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

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^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4826-4841
Number of pages	16
Journal	British journal of pharmacology
Volume	178
Issue number	24
DOIs	https://doi.org/10.1111/bph.15661
State	Published - Dec 2021

Funding

The authors gratefully acknowledge Barry and Joy Lambert for their continued support of the Lambert Initiative for Cannabinoid Therapeutics. J.A.K. acknowledges the US National Institutes of Health (NIH) (R01 NS084959). M.C., J.C.A., J.A.K. and I.S.M. acknowledge the Australian National Health and Medical Research Council (NHMRC) (GNT 1161571 and 1185122). In addition, we thank Katelyn Lambert for inspiring our work on novel cannabinoid therapies for childhood epilepsy. We also thank Ivan Low, Charlotte Fletcher and Declan Everett‐Morgan for technical assistance. The authors gratefully acknowledge Barry and Joy Lambert for their continued support of the Lambert Initiative for Cannabinoid Therapeutics. J.A.K. acknowledges the US National Institutes of Health (NIH) (R01 NS084959). M.C., J.C.A., J.A.K. and I.S.M. acknowledge the Australian National Health and Medical Research Council (NHMRC) (GNT 1161571 and 1185122). In addition, we thank Katelyn Lambert for inspiring our work on novel cannabinoid therapies for childhood epilepsy. We also thank Ivan Low, Charlotte Fletcher and Declan Everett-Morgan for technical assistance.

Keywords

CBGA
Dravet syndrome
cannabinoids
epilepsy

ASJC Scopus subject areas

Pharmacology

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10.1111/bph.15661

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Anderson, L. L., Heblinski, M., Absalom, N. L., Hawkins, N. A., Bowen, M. T., Benson, M. J., Zhang, F., Bahceci, D., Doohan, P. T., Chebib, M., McGregor, I. S., Kearney, J. A., & Arnold, J. C. (2021). Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy. British journal of pharmacology, 178(24), 4826-4841. https://doi.org/10.1111/bph.15661

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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.",

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author = "Anderson, {Lyndsey L.} and Marika Heblinski and Absalom, {Nathan L.} and Hawkins, {Nicole A.} and Bowen, {Michael T.} and Benson, {Melissa J.} and Fan Zhang and Dilara Bahceci and Doohan, {Peter T.} and Mary Chebib and McGregor, {Iain S.} and Kearney, {Jennifer A.} and Arnold, {Jonathon C.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.",

year = "2021",

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doi = "10.1111/bph.15661",

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Anderson, LL, Heblinski, M, Absalom, NL, Hawkins, NA, Bowen, MT, Benson, MJ, Zhang, F, Bahceci, D, Doohan, PT, Chebib, M, McGregor, IS, Kearney, JA & Arnold, JC 2021, 'Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy', British journal of pharmacology, vol. 178, no. 24, pp. 4826-4841. https://doi.org/10.1111/bph.15661

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T1 - Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy

AU - Anderson, Lyndsey L.

AU - Heblinski, Marika

AU - Absalom, Nathan L.

AU - Hawkins, Nicole A.

AU - Bowen, Michael T.

AU - Benson, Melissa J.

AU - Zhang, Fan

AU - Bahceci, Dilara

AU - Doohan, Peter T.

AU - Chebib, Mary

AU - McGregor, Iain S.

AU - Kearney, Jennifer A.

AU - Arnold, Jonathon C.

PY - 2021/12

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AB - 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.

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

Abstract

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