Cannabinoid pharmacology: the first 66 years

Abstract

Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB(1) and CB(2) receptors and of endogenous ligands for these receptors, to the development of CB(1)- and CB(2)-selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified.

Figure 1

The structures of five plant cannabinoids (phytocannabinoids), Δ⁹-tetrahydrocannabinol (Δ⁹-THC), Δ⁸-THC, cannabidiol (CBD), cannabinol (CBN) and Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV), and of two synthetic cannabinoids, Δ^6a,10a-THC and synhexyl.

Figure 2

The structures of two endocannabinoids, anandamide and 2-arachidonoyl glycerol.

Figure 3

Potential clinical strategies for the management of disorders in which an increased production of anandamide may lead to a reduction in the intensity of unwanted signs and symptoms (reviewed in Pertwee 2005c). These strategies rely on augmentation of apparent anandamide-mediated protective effects through inhibition of the cellular uptake of anandamide, through inhibition of its intracellular metabolism by fatty acid amide hydrolase or through allosteric enhancement of anandamide-induced CB₁ receptor activation.