A Potential Role of Δ9-Tetrahydrocannabinol in Epileptic Seizures

Abstract

Background: One of the main components of Cannabis sativa L is Δ-9-tetrahydrocannabinol (Δ9-THC), which primarily binds to cannabinoid receptor 1 (CB1) and CB2. These receptors and their endogenous molecules, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), constitute the endocannabinoid system (ECS), which has a significant regulatory role in processes throughout the body. Both Δ9-THC and cannabidiol (CBD), another major component of cannabis, have been found to affect epileptic seizures. While CBD exhibits anticonvulsant effects, Δ9-THC has been observed to both increase and decrease seizure activity. CBD has a low affinity for CB1 and CB2, and targets other macromolecules in the central nervous system (CNS) for its antiepileptic effect. Objective: This master's thesis aimed to elucidate a mechanism by which Δ9-THC impacts the ECS to alter seizure activity. To achieve this, the topological and conformational differences in Δ9-THC and CBD, and the effects of CB1 and CB2 on the release of gamma-aminobutyric acid (GABA) and glutamate were analysed to understand Δ9-THC’s pharmacology with the ECS. Additionally, we sought to highlight gaps in current knowledge about the pharmacological properties of phytocannabinoids to guide further research. Method: 19 literature searches in three databases were conducted to address the research questions. A selection of relevant articles was systematically reviewed, and a comprehensive structure-activity relationship (SAR) analysis of Δ9-THC for CB1 and CB2 was performed. Tables and figures were used to organise and analyse the findings to aid in answering the research questions. Results: 18 articles were reviewed, providing an extensive overview of existing research on cannabinoids and the ECS related to epilepsy. Based on the literature and SAR analysis, there is no scientific agreement on the pharmacological effect of Δ9-THC on CB1 and CB2. However, CB1 is likely the most relevant for the seizure effects as it is more abundant in the CNS. CB1 has shown to activate different G protein types on presynaptic neurons and astrocytes, and may also have multiple active receptor conformations. Based on this, our project identified two mechanisms via CB1 receptors through which Δ9-THC could potentially increase seizure activity, and one that might reduce it. The CB receptors may have three subpockets in their binding site that require an orthogonal orientation between the alkyl chain and the cyclic part of the molecule. The alkyl chain in cannabinoids was the most studied part of the pharmacophore and was observed to be crucial for biological activity, but there was limited research on the other pharmacophoric groups. Our conformational analyses show that the main difference between Δ9-THC and CBD results from the orthogonal relationship between the two ring groups in CBD. However, endogenous and synthetic cannabinoids often have high flexibility as well, making it challenging to determine what increases or decreases affinity to CB1 with today's existing knowledge. Conclusion: We have limited knowledge of the pharmacology of CB1 and Δ9-THC and cannot exclude either possibility that Δ9-THC could increase or reduce seizure activity. Multiple receptor conformations of CB1 and the activation of different G proteins may result in various pharmacological effects. As endogenous and synthetic cannabinoids are structurally and conformationally very different from Δ9-THC, understanding what makes molecules agonists or antagonists for CB1 and CB2 is challenging. Since the ECS is involved in many regulatory processes throughout the body, Δ9-THC and other ligands for the CB receptors could have many adverse effects, necessitating further research on Δ9-THC, other cannabinoids, and the ECS to elucidate the effects of cannabis and develop molecules that affect the ECS in a more selective and controlled manner.