Metabolite Profiling of Novel Psychoactive Substances

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 2601

Special Issue Editors


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Guest Editor
Department of Biomedical Sciences and Public Health, Marche Polytechnic University, 60121 Ancona, Italy
Interests: clinical/forensic toxicology; analytical chemistry; pharmacokinetics/pharmacodynamics; drugs of abuse; phytotoxins

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Guest Editor
Institute of Forensic Medicine, Medical Center-University of Freiburg, 79098 Freiburg, Germany
Interests: emergency toxicology; forensic science; analytical chemistry; organic chemistry; pharmacology; clinical pharmacology

Special Issue Information

Dear Colleagues,

Novel psychoactive substances (NPSs) have flooded the illicit drug market for almost two decades, either as alternatives to or adulterants of traditional drugs of abuse, attempting to reduce manufacturing and processing costs and evade legal controls and analytical detection. NPSs pose a tremendous threat to public health as they have caused thousands of deaths worldwide and due to their societal and legislative implications. Moreover, the turnover is also high: new NPSs emerge regularly on drug markets to replace newly banned substances or produce ever-more-potent psychotropic drugs.

Little to no pharmacological data are available on NPSs when they first surface on the market, which creates concerns as users are unaware of the potential risks associated with their consumption. From an analytical point of view, methods must be constantly updated to adapt to market dynamics, but NPSs are often challenging to detect as they may be active at extremely low concentrations in biological matrices and may undergo substantial metabolic degradation. Assessing the pharmacokinetics of NPSs is, therefore, essential to be able to document their consumption in clinical and forensic casework. In particular, the metabolic profiling of NPSs is a major step toward identifying the specific metabolite biomarkers of consumption that may be more easily detected than the corresponding parent drug.

This Special Issue of Metabolites is dedicated to studies on the metabolism of NPSs. This includes, but is not limited to, the identification of NPS metabolite biomarkers through in vitro (e.g., hepatocyte or liver microsome incubations) or in vivo models (e.g., controlled administration to rats), the reporting of authentic clinical or forensic cases with metabolite identification/quantification in biological specimens, the development of new analytical approaches for NPS metabolite profiling, and literature reviews on NPS metabolism.

Dr. Jeremy Carlier
Prof. Dr. Volker Auwärter
Guest Editors

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Keywords

  • new psychoactive substances
  • metabolism
  • case report
  • clinical toxicology
  • forensic toxicology

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Published Papers (1 paper)

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Research

15 pages, 1409 KiB  
Article
Exploring the Metabolism of Flubrotizolam, a Potent Thieno-Triazolo Diazepine, Using Human Hepatocytes and High-Resolution Mass Spectrometry
by Prince Sellase Gameli, Johannes Kutzler, Diletta Berardinelli, Jeremy Carlier, Volker Auwärter and Francesco Paolo Busardò
Metabolites 2024, 14(9), 506; https://doi.org/10.3390/metabo14090506 - 19 Sep 2024
Cited by 1 | Viewed by 2000
Abstract
Background: The abuse of psychoactive substances presents challenges in clinical and forensic toxicology. The emergence of novel and potent drugs that pose significant health risks, in particular towards frequent abusers and users unaware of the ingredients, further complicates the situation. Designer benzodiazepines have [...] Read more.
Background: The abuse of psychoactive substances presents challenges in clinical and forensic toxicology. The emergence of novel and potent drugs that pose significant health risks, in particular towards frequent abusers and users unaware of the ingredients, further complicates the situation. Designer benzodiazepines have become a fast-growing subgroup of these new psychoactive substances (NPSs), and their overdose may potentially turn fatal, especially when combined with other central nervous system depressants. In 2021, flubrotizolam, a potent thieno-triazolo designer benzodiazepine, emerged on the illicit market, available online as a “research chemical”. The identification of markers of consumption for this designer benzodiazepine is essential in analytical toxicology, especially in clinical and forensic cases. Methods: We therefore aimed to identify biomarkers of flubrotizolam uptake in ten-donor-pooled human hepatocytes, applying liquid chromatography high-resolution mass spectrometry and software-aided data mining supported by in silico prediction tools. Results: Prediction studies resulted in 10 and 13 first- and second-generation metabolites, respectively, mainly transformed through hydroxylation and sulfation, methylation, and glucuronidation reactions. We identified six metabolites after 3 h human hepatocyte incubation: two hydroxylated metabolites (α- and 6-hydroxy-flubrotizolam), two 6-hydroxy-glucuronides, a reduced-hydroxy-N-glucuronide, and an N-glucuronide. Conclusions: We suggest detecting flubrotizolam and its hydroxylated metabolites as markers of consumption after the glucuronide hydrolysis of biological samples. The results are consistent with the in vivo metabolism of brotizolam, a medically used benzodiazepine and a chloro-phenyl analog of flubrotizolam. Full article
(This article belongs to the Special Issue Metabolite Profiling of Novel Psychoactive Substances)
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