Mechanisms of cannabinoid action

The pharmacology of phytocannabinoids is complex, partly due to the large number and diversity of their molecular targets, responsible for their impact on physiological and pathological processes. However, most effects of THC, and other cannabinoids, directly depend on its action on a cell-communication system exerting eminent regulatory functions in every organ and anatomical system of the body, the so-called endocannabinoid system.

Cannabinol was the first cannabinoid identified from cannabis at the end of the 19th Century, while the discovery of CBD and the recognition of THC as the main active compound in cannabis was achieved by Roger Adams investigations around 1940’s. REF  The final isolation and characterization of the tridimensional structure of THC was accomplished by Raphael Mechoulam in 1964. REF


However, it took almost 30 years to identify the major effector of THC actions, a molecular receptor present in the cell membrane of many different cell types distributed all over our body, but particularly abundant in the brain, named cannabinoid receptor type 1, or CB1 receptor. REF Shortly after, an endogenous cannabinoid ligand or endocannabinoid (i.e., a naturally produced molecule which binds and activates the cannabinoid receptor) was also identified in porcine brain and named “anandamide”, after the Sanskrit word ananda, meaning bliss, and the chemical nature of the compound. REF Later, a second, peripheral receptor targeted by THC was also identified in the spleen and called cannabinoid receptor type 2, or CB2 receptor. REF Likewise, a second endogenous ligand of cannabinoid receptors, 2-arachidonoyl glycerol or 2-AG, was simultaneously identified in rat brain and canine gut samples. REFS

Collectively, these findings led to the discovery and characterization of the endocannabinoid system, which is mainly composed by the aforementioned CB1 and CB2 cannabinoid receptors, the endocannabinoids anandamide and 2-AG, as well as the metabolic enzymes responsible for the biosynthesis and degradation of endocannabinoids. REF

Over the following decades, thorough research has allowed for the expansion and better characterization of the actual elements of the endocannabinoid system, a deeper understanding of the role of this crucial system in the control of homeostasis and overall mammalian physiology, as well as the involvement of the endocannabinoid system in most pathological conditions, which serve as a basis for most of the therapeutic actions of cannabinoids.

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