Annual Meeting Abstracts: View
(Abst. 1.215), 2015
Analysis of Cannabidiol Interactions with Antiseizure Drugs
Authors: Misty D. Smith, Karen S. Wilcox, Steve White
Content: Rationale: Little is known concerning the interactions of cannabidiol (CBD) with anti-seizure (ASDs) and how these interactions will impact the efficacy and safety of CBD when given concomitantly with other ASDs to patients with pharmacoresistant epilepsy. The current project compares the relative anticonvulsant efficacy of CBD with five mechanistically-different ASDs (i.e., carbamazepine (CBZ), valproate (VPA), levetiracetam (LEV), clobazam (CBM), and lacosamide (LAC)). The studies herein will test the hypothesis that CBD will have supra-additive (synergistic) effects when administered in combination with mechanistically-different, yet compatible, ASDs without enhancing adverse events.Methods: Using Type I isobolographic analyses of the fixed ratio (1:3, 1:1, and 3:1) combinations, anticonvulsant efficacy was quantified in the low frequency (6Hz), long duration (3 sec) model of partial seizure activity to rapidly assess how effective the CBD:ASD fixed ratio combinations are against limbic seizure activity (32mA). Adult male CF#1 mice were injected i.p. with each antiseizure drug such that the rotorod and 6Hz testing were performed at the time of peak effect for each drug. Both brain and plasma were collected from each animal for subsequent pharmacokinetic analysis.Results: The table below summarizes the results to date for the isobolographic analysis studies. Briefly, significant synergistic interaction has been identified with LEV at the 1:1 fixed ratio (FR) combination (**P<0.01), whereas significant antagonistic interactions have been identified with CBM at the 1:3 FR combination (*P<0.05) and at the 1:3 and 3:1 FR combinations with CBZ (***P<0.001). Isobolographic studies on the FR combinations of cannabidiol and lacosamide are currently underway. Additional ongoing studies are evaluating the 1:1 FR combination of CBD:LEV in preclinical models of anxiety, depression, and locomotor activity.Conclusions: By identifying the synergistic, additive, or antagonist interactions CBD with other ASDs, we are now gaining a better understanding of the nature of the CBD:ASD interactions and this knowlege may inform rationale polytherapy to optimize therapeutic safety and efficacy. SUPPORT: Funding for this project was awarded through the Epilepsy Foundation’s Targeted Research Initiative for Research regarding Cannabidiol and Epilepsy program.