Advertisement

Drugs

, Volume 78, Issue 17, pp 1791–1804 | Cite as

Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis

  • Simona Lattanzi
  • Francesco Brigo
  • Eugen Trinka
  • Gaetano Zaccara
  • Claudia Cagnetti
  • Cinzia Del Giovane
  • Mauro Silvestrini
Systematic Review

Abstract

Background

Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.

Objective

The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.

Methods

Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).

Results

Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.

Conclusions

Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Notes

Compliance with Ethical Standards

Funding

No funding has been received for the conduct of this study.

Conflict of interest

Simona Lattanzi, Claudia Cagnetti, Cinzia Del Giovane and Mauro Silvestrini have no conflicts of interest directly relevant to the content of this study. Francesco Brigo acted as a consultant for Eisai. Eugen Trinka received speaker’s honoraria from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc., LivaNova, and Novartis; consultancy funds from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, GW Pharmaceuticals, Sunovion Pharmaceuticals Inc., and Novartis; and directorship funds from Neuroconsult GmbH. Eugen Trinka’s institution received grants from Biogen, Red Bull, Merck, UCB, the European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and Bundesministerium für Wissenschaft und Forschung. Gaetano Zaccara received speaker’s or consultancy fees from Eisai, Sanofi-Aventis, and UCB Pharma.

Supplementary material

40265_2018_992_MOESM1_ESM.doc (31 kb)
Supplementary material 1 (DOC 31 kb)

References

  1. 1.
    Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology. 2007;68:326–37.CrossRefGoogle Scholar
  2. 2.
    Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini M. Seizure course during pregnancy in catamenial epilepsy. Neurology. 2014;83:339–44.CrossRefGoogle Scholar
  3. 3.
    Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the national general practice study of epilepsy. Lancet. 1995;346:140–4.CrossRefGoogle Scholar
  4. 4.
    Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, et al. Antiepileptic mono-therapy in newly diagnosed focal epilepsy. A network meta-analysis. Acta Neurol Scand.  https://doi.org/10.1111/ane.13025 (Epub 2018 Sep 8).
  5. 5.
    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Lacosamide monotherapy for partial onset seizures. Seizure. 2015;27:71–4.CrossRefGoogle Scholar
  6. 6.
    Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9.CrossRefGoogle Scholar
  7. 7.
    Lattanzi S, Cagnetti C, Foschi N, Lorusso A, Provinciali L, Silvestrini M. Eslicarbazepine acetate as adjunctive treatment in partial-onset epilepsy. Acta Neurol Scand. 2018;137:29–32.CrossRefGoogle Scholar
  8. 8.
    Lattanzi S, Cagnetti C, Matricardi S, Silvestrini M. Palliative non-resective surgery for drug-resistant epilepsy. Brain Dev. 2018;40:512–3.CrossRefGoogle Scholar
  9. 9.
    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802.CrossRefGoogle Scholar
  10. 10.
    Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12:699–730.CrossRefGoogle Scholar
  11. 11.
    GW Pharmaceuticals plc and its U.S. subsidiary Greenwich Biosciences announce FDA approval of EPIDIOLEX® (cannabidiol) oral solution—the first plant-derived cannabinoid prescription medicine. https://www.gwpharm.com/about-us/news/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich-biosciences-announce-fda. Accessed Sep 2018.
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.CrossRefGoogle Scholar
  13. 13.
    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.CrossRefGoogle Scholar
  14. 14.
    Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. Higgins JPT, Green S, editors. The Cochrane Collaboration, 2011. http://handbook-5-1.cochrane.org/. Accessed Jun 2018.
  15. 15.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.CrossRefGoogle Scholar
  16. 16.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.CrossRefGoogle Scholar
  17. 17.
    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology. 2016;86:1344–52.CrossRefGoogle Scholar
  18. 18.
    Lattanzi S, Brigo F, Grillo E, Cagnetti C, Verrotti A, Zaccara G, et al. Adjunctive eslicarbazepine acetate in pediatric patients with focal epilepsy: a systematic review and meta-analysis. CNS Drugs. 2018;32:189–96.CrossRefGoogle Scholar
  19. 19.
    Lattanzi S, Grillo E, Brigo F, Silvestrini M. Efficacy and safety of perampanel in Parkinson’s disease. A systematic review with meta-analysis. J Neurol. 2018;265:733–40.CrossRefGoogle Scholar
  20. 20.
    Lattanzi S, Cagnetti C, Danni M, Provinciali L, Silvestrini M. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017;264:1697–704.CrossRefGoogle Scholar
  21. 21.
    Lattanzi S, Brigo F, Cagnetti C, Di Napoli M, Silvestrini M. Patent foramen ovale and cryptogenic stroke or transient ischemic attack: to close or not to close? A systematic review and meta-analysis. Cerebrovasc Dis. 2018;45:193–203.CrossRefGoogle Scholar
  22. 22.
    Lattanzi S, Brigo F, Di Napoli M, Cagnetti C, Corradetti T, Silvestrini M. Endovascular treatment of symptomatic vertebral artery stenosis: a systematic review and meta-analysis. J Neurol Sci. 2018;391:48–53.CrossRefGoogle Scholar
  23. 23.
    Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al.; GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–11.CrossRefGoogle Scholar
  24. 24.
    Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al.; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–2020.CrossRefGoogle Scholar
  25. 25.
    Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al.; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378:1888-1897.CrossRefGoogle Scholar
  26. 26.
    Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al.; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox–Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–96.Google Scholar
  27. 27.
    Lattanzi S, Brigo F, Cagnetti C, Trinka E, Silvestrini M. Efficacy and safety of adjunctive cannabidiol in patients with Lennox–Gastaut syndrome: a systematic review and meta-analysis. CNS Drugs.  https://doi.org/10.1007/s40263-018-0558-9 (Epub 2018 Aug 21).CrossRefGoogle Scholar
  28. 28.
    Morrison G, Sardu M, Rasmussen C, Sommerville K, Roberts C, Blakey GE. Exposure-response analysis of cannabidiol oral solution for the treatment of Lennox–Gastaut syndrome [abstract no. 2.281]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/344717. Accessed Jul 2018.
  29. 29.
    FDA. Cannabidiol oral solution. Full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed Jul 2018.
  30. 30.
    Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology. 2011;77:1473–81.CrossRefGoogle Scholar
  31. 31.
    Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology. 2008;70:1950–8.CrossRefGoogle Scholar
  32. 32.
    Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, d’Athis P, et al. Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol. 2006;21:496–502.CrossRefGoogle Scholar
  33. 33.
    FDA briefing document. Peripheral and central nervous system drugs. Advisory Committee Meeting. April 19, 2018. NDA 210365. Cannabidiol. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm604736.pdf. Accessed Jul 2018.
  34. 34.
    US Department of Health and Human Services. Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation. 2009. https://www.fda.gov/downloads/Guidances/UCM174090.pdf. Accessed Jul 2018.
  35. 35.
    Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51.CrossRefGoogle Scholar
  36. 36.
    Thiele EA, Devinsky O, Checketts D, Knappertz V. Cannabidiol (CBD) treatment responders analysis in patients with Lennox–Gastaut syndrome (LGS) on and off clobazam (CLB) [abstract no. 1.436]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381224. Accessed Jul 2018.
  37. 37.
    Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270.Google Scholar
  38. 38.
    Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of con-trolled and observational evidence. J Neurol Neurosurg Psychiatry. 2018;89:741–53.CrossRefGoogle Scholar
  39. 39.
    Rhodes KM, Turner RM, Savović J, Jones HE, Mawdsley D, Higgins JPT. Between-trial heterogeneity in meta-analyses may be partially explained by reported design characteristics. J Clin Epidemiol. 2018;95:45–54.CrossRefGoogle Scholar
  40. 40.
    Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Maintenance of long-term safety and efficacy of cannabidiol (CBD) treatment in Dravet syndrome (DS): results of the open-label extension (OLE) trial (GWPCARE5) [abstract no. 1.289]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/343046. Accessed Jul 2018.
  41. 41.
    Marsh ED, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Checketts D, Nichol K, et al. Maintained safety and efficacy of cannabidiol (CBD) in a long-term open-label trial in patients with Lennox–Gastaut syndrome (LGS) (GWPCARE 5) [abstract no. 2.271]. The American Epilepsy Society Annual Meeting; 1–5 Dec 2017; Washington, DC. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/344387. Accessed Jul 2018.
  42. 42.
    Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, et al.; CBD EAP study group. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59(8):1540–8.  https://doi.org/10.1111/epi.14477.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Experimental and Clinical Medicine, Neurological ClinicMarche Polytechnic UniversityAnconaItaly
  2. 2.Department of Neuroscience, Biomedicine and Movement ScienceUniversity of VeronaVeronaItaly
  3. 3.Division of Neurology“Franz Tappeiner” HospitalMeranoItaly
  4. 4.Department of Neurology, Christian Doppler KlinikParacelsus Medical UniversitySalzburgAustria
  5. 5.Center for Cognitive NeuroscienceSalzburgAustria
  6. 6.Public Health, Health Services Research and HTAUniversity for Health Sciences, Medical Informatics and TechnologyHall in TirolAustria
  7. 7.Health Agency of TuscanyFlorenceItaly
  8. 8.Institute of Primary Health Care (BIHAM)University of BernBernSwitzerland

Personalised recommendations