Open AccessEvaluation of the Possible Anticonvulsant Effect of Δ9-Tetrahydrocannabinolic Acid in Murine Seizure Models
Author(s) -
Melissa J. Benson,
Lyndsey L. Anderson,
Ivan K. Low,
Jia Lin Luo,
Richard C. Kevin,
Cilla Zhou,
Iain S. McGregor,
Jonathon C. Arnold
Publication year - 2022
Publication title -
cannabis and cannabinoid research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.156
H-Index - 17
eISSN - 2578-5125
pISSN - 2378-8763
DOI - 10.1089/can.2020.0073
Subject(s) - anticonvulsant , epilepsy , pharmacology , cannabinoid , cannabidiol , medicine , dravet syndrome , seizure threshold , chemistry , cannabis , psychiatry , receptor
The cannabinoid Δ 9 -tetrahydrocannabinolic acid (Δ 9 -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 Δ 9 -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 Δ 9 -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 Δ 9 -THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified Δ 9 -THCA was used in the studies or a mixture of Δ 9 -THCA and Δ 9 -THC. Results: We observed mixed anticonvulsant and proconvulsant effects of Δ 9 -THCA across the seizure models. Highly pure Δ 9 -THCA did not affect hyperthermia-induced seizures in Scn1a +/- mice. A Δ 9 -THCA/Δ 9 -THC mixture was anticonvulsant in the 6-Hz threshold test, but purified Δ 9 -THCA and Δ 9 -THC had no effect. Conversely, both Δ 9 -THCA and Δ 9 -THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a Δ 9 -THCA/Δ 9 -THC mixture. The Δ 9 -THCA/Δ 9 -THC mixture, however, increased spontaneous seizure severity and increased mortality of Scn1a +/- mice. Discussion: The anticonvulsant profile of Δ 9 -THCA was variable depending on the seizure model used and presence of Δ 9 -THC. Because of the unstable nature of Δ 9 -THCA, further exploration of Δ 9 -THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined Δ 9 -THCA and Δ 9 -THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.