Cannabidiol

CBD is extensively metabolized by the liver and has documented dose-dependent hepatotoxic potential. In vitro hepatotoxicity studies (HepaRG spheroids, iPSC hepatocytes) and clinical epilepsy trial data demonstrate liver injury risk. Patients with severe hepatic impairment face increased risk due to impaired clearance and pre-existing hepatocellular vulnerability.

Concurrent use of CBD and valproate significantly increases the risk of hepatic transaminase elevation. The mechanism is not fully elucidated but appears pharmacodynamic. Liver function tests should be obtained at baseline and at 1, 3, and 6 months during co-administration. Valproate dose reduction may be necessary.

Clobazam, Citalopram, Diazepam, Proton pump inhibitors, Other CYP2C19 substrates

CBD inhibits CYP2C19-mediated metabolism, increasing exposure to co-administered substrates. The most clinically significant interaction is with clobazam, where CBD elevates N-desmethylclobazam concentrations, often requiring clobazam dose reduction. CBD also increases citalopram exposure. Chronic CBD use can convert extensive CYP2C19 metabolizers to a functionally poor-metabolizer phenotype (phenoconversion), with implications for all CYP2C19 substrates.

Rifampicin, Phenytoin, Carbamazepine

Strong CYP3A4 inducers substantially reduce CBD plasma concentrations through enhanced hepatic metabolism. This may render CBD sub-therapeutic, particularly in epilepsy contexts where adequate plasma levels are required for seizure control. CBD dose adjustment may be necessary when co-administered with strong enzyme inducers.

Cannabidiol crosses the placental barrier, and animal studies demonstrate reproductive toxicity and neurodevelopmental effects following prenatal exposure. No controlled human reproductive toxicity data exist. EFSA (2026) explicitly concludes that safety of CBD cannot be established for pregnant or lactating women.

The EFSA 2026 safety review explicitly states that CBD safety cannot be established for individuals under 25 years of age except for approved medical indications (e.g., Epidiolex for epilepsy). This applies to non-medical/supplement use contexts only — FDA-approved pediatric epilepsy indications are unaffected.