Oral treatment with cannabidiol (CBD) is associated with a greater likelihood of adverse events and treatment withdrawal in children with rare forms of epilepsy, including those with Lennox-Gastaut syndrome, but appears safe for other indications, a review of clinical trials shows.
This is likely because childhood epilepsy patients take higher CBD doses than others and often are taking other epilepsy medications whose metabolism may be affected by CBD use, researchers say.
The study, “Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials,” was published in the journal Nature: Neuropsychopharmacology.
CBD, one of the most abundant compounds in the cannabis plant, has gained interest in past years for its potential to treat certain health conditions, including anxiety, Parkinson’s disease, diabetes, and schizophrenia.
The strongest scientific evidence, however, is for the treatment of severe childhood epilepsy syndromes, including LGS and Dravet syndrome, which typically fail to respond to standard seizure medications.
CBD has been approved by both the U.S. Food and Drug Administration and the European Commission for patients with these conditions starting at age 2. The product is sold as Epidiolex (cannabidiol) by GW pharmaceuticals in the U.S.; in the European Union it is branded as Epidyolex and used as an add-on therapy to clobazam.
CBD is regarded as generally safe, having few adverse events. But most review studies examining its safety and tolerability have investigated its use only in epilepsy, or also included data from other cannabinoids.
In this study, researchers in the U.K. and Australia have conducted a review of the literature to assess CBD’s safety in clinical trials across a range of indications. They included only clinical trials with a randomized, double-blind, placebo-controlled design, that lasted at least seven days, and reported on withdrawal and adverse events (side effects).
In total, 13 trials met the inclusion criteria and 12 provided suitable data for meta-analysis, including a total of 803 participants. Five of these trials involved patients with epilepsy, including two with Dravet children, two with LGS children and adults, and one with adults with epilepsy. The remaining involved healthy volunteers or patients with schizophrenia, problematic cannabis use, Huntington’s disease, type II diabetes, non-alcoholic fatty liver disease, and Crohn’s disease.
In these trials, patients were on CBD from one to 14 weeks, and received oral doses ranging from 200 to 3,000 mg a day. One study used under-the-tongue CBD at a dose of 20 mg per day.
The median dose in the entire population was 1,200 mg/day, but patients in the epilepsy studies had received higher doses (1,214 mg/day) than those in non-epilepsy studies (918 mg/day).
In the overall population, CBD use increased by about 2.6 times the likelihood that patients withdrew from the study due to any reason and due to adverse events. There was a trend toward higher withdrawal rates in people taking higher doses.
Compared to a placebo, CBD also increased the likelihood of serious adverse events by 2.3 times and of adverse events by 1.33 times. The serious adverse events that were significantly more common in the CBD group were pneumonia and abnormal levels of liver enzymes, while significantly increased adverse events of any grade included decreased appetite, diarrhea, sedation, and sonomlence.
Notably, most of these effects were replicated when researchers examined only epilepsy studies, but not with the non-epilepsy ones.
In epilepsy studies, CBD use also was associated with a significantly greater likelihood of withdrawal, of serious adverse events, and of adverse events of any grade. Of the adverse events reported as significantly elevated in the overall CBD group, only sedation was not significantly higher in epilepsy patients taking CBD, compared to those on placebo.
Contrastingly, in non-epilepsy studies, the only event that was more frequent with CBD was diarrhea of any grade, which was five times more likely than in the placebo group, potentially reflecting “the endocannabinoid system’s role in the regulation of gastrointestinal motility,” the researchers explained.
The team advanced a couple of reasons as to why epilepsy patients were more likely to experience the side effects of CBD. In addition to the higher doses taken by these patients, they believe that CBD is interfering with enzymes that are needed for the metabolism of other epilepsy medications.
For example, a considerable number of patients in the epilepsy studies were taking clobazam. CBD is not sedative by its own, but is known to interfere with clobazam’s metabolism in a way that increases a byproduct with a strong sedative effect.
This byproduct also can raise the chances of pneumonia, as the sedation increases the risk of respiratory depression and aspiration, they wrote. This is particularly evident when CBD is used at high doses, as was the case in these trials.
The researchers concluded that “CBD is well tolerated and has few adverse effects,” but that “its ability to inhibit the hepatic metabolism of other medications (such as clobazam and sodium valproate) has the potential to cause adverse effects.”
“Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of [over-the-counter] CBD products would be beneficial,” they added.