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

Abstract

BACKGROUND AND PURPOSEThe cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') 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 APPROACHRadiotelemetry 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 IMPLICATIONSOur 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.

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans

“…This finding is of interest, e.g., in terms of potential toxic effects of MDMA metabolites. Specifically, cardiovascular effects were demonstrated for DHMA with even greater increases in heart rate in rats compared with MDMA (Schindler et al, 2014). However, as our and other results (Segura et al, 2001) suggest, DHMA is not present in blood unconjugated in relevant concentrations.…”

“…MDMA metabolites were also discussed to play a role in acute cardiovascular effects observed after MDMA consumption (Schindler et al, 2014).…”

Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats

“…Additionally, as CYP enzymes are present in brain tissue, HHMC could be produced locally in the brain after systemic administration of methylone. In previous studies, we found that 3,4-dihydroxymethamphetamine, the O-demethylenated metabolite of MDMA, does not appear to penetrate into the brain but has powerful cardiovascular effects in vivo (Schindler et al, 2014). Thus further studies are needed to examine the possible cardiovascular effects of HHMC, based on its potent releasing activity at NET.…”

“…The mechanism of action for methylone resembles that of MDMA, which is not surprising considering methylone is the β-keto analog of MDMA. It is notable that MDMA is metabolized by hepatic mechanisms in rats and humans (de la Torre and Farre, 2004), and its bioactive metabolites may contribute to the profile of drug effects in vivo (Concheiro et al, 2014;Schindler et al, 2014). Moreover, MDMA displays non-linear pharmacokinetics (PKs) characterized by increases in plasma drug concentrations that are greater than dose-proportional (Baumann et al, 2009;Chu et al, 1996;de la Torre et al, 2000).…”

Acute and Chronic Effects of 3-4, Methylenedioxymethamphetamine on Pyramidal Cells of Hippocampus

“…After-effects can be sleep problems, anxiety and depression (3). It has been reported that repeated use of ecstasy produces long-term neurotoxicity in humans and primates (4,5). It can induce pathological cerebrovascular responses (6) and affect the immune system (7).…”