Journal of Neuroimmune Pharmacology

, Volume 10, Issue 2, pp 281–292

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids

  • Gareth Pryce
  • Dieter R. Riddall
  • David L. Selwood
  • Gavin Giovannoni
  • David Baker
INVITED REVIEW

Abstract

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

Keywords

Cannabinoid Cannabidiol Experimental autoimmune encephalomyelitis Multiple sclerosis Neuroprotection Δ9-tetrahydrocannabinol 

Supplementary material

11481_2014_9575_MOESM1_ESM.docx (18 kb)
ESM 1(DOCX 18 kb)

REFERENCES

  1. Al-Izki S, Pryce G, O’Neill JK, Butter C, Giovannoni G, Amor S, Baker D (2012) Practical guide to the induction of relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. Mult Scler Rel Dis 1:29–38CrossRefGoogle Scholar
  2. Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Edith Chan AW, Amor S, Perkins V, Gerritsen WH, Ummenthum K, Peferoen-Baert R, van der Valk P, Montoya A, Joel SP, Garthwaite J, Giovannoni G, Selwood DL, Baker D (2014) Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain 137:92–108PubMedCrossRefGoogle Scholar
  3. Baker D, Amor S (2012) Publication guidelines for refereeing and reporting on animal use in experimental autoimmune encephalomyelitis. J Neuroimmunol 242:78–83PubMedCrossRefGoogle Scholar
  4. Baker D, Amor S (2014) Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely. Mult Scler Rel Dis 3:555–564CrossRefGoogle Scholar
  5. Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404:84–87PubMedCrossRefGoogle Scholar
  6. Baker D, Gerritsen W, Rundle J, Amor S (2011) Critical appraisal of animal models of multiple sclerosis. Mult Scler 17:647–657PubMedCrossRefGoogle Scholar
  7. Baker D, Pryce G, Jackson SJ, Bolton C, Giovannoni G (2012) The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis. Mult Scler Rel Dis 1:64–75CrossRefGoogle Scholar
  8. Bernal-Chico A, Canedo M, Manterola A, Victoria Sánchez-Gómez M, Pérez-Samartín A, Rodríguez-Puertas R, Matute C, Mato S (2015) Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo. Glia 63:163–176PubMedCrossRefGoogle Scholar
  9. Bolton C, O’Neill JK, Allen SJ, Baker D (1997) Regulation of chronic relapsing experimental allergic encephalomyelitis by endogenous and exogenous glucocorticoids. Int Arch Allergy Immunol 114:74–80PubMedCrossRefGoogle Scholar
  10. Burgdorf JR, Kilmer B, Pacula RL (2011) Heterogeneity in the composition of marijuana seized in California. Drug Alcohol Depend 117:59–61PubMedCentralPubMedCrossRefGoogle Scholar
  11. Carroll CB, Zeissler ML, Hanemann CO, Zajicek JP (2012) Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol Appl Neurobiol 38:535–547PubMedCrossRefGoogle Scholar
  12. Chong MS, Wolff K, Wise K, Tanton C, Winstock A, Silber E (2006) Cannabis use in patients with multiple sclerosis. Mult Scler 12:646–651PubMedCrossRefGoogle Scholar
  13. Clark AJ, Ware MA, Yazer E, Murray TJ, Lynch ME (2004) Patterns of cannabis use among patients with multiple sclerosis. Neurology 62:2098–2100PubMedCrossRefGoogle Scholar
  14. Compston A, Coles A (2002) Multiple sclerosis. Lancet 359:1221–1231PubMedCrossRefGoogle Scholar
  15. Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517PubMedCrossRefGoogle Scholar
  16. Consroe P, Musty R, Rein J, Tillery W, Pertwee R (1997) The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol 38:44–48PubMedCrossRefGoogle Scholar
  17. Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, Gouaux B (2012) Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ 184:1143–1150PubMedCentralPubMedCrossRefGoogle Scholar
  18. Correa F, Docagne F, Mestre L, Clemente D, Hernangómez M, Loría F, Guaza C (2009) A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells. Biochem Pharmacol 77:86–100PubMedCrossRefGoogle Scholar
  19. Croxford JL, Pryce G, Jackson SJ, Ledent C, Giovannoni G, Pertwee RG, Yamamura T, Baker D (2008) Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J Neuroimmunol 193:120–129PubMedCrossRefGoogle Scholar
  20. Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB (1976) Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin Pharmacol Ther 19:300–309PubMedGoogle Scholar
  21. de Lago E, Moreno-Martet M, Cabranes A, Ramos JA, Fernández-Ruiz J (2012) Cannabinoids ameliorate disease progression in a model of multiple sclerosis in mice, acting preferentially through CB1 receptor-mediated anti-inflammatory effects. Neuropharmacology 62:2299–2308PubMedCrossRefGoogle Scholar
  22. Docagne F, Muñetón V, Clemente D, Ali C, Loría F, Correa F, Hernangómez M, Mestre L, Vivien D, Guaza C (2007) Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoidsthrough CB1 and CB2 receptor activation. Mol Cell Neurosci 34:551–561PubMedCrossRefGoogle Scholar
  23. Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O (2006) The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49:67–79PubMedCrossRefGoogle Scholar
  24. El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI (2003) Neuroprotective effect of (−)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol 163:1997–2008PubMedCentralPubMedCrossRefGoogle Scholar
  25. ElSohly MA, Ross SA, Mehmedic Z, Arafat R, Yi B, Banahan BF (2000) Potency trends of delta9-Δ9-THC and other cannabinoids in confiscated marijuana from 1980–1997. J Forensic Sci 45:24–30PubMedGoogle Scholar
  26. Espejo-Porras F, Fernández-Ruiz J, Pertwee RG, Mechoulam R, García C (2013) Motor effects of the non-psychotropic phytocannabinoidcannabidiol that are mediated by 5-HT1A receptors. Neuropharmacology 75:155–163PubMedCrossRefGoogle Scholar
  27. European Monitoring Centre for Drugs and Drug Addiction (2008) A cannabis reader: global issues and local experiences, Monograph series 8, vol 1. European Monitoring Centre for Drugs and Drug Addiction, LisbonGoogle Scholar
  28. Garthwaite G, Goodwin DA, Neale S, Riddall D, Garthwaite J (2002) Soluble guanylylcyclase activator YC-1 protects white matter axons from nitric oxide toxicity and metabolic stress, probably through Na(+) channel inhibition. Mol Pharmacol 61:97–104PubMedCrossRefGoogle Scholar
  29. Giovannoni G, Baker D, Schmierer K (2015) The problems with repurposing: is there really an alternative to ‘Big Pharma’ for developing new drugs for MS? Mult Scler Rel Dis. doi:10.1016/j.msard.2014.11.005
  30. Gnanapavan S, Grant D, Morant S, Furby J, Hayton T, Teunissen CE, Leoni V, Marta M, Brenner R, Palace J, Miller DH, Kapoor R, Giovannoni G (2013) Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression. PLoS One 8:e70019PubMedCentralPubMedCrossRefGoogle Scholar
  31. Gunnarsson M, Malmeström C, Axelsson M, Sundström P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J (2011) Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 69:83–89PubMedCrossRefGoogle Scholar
  32. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 95:8268–8273PubMedCentralPubMedCrossRefGoogle Scholar
  33. Hasseldam H, Johansen FF (2010) Neuroprotection without immunomodulation is not sufficient to reduce first relapse severity in experimental autoimmune encephalomyelitis. Neuroimmunomodulation 17:252–264PubMedCrossRefGoogle Scholar
  34. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, Orito K, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M (2007) Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem 102:1488–1496PubMedCrossRefGoogle Scholar
  35. Hernández-Torres G, Cipriano M, Hedén E, Björklund E, Canales A, Zian D, Feliú A, Mecha M, Guaza C, Fowler CJ, Ortega-Gutiérrez S, López-Rodríguez ML (2014) A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. Angew Chem Int Ed Engl 53:13765–13770PubMedCrossRefGoogle Scholar
  36. Hill AJ, Jones NA, Smith I, Hill CL, Williams CM, Stephens GJ, Whalley BJ (2014) Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se. Neurosci Lett 566:269–274PubMedCrossRefGoogle Scholar
  37. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202PubMedCrossRefGoogle Scholar
  38. Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ (2014) The non-psychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 5:1131–1141PubMedCrossRefGoogle Scholar
  39. Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, Chataway J, Hughes RA, Miller DH (2010) Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 9:681–688PubMedCrossRefGoogle Scholar
  40. Katona S, Kaminski E, Sanders H, Zajicek J (2005) Cannabinoid influence on cytokine profile in multiple sclerosis. Clin Exp Immunol 140:580–585PubMedCentralPubMedCrossRefGoogle Scholar
  41. Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, Nagelkerken L, Polman CH (2003) Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. J Neuroimmunol 137:140–143PubMedCrossRefGoogle Scholar
  42. Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R, Ben-Nun A, Juknat A, Vogel Z (2011) Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br J Pharmacol 16:1507–1519CrossRefGoogle Scholar
  43. Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, Ratcliffe S (2013) A double-blind, randomized, placebo-controlled, parallel-group study of Δ9-THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol 260:984–997PubMedCrossRefGoogle Scholar
  44. Leray E, Yaouanq J, Le Page E, Coustans M, Laplaud D, Oger J, Edan G (2010) Evidence for a two-stage disability progression in multiple sclerosis. Brain 133:1900–1913PubMedCentralPubMedCrossRefGoogle Scholar
  45. Lyman WD, Sonett JR, Brosnan CF, Elkin R, Bornstein MB (1989) Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol 23:73–81PubMedCrossRefGoogle Scholar
  46. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 97:9561–9566PubMedCentralPubMedCrossRefGoogle Scholar
  47. Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, Giovannoni G, Pertwee RG, Yamamura T, Buckley NE, Hillard CJ, Lutz B, Baker D, Dittel BN (2007) Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med 13:492–497PubMedCrossRefGoogle Scholar
  48. Marta M, Giovannoni G (2012) Disease modifying drugs in multiple sclerosis: mechanisms of action and new drugs in the horizon.CNSNeurolDisord Drug. Targets 11:610–623Google Scholar
  49. Masullo L, Papas MA, Cotugna N, Baker S, Mahoney L, Trabulsi J (2015) Complementary and alternative medicine use and nutrient intake among individuals with multiple sclerosis in the United States. J Community Health. Jul 1.2014 [Epub ahead of print]Google Scholar
  50. Mecha M, Torrao AS, Mestre L, Carrillo-Salinas FJ, Mechoulam R, Guaza C (2012) Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress. Cell Death Dis 3:e331PubMedCentralPubMedCrossRefGoogle Scholar
  51. Mecha M, Feliú A, Iñigo PM, Mestre L, Carrillo-Salinas FJ, Guaza C (2013) Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis 59:141–150PubMedCrossRefGoogle Scholar
  52. Mechoulam R, Parker LA, Gallily R (2002) Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol 42(11 Suppl):11S–19SPubMedCrossRefGoogle Scholar
  53. Morsali D, Bechtold D, Lee W, Chauhdry S, Palchaudhuri U, Hassoon P, Snell DM, Malpass K, Piers T, Pocock J, Roach A, Smith KJ (2013) Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain 136:1067–1082PubMedCrossRefGoogle Scholar
  54. Musella A, Sepman H, Mandolesi G, Gentile A, Fresegna D, Haji N, Conrad A, Lutz B, Maccarrone M, Centonze D (2014) Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis. Neuropharmacology 79:567–572PubMedCrossRefGoogle Scholar
  55. Nguyen BM, Kim D, Bricker S, Bongard F, Neville A, Putnam B, Smith J, Plurad D (2014) Effect of marijuana use on outcomes in traumatic brain injury. Am Surg 80:979–983PubMedGoogle Scholar
  56. Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, Gasperini C, Pozzilli C, Cefaro L, Comi G, Rossi P, Ambler Z, Stelmasiak Z, Erdmann A, Montalban X, Klimek A, Davies P, Sativex Spasticity Study Group (2011) A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®)), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 18:1122–1131PubMedCrossRefGoogle Scholar
  57. Oliviero A, Arevalo-Martin A, Rotondi M, García-Ovejero D, Mordillo-Mateos L, Lozano-Sicilia A, Panyavin I, Chiovato L, Aguilar J, Foffani G, Di Lazzaro V, Molina-Holgado E (2012) CB1 receptor antagonism/inverse agonism increases motor system excitability in humans. Eur Neuropsychopharmacol 22:27–35PubMedCrossRefGoogle Scholar
  58. Pauwels PJ, Leysen JE, Laduron PM (1986) [3H]Batrachotoxinin A 20-alpha-benzoate binding to sodium channels in rat brain: characterization and pharmacological significance. Eur J Pharmacol 124:291–298PubMedCrossRefGoogle Scholar
  59. Pryce G, Baker D (2007) Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors. Br J Pharmacol 150:519–525PubMedCentralPubMedCrossRefGoogle Scholar
  60. Pryce G, Ahmed Z, Hankey DJ, Jackson SJ, Croxford JL, Pocock JM, Ledent C, Petzold A, Thompson AJ, Giovannoni G, Cuzner ML, Baker D (2003) Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126:2191–2202PubMedCrossRefGoogle Scholar
  61. Pryce G, Visintin C, Ramagopalan SV, Al-Izki S, De Faveri LE, Nuamah RA, Mein CA, Montpetit A, Hardcastle AJ, Kooij G, de Vries HE, Amor S, Thomas SA, Ledent C, Marsicano G, Lutz B, Thompson AJ, Selwood DL, Giovannoni G, Baker D (2014) Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists. FASEB J 28:117–130PubMedCrossRefGoogle Scholar
  62. Ribeiro R, Yu F, Wen J, Vana A, Zhang Y (2013) herapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis. Neuroscience 254:427–442PubMedCrossRefGoogle Scholar
  63. Rossi S, Furlan R, De Chiara V, Muzio L, Musella A, Motta C, Studer V, Cavasinni F, Bernardi G, Martino G, Cravatt BF, Lutz B, Maccarrone M, Centonze D (2011a) Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis. Brain Behav Immun 25:1242–1248PubMedCrossRefGoogle Scholar
  64. Rossi S, Buttari F, Studer V, Motta C, Gravina P, Castelli M, Mantovani V, De Chiara V, Musella A, Fiore S, Masini S, Bernardi G, Maccarrone M, Bernardini S, Centonze D (2011b) The (AAT)n repeat of the cannabinoid CB1 receptor gene influences disease progression inrelapsing multiple sclerosis. Mult Scler 17:281–288PubMedCrossRefGoogle Scholar
  65. Rossi S, Bozzali M, Bari M, Mori F, Studer V, Motta C, Buttari F, Cercignani M, Gravina P, Mastrangelo N, Castelli M, Mancino R, Nucci C, Sottile F, Bernardini S, Maccarrone M, Centonze D (2013) Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis. PLoS One 8(12):e82848PubMedCentralPubMedCrossRefGoogle Scholar
  66. Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66:234–246PubMedCrossRefGoogle Scholar
  67. Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063PubMedCrossRefGoogle Scholar
  68. Sexton M, Cudaback E, Abdullah RA, Finnell J, Mischley LK, Rozga M, Lichtman AH, Stella N (2014) Cannabis use by individuals with multiple sclerosis: effects on specific immune parameters. Inflammopharmacology 2014(22):295–303CrossRefGoogle Scholar
  69. Sisay S, Pryce G, Jackson SJ, Tanner C, Ross RA, Michael GJ, Selwood DL, Giovannoni G, Baker D (2013) Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis. PLoS One 8(10):e76907PubMedCentralPubMedCrossRefGoogle Scholar
  70. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623PubMedCentralPubMedCrossRefGoogle Scholar
  71. Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin BR, Wiley JL (2008) Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol. Drug Alcohol Depend 94:191–198PubMedCentralPubMedCrossRefGoogle Scholar
  72. Varvel SA, Wiley JL, Yang R, Bridgen DT, Long K, Lichtman AH, Martin BR (2006) Interactions between Δ9-THC and cannabidiol in mouse models of cannabinoid activity. Psychopharmacology 186:226–234PubMedCrossRefGoogle Scholar
  73. Wade DT, Robson P, House H, Makela P, Aram J (2003) A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 17:21–219PubMedCrossRefGoogle Scholar
  74. Waxman SG (2002) Sodium channels as molecular targets in multiple sclerosis. J Rehabil Res Dev 39:233–242PubMedGoogle Scholar
  75. Webb M, Luo L, Ma JY, Tham CS (2008) Genetic deletion of Fatty Acid Amide Hydrolase results in improved long-term outcome in chronic autoimmune encephalitis. Neurosci Lett 439:106–110PubMedCrossRefGoogle Scholar
  76. Wilkinson JD, Whalley BJ, Baker D, Pryce G, Constanti A, Gibbons S, Williamson EM (2003) Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for all its effects? J Pharm Pharmacol 55:1687–1694PubMedCrossRefGoogle Scholar
  77. Yadav V, Bever C Jr, Bowen J, Bowling A, Weinstock-Guttman B, Cameron M, Bourdette D, Gronseth GS, Narayanaswami P (2014) Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 82:1083–1092PubMedCentralPubMedCrossRefGoogle Scholar
  78. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A, UK MS Research Group (2003) Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362:1517–1526PubMedCrossRefGoogle Scholar
  79. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ (2005) Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.J NeurolNeurosurg. Psychiatry 76:1664–1669Google Scholar
  80. Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG, MUSEC Research Group (2012) Multiple sclerosis and extract of cannabis: results of the MUSEC trial.J NeurolNeurosurg. Psychiatry 83:1125–1132Google Scholar
  81. Zajicek J, Ball S, Wright D, Vickery J, Nunn A, Miller D, Gomez Cano M, McManus D, Mallik S, Hobart J, CUPID investigator group (2013) Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol 12:857–865PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Gareth Pryce
    • 1
  • Dieter R. Riddall
    • 2
  • David L. Selwood
    • 2
  • Gavin Giovannoni
    • 1
  • David Baker
    • 1
  1. 1.Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
  2. 2.Wolfson Institute of Biomedical ResearchUniversity College LondonLondonUK

Personalised recommendations