Dose response effects of the cannabinoids as anti-seizure drugs in amygdala kindled rats

Abstract

Background Focal Impaired Awareness Seizures of temporal lobe origin (FIAS, also called “complex partial” seizures) are the most common seizures in adults, and are typically drug resistant. Management of FIAS is clinically challenging, and new interventions may be of use to achieve seizure freedom in these patients. The amygdala-kindling model is a pre-clinical model of FIAS with secondary generalization. Objective To assess the efficacy and safety of cannabidiol (CBD) alone, Δ 9-tetrahydrocannabinol (THC) alone, and a combination of CBD and THC (15:1) in suppressing generalized and focal seizures in the amygdala-kindled rat. Methods Fully kindled, Sprague–Dawley rats with bipolar electrodes implanted in the right amygdala were given intraperitoneal injections of either CBD (Dose: 0–320 mg/kg), THC (Dose: 0–80 mg/kg), or a combination of CBD and THC (15:1 ratio). Suprathreshold stimulation was given after injection (CBD 2 h, THC 1 h), and efficacy assessed using stereo-EEG and the Racine scale. Results CBD alone suppressed generalized seizures (ED50: 80 mg/kg) and focal seizures (ED50: 320 mg/kg) in the kindling model at sub-toxic doses. THC alone also suppressed generalized (ED50: 30 mg/kg) and focal seizures (ED50: 30 mg/kg), but only at doses that produced psychotoxic effects (present above 10 mg/kg). The addition of a low dose of THC to CBD (15:1) left-shifted the dose-response curve for CBD, producing lower ED50s for both generalized (ED50: 40 + 2.66 mg/kg) and focal seizures (ED50: 40 + 2.66 mg/kg). No toxicity was seen at these doses of THC. Conclusion CBD and THC both have anti-seizure properties in the amygdala kindling model, although THC acts only at psychotoxic doses. The addition of small (subtoxic) amounts of THC greatly improves the efficacy of CBD. A combination of CBD and THC may be useful in the clinical management of FIAS. The cannabinoids used in this study were donated by MedReleaf (Markham, ON). This study was supported in part by EpLink – The Epilepsy Research Program of the Ontario Brain Institute.