Cannabidiol: A promising drug for neurodegenerative disorders?

CNS Neuroscience and Therapeutics

Volumn 15, Issue 1, 2009, Pages 65-75

  Iuvone, Teresa ^a,c   Esposito, Giuseppe ^b   De Filippis, Daniele ^a,c   Scuderi, Caterina ^b   Steardo, Luca ^b  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

^c Endocannabinoid Research Group   (Italy)

Author keywords

Alzheimer disease; Cannabinoid; Movement disorders; Multiple sclerosis; Parkinson disease

Indexed keywords

CANNABIDIOL; CANNABIS; TETRABINEX; UNCLASSIFIED DRUG;

AMYOTROPHIC LATERAL SCLEROSIS; COGNITIVE DEFECT; DEGENERATIVE DISEASE; DRUG MECHANISM; HUNTINGTON CHOREA; INFLAMMATION; MOTOR PERFORMANCE; NEUROPROTECTION; PARKINSON DISEASE; REVIEW;

ALZHEIMER DISEASE; ANIMALS; CANNABIDIOL; CYTOPROTECTION; DISEASE MODELS, ANIMAL; HUMANS; HUNTINGTON DISEASE; MULTIPLE SCLEROSIS; NEURODEGENERATIVE DISEASES; NEUROPROTECTIVE AGENTS; PARKINSON DISEASE; PRION DISEASES;

EID: 60449084214     PISSN: 17555930     EISSN: 17555949     Source Type: Journal    
DOI: 10.1111/j.1755-5949.2008.00065.x     Document Type: Review

References (100)

1. Skovronsky DM, Lee VM, Trojanowski JQ. Neurodegenerative diseases: New concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol 2006 1 : 151 170.
2. Yankner BA, Lu T, Loerch P. The aging brain. Annu Rev Pathol 2008 3 : 41 66.
3. Soto C, Estrada LD. Protein misfolding and neurodegeneration. Arch Neurol 2008 65 : 184 189.
4. Skaper SD. The brain as a target for inflammatory processes and neuroprotective strategies. Ann N Y Acad Sci 2007 1122 : 23 34.
5. DeLegge MH, Smoke A. Neurodegeneration and inflammation. Nutr Clin Pract 2008 23 : 35 41.
6. Di Filippo M, Sarchielli P, Picconi B, Calabresi P. Neuroinflammation and synaptic plasticity: Theoretical basis for a novel, immune-centred, therapeutic approach to neurological disorders. Trends Pharmacol Sci 2008 29 : 402 412.
7. Maragakis NJ, Rothstein JD. Mechanisms of disease: Astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2006 2 : 679 689.
8. Zipp F, Aktas O. The brain as a target of inflammation: Common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 2006 29 : 518 527.
9. Centonze D, Finazzi-Agrò A, Bernardi G, Maccarrone M. The endocannabinoid system in targeting inflammatory neurodegenerative diseases. Trends Pharmacol Sci 2007 28 : 180 187.
10. de Lago E, Fernández-Ruiz J. Cannabinoids and neuroprotection in motor-related disorders. CNS Neurol Disord Drug Targets 2007 6 : 377 387.
11. Mechoulam R. Marihuana chemistry. Science 1970 168 : 1159 1166.
12. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006 58 : 389 462.
13. Pertwee RG. Cannabinoid pharmacology: The first 66 years. Br J Pharmacol 2006 147 (Suppl. 1 S163 S171.
14. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005 310 : 329 332.
15. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR. Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res 2006 1071 : 10 23.
16. Brown AJ. Novel cannabinoid receptors. Br J Pharmacol 2007 52 : 567 575.
17. Di Marzo V. Targeting the endocannabinoid system: To enhance or reduce? Nat Rev Drug Discov 2008 7 : 438 455.
18. Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML. Prevention of Alzheimer's disease pathology by cannabinoids: Neuroprotection mediated by blockade of microglial activation. J Neurosci 2005 25 : 1904 1913.
19. Esposito G, De Filippis D, Steardo L, Scuderi C, Savani C, Cuomo V, Iuvone T. CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons. Neurosci Lett 2006 404 : 342 346.
20. Van Der Stelt M, Mazzola C, Esposito G, Matias I, Petrosino S, De Filippis D, et al. Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: Effect of pharmacological elevation of endocannabinoid levels. Cell Mol Life Sci 2006 63 : 1410 1424.
21. Esposito G, Iuvone T, Savani C, Scuderi C, De Filippis D, Papa M, et al. Opposing control of cannabinoid receptor stimulation on amyloid-beta-induced reactive gliosis: In vitro and in vivo evidence. J Pharmacol Exp Ther 2007 322 : 1144 1152.
22. Iuvone T, Esposito G, De Filippis D, Bisogno T, Petrosino S, Scuderi C, et al. Cannabinoid CB(1) receptor stimulation affords neuroprotection in MPTP-induced neurotoxicity by attenuating S100B up-regulation in vitro. J Mol Med 2007 85 : 1379 1392.
23. Esposito G, Ligresti A, Izzo AA, Bisogno T, Ruvo M, Di Rosa M, et al. The endocannabinoid system protects rat glioma cells against HIV-1 Tat protein-induced cytotoxicity. Mechanism and regulation. J Biol Chem 2002 277 : 50348 50354.
24. Trapp BD, Nave KA. Multiple sclerosis: An immune or neurodegenerative disorder? Annu Rev Neurosci 2008 31 : 247 269.
25. Shoemaker JL, Seely KA, Reed RL, Crow JP, Prather PL. The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J Neurochem 2007 101 : 87 98.
26. Bilsland LG, Dick JR, Pryce G, Petrosino S, Di Marzo V, Baker D, Greensmith L. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J 2006 20 : 1003 1005.
27. Mechoulam R, Hanus L. Cannabidiol: An overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chem Phys Lipids 2002 121 : 35 43.
28. No author listed. Cannabis-based medicines-GW pharmaceuticals: High CBD, high THC, medicinal Cannabis-GW pharmaceuticals, THC:CBD. Drugs RD 2003 4 : 306 309.
29. Perras C. Sativex for the management of multiple sclerosis symptoms. Issues Emerg Health Technol 2005 72 : 1 4.
30. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9- tetrahydrocannabinol in man. Eur J Pharmacol 1974 28 : 172 177.
31. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl) 1982 76 : 245 250.
32. Russo E, Guy GW. A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 2006 66 : 234 246.
33. Mechoulam R, Shani A, Edery H, Grunfeld Y. Chemical basis of hashish activity. Science 1970 169 : 611 612.
34. Thomas BF, Gilliam AF, Burch DF, Roche MJ, Seltzman HH. Comparative receptor binding analyses of cannabinoid agonists and antagonists. J Pharmacol Exp Ther 1998 285 : 285 292.
35. Griffin G, Atkinson PJ, Showalter VM, Martin BR, Abood ME. Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5'-O-(3-35S] thio)-triphosphate binding assay in rat cerebellar membranes. J Pharmacol Exp Ther 1998 285 : 553 560.
36. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 2007 150 : 613 623.
37. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001 134 : 845 852.
38. De Filippis D, Iuvone T, D'Amico A, Esposito G, Steardo L, Herma AG, et al. Effect of cannabidiol on sepsis-induced motility disturbances in mice: Involvement of CB1 receptors and fatty acid amide hydrolase. Neurograstroenterol Motil 2008 20 : 919 927.
39. Ryan D, Drysdale AJ, Pertwee RG, Platt B. Interactions of cannabidiol with endocannabinoid signalling in hippocampal tissue. Eur J Neurosci 2007 25 : 2093 2102.
40. Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol 2004 143 : 247 250.
41. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1A receptors. Neurochem Res 2005 30 : 1037 1043.
42. Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 2006 372 : 354 361.
43. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 2003 42 : 327 360.
44. Samara E, Bialer M, Harvey DJ. Metabolism of cannabidiol by the rat. Eur J Drug Metab Pharmacokinet 1991 16 : 305 313.
45. Harvey DJ, Mechoulam R. Metabolites of cannabidiol identified in human urine. Xenobiotica 1990 20 : 303 320.
46. Samara E, Bialer M, Harvey DJ. Identification of glucose conjugates as major urinary metabolites of cannabidiol in the dog. Xenobiotica 1990 20 : 177 183.
47. Samara E, Bialer M, Harvey DJ. Pharmacokinetics of urinary metabolites of cannabidiol in the dog. Biopharm Drug Dispos 1990 11 : 785 795.
48. Rosenkrantz H, Fleischman RW, Grant RJ. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicol Appl Pharmacol 1981 58 : 118 131.
49. Rosenkrantz H, Hayden DW. Acute and subacute inhalation toxicity of Turkish marihuana, cannabichromene, and cannabidiol in rats. Toxicol Appl Pharmacol 1979 48 : 375 386.
50. Samara E, Brown NK, Harvey DJ. Microsomal metabolism of the 1",1"-dimethylheptyl analogue of cannabidiol: Relative percentage of monohydroxy metabolites in four species. Drug Metab Dispos 1990 18 : 548 549.
51. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 2006 318 : 1375 1387.
52. Ligresti A, Bisogno T, Matias I, De Petrocellis L, Cascio MG, Cosenza V, et al. Possible endocannabinoid control of colorectal cancer growth. Gastroenterology 2003 125 : 677 687.
53. Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 2005 144 : 1032 1036.
54. McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M. Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 2006 70 : 897 908.
55. Sacerdote P, Martucci C, Vaccani A, Bariselli F, Panerai AE, Colombo A, et al. The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro. J Neuroimmunol 2005 159 : 97 105.
56. Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, et al. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of Cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol 2004 369 : 294 299.
57. Formukong EA, Evans AT, Evans FJ. Analgesic and antiinflammatory activity of constituents of Cannabis sativa L. Inflammation 1988 12 : 361 371.
58. Watzl B, Scuderi P, Watson RR. Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1 alpha in vitro. Int J Immunopharmacol 1991 13 : 1091 1097.
59. Srivastava MD, Srivastava BI, Brouhard B. Delta9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 1998 40 : 179 185.
60. Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, et al. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 2003 23 : 1398 1405.
61. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 1998 95 : 8268 8273.
62. El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, et al. Neuroprotective effect of (-)delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: Involvement of peroxynitrite. Am J Pathol 2003 163 : 1997 2008.
63. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, et al. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 2004 89 : 134 141.
64. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, et al. Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem 2007 102 : 1488 1496.
65. Hayakawa K, Mishima K, Abe K, Hasebe N, Takamatsu F, Yasuda H, Ikeda T, Inui K, Egashira N, Iwasaki K, et al. Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism. Neuroreport 2004 15 : 2381 2385.
66. Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 2005 36 : 1077 1082.
67. Wettschureck N, Van Der Stelt M, Tsubokawa H, Krestel H, Moers A, Petrosino S, Schütz G, Di Marzo V, Offermanns S. Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation. Mol Cell Biol 2006 26 : 5888 5894.
68. Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R, Iuvone T. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 2006 399 : 91 95.
69. Esposito G, De Filippis D, Carnuccio R, Izzo AA, Iuvone T. The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med 2006 84 : 253 258.
70. Esposito G, Scuderi C, Savani C, Steardo L Jr., De Filippis D, Cottone P, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol 2007 151 : 1272 1279.
71. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernández-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: Relevance to Parkinson's disease. Neurobiol Dis 2005 19 : 96 107.
72. Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders. Int J Neurosci 1986 30 : 277 282.
73. Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, Parkin SG, Fox P, Wright D, Hobart J, et al. Cannabis for dyskinesia in Parkinson disease: A randomized double-blind crossover study. Neurology 2004 63 : 1245 1250.
74. Consroe P, Musty R, Conti L. Effects of cannabidiol in animal models of neurological dysfunctions. In : Chester G, Consroe P, Musty R, editors. Marijuana: An International Research Report: Proceedings of the Melbourne Symposium on Cannabis. Canberra : Australian Government Publishing Service, 1988 147 151.
75. Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernández-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur J Neurosci 2007 26 : 843 851.
76. Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, Kennedy K, Schram K. Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacol Biochem Behav 1991 40 : 701 708.
77. Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 2008 85 : 94 134.
78. Weydt P, Hong S, Witting A, Möller T, Stella N, Kliot M. Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival. Amyotroph Lateral Scler Other Motor Neuron Disord 2005 6 : 182 184.
79. Compston A, Coles A. Multiple sclerosis. Lancet 2002 359 : 1221 1231
80. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, et al. The window of therapeutic opportunity in multiple sclerosis: Evidence from monoclonal antibody therapy. J Neurol 2006 253 : 98 108.
81. Polman C, Schellekens H, Killestein J. Neutralizing antibodies to interferon-beta may persist after cessation of therapy: What impact could they have Mult Scler 2006 12 : 245 246.
82. Confavreux C, Vukusic S. Natural history of multiple sclerosis: A unifying concept. Brain 2006 129 : 606 616.
83. Metz I, Lucchinetti CF, Openshaw H, Garcia-Merino A, Lassmann H, Freedman MS, Atkins HL, Azzarelli B, Kolar OJ, Brück W. Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis. Brain 2007 130 : 1254 1262.
84. Consroe P, Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smoked Cannabis on patients with multiple sclerosis. Eur Neurol 1997 38 : 44 48.
85. Ni X, Geller EB, Eppihimer MJ, Eisenstein TK, Adler MW, Tuma RF. Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model. Mult Scler 2004 10 : 158 164.
86. Cabranes A, Venderova K, de Lago E, Fezza F, Sánchez A, Mestre L, Valenti M, García-Merino A, Ramos JA, Di Marzo V, et al. Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis. Neurobiol Dis 2005 20 : 207 217.
87. Sánchez AJ, González-Pérez P, Galve-Roperh I, García-Merino A. R-(+)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)- pyrrolo-1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (WIN-2) ameliorates experimental autoimmune encephalomyelitis and induces encephalitogenic T cell apoptosis: Partial involvement of the CB(2) receptor. Biochem Pharmacol 2006 72 : 1697 1706.
88. Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med 2007 13 : 492 497.
89. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ. Cannabinoids in multiple sclerosis (CAMS) study: Safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005 76 : 1664 1669.
90. Croxford JL, Pryce G, Jackson SJ, Ledent C, Giovannoni G, Pertwee RG, Yamamura T, Baker D. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J Neuroimmunol 2008 193 : 120 129.
91. Meinck HM, Schonle PW, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol 1989 236 : 120 122.
92. Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/ cannabidiol for neuropathic pain associated with multiple sclerosis: An uncontrolled, open-label, 2-year extension trial. Clin Ther 2007 29 : 2068 2079.
93. Collin C, Davies P, Mutiboko IK, Ratcliffe S, for the Sativex Spasticity in MS Study Group. Randomized controlled trial of Cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007 14 : 290 296.
94. Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: Lessons from therapeutic clinical trials of Sativex, a Cannabis-based medicine. Chem Biodivers 2007 4 : 1729 1743.
95. Iskedjian M, Bereza B, Gordon A, Piwko C, Einarson TR. Meta-analysis of Cannabis-based treatments for neuropathic and multiple sclerosis-related pain. Curr Med Res Opin 2007 23 : 17 24.
96. Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ. An open-label pilot study of Cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult Scler 2004 10 : 425 433.
97. Dirikoc S, Priola SA, Marella M, Zsürger N, Chabry J. Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. J Neurosci 2007 27 : 9537 9544.
98. Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J. Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci 2000 899 : 274 282.
99. Hayakawa K, Mishima K, Hazekawa M, Sano K, Irie K, Orito K, et al. Cannabidiol potentiates pharmacological effects of delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism. Brain Res 2008 1188 : 157 164.
100. Whittle BA, Guy GW, Robson P. Prospects for new Cannabis-based prescription medicines. J Cannabis Therap 2001 1 : 183 205.