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

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.