Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

The cannabis derivative marijuana is the most widely used recreational drug in the Western world and is consumed by an estimated 83 million indi-viduals (-3% of the world population). In recent years, there has been a marked transformation in society re-garding the risk perception of cannabis, driven by its le-galization and medical use in many states in the United States and worldwide. Compelling research evidence and the Food and Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, D9-tetrahydrocannabinol and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS)-made of receptors, metabolic enzymes, and transporters- that is also regulated by phytocannabinoids. The first en-docannabinoid to be discovered 30 years ago was ananda-mide (N-arachidonoyl-ethanolamine); since then, distinct elements of the ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here a critical review of our knowledge of the goods and bads of the ECS as a therapeu-tic target is presented to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health.Significance Statement--The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key pro-cesses of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, under-standing the structure, function, and pharmacology of the components of this complex system, and in particu-lar of key receptors (like cannabinoid receptors 1 and 2) and metabolic enzymes (like fatty acid amide hydrolase and monoacylglycerol lipase), will advance our under-standing of endocannabinoid signaling and activity at molecular, cellular, and system levels, providing new op-portunities to treat patients.