CBD and valproate: why can liver enzymes rise?

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, valproate is broken down mainly through pathways called glucuronidation and beta-oxidation. A small part is converted by CYP enzymes into a breakdown product called 4-ene-VPA; this product has been linked to liver damage. (PMID 30791225, PMID 32918835)

CBD does not change the blood level of valproate much. No change was seen in healthy volunteers; in people with epilepsy, the valproate level fell by about 17–21%, and 4-ene-VPA, which is thought to be harmful to the liver, also fell. Valproate did not change CBD levels significantly either. In other words, the rise in liver enzymes cannot be explained by a change in the blood levels of the two medicines. (FDA Epidiolex label §12.3 (05/2026), EMA Epidyolex prescribing information 5.2, PMID 30791225, PMID 32918835)

The reason for the interaction is unknown. In a computer-model study, three main pathways that directly cause liver damage did not explain this rise. A laboratory study using three-dimensional cell clusters made from human liver cells showed the interaction in the lab for the first time; the mechanism is being researched. (EMA Epidyolex prescribing information 4.5, PMID 37458709, PMID 40774642)

Each medicine can affect liver enzymes on its own: CBD can raise ALT and AST depending on the dose, and valproate can rarely cause severe liver damage. In addition, rises with CBD were more common in people whose liver enzymes were high at the start; the European product information states that valproate can increase this risk. (FDA Epidiolex label §5.1 (05/2026), EMA Epidyolex prescribing information 4.4, Valproate prescribing information §5.1)

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. Controlled study

   ALT rises much more common with valproate (prescribing information)

   In the Lennox–Gastaut and Dravet syndrome studies, among those taking CBD, ALT (a blood test that shows liver cell damage) above 3 times the upper limit of normal occurred in 30% of those using valproate and clobazam together, 21% of those using valproate alone, 4% of those using clobazam alone, and 3% of those using neither. In the tuberous sclerosis complex (TSC) study, the same rates were 20%, 25%, 0% and 6%. The European product information reports 23%, 19%, 3% and 3% across all studies. Among those taking placebo, the rate was about 1%.

   Source: FDA Epidiolex label §5.1 (05/2026), EMA Epidyolex prescribing information 4.8

2. Controlled study

   Dravet studies: everyone with a rise was taking valproate (2018, 2020)

   In a dose study in children with Dravet syndrome, liver enzymes rose in 6 patients taking CBD and valproate together; none met the criteria for drug-induced liver injury, and all recovered. In a placebo-controlled study of 199 patients, rises were seen in 13 patients in the group taking CBD 20 mg/kg a day and in 3 patients in the group taking 10 mg/kg a day; all of these patients were using valproate.

   Source: PMID 29540584, PMID 32119035

3. Controlled study

   TSC study: 79% of rises were in those taking valproate (2021)

   In the tuberous sclerosis complex study, liver enzymes above 3 times the upper limit of normal occurred in 28 of 148 patients taking CBD (18.9%) and in none of those taking placebo; 22 of these 28 patients were using valproate. Most rises began in the first 30 days; they resolved on their own, when treatment was stopped, or when the dose of CBD or another medicine was lowered. The rise was more marked at the high CBD dose and in those whose ALT was high at the start.

   Source: PMID 33346789

4. Systematic review

   Pooled analyses: the same picture (2020, 2021)

   In a pooled analysis of four controlled studies in Lennox–Gastaut and Dravet syndromes, among those who took CBD and had an AST rise reported as a side effect, 82% in the Lennox–Gastaut group and all in the Dravet group were using valproate; for ALT, the rates were 73% and 100%. In a meta-analysis of controlled studies, CBD clearly increased the likelihood of serious side effects related to abnormal liver tests; the authors state that this link was seen only in childhood epilepsy studies and may result from an interaction with valproate or clobazam.

   Source: PMID 32969022, PMID 32268347

5. Observational study

   Long-term and open studies: most people with rises were taking valproate

   In long-term open-label extension studies, liver enzymes above 3 times normal occurred in 15% of patients with Lennox–Gastaut syndrome (73% of whom were taking valproate) and 22% of patients with Dravet syndrome (84% of whom were taking valproate). In the TSC extension study, 12 of the 17 patients with enzyme rises were using valproate. In an interim analysis of the Lennox–Gastaut extension study, 34 of 37 cases resolved on their own or when medicine doses were adjusted. In an open-label study of 81 patients, AST and ALT were also significantly higher in those using valproate.

   Source: PMID 34287833, PMID 34406656, PMID 34957550, PMID 30740695, PMID 28782097

6. Drug-level study

   Valproate blood level did not change much (2018–2023)

   In healthy volunteers, approved CBD (750 mg twice a day) did not change the valproate level. In a placebo-controlled study in people with epilepsy, the valproate level fell by about 17–21%; the prescribing information does not consider this clinically significant. In children with Dravet syndrome, the valproate level did not change either. In an open-label study of 169 patients, the total valproate level did not change; free (not protein-bound) valproate rose only at high valproate doses and inconsistently. In all of these studies, CBD was taken by mouth. A two-part study (29 people in total, ClinicalTrials.gov NCT06930872) measuring in healthy volunteers the effect of a synthetic CBD gel applied to the skin on the level of valproate, among some other medicines, was completed in November 2025; as of October 2026, its results are neither in the registry nor in any publication we could find.

   Source: PMID 30791225, PMID 32918835, FDA Epidiolex label §12.3 (05/2026), PMID 29540584, PMID 37593907, ClinicalTrials.gov NCT06930872

7. Official drug information

   Diarrhea and decreased appetite are also more common

   According to the European product information, using CBD and valproate together also increases how often diarrhea and decreased appetite occur; the reason for this is also unknown.

   Source: EMA Epidyolex prescribing information 4.5

8. Official drug information

   Reports of raised ammonia

   After approved CBD came on the market, raised blood ammonia was reported in some patients who also had raised liver enzymes; most of the cases with available information were using valproate, clobazam or both. Valproate's prescribing information states that valproate can raise ammonia even when liver tests are normal.

   Source: FDA Epidiolex label §5.1 (05/2026), Valproate prescribing information §5.9

9. Controlled study

   Rises can happen without valproate too: healthy adults (2025)

   In a placebo-controlled study in healthy adults, liver enzymes went above 3 times normal in 5.6% of those who took CBD for 28 days at a dose close to the amounts used in over-the-counter products (5 mg/kg a day); this was not seen in those taking placebo. In seven of them, the criteria for withdrawal from the study because of possible drug-induced liver injury were met on day 21 or day 28. In approved CBD studies, too, the rate among those using neither valproate nor clobazam was 3–6%.

   Source: PMID 40622698, FDA Epidiolex label §5.1 (05/2026)

10. Official drug information

    What the prescribing information of both medicines says

    Valproate's prescribing information says that using it together with CBD increases the risk of ALT and AST rises, that this can be managed by lowering the dose or, in severe cases, by stopping one or both medicines, and that liver tests should be monitored. According to the US prescribing information, about two-thirds of cases resolved when CBD was stopped or the dose of CBD or valproate was lowered, and one-third resolved without a dose change. Rises usually began in the first two months; some cases, especially in those using valproate, were seen up to 18 months.

    Source: Valproate prescribing information §7.4, FDA Epidiolex label §5.1 (05/2026), EMA Epidyolex prescribing information 4.4 and 4.5

What is monitored?

• Liver tests (ALT, AST and bilirubin): these are measured before starting approved CBD. The US prescribing information recommends testing at months 1, 3 and 6 and then at regular intervals, and asks that more frequent monitoring be considered in people using valproate. The European product information recommends testing at week 2 and at months 1, 2, 3 and 6 for people using valproate. When the CBD dose changes or a medicine that affects the liver is added, testing becomes more frequent again. Your doctor decides how often to test. (FDA Epidiolex label §5.1 (05/2026), EMA Epidyolex prescribing information 4.4)
• Liver symptoms: unexplained nausea, vomiting, pain in the upper right part of the belly, fatigue, loss of appetite, yellowing of the eyes or skin, dark urine. Valproate's prescribing information states that malaise, weakness, lethargy, facial swelling and worsening seizure control can also be early signs of a severe liver problem. If you notice any such symptom, tell your doctor right away. (FDA Epidiolex label §5.1 and §17 (05/2026), Valproate prescribing information §5.1)
• Ammonia: if unexplained lethargy, vomiting or a change in consciousness occurs, your doctor may measure blood ammonia. (Valproate prescribing information §5.9, FDA Epidiolex label §5.1 (05/2026))
• Diarrhea, appetite and weight: diarrhea and decreased appetite are more common when the two are used together; because CBD can also cause weight loss, weight is tracked regularly. (EMA Epidyolex prescribing information 4.4 and 4.5)
• Other epilepsy medicines: if you also take clobazam, liver enzyme rises were more common and drowsiness may increase. (FDA Epidiolex label §5.1 and §5.2 (05/2026)) CBD and clobazam

Frequently asked questions

References

Last reviewed: October 30, 2026. On this date, each source was opened and checked against the related sentence.