Valproate Interactions

Valproate (valproic acid) depletes carnitine by sequestering it as valproyl-carnitine for mitochondrial transport and by inhibiting renal tubular reabsorption, which can impair the urea cycle and contribute to hyperammonemia, hepatotoxicity, and encephalopathy.

Aspirin (and other salicylates) displace valproate from plasma albumin binding sites and also inhibit valproate's beta-oxidation, leading to increases in the free (active) valproate fraction by up to fourfold. Even total valproate levels may not rise dramatically, masking the increase in pharmacologically active free drug and raising the risk of valproate toxicity (sedation, tremor, hyperammonemia, hepatotoxicity).

Concomitant CBD (Epidiolex) and valproate use produces a significantly higher rate of ALT/AST elevations than either drug alone - up to ~17% of patients in the combination group versus ~1-2% on valproate alone in pooled Epidiolex trial data. Postmarketing reports also describe hyperammonemia in patients on the combination.

Valproate appears to reduce biotinidase activity and impair mitochondrial biotin handling, leading to subnormal biotin status that has been linked to the drug's signature alopecia (hair loss) and brittle nails; biotin supplementation has reversed hair loss in case reports.