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

Lyndsey L Anderson; Marika Heblinski; Nathan L Absalom; Nicole A Hawkins; Michael T Bowen; Melissa J Benson; Fan Zhang; Dilara Bahceci; Peter T Doohan; Mary Chebib; Iain S McGregor; Jennifer A Kearney; Jonathon C Arnold

doi:10.1111/bph.15661

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. Epub 2021 Sep 30.

Authors

Lyndsey L Anderson^{1

2

3

4}, Marika Heblinski^{1

2

4}, Nathan L Absalom^{3

4}, Nicole A Hawkins⁵, Michael T Bowen^{1

4

6}, Melissa J Benson^{1

4

6}, Fan Zhang³, Dilara Bahceci^{1

2

4}, Peter T Doohan^{1

2

4}, Mary Chebib^{3

4}, Iain S McGregor^{1

4

6}, Jennifer A Kearney⁵, Jonathon C Arnold^{1

2

3

4}

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.

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 GABA_A 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anticonvulsants / pharmacology
Anticonvulsants / therapeutic use
Benzoates
Cannabidiol* / pharmacology
Cannabidiol* / therapeutic use
Cannabis*
Epilepsies, Myoclonic* / drug therapy
Epilepsy* / drug therapy
Mice
NAV1.1 Voltage-Gated Sodium Channel
Receptors, Cannabinoid
Seizures / drug therapy

Substances

Anticonvulsants
Benzoates
GPR55 protein, mouse
NAV1.1 Voltage-Gated Sodium Channel
Receptors, Cannabinoid
Scn1a protein, mouse
Cannabidiol
cannabigerolic acid

Grants and funding

R01 NS084959/NS/NINDS NIH HHS/United States