2. Academic Validation
  3. Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy

Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy

  • Br J Pharmacol. 2021 Dec;178(24):4826-4841. doi: 10.1111/bph.15661.
Lyndsey L Anderson 1 2 3 4,  Marika Heblinski 1 2 4,  Nathan L Absalom 3 4,  Nicole A Hawkins 5,  Michael T Bowen 1 4 6,  Melissa J Benson 1 4 6,  Fan Zhang 3,  Dilara Bahceci 1 2 4,  Peter T Doohan 1 2 4,  Mary Chebib 3 4,  Iain S McGregor 1 4 6,  Jennifer A Kearney 5,  Jonathon C Arnold 1 2 3 4
Affiliations

Affiliations

  • 1 Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.
  • 2 Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • 3 School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • 4 Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.
  • 5 Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 6 School of Psychology, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia.
PMID: 34384142 DOI: 10.1111/bph.15661
Abstract

Background and purpose: Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in Other phytocannabinoids. This raises the possibility that Other cannabis constituents might have anticonvulsant properties.

Experimental approach: We used the Scn1a+/- mouse model of Dravet syndrome to investigate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia-induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a+/- mice and in electroshock seizure models. Pharmacological effects of CBGA were surveyed across multiple drug targets.

Key results: The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia-induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a+/- mice. CBGA was found to interact with numerous epilepsy-relevant targets including GPR55, TRPV1 channels and GABAA receptors.

Conclusion and implications: These results suggest that CBGA, CBDVA and CBGVA may contribute to the effects of cannabis-based products in childhood epilepsy. Although these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programmes, several liabilities would need to be overcome before CBD is superseded by another in this class.

Keywords

CBGA; Dravet syndrome; cannabinoids; epilepsy.

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