Publication: https://onlinelibrary.wiley.com/doi/10.1111/epi.16355

Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox‐Gastaut syndrome. However, a drug-drug interaction occurs between CBD and clobazam, a first line medication. This recognized interaction has led to repeated suggestions that the anticonvulsant efficacy of CBD is overstated and its efficacy simply reflects CBD augmenting clobazam exposure. This study aimed to address the nature of the interaction between CBD and clobazam using a mouse model of Dravet syndrome (Scn1a+/- mice).

Results

We explored both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam. Combination CBD‐clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. A sub‐anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. Additionally, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABA A receptor activation.

This study re-affirms that CBD itself is anticonvulsant and demonstrated that combination CBD-clobazam treatment promoted a greater anticonvulsant effect than either of the drugs alone. The increased anticonvulsant efficacy of combined CBD and clobazam, however, required intrinsically anticonvulsant doses of both drugs. This study supports the view that the clinical efficacy of CBD may not simply be explained by CBD increasing clobazam exposure, as the presence of a pharmacokinetic interaction was not sufficient to augment anticonvulsant effects. Importantly, our study highlights involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.

Research Team: Dr Lyndsey Anderson, Dr Nathan Absalom, Sarah Abelev, Ivan Low, Peter Doohan, Lewis Martin, Professor Mary Collins, Associate Professor Jonathon Arnold, Professor Iain McGregor,