OBJECTIVE: "Ecstasy," or 3,4-methylenedioxymethamphetamine (MDMA), causes long-term impairment to the serotonin (5-HT) system in rats, dogs, and nonhuman primates. 5-HT dysfunction has also been observed in human recreational users of the drug, but whether 5-HT dysfunction in humans is caused by MDMA has not been established, since dysfunction may have preceded MDMA exposure. This ambiguity about causation is particularly important in MDMA research, because 5-HT deficiency is a predictor of risky behavior. METHOD: The 5-HT function of 22 long-term MDMA users was compared to that of 20 drug-naive comparison subjects and 19 cannabis users. 5-HT function was assessed with the intensity dependence paradigm, a tool that measures 5-HT-related attenuation of neural response to auditory stimuli (measured with EEG). RESULTS: Long-term MDMA users exhibited 5-HT dysfunction, relative to both cannabis users and drug-naive comparison subjects. This dysfunction was related to total MDMA consumption (after removing the effect of frequency of use) but not to frequency of use (after removing the effect of total consumption). CONCLUSIONS: These data show that 5-HT dysfunction occurs in MDMA users, is related to users’ MDMA consumption, and is independent of cannabis use. The results do not suggest that self-medication explains this relationship, because the deficit was related to total MDMA consumption but not frequency of consumption. The results are thus consistent with the thesis that MDMA consumption causes 5-HT impairment in humans.