Modulating the endocannabinoid system in human health and disease successes and failures

The discovery of the endocannabinoid system, comprising the G-protein coupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, has triggered an avalanche of experimental studies implicating the endocannabinoid system in a growing number of physiological/pathological functions. These studies have also suggested that modulating the activity of the endocannabinoid system holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders; obesity/metabolic syndrome; cachexia; chemotherapy-induced nausea and vomiting; and tissue injury and pain, amongst others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally-restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain, have introduced unexpected complexities, suggesting that a better understanding of the pathophysiological role of the endocannabinoid system is required to devise clinically successful treatment strategies.