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.