Pharmacology of MDMA in humans

This paper (2006, n=27) details the physiological effects of MDMA (50-150mg) in humans. There was a slight impairment of psychomotor (e.g. hand eye coordination) performance, higher plasma cortisol and prolactin (both hormones) levels, and (after a decrease in the first hour) an increase in oral/body temperature.

Abstract

“MDMA given at recreational doses (range tested 50 to 150 mg) to healthy volunteers, produced mydriasis and marked increases in systolic and diastolic blood pressure, heart rate, and pupillary diameter. MDMA induced changes on oral temperature. The time course of this observation was biphasic, as a slight decrease at 1 h and a slight increase at 2 and 4 h were observed. MDMA induced a slight dose‐dependent impairment on psychomotor performance. MDMA produced a marked rise in plasma cortisol and prolactin concentrations. The elimination half‐life of MDMA was about 8‐9 h. Drug concentrations increased, and a parallel increase in physiologic and hormonal measures was observed. Both peak concentrations and peak effects were obtained between 1 and 2 h and decreased to baseline values 4‐6 h after drug administration.”

Authors: R. de la Torre, M. Farré, P. N. Roset, C. Hernández López, M. Mas, J. Ortuño, E. Menoyo, N. Pizarro, J. Segura, J. Camí

Summary

MDMA pharmacology in humans has been recently described in two reports. New experimental data from a clinical trial administering an intermediate dose of 100 mg of MDMA to healthy volunteers are presented.

SUBJECTS AND METHODS

27 healthy male recreational users of MDMA participated in different randomized, double-blind, placebo-controlled, crossover clinical trials. None had a history of abuse or drug dependence according to DSM-IV criteria, or any medical or psychiatric adverse reaction after MDMA consumption.

In different studies, d,l-MDMA was administered in oral single doses to 27 volunteers. Data were collected on physiologic parameters, psychomotor performance, subjective effects, neuroendocrine changes, and pharmacokinetics.

Physiologic parameters were recorded using a DinamapTM 8100-T vital signs monitor, and an ECG was continuously monitored during the entire session.

The psychomotor performance battery included the simple reaction time, the DSST, and the Maddox-wing device. Results were expressed in milliseconds as the mean of the response time to 20 stimuli.

Samples were collected at 0 and at 15, 30, 45, 60, and 90 min, and at 2, 3, 4, 6, 8, 10, and 24 h after drug administration. Plasma and serum were removed and frozen at 20°C until analysis.

For MDMA and metabolite analysis, plasma samples were analyzed by gas chromatography coupled to a nitrogen phosphorous detector (GC/NPD) or to a mass selective detector (GC/MS).

Gas chromatography-mass spectrometry analysis was performed on a Hewlett Packard 6890 gas chromatograph coupled to a model 5973 quadrapole mass spectrometer. MDMA, HMMA, and pholedrine were identified and quantified using ion monitoring acquisition mode. MDMA, HMMA, MDA, and HMA were calibrated with linear concentration curves, and limits of quantification were 5.7 ng/ml for MDMA, 1.0 ng/ml for MDA, 2.9 ng/ml for HMMA, and 0.5 ng/ml for HMA.

Pharmacokinetic parameters of MDMA and its metabolites were determined using a computer program, and differences between active conditions and their corresponding placebo were compared using repeated measures ANOVA and post-hoc Tukey’s test.

RESULTS

MDMA induced increases in blood pressure, pulse rate, and pupillary diameter in all subjects except 50 mg, and some subjects met criteria for hypertension and sinusal tachycardia at doses of 75 mg and higher.

MDMA induced slight dose-dependent impairment of DSST and marginal increases in total reaction time and decision time, but not statistically significant differences.

Hormones were changed after the administration of MDMA (75, 100, and 125 mg) and placebo. The cortisol concentration peaked at 2 h after MDMA administration.

Plasma prolactin concentrations were higher after the use of MDMA 125 and 100 than after the administration of placebo and MDMA 75.

MDMA, MDA, HMMA, and HMA displayed plasma concentrations very similar to those corresponding to their metabolic precursors MDMA and MDA, respectively. MDMA had a tmax of 2 h, a mean elimination half-life of 9 h, and a formation rate constant of 0.63 h1.

DISCUSSION

MDMA produced hypertension, tachycardia, and mydriasis in humans at doses between 75 and 150 mg. These effects lasted longer than the cardiovascular effects.

MDMA administration causes mucocutaneous vasoconstriction and a slight increase in oral temperature, but only marginal increases in body temperature have been observed in healthy volunteers.

MDMA produced subjective feelings of confusion, mental slowing, and impaired attention, which were in contrast with the mild enhancement of performance usually observed with amphetamine. Moreover, MDMA induced esophoria in the Maddox wing, a finding opposed to the effect of sedatives.

MDMA produced significant increases in plasma cortisol and prolactin concentrations in humans. These increases are consistent with activation of serotonergic neurotransmission, but dopaminergic and noradrenergic mechanisms may also be involved.

MDMA and its metabolites pharmacokinetics was studied in a considerable number of subjects and the tmax was attained at 2 h. The elimination half-life was about 8 – 9 h, similar to that reported for methamphetamine or amphetamine.

MDMA nonlinear pharmacokinetics has been suggested, and several mechanisms have been proposed to explain it. Studies with a design specifically addressing this issue should be conducted.

MDA, formed by N-demethylation of MDMA, is a minor metabolite, and its urinary recovery is about 1% of the dose administered.

HMMA is the main metabolite of MDMA either in plasma or in urine, and its plasma concentrations are quite similar to those corresponding to MDMA. Its elimination half-life is probably overestimated, and additional samples should be collected after 24 h for a better estimate.

In analytical conditions applied for the determination of MDMA and its metabolites, intermediate metabolic products are not detected in plasma or urine. These products can be rapidly further metabolized.

MDMA produced mydriasis, increased blood pressure, heart rate, plasma cortisol and prolactin concentrations, and a short elimination half-life. It may be dangerous to use MDMA in crowded conditions, high ambient temperature, and physical activity.