Urinary Excretion Kinetics of 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) and Its Phase I and Phase II Metabolites in Humans following Controlled MDMA Administration

After oral MDMA (ecstasy) intake, human urine contains mostly sulfate and glucuronide conjugates of MDMA metabolites, with sulfates present at higher concentrations than glucuronides. More than 90% of the metabolites DHMA and HMMA were excreted as conjugates. HMMA sulfate had the longest detection window in urine. The ratio of HMMA sulfate to glucuronide was 2.0, and the ratio of DHMA 3-sulfate to 4-sulfate was 5.3 during the first 24 hours, matching predictions from earlier lab experiments. These findings can improve direct urine analysis for MDMA and its metabolites in clinical and forensic toxicology.

Study at a glance

Abstract

BACKGROUND 3,4-Methylendioxymethamphetamine (MDMA) is excreted in human urine as unchanged drug and phase I and II metabolites. Previous urinary excretion studies after controlled oral MDMA administration have been performed only after conjugate cleavage. Therefore, we investigated intact MDMA glucuronide and sulfate metabolite excretion. METHODS We used LC–high-resolution MS and GC-MS to reanalyze blind urine samples from 10 participants receiving 1.0 or 1.6 mg/kg MDMA orally. We determined median Cmax, tmax, first and last detection times, and total urinary recovery; calculated ratios of sulfates and glucuronides; and performed in vitro–in vivo correlations. RESULTS Phase II metabolites of 3,4-dihydroxymethamphetamine (DHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-dihydroxyamphetamine (DHA), and 4-hydroxy-3-methoxyamphetamine were identified, although only DHMA sulfates, HMMA sulfate, and HMMA glucuronide had substantial abundance. Good correlation was observed for HMMA measured after acid hydrolysis and the sum of unconjugated HMMA, HMMA glucuronide, and HMMA sulfate (R2 = 0.87). More than 90% of total DHMA and HMMA were excreted as conjugates. The analyte with the longest detection time was HMMA sulfate. Median HMMA sulfate/glucuronide and DHMA 3-sulfate/4-sulfate ratios for the first 24 h were 2.0 and 5.3, respectively, in accordance with previous in vitro calculations from human liver microsomes and cytosol experiments. CONCLUSIONS Human MDMA urinary metabolites are primarily sulfates and glucuronides, with sulfates present in higher concentrations than glucuronides. This new knowledge may lead to improvements in urine MDMA and metabolite analysis in clinical and forensic toxicology, particularly for the performance of direct urine analysis.