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

MDMA, its active metabolite MDA, and two lysine-conjugated prodrugs (lysine-MDMA and lysine-MDA) were compared in a randomized, double-blind, placebo-controlled crossover trial in 23 healthy participants. MDMA and MDA produced pronounced subjective and autonomic effects versus placebo, but MDA showed longer-lasting effects and stronger, more psychedelic-like perceptual changes. Compared with MDMA at equimolar doses, MDA had a longer mean effect duration and was associated with more stimulant-like effects, more negative effects, more fear, and more visual alterations. Lysine-MDMA did not produce detectable MDMA in blood and showed no corresponding subjective or autonomic effects, suggesting it is not a functional prodrug of MDMA. Lysine-MDA showed delayed onset and delayed time to peak relative to MDA while producing similar overall effect profiles, indicating lysine conjugation can slow release and onset for MDA-like effects.