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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.

Abstract

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.

References

  1. Adams, I. B. & Martin, B. R. Cannabis: pharmacology and toxicology in animals and humans. Addiction 91, 1585–1614 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Mechoulam, R. in Cannabis as Therapeutic Agent (ed. Mechoulam, R.) 1–19 (CRC Press Roca Ranton, 1986). The most comprehensive history of the recreational and medicinal use of Cannabis throughout the centuries.

    Google Scholar 

  3. Williamson, E. M. & Evans, F. J. Cannabinoids in clinical practice. Drugs 60 1303–1314 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Gaoni, Y. & Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647 (1964). The long-awaited conclusive chemical characterization of THC, the major psychoactive constituent of Cannabis.

    Article  CAS  Google Scholar 

  5. Walsh, D., Nelson, K. A. & Mahmoud, F. A. Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer 11, 137–143 (2003).

    Article  PubMed  Google Scholar 

  6. Devane, W. A., Dysarz, F. A., Johnson, M. R., Melvin, L. S. & Howlett, A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988). The first sound evidence for the existence of specific binding sites for THC.

    CAS  PubMed  Google Scholar 

  7. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Mechoulam, R. & Hanus, L. Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chem. Phys. Lipids 121, 35–43 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Di Marzo, V. & Fontana, A. Anandamide, an endogenous cannabinomimetic eicosanoid: 'killing two birds with one stone'. Prostaglandins Leukot. Essent. Fatty Acids 53, 1–11 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992). The study reporting the identification of the first endocannabinoid, anandamide.

    Article  CAS  PubMed  Google Scholar 

  12. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Commun. 215, 89–97 (1995).

    Article  CAS  Google Scholar 

  14. McAllister, S. D. & Glass, M. CB1 and CB2 receptor-mediated signalling: a focus on endocannabinoids. Prostaglandins Leukot. Essent. Fatty Acids 66, 161–171 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Di Marzo, V., De Petrocellis, L., Fezza, F., Ligresti, A. & Bisogno, T. Anandamide receptors. Prostaglandins Leukot. Essent. Fatty Acids 66, 377–391 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Piomelli, D. The molecular logic of endocannabinoid signalling. Nature Rev. Neurosci. 4, 873–884 (2003).

    Article  CAS  Google Scholar 

  17. De Petrocellis, L., Cascio, M. G. & Di Marzo, V. The endocannabinoid system: a general view and latest additions. Br. J. Pharmacol. 141, 765–774 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Pertwee, R. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther. 74, 129–180 (1997).

    CAS  PubMed  Google Scholar 

  19. Howlett, A. C. Pharmacology of cannabinoid receptors. Annu. Rev. Pharmacol. Toxicol. 35, 607–634 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Di Marzo, V., Melck, D., Bisogno, T. & De Petrocellis, L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Schlicker, E. & Kathmann, M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22, 565–572 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Wilson, R. I. & Nicoll, R. A. Endocannabinoid signaling in the brain. Science 296, 678–682 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Freund, T. F., Katona, I. & Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83, 1017–1066 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Parolaro, D. & Rubino, T. Is cannabinoid transmission involved in rewarding properties of drugs of abuse? Br. J. Pharmacol. 136, 1083–1084 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gerdeman, G. L., Partridge, J. G., Lupica, C. R. & Lovinger, D. M. It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci. 26, 184–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Iversen, L. & Chapman, V. Cannabinoids: a real prospect for pain relief? Curr. Opin. Pharmacol. 2, 50–55 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Randall, M. D., Harris, D., Kendall, D. A. & Ralevic, V. Cardiovascular effects of cannabinoids. Pharmacol. Ther. 95, 191–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Di Carlo, G. & Izzo, A. A. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert. Opin. Investig. Drugs 12, 39–49 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Schmid, K., Niederhoffer, N. & Szabo, B. Analysis of the respiratory effects of cannabinoids in rats. Naunyn Schmiedebergs Arch. Pharmacol. 368, 301–308 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Wenger, T. & Moldrich, G. The role of endocannabinoids in the hypothalamic regulation of visceral function. Prostaglandins Leukot. Essent. Fatty Acids 66, 301–307 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Park, B., McPartland, J. M. & Glass, M. Cannabis, cannabinoids and reproduction. Prostaglandins Leukot. Essent. Fatty Acids 70, 189–197 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Klein, T. W. et al. The cannabinoid system and immune modulation. J. Leukoc. Biol. 74, 486–496 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Guzman, M., Sanchez, C. & Galve-Roperh, I. Cannabinoids and cell fate. Pharmacol. Ther. 95, 175–184 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Di Marzo, V., Bisogno, T., De Petrocellis, L., Berger, A. & Mechoulam, R. in Biology of Marijuana (ed. Onaivi, E.) 125–173 (Harwood Academic, Reading, 2002).

    Google Scholar 

  35. Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003). An important study, together with reference 37, exemplifying the 'on-demand' character of endocannabinoid-mediated protective functions.

    Article  CAS  PubMed  Google Scholar 

  36. Kirkham, T. C., Williams, C. M., Fezza, F. & Di Marzo, V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br. J. Pharmacol. 136, 550–557 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Walker, J. M., Huang, S. M., Strangman, N. M., Tsou, K. & Sanudo-Pena, M. C. Pain modulation by release of the endogenous cannabinoid anandamide. Proc. Natl Acad. Sci. USA 96, 12198–12203 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001). The first study pointing to a role for the endocannabinoids as orexigenic mediators.

    Article  CAS  PubMed  Google Scholar 

  40. Cota, D. et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112, 423–431 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schabitz, W. R. et al. Release of fatty acid amides in a patient with hemispheric stroke: a microdialysis study. Stroke 33, 2112–2114 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Parmentier-Batteur, S., Jin, K., Mao, X. O., Xie, L. & Greenberg, D. A. Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J. Neurosci. 22, 9771–9775 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Panikashvili, D. et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Di Marzo, V., Hill, M. P., Bisogno, T., Crossman, A. R. & Brotchie, J. M. Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson's disease. FASEB J. 14, 1432–1438 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Maccarrone, M. et al. Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism. J. Neurochem. 85, 1018–1025 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Baker, D. et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 15, 300–302 (2001). The first example of the use of inhibitors of endocannabinoid inactivation as potential therapeutic agents.

    Article  CAS  PubMed  Google Scholar 

  47. Baker, D. et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404, 84–87 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Mazzola, C., Micale, V. & Drago, F. Amnesia induced by β-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade. Eur. J. Pharmacol. 477, 219–225 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Silverdale, M. A., McGuire, S., McInnes, A., Crossman, A. R. & Brotchie, J. M. Striatal cannabinoid CB1 receptor mRNA expression is decreased in the reserpine-treated rat model of Parkinson's disease. Exp. Neurol. 169, 400–406 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Berrendero, F. et al. Changes in cannabinoid CB1 receptors in striatal and cortical regions of rats with experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Synapse 41, 195–202 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Benito, C. et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. J. Neurosci. 23, 11136–11141 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lastres-Becker, I. et al. Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington's disease. Neuroreport 12, 2125–2129 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Denovan-Wright, E. M. & Robertson, H. A. Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington's disease mice. Neuroscience 98, 705–713 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Glass, M., Faull, R. L. & Dragunow, M. Loss of cannabinoid receptors in the substantia nigra in Huntington's disease. Neuroscience 56, 523–527 (1993). The first report of the possible involvement of cannabinoid receptors in a neurodegenerative disorder.

    Article  CAS  PubMed  Google Scholar 

  55. Bensaid, M. et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol. Pharmacol. 63, 908–914 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Ravinet Trillou, C. et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R345–R353 (2003).

    Article  PubMed  Google Scholar 

  57. Ravinet Trillou, C., Delgorge, C., Menet, C., Arnone, M. & Soubrie, P. CB1 cannabinoid receptor knockout in mice leads to leannes, resistence to diet-induced obesity and enhanced leptin sensitivity. Int. J. Obes. Relat. Metab. Disord. 28, 640–648 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Wagner, J. A. et al. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 390, 518–521 (1997). Possibly the first example of a pathological condition involving an altered endocannabinoid system.

    Article  CAS  PubMed  Google Scholar 

  59. Varga, K., Wagner, J. A., Bridgen, D. T. & Kunos, G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J. 12, 1035–1044 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Batkai, S. et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nature Med. 7, 827–832 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Wagner, J. A. et al. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J. Am. Coll. Cardiol. 38, 2048–2054 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Izzo, A. A. et al. Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br. J. Pharmacol. 134, 563–570 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Izzo, A. A. et al. An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice. Gastroenterology 125, 765–774 (2003). A typical example of a protective role played 'on demand' by endocannabinoids in a peripheral organ.

    Article  CAS  PubMed  Google Scholar 

  64. Mascolo, N. et al. The endocannabinoid system and the molecular basis of paralytic ileus in mice. FASEB J. 16, 1973–1975 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Massa, F. et al. The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Invest. 113, 1202–1209 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang, H. et al. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proc. Natl Acad. Sci. USA 100, 14914–14919 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Maccarrone, M. et al. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355, 1326–1329 (2000). The first human study pointing to the possible pathological consequences of over-active endocannabinoid signalling.

    Article  CAS  PubMed  Google Scholar 

  68. Maccarrone, M. et al. Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer. Mol. Hum. Reprod. 8, 188–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Ligresti, A. et al. Possible endocannabinoid control of colorectal cancer growth. Gastroenterology 125, 677–687 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Schmid, P. C., Wold, L. E., Krebsbach, R. J., Berdyshev, E. V. & Schmid, H. H. Anandamide and other N-acylethanolamines in human tumors. Lipids 37, 907–912 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Sanchez, C. et al. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 61, 5784–5789 (2001).

    CAS  PubMed  Google Scholar 

  72. De Petrocellis, L. et al. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc. Natl Acad. Sci. USA 95, 8375–8380 (1998). The antiproliferative effects of the endocannabinoids against cancer cells in vitro were examined for the first time in this study. Together with reference 73, this marked the beginning of studies on the possible anticancer function of the endocannabinoid system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Galve-Roperh, I. et al. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Med. 6, 313–319 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Bifulco, M. et al. Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. FASEB J. 15, 2745–2747 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Casanova, M. L. et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J. Clin. Invest. 111, 43–50 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Portella, G. et al. Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J. 17, 1771–1773 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Bifulco, M. et al. A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J. 2 August 2004 (doi:10-1096/fj.04-1754fje).

  78. Alberich Jorda, M. et al. The peripheral cannabinoid receptor CB2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner. Blood 104, 526–534 (2004).

    Article  PubMed  CAS  Google Scholar 

  79. Cravatt, B. F. & Lichtman, A. H. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr. Opin. Chem. Biol. 7, 469–475 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994). First proof that the endocannabinoid anandamide is an endogenous mediator in that it can be produced by neurons in an activity-dependent manner and inactivated by both neurons and astrocytes.

    Article  CAS  PubMed  Google Scholar 

  81. Di Marzo, V., De Petrocellis, L. Sepe, N. & Buono, A. Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. Biochem. J. 316, 977–984 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bisogno, T. et al. Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Biochem. J. 322, 671–677 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Schmid, P. C., Reddy, P. V., Natarajan, V. & Schmid, H. H. Metabolism of N-acylethanolamine phospholipids by a mammalian phosphodiesterase of the phospholipase D type. J. Biol. Chem. 258, 9302–9306 (1983).

    Article  CAS  PubMed  Google Scholar 

  85. Okamoto, Y., Morishita, J., Tsuboi, K., Tonai, T. & Ueda, N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J. Biol. Chem. 279, 5298–5305 (2004). Cloning of the major enzyme catalysing anandamide biosynthesis.

    Article  CAS  PubMed  Google Scholar 

  86. Sugiura, T. et al. Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. Eur. J. Biochem. 240, 53–62 (1996).

    Article  CAS  PubMed  Google Scholar 

  87. Cadas, H., di Tomaso, E. & Piomelli, D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17, 1226–1242 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bisogno, T. et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol. 163, 463–468 (2003). Reports the cloning of the first enzymes catalysing the biosynthesis of an endocannabinoid, 2-arachidonoylglycerol.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Williams, E. J., Walsh, F. S. & Doherty, P. The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J. Cell Biol. 160, 481–486 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fernandez-Ruiz, J., Berrendero, F., Hernandez, M. L. & Ramos, J. A. The endogenous cannabinoid system and brain development. Trends Neurosci. 23, 14–20 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Lichtman, A. H., Shelton, C. C., Advani, T. & Cravatt, B. F. Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109, 319–327 (2004). An important study confirming conclusively that FAAH can be targeted for the development of new antihyperalgesic drugs.

    Article  CAS  PubMed  Google Scholar 

  92. Clement, A. B., Hawkins, E. G., Lichtman, A. H. & Cravatt, B. F. Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase. J. Neurosci. 23, 3916–3923 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sipe, J. C., Chiang, K., Gerber, A. L., Beutler, E. & Cravatt, B. F. A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc. Natl Acad. Sci. USA 99, 8394–8399 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ligresti, A. et al. Further evidence for the specific process for the membrane transport of anandamide. Biochem. J. 380, 265–272 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hillard, C. J., Edgemond, W. S., Jarrahian, A. & Campbell, W. B. Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J. Neurochem. 69, 631–638 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Bisogno, T., Maurelli, S., Melck, D., De Petrocellis, L. & Di Marzo, V. Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J. Biol. Chem. 272, 3315–3323 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Bracey, M. H., Hanson, M. A., Masuda, K. R., Stevens, R. C. & Cravatt, B. F. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298, 1793–1796 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Glaser, S. T. et al. Evidence against the presence of an anandamide transporter. Proc. Natl Acad. Sci. USA 100, 4269–4274 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ortar, G., Ligresti, A., De Petrocellis, L., Morera, E. & Di Marzo, V. Novel selective and metabolically stable inhibitors of anandamide cellular uptake. Biochem. Pharmacol. 65, 1473–1481 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Lopez-Rodriguez, M. L. et al. Design, synthesis, and biological evaluation of new inhibitors of the endocannabinoid uptake: comparison with effects on fatty acid amidohydrolase. J. Med. Chem. 46, 1512–1522 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Fegley, D. et al. Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proc. Natl Acad. Sci. USA (in the press).

  103. Hillard, C. J. & Jarrahian, A. Cellular accumulation of anandamide: consensus and controversy. Br. J. Pharmacol. 140, 802–808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996). Reports the cloning of the first 'endocannabinoid enzyme', FAAH, a potential therapeutic target for analgesic and anxiolytic compounds.

    Article  CAS  PubMed  Google Scholar 

  105. Cravatt, B. F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl Acad. Sci. USA 98, 9371–9376 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Martin, B. R. et al. Cannabinoid properties of methylfluorophosphonate analogs. J. Pharmacol. Exp. Ther. 294, 1209–1218 (2000).

    CAS  PubMed  Google Scholar 

  107. Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 9, 76–81 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Leung, D., Hardouin, C., Boger, D. L. & Cravatt, B. F. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. Nature Biotechnol. 21, 687–691 (2003).

    Article  CAS  Google Scholar 

  109. Karlsson, M., Contreras, J. A., Hellman, U., Tornqvist, H. & Holm, C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J. Biol. Chem. 272, 27218–27223 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ben-Shabat, S. et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23–31 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Hanus, L. et al. HU-308: a specific agonist for CB2, a peripheral cannabinoid receptor. Proc. Natl Acad. Sci. USA 96, 14228–14233 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ibrahim, M. M. et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl Acad. Sci. USA 100, 10529–10533 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. McKallip, R. J. et al. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100, 627–634 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 240–244 (1994). Describes the development of the first selective cannabinoid CB 1 -receptor antagonist, rimonabant, which is now in Phase III clinical trials being tested as an anti-obesity agent and against nicotine dependence.

    Article  CAS  PubMed  Google Scholar 

  116. Pinto, L. et al. Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology 123, 227–234 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Van Sickle, M. D. et al. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology 121, 767–774 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Darmani, N. A. Δ(9)-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A Neuropsychopharmacology 24, 198–203 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Cichewicz, D. L. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 74, 1317–1324 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Naef, M. et al. The analgesic effect of oral Δ-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 105, 79–88 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Di Marzo, V. et al. Neurobehavioral activity in mice of N-vanillyl-arachidonyl-amide. Eur. J. Pharmacol. 406, 363–374 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Di Marzo, V. et al. Highly selective CB1 cannabinoid receptor ligands and novel CB1/VR1 vanilloid receptor 'hybrid' ligands. Biochem. Biophys. Res. Commun. 281, 444–451 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Brooks, J. W. et al. Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB1/CB2 receptors. Eur. J. Pharmacol. 439, 83–92 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Melck, D. et al. Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors. Biochem. Biophys. Res. Commun. 262, 275–284 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Wiley, J. L. et al. Paradoxical pharmacological effects of deoxy-tetrahydrocannabinol analogs lacking high CB1 receptor affinity. Pharmacology 66, 89–99 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Ross, R. A. et al. Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630. Br. J. Pharmacol. 126, 665–672 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. De Vry, J. M. et al. 3-[2-Cyano-3-(trifluoromethyl)phenoxy]phenyl 4,4,4-trifluoro-1-butanesulfonate (BAY 59-3074): a novel cannabinoid CB1/CB2 receptor partial agonist with antihyperalgesic and anti-allodynic effects. J. Pharmacol. Exp. Ther. 310, 620–632 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Pertwee, R. G. in Cannabinoids (ed. Di Marzo, V.) 32–83 (Kluwer Academic, New York, 2004).

    Google Scholar 

  129. Wade, D. T., Robson, P., House, H., Makela, P. & Aram, J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin. Rehabil. 17, 21–29 (2003).

    Article  PubMed  Google Scholar 

  130. Cannabis-based medicines — GW pharmaceuticals: high CBD, high THC, medicinal cannabis — GW pharmaceuticals, THC:CBD. Drugs RD 4, 306–309 (2003).

  131. Pop, E. Dexanabinol Pharmos. Curr. Opin. Investig. Drugs 1, 494–503 (2000).

    CAS  PubMed  Google Scholar 

  132. Burstein, S. H. Ajulemic acid (CT3): a potent analog of the acid metabolites of THC. Curr. Pharm. Des. 6, 1339–1345 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Sumariwalla, P. F. et al. A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis Rheum. 50, 985–998 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Bisogno, T. et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol. 134, 845–852 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Feigenbaum, J. J. et al. Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. Proc. Natl Acad. Sci. USA 86, 9584–9587 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu, J., Li, H., Burstein, S. H., Zurier, R. B. & Chen, J. D. Activation and binding of peroxisome proliferator-activated receptor-γ by synthetic cannabinoid ajulemic acid. Mol. Pharmacol. 63, 983–992 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Lange, J., Kruse, C., Tipker, J., Tulp, M. & van Vliet, B. (Solvay Pharmaceuticals) 4,5-Dihydro-1H-pyrazole derivatives having CB1-antagonistic activity. WO0170700 (2001).

  138. Makrijannis, A. & Deng, H. (Univ. Connecticut) Cannabimimetic indole derivatives. WO0128557 (2001).

  139. Makrijannis, A. & Deng, H. (Univ. Connecticut) Retro-anandamides, high affinity and stability cannabinoid receptor ligands. WO0128498 (2001).

  140. Mauler, F. et al. BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury. CNS Drug Rev. 9, 343–358 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rinaldi-Carmona, M. et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644–650 (1998).

    CAS  PubMed  Google Scholar 

  142. Iwamura, H., Suzuki, H., Ueda, Y., Kaya, T. & Inaba, T. In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. J. Pharmacol. Exp. Ther. 296, 420–425 (2001).

    CAS  PubMed  Google Scholar 

  143. Pertwee, R. G. et al. O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. Br. J. Pharmacol. 129, 1577–1584 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zajicek, J. et al. UK MS Research Group. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362, 1517–1526 (2003). The first very large controlled clinical study with THC and Cannabis extract as potential treatments for a human disorder.

    Article  CAS  PubMed  Google Scholar 

  145. Muller-Vahl, K. R. et al. Δ9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J. Clin. Psychiatry 64, 459–465 (2003).

    Article  PubMed  Google Scholar 

  146. Sieradzan, K. A. et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 57, 2108–2111 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Fox, S. H., Kellett, M., Moore, A. P., Crossman, A. R. & Brotchie, J. M. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Mov. Disord. 17, 145–149 (2002).

    Article  PubMed  Google Scholar 

  148. Porcella, A., Maxia, C., Gessa, G. L. & Pani, L. The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. Eur. J. Neurosci. 13, 409–412 (2001).

    Article  CAS  PubMed  Google Scholar 

  149. Buggy, D. J. et al. Lack of analgesic efficacy of oral Δ-9-tetrahydrocannabinol in postoperative pain. Pain 106, 169–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  150. Abrams, D. I. et al. Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Ann. Intern. Med. 139, 258–266 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Grant, I., Gonzalez, R., Carey, C. L., Natarajan, L. & Wolfson, T. Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J. Int. Neuropsychol. Soc. 9, 679–689 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. James, J. S. Marijuana safety study completed: weight gain, no safety problems. AIDS Treat. News 348, 3–4 (2000).

    Google Scholar 

  153. Tramer, M. R. et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323, 16–21 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Karst, M. et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 290, 1757–1762 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Knoller, N. et al. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit. Care Med. 30, 548–554 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Di Marzo, V. et al. Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur. J. Biochem. 264, 258–267 (1999).

    Article  CAS  PubMed  Google Scholar 

  157. Chevaleyre, V. & Castillo, P. E. Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003). The first study pointing to a possible functional difference between 2-AG and anandamide in the modulation of synaptic neurotransmission.

    Article  CAS  PubMed  Google Scholar 

  158. Egertova, M., Cravatt, B. F. & Elphick, M. R. Comparative analysis of fatty acid amide hydrolase and CB1 cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience 119, 481–496 (2003).

    Article  CAS  PubMed  Google Scholar 

  159. Hanus, L. et al. 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl Acad. Sci. USA 98, 3662–3665 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Porter, A. C. et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther. 301, 1020–1024 (2002).

    Article  CAS  PubMed  Google Scholar 

  161. Huang, S. M. et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl Acad. Sci. USA 99, 8400–8405 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Martin, B. R., Mechoulam, R. & Razdan, R. K. Discovery and characterization of endogenous cannabinoids. Life Sci. 65, 573–595 (1999).

    Article  CAS  PubMed  Google Scholar 

  163. Bisogno, T. et al. Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. Biochem. Biophys. Res. Commun. 248, 515–522 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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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DATABASES

Entrez

CB1 receptor

CB2 receptor

FAAH

NAPE-PLD

PPAR-γ

TRPV1

Online Mendelian Inheritance in Man

Alzheimer's disease

Huntington's chorea

multiple sclerosis

Parkinson's disease

Tourettes's syndrome

Glossary

Δ9-TETRAHYDROCANNABINOL

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

CANNABINOIDS

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.

CANNABINOID RECEPTORS

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

ENDOCANNABINOIDS

Endogenous agonists of cannabinoid receptors in animal organisms.

ANANDAMIDE

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

NEUROMODULATORY

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

ENDOCANNABINOID MEMBRANE TRANSPORTER(S)

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.

ANALYTICAL TECHNIQUES FOR ENDOCANNABINOID STUDIES

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.

'ON DEMAND'

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

NON-PSYCHOTROPIC CANNABINOID

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

PARTIAL AGONIST

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). https://doi.org/10.1038/nrd1495

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