Synthetic cathinone pharmacokinetics, analytical methods, and toxicological findings from human performance and postmortem cases

Synthetic cathinones are commonly abused novel psychoactive substances (NPS). We present a comprehensive systematic review addressing in vitro and in vivo synthetic cathinone pharmacokinetics, analytical methods for detection and quantification in biological matrices, and toxicological findings from human performance and postmortem toxicology cases. Few preclinical administration studies examined synthetic cathinone pharmacokinetic profiles (absorption, distribution, metabolism, and excretion), and only one investigated metabolite pharmacokinetics. Synthetic cathinone metabolic profiling studies, primarily with human liver microsomes, elucidated metabolite structures and identified suitable biomarkers to extend detection windows beyond those provided by parent compounds. Generally, cathinone derivatives underwent ketone reduction, carbonylation of the pyrrolidine ring, and oxidative reactions, with phase II metabolites also detected. Reliable analytical methods are necessary for cathinone identification in biological matrices to document intake and link adverse events to specific compounds and concentrations. NPS analytical methods are constrained in their ability to detect new emerging synthetic cathinones due to limited commercially available reference standards and continuous development of new analogs. Immunoassay screening methods are especially affected, but also gas-chromatography and liquid-chromatography mass spectrometry confirmation methods. Non-targeted high-resolution-mass spectrometry screening methods are advantageous, as they allow for retrospective data analysis and easier addition of new synthetic cathinones to existing methods. Lack of controlled administration studies in humans complicate interpretation of synthetic cathinones in biological matrices, as dosing information is typically unknown. Furthermore, antemortem and postmortem concentrations often overlap and the presence of other psychoactive substances are typically found in combination with cathinones derivatives, further confounding result interpretation.