Over three million Americans live with epilepsy, of whom one-third have seizures that are not controlled by medications. As the leading organization of clinical and research professionals specializing in the treatment of epilepsy, the American Epilepsy Society (AES) supports all well-controlled studies that will lead to a better understanding of the disease and the development of safe and effective treatments.
Cannabis has been legalized in many states in the US for the treatment of various health conditions, but United States Pharmacopeia (USP) standards do not exist to give patients information about the identity, purity, or quality of any cannabis product. An evidence-based approach to the discovery, development, and clinical application of cannabinoids is important, because over 100 active compounds (phytocannabinoids) derived from the cannabis plant have been isolated,1 many of which have various pharmacologic actions (including psychoactive compounds such as tetrahydrocannabinol (THC) which produce a “high”).
Over the last decade, there has been great interest in the medical and scientific communities to explore the potential of cannabidiol (CBD), a non-psychoactive phytocannabinoid, to treat difficult-to-control epilepsy. Randomized controlled clinical trials (RCTs) have demonstrated that a mostly purified, plantbased form of CBD has efficacy and adverse effects for seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex in patients one year of age and older.2-4 Currently, data supporting effectiveness of CBD is primarily derived from RCTs2-4 of the U.S. Food and Drug Administration (FDA) approved formulation of CBD, Epidiolex®,5 available by prescription only. Overall, the evidence for CBD’s efficacy suggest that it can be used in combinations with other FDAapproved antiseizure medications (ASMs). To date, RCT evidence is lacking to support CBD use as a monotherapy for any seizure type. Prospective, RCT data evaluating artisanal or over the counter (OTC) formulations of CBD are lacking, so there is no conclusive evidence for other, less rigorously prepared CBD preparations, such as those obtained from dispensaries.
Importantly, independent laboratory testing of samples of OTC CBD products have shown that the labels reporting amounts of CBD and THC are often inaccurate.6 When patients purchase cannabis-based products from a dispensary, or as an OTC product, it is extremely important to understand that the product they select may contain not only CBD but also other phytocannabinoids such as THC, pesticides, and other dangerous impurities, in unknown concentrations.7 Unlike drugs approved by regulatory authorities such as FDA, there is no assurance that OTC CBD products have been evaluated for effectiveness, appropriate dosage, potential interactions with other drugs, and dangerous side effects or other safety concerns. In addition, RCT data clearly demonstrate that CBD can cause drug-drug pharmacokinetic interactions that can be substantial.8,9 RCTs with the FDA-approved prescription product also demonstrate that CBD may have clinically meaningful adverse effects such as elevated liver functions tests, gastrointestinal intolerance, sleep disturbances, and others, particularly when combined with other ASMs.2-4
While anecdotal reports of positive effects of cannabis or other cannabis derivatives on seizures exist, they may be unreliable and subsequent scientifically rigorous investigations often find such reports to be incorrect. Scientific evidence for the use of cannabis itself in the treatment of epilepsy is highly limited. The lack of information does not mean that cannabis is ineffective for epilepsy, but rather that providers do not currently have the required data needed to adequately inform rational clinical decisions for patients with epilepsy.
AES calls on government, private funders, and manufacturers to support and develop well-designed, scientifically rigorous, controlled research trials on any cannabis-based products that have potential to have positive benefits in the treatment of resistant epilepsy. These high standards for research are necessary for optimal evaluation of the safety, efficacy, and drug-drug interactions of any potential ASM. To increase rigorous clinical research, AES urges that the status of cannabis as a United States Drug Enforcement Administration (DEA) Schedule I controlled substance10 be reviewed. The AES call for rescheduling is not an endorsement of the legalization of cannabis but rather is a recognition that the current restrictions on the use of cannabis products for research continue to significantly limit scientifically rigorous research into the development of cannabis-based treatments. AES also encourages USP to continue its efforts to establish recognized guidance for cannabis as well as individual, therapeutically promising cannabinoids.
AES is very sympathetic to the needs of people with severe, treatment-resistant epilepsy. AES members work with people with epilepsy and their families daily and are very aware of the need for compassionate use of promising new therapies in appropriate, safe, and controlled circumstances. AES urges all people touched by epilepsy to consult with an epilepsy specialist and explore the many existing treatment options so that patients and families can make informed decisions with their specialist that weigh the risks and benefits of the different treatment options.
- National Center for Complementary and Integrative Health, National Institutes of Health. Cannabis (Marijuana) and cannabinoids: what you need to know. Updated November 2019. Accessed September 8, 2022. https://www.nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-whatyou-need-to-know
- Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618
- Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096. doi:10.1016/S0140-6736(18)30136-3
- Thiele EA, Bebin EM, Bhathal H, et al. Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial. JAMA Neurol. 2021;78(3):285-292. doi:10.1001/jamaneurol.2020.4607
- U.S. Food and Drug Administration. Prescribing Information. Epidiolex. February 24, 2022. Accessed September 2, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210365s015lbl.pdf.
- Miller OS, Elder EJ Jr, Jones KJ, Gidal BE. Analysis of cannabidiol (CBD) and THC in nonprescription consumer products: Implications for patients and practitioners. Epilepsy Behav. 2022;127:108514. doi:10.1016/j.yebeh.2021.108514
- Gardener H, Wallin C, Bowen J. Heavy metal and phthalate contamination and labeling integrity in a large sample of US commercially available cannabidiol (CBD) products [published online ahead of print, 2022 Aug 17]. Sci Total Environ. 2022;851(Pt 1):158110. doi:10.1016/j.scitotenv.2022.158110
- Patsalos PN, Szaflarski JP, Gidal B, VanLandingham K, Critchley D, Morrison G. Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs. Epilepsia. 2020;61(9):1854-1868. doi:10.1111/epi.16674
- Greger J, Bates V, Mechtler L, Gengo F. A Review of Cannabis and Interactions With Anticoagulant and Antiplatelet Agents. J Clin Pharmacol. 2020;60(4):432-438. doi:10.1002/jcph.1557
- United States Drug Enforcement Administration. Drug Scheduling. Accessed September 2, 2022. https://www.dea.gov/drug-information/drug-scheduling.