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

Abstract

Introduction: The cannabinoid D 9 -tetrahydrocannabinolic acid (D 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 D 9 -THCA in various seizure models-the Scn1a + /À 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 D 9 -THCA treatment against hyperthermia-induced seizures, and subchronic treatment on spontaneous seizures and survival in the Scn1a + /À mice. We also studied the effect of acute D 9 -THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified D 9 -THCA was used in the studies or a mixture of D 9 -THCA and D 9 -THC. Results: We observed mixed anticonvulsant and proconvulsant effects of D 9 -THCA across the seizure models. Highly pure D 9 -THCA did not affect hyperthermia-induced seizures in Scn1a + /À mice. A D 9 -THCA/D 9 -THC mixture was anticonvulsant in the 6-Hz threshold test, but purified D 9 -THCA and D 9 -THC had no effect. Conversely, both D 9 -THCA and D 9 -THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a D 9 -THCA/D 9 -THC mixture. The D 9 -THCA/D 9 -THC mixture, however, increased spontaneous seizure severity and increased mortality of Scn1a + /À mice. Discussion: The anticonvulsant profile of D 9 -THCA was variable depending on the seizure model used and presence of D 9 -THC. Because of the unstable nature of D 9 -THCA, further exploration of D 9 -THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined D 9 -THCA and D 9 -THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.

Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses

“…Over 40 years ago Karler and Turkanis reported that THCA (200 mg/kg) reduces seizures in the mouse maximal electroshock test ( Karler and Turkanis, 1979 ). In a more recent mouse study the anticonvulsant effects of THCA were found to vary depending on the seizure model utilized and whether Δ 9 -THC was given along with the THCA ( Benson, et al, 2020 ). When used alone, THCA (2, 30, and 100 mg/kg) was ineffective in the 6-Hz threshold (6-HzT) model of psychomotor seizures, but had anticonvulsant activity when given with Δ 9 -THC.…”

A primer on medicinal cannabis safety and potential adverse effects

“…Other products contain CBD and/or THC with a 'full-spectrum' of cannabis plant constituents including other phytocannabinoids (eg cannabichromene, cannabigerol, ∆ 9 -tetrahydrocannabinolic acid or cannabidiolic acid) as well as terpenes and flavonoids, all of which may have therapeutic effects. [7][8][9][10] To ascertain exactly what is contained in a given medicinal cannabis product, a request can be made to the manufacturer for a certificate of analysis. Therapeutic daily doses of CBD are typically between 50 mg and 1500 mg, which are greater than those for THC, which are between 5 mg and 20 mg. 1 When evaluating the safety profile of medicinal cannabis products, it is important to consider the relative THC and CBD content, as CBD generally has fewer safety concerns than THC.…”

The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

“…Some of the residual 129 overlaps a modifier locus shown to influence survival in F1.Scn1a +/− mice (Miller et al, 2014;Hawkins and Kearney, 2016;Calhoun et al, 2017). Furthermore, survival of F1.Scn1a +/− mice is known to vary across laboratories and even across cohorts within the same laboratory (Anderson et al, 2019(Anderson et al, , 2020Benson et al, 2020).…”