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The cannabinoid receptors CB₁R and CB₂R are members of the G protein-coupled receptor (GPCR) family. These receptors have recently come to light as possible therapeutic targets for conditions affecting the central nervous system. However, because CB₁R is known to have psychoactive side effects, its potential as a drug target is constrained. Therefore, targeting CB₂R has become the primary focus of recent research. Using various molecular modeling studies, we analyzed the active, inactive, and intermediate states of both CBRs in this study. We conducted in-depth research on the binding properties of various groups of cannabinoid modulators, including agonists, antagonists, and inverse agonists, with all of the different conformational states of the CBRs. The binding effects of these modulators were studied on various CB structural features, including the movement of the transmembrane helices, the volume of the binding cavity, the internal fluids, and the important GPCR properties. Then, using in vitro experiments and computational modeling, we investigated how vitamin E functions as a lipid modulator to influence THC binding. This comparative examination of modulator binding to CBRs provides significant insight into the mechanisms of structural alterations and ligand affinity, which can directly help in the rational design of selective modulators that target either CB₁R or CB₂R.