In vitro characterization of the metabolic pathways of four new synthetic cannabinoids

Synthetic cannabinoids are a class of novel psychoactive substances originally developed to explore the function and structure of cannabinoid receptors. At present, they have found great popularity into the world of “recreational” drug use, being among the most widely diffused of the new psychoactive substances. Indeed more than a hundred different varieties of synthetic cannabinoids have been synthetized so far, making their detection in herbal products and in biological fluids a demanding challenge for forensic laboratories. Here the phase I and phase II biochemical reactions involved in the biotransformation pathways of four new cannabinoids (CUMYL-THPINACA, ADB-CHMICA, APP-FUBINACA, APP-CHMINACA) were characterized by LC–MS-based techniques and in vitro models to identify the most appropriate marker(s) of intake. Our data show that the compounds studied are extensively metabolized mainly by CYP3A4 and CYP3A5 isoforms to more than 10 oxidized metabolites, being the mono-hydroxylation the most abundant biotransformation pathways detected. Concerning the phase II metabolism our data suggest that for all the compounds under investigation, most of the phase I metabolites characterized once formed undergo glucuronidation.