The effects of intermittent repeated doses of MDMA ("binges") on rat cardiovascular responses was investigated by giving rats 3 identical repeated-dose regimens, with each regimen separated by 10 MDMA-free days. Each regimen consisted of 2 daily doses of 3 or 9 mg/kg MDMA i.v. given on 4 consecutive days, with the second daily dose given approximately 6.5 hours after the first dose. Mean arterial pressure (MAP) and heart rate (HR) were measured in freely moving rats via radiotelemetry systems. MAP and HR were recorded 1 h post-drug. 1 day before and 10 days after the second and third 4-day 2-dose treatment, cardiovascular responses to phenylephrine, sodium nitroprusside, acetylcholine and serotonin (5-HT) were assessed. Only rats receiving the 9 mg/kg dose regimen were also challenged with a combination of MDMA and 1 mg/kg atropine 11 days after the third regimen. The effect of each treatment on heart tissue was investigated by a pathologist blind to condition in a separate group of rats given saline or 9 mg/kg MDMA regimens without any further pharmacological challenge. Rats were killed either 1 day after the first, second or third MDMA-dosing regimen, and cardiac tissue removed and examined. Hematoxylin staining and immunohistochemistry were used to assess heart tissue for inflammation or other changes. MDMA initially produced slow HR (bradycardia) and hypotension followed by elevated HR (tachycardia). This occurred during all three dosing periods. However, initial bradycardia was even more pronounced after the second and third 4-day 2-dose treatments when compared with the first treatment. MAP was increased after every dose of 3 mg/kg or 9 mg/kg MDMA. Atropine abolished initial MDMA-induced bradycardia. While there were no arrhythmias reported pre-drug, 4 of 7 rats showed arrhythmia-like patterns after MDMA in each repeated dose regimen. Brief periods of sinus pause/heart block were seen after the first dose of MDMA in the first repeated dosing period in 2 of 7 rats. The number of rats with sinus pause/heart block after initial MDMA dose increased during the second and third regimen. MDMA produced ST segment depression on some occasions. Cardiovascular response to phenylephrine challenge were unaltered by successive regimens of either 3 or 9 mg/kg MDMA, and there was only an altered response to serotonin challenge in rats before the third regimen after 9 mg/kg MDMA. In contrast, depressor response to sodium nitroprusside was reduced after each successive 4-day MDMA regimen (there was only a trend toward reduced depressor response after 9 mg/kg MDMA). Each successive regimen of 3 or 9 mg/kg attenuated an acetylcholine-induced depressor response, excepting an increased depressor response 1 day prior to final 9 mg/kg MDMA treatment. Cardiac response to acetylcholine was unaltered by 3 or 9 mg/kg MDMA. Though there were no significant heart lesions after the first 4-day 9 mg/kg treatment, significantly more heart lesions were observed in hearts removed after successive treatments, and heart inflammation was seen in rats given all three repeated dose regimens. Repeated doses of methamphetamine produce similar effects on HR and MAP, but without the sensitization produced by successive methamphetamine treatments. The increasingly strong bradycardia with successive regimens might indicate either decrease in sympathetic nerve activity or decrease in cardiac output, and blockade of MDMA-induced bradycardia and hypotension by atropine suggests that these effects are mediated through the vagal nerve. Attenuated response to sodium nitroprusside challenge is hypothesized to be the result of vascular remodeling. The authors also suggest that bradycardia and hypotension after MDMA might be due to release of peripheral stores of 5-HT. Findings of bradycardia immediately after MDMA administration are surprising, given that human studies consistently report elevated heart rate and blood pressure (BP) after MDMA. It is possible that similar cardiovascular responses would be seen if humans were also continually monitored after MDMA administration. This is one of the first reports of damage to heart tissue from (repeated) administration of MDMA alone, as opposed to Gesi's studies combining MDMA with loud noise. However, it should be noted that the damage does not appear until after the first repeated dose regimen, and that regimen duration probably exceeds all but the most prolonged human binges.