Cannabidiol Use in Refractory Epilepsy

Marcia L. Buck, PharmD, FCCP, FPPAG, BCPPS

Disclosures

Pediatr Pharm. 2018;24(11) 

In This Article

Drug Interactions

Cannabidiol is a potent inhibitor of several enzymes, including CYP2C19. Concomitant administration of CBD with clobazam, a substrate for CYP2C19, has been shown to produce up to a 3-fold increase in the concentration of the active N-desmethylclobazam (norclobazam) metabolite, increasing the incidence of somnolence, sedation, and lethargy. In premarketing studies, these adverse effects were reported in 46% of patients taking clobazam with CBD, compared to 16% of patients taking CBD alone.[2] Similar findings were reported in an open-label safety study conducted by Gaston and colleagues at the University of Alabama CBD program.[13] These authors, as well as others, have suggested reducing the clobazam dose when starting CBD, although specific recommendations have not been determined.

Cannabidiol is also a strong inhibitor of CYP2C8 and CYP2C9, which may result in increased concentrations of drugs such as phenytoin, topiramate, and rufinamide. It also inhibits UGT1A9, increasing concentrations of diflunisal, fenofibrate, and propofol, as well as UGT2B7, increasing concentrations of gemfibrozil, lamotrigine, lorazepam, and morphine. Either inhibition or induction may occur with CBD use in patients taking drugs metabolized by CYP1A2 such as caffeine, theophylline, and zonisamide, as well as those metabolized by CYP2B6, such as bupropion and efavirenz. The effect of CBD on these medications is difficult to predict.[2,13]

The risk for hepatotoxicity is higher with concomitant use of CBD and clobazam or valproate. Elevations in ALT greater than 3 times the ULN occurred in 30% of patients taking CBD with both valproate and clobazam, 21% of those taking CBD with valproate, 4% in those taking CBD with clobazam, and 3% with CBD alone.[2] A significant increase in serum transaminases with concomitant CBD and valproate use was also reported by the UAB CBD program.[13] The mean ALT level in the CBD/valproate group was 35.3 U/L compared to 23.7 U/L in those not taking valproate (p = 0.026). Mean AST values were 37.1 U/L and 23.9 U/L in the two groups, respectively (p = 0.003). In both groups, the mean values were within the normal range.

Administration of moderate or strong CYP3A4 or CYP2C19 inhibitors will increase plasma CBD concentrations, resulting in a greater risk for adverse effects. Conversely, agents that are moderate or strong CYP3A4 or CYP2C19 inducers will decrease CBD concentrations and may reduce efficacy. Dosage adjustment should be considered when using these combinations. Use of CBD with opioids or other central nervous system depressants may result in excessive sedation and the need for close monitoring.

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