What are the frequency and risk of adverse events developing in patients with epilepsy who are using CBD?

In a recent study published in the JAMA Network Open Journal, researchers conducted a systematic review and meta-analysis among epilepsy patients to evaluate cannabidiol (CBD) use-related adverse events (AEs), including their frequency and risk.

Study: Adverse Events of Cannabidiol Use in Patients With Epilepsy. Image Credit: Tinnakornjorruang/Shutterstock.com

Background

Epilepsy is a common neurologic disorder impacting 67 people per 100,000 population every year. Although treatable, in nearly one-third of epilepsy cases, even surgical interventions fail to stop seizures in epileptic patients, thus, raising the need for novel, alternative therapies for epilepsy.

The United States Food and Drug Administration (US-FDA) and the European Medicines Agency (EMA) have approved CBD use in several severe epilepsy forms, e.g., Dravet and Lennox-Gastaut syndromes.

Although prior studies have examined CBD’s effectiveness and safety profile, there is a lack of systematic reviews reporting AEs related to CBD use in epileptic patients or addressing the limitations of previously published reviews.

About the study

In the present study, researchers extensively searched databases, such as PubMed and the Web of Science, for articles reporting AEs following CBD treatment. They manually searched for grey literature on Google Scholar and previous systematic reviews for additional eligible articles.

An extensive search of backward and forward citations helped researchers discover additional qualified studies from included studies. The search continued from the database inception date till August 4, 2022.

The team removed duplicates (if any) in EndNote, version 20. First, two authors independently skimmed through each article’s title and abstract and reviewed their full texts. They resolved discrepancies (if any) through a discussion with other authors.

Two other independent reviewers extracted all the basic data from each article in the study. Notably, they included randomized clinical trials (RCTs) evaluating a minimum of one AE related to CBD use in epileptic patients.

The researchers considered all negative clinical manifestations in study participants after CBD use or placebo as AEs. They categorized them per the Common Terminology Criteria for Adverse Events, v. 5.0. For quality assessments of the included RCTs. They reviewed the risk of bias in the risk-of-bias (RoB2) tool v.2. The researchers also determined the overall risk of bias for each study.

Further, the researchers extracted dichotomous raw data on the incidence of mild-to-severe and all grade AEs from each study. They computed the I2 statistics to determine the included RCTs’ heterogeneity.

If it was lower than 40% for the AEs, they used a fixed-effects model; otherwise, they used a random-effects model. The former used the inverse variance method, while the latter relied on the DerSimonian and Laird methods.

If AEs for at least one arm were zero, the team used a continuity correction of 0.5. They evaluated publication bias only when ten studies were included, with p<0.05 considered statistically significant.

Results

The systematic search helped the researchers identify 3280 RCTs, of which 1,350 were duplicates. Screening 1,930 publications, including 61 studies for full-text, fetched nine articles that met the eligibility criteria for qualitative and quantitative synthesis.

The RoB2 tool showed that three trials each had a low risk, some concerns, and a high risk of bias, respectively.

In domains such as the selection of reported results and the measurement of outcomes, the risk of bias was higher; thus, future studies should carefully consider the same, register the RCT protocol, and document all insignificant and significant outcomes.

Most of the included studies were multicenter RCTs published between 2017 and 2022, with participants aged ~1 to 57 years. The epileptic patients had various forms of epilepsy, e.g., Tuberous sclerosis–associated epilepsy.

The study results showed that the overall percentage of AEs (any grade) was more than twice in epileptic patients in the CBD arm compared to controls (9.7% vs. 4.0%). The three most common AEs in the CBD group were somnolence, loss of appetite, and pyrexia, found in 22%, 19.5%, and 15.3% of epileptic patients, respectively.

Notably, CBD use also increased the risk of alanine transaminase (ALT) or aspartate aminotransferase (AST) elevations. Likewise, The three most common AEs in the control group were upper respiratory tract (URT) infection, followed by diarrhea, and pyrexia, found in 11.8%, 10.9%, and 10.2% of people, respectively.

The percentages of mild, moderate, and severe AEs in the CBD  arm were 11.1.%, 3.1%, and 1.2%, respectively. In the control arm, AEs were relatively lowered, with overall percentages of mild, moderate, and severe AEs of 6.4%, 1.3%, and 0.7%, respectively.

As expected, the overall proportion of AEs that led to the trial’s discontinuation was markedly lower in the controls than in the CBD group (0.7% vs. 2.4%).

CBD use also markedly increased the risk of any grade AEs, severe grade AEs at respective percentages of 9.7% and 1.2%, as well as serious AEs, and AEs leading to dose reduction.

Analysis of pooled data from four studies showed that moderate manifestation of somnolence was statistically significantly higher in the CBD group than the control group, with a risk ratio of 3.62, 95% CI. In addition, the researchers noted an association between somnolence (CBD use-related AE) and taking clobazam, as evidenced in most of the included RCTs.

Conclusions

According to this systematic review, compared to other cannabinoids, CBD use is a relatively safe option for epileptic patients.

However, since CBD use led to several AEs, e.g., somnolence, AST, or ALT elevation, future studies should investigate its therapeutic effects and CBD use-related AEs side-by-side with other antiepileptic drugs. It could help ascertain a safe and effective dose of CBD for epileptic patients resistant to CBD therapy.