This double-blind placebo-controlled crossover trial (n=23) compared equimolar doses of MDMA (100mg), MDA (92mg), and their lysine-conjugated prodrugs, finding MDA produced stronger, longer-lasting effects (6.1 vs 4.1 hours) with more psychedelic-like perceptions and adverse effects than MDMA, whilst Lys-MDA successfully delayed onset and peak effects, but Lys-MDMA failed to release MDMA and showed no effects.
Abstract of Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA
“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.”
Authors: Isabelle Straumann, Patrick Vizeli, Isidora Avedisian, Livio Erne, Diana Noorshams, Ina Vukalovic, Anne Eckert, Dino Luethi, Deborah Rudin & Matthias E. Liechti
Summary of Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA
Straumann and colleagues set out to directly compare the acute effects of MDMA and its active metabolite MDA within the same participants, and to test whether lysine-conjugated “prodrug” versions could slow onset and potentially improve tolerability. MDMA is an entactogen (sometimes called an empathogen) that acutely increases feelings of well-being, empathy, trust, closeness, and connectedness. Pharmacologically, it promotes release of monoamines (serotonin, noradrenaline, dopamine) and reliably elevates circulating oxytocin, a peptide linked to social bonding. MDA shares the entactogenic profile but differs in receptor activity: it shows a higher dopamine-to-serotonin activity ratio and about ten-fold greater potency at the serotonin 5-HT2A receptor, the key receptor mediating psychedelic-like perceptual effects. The working expectation was that MDA would feel more stimulating and more perceptual than MDMA and would last longer because of different pharmacokinetics.
The team also synthesised lysine-conjugated forms—lysine-MDMA (Lys-MDMA) and lysine-MDA (Lys-MDA). These are designed as inactive precursors that, once absorbed, release the active drug more slowly, analogous to lisdexamfetamine for D-amphetamine. The hypotheses were: (1) MDA would produce longer and more psychedelic-like effects than MDMA; and (2) the lysine prodrugs would delay onset and peak effects (and corresponding plasma levels), potentially smoothing the experience.
Methods and materials
Study design
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https://doi.org/10.1038/s41386-025-02248-3
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Cite this paper (APA)
Straumann, I., Vizeli, P., Avedisian, I., Erne, L., Noorshams, D., Vukalovic, I., ... & Liechti, M. E. (2025). Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants. Neuropsychopharmacology, 1-10.
Study details
Compounds studied
MDMA
Topics studied
Healthy Subjects
Study characteristics
Original
Placebo-Controlled
Double-Blind
Within-Subject
Randomized
Participants
23
Humans
Compound Details
The psychedelics given at which dose and how many times
MDMA 100 mg | 1xLinked Clinical Trial
Effects of MDMA-like Substances in Healthy SubjectsThis Phase 1 interventional trial (n=24) will explore the effects of MDMA-like substances in healthy subjects. Conducted by the University Hospital, Basel, Switzerland.