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Cannabinoids used for medical purposes in children and adolescents come with a risk of adverse events, a systematic review and meta-analysis of 23 randomized clinical trials showed.

The risk ratio (RR) of developing adverse events was higher in the cannabinoid group than in the control group (1.09, 95% CI 1.02-1.16), Lauren Kelly, PhD, MSc, of the University of Manitoba in Winnipeg in Canada, and colleagues reported in .

Specific adverse events significantly linked to cannabinoid treatment -- cannabidiol (CBD) in about half of the trials -- included:

• Diarrhea (RR 1.82)
• Elevated serum aspartate aminotransferase (RR 5.69)
• Elevated alanine aminotransferase (RR 5.67)
• Somnolence (RR 2.28)

These events led to more trial withdrawals due to adverse events (RR 3.07, 95% CI 1.73-5.43), and serious adverse events were more common with medical cannabinoids than among controls (RR 1.81, 95% CI 1.21-2.71).

"The interest and use of cannabis-based medicines has increased, including in children with complex health concerns like epilepsy, autism, and cancer," Kelly told MedPage Today in an email. At the same time, adverse effects of medical use hadn't been systematically appraised in children, she added.

Her group concluded that "physicians considering cannabinoids for medical purposes in children and adolescents should weigh the risk and benefit profile of cannabinoids and available therapeutic options as well as the individual's underlying disease condition and prognosis."

When used, physicians and caregivers should monitor for somnolence, changes in appetite, dizziness, and other cannabinoid-related adverse events, they suggested.

Also watch for interactions with other drugs, particularly the combination of CBD and epilepsy drugs, like clobazam and valproate, they urged. "Children and adolescents treated with CBD and clobazam should be closely monitored for CNS-related adverse events, such as lethargy, fatigue, and somnolence, secondary to altered clobazam metabolism, and lowering of the clobazam dose accordingly should be considered."

Subgroup analysis suggested that cannabinoids, compared with the control, were associated with a higher risk of serious adverse events in trials of only children and adolescents (RR 1.87, 95% CI 1.30-2.70), with use of purified CBD (RR 2.16, 95% CI 1.55-3.02), with treatment of more than 12 weeks (RR 2.30, 95% CI 1.57-3.38), and among those with epilepsy (RR 2.16, 95% CI 1.55-3.02).

The most common indications for cannabinoids in young participants were drug-resistant epilepsy (nine trials) and chemotherapy-induced nausea and vomiting (seven trials). Additionally, autism spectrum disorder was the indication in three trials, traumatic brain injury in two, spasticity in one, and cannabis use disorder in one.

Overall, the systematic review and meta-analysis consisted of 15 parallel trials, seven crossover trials, and one adaptive dose-finding trial. Eleven trials included only children and adolescents. Interventions included purified cannabidiol in 11 trials, nabilone in four, tetrahydrocannabinol in three, cannabis herbal extract in another three, and dexanabinol in two.

Only some 18% of the 3,612 total participants in the trials were female, although data on gender were not available for two trials.

Limitations of the meta-analysis included heterogeneity in trial designs, indications, interventions, dose, and duration, Kelly and colleagues noted. For instance, duration of most of the trials was short (10-14 weeks or one to two cycles of cancer treatment), and there was a dearth of reports on concomitant medication use.

Additionally, there is no standardized method to capture cannabinoid-related adverse events in children and adolescents, "leading to inconsistencies in definitions and grading," they wrote. There also were discrepancies (based on dose or treatment group) in how serious adverse events were reported.

Furthermore, few trials evaluated cannabis herbal extract, "thus highlighting a need for a pathway for global research efforts to identify the safety and efficacy of these cannabis-based products," they added.

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