New Synthetic Cannabinoids Metabolism and Strategies to Best Identify Optimal Marker Metabolites

Synthetic cannabinoids (SCs) were initially developed as pharmacological tools to probe the endocannabinoid system and as novel pharmacotherapies, but are now highly abused. This is a serious public health and social problem throughout the world and it is highly challenging to identify which SC was consumed by the drug abusers, a necessary step to tie adverse health effects to the new drug's toxicity. Two intrinsic properties complicate SC identification, their often rapid and extensive metabolism, and their generally high potency relative to the natural psychoactive Δ⁹-tetrahydrocannabinol in cannabis. Additional challenges are the lack of reference standards for the major urinary metabolites needed for forensic verification, and the sometimes differing illicit and licit status and, in some cases, identical metabolites produced by closely related SC pairs, i.e., JWH-018/AM-2201, THJ-018/THJ-2201, and BB-22/MDMB-CHMICA/ADB-CHMICA. We review current SC prevalence, establish the necessity for SC metabolism investigation and contrast the advantages and disadvantages of multiple metabolic approaches. The human hepatocyte incubation model for determining a new SC's metabolism is highly recommended after comparison to human liver microsomes incubation, in silico prediction, rat in vivo, zebrafish, and fungus Cunninghamella elegans models. We evaluate SC metabolic patterns, and devise a practical strategy to select optimal urinary marker metabolites for SCs. New SCs are incubated first with human hepatocytes and major metabolites are then identified by high-resolution mass spectrometry. Although initially difficult to obtain, authentic human urine samples following the specified SC exposure are hydrolyzed and analyzed by high-resolution mass spectrometry to verify identified major metabolites. Since some SCs produce the same major urinary metabolites, documentation of the specific SC consumed may require identification of the SC parent itself in either blood or oral fluid. An encouraging trend is the recent reduction in the number of new SC introduced per year. With global collaboration and communication, we can improve education of the public about the toxicity of new SC and our response to their introduction.