Abstract
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.
