Investigation of the treatment of epilepsy with cannabinoids

Kollipara, Roshni S. (2023) Investigation of the treatment of epilepsy with cannabinoids. Masters thesis, Memorial University of Newfoundland.

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Abstract

Cannabis has been consumed by humans for millennia, and is currently used in Canada for the treatment of a variety of medical conditions including anxiety, PTSD, and chronic pain. The medical community is hesitant to accept the use of Cannabis and cannabinoids to treat epilepsy due to inadequate information on mechanism of action and long-term effects. Cannabidiol (CBD) is approved to treat pediatric patients with severe epilepsies such as Dravet Syndrome and Lennox-Gastaut Syndrome in the US and some European countries, but there are many individuals with less severe epilepsies whose quality of life is affected by negative side-effects from current anti-epileptic drugs. This research aims to globally evaluate which of the 6 most prevalent cannabinoids show seizure reduction and to investigate the mechanism of action of cannabinoids in an epilepsy model. Using a chemical model of epilepsy, zebrafish larvae were treated with phytocannabinoids, and their seizures measured through an optimized behaviour tracking method. Unique to this study, cannabinoid uptake was measured in larvae with a novel HPLC method developed in this project. This accomplishment is superior to previous attempts to quantify cannabinoid uptake by measuring losses in the water used to deliver cannabinoid to fish, which assumes that all losses are due to uptake and metabolism by the study organisms. CBD induced seizure reduction is partially mediated by the Gprotein coupled receptor GPR55 and potentially through CB1R. Treatment with cannabinol (CBN) and cannabichromene (CBC) decreased seizure intensity at lower concentrations than CBD. Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC), and cannabigerol (CBG) only showed antiepileptic effects at a high concentration, but when concentrationd in combination with CBD reduced seizures more than either treatment alone. RT-qPCR showed changes in expression of endocannabinoid system (napepld, gde1, faah, ptgs1, ptgs2a) and neural (fosab, pyya) genes in response to phytocannabinoid treatment. The data reported in this thesis supports the hypothesis that phytocannabinoids are promising anti-epileptics and could be used in combination therapies for more effective seizure relief.

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