Pharmacokinetic and pharmacodynamic properties of cannabigerol in male mice

Cannabigerol (CBG) is a nonintoxicating phytocannabinoid gaining popularity as a self-medication for anxiety and other conditions; however, its pharmacological properties remain poorly defined. Here, we report the development of a rapid and sensitive liquid chromatography-tandem mass spectrometry method for quantifying CBG and its primary oxidative metabolite, cyclo-CBG. This platform enabled the characterization of CBG's pharmacokinetic and biotransformation profile after intraperitoneal administration (10 mg/kg) in male mice. CBG exhibited rapid systemic distribution and clearance, with relatively low brain penetration (brain-to-plasma ratio = 0.26). In contrast, cyclo-CBG accumulated in brain tissue to a surprising extent (brain-to-plasma ratio = 7.1), suggesting local formation and a potentially important role in mediating central effects. Despite prior reports of anxiolytic effects, we found that CBG administered at its peak brain concentration produced anxiogenic-like effects in mice, as assessed using the elevated plus maze. This response was not affected by the CB₁ cannabinoid receptor inverse agonist, rimonabant (3 mg/kg, i.p.), indicating a mechanism independent of CB₁ signaling. As interest in CBG continues to rise, the analytical and pharmacokinetic framework presented here provides a valuable foundation for advancing preclinical and clinical investigations into its efficacy, safety, and mechanism of action. SIGNIFICANCE STATEMENT: Application of a new liquid chromatography-tandem mass spectrometry method to quantify cannabigerol reveals key pharmacokinetic properties of this phytocannabinoid in mice, including unexpectedly high brain accumulation of its metabolite cyclo-cannabigerol, which was accompanied by anxiogenic-like effects. The results offer valuable tools for advancing preclinical and clinical investigations into cannabigerol pharmacology.