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

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.