Randomized controlled trial (dose-ranging, double-blind, Class I evidence)Strong for safety characterization; underpowered for efficacy (n=34)2018

The Dose-Ranging Study That Explained CBD's Side Effects

Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome

Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K·Neurology·PubMed

A small but critical trial revealed that much of CBD's somnolence in epilepsy is caused by a drug interaction with clobazam, not by CBD itself. Also confirmed the CBD-valproate liver interaction and dose-proportional pharmacokinetics.

The Dravet NEJM trial tested one dose: 20 mg/kg/day. It worked. But clinical medicine needs to know more than whether a drug works at one dose. It needs to know: what happens at lower doses? Does the safety profile change? How does the drug interact with the medications these patients are already taking? What's the minimum effective dose and the maximum tolerable one?

This small, carefully designed dose-ranging trial answered those questions for the youngest Dravet patients — children aged 4 to 10.

The Study

The Key Findings

This trial's most important contributions weren't about seizures — they were about the pharmacology of CBD in combination with other epilepsy drugs.

The Clobazam Story

Myth vs. Reality

✕Myth

CBD's side effects in epilepsy trials are caused by CBD itself.

✓Reality

Many of the adverse effects reported in CBD epilepsy trials — particularly somnolence and sedation — are at least partially caused by drug interactions, not by CBD directly. CBD inhibits CYP2C19, which raises levels of N-desmethylclobazam (the active metabolite of clobazam, a commonly co-prescribed drug). CBD also interacts with valproate through CYP pathways, causing liver enzyme elevations. Understanding these interactions is essential for safe prescribing — and it means CBD's direct side effect profile may be milder than the trial data suggests.

The Evidence

Devinsky et al. (2018): CBD increased N-CLB levels in a dose-proportional manner except in patients on stiripentol. Six patients on CBD+valproate had elevated transaminases; none on CBD without valproate did.

Devinsky et al. (2018), Neurology 90:e1204-e1211

Small Trial, Big Impact on Practice

With only 34 patients, this study wasn't powered to measure seizure reduction with statistical confidence. Its value was different: it characterized the pharmacology that makes safe prescribing possible. Every neurologist who writes an Epidiolex prescription and adjusts the concurrent clobazam dose is relying on data from this trial.

Frequently Asked Questions

Based on the full Epidiolex trial program, 20 mg/kg/day is the established starting therapeutic dose for Dravet and Lennox-Gastaut syndromes. The TSC trial showed 25 mg/kg/day was as effective as 50 mg/kg/day with fewer side effects. This dose-ranging study showed that lower doses (5-10 mg/kg/day) are tolerated but may be less effective. Dose titration should be individualized by a neurologist, with particular attention to concurrent medications (clobazam, valproate) that interact with CBD.

Much of the somnolence seen in CBD epilepsy trials is likely caused by a drug interaction, not CBD directly. CBD inhibits the CYP2C19 enzyme, which causes the active metabolite of clobazam (N-desmethylclobazam) to accumulate to higher-than-expected levels. Since clobazam is a benzodiazepine (inherently sedating), elevated levels produce drowsiness. Reducing the clobazam dose when adding CBD often resolves the somnolence.

Epilepsy CBD dravet pharmacokinetics Drug Interactions safety

Cite this study

Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K. (2018). Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. https://doi.org/10.1212/WNL.0000000000005254

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Devinsky O(1)Patel AD(1)Thiele EA(2)