Fig. 2.

Main molecular targets of cannabidiol (CBD). The mechanisms of action of CBD primarily involve the endocannabinoid system. Unlike endocannabinoids, CBD does not bind to the orthostatic binding site of cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) with high affinity. Instead, CBD binds to the allosteric binding site of CB1R and CB2R, possibly acting as a negative allosteric modulator at these receptors. Cannabidiol also acts as an antagonist/inverse agonist at CB1R and CB2R, while it may also act as a partial agonist at CB2R. Importantly, CBD inhibits the activity of fatty acid amide hydrolase (FAAH), leading to an increase in extracellular N-arachidonoylethanolamine (AEA) levels and subsequent activation of CB1R, CB2R, and transient receptor potential cation channel subfamily V member 1 (TRPV1). Cannabidiol also acts as an agonist of transient receptor potential channels (TRPV1, TRPV2, TRPV3, TRPV4, and TRPA1) and peroxisome proliferator-activated receptor gamma (PPARγ), while acting as an antagonist of G protein-coupled receptor 55 (GPR55) and transient receptor potential cation channel subfamily M member 8 (TRPM8). However, the exact mechanisms of action of CBD remain elusive