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The endocannabinoid system and its therapeutic exploitation

Key Points

  • 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.


The term 'endocannabinoid' — originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Δ9-tetrahydrocannabinol and their endogenous ligands — now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.

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Figure 1: Chemical structures of some plant and synthetic cannabinoids.
Figure 2: Chemical structures of endocannabinoids.
Figure 3: Major signalling pathways associated with cannabinoid receptor activation by agonists.
Figure 4: Anabolic and catabolic pathways of endocannabinoids and their most likely subcellular localization.
Figure 5: Inhibitors of endocannabinoid inactivation.
Figure 6: Chemical structures of some therapeutically promising, patented drugs based on the endocannabinoid system.


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The work of the authors is currently supported by grants from the Ministry of Italian University and Research (MIUR, Fondo Italiano per la Ricerca di Base, to V.D.M.), the Volkswagen Stiftung (to V.D.M.), GW Pharm Ltd (to V.D.M., M.B. and L.D.P.), the Associazione Italiana per la Ricerca sul Cancro (AIRC, to M.B.) and the Associazione ERMES (to M.B.).

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Correspondence to Vincenzo Di Marzo.

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V.D.M, M.B. and L.D.P. receive research funding from G. W. Pharm and Sanofi-Synthelabo.

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CB1 receptor

CB2 receptor





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(THC). The major psychotropic component of Cannabis sativa, and one of about 66 'cannabinoids' found in the flowers of this plant.


Natural lipophilic products from the flower of Cannabis sativa, most of which have a typical bi-cyclic or tri-cyclic structure and a common biogenetic origin from olivetol.


G-protein-coupled receptors for THC, so far identified in most vertebrate phyla. Two subtypes are known: CB1 and CB2.


Endogenous agonists of cannabinoid receptors in animal organisms.


One of the most studied endocannabinoids, named from the Sanskrit word 'ananda' for 'bliss'.


A physiological action consisting of the capability of modulating neurotransmitter release and/or action.


Putative and elusive membrane protein(s) that has (have) been postulated to be capable of binding selectively to the endocannabinoids and to facilitate their transport across the plasma membrane according to concentration gradients.


Methodologies for quantifying the levels of the endocannabinoids and of cannabinoid receptors, consisting mostly of isotope-dilution mass-spectrometric techniques for anandamide and 2-AG, polymerase chain reaction and in situ hybridization techniques for receptor and enzyme mRNAs, western immunoblotting and immunohistochemistry for receptor and enzyme proteins.


A typical property of the production of endocannabinoids, which are made in the organism only 'when and where needed'.


Any plant or synthetic cannabinoid-like compound that does not induce, in animal models and in humans, the central cannabimimetic effects typical of THC.


Any receptor agonist that does not induce a full functional response in a given functional assay of receptor activation.

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Marzo, V., Bifulco, M. & Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3, 771–784 (2004).

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