Untargeted metabolomics approaches to improve casework in clinical and forensic toxicology—“Where are we standing and where are we heading?”

Abstract

: Clinical toxicology (CT) and forensic toxicology (FT) represent two disciplines of toxicology dedicated to the qualitative and quantitative analysis and respective interpretation of alcohol, drugs of abuse (DOA), over the counter (OTC), and prescription drugs or poisons, mainly in humans. Analytical challenges, such as the transient occurrence of new psychoactive substances (NPS) on the (il)legal drug market, insufficiently long detection windows of some DOAs, or the lack of objective measures to unambiguously proof sample manipulation as well as interpretative issues, for instance, the difficulty to discriminate occasional users from chronic/addictive ones still require further evaluation and research, though. Metabolomics is a rather new research field, aiming for qualitative, and quantitative analysis of endogenous compounds (small molecules with a molecular weight < 1000 Da) in an organism to identify changes related to a certain stimulus, for example, a drug intake. Over the last years, metabolomics has been established as a valuable tool in different disciplines, including very recently CT and FT. Analytical techniques usually applied include nuclear magnetic resonance and majorly hyphenated high-resolution mass spectrometry (HR-MS), similar to the instrumentation used in CT and FT. We will summarize practical considerations for each step of a typical untargeted metabolome workflow (experimental set-up, sample collection and storage, analysis, data processing, statistics, and identification) in CT and FT, provide an update on the current applications of untargeted metabolome profiling and will critically discuss its benefits or lack thereof within the particular field. Abstract Clinical toxicology (CT) and forensic toxicology (FT) represent two disciplines of toxicology dedicated to the qualitative and quantitative analysis and respective interpretation of alcohol, drugs of abuse (DOA), over the counter (OTC), and prescription drugs or poisons, mainly in humans. Analytical challenges, such as the transient occurrence of new psychoactive substances (NPS) on the (il)legal drug market, insufficiently long detection windows of some DOAs, or the lack of objective measures to unambiguously proof sample manipulation as well as interpretative issues, for instance, the difficulty to discriminate occasional users from chronic/addictive ones still require further evaluation and research, though. Metabolomics is a rather new research field, aiming for qualitative, and quantitative analysis of endogenous compounds (small molecules with a molecular weight < 1000 Da) in an organism to identify changes related to a certain stimulus, for example, a drug intake. Over the last years, metabolomics has been established as a valuable tool in different disciplines, including very recently CT and FT. Analytical techniques usually applied include nuclear magnetic resonance and majorly hyphenated high-resolution mass spectrometry (HR-MS), similar to the instrumentation used in CT and FT. We will summarize practical considerations for each step of a typical untargeted metabolome workflow (experimental set-up, sample collection and storage, analysis, data processing, statistics, and identification) in CT and FT, provide an update on the current applications of untargeted