# Toxicometabolomics Characterization of Two N1-Sulfonated Dimethyltryptamine Derivatives in Zebrafish Larvae and Human Liver S9 Fractions Using Liquid Chromatography–High-Resolution Mass Spectrometry

## TL;DR

This study uses advanced chemical analysis to explore how two new psychoactive substances are processed in zebrafish and human liver samples, revealing important metabolic changes.

## Contribution

The study introduces a toxicometabolomics approach to identify novel psychoactive substance metabolites and their effects in zebrafish and human liver fractions.

## Key findings

- Metabolic pathways and key biotransformations of two N1-sulfonated dimethyltryptamine derivatives were identified in zebrafish and human liver S9 fractions.
- Exposure to the compounds caused significant downregulation of L-threonine, indicating potential biochemical impacts.

## Abstract

Introduction: The availability of toxicokinetic data is critical for detecting and monitoring the intake of psychoactive substances. Timely characterization of novel psychoactive substances (NPS) is particularly important to assess their abuse potential and inform public health responses. Methods: Toxicometabolomics offers a powerful approach to characterize xenobiotic metabolism through high-resolution profiling of biochemical transformations. It thus allows the finding of exogenous biomarkers, such as new drug metabolites, and endogenous biomarkers, which could be indications of acute drug ingestions or sample manipulation, as well as offering information on the mode of action of drugs. In this study, we applied a liquid chromatography–high-resolution mass spectrometry workflow to investigate the toxicometabolomics of two N1-sulfonated N,N-dimethyltryptamine derivatives with potential for both therapeutic use and recreational abuse. Results: Zebrafish (Danio rerio), an increasingly valuable model for preclinical pharmacology and toxicology studies, along with pooled human liver S9 fractions were used to elucidate metabolic pathways and identify key phase I and phase II biotransformations. Furthermore, untargeted metabolomics revealed significant downregulation of L-threonine associated with compound exposure. Conclusions: These findings advance the current understanding of tryptamine metabolism and underscore the utility of toxicometabolomics in the analytical evaluation of NPS.