Therapeutic Potential of Cannabinoid-Based Drugs

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 601)

Abstract

Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid- based drugs such as ?9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer’s disease, atherosclerosis, and osteoporosis.

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References

  1. Anday, J.K. and Mercier, R.W. (2005) Gene ancestry of the cannabinoid receptor family. Pharmacol. Res. 20, 20.Google Scholar
  2. Baker, D., Pryce, G., Croxford, J.L., Brown, P., Pertwee, R.G., Huffman, J.W. and Layward, L. (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404, 84–87.CrossRefPubMedGoogle Scholar
  3. Baker, D., Pryce, G., Davies, W.L. and Hiley, C.R. (2006) In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol. Sci. 27, 1–4.CrossRefPubMedGoogle Scholar
  4. Baldwin, G.C., Tashkin, D.P., Buckley, D.M., Park, A.N., Dubinett, S.M. and Roth, M.D. (1997) Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am. J. Respir. Crit. Care Med. 156, 1606–1613.PubMedGoogle Scholar
  5. Blake, D.R., Robson, P., Ho, M., Jubb, R.W. and McCabe, C.S. (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 45, 50–52.CrossRefGoogle Scholar
  6. Breivogel, C.S., Griffin, G., Di Marzo, V. and Martin, B.R. (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol. 60, 155–163.PubMedGoogle Scholar
  7. Burstein, S.H., Friderichs, E., Kogel, B., Schneider, J. and Selve, N. (1998) Analgesic effects of 1’,1’ dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice. Life Sci. 63, 161–168.CrossRefPubMedGoogle Scholar
  8. Cabral, G. and Dove Pettit, D. (1998) Drugs and immunity: cannabinoids and their role in decreased resistance to infectious diseases. J. Neuroimmunol. 83, 116–123.CrossRefPubMedGoogle Scholar
  9. Calignano, A., La Rana, G., Giuffrida, A. and Piomelli, D. (1998) Control of pain initiation by endogenous cannabinoids. Nature 394, 277–281.CrossRefPubMedGoogle Scholar
  10. Chang, Y.H., Lee, S.T. and Lin, W.W. (2001) Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J. Cell. Biochem. 81, 715–723.CrossRefPubMedGoogle Scholar
  11. Croxford, J.L. and Miller, S.D. (2003) Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212. J. Clin. Invest. 111, 1231–1240.PubMedGoogle Scholar
  12. Dajani, E.Z., Larsen, K.R., Taylor, J., Dajani, N.E., Shahwan, T.G., Neeleman, S.D., Taylor, M.S., Dayton, M.T. and Mir, G.N. (1999) 1’,1’-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties. J. Pharmacol. Exp. Ther. 291, 31–38.PubMedGoogle Scholar
  13. Derocq, J.M., Jbilo, O., Bouaboula, M., Segui, M., Clere, C. and Casellas, P. (2000) Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL-60. Possible involvement of the CB2 receptor in cell differentiation. J. Biol. Chem. 275, 15621–15628.CrossRefPubMedGoogle Scholar
  14. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A. and Mechoulam, R. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949.CrossRefPubMedGoogle Scholar
  15. Di Filippo, C., Rossi, F., Rossi, S. and D’Amico, M. (2004) Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN. J. Leukoc. Biol. 75, 453–459. Epub 2003 Dec 2004.CrossRefPubMedGoogle Scholar
  16. Di Marzo, V. and Izzo, A.A. (2006) Endocannabinoid overactivity and intestinal inflammation. Gut 55, 1373–1376.CrossRefPubMedGoogle Scholar
  17. Ehrhart, J., Obregon, D., Mori, T., Hou, H., Sun, N., Bai, Y., Klein, T., Fernandez, F., Tan, J. and Shytle, R.D. (2005) Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J. Neuroinflammation 2, 29.CrossRefPubMedGoogle Scholar
  18. Elmes, S.J., Winyard, L.A., Medhurst, S.J., Clayton, N.M., Wilson, A.W., Kendall, D.A. and Chapman, V. (2005) Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain 118, 327–335.CrossRefPubMedGoogle Scholar
  19. Eubanks, L.M., Rogers, C.J., Beuscher, A.E., Koob, G.F., Olson, A.J., Dickerson, T.J. and Janda, K.D. (2006) A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol. Pharm. 3, 773–777.CrossRefPubMedGoogle Scholar
  20. Fischer-Stenger, K., Dove Pettit, D.A. and Cabral, G.A. (1993) δ 9-Tetrahydrocannabinol inhibition of tumor necrosis factor-α : suppression of post-translational events. J. Pharm. Exp. Ther. 267, 1558–1565.Google Scholar
  21. Fowler, C.J., Holt, S., Nilsson, O., Jonsson, K.O., Tiger, G. and Jacobsson, S.O. (2005) The endocannabinoid signaling system: pharmacological and therapeutic aspects. Pharmacol. Biochem. Behav. 81, 248–262.CrossRefPubMedGoogle Scholar
  22. Gaoni, Y. and Mechoulam, R. (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647.CrossRefGoogle Scholar
  23. Gerard, C.M., Mollereau, C., Vassart, G. and Parmentier, M. (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem. J. 279, 129–134.PubMedGoogle Scholar
  24. Hanus, L., Abu-Lafi, S., Fride, E., Breuer, A., Vogel, Z., Shalev, D.E., Kustanovich, I. and Mechoulam, R. (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. USA 98, 3662–3665.CrossRefPubMedGoogle Scholar
  25. Hohmann, A. and Suplita, R. (2006) Endocannabinoid mechanisms of pain modulation. AAPS J. 8, E693–E708.CrossRefPubMedGoogle Scholar
  26. Howlett, A.C., Breivogel, C.S., Childers, S.R., Deadwyler, S.A., Hampson, R.E. and Porrino, L.J. (2004) Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47, 345–358.CrossRefPubMedGoogle Scholar
  27. Ibrahim, M.M., Deng, H., Zvonok, A., Cockayne, D.A., Kwan, J., Mata, H.P., Vanderah, T.W., Lai, J., Porreca, F., Makriyannis, A. and Malan, T.P., Jr. (2003) 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.CrossRefPubMedGoogle Scholar
  28. Idris, A.I., van ‘t Hof, R.J., Greig, I.R., Ridge, S.A., Baker, D., Ross, R.A. and Ralston, S.H. (2005) Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat. Med. 11, 774–779.CrossRefPubMedGoogle Scholar
  29. Iskedjian, M., Bereza, B., Gordon, A., Piwko, C. and Einarson, T.R. (2007)Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr. Med. Res. Opin. 23, 17–24.CrossRefPubMedGoogle Scholar
  30. Jarai, Z., Wagner, J.A., Varga, K., Lake, K.D., Compton, D.R., Martin, B.R., Zimmer, A.M., Bonner, T.I., Buckley, N.E., Mezey, E., Razdan, R.K., Zimmer, A. and Kunos, G. (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc. Natl. Acad. Sci. USA 96, 14136–14141.CrossRefPubMedGoogle Scholar
  31. Karsak, M., Cohen-Solal, M., Freudenberg, J., Ostertag, A., Morieux, C., Kornak, U., Essig, J., Erxlebe, E., Bab, I., Kubisch, C., de Vernejoul, M.C. and Zimmer, A. (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum. Mol. Genet. 14, 3389–3396.CrossRefPubMedGoogle Scholar
  32. Karst, M., Salim, K., Burstein, S., Conrad, I., Hoy, L. and Schneider, U. (2003) Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 290, 1757–1762.CrossRefPubMedGoogle Scholar
  33. Kishimoto, S., Kobayashi, Y., Oka, S., Gokoh, M., Waku, K. and Sugiura, T. (2004) 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces accelerated production of chemokines in HL-60 cells. J. Biochem. (Tokyo) 135, 517–524.Google Scholar
  34. Klein, T.W. (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat. Rev. Immunol. 5, 400–411.CrossRefPubMedGoogle Scholar
  35. Klein, T.W. and Cabral, G. (2006) Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J. Neuroimmune Pharmacol. 1, 50–64.CrossRefPubMedGoogle Scholar
  36. Klein, T.W., Lane, B., Newton, C.A. and Friedman, H. (2000a) The cannabinoid system and cytokine network. Proc. Soc. Exp. Biol. Med. 225, 1–8.CrossRefPubMedGoogle Scholar
  37. Klein, T., Newton, C. and Friedman, H. (1998) Cannabinoid receptors and immunity. Immunol. Today 19, 373–381.CrossRefPubMedGoogle Scholar
  38. Klein, T.W., Newton, C., Larsen, K., Lu, L., Perkins, I., Nong, L. and Friedman, H. (2003) The cannabinoid system and immune modulation. J. Leukoc. Biol. 74, 486–496.CrossRefPubMedGoogle Scholar
  39. Klein, T.W., Newton, C.A., Nakachi, N. and Friedman, H. (2000b) δ 9-Tetrahydrocannabinol treatment suppresses immunity and early IFNγ , IL-12, and IL-12 receptor β 2 responses to Legionella pneumophila infection. J. Immunol. 164, 6461–6466.PubMedGoogle Scholar
  40. Klein, T.W., Newton, C., Widen, R. and Friedman, H. (1993) δ 9- Tetrahydrocannabinol injection induces cytokine-mediated mortality of mice infected with Legionella pneumophila. J. Pharmacol. Exp. Ther. 267, 635–640.PubMedGoogle Scholar
  41. Knoller, N., Levi, L., Shoshan, I., Reichenthal, E., Razon, N., Rappaport, Z.H. and Biegon, A. (2002) 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.CrossRefPubMedGoogle Scholar
  42. Liu, J., Li, H., Burstein, S.H., Zurier, R.B. and Chen, J.D. (2003) Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol. Pharmacol. 63, 983–992.CrossRefPubMedGoogle Scholar
  43. Lu, T., Newton, C., Perkins, I., Friedman, H. and Klein, T.W. (2006) Role of cannabinoid receptors in Delta-9-tetrahydrocannabinol suppression of IL-12p40 in mouse bone marrow-derived dendritic cells infected with Legionella pneumophila. Eur. J. Pharmacol. 532, 170–177.CrossRefPubMedGoogle Scholar
  44. Lyman, W.D., Sonett, J.R., Brosnan, C.F., Elkin, R. and Bornstein, M.B. (1989) δ 9-Tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J. Neuroimmunol. 23, 73–81.CrossRefPubMedGoogle Scholar
  45. Maas, A.I., Murray, G., Henney, H., 3rd, Kassem, N., Legrand, V., Mangelus, M., Muizelaar, J.P., Stocchetti, N. and Knoller, N. (2006) Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 5, 38–45.CrossRefPubMedGoogle Scholar
  46. Mackenzie, I.R., Hao, C. and Munoz, D.G. (1995) Role of microglia in senile plaque formation. Neurobiol. Aging 16, 797–804.CrossRefPubMedGoogle Scholar
  47. Malfait, A.M., Gallily, R., Sumariwalla, P.F., Malik, A.S., Andreakos, E., Mechoulam, R. and Feldmann, M. (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis [see comments]. Proc. Natl. Acad. Sci. USA 97, 9561–9566.CrossRefPubMedGoogle Scholar
  48. Marsicano, G., Goodenough, S., Monory, K., Hermann, H., Eder, M., Cannich, A., Azad, S.C., Cascio, M.G., Gutierrez, S.O., van der Stelt, M., Lopez-Rodriguez, M.L., Casanova, E., Schutz, G., Zieglgansberger, W., Di Marzo, V., Behl, C. and Lutz, B. (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 302, 84–88.CrossRefPubMedGoogle Scholar
  49. Massa, F., Storr, M. and Lutz, B. (2005) The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J. Mol. Med. 26, 26.Google Scholar
  50. Mathison, R., Ho, W., Pittman, Q.J., Davison, J.S. and Sharkey, K.A. (2004) Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br. J. Pharmacol. 142, 1247–1254.CrossRefPubMedGoogle Scholar
  51. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C. and Bonner, T.I. (1990) Structure of cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564.CrossRefPubMedGoogle Scholar
  52. Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Griffin, G., Bayewitch, M., Barg, J. and Vogel, Z. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharm. 50, 83–90.CrossRefPubMedGoogle Scholar
  53. Mechoulam, R., Panikashvili, D. and Shohami, E. (2002) Cannabinoids and brain injury: therapeutic implications. Trends Mol. Med. 8, 58–61.CrossRefPubMedGoogle Scholar
  54. Milton, N.G. (2002) Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Neurosci. Lett. 332, 127–130.CrossRefPubMedGoogle Scholar
  55. Mitchell, V.A., Aslan, S., Safaei, R. and Vaughan, C.W. (2005) Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neurosci. Lett. 382, 231–235.CrossRefPubMedGoogle Scholar
  56. Munro, S., Thomas, K.L. and Abu-Shaar, M. (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65.CrossRefPubMedGoogle Scholar
  57. Nahas, G.G., Suciu-Foca, N., Armand, J.-P. and Morishima, A. (1974) Inhibition of cellular mediated immunity in marihuana smokers. Science 183, 419–420.CrossRefPubMedGoogle Scholar
  58. Newton, C.A., Klein, T.W. and Friedman, H. (1994) Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by delta- 9-tetrahydrocannabinol injection. Infect. Immun. 62, 4015–4020.PubMedGoogle Scholar
  59. Nogid, A. and Pham, D.Q. (2006) Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 28, 1764–1778.CrossRefPubMedGoogle Scholar
  60. Ofek, O., Karsak, M., Leclerc, N., Fogel, M., Frenkel, B., Wright, K., Tam, J., Attar-Namdar, M., Kram, V., Shohami, E., Mechoulam, R., Zimmer, A. and Bab, I. (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc. Natl. Acad. Sci. U S A. 103, 696–701.CrossRefPubMedGoogle Scholar
  61. Offertaler, L., Mo, F.M., Batkai, S., Liu, J., Begg, M., Razdan, R.K., Martin, B.R., Bukoski, R.D. and Kunos, G. (2003) Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol. Pharmacol. 63, 699–705.CrossRefPubMedGoogle Scholar
  62. Pacher, P., Batkai, S. and Kunos, G. (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58, 389–462.CrossRefPubMedGoogle Scholar
  63. Pacifici, R., Zuccaro, P., Pichini, S., Roset, P.N., Poudevida, S., Farre, M., Segura, J. and De la Torre, R. (2003) Modulation of the immune system in cannabis users. JAMA 289, 1929–1931.CrossRefPubMedGoogle Scholar
  64. Panikashvili, D., Simeonidou, C., Ben-Shabat, S., Hanus, L., Breuer, A., Mechoulam, R. and Shohami, E. (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531.CrossRefPubMedGoogle Scholar
  65. Pertwee, R.G. (2005) The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J. 7, E625–E654.CrossRefPubMedGoogle Scholar
  66. Pinto, L., Izzo, A.A., Cascio, M.G., Bisogno, T., Hospodar-Scott, K., Brown, D.R., Mascolo, N., Di Marzo, V. and Capasso, F. (2002) Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology 123, 227–234.CrossRefPubMedGoogle Scholar
  67. Porter, A.C., Sauer, J.M., Knierman, M.D., Becker, G.W., Berna, M.J., Bao, J., Nomikos, G.G., Carter, P., Bymaster, F.P., Leese, A.B. and Felder, C.C. (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther. 301, 1020–1024.CrossRefPubMedGoogle Scholar
  68. Pryce, G., Ahmed, Z., Hankey, D.J., Jackson, S.J., Croxford, J.L., Pocock, J.M., Ledent, C., Petzold, A., Thompson, A.J., Giovannoni, G., Cuzner, M.L. and Baker, D. (2003) Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126, 2191–2202.CrossRefPubMedGoogle Scholar
  69. Pryce, G. and Baker, D. (2007) Control of spasticity in a multiple sclerosis model is mediated by CB(1), not CB(2), cannabinoid receptors. Br. J. Pharmacol. 15, 15.Google Scholar
  70. Ramirez, B.G., Blazquez, C., Gomez del Pulgar, T., Guzman, M. and de Ceballos, M.L. (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 25, 1904–1913.CrossRefPubMedGoogle Scholar
  71. Rodan, G.A. and Martin, T.J. (2000) Therapeutic approaches to bone diseases. Science 289, 1508–1514.CrossRefPubMedGoogle Scholar
  72. Rog, D.J., Nurmikko, T.J., Friede, T. and Young, C.A. (2005) Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 65, 812–819.CrossRefPubMedGoogle Scholar
  73. Rousseaux, C., Thuru, X., Gelot, A., Barnich, N., Neut, C., Dubuquoy, L., Dubuquoy, C., Merour, E., Geboes, K., Chamaillard, M., Ouwehand, A., Leyer, G., Carcano, D., Colombel, J.F., Ardid, D. and Desreumaux, P. (2007) Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35–37.CrossRefPubMedGoogle Scholar
  74. Salim, K., Schneider, U., Burstein, S., Hoy, L. and Karst, M. (2005) Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology 48, 1164–1171.CrossRefPubMedGoogle Scholar
  75. Shohami, E., Gallily, R., Mechoulam, R., Bass, R. and Ben-Hur, T. (1997) Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant. J. Neuroimmunol. 72, 169–177.CrossRefPubMedGoogle Scholar
  76. Shohami, E., Novikov, M. and Bass, R. (1995) Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat. Brain Res. 674, 55–62.CrossRefPubMedGoogle Scholar
  77. Smith, S.R., Terminelli, C. and Denhardt, G. (2000) Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice. J. Pharmacol. Exp. Ther. 293, 136–150.PubMedGoogle Scholar
  78. Steffens, S., Veillard, N.R., Arnaud, C., Pelli, G., Burger, F., Staub, C., Karsak, M., Zimmer, A., Frossard, J.L. and Mach, F. (2005) Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. 434, 782–786.CrossRefPubMedGoogle Scholar
  79. Sumariwalla, P.F., Gallily, R., Tchilibon, S., Fride, E., Mechoulam, R. and Feldmann, M. (2004) A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis Rheum. 50, 985–998.Google Scholar
  80. Sun, Y., Alexander, S.P., Kendall, D.A. and Bennett, A.J. (2006) Cannabinoids and PPARalpha signalling. Biochem. Soc. Trans. 34, 1095–1097.CrossRefPubMedGoogle Scholar
  81. Svendsen, K.B., Jensen, T.S. and Bach, F.W. (2004) Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 329, 253.Google Scholar
  82. Takeda, S., Elefteriou, F., Levasseur, R., Liu, X., Zhao, L., Parker, K.L., Armstrong, D., Ducy, P. and Karsenty, G. (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317.CrossRefPubMedGoogle Scholar
  83. Tomida, I., Pertwee, R.G. and Azuara-Blanco, A. (2004) Cannabinoids and glaucoma. Br. J. Ophthalmol. 88, 708–713.CrossRefPubMedGoogle Scholar
  84. Van Gaal, L.F., Rissanen, A.M., Scheen, A.J., Ziegler, O. and Rossner, S. (2005) 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, 1389–1397.CrossRefPubMedGoogle Scholar
  85. Vaney, C., Heinzel-Gutenbrunner, M., Jobin, P., Tschopp, F., Gattlen, B., Hagen, U., Schnelle, M. and Reif, M. (2004) Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult. Scler. 10, 417–424.CrossRefPubMedGoogle Scholar
  86. Varga, K., Wagner, J.A., Bridgen, D.T. and Kunos, G. (1998) Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J. 12, 1035–1044.PubMedGoogle Scholar
  87. Wade, D.T., Makela, P., Robson, P., House, H. and Bateman, C. (2004) Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult. Scler. 10, 434–441.CrossRefPubMedGoogle Scholar
  88. Wagner, J.A., Varga, K., Kunos, G. and Bridgen, D.T. (1998) Cardiovascular actions of cannabinoids and their generation during shock: platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. J. Mol. Med. 76, 824–836.CrossRefPubMedGoogle Scholar
  89. Wang, Y., Liu, Y., Ito, Y., Hashiguchi, T., Kitajima, I., Yamakuchi, M., Shimizu, H., Matsuo, S., Imaizumi, H. and Maruyama, I. (2001) Simultaneous measurement of anandamide and 2-arachidonoylglycerol by polymyxin B-selective adsorption and subsequent high-performance liquid chromatography analysis: increase in endogenous cannabinoids in the sera of patients with endotoxic shock. Anal. Biochem. 294, 73–82.CrossRefPubMedGoogle Scholar
  90. Wirguin, I., Mechoulam, R., Breuer, A., Schezen, E., Weidenfeld, J. and Brenner, T. (1994) Suppression of experimental autoimmune encephalomyelitis by cannabinoids. Immunopharmacolology 28, 209–214.CrossRefGoogle Scholar
  91. Wright, K., Rooney, N., Feeney, M., Tate, J., Robertson, D., Welham, M. and Ward, S. (2005) Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology 129, 437–453.PubMedGoogle Scholar
  92. Yuan, M., Kiertscher, S.M., Cheng, Q., Zoumalan, R., Tashkin, D.P. and Roth, M.D. (2002) D9-tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J. Neuroimmunol. 133, 124–131.CrossRefPubMedGoogle Scholar
  93. Zajicek, J., Fox, P., Sanders, H., Wright, D., Vickery, J., Nunn, A. and Thompson, A. (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
  94. Zajicek, J.P., Sanders, H.P., Wright, D.E., Vickery, P.J., Ingram, W.M., Reilly, S.M., Nunn, A.J., Teare, L.J., Fox, P.J. and Thompson, A.J. (2005)Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J. Neurol. Neurosurg. Psychiatry 76, 1664–1669.CrossRefPubMedGoogle Scholar
  95. Zhu, W., Newton, C., Daaka, Y., Friedman, H. and Klein, T.W. (1994) δ 9-Tetrahydrocannabinol enhances the secretion of interleukin 1 from endotoxin-stimulated macrophages. J. Pharmacol. Exp. Ther. 270, 1334–1339.PubMedGoogle Scholar
  96. Zhu, L.X., Sharma, S., Stolina, M., Gardner, B., Roth, M.D., Tashkin, D.P.and Dubinett, S.M. (2000) δ -9-Tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J. Immunol. 165, 373–380.PubMedGoogle Scholar
  97. Zurier, R.B., Rossetti, R.G., Burstein, S.H. and Bidinger, B. (2003) Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid. Biochem. Pharmacol. 65, 649–655.CrossRefPubMedGoogle Scholar
  98. Zurier, R.B., Rossetti, R.G., Lane, J.H., Goldberg, J.M., Hunter, S.A. and Burstein, S.H. (1998) Dimethylheptyl-THC-11-oic acid. A nonpsychoactive antiinflammatory agent with a cannabinoid template structure. Arthritis Rheum. 41, 163–170.CrossRefPubMedGoogle Scholar
  99. Zygmunt, P.M., Petersson, J., Andersson, D.A., Chuang, H., Sorgard, M., Di Marzo, V., Julius, D. and Hogestatt, E.D. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Molecular MedicineUniversity of South FloridaTampaUSA

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