Stereoselective urinary MDMA (ecstasy) and metabolites excretion kinetics following controlled MDMA administration to humans

Abstract

The R- and S-enantiomers of racemic 3,4-methylenedioxymethamphetamine (MDMA) exhibit different dose-concentration curves. In plasma, S-MDMA was eliminated at a higher rate, most likely due to stereoselective metabolism. Similar data were shown in various in vitro experiments. The aim of the present study was the in vivo investigation of stereoselective elimination of MDMA's phase I and phase II metabolites in human urine following controlled oral MDMA administration. Urine samples from 10 participants receiving 1.0 and 1.6 mg/kg MDMA separated by at least one week were analyzed blind by liquid chromatography-high resolution-mass spectrometry and gas chromatography-mass spectrometry after chiral derivatization with S-heptafluorobutyrylprolyl chloride. R/S ratios at Cmax were comparable after low and high doses with ratios >1 for MDMA, free DHMA, and HMMA sulfate, and with ratios <1 for MDA, free HMMA, DHMA sulfate and HMMA glucuronide. In the five days after the high MDMA dose, a median of 21% of all evaluated compounds were excreted as R-stereoisomers and 17% as S-stereoisomers. Significantly greater MDMA, DHMA, and HMMA sulfate R-enantiomers and HMMA and HMMA glucuronide S-stereoisomers were excreted. No significant differences were observed for MDA and DHMA sulfate stereoisomers. Changes in R/S ratios could be observed over time for all analytes, with steady increases in the first 48 h. R/S ratios could help to roughly estimate time of MDMA ingestion and therefore, improve interpretation of MDMA and metabolite urinary concentrations in clinical and forensic toxicology.

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

“…For HMMA, also the respective glucuronide was present in abundant concentrations. In initial experiments, glucuronides of DHMA were not detected in blood, which is in line with previous findings (Schwaninger et al, 2012). Consistently, Segura et al (2001), using different cleavage procedures, concluded that DHMA glucuronides were minor metabolites.…”

“…Variation of MDMA R/S ratios based on time postdose, were used to estimate MDMA ingestion time (Fallon et al, 1999). In urine, better accuracy for such estimations was obtained through metabolite ratios (Schwaninger et al, 2012). However, in blood plasma only MDMA R/S ratio follows a steady trend.…”

How MDMA's Pharmacology and Pharmacokinetics Drive Desired Effects and Harms

“…MDMA is structurally related to amphetamines and hallucinogenic compounds such as mescaline and catinone . Figure is an analytic framework that ties together intermediate and final health outcomes associated with MDMA use and the underlying mechanism of action …”

“…MDMA is mostly cleared through cytochrome (CYP) metabolism (mostly CYP2D6), although 3–8% of MDMA is eliminated unchanged in the urine over 36 hours post‐ingestion . MDMA metabolites (Figure ) are primarily cleared by CYP isoenzymes, catechol‐O‐methyltransferase (COMT), glucuronidation, or sulfation …”

Evaluation of drug incorporation into hair segments and nails by enantiomeric analysis following controlled single MDMA intakes

“…MDMA is used for its entactogenic effects and stimulation of the central nervous system [28] which are mainly attributed to the S-MDMA enantiomer [29]. The R-enantiomer was reported to be more abundant in human tissues and fluids representing its enantioselective metabolism most likely because of the elimination of the S-enantiomer from plasma at a higher rate [30][31][32][33]. MDMA is primarily metabolized to 3,4-dihydroxymethamphetamine (DHMA) by the cytochrome P450 isoenzyme CYP2D6 [29], which is polymorphic [34].…”