JWH-018

Synthetic cannabinoid receptor agonists (SCRAs) are a class of synthetic drugs that mimic and greatly surpass the effect of recreational cannabis. Acute SCRA intoxications are in general difficult to assess due to the large number of compounds involved, differing widely in both chemical structure and pharmacological properties. The rapid pace of emergence of unknown SCRAs hampers on one hand the timely availability of methods for identification and quantification to confirm and estimate the extent of the SCRA intoxication. On the other hand, lack of knowledge about the harm potential of emerging SCRAs hampers adequate interpretation of serum concentrations in intoxication cases. In the present study, a novel comparative measure for SCRA intoxications was evaluated, focusing on the cannabinoid activity (versus serum concentrations), which can be measured in serum extracts with an untargeted bioassay assessing ex vivo CB₁ activity. Application of this principle to a series of SCRA intoxication cases (n = 48) allowed for the determination of activity equivalents, practically entailing a conversion from different SCRA serum concentrations to a JWH-018 equivalent. This allowed for the interpretation of both mono- (n = 34) and poly-SCRA (n = 14) intoxications, based on the intrinsic potential of the present serum levels to exert cannabinoid activity (cf. pharmacological/toxicological properties). A non-distinctive toxidrome was confirmed, showing no relation to CB₁ activity. The JWH-018 equivalent was partly related to the poison severity score (PSS) and causality of the clinical intoxication elicited by the SCRA. Altogether, this equivalent concept allows to comparatively and timely interpret (poly-)SCRA intoxications based on CB₁ activity.

The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRAs consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used in silico, in vivo, and ex vivo approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with in silico predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25 mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The in silico findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lung, kidney, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.