In recent years, interest in the therapeutic potential of cannabidiol (CBD) has skyrocketed. The cannabinoid has been investigated in various medical conditions and disorders, while consumer CBD products are increasingly available.
With respect to pharmaceutical-quality CBD, in the form of Epidyolex, it has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as an add-on treatment for two forms of rare childhood epilepsies. Furthermore, recent clinical trials have assessed the compound in other settings.
However, despite the growing popularity of CBD among medical and wellness communities, there remains uncertainty around the safety of the compound. However, clinical trials to date have suggested that CBD has few adverse effects, which has helped to boost its popularity among wellness consumers. However, the authors of a recent study note that previous reviews of the safety and tolerability of CBD “did not include meta-analysis, included data from other cannabinoids, or were limited to studies in epilepsy.”
Therefore, researchers conducted a systematic review and meta-analysis of randomised clinical trials to assess the adverse effects of CBD across all medical indications.
Design and Methods of the Study
The authors included double-blind randomised placebo-controlled clinical trials that reported data on withdrawal, serious adverse events, or adverse events. Trials that were open-label, did not include a placebo comparison, were quasi-randomised, or lasted less than 7 days were excluded from the review.
Each study was assessed for bias using the Cochrane Risk of Bias Tool by two independent raters. The researchers also conducted a pairwise meta-analysis of all outcomes for CBD against placebo where more than eight events were recorded across both arms of all studies.
Results of the Study
A total of 28 randomised double-blind placebo-controlled clinical trials were initially identified; however, 10 of these were excluded from further analysis because they were only reported in abstracts, posters, or secondary descriptions from the grey literature. A further five were excluded because they did not report data on withdrawal or adverse events in a systematic way. Therefore, 13 clinical trials comprising data from 822 participants were included in the final systematic review.
Of the 13 studies included in the systematic review, 5 involved patients with epilepsy and 2 involved patients with schizophrenia. The remaining six studies involved subjects with problematic cannabis use, Huntington’s disease, type II diabetes, non-alcoholic fatty liver disease, Crohn’s disease, and healthy volunteers. All trials are believed to have used pharmaceutical-grade CBD, with minimal other cannabinoids.
The included studies reported a total of 266 different adverse outcomes, of which 33 provided sufficient data for meta-analysis. One study met all inclusion criteria but none of the events it reported occurred in outcomes relevant to the meta-analysis. Therefore, 12 trials using data from 803 participants contributed to the meta-analysis.
Adverse Events
Withdrawal
Those administered CBD were more likely to withdraw from each study, compared to those receiving placebo. The likelihood of withdrawal appeared to be dose-dependent: at high doses, 12.9% of participants withdrew compared with 8.8% at medium doses and 4.3% at low doses. In epilepsy studies, withdrawal due to any reason or due to adverse events was more common in placebo groups.
Adverse Events
CBD was associated with a greater likelihood of decreased appetite, diarrhoea, sedation, and somnolence. In epilepsy studies, CBD was associated with decreased appetite, diarrhoea, and somnolence, while the incidence of sedation was not statistically significant from placebo. In non-epilepsy trials, the only event that was more frequent with CBD than with placebo was diarrhoea.
In total, 67.6% of participants receiving CBD treatment reported an adverse event, compared with 54.5% of those in placebo arms. Furthermore, the likelihood of an adverse event was related to the dose of CBD and differed according to the clinical group being treated. For example, in the five studies involving children with epilepsy, 67.8% of those given CBD experienced adverse events, compared with 51.5% on placebo; in contrast, in the five non-epilepsy studies, the rates were similar: 67.0% and 62.2%, respectively.
Serious Adverse Events
A total of 61 serious adverse events in 415 participants (14.7%) were reported in the CBD arms compared with 18 among 295 participants (6.1%) receiving placebo. In epilepsy studies, the odds ratio of serious adverse events was 2.7 compared with 0.34 in non-epilepsy trials. This results from serious adverse events associated with CBD treatment being limited to studies in children with epilepsy.
There was an increased likelihood of pneumonia and abnormal liver function. An additional two cases of pneumonia were recorded as non-serious adverse events in CBD groups; however, pneumonia was only reported in studies of patients with epilepsy. Differences in the likelihood of abnormal liver function were also only evident in studies involving childhood epilepsy, and most events occurred in individuals prescribed high doses of CBD.
Conclusions
Whilst the results of this systematic review and meta-analysis are promising with respect to the rates of adverse events among CBD, there is clearly still a potential for adverse events such as pneumonia or abnormal liver function. These adverse events were most common in children with childhood epilepsy, which may be due to the relatively higher doses they consume per body weight relative to adult patients who are prescribed CBD for other conditions. Moreover, CBD affects the metabolism of medications commonly prescribed for epilepsy which may further increase the risk for adverse events. The authors suggest that additional data, particularly from trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products, is needed. This is one of the reasons given by the Food Standards Agency when they updated their guidance on the recommended daily dose of CBD products. What is clear is the importance of medical oversight when using CBD for health reasons.
