Pharmacodynamic synergism contributes to the antiseizure action of cannabidiol and clobazam

The management of refractory epilepsy involves treatment with more than one antiseizure medication (ASM). Combination of ASMs with distinct mechanisms of action are hypothesized to improve overall treatment effectiveness. In clinical trials, concomitant use of cannabidiol (CBD) and clobazam (CLB) was associated with increased seizure reduction and bidirectional elevation in levels of their active metabolites, 7-hydroxy-cannabidiol (7-OH-CBD) and nor-clobazam (n-CLB). Using isobolographic analysis, we investigated whether CBD and CLB interacted pharmacodynamically. In the mouse maximal electroshock seizure (MES) test, brain tissue levels of CBD and CLB corresponding to seizure prevention in 50% of animals (brain Effective Exposure, bEE₅₀) were 7.9 μM and 1.6 μM, respectively. In the 6 Hz psychomotor seizure model, 7-OH-CBD displayed a 5-fold greater potency than CBD (b-EE₅₀, 8.7 μM vs 47.3 μM). Isobolographic analysis performed on combination of CBD/CLB at 1:1, 3:1, and 1:3 ratios based on equi-effective bEE₅₀ values revealed synergism at all doses with combination indices (CI) of 0.43, 0.62 and 0.75 respectively. These outcomes were independent of pharmacokinetic interaction between CBD and CLB. These findings identify pharmacodynamic synergism as an important factor underlying enhanced antiseizure effect during concomitant CBD and CLB use.