Investigating selectivity and bias for G protein subtypes and β-arrestins by synthetic cannabinoid receptor agonists at the cannabinoid CB1 receptor

Synthetic cannabinoid receptor agonists (SCRAs) at the CB1 receptor can produce serious adverse health effects, and this study tests whether signalling bias explains differences versus THC. Using real-time BRET reporters, the authors measure G protein dissociation and β-arrestin 1 and 2 translocation across Gαi/o subtypes, applying operational analysis to quantify bias without relying on heavily amplified signals. Results show SCRAs behave as balanced, high-efficacy ligands relative to the lower efficacy ligand THC, with only one SCRA (4CN-MPP-BUT7IACA) showing statistically significant bias in a single pathway comparison (toward β-arrestin 1 versus GαoA/oB). The overall conclusion is that SCRA adverse effects are more consistent with high potency and efficacy at CB1 than with biased agonism.