Evaluation of the Possible Anticonvulsant Effect of Δ9-Tetrahydrocannabinolic Acid in Murine Seizure Models

Melissa J Benson; Lyndsey L Anderson; Ivan K Low; Jia Lin Luo; Richard C Kevin; Cilla Zhou; Iain S McGregor; Jonathon C Arnold

doi:10.1089/can.2020.0073

Evaluation of the Possible Anticonvulsant Effect of Δ⁹-Tetrahydrocannabinolic Acid in Murine Seizure Models

Cannabis Cannabinoid Res. 2022 Feb;7(1):46-57. doi: 10.1089/can.2020.0073. Epub 2020 Sep 9.

Authors

Melissa J Benson^{1

2

3}, Lyndsey L Anderson^{1

2

4}, Ivan K Low^{1

2}, Jia Lin Luo^{1

2

3}, Richard C Kevin^{1

2

3}, Cilla Zhou^{1

2

4}, Iain S McGregor^{1

2

3}, Jonathon C Arnold^{1

2

4}

Affiliations

¹ Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.
² Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.
³ Faculty of Science, School of Psychology, The University of Sydney, Sydney, New South Wales, Australia.
⁴ Discipline of Pharmacology, Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia.

Abstract

Introduction: The cannabinoid Δ⁹-tetrahydrocannabinolic acid (Δ⁹-THCA) has long been suggested in review articles and anecdotal reports to be anticonvulsant; yet, there is scant evidence supporting this notion. The objective of this study was to interrogate the anticonvulsant potential of Δ⁹-THCA in various seizure models-the Scn1a^+/- mouse model of Dravet syndrome, the 6-Hz model of psychomotor seizures and the maximal electroshock (MES) model of generalized tonic-clonic seizures. Materials and Methods: We examined the effect of acute Δ⁹-THCA treatment against hyperthermia-induced seizures, and subchronic treatment on spontaneous seizures and survival in the Scn1a^+/- mice. We also studied the effect of acute Δ⁹-THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified Δ⁹-THCA was used in the studies or a mixture of Δ⁹-THCA and Δ⁹-THC. Results: We observed mixed anticonvulsant and proconvulsant effects of Δ⁹-THCA across the seizure models. Highly pure Δ⁹-THCA did not affect hyperthermia-induced seizures in Scn1a^+/- mice. A Δ⁹-THCA/Δ⁹-THC mixture was anticonvulsant in the 6-Hz threshold test, but purified Δ⁹-THCA and Δ⁹-THC had no effect. Conversely, both Δ⁹-THCA and Δ⁹-THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a Δ⁹-THCA/Δ⁹-THC mixture. The Δ⁹-THCA/Δ⁹-THC mixture, however, increased spontaneous seizure severity and increased mortality of Scn1a^+/- mice. Discussion: The anticonvulsant profile of Δ⁹-THCA was variable depending on the seizure model used and presence of Δ⁹-THC. Because of the unstable nature of Δ⁹-THCA, further exploration of Δ⁹-THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined Δ⁹-THCA and Δ⁹-THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.

Keywords: Dravet syndrome; THCA; epilepsy; medicinal cannabis; seizure.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anticonvulsants / pharmacology
Dronabinol* / analogs & derivatives
Dronabinol* / pharmacology
Epilepsies, Myoclonic* / drug therapy
Mice
NAV1.1 Voltage-Gated Sodium Channel / genetics
Seizures* / drug therapy

Substances

Anticonvulsants
NAV1.1 Voltage-Gated Sodium Channel
Scn1a protein, mouse
Dronabinol
delta(9)-tetrahydrocannabinolic acid