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
