Evaluation of the Possible Anticonvulsant Effect of Δ <sup>9</sup> -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
Abstract
Introduction: 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.