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3,4-Methylenedioxymethamphetamine (MDMA) and metabolites disposition in blood and plasma following controlled oral administration

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Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit phenethylamine ingested for entactogenic and euphoric effects. Although blood is more commonly submitted for forensic analysis, previous human MDMA pharmacokinetics research focused on plasma data; no direct blood–plasma comparisons were drawn. Blood and plasma specimens from 50 healthy adult volunteers (33 males, 17 females, 36 African-American) who ingested recreational 1.0 and 1.6 mg/kg MDMA doses were quantified for MDMA and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) by two-dimensional gas chromatography–mass spectrometry. Specimens were collected up to 3 h post-dose and evaluated for maximum concentration (C max), first detection time (t first), time of C max (t max), and 3-h area under the curve (AUC0–3 h); as well as blood metabolite ratios and blood/plasma ratios. Median blood MDMA and MDA C max were significantly greater (p < 0.0005) than in plasma, but HMMA was significantly less (p < 0.0005). HMA was detected in few blood specimens, at low concentrations. Nonlinear pharmacokinetics were not observed for MDMA or MDA in this absorptive phase, but HMMA C max and AUC0–3 h were similar for both doses despite the 1.6-fold dose difference. Blood MDA/MDMA and MDA/HMMA significantly increased (p < 0.0001) over the 3-h time course, and HMMA/MDMA significantly decreased (p < 0.0001). Blood MDMA C max was significantly greater in females (p = 0.010) after the low dose only. Low-dose HMMA AUC0–3 h was significantly decreased in females’ blood and plasma (p = 0.027) and in African-Americans’ plasma (p = 0.035). These data provide valuable insight into MDMA blood–plasma relationships for forensic interpretation and evidence of sex- and race-based differential metabolism and risk profiles.

Median (interquartile range) blood/plasma 3,4-methylenedioxymethamphetamine (MDMA) (a), 4-hydroxy-3-methoxymethamphetamine (HMMA) (b), and 3,4-methylenedioxyamphetamine (MDA) (c) ratios for 3 h after controlled MDMA administration. Changes over time were significant after the 1.6 mg/kg dose for HMMA and MDA (p = 0.013 and p = 0.021), but not for MDMA. No changes over time were significant after the 1.0 mg/kg dose. Note: y-axes do not begin at 0. *p  < 0.05 (low vs. high)

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Acknowledgments

We thank the National Institute on Drug Abuse Intramural Research Program and Johns Hopkins Bayview Medical Center Behavioral Pharmacology Research Unit clinical staff. We further acknowledge the Graduate Partnership Program, National Institutes of Health. This research was funded by the Intramural Research Program, National Institute on Drug Abuse, NIH.

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Authors and Affiliations

  1. Chemistry and Drug Metabolism Section, Clinical Pharmacology and Therapeutic Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Suite 200 Room 05A721, Baltimore, MD, 21224, USA

    Rebecca L. Hartman, Nathalie A. Desrosiers, Allan J. Barnes, Keming Yun, Karl B. Scheidweiler, David A. Gorelick & Marilyn A. Huestis

  2. Program in Toxicology, University of Maryland Baltimore, 660 West Redwood Street, Baltimore, MD, 21201, USA

    Rebecca L. Hartman & Nathalie A. Desrosiers

  3. School of Forensic Medicine, Shanxi Medical University, 030001, Taiyuan, China

    Keming Yun

  4. Southwestern Institute of Forensic Sciences, 2355 North Stemmons Freeway, Dallas, TX, 75207, USA

    Erin A. Kolbrich-Spargo

  5. 800 Ingleside Avenue, Catonsville, MD, 21228, USA

    Robert S. Goodwin

  6. Maryland Psychiatric Research Center, University of Maryland, Tawes Bldg, PO Box 21247, Baltimore, MD, 21228, USA

    David A. Gorelick

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  1. Rebecca L. Hartman
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Correspondence to Marilyn A. Huestis.

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Hartman, R.L., Desrosiers, N.A., Barnes, A.J. et al. 3,4-Methylenedioxymethamphetamine (MDMA) and metabolites disposition in blood and plasma following controlled oral administration. Anal Bioanal Chem 406, 587–599 (2014). https://doi.org/10.1007/s00216-013-7468-y

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