Understanding Cannabinoid Binding

Scientists are beginning to gain insight into the complex mechanisms involved in the operation of the endocannabinoid system, or ECS. Recent research studies have indicated that cellular and neurotransmitter signaling in the human body may be significantly modified via the interaction with phytocannabinoids (including CBC, CBD, CBG, and their molecular analogs).

Individual phytocannabinoids display something called a binding affinity that is basically their likelihood of attaching to an endocannabinoid receptor and the strength of that bond. Some cannabinoids, such as the phytocannabinoid CBN and the endocannabinoid 2-AG, bind with both CB1 and CB2 receptors. Other cannabinoids bind with only one receptor or display different signalling effects when binding with different receptor types.

A 2020 study entitled "Pharmacological Data of Cannabidiol- and Cannabigerol-type Phytocannabinoids Acting on Cannabinoid CB1, CB2, and CB1/CB2 Heteromer Receptors" shed light on the fact that neurotransmitter signalling characteristics are significantly different from one phytocannabinoid to another.

Thus, while two different cannabinoids might bind with the same type of cellular receptor, this molecular flirtation will typically result in vastly different signalling by the neurotransmitter. This, in turn, equals different physical manifestations within the organs, glands, and tissues in which the ECS operates (within nearly all areas of the body). In terms of core binding affinity, the study observed that "CBGV displayed enhanced potency in many of the functional outputs."

The study's authors concluded that the "most interesting" result of the study was "a biased [ECS receptor] signaling that correlated with differential affinity, i.e. the overall results suggest that the binding mode of each ligand leads to specific receptor conformations underlying biased signaling outputs."

A 2018 study entitled "Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System" identified the different binding affinities held by the endocannabinoids anandamide and 2-AG for the primary ECS receptors CB1 and CB2.

Wrote the researchers, "AEA [anandamide] turns out to be a high-affinity, partial agonist of CB1R and almost inactive at CB2R, whereas 2-AG acts as a full agonist at both CBRs with moderate-to-low affinity." This study also revealed the relative levels of these two endocannabinoids within the brain, noting the significantly greater volumes of 2-AG. "The basal level of 2-AG is approximately 1000 times higher than AEA in the brain," reported the scientists.