Efficacy and Safety of Adjunctive Cannabidiol in Patients with Lennox–Gastaut Syndrome: A Systematic Review and Meta-Analysis
Lennox–Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy, and available interventions fail to control seizures in most patients. Cannabidiol (CBD) is a major chemical of marijuana, which has anti-seizure properties and different mechanisms of action compared with other approved antiepileptic drugs (AEDs).
The aim was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with LGS using meta-analytical techniques.
Randomized, placebo-controlled, single- or double-blinded trials were identified. Main outcomes included the ≥ 50% reduction in baseline drop and non-drop seizure frequency, and the incidence of treatment withdrawal and adverse events (AEs). Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated through the inverse variance method.
Two trials were included involving 396 participants. Patients presenting ≥ 50% reduction in drop seizure frequency during the treatment were 40.0% with CBD and 19.3% with placebo [RR 2.12 (95% CI 1.48–3.03); p < 0.001]. The rate of non-drop seizure frequency was reduced by 50% or more in 49.4% of patients in the CBD and 30.4% in the placebo arms [RR 1.62 (95% CI 1.09–2.43); p = 0.018]. The RR for CBD withdrawal was 4.93 (95% CI 1.50–16.22; p = 0.009). The RR to develop any AE during CBD treatment was 1.24 (95% CI 1.11–1.38; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea and increased serum aminotransferases.
Adjunctive CBD resulted in a greater reduction in seizure frequency and a higher rate of AEs than placebo in patients with LGS presenting seizures uncontrolled by concomitant AEDs.
Compliance with Ethical Standards
No funding was received to conduct this study.
Conflict of interest
Simona Lattanzi, Claudia Cagnetti 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. E. Trinka’s Institution received grants from Biogen, Red Bull, Merck, UCB, European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and Bundesministerium für Wissenschaft und Forschung.
- 19.Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.CrossRefGoogle Scholar
- 20.Ružić Zečević D, Folić M, Tantoush Z, Radovanović M, Babić G, Janković SM. Investigational cannabinoids in seizure disorders, what have we learned thus far? Expert Opin Investig Drugs. 2018 Jun 6. https://doi.org/10.1080/13543784.2018.1482275. [Epub ahead of print].
- 23.Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Higgins JPT, Green S, editors. The Cochrane Collaboration, 2011. Available at http://handbook-5-1.cochrane.org/. Accessed October 2017.
- 33.Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C. Sommerville K; 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.CrossRefGoogle Scholar
- 38.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). The American Epilepsy Society Annual Meeting; Washington, DC; December 1–5, 2017. Abst. 1.436. Available at: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381224 (Accessed on July, 2018)].
- 39.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 Jun 11, 2018.
- 40.Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, Herkes GK, Farrell M, Degenhardt L. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018 Mar 6. https://doi.org/10.1136/jnnp-2017-317168. [Epub ahead of print].
- 41.Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270.Google Scholar
- 42.Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, Beal JC, Laux LC, De Boer LM, Wong MH, Lopez M, Devinsky O, Lyons PD, Zentil PP, Wechsler R; 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 Jul 12. https://doi.org/10.1111/epi.14477. [Epub ahead of print].