men)
Interventions	MDMA MDA Lys-MDMA Lys-MDA
Dose	100 mg MDMA, 92 mg MDA, 172 mg Lys-MDMA, 164 mg Lys-MDA
Topics	MDMA
Citations	5
Registration	NCT04847206
Key findings	MDA produced longer-lasting, stronger, and more psychedelic-like perceptual effects and more adverse effects than MDMA at equimolar doses, while Lys-MDMA did not release MDMA and produced no effects.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally, as a research tool, and in MDMA-assisted therapy in patients with posttraumatic stress disorder. 3,4-Methylenedioxyamphetamine (MDA) is a psychoactive metabolite of MDMA. Acute effects of MDMA and MDA have never been directly compared in humans. Lysine-conjugated amphetamines slowly release active amphetamine once absorbed, suggesting pharmaceutical strategies to enhance tolerability and reduce abuse potential. Therefore, lysine-MDMA (Lys-MDMA) and lysine-MDA (Lys-MDA) were developed as prodrugs of MDMA and MDA, respectively. We used a double-blind, randomized, placebo-controlled, crossover design to compare acute responses to MDMA (100 mg), MDA (92 mg), Lys-MDMA (172 mg), and Lys-MDA (164 mg) at equimolar doses and placebo in 23 healthy participants (12 women, 11 men). Outcome measures included acute subjective, autonomic, and endocrine effects and pharmacokinetics. Compared with placebo, MDMA and MDA produced pronounced subjective and autonomic effects. After Lys-MDMA administration, no MDMA was detected in blood samples, and no corresponding subjective or autonomic effects were observed. MDA produced stronger and longer-lasting subjective "any drug effects" compared with MDMA, with effect durations of (mean ± SEM) 6.1 ± 0.5 vs 4.1 ± 0.4 h, respectively. Additionally, compared with MDMA, MDA induced greater subjective "stimulant effects," more negative "bad drug effects," more "fear," and more "visual alterations." Lys-MDA, compared with MDA, showed longer times to onset and maximal effect (1.1 ± 0.2 h and 3.0 ± 0.4 h vs. 0.7 ± 0.1 h and 2.0 ± 0.1 h) but otherwise induced similar effects. The plasma elimination half-lives (geometric mean) of MDMA and MDA were 7.3 and 8.4 h, respectively. In summary, MDA produced longer-lasting, stronger, more psychedelic-like perceptual acute effects and more adverse effects compared with MDMA when administered at equimolar doses. Lys-MDA represents a functional slow-release prodrug form of MDA, delaying both the onset and peak of subjective effects. In contrast, Lys-MDMA did not release MDMA, likely because of its tertiary amine structure, and thus does not represent a functional prodrug of MDMA. These results highlight MDA's less favorable therapeutic profile relative to MDMA and identify lysine conjugation as a potential strategy for modulating, but not necessarily improving, the tolerability of its effects. Trial registration: ClinicalTrials.gov identifier: NCT04847206.

Comparable studies

Other randomized controlled trials on MDMA, most cited first.

Study	Year	Design	Participants
MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Patients with severe PTSD, including those with comorbidities such as dissociation,...	2021	Randomized controlled trial	n = 90
The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Patients with chronic post-traumatic stress disorder refractory to both psychotherapy...	2010	Randomized controlled trial	n = 20
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Military veterans and first responders aged 18 or older with chronic PTSD lasting 6...	2018	Randomized, double-blind, dose-response, phase 2 clinical trial	n = 26
A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD) Patients with treatment-resistant PTSD	2012	Randomized controlled trial	n = 12
MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Adults with moderate to severe post-traumatic stress disorder	2023	Randomized controlled trial	n = 104

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