Cannabinoid-MDMA interactions were examined in male Wistar rats. MDMA (4×5 mg/kg or 2×10 mg/kg over 4 h on each of 2 days) was administered with or without Δ9-tetrahydrocannabinol (THC) (4×2.5 mg/kg), the synthetic cannabinoid receptor agonist CP 55,940 (2×0.1 or 0.2 mg/kg) or the cannabinoid receptor antagonist SR 141716 (2×5 mg/kg). Co-administered Δ9-THC and CP 55,940 but not SR 141716 prevented MDMA-induced hyperthermia, causing a powerful hypothermia. Co-administered Δ9-THC, CP 55,940 and SR 141716 all tended to decrease MDMA-induced hyperactivity. Co-administered Δ9-THC provided protection against the long-term increases in anxiety seen in the emergence test, but not the social interaction test, 6 weeks after MDMA treatment. Co-administered Δ9-THC and CP 55,940, but not SR 141716, partly prevented the long-term 5-HT and 5-HIAA depletion caused by MDMA in various brain regions. SR 141716 administered with CP 55,940 and MDMA prevented the hypothermic response to the CP 55,940/MDMA combination but did not alter the CP 55,940 attenuation of MDMA-induced 5-HT depletion. These results suggest a partial protective effect of co-administered cannabinoid receptor agonists on MDMA-induced 5-HT depletion and long-term anxiety. This action appears to operate independently of cannabinoid CB1 receptors.