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

The cannabinoid Δ-tetrahydrocannabinolic acid (Δ-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-THCA in various seizure models-the mouse model of Dravet syndrome, the 6-Hz model of psychomotor seizures and the maximal electroshock (MES) model of generalized tonic-clonic seizures. We examined the effect of acute Δ-THCA treatment against hyperthermia-induced seizures, and subchronic treatment on spontaneous seizures and survival in the mice. We also studied the effect of acute Δ-THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified Δ-THCA was used in the studies or a mixture of Δ-THCA and Δ-THC. We observed mixed anticonvulsant and proconvulsant effects of Δ-THCA across the seizure models. Highly pure Δ-THCA did not affect hyperthermia-induced seizures in mice. A Δ-THCA/Δ-THC mixture was anticonvulsant in the 6-Hz threshold test, but purified Δ-THCA and Δ-THC had no effect. Conversely, both Δ-THCA and Δ-THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a Δ-THCA/Δ-THC mixture. The Δ-THCA/Δ-THC mixture, however, increased spontaneous seizure severity and increased mortality of mice. The anticonvulsant profile of Δ-THCA was variable depending on the seizure model used and presence of Δ-THC. Because of the unstable nature of Δ-THCA, further exploration of Δ-THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined Δ-THCA and Δ-THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.