Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis
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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.
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.
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).
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.
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.
Compliance with Ethical Standards
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.
- 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).
- 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.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.Google Scholar
- 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.
- 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.Google Scholar
- 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.Google Scholar
- 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.Google Scholar
- 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.Google Scholar
- 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.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).
- 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.FDA. Cannabidiol oral solution. Full prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed Jul 2018.
- 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.Google Scholar
- 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.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.
- 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.Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270.Google Scholar
- 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.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.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.