, Volume 140, Issue 1–2, pp 73–82 | Cite as

Pharmacological and therapeutic targets for Δ9 tetrahydrocannabinol and cannabidiol

  • Roger G. PertweeEmail author


Cannabis is the unique source of a set of at least 66 compounds known collectively as cannabinoids. Of these, most is known about the pharmacology of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, and about cannabidiol (CBD), which lacks psychoactivity. Accordingly, this paper focuses on the pharmacological and therapeutic targets of these two cannabinoids. Many of the effects of Δ9-THC are mediated by cannabinoid receptors of which at least two types, CB1 and CB2, are present in mammalian tissues. Endogenous agonists for cannabinoid receptors have also been discovered. CB1 receptors are present at the terminals of central and peripheral neurones, where they modulate transmitter release. They also exist in some non-neuronal cells. CB2 receptors are expressed mainly by immune cells, one of their roles being to alter cytokine release. Δ9-THC also appears to have non-CB1, non-CB2 pharmacological targets. It is already licensed for clinical use in the U.S.A. as an anti-emetic and appetite stimulant and both Δ9-THC and Δ9-THC-rich cannabis extracts show therapeutic potential as neuroprotective and anticancer agents and for the management of glaucoma, pain and various kinds of motor dysfunction associated, for example, with multiple sclerosis and spinal cord injury. CBD has much less affinity for CB1 and CB2 receptors than Δ9-THC and its pharmacological actions have been less well characterized. Potential clinical applications of CBD and CBD-rich cannabis extracts include the production of anti-inflammatory and neuroprotective effects, the management of epilepsy, anxiety disorders, glaucoma and nausea, and the modulation of some effects of Δ9-THC.

Key words

cannabidiol cannabinoid receptors clinical applications of cannabinoids pharmacological actions of cannabinoids tetrahydrocannabinol tolerance to cannabinoids 





Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barann, M., G. Molderings, M. Brüss, H. Bönisch, B.W. Urban & M. Göthert, 2002. Direct inhibition by cannabinoids of human 5-HT3A receptors: Probable involvement of an allosteric modulatory site. Br J Pharmacol 137: 589–596.CrossRefPubMedGoogle Scholar
  2. Bayewitch, M., M.-H. Rhee, T. Avidor-Reiss, A. Breuer, R. Mechoulam & Z. Vogel, 1996. (–)-Δ9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase. J Biol Chem 271: 9902– 9905.PubMedGoogle Scholar
  3. Cravatt, B.F. & A.H. Lichtman, 2002. The enzymatic inactivation of the fatty acid amide class of signaling lipids. Chem Phys Lipids 121: 135–148.PubMedGoogle Scholar
  4. De Vry, J., K.R. Jentzsch, E. Kuhl & G. Eckel, 2004. Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development. Behav Pharm 15: 1–12.Google Scholar
  5. Dinh, T.P., T.F. Freund & D. Piomelli, 2002. A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids 121: 149–158.PubMedGoogle Scholar
  6. Downer, E.J., M.P. Fogarty & V.A. Campbell, 2003. Tetrahydrocannabinol-induced neurotoxicity depends on CB1 receptor-mediated c-Jun N-terminal kinase activation in cultured cortical neurons. Br J Pharmacol 140: 547–557.PubMedGoogle Scholar
  7. Drysdale, A.J., R.G. Pertwee & B. Platt, 2004. Modulation of calcium homeostasis by cannabidiol in primary hippocampal culture. Br J Pharmacol (Proc Suppl) In press.Google Scholar
  8. El-Remessy, A.B., I.E. Khalil, S. Matragoon, G. Abou-Mohamed, N.-J. Tsai, P. Roon, R.B. Caldwell, R.W. Caldwell, K. Green & G.I. Liou, 2003. Neuroprotective effect of (-)Δ9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: Involvement of peroxynitrite. Am J Pathol 163: 1997–2008.PubMedGoogle Scholar
  9. ElSohly, M.A., 2002. Chemical constituents of cannabis. In: F. Grotenhermen, E. Russo, (Eds.), Cannabis and Cannabinoids. Pharmacology, Toxicology and Therapeutic Potential, pp. 27–36. Haworth Press, New York.Google Scholar
  10. Fowler, C.J., 2003. Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents: non-psychoactive cannabinoids, ‘entourage’ compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strategies to avoid psychotropic effects. Brain Res Rev 41: 26–43.PubMedGoogle Scholar
  11. Gallily, R., T. Even-Chen, G. Katzavian, D. Lehmann, A. Dagan & R. Mechoulam, 2003. γ-Irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk Lymphoma 44: 1767–1773.PubMedGoogle Scholar
  12. Grotenhermen, F., 2002. Effects of cannabis and cannabinoids. In: F. Grotenhermen, E. Russo, (Eds.), Cannabis and Cannabinoids: Pharmacology Toxicology and Therapeutic Potential, pp. 55–65. Haworth Press, New York.Google Scholar
  13. Guzmán, M., 2003. Cannabinoids: Potential anticancer agents. Nature Rev Cancer 3: 745–755.Google Scholar
  14. Hampson, A.J., M. Grimaldi, J. Axelrod & D. Wink, 1998. Cannabidiol and (–)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95: 8268–8273.PubMedGoogle Scholar
  15. Hampson, A.J., M. Grimaldi, M. Lolic, D. Wink, R. Rosenthal & J. Axelrod, 2000. Neuroprotective antioxidants from marijuana. In: Reactive oxygen species: From radiation to molecular biology; Annals NY Acad Sci 899: 274–282.CrossRefGoogle Scholar
  16. Hanus, L., A. Breuer, S. Tchilibon, S. Shiloah, D. Goldenberg, M. Horowitz, R.G. Pertwee, R.A. Ross, R. Mechoulam & E. Fride, 1999. HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 96: 14228–14233.PubMedGoogle Scholar
  17. Herkenham, M., A.B. Lynn, M.R. Johnson, L.S. Melvin, B.R. de Costa & K.C. Rice, 1991. Characterization and localization of cannabinoid receptors in rat brain: A quantitative in vitro autoradiographic study. J Neurosci 11: 563–583.PubMedGoogle Scholar
  18. Hillard, C.J. & A. Jarrahian, 2003. Cellular accumulation of anandamide: consensus and controversy. Br J Pharmacol 140: 802–808.PubMedGoogle Scholar
  19. Hohmann, A.G., J.N. Farthing, A.M. Zvonok & A. Makriyannis, 2004. Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. J Pharmacol Exp Ther 308: 446–453.CrossRefPubMedGoogle Scholar
  20. Howlett, A.C., F. Barth, T.I. Bonner, G. Cabral, P. Casellas, W.A. Devane, C.C. Felder, M. Herkenham, K. Mackie, B.R. Martin, R. Mechoulam & R.G. Pertwee, 2002. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54: 161–202.CrossRefPubMedGoogle Scholar
  21. Hsieh, C., S. Brown, C. Derleth & K. Mackie, 1999. Internalization and recycling of the CB1 cannabinoid receptor. J Neurochem 73: 493–501.CrossRefPubMedGoogle Scholar
  22. Iversen, L.L., 2000. The Science of Marijuana. Oxford University Press, New York.Google Scholar
  23. Iversen, L.L., 2003. Cannabis and the brain. Brain 126: 1252– 1270.CrossRefPubMedGoogle Scholar
  24. Jordt, S.-E., D.M. Bautista, H. Chuang, D.D. McKemy, P.M. Zygmunt, E.D. Högestätt, I.D. Meng & D. Julius, 2004. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427: 260–265.CrossRefPubMedGoogle Scholar
  25. Keren, O. & Y. Sarne, 2003. Multiple mechanisms of CB1 cannabinoid receptors regulation. Brain Res 980: 197–205.CrossRefPubMedGoogle Scholar
  26. Maldonado, R., 2002. Study of cannabinoid dependence in animals. Pharmacol Ther 95: 153–164.CrossRefPubMedGoogle Scholar
  27. Mamas, M.A. & D.A. Terrar, 1998. Differential sensitivity to cannabidiol of the two components of delayed rectifier potassium current in guinea-pig isolated ventricular myocytes. Br J Pharmacol 123: 319P.Google Scholar
  28. Marsicano, G., B. Moosmann, H. Hermann, B. Lutz & C. Behl, 2002. Neuroprotective properties of cannabinoids against oxidative stress: Role of the cannabinoid receptor CB1. J Neurochem 80: 448–456.PubMedGoogle Scholar
  29. Martin, B., L.A. Stevenson, R.G. Pertwee, C.S. Breivogel, W. Williams, A. Mahadevan & R.K. Razdan, 2002. Agonists and silent antagonists in a series of cannabinoid sulfonamides. Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, p. 2.Google Scholar
  30. Martin, B.R., B.F. Thomas & R.K. Razdan, 1995. Structural requirements for cannabinoid receptor probes. In: R.G. Pertwee (Ed.), Cannabinoid Receptors, pp. 35–85. Academic Press, London.Google Scholar
  31. McKallip, R.J., C. Lombard, B.R. Martin, M. Nagarkatti & P.S. Nagarkatti, 2002. Δ9-Tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo. J Pharmacol Exp Ther 302: 451–465.PubMedGoogle Scholar
  32. Mechoulam, R., D. Panikashvili & E. Shohami, 2002. Cannabinoids and brain injury: Therapeutic implications. Trends Mol Med 8: 58–61.PubMedGoogle Scholar
  33. Molina-Holgado, E., C. Guaza, J. Borrell & F. Molina-Holgado, 1999. Effects of cannabinoids on the immune system and central nervous system: Therapeutic implications. Biodrugs 12: 317–326.PubMedGoogle Scholar
  34. Murphy, L.L., 2002. Hormonal system and reproduction. In: F. Grotenhermen & E. Russo, (Eds.), Cannabis and Cannabinoids: Pharmacology Toxicology and Therapeutic Potential, pp. 289–297. Haworth Press, New York.Google Scholar
  35. Paton, W.D.M. & R.G. Pertwee, 1973a. The actions of cannabis in man. In R. Mechoulam (Ed.), Marijuana, pp. 287–333. Academic Press, New York.Google Scholar
  36. Paton, W.D.M. & R.G. Pertwee, 1973b. The pharmacology of cannabis in animals. In: R. Mechoulam (Ed.), Marijuana, pp. 191–285. Academic Press, New York.Google Scholar
  37. Pertwee, R.G., 1985. Effects of cannabinoids on thermoregulation: A brief review. In: D.J. Harvey (Ed.), Marihuana ‘84, pp. 263–277. IRL Press, Oxford.Google Scholar
  38. Pertwee, R.G., 1988. The central neuropharmacology of psychotropic cannabinoids. Pharmacol Ther 36: 189–261.PubMedGoogle Scholar
  39. Pertwee, R.G., 1991. Tolerance to and dependence on psychotropic cannabinoids. In: J.A. Pratt (Ed.), The Biological Bases of Drug Tolerance and Dependence, pp. 231–263. Academic Press, {London}.Google Scholar
  40. Pertwee, R.G., 1995. Pharmacological, physiological and clinical implications of the discovery of cannabinoid receptors: An overview. In R.G. Pertwee (Ed.), Cannabinoid Receptors, pp. 1–34. Academic Press, London.Google Scholar
  41. Pertwee, R.G., 1997. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74: 129–180.CrossRefPubMedGoogle Scholar
  42. Pertwee, R.G., 2000a. Cannabinoid receptor ligands: Clinical and neuropharmacological considerations relevant to future drug discovery and development. Exp Opin Invest Drugs 9: 1553–1571.Google Scholar
  43. Pertwee, R.G., 2000b. Neuropharmacology and therapeutic potential of cannabinoids. Addict Biol 5: 37–46.Google Scholar
  44. Pertwee, R.G., 2001. Cannabinoid receptors and pain. Prog Neurobiol 63: 569–611.CrossRefPubMedGoogle Scholar
  45. Pertwee, R.G., 2002. Cannabinoids and multiple sclerosis. Pharmacol Ther 95: 165–174.CrossRefPubMedGoogle Scholar
  46. Pertwee, R.G., 2003a. Cannabinoids. In: C. Bountra, R. Munglani & W.K. Schmidt, (Eds.), Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discovery, pp. 683–706. Marcel Dekker, New York.Google Scholar
  47. Pertwee, R.G., 2003b. Inverse agonism at cannabinoid receptors. In: A.P. IJzerman (Ed.), Inverse Agonism, pp. 75–86. Elsevier, Amsterdam.Google Scholar
  48. Pertwee, R.G., 2004a. Novel pharmacological targets for cannabinoids. Curr Neuropharmacol 2: 9–29.Google Scholar
  49. Pertwee, R.G., 2004b. Pharmacological actions of cannabinoids. In: R.G. Pertwee (Ed.), Cannabinoids. Handbook of Experimental Pharmacology. Springer-Verlag, Berlin. In press.Google Scholar
  50. Pertwee, R.G., 2004c. The pharmacology and therapeutic potential of cannabidiol. In: V. Di Marzo (Ed.), Cannabinoids, Kluwer Academic/Plenum Publishers, pp. 32–83.Google Scholar
  51. Pertwee, R.G., 2004d. The therapeutic potential of cannabidiol. In: R. Mechoulam (Ed.), Cannabinoids as Therapeutics, Birkhauser Publishing, Basle, In press.Google Scholar
  52. Pertwee, R.G. & G. Griffin, 1995. A preliminary investigation of the mechanisms underlying cannabinoid tolerance in the mouse vas deferens. Eur J Pharmacol 272: 67–72.PubMedGoogle Scholar
  53. Pertwee, R.G., R.A. Ross, S.J. Craib & A. Thomas, 2002. (–)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol 456: 99–106.PubMedGoogle Scholar
  54. Pertwee, R.G., L.A. Stevenson & G. Griffin, 1993. Cross-tolerance between delta-9-tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212–2 and anandamide. Br J Pharmacol 110: 1483–1490.PubMedGoogle Scholar
  55. Platt, B. & A.J. Drysdale, 2004. Search and rescue: Identification of cannabinoid actions relevant for neuronal survival and protection. Curr Neuropharmacol 2: 103–114.Google Scholar
  56. Poling, J.S., M.A. Rogawski, N. Salem & S. Vicini, 1996. Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K+ channels. Neuropharmacology 35: 983–991.PubMedGoogle Scholar
  57. Quartilho, A., H.P. Mata, M.M. Ibrahim, T.W. Vanderah, F. Porreca, A. Makriyannis & T.P. Malan, 2003. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 99: 955–960.CrossRefPubMedGoogle Scholar
  58. Thomas, A., R.A. Ross, B. Saha, A. Mahadevan, R.K. Razdan & R.G. Pertwee, 2004. 6″-Azidohex-2″-yne-cannabidiol: A potential neutral, competitive cannabinoid CB1 receptor antagonist. Eur J Pharmacol 487: 213–221.PubMedGoogle Scholar
  59. Tomida, I., R.G. Pertwee & A. Azuara-Blanco, 2004. Cannabinoids and glaucoma. Br Ophthalmol 88: 708–713.Google Scholar
  60. Ueda, N., 2002. Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat 68–9: 521–534.Google Scholar
  61. van der Stelt, M. & V. Di Marzo, 2004. Metabolic fate of endocannabinoids. Curr Neuropharmacol 2: 37–48.Google Scholar
  62. van der Stelt, M., W.B. Veldhuis, M. Maccarrone, P.R. Bär, K. Nicolay, G.A. Veldink, V. Di Marzo & J.F.G. Vliegenthart, 2002. Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol Neurobiol 26: 317–346.PubMedGoogle Scholar
  63. Whittle, B.A., G.W. Guy & P. Robson, 2001. Prospects for new cannabis-based prescription medicines. J Cannabis Ther 1: 183–205.Google Scholar
  64. Zajicek, J., P. Fox, H. Sanders, D. Wright, J. Vickery, A. Nunn & A. Thompson, 2003. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): Multicentre randomised placebo-controlled trial. Lancet 362: 1517–1526.CrossRefPubMedGoogle Scholar
  65. Zygmunt, P.M., D.A. Andersson & E.D. Högestätt, 2002. Δ9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci 22: 4720–4727.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  1. 1.School of Medical Sciences, Institute of Medical SciencesUniversity of AberdeenAberdeenScotland, U.K.

Personalised recommendations