CBD-Epilepsy Medications Come With Drowsiness Risk, Researchers Warn

Numerous clinical trials have established the safety and efficacy of CBD formulations for controlling epileptic seizures. But while CBD is generally well tolerated, relatively little attention has been paid to those cases where adverse events do materialize.

Now, a new study published in JAMA Network Open presents the first systematic review and meta-analysis focusing on CBD-related adverse events (AEs) among people with epilepsy.

The researchers found that adverse events were more than twice as common with CBD compared to a placebo, with drowsiness and appetite loss being the most common events reported. However, the researchers also noted that several of the studies identified by their literature search had significant concerns with study bias.

Based on these findings, the researchers say that additional research into CBD-related AEs is still needed.

Adverse events twice as likely for CBD compared to placebo

For this new systematic review and meta-analysis, the researchers searched through the PubMed, Scopus, and the Web of Science databases for any articles published before August 2022 that included the keywords “cannabidiol OR epidiolex” and “epilepsy OR seizures”.

After combing through the initial search results, the researchers identified 61 papers for a full-text review. Of these, 52 were excluded for reasons such as not being a randomized controlled trial, not reporting AEs, or being re-analyses of existing data. A final number of nine articles met all of the inclusion criteria and were analyzed in this latest review.

Eight of the studies used an oral formulation of CBD at doses ranging between 5 to 50 milligrams per kilogram per day (mg/kg daily). The remaining study was evaluating the use of twice-daily 390 mg and 195 mg transdermal CBD gels for controlling seizures. The age of the participants in these trials varied between 1 to 56 years old. A wide range of other concomitant antiepileptic drugs were taken alongside CBD administration, including valproate, clobazam, ethosuximide, and lamotrigine.

From a meta-analysis of the results of these studies, the researchers observed that somnolence, decreased appetite, and pyrexia (fever) were the most commonly reported AEs among those given CBD. In the placebo arm of the trials, upper respiratory tract infection, diarrhea, and fever were the most common.

The researchers found that any grade (mild, moderate, or severe) AEs were more frequently reported by those in the CBD arm of the trials than those given a placebo. The overall percentage of any-grade AEs was 9.7% among those given CBD, versus 4% for placebo.

Additionally, the frequency of severe grade-only AEs was higher for CBD (1.2%) than for placebo (0.7%). The percentage of reported AEs that led to discontinuation in trial participation was also higher in the CBD arm, at 2.4% to 0.7%.

Researchers raise concerns over study bias

While the prevalence of any-level and severe AEs was significantly higher in the CBD group, the researchers believe that CBD is still a relatively safe option for controlling seizures. As is highlighted in this paper, a previous systematic review has already shown that serious or severe AEs occurred less frequently for any indications treated with CBD compared to other cannabinoids, such as the synthetic THC drugs dronabinol or nabilone.

However, the researchers do highlight a few additional points of note. Firstly, the fact that just nine studies met the inclusion criteria meant for this review meant that they were unable to reach the 10-study threshold needed for small-study bias or publication bias evaluations.

The researchers also noted some significant problems with study bias. Applying the Cochrane risk-of-bias tool for assessing randomized trials, they found that only three of the trials could be considered to be at low risk of bias. A further three trials had some concerns, while the remaining three were deemed to have a high risk of bias due to outcome measurement or the selection/reporting of certain results.

CBD and epilepsy

Epidiolex became the first plant-derived cannabinoid drug formulation to receive approval from the US Food and Drug Administration in 2018, when it was officially approved for use in treating seizures in two rare forms of epilepsy.

But despite its proven safety and effectiveness, questions remain over how exactly CBD works to combat seizures in the brain.

In 2019, a study published in the British Journal of Clinical Pharmacology suggested that CBD’s anti-seizure effects may be down to a specific drug-drug interaction taking place between CBD and the common antiseizure medication clobazam. On re-examining the studies that formed the basis of the FDA approval, the researchers noted significant numbers of patients had been taking concomitant clobazam while going through the trials.

“I’m not saying that I know for a fact that cannabidiol does not have any anti-epileptic effects,” Geert Jan Groeneveld, chief scientific officer at the Centre for Human Drug Research in the Netherlands and lead author of the study, told Analytical Cannabis at the time. “What I am saying is, I can explain the effects that you've observed through elevated blood levels of clobazam.”

However, more recent studies have suggested that while CBD may amplify the active metabolites of both drugs in the body, in high doses, CBD can still reduce seizure frequency and increase the number of seizure-free days that patients experience.