Article series: The endocannabinoid system

Early phytocannabinoid chemistry to endocannabinoids and beyond

Journal name:
Nature Reviews Neuroscience
Year published:
Published online


Isolation and structure elucidation of most of the major cannabinoid constituents — including Δ9-tetrahydrocannabinol (Δ9-THC), which is the principal psychoactive molecule in Cannabis sativa — was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.

At a glance


  1. Cannabinoid and endocannabinoid research [mdash] a timeline.
    Figure 1: Cannabinoid and endocannabinoid research — a timeline.

    Almost all early research was devoted to clarification of cannabinoid chemistry3, 4, 104, 105, and pharmacology was mainly done using synthetic compounds5. Following the isolation and structure elucidation of the plant cannabinoids, particularly of cannabidiol106 and of Δ9-tetrahydrocannabinol (Δ9-THC)6, pharmacological and physiological work was initiated8, 9, 15. The identification of cannabinoid receptors24, 29, 31, of endogenous cannabinoids30, 32, 107 and of receptor antagonists50, 66 made possible extensive pharmacological and neurobiological research leading to cloning of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH)108, the discovery of retrograde signaling by 2-arachidonoyl glycerol (2-AG)45, the discovery of allosteric sites on cannabinoid receptor 1 (CB1)33, the discovery that endocannabinoids bind to receptors other than CB1 and CB2 (Refs 109,110,111), the discovery and evaluation of endocannabinoid-like molecules in the brain95, 96 and the discovery and function of inhibitors of the endocannabinoid-degrading enzymes112, 113. Cell biology114 and neuroscience115, 116 investigations were also carried out, and clinical trials were initiated101, 117, 118. Cloning of DAG lipase was also reported119.

  2. A major metabolic pathway of [Delta]9-THC and the structures of some plant and synthetic cannabinoids.
    Figure 2: A major metabolic pathway of Δ9-THC and the structures of some plant and synthetic cannabinoids.

    a | The major psychoactive cannabis constituent, Δ9-tetrahydrocannabinol (Δ9-THC), is first metabolized by enzymatic hydroxylation to produce psychoactive 11-hydroxy-Δ9-THC (11-OH-Δ9-THC) and then by enzymatic oxidation to non-psychoactive Δ9-THC-11-oic acid, which is stored in fatty tissues as a glucuronide and is slowly released. The glucuronide may be detected in the urine for several weeks after a single cannabis use. b | The structures of some plant and synthetic cannabinoids. Δ9-THC, the plant constituents cannabinol and Δ8-THC, and synthetic Δ6a,10a-THC and CP-55940 cause cannabis-type psychoactivity, wherease cannabidiol does not.

  3. Structures of the main endocannabinoids, anandamide and 2-AG, which bind to CB1 and CB2 endocannabinoid receptors.
    Figure 3: Structures of the main endocannabinoids, anandamide and 2-AG, which bind to CB1 and CB2 endocannabinoid receptors.

    Arachidonoyl ethanolamide (also known as anandamide) and 2-arachidonoyl glycerol (2-AG) are hydrolysed to arachidonic acid by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Blocking these enzymes with various synthetic compounds leads to increased levels of these endocannabinoids.


  1. Mechoulam, R. in Cannabinoids as Therapeutic Agents, (ed. Mechoulam, R.), 119 (CRC Press Inc., 1986).
  2. O'Shaugnessy, W. B. in The Bengal Dispensatory and Pharmacopoeia, 579 (Bishop's College Press, 1841).
  3. Adams, R. Marihuana. Harvey Lectures 37, 168197 (19411942).
  4. Todd, A. R. Hashish. Experientia 2, 5560 (1946).
  5. Loewe, S. Cannabiswirkstoffe und Pharmacologie der Cannabinole. Arch. Exp. Pathol. Pharmacol. 211, 175193 (1950).
  6. Gaoni, Y. & Mechoulam, R. Isolation, structure and partial synthesis of an active constituent of hashish. J. Amer. Chem. Soc. 86, 16461647 (1964).
  7. Mechoulam, R., McCallum, N. K. & Burstein, S. Recent advances in the chemistry and biochemistry of cannabis. Chem. Rev. 76, 75112 (1976).
  8. Agurell, S. et al. Pharmacokinetics and metabolism of Δ-1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol. Rev. 38, 2143 (1986).
  9. Pertwee, R. G. The ring test: a quantitative method for assessing the 'cataleptic' effect of cannabis in mice. Br. J. Pharmacol. 46, 753763 (1972).
  10. Pertwee, R. G. Cannabinoid pharmacology: the first 66 years. Br. J. Pharmacol. 147, S163S171 (2006).
  11. Pertwee, R. G. The central neuropharmacology of psychotropic cannabinoids. Pharmacol. Ther. 36, 189261 (1988).
  12. Pertwee, R. G. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol. 156, 397411 (2009).
  13. Mechoulam, R. et al. Stereochemical requirements for cannabinoid activity. J. Med. Chem. 23, 10681072 (1980).
  14. Mechoulam, R. et al. Enantiomeric cannabinoids: stereospecificity of psychotropic activity. Experientia 44, 762764 (1988).
  15. Dewey, W. L. Cannabinoid pharmacology. Pharmacol. Rev. 38, 151178 (1986).
  16. Hollister, L. E. Health aspects of cannabis. Pharmacol. Rev. 38, 120 (1986).
  17. Klee, W. A., Sharma, S. K. & Nirenberg, M. Opiate receptors as regulators of adenylate cyclase. Life Sci. 16, 18691874 (1975).
  18. Nathanson, N. M., Klein, W. L. & Nirenberg, M. Regulation of adenylate cyclase activity mediated by muscarinic acetylcholine receptors. Proc. Natl Acad. Sci. USA 75, 17881791 (1978).
  19. Sabol, S. L. & Nirenberg, M. Regulation of adenylate cyclase of neuroblastoma x glioma hybrid cells by α-adrenergic receptors. I. Inhibition of adenylate cyclase mediated by α receptors. J. Biol. Chem. 254, 19131920 (1979).
  20. Howlett, A. C. & Fleming, R. M. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol. Pharmacol. 26, 532538 (1984).
  21. Howlett, A. C. Inhibition of neuroblastoma adenylate cyclase by cannabinoid and nantradol compounds. Life Sci. 35, 18031810 (1984).
  22. Howlett, A. C. Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. Mol. Pharmacol. 27, 429436 (1985).
  23. Howlett, A. C., Qualy, J. M. & Khachatrian, L. L. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol. Pharmacol. 29, 307313 (1986).
  24. Howlett, A. C., Champion, T. M., Wilken, G. H. & Mechoulam, R. Stereochemical effects of 11-OH-Δ 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor. Neuropharmacology 29, 161165 (1990).
  25. Melvin, L. S. et al. Structure–activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. Mol. Pharmacol. 44, 10081015 (1993).
  26. Melvin, L. S., Milne, G. M., Johnson, M. R., Wilken, G. H. & Howlett, A. C. Structure–activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity. Drug Des. Discov. 13, 155166 (1995).
  27. Devane, W. A., Dysarz F. A. 3rd, Johnson M. R., Melvin L. S. & Howlett A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605613 (1988).
  28. Gerard, C., Mollereau, C., Vassart, G. & Parmentier, M. Nucleotide sequence of a human cannabinoid receptor cDNA. Nucleic Acids Res. 18, 7142 (1990).
  29. 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, 561564 (1990).
  30. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 19461949 (1992).
  31. Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 6165 (1993).
  32. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 8390 (1995).
  33. Pertwee, R. G. et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol. Rev. 62, 588631 (2010).
  34. Pamplona, F. A. et al. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc. Natl Acad. Sci. USA 109, 2113421139 (2012).
  35. Bauer, M. et al. Identification and quantification of a new family of peptide endocannabinoids (pepcans) showing negative allosteric modulation at CB1 receptors. J. Biol. Chem. 287, 3694436967 (2012).
  36. Heimann, A. S. et al. Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc. Natl Acad. Sci. USA 104, 2058820593 (2007).
  37. Huffman, J. W. et al. Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J. Med. Chem. 39, 38753877 (1996).
  38. Hanuš, L. et al. HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor. Proc. Natl Acad. Sci. USA 96, 1422814233 (1999).
  39. Anand, P., Whiteside, G., Fowler, C. J. & Hohmann, A. G. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res. Rev. 60, 255266 (2009).
  40. Fernandez-Ruiz, J., Pazos, M. R., Garcia-Arencibia, M., Sagredo, O. & Ramos, J. A. Role of CB2 receptors in neuroprotective effects of cannabinoids. Mol. Cell. Endocrinol. 286, S91S96 (2008).
  41. Marriott, K. S. & Huffman, J. W. Recent advances in the development of selective ligands for the cannabinoid CB2 receptor. Curr. Top. Med. Chem. 8, 187204 (2008).
  42. Pacher, P. & Mechoulam, R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Progr. Lipid Res. 50, 193211 (2011).
  43. Horváth, B. et al. A new cannabinoid 2 receptor agonist HU-910 attenuates oxidative stress, inflammation, and cell death associated with hepatic ischemia/reperfusion injury. Br. J. Pharmacol. 165, 24622478 (2012).
  44. Di Marzo, V., De Petrocellis, L. & Bisogno, T. in Cannabinoids. Handbook of Expermimental Pharmacology (ed. Pertwee, R. G.) 168, 147185 (Springer, 2005).
  45. Wilson, R. I. & Nicoll R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588592 (2001).
  46. Vaughan, C. W. & Christie, M. J. in Cannabinoids. Handbook of Expermimental Pharmacology (ed. Pertwee, R. G.) 168, 367383 (Springer, 2005).
  47. Ohno-Shosaku, T., Tanimura, A., Hashimotodani, Y. & Kano, M. Endocannabinoids and retrograde modulation of synaptic transmission. Neuroscientist 18, 119132 (2012).
  48. Alger, B. E. Endocannabinoids at the synapse a decade after the dies mirabilis: what we still do not know. J. Physiol. 590, 22032212 (2012).
  49. Gregg, L. C. et al. Activation of type 5 metabotropic glutamate receptors and diacylglycerol lipase-α initiates 2-arachidonoylglycerol formation and endocannabinoid-mediated analgesia. J. Neurosci. 32, 94579468 (2012).
  50. Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 240244 (1994).
  51. Rinaldi-Carmona, M. et al. Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain. Life Sci. 58, 12391247 (1996).
  52. Mathews, W. B. et al. Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors. Nucl. Med. Biol. 27, 757762 (2000).
  53. Bouaboula, M. et al. Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J. Biol. Chem. 270, 1397313980 (1995).
  54. Bouaboula, M. et al. Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. 312, 637641 (1995).
  55. Bouaboula, M. et al. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J. Biol. Chem. 272, 2233022339 (1997).
  56. Compton, D. R., Aceto, M. D., Lowe, J. & Martin, B. R. In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of Δ 9-tetrahydrocannabinol-induced responses and apparent agonist activity. J. Pharmacol. Exp. Ther. 277, 586594 (1996).
  57. Gueudet, C., Santucci, V., Rinaldi-Carmona, M., Soubrie, P. & Le Fur, G. The CB1 cannabinoid receptor antagonist SR141716A affects A9 dopamine neuronal activity in the rat. Neuroreport 6, 14211425 (1995).
  58. Perio, A. et al. Central mediation of the cannabinoid cue: activity of a selective CB1 antagonist, SR141716A. Behav. Pharmacol. 7, 6571 (1996).
  59. Aceto, M. D., Scates, S. M., Lowe, J. A. & Martin, B. R. Cannabinoid precipitated withdrawal by the selective cannabinoid receptor antagonist, SR141716A. Eur. J. Pharmacol. 282, R1R2 (1995).
  60. Tsou, K., Patrick, S. L. & Walker, J. M. Physical withdrawal in rats tolerant to Δ 9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. Eur. J. Pharmacol. 280, R13R15 (1995).
  61. Felder, C. C. et al. LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J. Pharmacol. Exp. Ther. 284, 291297 (1998).
  62. Meschler, J. P., Kraichely, D. M., Wilken, G. H. & Howlett, A. C. Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) for the CB1 cannabinoid receptor. Biochem. Pharmacol. 60, 13151323 (2000).
  63. Cosenza, M. et al. Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281. Synapse 38, 477482 (2000).
  64. Lan, R. et al. Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand. AAPS Pharm. Sci. 1, E4 (1999).
  65. Pertwee, R. et al. AM630, a competitive cannabinoid receptor antagonist. Life Sci. 56, 19491955 (1995).
  66. Rinaldi-Carmona, M. et al. SR144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644650 (1998).
  67. Cascio, M. G. et al. In vitro and in vivo pharmacological characterization of two novel selective cannabinoid CB2 receptor inverse agonists. Pharmacol. Res. 61, 349354 (2010).
  68. Miller, A. M. & Stella, N. CB2 receptor-mediated migration of immune cells: it can go either way. Br. J. Pharmacol. 153, 299308 (2008).
  69. Fernandez-Ruiz, J. et al. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol. Sci. 28, 3945 (2007).
  70. Wright, K. L., Duncan, M. & Sharkey, K. A. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br. J. Pharmacol. 153, 263270 (2008).
  71. Lunn, C. A. et al. Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists. Br. J. Pharmacol. 153, 226239 (2008).
  72. Scheen, A. J. et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368, 16601672 (2006).
  73. Nissen, S. E. et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299, 15471560 (2008).
  74. Van Gaal, L. F., Rissanen, A. M., Scheen, A. J., Ziegler, O. & Rossner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 13891397 (2005).
  75. Moreira, F. A., Grieb, M. & Lutz, B. Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract. Res. Clin. Endocrinol. Metab. 23, 133144 (2009).
  76. Nathan, P. J., O'Neill, B. V., Napolitano, A. & Bullmore, E. T. Neuropsychiatric adverse effects of centrally acting antiobesity drugs. CNS Neurosci. Ther. 17, 490505 (2011).
  77. Di Marzo, V. & Despres, J. P. CB1 antagonists for obesity — what lessons have we learned from rimonabant? Nature Rev. Endocrinol. 5, 633638 (2009).
  78. Kirilly, E., Gonda, X. & Bagdy, G. CB1 receptor antagonists: new discoveries leading to new perspectives. Acta Physiol. 205, 4160 (2012).
  79. Tam, J. et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell. Metab. 16, 167179 (2012).
  80. Lazary, J., Juhasz, G., Hunyady, L. & Bagdy, G. Personalized medicine can pave the way for the safe use of CB1 receptor antagonists. Trends Pharmacol. Sci. 32, 270280 (2011).
  81. Blankman, J. L. & Cravatt, B. F. Chemical probes of endocannabinoid metabolism. Pharmacol. Rev. 65, 849871 (2013).
  82. Pertwee, R. G. Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc. Nutr. Soc. 73, 96105 (2014).
  83. Pertwee, R. G. The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J. 7, E625E654 (2005).
  84. Pacher, P. & Kunos, G. Modulating the endocannabinoid system in human health and disease — successes and failures. FEBS J. 280, 19181943 (2013).
  85. Pertwee, R. G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br. J. Pharmacol. 153, 199215 (2008).
  86. Pertwee, R. G. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem. 17, 13601381 (2010).
  87. Pertwee, R. G. & Cascio, M. G. in Handbook of Cannabis (ed. Pertwee, R. G.) 115136 (Oxford University Press, 2014).
  88. Pertwee, R. G. Pharmacology of cannabinoid receptor ligands. Curr. Med. Chem. 6, 635664 (1999).
  89. McHugh, D., Page, J., Dunn, E. & Bradshaw, H. B. Δ9-Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br. J. Pharmacol. 165, 24142424 (2012).
  90. De Petrocellis, L. et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 163, 14791494 (2011).
  91. Di Marzo, V. A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the work of British scientists. Trends Pharmacol. Sci. 27, 134140 (2006).
  92. Howlett, A. C., Blume, L. C. & Dalton, G. D. CB1 cannabinoid receptors and their associated proteins. Curr. Med. Chem. 17, 13821393 (2010).
  93. Smith, T. H., Sim-Selley, L. J. & Selley, D. E. Cannabinoid CB1 receptor-interacting proteins: novel targets for central nervous system drug discovery? Br. J. Pharmacol. 160, 454466 (2010).
  94. Tan, B. et al. Targeted lipidomics: discovery of new fatty acyl amides. AAPS J. 8, E461E465 (2006).
  95. Tan, B. et al. Identification of endogenous acyl amino acids based on a targeted lipidomics approach. J. Lipid Res. 51, 112119 (2010).
  96. Milman, G. et al. N-Arachidonoyl l-serine, a novel endocannabinoid-like brain constituent with vasodilatory properties. Proc. Natl Acad. Sci. USA 103, 24282433 (2006).
  97. Cohen-Yeshurun, A. et al. N-Arachidonoyl-l-serine is neuroprotective after traumatic brain injury by reducing apoptosis. J. Cereb. Blood Flow Metab. 31, 17681777 (2011).
  98. Cohen-Yeshurun, A. et al. N-arachidonoyl-l-serine (AraS) possesses pro-neurogenic properties in vitro and in vivo following traumatic brain injury. J. Cereb. Blood Flow Metab. 33, 12421250 (2013).
  99. Pucci, M. et al. Epigenetic control of skin differentiation genes by phytocannabinoids. Br. J. Pharmacol. 170, 581591 (2013).
  100. Pasquariello, N., Oddi, S., Malaponti, M. & Maccarrone, M. Regulation of gene transcription and keratinocyte differentiation by anandamide. Vitam. Horm. 81, 441467 (2009).
  101. Leweke, F. M. et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2, e94 (2012).
  102. Porter, B. E. & Jacobson, C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 29, 574577 (2013).
  103. Cunha, J. M. et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacol. 21, 175185 (1980).
  104. Wood, T. B., Spivey, W. T. N. & Easterfield, T. H. Cannabinol. Part I. J. Chem. Soc. 75, 2036 (1899).
  105. Cahn, R. S. Cannabis indica resin, Part, III The constitution of Cannabinol. J. Chem. Soc. 13421353 (1932).
  106. Mechoulam, R. & Shvo, Y. The structure of cannabidiol. Tetrahedron 19, 20732078 (1963).
  107. Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 8997 (1995).
  108. Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 8387 (1996).
  109. Zygmunt, P. M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452457 (1999).
  110. Smart, D. et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol. 129, 227230 (2000).
  111. Piomelli, D. A fatty gut feeling. Trends Endocrinol. Metab. 24, 332341 (2013).
  112. Bandiera, T., Ponzano, S. & Piomelli, D. Advances in the discovery of N-acylethanolamine acid amidase inhibitors. Pharmacol. Res. 86C, 1117 (2014).
  113. Schlosburg, J. E. et al. Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice. J. Pharmacol. Exp. Ther. 350, 196204 (2014).
  114. Galve-Roperh, I. et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog. Lipid Res. 52, 633650 (2013).
  115. Katona, I. & Freund, T. F. Multiple functions of endocannabinoid signaling in the brain. Annu. Rev. Neurosci. 35, 529558 (2012).
  116. Piomelli, D. & Sasso, O. Peripheral gating of pain signals by endogenous lipid mediators. Nature Neurosci. 17, 164174 (2014).
  117. Syed, Y. Y., McKeage, K. & Scott, L. J. Δ-9-tetrahydrocannabinol/cannabidiol (Sativex): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs 74, 563578 (2014).
  118. Roitman, P., Mechoulam, R., Cooper-Kazaz, R. & Shalev, A. Preliminary, open-label, pilot study of add-on oral δ(9)-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin. Drug Investig. 34, 587591 (2014).
  119. 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, 463468 (2003).

Download references

Author information


  1. Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, 91120, Israel.

    • Raphael Mechoulam
  2. Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, 91120, Israel.

    • Lumír O. Hanuš
  3. Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.

    • Roger Pertwee
  4. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, One Medical Center Blvd, Winston-Salem, North Carolina 27157, USA.

    • Allyn C. Howlett

Competing interests statement

The authors declare no competing interests.

Corresponding author

Correspondence to:

Author details

  • Raphael Mechoulam

    Raphael Mechoulam studied for his M.Sc in biochemistry at the Hebrew University in Jerusalem, Israel and studied for his Ph.D. in organic chemistry at the Weizmann Institute in Rehovot, Israel. He is Professor Emeritus in the Faculty of Medicine at the Hebrew University and is a member of the Israel Academy of Sciences. His research over the years has focused on the chemistry and pharmacology of natural products, mainly on cannabinoids and endocannabinoids. He has received numerous awards.

  • Lumír O. Hanuš

    Lumír O. Hanuš earned his M.S. and Ph.D. in analytical chemistry at Palacký University, Olomouc, Czech Republic, in 1972 and his D.Sc. in pharmaceutical chemistry at Charles University, Prague, Czech Republic, in 1995. Between 1971 and 1990 he was Associate Professor in the Medical Faculty, Palacký University. Between 1978 and 1979 he was a research associate at the School of Pharmacy, University of Mississippi, USA. Since 1990 he has been a research fellow at the Hebrew University in Jerusalem, Israel.

  • Roger Pertwee

    Roger Pertwee is Professor of Neuropharmacology at the University of Aberdeen, UK. His research has mainly focused on the pharmacology of cannabinoids, first at the University of Oxford, UK, and then at Aberdeen. He has received several awards, including the 2011 Wellcome Gold Medal from the British Pharmacological Society “for outstanding contributions to pharmacology, based mainly on research achievements”.

  • Allyn C. Howlett

    Allyn C. Howlett earned her Ph.D. in Phamacology and Toxicology at Rutgers University, New Jersey, USA, and carried out her postdoctoral studies with Alfred G. Gilman at the University of Virginia, USA. She was on the faculty at Saint Louis University, Missouri, USA, where she identified and pharmacologically characterized the neuronal cannabinoid receptor and developed the first cannabinoid receptor radioligand binding assay. She is currently on the faculty of Wake Forest School of Medicine, North Carolina, USA, where she continues to investigate cellular signalling mechanisms of the cannabinoid receptors. She was awarded the first Mechoulam Award for her contributions to the cannabinoid field.

Additional data