3,4-Methylenedioxymethamphetamine (MDMA) and metabolites disposition in blood and plasma following controlled oral administration.
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. Figure 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).
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.|Program in Toxicology, University of Maryland Baltimore, 660 West Redwood Street, Baltimore, MD, 21201, USA.
Rebecca L
RL
Hartman
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.|Program in Toxicology, University of Maryland Baltimore, 660 West Redwood Street, Baltimore, MD, 21201, USA.
Nathalie A
NA
Desrosiers
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.
Allan J
AJ
Barnes
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.|School of Forensic Medicine, Shanxi Medical University, 030001, Taiyuan, China.
Keming
K
Yun
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.
Karl B
KB
Scheidweiler
Southwestern Institute of Forensic Sciences, 2355 North Stemmons Freeway, Dallas, TX, 75207, USA.
Erin A
EA
Kolbrich-Spargo
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.|Maryland Psychiatric Research Center, University of Maryland, Tawes Bldg, PO Box 21247, Baltimore, MD, 21228, USA.
David A
DA
Gorelick
, 800 Ingleside Avenue, Catonsville, MD, 21228, USA.
Robert S
RS
Goodwin
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. mhuestis@intra.nida.nih.gov.
Marilyn A
MA
Huestis
Blood; Ecstasy; MDMA; Metabolites; Pharmacokinetics; Plasma