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Abstract
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.
Highlights
The endogenous cannabinoid system includes neurotransmitters or endogenous cannabinoids, receptors, cannabinoid receptor 1 (CB1, mainly expressed in brain) and CB2, and synthetic and degradation pathways (Pertwee, 2012; Le Boisselier et al, 2017)
Synthetic cannabinoids (SCs) were developed as pharmacological probes to explore the endogenous cannabinoid system with potential treatment for inflammatory diseases and cancer pain (Pertwee, 2006; Castaneto et al, 2014), but such endeavors failed to date, with no SC progressing to clinical use
We attempted to obtain authentic human urine samples following specific SC ingestion through international collaborations, enabling comparison of in vitro and in vivo metabolites and clarifying the targets for SCs drug testing. This workflow was successful in predicting major urinary metabolites of many SCs, including AB-PINACA/5F-ABPINACA (Wohlfarth et al, 2015), AB-FUBINACA (Castaneto et al, 2015), FDU-PB-22/FUB-PB-22 (Diao et al, 2016a), and NM-2201 (Diao et al, 2017b) etc
Summary
The endogenous cannabinoid system includes neurotransmitters or endogenous cannabinoids, receptors, cannabinoid receptor 1 (CB1, mainly expressed in brain) and CB2 ( abundant in immune tissues), and synthetic and degradation pathways (Pertwee, 2012; Le Boisselier et al, 2017). Synthetic cannabinoids (SCs) were developed as pharmacological probes to explore the endogenous cannabinoid system with potential treatment for inflammatory diseases and cancer pain (Pertwee, 2006; Castaneto et al, 2014), but such endeavors failed to date, with no SC progressing to clinical use. In June 2018, the US Food and Drug Administration approved the first cannabinoid plant extract (Epidiolex R ) for the treatment of seizures associated with two rare and severe forms of epilepsy, Dravet’s and LennoxGastaut seizure syndromes (US Food Drug Administration, 2018). A notorious outbreak associated with SCs occurred in the State of Mississippi in April and May 2015 This public health emergency claimed 17 lives and involved 1,243 emergency room visits (Mississippi State Department of Health, 2015; Kemp et al, 2016). Do drug-abusers know which SC or SCs they consumed, and severe potential drug-drug interactions with other abused illegal drugs or therapeutics can occur (Chimalakonda et al, 2012)
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