Effects of 3,4‐methylenedioxymethamphetamine (MDMA) and its metabolites on cardiovascular function in rats

Abstract

The abuse of MDMA (Ecstasy) peaked in the early 2000s, yet reports of MDMA use from emergency room admission data continue to increase. The potential for cardiovascular effects of MDMA to contribute to its acute toxicity has long been recognized. However, the role of MDMA metabolites in mediating the drug's cardiovascular actions has not been studied. Here we employed radiotelemetry to evaluate the effects of racemic MDMA and its metabolites on blood pressure (BP), heart rate (HR) and locomotor activity in conscious rats. MDMA (1–20 mg/kg, s.c.) increased BP, HR, and activity. The rise in HR peaked at lower doses than the effects on BP and activity. The MDMA metabolite 3,4‐methylenedioxyamphetamine (MDA) produced effects that were similar to MDMA. The metabolite 3,4‐ dihydroxymethamphetamine (1–10 mg/kg, HHMA) increased HR to a greater degree than MDMA. The metabolite 3,4‐ dihydroxyamphetamine increased HR, but less than HHMA. These dihydroxy metabolites did not alter motor activity. The metabolites 4‐hydroxy‐3‐methoxymethamphetamine and 4‐ hydroxy‐3‐methoxyamphetamine (3–10 mg/kg) did not affect BP, HR or activity. The tachycardia produced by MDMA and HHMA may be mediated via beta‐adrenergic receptors as propranolol attenuated the HR increase. Our results suggest that HHMA may contribute significantly to the overall cardiovascular effects of MDMA in vivo. Supported by NIH/NIDA Intramural Research Funds.