A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease


Huntington’s disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD. We conducted a double-blind, randomized, placebo-controlled, cross-over pilot clinical trial with Sativex®, a botanical extract with an equimolecular combination of delta-9-tetrahydrocannabinol and cannabidiol. Both Sativex® and placebo were dispensed as an oral spray, to be administered up to 12 sprays/day for 12 weeks. The primary objective was safety, assessed by the absence of more severe adverse events (SAE) and no greater deterioration of motor, cognitive, behavioral and functional scales during the phase of active treatment. Secondary objectives were clinical improvement of Unified Huntington Disease Rating Scale scores. Twenty-six patients were randomized and 24 completed the trial. After ruling-out period and sequence effects, safety and tolerability were confirmed. No differences on motor (p = 0.286), cognitive (p = 0.824), behavioral (p = 1.0) and functional (p = 0.581) scores were detected during treatment with Sativex® as compared to placebo. No significant molecular effects were detected on the biomarker analysis. Sativex® is safe and well tolerated in patients with HD, with no SAE or clinical worsening. No significant symptomatic effects were detected at the prescribed dosage and for a 12-week period. Also, no significant molecular changes were observed on the biomarkers. Future study designs should consider higher doses, longer treatment periods and/or alternative cannabinoid combinations.

Clincaltrals.gov identifier: NCT01502046

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Walker FO (2007) Huntington’s disease. Lancet 369(9557):218–228

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6):971–983

    Article  Google Scholar 

  3. 3.

    Rosas HD, Salat DH, Lee SY et al (2008) Cerebral cortex and the clinical expression of Huntington’s disease: complexity and heterogeneity. Brain 131(Pt 4):1057–1068

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Marsicano G, Goodenough S, Monory K et al (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302(5642):84–88

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Cota D (2007) CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Diabetes Metab Res Rev 23(7):507–517

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89(1):309–380

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Wright S (2007) Cannabinoid-based medicines for neurological disorders–clinical evidence. Mol Neurobiol 36(1):129–136

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Fernandez-Ruiz J (2009) The endocannabinoid system as a target for the treatment of motor dysfunction. Br J Pharmacol 156(7):1029–1040

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Pazos MR, Sagredo O, Fernandez-Ruiz J (2008) The endocannabinoid system in Huntington’s disease. Curr Pharm Des 14(23):2317–2325

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Fernandez-Ruiz J, Romero J, Velasco G, Tolon RM, Ramos JA, Guzman M (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28(1):39–45

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Fernandez-Ruiz J, Garcia C, Sagredo O, Gomez-Ruiz M, de Lago E (2010) The endocannabinoid system as a target for the treatment of neuronal damage. Expert Opin Ther Targets 14(4):387–404

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Pertwee RG (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 156(3):397–411

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Gowran A, Noonan J, Campbell VA (2011) The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther 17(6):637–644

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Kluger B, Triolo P, Jones W, Jankovic J (2015) The therapeutic potential of cannabinoids for movement disorders. Mov Disord 30(3):313–327

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11(2):563–583

    CAS  PubMed  Google Scholar 

  16. 16.

    Nunez E, Benito C, Tolon RM, Hillard CJ, Griffin WS, Romero J (2008) Glial expression of cannabinoid CB(2) receptors and fatty acid amide hydrolase are beta amyloid-linked events in Down’s syndrome. Neuroscience 151(1):104–110

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Toth A, Blumberg PM, Boczan J (2009) Anandamide and the vanilloid receptor (TRPV1). Vitam Horm 81:389–419

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    van der Stelt M, Veldhuis WB, Maccarrone M et al (2002) Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol Neurobiol 26(2–3):317–346

    Article  PubMed  Google Scholar 

  19. 19.

    Chiarlone A, Bellocchio L, Blazquez C et al (2014) A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc Natl Acad Sci USA 111(22):8257–8262

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Palazuelos J, Aguado T, Pazos MR et al (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132(Pt 11):3152–3164

    Article  PubMed  Google Scholar 

  21. 21.

    Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95(14):8268–8273

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Muller-Vahl KR, Schneider U, Emrich HM (1999) Nabilone increases choreatic movements in Huntington’s disease. Mov Disord 14(6):1038–1040

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Curtis A, Rickards H (2006) Nabilone could treat chorea and irritability in Huntington’s disease. J Neuropsychiatry Clin Neurosci 18(4):553–554

    Article  PubMed  Google Scholar 

  24. 24.

    Curtis A, Mitchell I, Patel S, Ives N, Rickards H (2009) A pilot study using nabilone for symptomatic treatment in Huntington’s disease. Mov Disord 24(15):2254–2259

    Article  PubMed  Google Scholar 

  25. 25.

    Consroe P, Laguna J, Allender J et al (1991) Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav 40(3):701–708

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66(2):234–246

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Lastres-Becker I, Bizat N, Boyer F, Hantraye P, Fernandez-Ruiz J, Brouillet E (2004) Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivo. NeuroReport 15(15):2375–2379

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernandez-Ruiz J (2007) 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 26(4):843–851

    Article  PubMed  Google Scholar 

  29. 29.

    Valdeolivas S, Satta V, Pertwee RG, Fernandez-Ruiz J, Sagredo O (2011) Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: role of CB1 and CB2 receptors. ACS Chem Neurosci 3(5):400–406

    Article  Google Scholar 

  30. 30.

    Huntington Study Group (1996) Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 11(2):136–142

    Article  Google Scholar 

  31. 31.

    Gomez-Tortosa E, Gonzalo I, Fanjul S et al (2003) Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease. Arch Neurol 60(9):1218–1222

    Article  PubMed  Google Scholar 

  32. 32.

    Reiriz J, Mena MA, Bazan E et al (1989) Temporal profile of levels of monoamines and their metabolites in striata of rats implanted with dialysis tubes. J Neurochem 53(3):789–792

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Gaughwin PM, Ciesla M, Lahiri N, Tabrizi SJ, Brundin P, Bjorkqvist M (2011) Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington’s disease. Hum Mol Genet 20(11):2225–2237

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Hernandez-Torres G, Cipriano M, Heden E et al (2014) A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. Angew Chem Int Ed Engl 53(50):13765–13770

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Bisogno T, Martire A, Petrosino S, Popoli P, Di Marzo V (2008) Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington’s disease. Neurochem Int 52(1–2):307–313

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Fernandez-Estevez MA, Casarejos MJ, Lopez Sendon J et al (2014) Trehalose reverses cell malfunction in fibroblasts from normal and Huntington’s disease patients caused by proteosome inhibition. PLoS One 9(2):e90202

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Battista N, Bari M, Tarditi A et al (2007) Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington’s disease mutation in peripheral lymphocytes. Neurobiol Dis 27(1):108–116

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Casarejos MJ, Perucho J, Gomez A et al (2013) Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J Alzheimers Dis 35(3):525–539

    CAS  PubMed  Google Scholar 

  39. 39.

    Tapiola T, Alafuzoff I, Herukka SK et al (2009) Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol 66(3):382–389

    Article  PubMed  Google Scholar 

  40. 40.

    Giampa C, Montagna E, Dato C, Melone MA, Bernardi G, Fusco FR (2013) Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington’s disease. PLoS One 8(5):e64037

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Zuccato C, Ciammola A, Rigamonti D et al (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293(5529):493–498

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Chang KH, Chen YC, Wu YR, Lee WF, Chen CM (2012) Downregulation of genes involved in metabolism and oxidative stress in the peripheral leukocytes of Huntington’s disease patients. PLoS One 7(9):e46492

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Sagredo O, Gonzalez S, Aroyo I et al (2009) Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease. Glia 57(11):1154–1167

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Butovsky E, Juknat A, Goncharov I et al (2005) In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol. J Neurochem 93(4):802–811

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    D’Souza DC, Pittman B, Perry E, Simen A (2009) Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology 202(4):569–578

    Article  PubMed  Google Scholar 

  46. 46.

    De Petrocellis L, Ligresti A, Moriello AS et al (2011) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163(7):1479–1494

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Thieme D, Sachs H, Uhl M (2014) Proof of cannabis administration by sensitive detection of 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid in hair using selective methylation and application of liquid chromatography- tandem and multistage mass spectrometry. Drug Test Anal 6(1–2):112–118

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Blazquez C, Chiarlone A, Sagredo O et al (2011) Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease. Brain 134(Pt 1):119–136

    Article  PubMed  Google Scholar 

  49. 49.

    Van Laere K, Casteels C, Dhollander I et al (2010) Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. J Nucl Med 51(9):1413–1417

    Article  PubMed  Google Scholar 

Download references


We thank the patients and their families who participated in the trial for their endeavor. We also thank GW Pharmaceuticals for their kind support.

Author information



Corresponding author

Correspondence to Jose Luis López-Sendón Moreno.

Ethics declarations

Funding sources for the study

This study was sponsored by Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal, GW Pharmaceuticals Ltd and Comunidad de Madrid (Grant S2010/BMD-2308).

Financial disclosure

García Caldentey, J, Trigo Cubillo, P; Ruiz Romero, C; García Ribas, G; Alonso Arias, MA; García de Yébenes M.J; Tolón Rafael, RM; Galve-Roperh, I; Resel, E; Ortega-Gutierrez, S; García-Bermejo, ML; Guzmán, M; García de Yébenes Prous, J report no disclosures.

Conflicts of interest

López-Sendón Moreno J.L.: has received travel grants from Lundbeck and Krka pharmaceuticals. No conflicts of interest to disclose. Sagredo O, Valdeolibas S and Fernández-Ruiz J are recipient of a grant from GW Pharmaceuticals.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

López-Sendón Moreno, J., García Caldentey, J., Trigo Cubillo, P. et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. J Neurol 263, 1390–1400 (2016). https://doi.org/10.1007/s00415-016-8145-9

Download citation


  • Huntington’s disease
  • Cannabinoid
  • Sativex
  • Clinical trial