Cannabinoids: a class of unique natural products with unique pharmacology

The full understanding of the real therapeutic potential of cannabis preparations and of the dangers that their recreational use pose can only stem from the assessment of the chemical composition of such preparations and the knowledge of the pharmacology of their main components, the cannabinoids. Much in the same way cannabis is not just one plant, cannabinoids were not made all equal, and profound differences exist between the pharmacological properties of Δ9-tetrahydrocannabinol (Δ9-THC), the most abundant euphoric and psychotropic cannabinoid, and the other over one hundred natural products belonging to the same class of compounds. So far, only the bioactivity of Δ9-THC, the main component of marijuana, and a handful of cannabinoids, including cannabidiol (CBD), the most abundant cannabinoid in industrial varieties of cannabis, has been thoroughly investigated. While pharmacological studies on Δ9-THC led to the discovery of cannabinoid receptors, endocannabinoids (eCBs) and the endocannabinoid (eCB) system, which underlie most of the effects of this compound in mammals, the mechanisms of action of CBD and other non-euphoric cannabinoids are much more complex and are based on several molecular targets, including, but not limited to, the proteins (receptors and enzymes) of the “expanded eCB system,” or “endocannabinoidome” (eCBome), and hence on their capability of modulating the actions or tissue concentrations of eCB-related lipid mediators. In this article, we discuss to what extent the pharmacology of cannabinoids, and of Δ9-THC and CBD in particular, can be explained by the existence of the eCB system and the eCBome.