Abstract
Synthetic cannabinoids (SCs) are a structurally diverse and fast-evolving class of "designer drugs". In New Zealand, a specific SC, AMB-FUBINACA (AMB-FUB), has been implicated in 58 deaths. SCs are commonly abused alongside other drugs and medications, including a "party pill" drug, para-fluorophenylpiperazine (pFPP), and the antipsychotic risperidone. There is currently no overdose treatment for SC intoxication. This research aimed to investigate the mechanisms underpinning AMB-FUB toxicity and the impact of clinically relevant drugs on AMB-FUB activity in vivo.
Male and female C57BL/6 mice received a single dose of AMB-FUB (3 or 6 mg/kg), pFPP (10 mg/kg), or vehicle intraperitoneally (n = 6 per group). Mice were co-exposed to AMB-FUB (3 mg/kg) and pFPP (10 mg/kg) or risperidone (0.5 mg/kg) to investigate the impact of these drug combinations. To study the potential rescue of AMB-FUB toxicity, Rimonabant (3 mg/kg) was administered 15 minutes after 6 mg/kg AMB-FUB. Adverse effects caused by drug administration, including hypothermia and convulsions, were recorded. Data are presented as mean ± SD and were analysed by a two-way, repeated measures ANOVA followed by Tukey’s post-hoc tests (P<0.05 considered significant).
Risperidone and pFPP in combination with AMB-FUB both exacerbated AMB-FUB-induced hypothermia in male and female mice. Risperidone significantly reduced convulsion number by 2.6-fold in female mice, with a mean convulsion number of 37 ± 17 in the AMB-FUB alone group, compared to 14 ± 7 convulsions in the combination treatment (P<0.05). Rimonabant post-treatment attenuated AMB-FUB-induced hypothermia in males and significantly reduced convulsions in both sexes. Specifically, males and females averaged 5 convulsions post-Rimonabant, compared to 24 and 27 convulsions, respectively, in the 6 mg/kg AMB-FUB alone treatment groups.
Co-exposure to other drugs of abuse or medications is especially prevalent in SC users. These results highlight the complexity of AMB-FUB toxicity and further the development of potential overdose treatments.