Research on medical cannabis is progressing, with several cannabinoids emerging as promising compounds for clinical use. The available evidence suggests that cannabinoids may modulate glycine (GlyR) and GABA _A receptors, which are part of the pentameric ligand-gated ion channels (pLGICs) superfamily and facilitate chemical communication in the nervous system. In a previous study, we employed molecular dynamics (MD) simulations to elucidate the dynamics of the GlyR/Δ ⁹-tetrahydrocannabinol (THC) complex and successfully identified a representative binding mode. Given the structural similarity between GlyR and GABA _AR, we employed a similar strategy to investigate GABA _AR-cannabinoid interactions. We initially assessed the binding mode of THC to GABA _AR-α1β2γ2 at the equivalent binding site of the GlyR —i. e., on its two α-subunits— as well as the impact of this binding on the channel’s dimensions. Our results indicate, first, that the binding modes of THC to GABA _AR and GlyR exhibit comparable characteristics; and second, that THC may function as a potentiator of GABA activity due to a significant opening of the channel pore. Additionally, we aimed to reduce the overall computational cost associated with exploring binding modes. To this end, we developed and validated a simplified model comprising a single-monomer system for cannabinoid binding studies. This model proved to be accurate and cost-effective, accelerating the in silico screening process and allowing for the study of GABA _AR-cannabinoid binding through docking and MD simulations. Moreover, the analysis of different cannabinoids in this system suggests that cannabigerol (CBG) could act as a ligand for GABA _AR, opening unexplored avenues for research.