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.

• Authors: Lyndsey L Anderson, Ivan K Low, Iain S McGregor, Jonathon C Arnold
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 177 Issue 18 Pg. 4261-4274 (09 2020) ISSN: 1476-5381 [Electronic] England
• PMID: 32608111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The British Pharmacological Society.

Chemical References

• NAV1.1 Voltage-Gated Sodium Channel
• Scn1a protein, mouse
• Cannabidiol
• Dronabinol

Topics

• Animals
• Cannabidiol (pharmacology)
• Dronabinol (pharmacology)
• Epilepsies, Myoclonic (drug therapy)
• Mice
• Mice, Inbred C57BL
• NAV1.1 Voltage-Gated Sodium Channel (genetics)
• Seizures (drug therapy)