Interactions between cannabidiol and Δ 9 ‐tetrahydrocannabinol in modulating seizure susceptibility and survival in a mouse model of Dravet syndrome

Background and Purpose Extracts from the cannabis plant can dramatically improve the health of children suffering from refractory epilepsies such as Dravet syndrome. These extracts typically contain cannabidiol (CBD), a phytocannabinoid with well‐documented anticonvulsant effects, but may also contain Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC). It is unclear whether the presence of Δ 9 ‐THC modulates the anticonvulsant efficacy of CBD. Here, we utilized the Scn1a +/− mouse model of Dravet syndrome to examine this question. Experimental Approach Scn1a +/− mice recapitulate core features of Dravet syndrome, including hyperthermia‐induced seizures, early onset spontaneous seizures and sudden death. We assessed the effects on CBD and Δ 9 ‐THC alone, and in combination on hyperthermia‐induced seizures, spontaneous seizures and premature mortality. Key Results Administered alone, CBD (100 mg·kg −1 i.p.) was anticonvulsant against hyperthermia‐induced seizures as were low (0.1 and 0.3 mg·kg −1 i.p.) but not higher doses of Δ 9 ‐THC. A subthreshold dose of CBD (12 mg·kg −1 ) enhanced the anticonvulsant effects of Δ 9 ‐THC (0.1 mg·kg −1 ). Sub‐chronic oral administration of Δ 9 ‐THC or CBD alone did not affect spontaneous seizure frequency or mortality while, surprisingly, their co‐administration increased the severity of spontaneous seizures and overall mortality. Conclusion and Implications Low doses of Δ 9 ‐THC are anticonvulsant against hyperthermia‐induced seizures in Scn1a +/− mice, effects that are enhanced by a sub‐anticonvulsant dose of CBD. However, proconvulsant effects and increased premature mortality are observed when CBD and Δ 9 ‐THC are sub‐chronically dosed in combination. The possible explanations and implications of this are discussed.