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How does CBD compare and interact with other AEDs?



The efficacy and side effects of cannabidiol (CBD) in severe pediatric epilepsies are similar to those of other antiepileptic drugs (AEDs), according to a review published in Developmental Medicine & Child Neurology. “Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD,” the authors said.

Although CBD’s antiepileptic mechanisms “are not fully elucidated, it is clear that administration of CBD as adjunct therapy decreases seizure frequency in patients with Dravet syndrome and Lennox-Gastaut syndrome,” wrote Shayma Ali, a doctoral student in the department of pediatrics and child health at the University of Otago in Wellington, New Zealand, and her colleagues. “Contrary to public expectation of miraculous results, CBD has a similar antiepileptic and side effect profile to other AEDs. Nevertheless, as individual children with these developmental and epileptic encephalopathies are often refractory to available AEDs, the addition of another potentially effective therapeutic medicine will be warmly welcomed by families and physicians.”

The FDA approved Epidiolex, a pharmaceutical-grade oral solution that is 98% CBD, in June of 2018. In September of 2018, the Drug Enforcement Administration classified it as a Schedule V controlled substance. Patients’ use of nonpharmaceutical grade CBD products, including those combined with tetrahydrocannabinol (THC), “raises concerns about the use of products with THC on the developing brain,” the review authors said.

Randomized trials

Three randomized, controlled, double-blind trials in patients with Dravet syndrome and Lennox-Gastaut syndrome found that CBD, compared with placebo, results in greater median seizure reductions (38%-41% vs. 13%-19%) and responder rates (i.e., the proportion of patients with 50% reductions in convulsive or drop seizures; 39%-46% vs. 14%-27%).

Common adverse effects include somnolence, diarrhea, decreased appetite, fatigue, lethargy, pyrexia, and vomiting. Hepatic transaminases became elevated in some patients, and this result occurred more often in patients taking valproate.

No phase 2 or phase 3 trials have assessed the efficacy of CBD without coadministration of other AEDs, and CBD’s efficacy may relate to its impact on the pharmacokinetics of coadministered AEDs. “The most important clinical interaction is between CBD and clobazam, as [the dose of] clobazam often needs to be lowered because of excessive sedation,” wrote Ms. Ali and her colleagues. CBD inhibits CYP2C19 and CYP3A4 – enzymes that are involved in clobazam metabolism – which results in high plasma concentrations of clobazam’s active metabolite, norclobazam. Plasma levels of topiramate, rufinamide, zonisamide, and eslicarbazepine also may increase when these drugs are taken with CBD.

Challenges and opportunities

Of the hundreds of compounds in the marijuana plant, CBD “has the most evidence of antiepileptic efficacy and does not have the psychoactive effects” of THC, the authors said. Little evidence supports the combination of THC and CBD for the treatment of epilepsy. In addition, research indicates that THC can have a proconvulsive effect in animal models and harm the development of the human brain.

Investigators are evaluating alternative routes of CBD delivery to avoid first-pass metabolism, such as oromucosal sprays, transdermal gels, eye drops, intranasal sprays, and rectal suppositories. “Alternative methods of administration ... deserve consideration, particularly for the developmental and epileptic encephalopathies population, as administration of oral medication can be challenging,” they said.

SOURCE: Ali S et al. Dev Med Child Neurol. 2018. doi: 10.1111/dmcn.14087.

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