Abstract
Synthetic cannabinoids are a rapidly evolving group of novel psychoactive substances. The structural evolution of these compounds results in persistent circumvention of regulatory controls, making it difficult to manage the manufacturing, trafficking, and use of synthetic cannabinoids. The recreational use of synthetic cannabinoids in New Zealand placed a large burden on emergency care services, resulting in hundreds of ambulance call-outs, over one hundred cases of adverse events and numerous fatalities. In particular, the synthetic cannabinoid, AMB-FUBINACA, was associated with 64 deaths in New Zealand from May 2017 to February 2019. The adverse effects and toxicity from synthetic cannabinoids are proposedly mediated through activation of the cannabinoid CB1 receptor. However, the wide range of symptoms and adverse effects following synthetic cannabinoid intoxication suggest that several factors influence these outcomes. Therefore, this study aimed to investigate the impact of dose, CB1 signalling, relevant drug co-exposures and metabolic interactions on synthetic cannabinoid toxicity, with a focus on AMB-FUBINACA. To assess the influence of these factors, methodologies spanning human case study analysis, in vivo and in vitro models were utilised.
Through the analysis of 220 human cases of synthetic cannabinoid intoxication or mortality, 657 co-exposure substances were detected. The most common co-exposure substances were alcohol, antipsychotic medications, and cannabis. Of further interest, history of drug use (54.5%) and mental illness (22.5%) were prevalent characteristics in patients. With a particular focus on AMB-FUBINACA, the impact of dose, sex, and CB1-dependency on toxicity were investigated in C57Bl/6 mice. Dose significantly affected the severity and duration of hypothermia in both sexes. Furthermore, AMB-FUBINACA-induced hypothermia and convulsions were dependent on CB1 signalling. There were no toxicological effects to organs following an acute administration of AMB-FUBINACA. In addition to these findings, the in vivo effects of AMB-FUBINACA were studied in the presence of relevant co-exposure drugs. The party pill drug, para-fluorophenylpiperazine (10 mg/kg), significantly potentiated AMB-FUBINACA-induced hypothermia, prolonging the duration by an average of 7 hours. The CB1 antagonist/inverse agonist, rimonabant (3 mg/kg), significantly attenuated both hypothermia and convulsions when administered as a post-treatment after AMB-FUBINACA (6 mg/kg). Additionally, pre-treatment with the antipsychotic, risperidone (0.5 mg/kg), provided significant protection from AMB-FUBINACA-induced convulsions in females. Finally, interactions between antipsychotic and antidepressant medications and the primary metabolic enzymes for AMB-FUBINACA, carboxylesterases, were assessed in vitro. Clozapine, fluoxetine, and risperidone all selectively inhibited carboxylesterase isoforms. Notably, clozapine was a strong, uncompetitive inhibitor of carboxylesterase 2, with a Ki of 3.11 µM. Interactions with antipsychotics, other carboxylesterase substrates or inhibitors could significantly impact AMB-FUBINACA toxicity.
Factors such as dose, CB1 signalling, and the effect of co-exposure substances significantly contribute to the toxicity of AMB-FUBINACA. However, several potential factors remain unassessed. Specifically, chronic studies with more realistic routes of administration are needed to understand the progression of toxicity and long-term effects of synthetic cannabinoids in vivo. Mechanistic understanding of the causative factors behind synthetic cannabinoid toxicity and fatality can help inform overdose treatment strategies, where there is currently no specific treatment for intoxication or overdose, and reduce harm in vulnerable populations of synthetic cannabinoid users.