A possible role for the endocannabinoid system in modulating the rewarding effects of MDMA was investigated by comparing number of lever presses made to obtain i.c.v. injections of MDMA alone with number of responses made to obtain combinations of MDMA and an endocannabinoid agonist (CP 55,940) or an antagonist (SR141716A). After being trained to press a lever for water reinforcement, rats were trained to press levers for i.c.v injections of MDMA. The ICV dose producing maximal responses was 1 mcg MDMA, out of the tested doses of 0.01, 0.1, 1 and 2 mcg, with responses for MDMA decreasing at 2 mcg. Rats who had demonstrated 5 days of stable responses for 1 mcg MDMA were then tested with a combination of MDMA and cannabinoid agonist or MDMA and cannabinoid antagonist. Doses of cannabinoid agonist and antagonist were derived from findings in previous studies as producing maximal responding (for the agonist) or as completely blocking the effects of the agonist (for the antagonist). Rats pressed the MDMA (drug) lever less when given a combination of MDMA and cannabinoid agonist, and pressed the MDMA lever more when receiving a combination of MDMA and cannabinoid antagonist. Since the authors had pre-selected the dose of MDMA used in the drug combinations to be one producing maximal self-administration, they interpreted these findings as a reflection of a synergistic action of MDMA and the cannabinoid agonist that enhances the rewarding effects of MDMA. Likewise, the increase in response seen after the combination of MDMA and cannabinoid antagonist is interpreted as indicating that MDMA is less rewarding when cannabinoid receptors are not activated. The authors suggest that the cannabinoid system modulates dopamine release in specific brain areas. Since most ecstasy users use cannabis before or after ecstasy use, such findings might shed light on the popularity of this combination of substances. There are two different cannabinoid receptors, CB1 and CB2, and this report does not indicate whether the agonists and antagonists they used activate both receptors equally, or interact with one receptor more than another.