Abstract

Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB1) receptor and produce effects similar to those of THC, the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for their potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects including cardiotoxicity, seizure activity, and kidney damage and can result in death. Six synthetic cannabinoids, recently detected in illicit preparations, MMB-FUBINACA, MDMB-FUBINACA, CUMYL-PICA, 5F-CUMYL-PICA, NNEI and MN-18 were assessed for 1) receptor binding affinity at the human CB1 and human CB2 receptors, 2) function in [35S]GTPγS and cAMP signaling, and 3) THC-like effects in a mouse drug discrimination assay. All six synthetic cannabinoids exhibited high affinity for hCB1 and hCB2 receptors and produced greater maximal effects than THC in [35S]GTPγS and cAMP signaling. Additionally, all six synthetic cannabinoids substituted for THC in drug discrimination, suggesting they likely possess similar subjective effects to that of cannabis. Notably, MDMB-FUBINACA, methylated analog of MMB-FUBINACA, had higher affinity for CB1 than the parent, showing that minor structural modifications being introduced can have a large impact on the pharmacological properties of these drugs. This study demonstrates that novel structures being sold and used illicitly as substitutes for cannabis are retaining high affinity at the CB1 receptor, exhibiting greater efficacy than THC and producing THC-like effects in models relevant to subjective effects in humans.