Mechanistic Insights on the Neuro-Modulatory Potential of Cannabis sativa: A Network Pharmacology- and Molecular Dynamics Simulation-Based Approach

Background: Although, studies have reported the use of cannabis as a temporary antidepressant and implicated its chronic use in neurological diseases, the exact mechanisms through which these happen remain elusive. Objective: This study aims to investigate the neuro-modulatory potential of cannabis as antidepressant and its role in neurological disorders Methodology: Network pharmacology and molecular dynamics simulation were employed to unveil the mechanism of cannabis as a temporary antidepressant and potential agent implicated in neurological disorders. Results: A total of 156 cannabis metabolites were retrieved from data mining. 22 genes were common in cannabis metabolites and central nervous system (CNS) neurotransmitters’ genes. Glutamate receptor activity and neuroactive ligand receptor activity (NALR) were the most enriched biological process and signalling pathway, respectively, with cannabinoid receptor 1 (CNR1) and glutamate metabotropic receptor 2 (GRM2) being the hub targets in the NALR pathway. A probe into the structural stability of top-ranked metabolites identified cholesterol- CNR1 (-73.88 kcal/mol) and campesterol-CNR1 (-65.96 kcal/mol) with lower free binding energy than reference antidepressant drug (anandamide) (-65.08 kcal/mol), whereas for GRM2, the binding free energy of nerolidol (-43.57 kcal/mol) which was the least among the top ranked metabolites was higher compared to anandamide (-58.78 kcal/mol). Conclusion: Data from this study shows that the profiled cannabis metabolites displayed modulatory effects on key neurotransmitters of the CNS and their receptors and formed stable binding interaction with genes implicated in brain functioning suggestive of the mechanistic effect of cannabis on brain activity during depression and chronic use.