CBD and clobazam: why can drowsiness increase?

Medicines and the importance of the interaction

From peer-reviewed publications and drug labels: the warning. The same warning also appears in the interaction checker.

How does the interaction happen?

In the liver, clobazam is converted to N-desmethylclobazam mostly by the enzyme CYP3A4. At usual doses, this active breakdown product is present in the blood at 3–5 times the level of clobazam; its anti-seizure strength is estimated to be between one-fifth of clobazam's and the same as clobazam's. N-desmethylclobazam, in turn, is broken down mainly by the enzyme CYP2C19. (Clobazam prescribing information §12.3)

CBD moderately slows down the CYP2C19 enzyme. As a result, N-desmethylclobazam builds up because it cannot be broken down, while the level of clobazam itself changes little. In people whose CYP2C19 enzyme naturally works slowly from birth, N-desmethylclobazam is also 3–5 times higher; clobazam's prescribing information says the clobazam dose may need to be adjusted in these people and when it is taken with other medicines that slow down CYP2C19. (FDA Epidiolex label §7.2 and §12.3 (05/2026), EMA Epidyolex prescribing information 4.5, Clobazam prescribing information §7.4 and §12.5)

The interaction works both ways: clobazam also raises the peak level of CBD's active breakdown product, 7-OH-CBD, by 73% and its total exposure (AUC, the total amount of drug that stays in the blood) by 47%; the reason for this is not fully known. The rise in both active substances may contribute to the anti-seizure effect, but it can also increase side effects. (FDA Epidiolex label §12.3 (05/2026), EMA Epidyolex prescribing information 4.5 and 5.1, PMID 30791225, PMID 32918835)

On top of this, both CBD and clobazam can cause drowsiness; with alcohol and other medicines that cause sleepiness, this effect can add up. In children with Dravet syndrome who were taking stiripentol, no rise in N-desmethylclobazam was seen; because stiripentol also strongly slows down CYP2C19, one possible explanation is that this enzyme was already suppressed. (FDA Epidiolex label §5.2 and §7.4 (05/2026), Clobazam prescribing information §5.4, PMID 29540584, PMID 32918835)

What do studies and official drug information say?

Each finding shows the type of evidence it rests on. A case report describes a single patient; it does not prove cause and effect.

1. Drug-level study

   Breakdown product rose 3.4-fold in healthy volunteers (2019)

   In a study in which approved CBD (750 mg twice a day; about 20 mg/kg a day for a 75 kg adult) was given together with clobazam 5 mg twice a day, the clobazam level rose about 1.2-fold and the N-desmethylclobazam level rose 3.4-fold. Clobazam also raised CBD's active breakdown product about 1.5-fold. In this small group of volunteers, no clear difference in how often side effects occurred was seen.

   Source: PMID 30791225

2. Drug-level study

   2.2–2.6-fold in people with epilepsy (2020)

   In a placebo-controlled study in people with epilepsy taking a stable dose of clobazam, approved CBD at 20 mg/kg a day did not change the level of clobazam itself; the peak level of N-desmethylclobazam rose 2.2-fold and its total exposure 2.6-fold. The authors, who assessed six interaction studies, state that among epilepsy medicines the only interaction that may be clinically important is the one with clobazam.

   Source: PMID 32918835

3. Case series

   Breakdown product rose by an average of 500% in children (2015)

   In 13 children with treatment-resistant epilepsy who were using clobazam and CBD together, N-desmethylclobazam rose by an average of 500% after four weeks. The clobazam dose was lowered in 10 of the children; side effects occurred in 10 children and eased when the clobazam dose was lowered. The authors recommend monitoring the blood levels of clobazam and its breakdown product.

   Source: PMID 26114620

4. Controlled study

   In placebo-controlled studies, drowsiness was 3 times as common with clobazam

   In the Lennox–Gastaut and Dravet syndrome studies, drowsiness and sedation (including lethargy) occurred in 46% of those taking CBD who used clobazam and in 16% of those who did not; the rate among those taking placebo was 11%. In the tuberous sclerosis complex (TSC) study, the rates were 33% and 14%. The European product information reports 43% and 14% across all studies.

   Source: FDA Epidiolex label §5.2 (05/2026), EMA Epidyolex prescribing information 4.8

5. Systematic review

   Pooled analysis of four studies (2021)

   In a pooled analysis of four controlled studies in Lennox–Gastaut and Dravet syndromes, among those who took CBD and had drowsiness, 67% in the Lennox–Gastaut group and 84% in the Dravet group were using clobazam. The large majority of those who had sedation were also taking clobazam. Decreased appetite and diarrhea, however, were not more common in those using clobazam. In the overall group, in which patients taking and not taking clobazam were assessed together, CBD also reduced seizures compared with placebo.

   Source: PMID 32969022

6. Controlled study

   TSC study: drowsiness more common with clobazam (2021)

   In the tuberous sclerosis complex study, among those taking CBD 25 mg/kg a day, drowsiness occurred in 29% of those using clobazam and 9% of those not using it; among those taking 50 mg/kg a day, the rates were 53% and 17%. Most patients were not using clobazam, and CBD's seizure-reducing effect was also seen independently of clobazam.

   Source: PMID 33346789

7. Controlled study

   Pneumonia was more common in those taking clobazam

   In the Lennox–Gastaut and Dravet studies, pneumonia occurred in 10–17% of those taking CBD with clobazam and in 1% of those taking placebo with clobazam; in those not using clobazam, the rates were 0–4%. In the TSC study, pneumonia was also seen in 17% of those taking CBD with clobazam. The patient numbers are small; the prescribing information does not explain the reason.

   Source: FDA Epidiolex label §6.1 (05/2026), PMID 33346789

8. Observational study

   Open studies: drowsiness increased as the breakdown product rose (2017, 2023)

   In an open-label study of 81 patients using approved CBD, N-desmethylclobazam rose as the CBD dose increased, and in adults sedation was more common in those with high levels. In the final analysis of the same program, with 169 patients, the rise in N-desmethylclobazam was consistent across all clobazam doses; the clobazam dose was adjusted mostly because of drowsiness. In drug-level measurement data from Norway, the ratio of N-desmethylclobazam to clobazam also rose by an average of 140%.

   Source: PMID 28782097, PMID 37593907, PMID 39985501

9. Official drug information

   Liver enzymes: clobazam also raises the risk somewhat

   According to the US prescribing information, among patients with Lennox–Gastaut and Dravet syndromes taking CBD, ALT (a blood test that shows liver cell damage) above 3 times the upper limit of normal occurred in 4% of those using clobazam alone, 3% of those using neither clobazam nor valproate, and 30% of those using valproate and clobazam together. The prescribing information says that if liver enzymes rise, adjusting the valproate or clobazam dose should be considered.

   Source: FDA Epidiolex label §5.1 (05/2026), EMA Epidyolex prescribing information 4.4

10. Official drug information

    Prescribing information for approved CBD

    The US prescribing information recommends considering a lower clobazam dose if clobazam-related side effects occur; the European product information recommends considering a lower clobazam dose if drowsiness or sedation occurs. In Europe, approved CBD is authorized for use together with clobazam in Lennox–Gastaut and Dravet syndromes; the European product information states that in these two syndromes, effectiveness has not been clearly shown in patients not using clobazam.

    Source: FDA Epidiolex label §7.2 (05/2026), EMA Epidyolex prescribing information 4.1 4.5 and 5.1

What is monitored?

• Drowsiness, sedation and lethargy: watch for these especially when starting CBD and when the dose is increased. These effects are usually more common at the start of treatment and may lessen over time. Do not drive or use machines until you know how it affects you. (FDA Epidiolex label §5.2 (05/2026), EMA Epidyolex prescribing information 4.4 and 4.7, Clobazam prescribing information §5.5)
• Clobazam and N-desmethylclobazam blood levels: your doctor may measure them if needed. The European product information recommends considering blood level measurements of the epilepsy medicines used together with CBD. (EMA Epidyolex prescribing information 4.5, PMID 26114620)
• Pneumonia: it was more common in those taking CBD with clobazam. If you or your child have signs that suggest a lung infection, tell your doctor. (FDA Epidiolex label §6.1 (05/2026))
• Liver tests: these are measured before starting approved CBD and regularly in the months after. Clobazam raises the risk slightly and valproate clearly; if you also take valproate, more frequent monitoring is recommended. (FDA Epidiolex label §5.1 (05/2026), EMA Epidyolex prescribing information 4.4) CBD and valproate
• Alcohol and other medicines that cause sleepiness: these can increase drowsiness. Alcohol also raises the blood levels of CBD and clobazam: according to the prescribing information, with alcohol the total amount of CBD in the blood rose by 63% and its peak level by 93%; the peak level of clobazam has also been reported to rise by about 50%. (FDA Epidiolex label §7.4 and §12.3 (05/2026), Clobazam prescribing information §7.2) CBD and anxiety and sleep medicines

Frequently asked questions

References

Last reviewed: October 27, 2026. On this date, each source was opened and checked against the related sentence.