The phytocannabinoid Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the main psychoactive cannabinoid in cannabis, activates a number of signalling cascades including p53. This study examines the role of Delta(9)-THC in regulating the p53 post-translational modifier proteins, Murine double minute (Mdm2) and Small Ubquitin-like MOdifier protein 1 (SUMO-1) in cortical neurons. Delta(9)-THC increased both Mdm2 and SUMO-1 protein expression and induced the deSUMOylation of p53 in a cannabinoid receptor type 1 (CB(1))-receptor dependent manner. We demonstrate that Delta(9)-THC decreased the SUMOylation of the CB(1) receptor. The data reveal a novel role for cannabinoid receptor activation in modulating the SUMO regulatory system.