Interactions between cannabidiol and Δ ⁹ -tetrahydrocannabinol in modulating seizure susceptibility and survival in a mousae 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 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 i.p.) was anticonvulsant against hyperthermia-induced seizures as were low (0.1 and 0.3 mg/kg i.p.) but not higher doses of Δ⁹ -THC. A subthreshold dose of CBD (12 mg/kg) enhanced the anticonvulsant effects Δ⁹ -THC (0.1 mg/kg). Subchronic 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 subchronically dosed in combination. The possible explanations and implications of this are discussed.

Keywords: Cannabidiol (CBD); Dravet syndrome; epilepsy; mice; Δ9-tetrahydrocannabinol (Δ9-THC).