In vitro metabolic profile characterization for synthetic cannabinoids MDMB-BINACA, MDMB-PICA, and AB-CHMINACA

The illicit synthetic cannabinoid receptor agonist (SCRA) market has experienced multiple changes since its appearance in the 2010s and, most recently, in response to a class-wide SCRA ban imposed by China in 2021. The reemergence of "older" SCRAs, such as the highly potent indole- and indazole-3-carboxamide-containing drugs, has occurred due to the sale of unregulated precursors on grey-market and dark websites. This shift poses a significant threat to public health, and recent intoxication outbreaks associated with these types of SCRAs demonstrate the need for further toxicological research to aid in better understanding their metabolism and appropriate targets for toxicological testing. Testing for metabolites can extend the detection window of SCRAs as parent drugs are rapidly metabolized and present at low or potentially undetectable concentrations in biological samples, including urine. In these instances, metabolites may be more sensitive biomarkers of SCRA use. This study characterized the metabolites for the synthetic cannabinoids MDMB-BINACA (also known as MDMB-BUTINACA), MDMB-PICA, and AB-CHMINACA via in vitro human liver microsome (HLM) incubation and analysis by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Biotransformations observed in this study included ester and amide hydrolysis, oxidation, carboxylation, and dealkylation. Nine metabolites were identified for MDMB-BINACA, five of which were verified through retrospective analysis of authentic samples. Nine metabolites were also identified for both MDMB-PICA and AB-CHMINACA, with two metabolites of AB-CHMINACA verified in authentic samples. Characterization of the metabolism of these potent drugs allows for the use of the identified biomarker to improve forensic toxicology analyses and interpretation, especially when the use of synthetic cannabinoids is suspected.