Chapter 2: Phytocannabinoids Versus Endocannabinoids. A Modern View of the Endocannabinoid System

Phytocannabinoids, the most singular chemical constituents present in the Cannabis sativa plant, were discovered and characterized up to the 1960s. By contrast, endocannabinoids and their receptors were discovered in the late 1980s and early 1990s, as a result of the efforts to identify the mechanism(s) of action of plant-derived cannabinoids. The discovery of this system, the so-called “endogenous cannabinoid system”, enabled by itself important advances in the knowledge of the biology of numerous cells, tissues and organs in the human body, but it has also provided a strong rationale to understand why the cannabis plant has been used from ancient times with therapeutic purposes for human pathologies. It also explained the recent advances in the development of cannabinoid-based medicines, including medicinal cannabis and also plant-derived and synthetic molecules formulated as Marinol^®, Cesamet^®, Sativex^® and, more recently, Epidiolex^®. The latter drugs have been approved in many countries for the treatment of vomiting and nausea, anorexia–cachexia syndrome, spasticity in multiple sclerosis, and seizures in infantile refractory epilepsies, respectively. This chapter aims to review the scientific knowledge generated around the research on plant-derived cannabinoids and the discovery of endocannabinoids, their receptors and molecular machinery for generating and inactivating these endogenous compounds, as a necessary step to develop novel medicines based on the activation, inhibition or modulation of the endocannabinoid system for the treatment of different central and peripheral pathologies.