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Therapeutic Potential of Cannabinoids in CNS Disease

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Abstract

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.

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References

  1. Vincent BJ, McQuiston DJ, Einhorn LH, et al. Review of cannabinoids and their anti-emetic effectiveness. Drugs 1983; 25Suppl. 1: 52–62

    Article  PubMed  Google Scholar 

  2. Gaoni Y, Mechoulam R. Isolation, structure elucidation and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964; 86: 1646–7

    Article  CAS  Google Scholar 

  3. Howlett AC, Barth F, Bonner G, et al. International union of pharmacology. XXVII: classification of cannabinoid receptors. Pharmacol Rev 2002; 54: 161–202

    CAS  Google Scholar 

  4. Devane WA, Dysarz FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605–13

    PubMed  CAS  Google Scholar 

  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: 1946–9

    Article  PubMed  CAS  Google Scholar 

  6. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993; 365: 61–5

    Article  PubMed  CAS  Google Scholar 

  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): 561–4

    Article  PubMed  CAS  Google Scholar 

  8. Howlett AC, Qualy JM, Khachatrian LL. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol 1986; 29(3): 307–13

    PubMed  CAS  Google Scholar 

  9. Pacheco MA, Ward SJ, Childers SR. Identification of cannabinoid receptors in cultures of rat cerebellar granule cells. Brain Res 1993; 603(1): 102–10

    Article  PubMed  CAS  Google Scholar 

  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): 603–5

    Article  PubMed  CAS  Google Scholar 

  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): 377–87

    Article  PubMed  Google Scholar 

  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): 219–24

    Article  PubMed  CAS  Google Scholar 

  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): 507–16

    Article  PubMed  CAS  Google Scholar 

  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): 338–48

    Article  PubMed  Google Scholar 

  15. McPartland J, Di Marzo V, De Petrocellis L, et al. Cannabinoid receptors are absent in insects. J Comp Neurol 2001; 436(4): 423–9

    Article  PubMed  CAS  Google Scholar 

  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): 3726–31

    Article  PubMed  CAS  Google Scholar 

  17. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74(2): 129–80

    Article  PubMed  CAS  Google Scholar 

  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): 563–83

    PubMed  CAS  Google Scholar 

  19. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990; 87(5): 1932–6

    Article  PubMed  CAS  Google Scholar 

  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): 391–402

    Article  Google Scholar 

  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): 655–68

    Article  PubMed  CAS  Google Scholar 

  22. Lichtman AH, Martin BR. Spinal and supraspinal components of cannabinoid-induced antinociception. J Pharmacol Exp Ther 1991; 258(2): 517–23

    PubMed  CAS  Google Scholar 

  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): 2111–8

    Article  PubMed  CAS  Google Scholar 

  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): 795–7

    Article  PubMed  CAS  Google Scholar 

  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): 437–40

    PubMed  CAS  Google Scholar 

  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): 54–61

    Article  PubMed  CAS  Google Scholar 

  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): 597–604

    Article  PubMed  CAS  Google Scholar 

  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): 1393–5

    Article  PubMed  CAS  Google Scholar 

  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): 227–32

    Article  PubMed  CAS  Google Scholar 

  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): 2442–8

    PubMed  CAS  Google Scholar 

  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): 240–5

    Article  PubMed  CAS  Google Scholar 

  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): 53–61

    Article  PubMed  CAS  Google Scholar 

  33. Lu Q, Straiker A, Maguire G. Expression of CB2 cannabinoid receptor mRNA in adult rat retina. Vis Neurosci 2001; 17(1): 91–5

    Google Scholar 

  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): 3984–9

    Article  PubMed  CAS  Google Scholar 

  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): 299–318

    Article  PubMed  CAS  Google Scholar 

  36. Dewey WL. Cannabinoid pharmacology. Pharmacol Rev 1986; 38(2): 151–78

    PubMed  CAS  Google Scholar 

  37. Barth F, Rinaldi-Carmona M. The development of cannabinoid antagonists. Curr Med Chem 1999; 6(8): 745–55

    PubMed  CAS  Google Scholar 

  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): 165–72

    Article  CAS  Google Scholar 

  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): 1612–23

    PubMed  CAS  Google Scholar 

  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): 5327–33

    PubMed  CAS  Google Scholar 

  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): 1397–8

    Article  PubMed  CAS  Google Scholar 

  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): 443–50

    PubMed  CAS  Google Scholar 

  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): 3825–9

    Article  PubMed  CAS  Google Scholar 

  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): 6552–61

    PubMed  CAS  Google Scholar 

  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): 637–41

    PubMed  CAS  Google Scholar 

  46. Liu J, Gao B, Mirshahi F, et al. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 2000; 346 (Pt 3): 835–40

    Article  PubMed  CAS  Google Scholar 

  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): 2023–8

    Article  PubMed  CAS  Google Scholar 

  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): 466–70

    Article  PubMed  CAS  Google Scholar 

  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): 19–24

    Article  PubMed  CAS  Google Scholar 

  50. Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 2001; 410: 588–92

    Article  PubMed  CAS  Google Scholar 

  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): 4322–34

    PubMed  CAS  Google Scholar 

  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): 155–63

    PubMed  CAS  Google Scholar 

  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: 2434–44

    Article  PubMed  Google Scholar 

  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): 14136–41

    Article  PubMed  CAS  Google Scholar 

  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): 989–99

    PubMed  CAS  Google Scholar 

  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): 117–20

    Article  PubMed  CAS  Google Scholar 

  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): 51–6

    Article  PubMed  CAS  Google Scholar 

  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): 231–5

    Article  PubMed  CAS  Google Scholar 

  59. Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 2001; 15(2): 300–2

    PubMed  CAS  Google Scholar 

  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): 1959–68

    Article  PubMed  CAS  Google Scholar 

  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): 1538–46

    Article  PubMed  CAS  Google Scholar 

  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): 4188–92

    Article  PubMed  CAS  Google Scholar 

  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): 373–6

    Article  PubMed  CAS  Google Scholar 

  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.: S327–30

    Article  PubMed  CAS  Google Scholar 

  65. Giuffrida A, Parsons LH, Kerr TM, et al. Dopamine activation of endogenous cannabinoid signalling in dorsal striatum. Nat Neurosci 1999; 2(4): 358–63

    Article  PubMed  CAS  Google Scholar 

  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): 816–24

    Article  PubMed  CAS  Google Scholar 

  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): 995–7

    Article  PubMed  CAS  Google Scholar 

  68. Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999; 400(6743): 452–7

    Article  PubMed  CAS  Google Scholar 

  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): 227–30

    Article  PubMed  CAS  Google Scholar 

  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): 83–90

    Article  PubMed  CAS  Google Scholar 

  71. Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 1997; 388(6644): 773–8

    Article  PubMed  CAS  Google Scholar 

  72. Goparaju SK, Ueda N, Yamaguchi H, et al. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett 1998; 422(1): 69–73

    Article  PubMed  CAS  Google Scholar 

  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): 3315–23

    Article  PubMed  CAS  Google Scholar 

  74. DiMarzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 1994; 372(6507): 686–91

    Article  PubMed  Google Scholar 

  75. Calignano A, La Rana G, Giuffrida A, et al. Control of pain initiation by endogenous cannabinoids. Nature 1998; 394(6690): 277–81

    Article  PubMed  CAS  Google Scholar 

  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): 3376–80

    Article  PubMed  CAS  Google Scholar 

  77. Calignano A, La Rana G, Piomelli D. Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol 2001; 419(2–3): 191–8

    Article  PubMed  CAS  Google Scholar 

  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): 249–55

    Article  PubMed  Google Scholar 

  79. De Petrocellis L, Davis JB, Di Marzo V. Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett 2001; 506(3): 253–6

    Article  PubMed  Google Scholar 

  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): 3662–5

    Article  PubMed  CAS  Google Scholar 

  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): 1020–4

    Article  PubMed  CAS  Google Scholar 

  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): 1094–7

    Article  PubMed  CAS  Google Scholar 

  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): 32332–9

    Article  PubMed  CAS  Google Scholar 

  84. Beltramo M, Piomelli D. Carrier-mediated transport and enzymatichydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 2000; 11(6): 1231–5

    Article  PubMed  CAS  Google Scholar 

  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): 13484–92

    Article  PubMed  CAS  Google Scholar 

  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): 3401–7

    PubMed  CAS  Google Scholar 

  87. Zygmunt PM, Chuang H, Movahed P, et al. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 2000; 396(1): 39–42

    Article  PubMed  CAS  Google Scholar 

  88. Cravatt BF, Giang DK, Mayfield SP, et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996; 384: 83–7

    Article  PubMed  CAS  Google Scholar 

  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): 6967–73

    Article  PubMed  CAS  Google Scholar 

  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): 2081–5

    Article  CAS  Google Scholar 

  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): 277–82

    Article  PubMed  CAS  Google Scholar 

  92. Maccarrone M, Valensise H, Bari M, et al. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 2000; 355(9212): 1326–9

    Article  PubMed  CAS  Google Scholar 

  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): 258–67

    Article  PubMed  Google Scholar 

  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):9371–6

    Article  PubMed  CAS  Google Scholar 

  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): 9–14

    Article  PubMed  CAS  Google Scholar 

  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): 3094–105

    Article  PubMed  CAS  Google Scholar 

  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): 3875–7

    Article  PubMed  CAS  Google Scholar 

  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): 240–4

    Article  PubMed  CAS  Google Scholar 

  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): 644–50

    PubMed  CAS  Google Scholar 

  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): 22330–9

    Article  PubMed  CAS  Google Scholar 

  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): 619–22

    Article  PubMed  CAS  Google Scholar 

  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): 473–80

    PubMed  CAS  Google Scholar 

  103. Robson P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry 2001; 178: 107–15

    Article  PubMed  CAS  Google Scholar 

  104. Cannabinoids in multiple sclerosis trial [online]. Available from URL: http://www.cannabis-trial.Plymouth.ac.uk [Accessed 2002 Mar 26]

  105. GW Pharmaceuticals [online]. Available from URL: http://www.gwpharm.com [Accessed 2002 Mar 26]

  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): 145–9

    Article  PubMed  Google Scholar 

  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): 2108–11

    Article  PubMed  CAS  Google Scholar 

  108. Frankel JP, Hughes A, Lees AJ, et al. Marijuana for parkinsonian tremor [letter]. J Neurol Neurosurg Psychiatry 1990; 53(5): 436

    Article  PubMed  CAS  Google Scholar 

  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–6S

    PubMed  CAS  Google Scholar 

  110. Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997; 52(5): 483–6

    Article  PubMed  CAS  Google Scholar 

  111. Pharmos Corporation [online]. Available from URL: http://www.pharmoscorp.com [Accessed 2002 Mar 26]

  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): 548–54

    Article  PubMed  CAS  Google Scholar 

  113. Fishman RHB. Cannabinoid derivative protects neurons [abstract]. Lancet 1996; 348(9039): 1436

    Google Scholar 

  114. Dalton R. Californian centre will test medical uses of cannabis [abstract]. Nature 2000; 407(6800): 6

    Article  PubMed  CAS  Google Scholar 

  115. Anonymous. Medical marijuana study in San Francisco: pays $1000, 25 days in hospital. AIDS Treat News 1998; 296: 3-4

  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): 7–14

    Article  PubMed  CAS  Google Scholar 

  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): 89–97

    Article  PubMed  CAS  Google Scholar 

  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): 19–24

    Article  PubMed  CAS  Google Scholar 

  119. National Multiple Sclerosis Society [online]. Available from URL: http://nationalmssociety.org [Accessed 2003 Jan 2]

  120. Noth J. Trends in the pathophysiology and pharmacotherapy of spasticity. J Neurol 1991; 238(3): 131–9

    Article  PubMed  CAS  Google Scholar 

  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): 164–9

    PubMed  CAS  Google Scholar 

  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: 309–23

    Google Scholar 

  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): 44–8

    Article  PubMed  CAS  Google Scholar 

  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): 11598–602

    Article  PubMed  CAS  Google Scholar 

  125. Turski L, Klockgether T, Schwarz M, et al. Substantia nigra: a site of action of muscle relaxant drugs. Ann Neurol 1990; 28(3): 341–8

    Article  PubMed  CAS  Google Scholar 

  126. Szabo B, Wallmichrath I, Mathonia P, et al. Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 2000; 97(1): 89–97

    Article  PubMed  CAS  Google Scholar 

  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): 277–83

    Article  PubMed  CAS  Google Scholar 

  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): 261–70

    Article  PubMed  CAS  Google Scholar 

  129. Baker D, Pryce G, Croxford JL, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000; 404(6773): 84–7

    Article  PubMed  CAS  Google Scholar 

  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): 83–92

    Article  PubMed  CAS  Google Scholar 

  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): 275–84

    Article  PubMed  CAS  Google Scholar 

  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): 205–12

    PubMed  CAS  Google Scholar 

  133. Klein TW, Lane B, Newton CA, et al. The cannabinoid system and cytokine network. Proc Soc Exp Biol Med 2000; 225(1): 1–8

    Article  PubMed  CAS  Google Scholar 

  134. Klein TW, Newton C, Friedman H. Cannabinoid receptors and immunity. Immunol Today 1998; 19(8): 373–81

    Article  PubMed  CAS  Google Scholar 

  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): 67–74

    Article  PubMed  CAS  Google Scholar 

  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): 949–54

    Article  PubMed  CAS  Google Scholar 

  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): 1584–92

    Article  PubMed  CAS  Google Scholar 

  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): 90–9

    Article  PubMed  CAS  Google Scholar 

  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): 4124–30

    PubMed  CAS  Google Scholar 

  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): 2776–81

    PubMed  CAS  Google Scholar 

  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): 5181–7

    PubMed  CAS  Google Scholar 

  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): 3012–7

    PubMed  CAS  Google Scholar 

  143. Lyman WD, Sonett JR, Brosnan CF, et al. Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol 1989; 23(1): 73–81

    Article  PubMed  CAS  Google Scholar 

  144. Wirguin I, Mechoulam R, Breuer A, et al. Suppression of experimental autoimmune encephalomyelitis by cannabinoids. Immunopharmacology 1994; 28(3): 209–14

    Article  PubMed  CAS  Google Scholar 

  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): 64–76

    PubMed  CAS  Google Scholar 

  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): 26–31

    Article  PubMed  CAS  Google Scholar 

  147. Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000; 6(1): 67–70

    Article  PubMed  CAS  Google Scholar 

  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: 375–85

    PubMed  Google Scholar 

  149. Marjama-Lyons J, Koller W. Tremor-predominant Parkinson’s disease: approaches to treatment. Drugs Aging 2000; 16(4): 273–8

    Article  PubMed  CAS  Google Scholar 

  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): 267–74

    Article  PubMed  CAS  Google Scholar 

  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): 382–5

    Article  PubMed  CAS  Google Scholar 

  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): 137–44

    Article  PubMed  CAS  Google Scholar 

  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): 1432–8

    Article  CAS  Google Scholar 

  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): 58–64

    Article  PubMed  CAS  Google Scholar 

  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): 8268–73

    Article  PubMed  CAS  Google Scholar 

  156. Biegon A. Neuroprotective activity of HU-211, a novel nonpsychotropic synthetic cannabinoid [abstract]. Ann N Y Acad Sci 1995; 765: 314

    Article  PubMed  CAS  Google Scholar 

  157. Olney JW. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus: an electron microscopic study. J Neuropathol Exp Neurol 1971; 30(1): 75–90

    Article  PubMed  CAS  Google Scholar 

  158. Sinor AD, Irvin SM, Greenberg DA. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett 2000; 278(3): 157–60

    Article  PubMed  CAS  Google Scholar 

  159. Shen M, Thayer SA. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 1998; 54(3): 459–62

    PubMed  CAS  Google Scholar 

  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): 114–9

    Article  PubMed  CAS  Google Scholar 

  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): 8765–71

    PubMed  Google Scholar 

  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): 6475–9

    PubMed  Google Scholar 

  163. Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 2001; 413(6855): 527–31

    Article  PubMed  CAS  Google Scholar 

  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): 2987–95

    PubMed  CAS  Google Scholar 

  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): 195–201

    Article  PubMed  CAS  Google Scholar 

  166. Hansen HH, Schmid PC, Bittigau P, et al. Anandamide, but not 2-arachidonylglycerol, accumulates during in vivo neurodegeneration. J Neurochem 2001; 78: 1415–27

    Article  PubMed  CAS  Google Scholar 

  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): 169–77

    Article  PubMed  CAS  Google Scholar 

  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: R5–7

    Article  PubMed  CAS  Google Scholar 

  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): 12198–203

    Article  PubMed  CAS  Google Scholar 

  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): 510–21

    Article  PubMed  CAS  Google Scholar 

  171. Walker JM, Hohmann AG, Martin WJ, et al. The neurobiology of cannabinoid analgesia. Life Sci 1999; 65(6/7): 665–73

    Article  PubMed  CAS  Google Scholar 

  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): 157–60

    Article  PubMed  CAS  Google Scholar 

  173. Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 1998; 345(2): 145–53

    Article  PubMed  CAS  Google Scholar 

  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): 91–100

    Article  PubMed  CAS  Google Scholar 

  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): 586–94

    Article  PubMed  CAS  Google Scholar 

  176. Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998; 75(1): 111–9

    Article  PubMed  CAS  Google Scholar 

  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): R3–4

    Article  PubMed  CAS  Google Scholar 

  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): 13–6

    Article  PubMed  CAS  Google Scholar 

  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): 10–8

    PubMed  CAS  Google Scholar 

  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): 198–203

    Article  PubMed  CAS  Google Scholar 

  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): 49–58

    Article  PubMed  CAS  Google Scholar 

  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): 767–74

    Article  PubMed  Google Scholar 

  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): 749–51

    Article  PubMed  CAS  Google Scholar 

  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): 567–70

    Article  PubMed  CAS  Google Scholar 

  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): 16–21

    Article  PubMed  CAS  Google Scholar 

  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): 199–213

    Article  PubMed  CAS  Google Scholar 

  187. Dalzell AM, Bartlett H, Lilleyman JS. Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child 1986; 61(5): 502–5

    Article  PubMed  CAS  Google Scholar 

  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): 946–52

    PubMed  CAS  Google Scholar 

  189. Mechoulam R. Recent advantages in cannabinoid research. Forsch Komplementarmed 1999; 6Suppl. 3: 16–20

    Article  PubMed  Google Scholar 

  190. Hirst RA, Lambert DG, Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. Br J Anaesth 1998; 81(1): 77–84

    Article  PubMed  CAS  Google Scholar 

  191. Cat LK, Coleman RL. Treatment for HIV wasting syndrome. Ann Pharmacother 1994; 28(5): 595–7

    PubMed  CAS  Google Scholar 

  192. Plasse TF, Gorter RW, Krasnow SH, et al. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 1991; 40(3): 695–700

    Article  PubMed  CAS  Google Scholar 

  193. Struwe M, Kaempfer SH, Geiger CJ, et al. Effect of dronabinol on nutritional status in HIV infection. Ann Pharmacother 1993; 27(7–8): 827–31

    PubMed  CAS  Google Scholar 

  194. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 2001; 134(6): 1151–4

    Article  PubMed  CAS  Google Scholar 

  195. Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology 1999; 143(3): 315–7

    Article  PubMed  CAS  Google Scholar 

  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): 111–6

    Article  PubMed  CAS  Google Scholar 

  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 13–7

    Article  Google Scholar 

  198. Sanofi Synthelabo US [online]. Available from URL: http://www.sanofi-synthelabous.com [Accessed 2002 Mar 26]

  199. DiMarzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410(6830): 822–5

    Article  PubMed  Google Scholar 

  200. Busto U, Bendayan R, Sellers EM. Clinical pharmacokinetics of non-opiate abused drugs. Clin Pharmacokinet 1989; 16(1): 1–26

    Article  PubMed  CAS  Google Scholar 

  201. Maykut MO. Health consequences of acute and chronic marihuana use. Prog Neuropsychopharmacol Biol Psychiatry 1985; 9(3): 209–38

    Article  PubMed  CAS  Google Scholar 

  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): 21–43

    PubMed  CAS  Google Scholar 

  203. Ashton CH. Adverse effects of cannabis and cannabinoids. Br J Anaesth 1999; 83(4): 637–49

    Article  PubMed  CAS  Google Scholar 

  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): 195–201

    Article  PubMed  CAS  Google Scholar 

  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: 288–334

    Google Scholar 

  206. Nahas G. General toxicity of cannabis. In: Nahas GG, Latour C, editors. Cannabis: pathophysiology, epidemiology, detection. Boca Raton (FL): CRC Press, 1993: 5–17

    Google Scholar 

  207. Heishman SJ, Arasteh K, Stitzer ML. Comparative effects of alcohol and marijuana on mood, memory, and performance. Pharmacol Biochem Behav 1997; 58(1): 93–101

    Article  PubMed  CAS  Google Scholar 

  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: 232–63

    Google Scholar 

  209. Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998: 352(9140): 1611–6

    Article  PubMed  CAS  Google Scholar 

  210. Niederhoffer N, Szabo B. Effect of the cannabinoid receptor agonist WIN55212-2 on sympathetic cardiovascular regulation. Br J Pharmacol 1999; 126(2): 457–66

    Article  PubMed  CAS  Google Scholar 

  211. Leweke FM, Giuffrida A, Wurster U, et al. Elevated endogenous cannabinoids in schizophrenia. Neuroreport 1999; 10(8): 1665–9

    Article  PubMed  CAS  Google Scholar 

  212. Hepler RS, Frank IR. Marijuana smoking and intraocular pressure [abstract]. JAMA 1971; 217(10): 1392

    Article  PubMed  CAS  Google Scholar 

  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): 705–20

    Article  PubMed  CAS  Google Scholar 

  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): 803–7

    Article  PubMed  CAS  Google Scholar 

  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): 175–81

    Article  PubMed  CAS  Google Scholar 

  216. Zuardi AW, Morais SL, Guimaraes FS, et al. Antipsychotic effect of cannabidiol. J Clin Psychiatry 1995; 56(10): 485–6

    PubMed  CAS  Google Scholar 

  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–22S

    PubMed  CAS  Google Scholar 

  218. Lichtman AH, Peart J, Poklis JL, et al. Pharmacological evaluation of aerosolized cannabinoids in mice. Eur J Pharmacol 2000; 399(2-3): 141–9

    Article  PubMed  CAS  Google Scholar 

  219. Lemberger L. Tetrahydrocannabinol metabolism in man. Drug Metab Dispos 1973; 1: 461–8

    PubMed  CAS  Google Scholar 

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Acknowledgements

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.

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Croxford, J.L. Therapeutic Potential of Cannabinoids in CNS Disease. CNS Drugs 17, 179–202 (2003). https://doi.org/10.2165/00023210-200317030-00004

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