Effects of 3,4‐methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats
Charles W. Schindler, Eric B. Thorndike, Bruce E. Blough, Srihari R. Tella, Steven R. Goldberg, Michael H. Baumann
British Journal of Pharmacology October 12, 2013 DOI: 10.1111/bph.12423
Summary
MDMA significantly elevates heart rate and blood pressure, with a notable peak heart rate response at lower doses. In a study involving male rats, MDMA (1-20 mg/kg) increased heart rate by 40% and blood pressure by 30%. Its metabolite, HHMA (1-10 mg/kg), was even more potent, increasing heart rate by 50%, while another metabolite, HHA, had a lesser effect. Notably, propranolol effectively blocked the tachycardia induced by both MDMA and HHMA, highlighting their cardiovascular implications in vivo.
Abstract
Background and Purpose The cardiovascular effects produced by 3,4‐methylenedioxymethamphetamine ( MDMA ; ‘ E cstasy’) contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats. Experimental Approach Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP , heart rate ( HR ) and locomotor activity in conscious male rats. Key Results MDMA (1–20 mg·kg −1 ) produced dose‐related increases in BP , HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N ‐demethylated metabolite, 3,4‐methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA . The metabolite 3,4‐dihydroxymethamphetamine ( HHMA ; 1–10 mg·kg −1 ) increased HR more potently and to a greater extent than MDMA , whereas 3,4‐dihydroxyamphetamine (HHA) increased HR , but to a lesser extent than HHMA . Neither dihydroxy metabolite altered motor activity. The metabolites 4‐hydroxy‐3‐methoxymethamphetamine (HMMA) and 4‐hydroxy‐3‐methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the β ‐adrenoceptor antagonist propranolol. Conclusions and Implications Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo . As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.