Interactions between cannabidiol and Δ9-tetrahydrocannabinol in modulating seizure susceptibility and survival in a mouse model of Dravet syndrome

Abstract

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 Δ9-tetrahydrocannabinol (Δ9-THC). It is unclear whether the presence of Δ9-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 Δ9-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 Δ9-THC. A subthreshold dose of CBD (12 mg·kg−1) enhanced the anticonvulsant effects of Δ9-THC (0.1 mg·kg−1). Sub-chronic oral administration of Δ9-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 Δ9-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 Δ9-THC are sub-chronically dosed in combination. The possible explanations and implications of this are discussed.