The challenge of developing selective drugs towards the complex endocannabinoid system Mauro Maccarrone 1,2 1 University of L'Aquila, Italy, 2 European Center for Brain Research, IRCCS Santa Lucia, Foundation, Italy The cannabis (Cannabis sativa) derivative marijuana is the most widely used recreational drug in the Western world, and cannabis-derived Δ9-tetrahydrocannabinol (THC), cannabidiol and additional terpenophenolic substances – collectively termed phytocannabinoids – hold huge therapeutic potential to treat human diseases. Remarkably, our body has its own endocannabinoid system (ECS), made of a complex ensemble of bioactive lipids, their receptors, metabolic enzymes and transporters that can be hit by phytocannabinoids along with unexpected off-targets. Since the discovery of the first endocannabinoid anandamide (N-arachidonoylethanolamine) 30 years ago, distinct elements of the ECS have been the target of drug design programmes aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here, the challenge of developing selective drugs towards the complex ECS will be discussed, in order to define whether ECS-active phytocannabinoids and ECS-oriented synthetic drugs should be considered the root of all evil, or a panacea for human health. References 1. Maccarrone M, Guzmán M, Mackie K, Doherty P, Harkany T. Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci. 2014 Dec;15(12):786-801. doi: 10.1038/nrn3846. 2. Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, Zimmer A. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015 May;36(5):277-96. doi: 10.1016/j.tips.2015.02.008. 3. Friedman D, French JA, Maccarrone M. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol. 2019 May;18(5):504-512. doi: 10.1016/S1474-4422(19)30032-8.
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