CNS Drugs

, Volume 17, Issue 3, pp 179–202 | Cite as

Therapeutic Potential of Cannabinoids in CNS Disease

  • J. Ludovic CroxfordEmail author
Review Article


The major psychoactive constituent of Cannabis sativa, Δ9-tetrahydrocannabinol (Δ9-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial.

Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson’s disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of Δ9-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity.

Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB1 receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB1 receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment.

This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.


Anandamide Rimonabant Fatty Acid Amide Hydrolase Vanilloid Receptor Nabilone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author wishes to thank Dr David Baker and Jennifer Driscoll for their helpful and constructive comments on this manuscript. Dr Croxford is a fellow of the National Multiple Sclerosis Society (FG-1456-A-1) and has no conflicts of interest directly relevant to the content of this review. No sources of funding were used to assist in the preparation of this manuscript.


  1. 1.
    Vincent BJ, McQuiston DJ, Einhorn LH, et al. Review of cannabinoids and their anti-emetic effectiveness. Drugs 1983; 25Suppl. 1: 52–62PubMedCrossRefGoogle Scholar
  2. 2.
    Gaoni Y, Mechoulam R. Isolation, structure elucidation and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964; 86: 1646–7CrossRefGoogle Scholar
  3. 3.
    Howlett AC, Barth F, Bonner G, et al. International union of pharmacology. XXVII: classification of cannabinoid receptors. Pharmacol Rev 2002; 54: 161–202Google Scholar
  4. 4.
    Devane WA, Dysarz FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605–13PubMedGoogle Scholar
  5. 5.
    Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946–9PubMedCrossRefGoogle Scholar
  6. 6.
    Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993; 365: 61–5PubMedCrossRefGoogle Scholar
  7. 7.
    Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346(6284): 561–4PubMedCrossRefGoogle Scholar
  8. 8.
    Howlett AC, Qualy JM, Khachatrian LL. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol 1986; 29(3): 307–13PubMedGoogle Scholar
  9. 9.
    Pacheco MA, Ward SJ, Childers SR. Identification of cannabinoid receptors in cultures of rat cerebellar granule cells. Brain Res 1993; 603(1): 102–10PubMedCrossRefGoogle Scholar
  10. 10.
    Yamaguchi F, Macrae AD, Brenner S. Molecular cloning of two cannabinoid type 1 -like receptor genes from the puffer fish Fugu rubripes. Genomics 1996; 35(3): 603–5PubMedCrossRefGoogle Scholar
  11. 11.
    De Petrocellis L, Melck D, Bisogno T, et al. Finding of the endocannabinoid signalling system in Hydra, a very primitive organism: possible role in the feeding response. Neuroscience 1999; 92(1): 377–87PubMedCrossRefGoogle Scholar
  12. 12.
    Stefano GB, Salzet B, Salzet M. Identification and characterization of the leech CNS cannabinoid receptor: coupling to nitric oxide release. Brain Res 1997; 753(2): 219–24PubMedCrossRefGoogle Scholar
  13. 13.
    Chang MC, Berkery D, Schuel R, et al. Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction. Mol Reprod Dev 1993; 36(4): 507–16PubMedCrossRefGoogle Scholar
  14. 14.
    Bisogno T, Ventriglia M, Milone A, et al. Occurrence and metabolism of anandamide and related acyl-ethanolamides in ovaries of the sea urchin Paracentrotus lividus. Biochim Biophys Acta 1997; 1345(3): 338–48PubMedCrossRefGoogle Scholar
  15. 15.
    McPartland J, Di Marzo V, De Petrocellis L, et al. Cannabinoid receptors are absent in insects. J Comp Neurol 2001; 436(4): 423–9PubMedCrossRefGoogle Scholar
  16. 16.
    Shire D, Carillon C, Kaghad M, et al. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J Biol Chem 1995; 270(8): 3726–31PubMedCrossRefGoogle Scholar
  17. 17.
    Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74(2): 129–80PubMedCrossRefGoogle Scholar
  18. 18.
    Herkenham M, Lynn AB, Johnson MR, et al. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 1991; 11(2): 563–83PubMedGoogle Scholar
  19. 19.
    Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990; 87(5): 1932–6PubMedCrossRefGoogle Scholar
  20. 20.
    Dove Pettit DA, Harrison MP, Olson JM, et al. Immunohistochemical localization of the neural cannabinoid receptor in rat brain. J Neurosci Res 1998; 51(3): 391–402CrossRefGoogle Scholar
  21. 21.
    Mailleux P, Vanderhaeghen JJ. Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 1992; 48(3): 655–68PubMedCrossRefGoogle Scholar
  22. 22.
    Lichtman AH, Martin BR. Spinal and supraspinal components of cannabinoid-induced antinociception. J Pharmacol Exp Ther 1991; 258(2): 517–23PubMedGoogle Scholar
  23. 23.
    Hohmann AG, Martin WJ, Tsou K, et al. Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55,212-2. Life Sci 1995; 56(23-24): 2111–8PubMedCrossRefGoogle Scholar
  24. 24.
    Sallan SE, Zinberg NE, Frei E. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 1975; 293(16): 795–7PubMedCrossRefGoogle Scholar
  25. 25.
    London SW, McCarthy LE, Borison HL. Suppression of cancer chemotherapy-induced vomiting in the cat by nabilone, a synthetic cannabinoid. Proc Soc Exp Biol Med 1979; 160(4): 437–40PubMedGoogle Scholar
  26. 26.
    Galiegue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995; 232(1): 54–61PubMedCrossRefGoogle Scholar
  27. 27.
    Holland M, John Challiss RA, Standen NB, et al. Cannabinoid CB1 receptors fail to cause relaxation, but couple via Gi/Go to the inhibition of adenylyl cyclase in carotid artery smooth muscle. Br J Pharmacol 1999; 128(3): 597–604PubMedCrossRefGoogle Scholar
  28. 28.
    Croci T, Manara L, Aureggi G, et al. In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum. Br J Pharmacol 1998; 125(7): 1393–5PubMedCrossRefGoogle Scholar
  29. 29.
    Rice W, Shannon JM, Burton F, et al. Expression of a brain-type cannabinoid receptor (CB1) in alveolar Type II cells in the lung: regulation by hydrocortisone. Eur J Pharmacol 1997; 327(2–3): 227–32PubMedCrossRefGoogle Scholar
  30. 30.
    Straiker AJ, Maguire G, Mackie K, et al. Localization of cannabinoid CB1 receptors in the human anterior eye and retina. Invest Ophthalmol Vis Sci 1999; 40(10): 2442–8PubMedGoogle Scholar
  31. 31.
    Porcella A, Casellas P, Gessa GL, et al. Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana. Mol Brain Res 1998; 58(1–2): 240–5PubMedCrossRefGoogle Scholar
  32. 32.
    Griffin G, Fernando SR, Ross RA, et al. Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 1997; 339(1): 53–61PubMedCrossRefGoogle Scholar
  33. 33.
    Lu Q, Straiker A, Maguire G. Expression of CB2 cannabinoid receptor mRNA in adult rat retina. Vis Neurosci 2001; 17(1): 91–5Google Scholar
  34. 34.
    Skaper SD, Buriani A, Dal Toso R, et al. The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Natl Acad Sci U S A 1996; 93(9): 3984–9PubMedCrossRefGoogle Scholar
  35. 35.
    Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 1997; 77(2): 299–318PubMedCrossRefGoogle Scholar
  36. 36.
    Dewey WL. Cannabinoid pharmacology. Pharmacol Rev 1986; 38(2): 151–78PubMedGoogle Scholar
  37. 37.
    Barth F, Rinaldi-Carmona M. The development of cannabinoid antagonists. Curr Med Chem 1999; 6(8): 745–55PubMedGoogle Scholar
  38. 38.
    Terranova JP, Storme JJ, Lafon N, et al. Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716. Psychopharmacologia 1996; 126(2): 165–72CrossRefGoogle Scholar
  39. 39.
    Lynn AB, Herkenham M. Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther 1994; 268(3): 1612–23PubMedGoogle Scholar
  40. 40.
    Glass M, Felder CC. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 1997; 17(14): 5327–33PubMedGoogle Scholar
  41. 41.
    Maneuf YP, Brotchie JM. Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br J Pharmacol 1997; 120(8): 1397–8PubMedCrossRefGoogle Scholar
  42. 42.
    Felder CC, Joyce KE, Briley EM, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 1995; 48(3): 443–50PubMedGoogle Scholar
  43. 43.
    Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci U S A 1992; 89(9): 3825–9PubMedCrossRefGoogle Scholar
  44. 44.
    Mackie K, Lai Y, Westenbroek R, et al. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci 1995; 15(10): 6552–61PubMedGoogle Scholar
  45. 45.
    Bouaboula M, Poinot-Chazel C, Bourrie B, et al. Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 1995; 312 (Pt 2): 637–41PubMedGoogle Scholar
  46. 46.
    Liu J, Gao B, Mirshahi F, et al. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 2000; 346 (Pt 3): 835–40PubMedCrossRefGoogle Scholar
  47. 47.
    Ishac EJ, Jiang L, Lake KD, et al. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 1996; 118(8): 2023–8PubMedCrossRefGoogle Scholar
  48. 48.
    Kathmann M, Bauer U, Schlicker E, et al. Cannabinoid CB1 receptor-mediated inhibition of NMD A- and kainate-stimulated noradrenaline and dopamine release in the brain. Naunyn Schmiedebergs Arch Pharmacol 1999; 359(6): 466–70PubMedCrossRefGoogle Scholar
  49. 49.
    Nakazi M, Bauer U, Nickel T, et al. Inhibition of serotonin release in the mouse brain via presynaptic cannabinoid CB1 receptors. Naunyn Schmiedebergs Arch Pharmacol 2000; 361(1): 19–24PubMedCrossRefGoogle Scholar
  50. 50.
    Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 2001; 410: 588–92PubMedCrossRefGoogle Scholar
  51. 51.
    Shen M, Piser TM, Seybold VS, et al. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 1996; 16(14): 4322–34PubMedGoogle Scholar
  52. 52.
    Breivogel CS, Griffin G, Di Marzo V, et al. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 2001; 60(1): 155–63PubMedGoogle Scholar
  53. 53.
    Di Marzo V, Beivogel CS, Tao Q, et al. Levels, metabolism, and pharmacological activity in CB1 cannabinoid receptor knockout mice: evidence for non-CBl, non-CB2 receptor-mediated actions of anandamide in mouse brain. J Neurochem 2000; 75: 2434–44PubMedCrossRefGoogle Scholar
  54. 54.
    Jarai Z, Wagner JA, Varga K, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A 1999; 96(24): 14136–41PubMedCrossRefGoogle Scholar
  55. 55.
    Showalter VM, Compton DR, Martin BR, et al. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther 1996; 278(3): 989–99PubMedGoogle Scholar
  56. 56.
    Schmid PC, Krebsbach RJ, Perry SR, et al. Occurrence and postmortem generation of anandamide and other long-chain N-acylethanolamines in mammalian brain. FEBS Lett 1995; 375(1–2): 117–20PubMedCrossRefGoogle Scholar
  57. 57.
    Sugiura T, Kondo S, Sukagawa A, et al. N-arachidonoylethano-lamine (anandamide), an endogenous cannabinoid receptor ligand, and related lipid molecules in the nervous tissues. J Lipid Mediat Cell Signal 1996; 14(1–3): 51–6PubMedCrossRefGoogle Scholar
  58. 58.
    Felder CC, Nielsen A, Briley EM, et al. Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat. FEBS Letters 1996; 393(2–3): 231–5PubMedCrossRefGoogle Scholar
  59. 59.
    Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 2001; 15(2): 300–2PubMedGoogle Scholar
  60. 60.
    Yang HY, Karoum F, Felder C, et al. GC/MS analysis of anandamide and quantification of N-arachidonoylphosphatidylethanolamides in various brain regions, spinal cord, testis, and spleen of the rat. J Neurochem 1999; 72(5): 1959–68PubMedCrossRefGoogle Scholar
  61. 61.
    Deutsch DG, Goligorsky MS, Schmid PC, et al. Production and physiological actions of anandamide in the vasculature of the rat kidney. J Clin Invest 1997; 100(6): 1538–46PubMedCrossRefGoogle Scholar
  62. 62.
    Schmid PC, Paria BC, Krebsbach RJ, et al. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc Natl Acad Sci U S A 1997; 94(8): 4188–92PubMedCrossRefGoogle Scholar
  63. 63.
    Giuffrida A, Piomelli D. Isotope dilution GC/MS determination of anandamide and other fatty acylethanolamides in rat blood plasma. FEBS Lett 1998; 422(3): 373–6PubMedCrossRefGoogle Scholar
  64. 64.
    Hansen HS, Moesgaard B, Hansen HH, et al. Formation of Nacyl-phosphatidylethanolamine and N-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity. Lipids 1999; 34 Suppl.: S327–30PubMedCrossRefGoogle Scholar
  65. 65.
    Giuffrida A, Parsons LH, Kerr TM, et al. Dopamine activation of endogenous cannabinoid signalling in dorsal striatum. Nat Neurosci 1999; 2(4): 358–63PubMedCrossRefGoogle Scholar
  66. 66.
    Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389(6653): 816–24PubMedCrossRefGoogle Scholar
  67. 67.
    Nagy I, Rang H. Noxious heat activates all capsaicin-sensitive and also a sub-population of capsaicin-insensitive dorsal root ganglion neurons. Neuroscience 1999; 88(4): 995–7PubMedCrossRefGoogle Scholar
  68. 68.
    Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999; 400(6743): 452–7PubMedCrossRefGoogle Scholar
  69. 69.
    Smart D, Gunthorpe MJ, Jerman JC, et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 2000; 129(2): 227–30PubMedCrossRefGoogle Scholar
  70. 70.
    Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995; 50(1): 83–90PubMedCrossRefGoogle Scholar
  71. 71.
    Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 1997; 388(6644): 773–8PubMedCrossRefGoogle Scholar
  72. 72.
    Goparaju SK, Ueda N, Yamaguchi H, et al. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett 1998; 422(1): 69–73PubMedCrossRefGoogle Scholar
  73. 73.
    Bisogno T, Maurelli S, Melck D, et al. Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem 1997; 272(6): 3315–23PubMedCrossRefGoogle Scholar
  74. 74.
    DiMarzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 1994; 372(6507): 686–91PubMedCrossRefGoogle Scholar
  75. 75.
    Calignano A, La Rana G, Giuffrida A, et al. Control of pain initiation by endogenous cannabinoids. Nature 1998; 394(6690): 277–81PubMedCrossRefGoogle Scholar
  76. 76.
    Facci L, Dal Toso R, Romanello S, et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 1995; 92(8): 3376–80PubMedCrossRefGoogle Scholar
  77. 77.
    Calignano A, La Rana G, Piomelli D. Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol 2001; 419(2–3): 191–8PubMedCrossRefGoogle Scholar
  78. 78.
    Di Marzo V, Melck D, Orlando P, et al. Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells. Biochem J 2001; 358 (Pt 1): 249–55PubMedCrossRefGoogle Scholar
  79. 79.
    De Petrocellis L, Davis JB, Di Marzo V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett 2001; 506(3): 253–6PubMedCrossRefGoogle Scholar
  80. 80.
    Hanus L, Abu-Lafi S, Fride E, et al. 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci U S A 2001; 98(7): 3662–5PubMedCrossRefGoogle Scholar
  81. 81.
    Porter AC, Sauer J-M, Knierman MD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 2002; 301(3): 1020–4PubMedCrossRefGoogle Scholar
  82. 82.
    Beltramo M, Stella N, Calignano A, et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 1997; 277(5329): 1094–7PubMedCrossRefGoogle Scholar
  83. 83.
    Maccarrone M, van der Stelt M, Rossi A, et al. Anandamide hydrolysis by human cells in culture and brain. J Biol Chem 1998; 273(48): 32332–9PubMedCrossRefGoogle Scholar
  84. 84.
    Beltramo M, Piomelli D. Carrier-mediated transport and enzymatichydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 2000; 11(6): 1231–5PubMedCrossRefGoogle Scholar
  85. 85.
    Maccarrone M, Bari M, Lorenzon T, et al. Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J Biol Chem 2000; 275(18): 13484–92PubMedCrossRefGoogle Scholar
  86. 86.
    Beltramo M, de Fonseca FR, Navarro M, et al. Reversal of dopamine D (2) receptor responses by an anandamide transport inhibitor. J Neurosci 2000; 20(9): 3401–7PubMedGoogle Scholar
  87. 87.
    Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000; 396(1): 39–42PubMedCrossRefGoogle Scholar
  88. 88.
    Cravatt BF, Giang DK, Mayfield SP, et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996; 384: 83–7PubMedCrossRefGoogle Scholar
  89. 89.
    Deutsch DG, Glaser ST, Howell JM, et al. The cellular uptake of anandamide is coupled to its breakdown by fatty-acid amide hydrolase. J Biol Chem 2001; 276(10): 6967–73PubMedCrossRefGoogle Scholar
  90. 90.
    Egertova M, Giang DK, Cravatt BF, et al. A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc R Soc Lond B Biol Sci 1998; 265(1410): 2081–5CrossRefGoogle Scholar
  91. 91.
    Maccarrone M, Bari M, Menichelli A, et al. Anandamide activates human platelets through a pathway independent of the arachidonate cascade. FEBS Lett 1999; 447(2–3): 277–82PubMedCrossRefGoogle Scholar
  92. 92.
    Maccarrone M, Valensise H, Bari M, et al. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 2000; 355(9212): 1326–9PubMedCrossRefGoogle Scholar
  93. 93.
    Di Marzo V, Bisogno T, De Petrocellis L, et al. Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur J Biochem 1999; 264(1): 258–67PubMedCrossRefGoogle Scholar
  94. 94.
    Cravatt BF, Demarest K, Patricelli MP, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signalling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 2001;98(16):9371–6PubMedCrossRefGoogle Scholar
  95. 95.
    Gifford AN, Bruneus M, Lin S, et al. Potentiation of the action of anandamide on hippocampal slices by the fatty acid amide hydrolase inhibitor, palmitylsulphonyl fluoride (AM 374). Eur J Pharmacol 1999; 383(1): 9–14PubMedCrossRefGoogle Scholar
  96. 96.
    Eissenstat MA, Bell MR, D’Ambra TE, et al. Amino-alkylindoles: structure-activity relationships of novel cannabinoid mimetics. J Med Chem 1995; 38(16): 3094–105PubMedCrossRefGoogle Scholar
  97. 97.
    Huffman JW, Yu S, Showalter V, et al. Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J Med Chem 1996; 39(20): 3875–7PubMedCrossRefGoogle Scholar
  98. 98.
    Rinaldi-Carmona M, Barth F, Heaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994; 350(2–3): 240–4PubMedCrossRefGoogle Scholar
  99. 99.
    Rinaldi-Carmona M, Barth F, Millan J, et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther 1998; 284(2): 644–50PubMedGoogle Scholar
  100. 100.
    Bouaboula M, Perrachon S, Milligan L, 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 1997; 272(35): 22330–9PubMedCrossRefGoogle Scholar
  101. 101.
    MacLennan SJ, Reynen PH, Kwan J,et al. Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors. Br J Pharmacol 1998; 124(4): 619–22PubMedCrossRefGoogle Scholar
  102. 102.
    Bouaboula M, Desnoyer N, Carayon P, et al. Gi protein modulation induced by a selective inverse agonist for the peripheral cannabinoid receptor CB2: implication for intracellular signalization cross-regulation. Mol Pharmacol 1999; 55(3): 473–80PubMedGoogle Scholar
  103. 103.
    Robson P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry 2001; 178: 107–15PubMedCrossRefGoogle Scholar
  104. 104.
    Cannabinoids in multiple sclerosis trial [online]. Available from URL: [Accessed 2002 Mar 26]
  105. 105.
    GW Pharmaceuticals [online]. Available from URL: [Accessed 2002 Mar 26]
  106. 106.
    Fox SH, Kellett M, Moore AP, et al. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Mov Disord 2002; 17(1): 145–9PubMedCrossRefGoogle Scholar
  107. 107.
    Sieradzan KA, Fox SH, Hill M, et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 2001; 57(11): 2108–11PubMedCrossRefGoogle Scholar
  108. 108.
    Frankel JP, Hughes A, Lees AJ, et al. Marijuana for parkinsonian tremor [letter]. J Neurol Neurosurg Psychiatry 1990; 53(5): 436PubMedCrossRefGoogle Scholar
  109. 109.
    Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 1981; 21(8–9 Suppl.): 320S–6SPubMedGoogle Scholar
  110. 110.
    Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997; 52(5): 483–6PubMedCrossRefGoogle Scholar
  111. 111.
    Pharmos Corporation [online]. Available from URL: [Accessed 2002 Mar 26]
  112. 112.
    Knoller N, Levi L, Shoshan I, et al. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled phase II clinical trial. Crit Care Med 2002; 30(3): 548–54PubMedCrossRefGoogle Scholar
  113. 113.
    Fishman RHB. Cannabinoid derivative protects neurons [abstract]. Lancet 1996; 348(9039): 1436Google Scholar
  114. 114.
    Dalton R. Californian centre will test medical uses of cannabis [abstract]. Nature 2000; 407(6800): 6PubMedCrossRefGoogle Scholar
  115. 115.
    Anonymous. Medical marijuana study in San Francisco: pays $1000, 25 days in hospital. AIDS Treat News 1998; 296: 3-4Google Scholar
  116. 116.
    Beal JE, Olson R, Lefkowitz L, et al. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 1997; 14(1): 7–14PubMedCrossRefGoogle Scholar
  117. 117.
    Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995; 10(2): 89–97PubMedCrossRefGoogle Scholar
  118. 118.
    Muller-Vahl KR, Koblenz A, Jobges M, et al. Influence of treatment of Tourette syndrome with delta9-tetrahydrocan-nabinol (delta9-THC) on neuropsychological performance. Pharmacopsychiatry 2001; 34(1): 19–24PubMedCrossRefGoogle Scholar
  119. 119.
    National Multiple Sclerosis Society [online]. Available from URL: [Accessed 2003 Jan 2]
  120. 120.
    Noth J. Trends in the pathophysiology and pharmacotherapy of spasticity. J Neurol 1991; 238(3): 131–9PubMedCrossRefGoogle Scholar
  121. 121.
    Cutter NC, Scott DD, Johnson JC, et al. Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial. Arch Phys Med Rehabil 2000; 81(2): 164–9PubMedGoogle Scholar
  122. 122.
    Goodkin DE. Current disease-modifying therapies in multiple sclerosis. In: Raine CS, McFarlin HF, Tourtellotte WW, editors. Multiple sclerosis: clinical and pathogenetic basis. London: Chapman and Hall, 1997: 309–23Google Scholar
  123. 123.
    Consroe P, Musty R, Rein J, et al. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol 1997; 38(1): 44–8PubMedCrossRefGoogle Scholar
  124. 124.
    Black JA, Dib-Hajj S, Baker D, et al. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Proc Natl Acad Sci U S A 2000; 97(21): 11598–602PubMedCrossRefGoogle Scholar
  125. 125.
    Turski L, Klockgether T, Schwarz M, et al. Substantia nigra: a site of action of muscle relaxant drugs. Ann Neurol 1990; 28(3): 341–8PubMedCrossRefGoogle Scholar
  126. 126.
    Szabo B, Wallmichrath I, Mathonia P, et al. Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 2000; 97(1): 89–97PubMedCrossRefGoogle Scholar
  127. 127.
    Garcia-Gil L, de Miguel R, Romero J, et al. Perinatal delta9-te-trahydrocannabinol exposure augmented the magnitude of motor inhibition caused by GABA (B), but not GABA (A), receptor agonists in adult rats. Neurotoxicol Teratol 1999; 21(3): 277–83PubMedCrossRefGoogle Scholar
  128. 128.
    Baker D, O’Neill JK, Gschmeissner SE, et al. Induction of chronic relapsing experimental allergic encephalomyelitis in Biozzi mice. J Neuroimmunol 1990; 28(3): 261–70PubMedCrossRefGoogle Scholar
  129. 129.
    Baker D, Pryce G, Croxford JL, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000; 404(6773): 84–7PubMedCrossRefGoogle Scholar
  130. 130.
    Brooks JW, Pryce G, Bisogno T, et al. Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB(1)/CB(2) receptors. Eur J Pharmacol 2002; 439(1-3): 83–92PubMedCrossRefGoogle Scholar
  131. 131.
    Melck D, Bisogno T, De Petrocellis L, et al. Unsaturated long-chain N-acylvanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors. Biochem Biophys Res Commun 1999; 262(1): 275–84PubMedCrossRefGoogle Scholar
  132. 132.
    Klein TW, Newton C, Zhu W, et al. Delta9-tetrahydrocannabinol, cytokines, and immunity to Legionella pneumophila. Proc Soc Exp Biol Med 1995; 209(3): 205–12PubMedGoogle Scholar
  133. 133.
    Klein TW, Lane B, Newton CA, et al. The cannabinoid system and cytokine network. Proc Soc Exp Biol Med 2000; 225(1): 1–8PubMedCrossRefGoogle Scholar
  134. 134.
    Klein TW, Newton C, Friedman H. Cannabinoid receptors and immunity. Immunol Today 1998; 19(8): 373–81PubMedCrossRefGoogle Scholar
  135. 135.
    Maimone D, Gregory S, Arnason BG, et al. Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J Neuroimmunol 1991; 32(1): 67–74PubMedCrossRefGoogle Scholar
  136. 136.
    Selmaj K, Raine CS, Cannella B, et al. Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest 1991; 87(3): 949–54PubMedCrossRefGoogle Scholar
  137. 137.
    Mageed RA, Adams G, Woodrow D, et al. Prevention of collagen-induced arthritis by gene delivery of soluble p75 tumour necrosis factor receptor. Gene Ther 1998; 5(12): 1584–92PubMedCrossRefGoogle Scholar
  138. 138.
    Triantaphyllopoulos KA, Williams RO, Tailor H, et al. Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin-12, and tumor necrosis factor alpha production by interferon-beta gene therapy. Arthritis Rheum 1999; 42(1): 90–9PubMedCrossRefGoogle Scholar
  139. 139.
    Croxford JL, Feldmann M, Chernajovsky Y, et al. Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system. J Immunol 2001; 166(6): 4124–30PubMedGoogle Scholar
  140. 140.
    Croxford JL, Triantaphyllopoulos KA, Neve RM, et al. Gene therapy for chronic relapsing experimental allergic encephalomyelitis using cells expressing a novel soluble p75 dimeric TNF receptor. J Immunol 2000; 164(5): 2776–81PubMedGoogle Scholar
  141. 141.
    Croxford JL, Triantaphyllopoulos K, Podhajcer OL, et al. Cytokine gene therapy in experimental allergic encephalomyelitis by injection of plasmid DNA-cationic liposome complex into the central nervous system. J Immunol 1998; 160(10): 5181–7PubMedGoogle Scholar
  142. 142.
    Racke MK, Dhib-Jalbut S, Cannella B, et al. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta1. J Immunol 1991; 146(9): 3012–7PubMedGoogle Scholar
  143. 143.
    Lyman WD, Sonett JR, Brosnan CF, et al. Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol 1989; 23(1): 73–81PubMedCrossRefGoogle Scholar
  144. 144.
    Wirguin I, Mechoulam R, Breuer A, et al. Suppression of experimental autoimmune encephalomyelitis by cannabinoids. Immunopharmacology 1994; 28(3): 209–14PubMedCrossRefGoogle Scholar
  145. 145.
    Burnette-Curley D, Cabrai GA. Differential inhibition of RAW264.7 macrophage tumoricidal activity by delta 9-tetrahydrocannabinol. Proc Soc Exp Biol Med 1995; 210(1): 64–76PubMedGoogle Scholar
  146. 146.
    Achiron A, Miron S, Lavie V, et al. Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis. J Neuroimmunol 2000; 102(1): 26–31PubMedCrossRefGoogle Scholar
  147. 147.
    Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000; 6(1): 67–70PubMedCrossRefGoogle Scholar
  148. 148.
    Werner P, Pitt D, Raine CS. Glutamate excitotoxicity: a mechanism for axonal damage and oligodendrocyte death in multiple sclerosis? J Neural Transm Suppl 2000; 60: 375–85PubMedGoogle Scholar
  149. 149.
    Marjama-Lyons J, Koller W. Tremor-predominant Parkinson’s disease: approaches to treatment. Drugs Aging 2000; 16(4): 273–8PubMedCrossRefGoogle Scholar
  150. 150.
    Herkenham M, Lynn AB, de Costa BR, et al. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res 1991; 547(2): 267–74PubMedCrossRefGoogle Scholar
  151. 151.
    Maneuf YP, Crossman AR, Brotchie JM. Modulation of GAB Aergic transmission in the globus pallidus by the synthetic cannabinoid WIN 55,212-2. Synapse 1996; 22(4): 382–5PubMedCrossRefGoogle Scholar
  152. 152.
    Gough AL, Olley JE. Catalepsy induced by intrastriatal injections of delta9-THC and 11-OH-delta9-THC in the rat. Neuropharmacology 1978; 17(2): 137–44PubMedCrossRefGoogle Scholar
  153. 153.
    DiMarzo V, Hill MP, Bisogno T, et al. 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 2000; 14(10): 1432–8CrossRefGoogle Scholar
  154. 154.
    Vingerhoets FJ, Schulzer M, Calne DB, et al. Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 1997; 41(1): 58–64PubMedCrossRefGoogle Scholar
  155. 155.
    Hampson AJ, Grimaldi M, Axelrod J, et al. Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 1998; 95(14): 8268–73PubMedCrossRefGoogle Scholar
  156. 156.
    Biegon A. Neuroprotective activity of HU-211, a novel nonpsychotropic synthetic cannabinoid [abstract]. Ann N Y Acad Sci 1995; 765: 314PubMedCrossRefGoogle Scholar
  157. 157.
    Olney JW. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus: an electron microscopic study. J Neuropathol Exp Neurol 1971; 30(1): 75–90PubMedCrossRefGoogle Scholar
  158. 158.
    Sinor AD, Irvin SM, Greenberg DA. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett 2000; 278(3): 157–60PubMedCrossRefGoogle Scholar
  159. 159.
    Shen M, Thayer SA. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 1998; 54(3): 459–62PubMedGoogle Scholar
  160. 160.
    Leker RR, Shohami E, Abramsky O, et al. Dexanabinol; a novel neuroprotective drug in experimental focal cerebral ischemia. J Neurol Sci 1999; 162(2): 114–9PubMedCrossRefGoogle Scholar
  161. 161.
    van der Stelt M, Veldhuis WB, van Haaften GW, et al. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci 2001; 21(22): 8765–71PubMedGoogle Scholar
  162. 162.
    van der Stelt M, Veldhuis WB, Bar PR, et al. Neuroprotection by A9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neurosci 2001; 21(17): 6475–9PubMedGoogle Scholar
  163. 163.
    Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 2001; 413(6855): 527–31PubMedCrossRefGoogle Scholar
  164. 164.
    Nagayama T, Sinor AD, Simon RP, et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 1999; 19(8): 2987–95PubMedGoogle Scholar
  165. 165.
    Lavie G, Teichner A, Shohami E, et al. Long term cerebroprotective effects of dexanabinol in a model of focal cerebral ischemia. Brain Res 2001; 901(1–2): 195–201PubMedCrossRefGoogle Scholar
  166. 166.
    Hansen HH, Schmid PC, Bittigau P, et al. Anandamide, but not 2-arachidonylglycerol, accumulates during in vivo neurodegeneration. J Neurochem 2001; 78: 1415–27PubMedCrossRefGoogle Scholar
  167. 167.
    Shohami E, Gallily R, Mechoulam R, et al. Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant. J Neuroimmunol 1997; 72(2): 169–77PubMedCrossRefGoogle Scholar
  168. 168.
    Gallily R, Breuer A, Mechoulam R. 2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-α production in murine macrophages, and in mice. Eur J Pharmacol 2000; 406: R5–7PubMedCrossRefGoogle Scholar
  169. 169.
    Walker JM, Huang SM, Strangman NM, et al. Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 1999; 96(21): 12198–203PubMedCrossRefGoogle Scholar
  170. 170.
    Farquhar-Smith WP, Egertova M, Bradbury EJ, et al. Cannabinoid CB (1) receptor expression in rat spinal cord. Mol Cell Neurosci 2000; 15(6): 510–21PubMedCrossRefGoogle Scholar
  171. 171.
    Walker JM, Hohmann AG, Martin WJ, et al. The neurobiology of cannabinoid analgesia. Life Sci 1999; 65(6/7): 665–73PubMedCrossRefGoogle Scholar
  172. 172.
    Herzberg U, Eliav E, Bennett GJ, et al. The analgesic effects of R (+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett 1997; 221(2–3): 157–60PubMedCrossRefGoogle Scholar
  173. 173.
    Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 1998; 345(2): 145–53PubMedCrossRefGoogle Scholar
  174. 174.
    Fox A, Kesingland A, Gentry C, et al. The role of central and peripheral cannabinoid 1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 2001; 92(1–2): 91–100PubMedCrossRefGoogle Scholar
  175. 175.
    Bridges D, Ahmad K, Rice AS. The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol 2001; 133(4): 586–94PubMedCrossRefGoogle Scholar
  176. 176.
    Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998; 75(1): 111–9PubMedCrossRefGoogle Scholar
  177. 177.
    Richardson JD, Aanonsen L, Hargreaves KM. SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur J Pharmacol 1997; 319(2–3): R3–4PubMedCrossRefGoogle Scholar
  178. 178.
    Campbell FA, Tramer MR, Carroll D, et al. Are cannabinoids an effective and safe treatment option in the management of pain?: a qualitative systematic review. BMJ 2001; 323(7303): 13–6PubMedCrossRefGoogle Scholar
  179. 179.
    Welch SP, Stevens DL. Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther 1992; 262(1): 10–8PubMedGoogle Scholar
  180. 180.
    Darmani NA. Delta (9)-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB (1) receptor antagonist/inverse agonist SR 141716A. Neuropsychopharmacology 2001; 24(2): 198–203PubMedCrossRefGoogle Scholar
  181. 181.
    Darmani NA. The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2. Eur J Pharmacol 2001; 430(1): 49–58PubMedCrossRefGoogle Scholar
  182. 182.
    Van Sickle MD, Oland LD, Ho W, et al. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology 2001; 121(4): 767–74PubMedCrossRefGoogle Scholar
  183. 183.
    Parker LA, Kemp SW. Tetrahydrocannabinol (THC) interferes with conditioned retching in Suncus murinus: an animal model of anticipatory nausea and vomiting (ANV). Neuroreport 2001; 12(4): 749–51PubMedCrossRefGoogle Scholar
  184. 184.
    Parker LA, Mechoulam R, Schlievert C. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport 2002; 13(5): 567–70PubMedCrossRefGoogle Scholar
  185. 185.
    Tramer MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001; 323(7303): 16–21PubMedCrossRefGoogle Scholar
  186. 186.
    Ye JH, Ponnudurai R, Schaefer R. Ondansetron: a selective 5-HT (3) receptor antagonist and its applications in CNS-related disorders. CNS Drug Rev 2001; 7(2): 199–213PubMedCrossRefGoogle Scholar
  187. 187.
    Dalzell AM, Bartlett H, Lilleyman JS. Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child 1986; 61(5): 502–5PubMedCrossRefGoogle Scholar
  188. 188.
    Chan HS, Correia JA, MacLeod SM. Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 1987; 79(6): 946–52PubMedGoogle Scholar
  189. 189.
    Mechoulam R. Recent advantages in cannabinoid research. Forsch Komplementarmed 1999; 6Suppl. 3: 16–20PubMedCrossRefGoogle Scholar
  190. 190.
    Hirst RA, Lambert DG, Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. Br J Anaesth 1998; 81(1): 77–84PubMedCrossRefGoogle Scholar
  191. 191.
    Cat LK, Coleman RL. Treatment for HIV wasting syndrome. Ann Pharmacother 1994; 28(5): 595–7PubMedGoogle Scholar
  192. 192.
    Plasse TF, Gorter RW, Krasnow SH, et al. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 1991; 40(3): 695–700PubMedCrossRefGoogle Scholar
  193. 193.
    Struwe M, Kaempfer SH, Geiger CJ, et al. Effect of dronabinol on nutritional status in HIV infection. Ann Pharmacother 1993; 27(7–8): 827–31PubMedGoogle Scholar
  194. 194.
    Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 2001; 134(6): 1151–4PubMedCrossRefGoogle Scholar
  195. 195.
    Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology 1999; 143(3): 315–7PubMedCrossRefGoogle Scholar
  196. 196.
    Rowland NE, Mukherjee M, Robertson K. Effects of the cannabinoid receptor antagonist SR 141716, alone and in combination with dexfenfluramine or naloxone, on food intake in rats. Psychopharmacology 2001; 159(1): 111–6PubMedCrossRefGoogle Scholar
  197. 197.
    Colombo G, Agabio R, Diaz G, et al. Appetite suppression and weight loss after the cannabinoid antagonist SR141716. Life Sci 1998; 63(8): PLI 13–7CrossRefGoogle Scholar
  198. 198.
    Sanofi Synthelabo US [online]. Available from URL: [Accessed 2002 Mar 26]
  199. 199.
    DiMarzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410(6830): 822–5PubMedCrossRefGoogle Scholar
  200. 200.
    Busto U, Bendayan R, Sellers EM. Clinical pharmacokinetics of non-opiate abused drugs. Clin Pharmacokinet 1989; 16(1): 1–26PubMedCrossRefGoogle Scholar
  201. 201.
    Maykut MO. Health consequences of acute and chronic marihuana use. Prog Neuropsychopharmacol Biol Psychiatry 1985; 9(3): 209–38PubMedCrossRefGoogle Scholar
  202. 202.
    Agurell S, Halldin M, Lindgren J-E, et al. Pharmacokinetics and metabolism of Δ1-tetrahydrocannabinol and other compounds with emphasis on man. Pharmacol Rev 1986; 38(10): 21–43PubMedGoogle Scholar
  203. 203.
    Ashton CH. Adverse effects of cannabis and cannabinoids. Br J Anaesth 1999; 83(4): 637–49PubMedCrossRefGoogle Scholar
  204. 204.
    Kovasznay B, Fleischer J, Tanenberg-Karant M, et al. Substance use disorder and the early course of illness in schizophrenia and affective psychosis. Schizophr Bull 1997; 23(2): 195–201PubMedCrossRefGoogle Scholar
  205. 205.
    Paton WDM, Pertwee RG. The actions of cannabis in man. In: Mechoulam R, editor. Marijuana: chemistry, pharmacology, metabolism and clinical effects. New York: Academic Press, 1973: 288–334Google Scholar
  206. 206.
    Nahas G. General toxicity of cannabis. In: Nahas GG, Latour C, editors. Cannabis: pathophysiology, epidemiology, detection. Boca Raton (FL): CRC Press, 1993: 5–17Google Scholar
  207. 207.
    Heishman SJ, Arasteh K, Stitzer ML. Comparative effects of alcohol and marijuana on mood, memory, and performance. Pharmacol Biochem Behav 1997; 58(1): 93–101PubMedCrossRefGoogle Scholar
  208. 208.
    Pertwee RG. Tolerance to and dependence on psychotropic cannabinoids. In: Pratt JA, editor. The biological basis of drug tolerance and dependence. New York: Academic Press, 1991: 232–63Google Scholar
  209. 209.
    Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998: 352(9140): 1611–6PubMedCrossRefGoogle Scholar
  210. 210.
    Niederhoffer N, Szabo B. Effect of the cannabinoid receptor agonist WIN55212-2 on sympathetic cardiovascular regulation. Br J Pharmacol 1999; 126(2): 457–66PubMedCrossRefGoogle Scholar
  211. 211.
    Leweke FM, Giuffrida A, Wurster U, et al. Elevated endogenous cannabinoids in schizophrenia. Neuroreport 1999; 10(8): 1665–9PubMedCrossRefGoogle Scholar
  212. 212.
    Hepler RS, Frank IR. Marijuana smoking and intraocular pressure [abstract]. JAMA 1971; 217(10): 1392PubMedCrossRefGoogle Scholar
  213. 213.
    Ashton H, Golding J, Marsh VR, et al. The seed and the soil: effect of dosage, personality and starting state on the response to delta 9 tetrahydrocannabinol in man. Br J Clin Pharmacol 1981; 12(5): 705–20PubMedCrossRefGoogle Scholar
  214. 214.
    Emrich HM, Leweke FM, Schneider U. Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol Biochem Behav 1997; 56(4): 803–7PubMedCrossRefGoogle Scholar
  215. 215.
    Leweke FM, Schneider U, Radwan M, et al. Different effects of nabilone and cannabidiol on binocular depth inversion in man. Pharmacol Biochem Behav 2000; 66(1): 175–81PubMedCrossRefGoogle Scholar
  216. 216.
    Zuardi AW, Morais SL, Guimaraes FS, et al. Antipsychotic effect of cannabidiol. J Clin Psychiatry 1995; 56(10): 485–6PubMedGoogle Scholar
  217. 217.
    Penta JS, Poster DS, Bruno S, et al. Clinical trials with antiemetic agents in cancer patients receiving chemotherapy. J Clin Pharmacol 1981; 21(8–9 Suppl.): 11S–22SPubMedGoogle Scholar
  218. 218.
    Lichtman AH, Peart J, Poklis JL, et al. Pharmacological evaluation of aerosolized cannabinoids in mice. Eur J Pharmacol 2000; 399(2-3): 141–9PubMedCrossRefGoogle Scholar
  219. 219.
    Lemberger L. Tetrahydrocannabinol metabolism in man. Drug Metab Dispos 1973; 1: 461–8PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Department of Microbiology — ImmunologyNorthwestern University Medical SchoolChicagoUSA

Personalised recommendations