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

Introduction:The cannabinoid Delta(9)-tetrahydrocannabinolic acid (Delta(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 Delta(9)-THCA in various seizure models-theScn1a(+/-)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 Delta(9)-THCA treatment against hyperthermia-induced seizures, and subchronic treatment on spontaneous seizures and survival in theScn1a(+/-)mice. We also studied the effect of acute Delta(9)-THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified Delta(9)-THCA was used in the studies or a mixture of Delta(9)-THCA and Delta(9)-THC. Results:We observed mixed anticonvulsant and proconvulsant effects of Delta(9)-THCA across the seizure models. Highly pure Delta(9)-THCA did not affect hyperthermia-induced seizures inScn1a(+/-)mice. A Delta(9)-THCA/Delta(9)-THC mixture was anticonvulsant in the 6-Hz threshold test, but purified Delta(9)-THCA and Delta(9)-THC had no effect. Conversely, both Delta(9)-THCA and Delta(9)-THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a Delta(9)-THCA/Delta(9)-THC mixture. The Delta(9)-THCA/Delta(9)-THC mixture, however, increased spontaneous seizure severity and increased mortality ofScn1a(+/-)mice. Discussion:The anticonvulsant profile of Delta(9)-THCA was variable depending on the seizure model used and presence of Delta(9)-THC. Because of the unstable nature of Delta(9)-THCA, further exploration of Delta(9)-THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined Delta(9)-THCA and Delta(9)-THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.

Automated summary

Delta(9)-tetrahydrocannabinolic acid (Delta(9)-THCA) has variable anticonvulsant effects depending on the seizure model used and the presence of Delta(9)-THC. Its unstable nature poses challenges for further drug development. Future studies should focus on understanding the mechanisms by which combined Delta(9)-THCA and Delta(9)-THC alter seizure thresholds.