The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management and metabolic diseases. However, around 2007 the tide began to turn when several cannabinoid receptor type 1 (CB1) antagonists/inverse agonists failed as therapeutics against overweight and its complications. More recently, the development of FAAH (Fatty Acid Amide Hydrolase) inhibitors against pain has also faced serious setbacks. In retrospect the much greater complexity of the ECS than originally assumed has played a fundamental role in these difficulties. Although there is no doubt that endocannabinoids and their receptors are of great (patho-)physiological relevance, it has become clear that the ECS is intimately intertwined with other biological systems. Endocannabinoids exist in equilibrium with fatty acids and their metabolic derivatives, including eicosanoids and prostamides. Furthermore, there are several biologically active analogues of endocannabinoids, in particular fatty acid amides, with metabolic pathways overlapping those of the ECS. Finally, endocannabinoids per se and their congeners show “promiscuous” behaviour going beyond interactions with CB1 and CB2 receptors. It has become clear that the complexity of what may be called the “endocannabinoidome” demands for pharmacological approaches that take into account these dynamics. Targeting the “endocannabinoidome” continues to offer opportunities for prevention and therapy, in particular for chronic diseases. However, chances for success are more likely to come from “multiple-target” than from “single-target” approaches