ArticleDrug testing and analysis2026
Bioactivation and Metabolism of Amino Acid MDMA Prodrugs in Zebrafish Embryos, Human Liver S9, Whole Blood, and Microdosed Human Urine.
Article in Drug testing and analysis, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
3,4-Methylenedioxymethamphetamine (MDMA) remains unapproved for therapeutic use despite the promising results of MDMA-assisted psychotherapy. There is a need to better understand the safety, pharmacokinetics, and toxicology of possible MDMA-based prodrugs. Like lisdexamfetamine, amino acid prodrugs of MDMA may enable more controlled systemic exposure, but their metabolic activation pathways and metabolites are not known yet. This study investigated the bioactivation and metabolism of the MDMA prodrugs, MDMA-tryptophan (MDMA-Trp), MDMA-lysine (MDMA-Lys), and MDMA-glycine (MDMA-Gly), in zebrafish embryos (ZE), pooled human liver S9 fraction (pHLS9), pooled fresh human whole blood (pFHWB), and human urine after microdosing (HMD). It elucidated mechanistic activation routes and identified screening targets relevant for drug testing and safety assessment. In ZE, MDMA-Trp underwent hydroxylation and N-dealkylation prior to amide cleavage, indicating a stepwise bioactivation pathway that differs from direct conversion observed for the other prodrugs. All three prodrugs were cleaved to MDMA in ZE, pHLS9, and HMD, with known MDMA metabolites additionally formed in ZE and pHLS9, whereas no metabolites were detected in pFHWB, suggesting that amide cleavage is not mediated in blood under the tested conditions. Unique urine screening targets were identified only for MDMA-Trp, while biomarkers for MDMA-Lys and MDMA-Gly consisted of MDMA and known MDMA metabolites. This study demonstrated conversion of amino acid prodrugs to MDMA in pHLS9- and ZE-based systems and in humans after microdosing, but not in blood. There is a need for further studies such as their pharmacokinetic profiles in humans.
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