By David Kiefer, MD, Editor
Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson
Dr. Kiefer reports no financial relationships relevant to this field of study.
Three months of cannabidiol-enriched cannabis extract decreased mean monthly seizure frequency in children and young adults with refractory epilepsy.
Hausman-Kedem M, Menascu S, Kramer U. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents — An observational, longitudinal study. Brain Dev 2018;40:544-551.
- This uncontrolled, open-label study in 57 children and young adults with epilepsy showed a decrease in seizure frequency when, on average, 11.7 mg/kg/day of cannabidiol was added to their pharmaceutical regimen.
At times, herbal medicines make headlines, and the use of cannabidiol (CBD) oil for pediatric seizure disorders is a perfect example. CBD is one of the physiologically active phytochemicals extracted from the hemp plant, or Cannabis sativa. It is a different type of compound from another well-known hemp extract, tetrahydrocannabinol (THC), which is considered the plant’s psychoactive constituent and is subject to federal oversight and a variety of state laws governing its recreational and medicinal use. CBD falls into more of a “gray area,” although it still is listed as a DEA Schedule 1 substance because of the fact that it is extracted from the cannabis plant.1 However, in some states, it is possible to purchase CBD as an over-the-counter supplement.
Related to the recent FDA press release about the approval of a 99%-purified CBD extract, Epidiolex, for pediatric seizures,1 are several randomized, controlled trials and review articles exploring CBD oil for this purpose and other neurological conditions.2,3,4 In one clinical trial, Hausman-Kedem et al illustrated some of the clinical pearls of this treatment. Study participants, who were 1 to 20 years of age with “refractory” epilepsy being treated as outpatients, were offered cannabis treatment in addition to their current pharmaceutical regimen. “Refractory” was defined as failing at least four treatments, which also could include the ketogenic diet or vagal nerve stimulation. The cannabis extract was CBD-enriched, containing a 20:1 ratio of CBD to THC, and initially was dosed at a CBD content of 2 to 5 mg/kg per day, divided three times daily. The CBD dose was increased to 50 mg/kg per day, as tolerated, although none of the participants reached this level. None of the participants consumed more than 0.15-1.35 mg/kg per day of THC. The primary outcome was mean monthly seizure frequency. The statistical analysis compared two groups: those with no response or < 49% reduction in seizure frequency vs. those with 50-75% and 75-100% reduction in seizure frequency.
The researchers enrolled 69 participants, average age 9.6 years, to add CBD oil to their regular regimen, then excluded 12 (five because of inadequate reporting of seizure frequency and seven because of lack of follow-up at three months). Of the 57 participants who made it through the enrollment process, 17 dropped out of the study (10 because of “bothersome” side effects, six because of poor follow-up, and one who was “unable to take the extract”). The total daily CBD dose ranged between 77 to 800 mg (4 to 32 mg/kg/day, average 11 mg/kg/day). The researchers included 46 patients in the efficacy analysis, although it is unclear why 46, rather than 57, were analyzed here. Of these 46, 20 had a seizure reduction of 0-49%, 10 had a reduction of 50-75%, 14 had a reduction of 75-99%, and two were seizure-free (100% reduction). The analysis also showed statistically better responses in participants younger than 10 years of age, those taking more than 11 mg/kg/day, and those taking the extract for a longer period of time (20 months vs. 14 months). With respect to tolerability, 46% of study participants had adverse effects, most often somnolence, aggressiveness, loss of appetite, and vomiting.
Putting these results into context, the authors mentioned that the efficacy agrees with other published studies, although the 11.7 mg/kg/day average dose in this study was a bit less than published levels; CBD dosing for adults ranges between 200 to 300 mg daily, and published pediatric dosing can be as much as 25 mg/kg/day (FDA-approved Epidiolex is 50 mg/kg/day). The authors lamented the fact that adverse effects limited achieving higher dose levels.
This trial is difficult to interpret, not only from the statistics on efficacy (were the four groups different, statistically, from each other?), but also because of the lack of a control group and randomization. The authors acknowledged these latter flaws, clearly pointing the way toward future clinical trials on the topic. The adverse effects listed (including two participants with worsening seizures and another with psychosis) are a concern, and may limit the use of CBD in this population. Perhaps that is why the FDA only approved Epidiolex in “…two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.” Severe and refractory epilepsy can have disastrous consequences; in these cases, it may be worth the possible adverse effects to achieve some benefit. On that note, two study participants had their seizures remit completely, a wonderful outcome for this demographic.
Both the authors and the FDA press release referenced in this review bring up the issues surrounding CBD sourcing and the difficulties finding a reliably dosed product, given the politics and state-by-state variation in availability. Perhaps, for now, this study’s results provide some context for clinicians to tailor their CBD risk-benefit counseling to this specific demographic, and at a very specific dosing regimen.
REFERENCES
- U.S. Food and Drug Administration. FDA News Release. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. June 25, 2018. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm611046.htm. Accessed July 2, 2018.
- O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav 2017;70(Pt B):341-348.
- Stockings E, Zagic D, Campbell G, et al. Evidence for cannabis and cannabinoids for epilepsy: A systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry 2018;89:741-753.
- Libzon S, Schleider LB, Saban N, et al. Medical cannabis for pediatric moderate to severe complex motor disorders. J Child Neurol 2018;33:565-571.
