Evaluation of the Possible Anticonvulsant Effect of Δ(9)-Tetrahydrocannabinolic Acid in Murine Seizure Models

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.