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Modulating the endocannabinoid system in human health and disease

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Modulating the endocannabinoid system in human health and disease ( modulating-endocannabinoid-system-human-health-and-disease )

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NIH Public Access Author Manuscript FEBS J. Author manuscript; available in PMC 2014 May 01. Published in final edited form as: FEBS J. 2013 May ; 280(9): 1918–1943. doi:10.1111/febs.12260. Modulating the endocannabinoid system in human health and disease: successes and failures Pál Pacher and George Kunos Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA Abstract The discovery of the endocannabinoid system (ECS; comprising of G-protein coupled cannabinoid 1 and 2 receptors, their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, triggered an avalanche of experimental studies that have implicated the ECS in a growing number of physiological/pathological functions. They also suggested that modulating ECS activity holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders, obesity/metabolic syndrome, cachexia, chemotherapy-induced nausea and vomiting, tissue injury and pain, among 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 introduced unexpected complexities, and suggested that better understanding of the pathophysiological role of the ECS is required in order to devise clinically successful treatment strategies, which will be critically reviewed in this brief synopsis. Keywords endocannabinoid system; disease; cannabinoids; human; clinical trials; therapeutic potential; pharmacology Introduction Although Cannabis sativa (marijuana plant) is one of the most ancient medicinal plants in the history of medicine[1], the clinical use of synthetic cannabinoids or medicinal plant extracts have been largely empirical and limited to a few specific indications related to pain, wasting disorders, and chemotherapy-induced nausea and vomiting, because of their socially undesirable psychoactive properties[2]. The discovery of endocannabinoids (ECs), which mimic some of the effects of synthetic cannabinoids in vivo, their G-protein coupled receptors (GPCR) as well as their synthetic and metabolizing enzymes, has prompted preclinical studies to explore the role of the ECS in health and disease[2–4]. These studies have been greatly facilitated by the introduction of mice deficient in cannabinoid receptors or the EC degrading enzymes, as well as selective cannabinoid receptor ligands and inhibitors of EC metabolism. The results of these studies have implicated the ECS in a variety of physiopathological processes, both in the peripheral and central nervous systems and in various peripheral organs[2]. They further suggested that modulating ECS activity may have therapeutic potential in almost all diseases affecting humans, including obesity/ metabolic syndrome[5], diabetes and diabetic complications[6], neurodegenerative[7,8], Correspondence: Pál Pacher M.D., Ph.D., Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, Maryland 20892-9413, USA., Pacher@mail.nih.gov, Phone: (301)443-4830, Fax: (301)480-0257. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

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