Recreational use of marijuana is associated with few adverse effects, but abuse of synthetic
cannabinoids (SCBs) can result in anxiety,
psychosis,
chest pain,
seizures and death. To potentially explain higher toxicity associated with SCB use, we hypothesized that
AB-PINACA, a common second generation SCB, exhibits atypical pharmacodynamic properties at CB1
cannabinoid receptors (CB1Rs) and/or a distinct metabolic profile when compared to Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive
cannabinoid present in marijuana. Liquid chromatography tandem mass spectrometry (LC/MS) identified
AB-PINACA and monohydroxy metabolite(s) as primary phase I metabolites (4OH-
AB-PINACA and/or 5OH-
AB-PINACA) in human urine and serum obtained from forensic samples. In vitro experiments demonstrated that when compared to Δ9-THC,
AB-PINACA exhibits similar affinity for CB1Rs, but greater efficacy for
G-protein activation and higher potency for
adenylyl cyclase inhibition. Chronic treatment with
AB-PINACA also results in greater desensitization of CB1Rs (e.g., tolerance) than Δ9-THC. Importantly, monohydroxy metabolites of
AB-PINACA retain affinity and full agonist activity at CB1Rs. Incubation of 4OH-AB-PINACA and 5OH-AB-PINACA with human liver microsomes (HLMs) results in limited
glucuronide formation when compared to that of JWH-018-M2, a major monohydroxylated metabolite of the first generation SCB
JWH-018. Finally,
AB-PINACA and 4OH-AB-PINACA are active in vivo, producing CB1R-mediated
hypothermia in mice. Taken collectively, the atypical pharmacodynamic properties of
AB-PINACA at CB1Rs relative to Δ9-THC (e.g., higher potency/efficacy and greater production of desensitization), coupled with an unusual metabolic profile (e.g., production of metabolically stable active phase I metabolites) may contribute to the pronounced adverse effects observed with abuse of this SCB compared to marijuana.