Epilepsy affects 1 of 23 persons of the general population, making it one of the most common neurologic disorders. Patients with epilepsy suffer adverse effects on quality of life secondary to the effects of the disease and its therapies. One-third of patients with epilepsy develop treatment-refractory epilepsy (TRE), in which seizures persist despite adequate trials of 2 appropriate antiseizure drugs (ASDs). Although there are more than 25 ASDs currently available, there is still a need for additional treatments with unique mechanisms of action to help those with continued seizures.
The endocannabinoid system
Cannabis contains numerous bioactive compounds called cannabinoids; the most abundant of these are delta-9-tetrahydrocannabidiol (THC) and cannabidiol (CBD). Cannabinoids target G-protein-coupled cannabinoid receptor type 1 (CB1) and type 2 (CB2). The CB1 is widely expressed throughout the central nervous system, where it is involved in the regulation of neuronal excitation/inhibition.1 The CB2 is mainly expressed in the immune system and present in much lower concentrations in the brain.2 Cannabidiol has antiseizure activity without psychotropic effects, but the mechanism underlying CBD’s therapeutic properties is not yet understood. Preclinical data suggest potential allosteric modulation of CB1, as well as actions on targets outside this system.3
Cannabis use has become increasingly prevalent in patients with epilepsy. Public interest was fueled in part by anecdotal reports of individual children with TRE who had miraculous response with CBD use. The first widely publicized story in 2013 was of a 5-year-old girl named Charlotte, with SCN1A-confirmed Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy (SMEI).4 At baseline, Charlotte had up to 50 generalized tonic-clonic seizures daily, and after failing many ASDs, her family was told that they had “reached the end of the road.” Her parents obtained a high-CBD-strain cannabis extract (later marketed as “Charlotte’s Web”) and saw a greater than 90% reduction in her seizures after 3 months of treatment.5 Similar case reports, surveys, and small retrospective chart reviews suggested CBD may improve seizure control, alertness, mood, and sleep.3
Artisanal cannabis products with high ratios of CBD:THC soon became available across many countries and states. Users obtained products from local growers, government dispensaries, and Internet purchase (including Charlotte’s Web). Public interest in CBD products was partly based on the belief that “natural” products may be safer with fewer adverse effects than conventional ASDs. However, lack of regulatory measures resulted in insufficient quality control of artisanal preparations. Laboratory analyses showed that most products had significantly different contents of individual cannabinoids compared with their marketing label,6 and reports emerged of children with TRE presenting to medical attention with signs of THC toxicity.5
Despite the growing ubiquity of cannabis, quality scientific evidence was lacking and no reliable conclusion could be drawn about the safety or efficacy of cannabis products.7 The Epilepsy Foundation released a statement in 2014 affirming its support for the rights of patients and families in the use of medical marijuana.8 In response, the American Epilepsy Society recommended caution and stressed the risk-to-benefit ratio did not yet support the use of marijuana for epilepsy treatment.9
In recent years, results from the first few randomized controlled trials (RCTs) on the safety and efficacy of CBD use for epilepsy have been published. Pharmaceutical-grade purified CBD solution (Epidiolex [CBD]; GW Pharmaceuticals, Cambridge, United Kingdom) was supplied to clinical investigators at trial sites throughout the United States and Europe. Across 3 RCTs in patients with DS10 and Lennox-Gastaut syndrome (LGS),11,12 patients taking adjunctive CBD showed significantly reduced seizure frequency compared with placebo. Moreover, some patients taking CBD achieved seizure freedom despite having failed numerous previous ASDs and taking 2 to 3 ASDs at the time of the trial.
Therapeutic and adverse effects of Epidiolex were found to be dose dependent.13 The most common adverse effects were somnolence, diarrhea, and decreased appetite. Somnolence was particularly common in patients who were concurrently taking clobazam. Epidiolex is known to modulate cytochrome P450 and glucuronosyltransferase (UGT) isoenzymes and has been associated with changes in levels of conventional ASDs.13,14 It is estimated that clobazam levels may increase approximately 60% in those receiving Epidiolex.13 Elevated transaminases also were reported in patients concurrently taking Epidiolex and valproate.14
The US Food and Drug Administration (FDA) approved Epidiolex in June 2018 for adjuvant treatment in patients with DS and LGS aged 2 years and older. Product availability was pending reclassification of CBD by the US Drug Enforcement Administration (DEA), as it was previously classified as a Schedule 1 drug. On September 28, 2018, the DEA rescheduled Epidiolex as Schedule 5, and the product is expected to be available to consumers by the end of the year.
Epidiolex will be marketed in the United States by Greenwich Biosciences (Carlsbad, California) as a 100-mg/mL oral solution. The FDA drug information15 indicates initial dosing recommendations of 5 mg/kg/day divided twice daily, with titration to the initial maintenance dose of 10 mg/kg/day after 1 week. Further increases in dose can be made in weekly increments of 5 mg/kg/day as tolerated (max 20 mg/kg/day). Reduced dosages are recommended for patients with hepatic impairment. The cost for Epidiolex is expected to be more than $30,000 per year, raising concerns regarding insurance company approval.16 The cost also may limit future investigator-initiated trials for novel indications.
We are finally beginning to accumulate evidence through rigorous scientific investigation that supports the efficacy and safety for adjuvant CBD use in TRE. Studies are underway to evaluate cannabidiol efficacy for a broader range of epileptic syndromes,17-20 and more than 20 trials are currently listed on ClinicalTrials.gov.
1. Mardani P, Oryan S, Sarihi A, Alaei E, Komaki A, Mirnajafi-Zadeh J. Endocannabinoid CB1 receptors are involved in antiepileptogenic effect of low frequency electrical stimulation during perforant path kindling in rats. Epilepsy Res. 2018;144:71-81.
2. Stumpf A, Parthier D, Sammons RP, et al. Cannabinoid type 2 receptors mediate a cell type-specific self-inhibition in cortical neurons. Neuropharmacology. 2018;139:217-225.
3. Schonhofen P, Bristot IJ, Crippa JA, et al. Cannabinoid-based therapies and brain development: potential harmful effect of early modulation of the endocannabinoid system. CNS Drugs. 2018;32(8):697-712.
4. Young S. Marijuana stops child’s severe seizures. CNN. Available at: https://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/. Published August 7, 2013. Accessed October 9, 2018.
5. Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014:55(6):783-786.
6. Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, Bonn-Miller MO. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA. 2015;313(24):2491-2493.
7. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270
8. Epilepsy Foundation. Epilepsy Foundation calls for increased medical marijuana access and research. Available at: http://www.epilepsy.com/article/2014/2/epilepsy-foundation-calls-increasedmedical-marijuana-access-and-research. Published February 20, 2014. Accessed October 9, 2018.
9. American Epilepsy Society (AES). AES position on medical marijuana. Available at: https://www.aesnet.org/sites/default/files/file_attach/AboutAES/PositionStatements/AES Position on Medical Marijuana.pdf. Updated February 28, 2014. Accessed October 9, 2018.
10. Devinsky O, Cross JH, Laux L, 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(21):2011-2020.
11. Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888-1897.
12. Thiele EA, Marsh ED, French JA, et al; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, doubleblind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096.
13. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246-1251.
14. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586-1592.
15. US Food and Drug Administration; Greenwich Biosciences Inc. Highlights of prescribing information: Epidiolex (cannabidiol) oral solution. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Approved June 2018. Accessed October 9, 2018.
16. Brochstein A. GW Pharma reveals Epidiolex pricing. NCV Media website. Available at: https://www.newcannabisventures.com/gw-pharma-reveals-epidiolex-pricing/. Published August 1, 2018. Accessed October 9, 2018.
17. Hess EJ, Moody KA, Gef frey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(10):1617-1624.
18. Kaplan EH, Offermann EA, Sievers JW, Comi AM. Cannabidiol treatment for refractory seizures in Sturge-Weber syndrome. Pediatr Neurol. 2017;71:18.e2-23.e2.
19. Gofshteyn JS, Wilfong A, Devinsky O, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017;32(1):35-40.
20. Devinsky O, Verducci C, Thiele EA, et al. Open-label use of highly purified CBD (Epidiolex) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 2018;86:131-137.