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

Abstract

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. 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. 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. 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.