Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Saarbrücken, Germany.
3 papers in the library · 11 citations · publishing 2024-2026
Two new hallucinogenic drugs, 1cP-LSD and 4-AcO-DET, were metabolized in human liver S9 fraction and in zebrafish larvae, with several phase I and phase II metabolites identified. Some metabolites were unique to zebrafish larvae. Neither compound showed toxic effects on human liver cells, though 4-AcO-DET combined with a CYP inhibitor altered two cellular parameters at concentrations far above expected in vivo levels. The authors suggest further testing with other liver cell lines that express more CYP enzymes.
Amino acid prodrugs of MDMA—MDMA-tryptophan, MDMA-lysine, and MDMA-glycine—are cleaved to release MDMA in zebrafish embryos, human liver S9 fraction, and human urine after microdosing, but not in human blood under the tested conditions. MDMA-tryptophan follows a stepwise bioactivation pathway involving hydroxylation and N-dealkylation before amide cleavage, unlike the other prodrugs which convert directly. Known MDMA metabolites also form in zebrafish and liver systems. Unique urine screening targets appear only for MDMA-tryptophan; biomarkers for the other prodrugs are MDMA and its known metabolites. Further studies of human pharmacokinetic profiles are needed.
A liquid chromatography–high-resolution mass spectrometry workflow was used to investigate the metabolism of two N1-sulfonated N,N-dimethyltryptamine derivatives, which have potential for both therapeutic use and recreational abuse. Zebrafish larvae and pooled human liver S9 fractions revealed key phase I and phase II biotransformations. Untargeted metabolomics showed significant downregulation of L-threonine associated with compound exposure. These findings advance the understanding of tryptamine metabolism and highlight the value of toxicometabolomics for evaluating novel psychoactive substances.