Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults

Abstract

This study examines the plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) in young adults for up to 143 hours after drug administration. Seventeen female and male participants (black, white, and Hispanic) received placebo, low (1.0 mg/kg), and high (1.6 mg/kg) oral MDMA doses (comparable to recreational doses) in a double-blind, randomized, balanced, within-subject design while residing on a closed research unit. Doses were separated by 1 week or more. A fully validated two-dimensional gas chromatography/mass spectrometry method simultaneously quantified MDMA, HMMA, MDA, and HMA. Calibration curves were MDA, 1 to 100 ng/mL; HMA, 2.5 to 100 ng/mL; and MDMA and HMMA, 2.5 to 400 ng/mL. Mean +/- standard deviation maximum plasma concentrations (C(max)) of 162.9 +/- 39.8 and 171.9 +/- 79.5 ng/mL were observed for MDMA and HMMA, respectively, after low-dose MDMA. After the high dose, mean MDMA Cmax significantly increased to 291.8 +/- 76.5 ng/mL, whereas mean HMMA C(max) was unchanged at 173.5 +/- 66.3 ng/mL. High intersubject variability in C(max) was observed. Mean MDA C(max) were 8.4 +/- 2.1 (low) and 13.8 +/- 3.8 (high) ng/mL. HMA Cmax were 3.5 +/- 0.4 and 3.9 +/- 0.9 ng/mL after the low and high doses, respectively. AUC infinity displayed similar trends to C(max), demonstrating nonlinear pharmacokinetics. Times of last plasma detection were generally HMA < MDA < MDMA < HMMA. Mean half-lives (t1/2) of MDMA, MDA, and HMMA were approximately 7 to 8 hours, 10.5 to 12.5 hours, and 11.5 to 13.5 hours, respectively. HMA t1/2 showed high variability. Mean MDMA volume of distribution was constant for low and high doses; clearance was significantly higher after the low dose. This study presents MDMA plasma pharmacokinetic data for the first time from blacks and females as well as measurement of HMMA and HMA concentrations after low and high MDMA doses and more frequent and extended plasma sampling than in prior studies.

FIGURE 1

Metabolism of 3,4-methylenedioxymethamphetamine (MDMA). MDA, 3,4-methylenedioxyamphetamine; HHMA, 3,4-dihydroxymethamphetamine; HHA, 3,4-dihydroxyamphetamine; HMMA, 4-hydroxy-3-methoxymethamphetamine; HMA, 4-hydroxy-3-methoxyamphetamine.

FIGURE 2

Mean ± standard deviation concentrations of (A) 3,4-methylenedioxymethamphetamine (MDMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) and (B) 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxyamphetamine (HMA) after administration of 1.0 (low) and 1.6 (high) mg/kg oral MDMA to 17 volunteers. Note: Plasma concentrations of 0 occurring at the beginning and end of the time course were included in mean calculations. If concentrations were less than limit of quantification (LOQ) during the entire time course, the participant was excluded from calculations for that analyte and dose only. ^an = 14, because HMA concentrations were always less than LOQ in plasma specimens from three participants. ^bn = 16, because HMA concentrations were always less than LOQ in plasma specimens from one participant.

FIGURE 3

Individual 4-hydroxy-3-methoxymethamphetamine (HMMA) and 3,4-methylenedioxymethamphetamine (MDMA) maximum plasma concentrations (C_max) after low- (1.0 mg/kg) and high- (1.6 mg/kg) dose oral MDMA administration with participants’ gender and race identified. F, female; AA, African-American; M, male; C, Caucasian; H, Hispanic. ^aNo HMMA low-dose C_max as a result of unavailable plasma concentration at/near peak.

FIGURE 4

Plasma profiles of 3,4-methylenedioxymethamphetamine (MDMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) in two subjects, (B), male and (C), female, administered approximately 80 (low) and 130 (high) mg MDMA.

FIGURE 5

Metabolite ratios after administration of 1.0- (low) and 1.6- (high) mg/kg 3,4-methylenedioxymethamphetamine (MDMA) to healthy volunteers. (A) 4-hydroxy-3-methoxymethamphetamine (HMMA)/MDMA; (B) 3,4-methylenedioxyamphetamine (MDA)/MDMA; (C) 4-hydroxy-3-methoxyamphetamine (HMA)/MDMA; (D) HMA/HMMA; and e) HMA/MDA.