“The article is a thorough and up to date review of all biochemical aspects of the "endocannabinoid system".”

The article is a thorough and up-to-date review of all biochemical aspects of the "endocannabinoid system." This is a relatively novel field in molecular pharmacology, dealing with a signalling system based on endogenous lipid mediators and their G-protein-coupled receptors—the cannabinoid receptors—which are the same receptors activated by cannabis’ and marijuana’s principle psychoactive component delta9-tetrahydrocannabinol. Originally, the endogenous agonists of cannabinoid receptors were described as the "body's marijuana," and in fact they were christened "endocannabinoids" by our group in 1995 by analogy with plant cannabinoids. However, we know now that there are substantial differences between endocannabinoids and delta9-tetrahydrocannabinol. These differences are discussed in the article for the first time in the light of very recent biochemical and pharmacological advancements, which were reported only a few months before the publication of our review. For this reason the article turned out to be quite timely, and maybe this is also why it was highly cited by scientists working in this field.

The article summarizes new data from several laboratories on the regulation of endocannabinoid levels and on their multi-faceted mechanisms of action. It describes how endocannabinoid biosynthesis occurs "on demand," i.e., only in those cells and tissues where endocannabinoids are needed and only when they are needed; how it is tightly regulated by intracellular calcium, and how the expression of enzymes for endocannabinoid degradation is subject to multiple types of control. All this makes of these lipids a new family of very flexible chemical signals, capable of quickly responding to differing physiological and pathological stimuli with rapid changes in their levels and, subsequently, in the activity of cannabinoid receptors. Furthermore, the existence of molecular targets, some of which still await full molecular characterization, other than the two cloned cannabinoid receptors, enhances even further the flexibility of endocannabinoids. This is certainly one of the reasons, but not the only one, why this new field is attracting so much interest.

The "protagonist" is the endocannabinoid system. This system is based on endogenous chemical signals, the endocannabinoids, which act through specific proteins—the cannabinoid receptors, which are present on the outer membrane of the cell. These receptors then transform the signal conveyed by endocannabinoids into a series of intracellular reactions that result in profound changes in cell life. The article describes how endocannabinoids are made and degraded, which enzymes are involved in these processes, and the "canonical" receptors—the cannabinoid CB1 and CB2 receptors—and also other emerging molecular targets for the endocannabinoids. The understanding of the complexity of the molecular mechanisms regulating endocannabinoid levels and action, and of how they can be used for therapeutic purposes in a variety of disorders, requires a great multi-disciplinary effort, which renders this ever-expanding field both challenging and fascinating at once.