The endocannabinoid system and its therapeutic exploitation

Abstract

Cannabis has long been used for the relief of cramps and rheumatic pain, and in 1964 its main psychoactive ingredient — (−)-Δ9-tetrahydrocannabinol (THC) — was finally isolated and characterized. The development by Pfizer of a non-classical cannabinoid led to the cloning of the first cannabinoid receptor, CB₁, which was swiftly followed in 1993 by the cloning of the second receptor, CB₂, and the isolation of endogenous ligands, the endocannabinoids, in 1992–1995. Knowledge of the physiological function of the cannabinoid system is still emerging. However, the pathological alteration of cannabinoid signalling has been observed in psychiatric disorders; stroke; neurodegenerative conditions such as Parkinson's and Alzheimer's diseases; cancer; reproductive, cardiovascular and gastrointestinal disorders; and, perhaps most famously, in multiple sclerosis, making this signalling pathway a cornucopia of potential therapeutic targets. Many of the enzymes involved in endocannabioid synthesis and degradation have now been characterized and are currently being pursued as therapeutic targets, including N-acylphosphatidylethanolamine-selective phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase isozymes α and β, and monoacylglycerol lipase. Other therapeutic strategies include small-molecule cannabinoid receptor agonists and antagonists, and the use of non-psychotropic plant cannabinoids. A CB₁ receptor antagonist looks promising against obesity, metabolic syndrome and nicotine dependence after completing initial Phase III clinical trials. Clinical trials carried out so far with oral THC and plant cannabinoids for the treatment of multiple sclerosis and Parkinson's disease have shown some efficacy and few side effects.