The purpose of the experiments was to examine the anxiety-related effects of d-amphetamine and nicotine, and the possible involvement of the endocannabinoid system. D-amphetamine (2 mg/kg, ip) was administered acutely or daily for 8 days. On the 9th day, mice were challenged with d-amphetamine (2 mg/kg, ip) or nicotine (0.1 mg/kg, sc), and were tested in the elevated plus maze. Additionally, a distinct group of mice was pretreated with an acute (0.1 mg/kg,sc) or subchronic nicotine (6 days), and subjected to nicotine (0.1 mg/kg, sc) or d-amphetamine (2 mg/kg, ip) challenge on the 7th day. The cannabinoid receptor ligands, WIN 55,212-2, a non-selective cannabinoid receptor agonist (0.25; 0.5 and 1 mg/kg, ip) and rimonabant, a CB1 cannabinoid receptor antagonist (0.25; 0.5; 1 and 2 mg/kg, ip) were injected prior to each injection of saline or acute and subchronic d-amphetamine or nicotine. We observed that acute anxiogenic and subchronic anxiolytic effects of both psychostimulants as well as the development of full cross-tolerance to their anxiogenic effects were dose-dependently blunted by ineffective doses of WIN 55,212-2 (0.25 and 0.5 mg/kg) and rimonabant (0.5 and 1 mg/kg). These results provide evidence that the endogenous cannabinoid system is involved in the anxiety-related responses to d-amphetamine and/or nicotine.