Valproic acid

For an informed discussion with your doctor or pharmacist. This information collection is not a clinically validated interaction checker. Missing data do not establish safety. Do not change or stop prescribed medicines on the basis of this information. The findings apply to the specific conditions studied; laboratory and animal studies cannot be directly extrapolated to humans.

Active substance: Valproic acid

Examples of brand names: Ergenyl [DE]

ATC code: N03AG01

Main use (for orientation): Epilepsy; bipolar disorder

Documented research summary

Increased liver risks with CBD despite controlled studies without relevant changes in total valproate/4-en-valproate. An open-label cohort found increased free valproate; a retrospective series additionally found a thrombocytopenia signal (9/23 with valproate versus 0/57 without).

Uncertainties and limitations

Thrombocytopenia subgroups total 80, overall cohort 87; do not fill the discrepancy without evidence. CBDV combination only preclinical.

Separately recorded findings

5 separately recorded findings. Each statement applies to its documented study context.

CBD – clinically studied

Finding ID: B0001

Type of result: Positive finding / indication

Observation: More frequent transaminase elevations with the combination.

Mechanism: Mechanism unresolved

Study type: Clinical studies evaluated by regulators

Context studied: Epidyolex, epilepsy treatment.

Clinical interpretation: High: professional liver monitoring required

Limitations and uncertainties: Not explained by a blanket increase in valproate concentrations.

Original sources for this finding: Epidyolex: EPAR – Product Information [CL01]

CBD – clinically studied

Finding ID: B0012

Type of result: No / minor effect under the conditions studied

Observation: No clinically relevant change in valproate exposure.

Mechanism: Pharmacokinetics investigated

Study type: Open-label phase I pharmacokinetics

Context studied: Healthy people; CBD 750 mg twice daily.

Clinical interpretation: Pharmacokinetic null finding

Limitations and uncertainties: Liver risk remains separately relevant.

Original sources for this finding: A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects [CL03]

CBD – clinically studied

Finding ID: B0017

Type of result: No / minor effect under the conditions studied

Observation: Total valproate: AUCtau geometric mean ratio 0.83 (90% CI 0.75–0.92), Cmax ratio 0.87 (0.79–0.95); 4-ene-VPA: AUCtau ratio 0.70 (0.62–0.80), Cmax ratio 0.77 (0.66–0.90). Assessed as not clinically important within the predefined no-effect band of 0.5–2.0.

Mechanism: Pharmacokinetics investigated

Study type: Randomised phase II pharmacokinetics

Context studied: Epilepsy; CBD 20 mg/kg/day. Valproate safety arm n=20 (16 CBD, 4 placebo); paired pharmacokinetic treatment effect for valproate/4-ene-VPA each n=10 receiving CBD.

Clinical interpretation: No increase in total-valproate pharmacokinetics assessed as clinically important; measurable pharmacokinetic decreases

Limitations and uncertainties: Small group; the study-specific no-effect band of 0.5–2.0 is not standard bioequivalence evidence. Free valproate not measured as clinical pharmacokinetics; additional protein-binding analysis in vitro. Liver-enzyme elevations are not excluded.

Original sources for this finding: A Phase II Randomized Trial to Explore the Potential for Pharmacokinetic Drug-Drug Interactions with Stiripentol or Valproate when Combined with Cannabidiol in Patients with Epilepsy [CL05]

CBD – clinical signals

Finding ID: B0054

Type of result: Positive finding / indication

Observation: Free concentration ↑; p=0.0036.

Mechanism: Mechanism uncertain

Study type: Observational study

Context studied: 51 people in total receiving valproate (16 adults, 35 children); number with an actually available free-valproate concentration not separately reported in Table 2.

Clinical interpretation: Clinical significance unclear

Limitations and uncertainties: Association; CL20 context/limitations.

Original sources for this finding: Final analysis of potential drug-drug interactions between highly purified cannabidiol and anti-seizure medications in an open-label expanded access program [CL20]

CBD – clinical signals

Finding ID: B0072

Type of result: No / minor effect under the conditions studied

Observation: No concentration signal; p=0.3386.

Mechanism: PK observation

Study type: Observational study: no signal detected

Context studied: n=51.

Clinical interpretation: Not ruled out

Limitations and uncertainties: Context/limitations CL20; total concentration here, free valproate separately.

Original sources for this finding: Final analysis of potential drug-drug interactions between highly purified cannabidiol and anti-seizure medications in an open-label expanded access program [CL20]

References and access status

[CA_L_D0040] VALPROIC (VALPROIC ACID) CAPSULE, LIQUID FILLED [ACTAVIS PHARMA, INC.]

Original source / bibliographic reference

Authors: Actavis Pharma, Inc.

Year: 2026

Source type: Current published human-use SPL / product information

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

[CL01] Epidyolex: EPAR – Product Information

Original source / bibliographic reference

Authors: European Medicines Agency / marketing authorisation holder

Year: 2026

Source type: Regulatory product information

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

[CL03] A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects

Original source / bibliographic reference

Authors: Morrison G; Crockett J; Blakey G; Sommerville K

Year: 2019

Source type: Open-label phase I study with a fixed sequence

DOI: 10.1002/cpdd.665

PMID: 30791225

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CL05] A Phase II Randomized Trial to Explore the Potential for Pharmacokinetic Drug-Drug Interactions with Stiripentol or Valproate when Combined with Cannabidiol in Patients with Epilepsy

Original source / bibliographic reference

Authors: Ben-Menachem E; Gunning B; Arenas Cabrera CM; VanLandingham K; Crockett J; Critchley D; Wray L; Tayo B; Morrison G; Toledo M

Year: 2020

Source type: Randomised phase II study

DOI: 10.1007/s40263-020-00726-4

PMID: 32350749

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CL20] Final analysis of potential drug-drug interactions between highly purified cannabidiol and anti-seizure medications in an open-label expanded access program

Original source / bibliographic reference

Authors: Gaston TE; Bebin EM; Cutter GR; Grayson L; Szaflarski JP

Year: 2023

Source type: Open-label longitudinal observational study

DOI: 10.1002/epi4.12815

PMID: 37593907

Source access – 23 October 2026: Automated direct retrieval was restricted; this does not establish that the link is broken.

Bibliographic attribution or source identity cross-checked.

PubMed – bibliographic reference / abstract

DOI – publisher access (access restrictions may apply)

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CA_P_32614070] Thrombocytopenia in pediatric patients on concurrent cannabidiol and valproic acid.

Original source / bibliographic reference

Authors: McNamara NA, Dang LT, Sturza J, Ziobro JM, Fedak Romanowski EM, Smith GC, Joshi SM, Leber SM, Carlson M, Robertson P, Shellhaas RA.

Year: 2020

Source type: Research Support, Non-U.S. Gov't; Journal Article

DOI: 10.1111/epi.16596

PMID: 32614070

Source access – 23 October 2026: Source destination was accessible when checked.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

[CA_P_22970845] Cannabidivarin is anticonvulsant in mouse and rat.

Original source / bibliographic reference

Authors: Hill AJ, Mercier MS, Hill TD, Glyn SE, Jones NA, Yamasaki Y, Futamura T, Duncan M, Stott CG, Stephens GJ, Williams CM, Whalley BJ.

Year: 2012

Source type: Research Support, Non-U.S. Gov't; research-article; Journal Article

DOI: 10.1111/j.1476-5381.2012.02207.x

PMID: 22970845

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

PubMed Central – full-text access according to the literature database – Archive attribution confirmed by Europe PMC metadata. Direct retrieval was not fully verified here; access may require a browser check.

Europe PMC – full-text access according to the literature database – Listed as freely available HTML full text in the official Europe PMC metadata. Direct retrieval was not fully verified here.

[CA_P_42728549] Potential Role of CYP3A4 in Determining In Vivo Exposure to Cannabidiol (CBD) and its Active Metabolite 7-OH-CBD: Evidence from an In Vitro Study.

Original source / bibliographic reference

Authors: Jaisupa N, Birgersson S, Ashton M.

Year: 2026

Source type: Journal Article

DOI: 10.1007/s13318-026-01032-y

PMID: 42728549

Source access – 23 October 2026: Direct retrieval could not be fully verified; availability remains unresolved.

Bibliographic attribution or source identity cross-checked.

DOI – publisher access (access restrictions may apply)

Research as of 23 October 2026. Not all original full texts could be reviewed in full. Source accessibility and the strength of scientific evidence must be assessed separately. An accessible link does not establish medical approval; a bibliographic record with an abstract does not replace the original full text.

Drug search and explanation of the evidence · Guide: cannabinoids and medicines · Author and responsibility