Cannabis has long been used to treat seizures and suggestions that it may reduce symptom severity of seizure disorders like epilepsy have existed in medical literature since at least the 1940s, and the Food and Drug Administration approved the use of Epidiolex, a formulation of cannabidiol (CBD), to treat Dravet syndrome and Lennox Gestaut syndrome in 2018. Despite evidence of CBD’s efficacy, a clear mechanism of action remained elusive—until now.
In a new study published in Neuron, a research team based at NYU Langone Health claims that CBD’s anti-seizure property is based on its ability to disrupt lysophosphatidylinositol (LPI) signaling. LPI amplifies synaptic signaling during normal functioning and influences nerve signals by binding to orphan G protein-coupled receptor 55 (GPR55). Presynaptic activation of GPR55 by LPI leads to the release of calcium ions within the neuron, thereby triggering the release of excitatory neurotransmitter glutamate. Postsynaptic activation of GPR55 by LPI weakened inhibitory neurotransmitter signaling. Conversely, endocannabinoids like 2-arachidonoylglycerol (2-AG) and anandamide attenuate synaptic signaling by activating endocannabinoid receptors 1 and 2.
This model suggests that excessive LPI expression can disrupt the balance between inhibitory and excitatory transmission, leading to positive feedback loops wherein excess excitatory transmission ultimately encourage seizures. By disrupting LPI signaling at GRP55, which some have argued could be considered a third endocannabinoid receptor, CBD prevents these positive feedback loops from developing.
Read the full study here.