MDMA at recreational doses (50–150 mg) produces sympathetic stimulation (mydriasis, marked increases in systolic and diastolic blood pressure and heart rate), a biphasic small change in oral temperature, slight dose‑dependent psychomotor impairment, and marked rises in plasma cortisol and prolactin. Peak concentrations and effects occurred at 1–2 h and returned to baseline by 4–6 h, with an elimination half‑life of about 8–9 h.
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.
De and colleagues situate MDMA (3,4-methylenedioxymethamphetamine) as an amphetamine derivative with both stimulant and serotonergic (hallucinogenic-like) actions that distinguish it from classical amphetamines. Earlier human reports have documented prominent sympathomimetic cardiovascular and autonomic effects (increased blood pressure, pulse, mydriasis, diaphoresis, jaw clenching) together with subjective confusion and modest psychomotor impairment. Metabolically, MDMA undergoes N‑demethylation to MDA and subsequent O‑demethylenation and O‑methylation steps producing HMMA and HMA; however, plasma data and urinary quantitative recoveries for these metabolites remain limited. This paper reports experimental data from a new clinical trial administering a single oral 100 mg dose of MDMA to healthy volunteers and compares those findings with prior controlled doses (50, 75, 125, and 150 mg) examined in the authors’ earlier pilot and controlled studies. The study aims to characterise physiologic, psychomotor, neuroendocrine, and pharmacokinetic effects of MDMA and its main metabolites across the recreational dose range, including examination of dose–response patterns and possible nonlinear kinetics.
Papers in Blossom that reference this study
Martinez, R. L., Radošić, N., Molla, H. et al. · Journal of Psychopharmacology (2025)
Miner, N. B. · Pharmacometrics and Systems Pharmacology (2024)
Sarmanlu, M., Kuypers, K. P. C., Vizeli, P. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2023)
Kloft, L., Otgaar, H., Blokland, A. et al. · European Neuropsychopharmacology (2022)
The investigators conducted randomized, double‑blind, placebo‑controlled, crossover clinical trials in a total of 27 healthy male recreational MDMA users. Inclusion characteristics reported that participants had used MDMA on 5–50 prior occasions (mean about 25), had previous exposure to cannabis, cocaine, and methamphetamine, and did not meet DSM‑IV criteria for substance abuse or dependence (except nicotine). Different single oral d,l‑MDMA doses were given across studies: 50 mg (n = 2), 75 mg (n = 10), 100 mg (n = 13), 125 mg (n = 8), and 150 mg (n = 2); eight subjects received both 75 mg and 125 mg in one crossover study. All participants provided informed consent and studies had ethical and regulatory approvals. Physiologic monitoring included noninvasive heart rate, systolic and diastolic blood pressure, oral temperature, pupillary diameter and continuous ECG. Psychomotor assessment used a battery comprising simple reaction time (Vienna Reaction Unit), a computerized Digit Symbol Substitution Test (DSST), and the Maddox‑wing device to detect ocular alignment changes (esophoria/exophoria). Blood sampling was performed via an indwelling catheter with timed collections for MDMA and metabolites (MDA, HMMA, HMA) at 0, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 10, and 24 h. Hormone samples for cortisol and prolactin were taken at 0, 30, 60, 90 min, and 2, 3, 4, and 6 h. Plasma/serum were frozen at −20°C until assay. Drug assays for MDMA and metabolites used gas chromatography with nitrogen‑phosphorus detection or GC‑mass spectrometry with deuterated internal standards. Calibration ranges and limits of quantification for each analyte are reported; intra‑ and interday precision and accuracy metrics are provided. Cortisol and prolactin were measured by fluorescence polarisation immunoassay and microparticle enzyme immunoassay, respectively. Pharmacokinetic parameters derived included Cmax, tmax, AUC0‑24, AUCtotal, absorption and elimination half‑lives, calculated with PKCALC. Outcome data were expressed as change from baseline; when sample size allowed, repeated measures ANOVA with drug condition and time factors and Tukey post‑hoc tests were used. Statistical significance was set at p < 0.05.
Sample and dosing: Data were obtained from 27 male recreational MDMA users with the following subject‑dose counts: 50 mg (n = 2), 75 mg (n = 10), 100 mg (n = 13), 125 mg (n = 8), 150 mg (n = 2); eight subjects received both 75 mg and 125 mg in one study arm. Sympathomimetic and autonomic effects: Except at 50 mg, MDMA produced dose‑related increases in systolic and diastolic blood pressure, pulse rate, and pupillary diameter. At doses of 75 mg and above some participants met criteria for hypertension and sinus tachycardia. Mydriasis persisted longer than cardiovascular effects. Oral temperature followed a biphasic course with a small decrease at 1 h and slight increases at 2 and 4 h. Peak physiologic effects and concentrations typically occurred between 1 and 2 h and returned toward baseline by 4–6 h. Psychomotor and ocular findings: MDMA induced a slight dose‑dependent impairment on the DSST. Total reaction time showed a marginal, non‑statistically significant increase, mainly attributable to longer decision time rather than motor time. The Maddox‑wing test indicated esophoria at all active doses except 50 mg. Neuroendocrine effects: Plasma cortisol and prolactin rose significantly after MDMA compared with placebo. Reported peak differences for cortisol were: MDMA 125 vs placebo +17.3 µg/dl; MDMA 100 vs placebo +19.6 µg/dl; MDMA 75 vs placebo +13.4 µg/dl, with cortisol peaking at about 2 h. For prolactin the peak differences were: MDMA 125 vs placebo +17.4 ng/ml; MDMA 100 vs placebo +22.1 ng/ml; and MDMA 100 vs MDMA 75 +15.7 ng/ml; prolactin also peaked near 2 h. The authors note a plateau in hormonal responses between 100 and 125 mg. Pharmacokinetics and metabolites: For the 100 mg MDMA dose, tmax for MDMA was observed at about 2 h and plasma decline followed a monoexponential profile with a mean elimination half‑life of approximately 8–9 h. MDA appeared slowly, with a Cmax of about 13.1 ng/ml reached at 5–7 h after a 100 mg MDMA dose; the estimated MDA formation rate constant for the 100 mg dose was ~0.63 h−1 and MDA elimination half‑life around 25 h. HMMA and HMA plasma concentration profiles were similar to those of their precursors (MDMA and MDA, respectively). HMMA was identified as the major metabolite in plasma and urine; urinary recovery at 100 mg was roughly 13–14% for HMMA and about 24% for parent MDMA in 24 h. MDA represented a minor metabolite (about 8–9% of MDMA AUC) with low urinary recovery (~1%). The intermediate dihydroxy metabolites (HHMA, HHA) were not detected in plasma and only at very low levels in urine under the applied analytical conditions. Dose linearity observations: The authors observed a disproportionate increase in MDMA plasma concentrations after 150 mg in two volunteers, suggesting possible nonlinear pharmacokinetics, although they state this requires confirmation in studies specifically designed to evaluate nonlinearity.
De and colleagues interpret their results as confirmation that single oral MDMA doses in the recreational range (75–150 mg) produce marked sympathomimetic effects—hypertension, tachycardia—and pronounced mydriasis, consistent with prior human studies and with effects seen after related phenethylamines such as MDEA. They emphasise that temperature showed a biphasic pattern with a small early decrease followed by modest increases at 2–4 h; while laboratory increases in oral temperature were marginal, the authors note that environmental factors (crowded settings, high ambient temperature, physical activity) could convert these modest changes into clinically relevant hyperthermia in real‑world intoxications. On psychomotor function, the observed slight impairment on DSST and subjective reports of confusion and mental slowing are discussed as possibly attributable to the serotonergic/hallucinogenic profile of MDMA, in contrast with the performance enhancement typically seen with classical amphetamines. The differential effects across specific cognitive tests are suggested to reflect varying task complexity and attentional demands. Regarding neuroendocrine responses, the study documents significant cortisol and prolactin increases peaking around 2 h; the lack of large differences between 100 mg and 125 mg led the authors to propose a plateau effect for these hormonal responses. They acknowledge that multiple neurotransmitter systems (serotonergic, dopaminergic, noradrenergic) likely contribute to the endocrine changes. Pharmacokinetic conclusions highlight a tmax near 2 h and an elimination half‑life for MDMA of about 8–9 h at 100 mg, shorter than those reported for methamphetamine or amphetamine. The investigators present HMMA as the principal metabolite and note practical analytical challenges—in particular, HMMA detection often requires enzymatic hydrolysis and intermediate catechol metabolites (HHMA, HHA) were not observed in plasma under their assay conditions. The authors discuss evidence suggestive of nonlinear kinetics at higher doses and propose mechanisms such as metabolic saturation or metabolite–enzyme interactions; they caution that confirmation requires targeted study designs. Limitations and implications noted by the authors include the small numbers at the extreme doses (50 mg and 150 mg), potential overestimation of elimination half‑life for HMA due to sampling limited to 24 h, and analytical limitations for unstable intermediate metabolites. They conclude that, given the pharmacologic profile observed in controlled settings, MDMA use in hot, crowded, physically active environments could substantially increase the risk of life‑threatening toxicity.
Sympathomimetic activity. MDMA administration at doses between 75 and 150 mg produced marked increases in blood pressure and heart rate. These findings agree with previous studies,taking into account the dose differences between studies: approximately 15-75 mg and 120 mg, respectively. A related substance, 3,4-methylenedioxyethylamphetamine (MDEA, approximately 100-140 mg), produced a similar response pattern.MDMA also induced a pronounced mydriasis that lasted longer than the cardiovascular effects. Hypertension, tachycardia, and mydriasis are common features of MDMA intoxication, and are attributable to its symphatomimetic properties. In our studies, a slight decrease in oral temperature is observed at 1 h, which could be related to the important mucocutaneous vasoconstriction observed during the earliest phase of MDMA effects manifestation. Furthermore, for the first time a significant slight increase in oral temperature was evidenced at 2 and 4 h after MDMA administration. Such changes in body temperature have been associated with neurotoxicity of amphetamines. Nevertheless, when reviewing data on oral temperature in healthy volunteers administered with MDMA in a laboratory Results were obtained from 27 male healthy recreational MDMA users: 50 mg (n = 2); 75 mg (n = 10); 100 mg (n = 13); 125 mg (n = 8); 150 mg (n = 2); (eight subjects took 75 and 125 mg). Symbols: * p < 0.05); * * p < 0.01, compared to corresponding placebo. setting,only marginal increases in body temperature have been observed as compared with reported hyperthermia in cases of acute intoxication. Psychomotor performance. In our study a slight decrease in psychomotor performance results was evidenced. These results are in contrast with the mild enhancement of performance usually observed with amphetamine. Moreover, volunteers experienced subjective feelings of confusion, mental slowing, and impaired attention. Similar feelings were reported in a previous study, along with a slight but not significant psychomotor impairment in the Stroop task.The mechanism of this impairment is unknown, but could be related to a mild hallucinogenic-like effect induced by the serotonergic activity of MDMA. The discrepancy between the results on Stroop tests, simple reaction time and DSST could be attributable to the fact that DSST requires more complex cognitive involvement and attention. This explanation is consistent with the finding that MDMA impaired total reaction time mainly because of an increase in decision time. MDMA induced esophoria in the Maddox wing, a finding opposed to the effect of sedatives, which generally produce a clear-cut exophoria caused by extraocular musculature relaxation. In contrast, cocaine did not produce changes in this test.A possible explanation could be related to an alteration of accommodation due to mydriasis or sympathomimetic activation. Hormones. In relation to the neuroendocrine effects, MDMA produced significant increases in plasma cortisol and prolactin concentrations. The lack of global dif- ferences between MDMA doses of 100 and 125 mg, even if different sets of subjects are compared, suggest that a plateau in the rise of cortisol and prolactin concentrations is reached. Intermediate responses as demonstrated with the MDMA 75 mg dose are possible. These results are consistent with previous studies where increases in ACTH and prolactin concentrations were reported after use of 0.75-1 mg/kg of MDMA.Although cortisol increases are consistent with activation of serotonergic neurotransmission, dopaminergic and noradrenergic mechanisms may also be involved. Prolactin secretion is mainly mediated by dopaminergic and serotonergic systems. In humans, MDEA also increases cortisol and prolactin plasma concentrations.MDMA and metabolites pharmacokinetics. To our knowledge, this is the first complete description of the pharmacokinetics of MDMA and its metabolites after its administration to a considerable number of subjects in the range of doses used for recreational purposes. Previous reports described mainly MDMA and MDA pharmacokinetic parameters. The t max was attained at 2 h, a result similar to that reported by Helmlin et al.and Verebey et al.,although it was reached at 4 h in the study of Henry et al.Peak concentrations, taking into account the proportions between doses, are also in agreement with the mentioned previous findings. The elimination half-life of MDMA 100 mg was about 8-9 h, similar to that reported after 50, 75, and 125 mg. These values are lower than those reported for methamphetamine (10-12 h) or amphetamine (12-15 h). ABBREVIATIONS: C max = peak plasma concentration; t max = time of peak plasma concentration; AUC 0-24 = area under the curve from 0 to 24 h; AUC total = area under the curve from 0 to infinite; k a = absorption constant; k e = elimination constant; t ½a = absorption half-life; t ½ = elimination half-life. a Not calculated for MDA. b Formation constant rate in the case of MDA, HMMA or HMA. c Formation half-life in the case of MDA, HMMA, or HMA. A possible nonlinear pharmacokinetics of MDMA has been suggested when considering together the present results and those of the pilot studies and controlled ones at doses of 75 and 125 mg. After the administration of 150 mg to two volunteers, a disproportional increase in MDMA plasma concentrations was observed.Several mechanisms have been proposed to explain the nonlinear kinetics of MDMA and include either a simple saturation of drug metabolism or the formation of a complex between a metabolite and the enzyme.The MDMA nonlinear kinetics should be confirmed in studies with a design specifically addressing this issue. MDA, formed by N-demethylation of MDMA, appears to be a minor metabolite, representing 8-9% of the concentrations of MDMA (AUC comparisons) for all the doses tested. This finding is further supported by the fact that MDA urinary recovery is about 1% of the dose administered, while for methamphetamine the N-demethylated product (amphetamine) is about 10%. HMMA is the main metabolite of MDMA either in plasma or in urine. Plasma concentrations observed are quite similar to those corresponding to MDMA. Interestingly, this metabolite is close to the detection limit when analyzed in its free form, being necessary an enzymatic hydrolysis of the plasma samples for its determination. Urinary recovery of this metabolite at a dose of 100 mg is about 13-14% of the dose in 24 h, while MDMA recovery is 24%. Higher recoveries are observed with lower MDMA doses while the contrary is observed at higher doses. These findings are consistent with the nonlinear pharmackinetics phenomenon described for MD-MA. Body clearance of HMMA is a little longer than that described for MDMA, as the estimated elimination half-life is about 11 h. HMA is a minor MDMA metabolite; AUC 0-24 h is similar to the one observed for MDA, its metabolic precursor. The same observation is applicable to MDMA and HMMA. Urinary recovery of this metabolite is very low, about 1.5% of the dose in 24 h. Its elimination half-life presented in TABLE 3 is probably overestimated, and addtional samples should be collected after 24 h for a better estimate. In the analytical conditions applied for the determination of MDMA and its metabolites, intermediate metabolic products dihydroxymethamphetamine (HHMA) and dihydroxyamphetamine (HHA) are not detected in plasma and only at very low concentrations in urine. Both metabolic products are very unstable and can be either rapidly further metabolized by the catechol-methyltransferase, observing in biological fluids only the final product HMMA or HMA; or analytical conditions should be improved for a better determination. In any case, the analysis of these inetrmediate metabolites deserves further research in the light of the complexity of MDMA metabolism. The time course of blood concentrations of MDMA and its pharmacological effects rise and fall with a similar profile. Drug concentrations increased, and parallel increases in physiologic and hormonal measures were observed. Both peak concentrations and peak effects were obtained between 1 and 2 h and decreased to return to baseline values 4-6 h after drug administration. In summary, MDMA given at recreational doses produced mydriasis and marked increases in blood pressure, heart rate, and plasma cortisol and prolactin concentrations. Its elimination half-life was about 8-9 h. According to these findings obtained in the laboratory setting, MDMA consumption in crowded conditions, high ambient temperature, and physical activity ("rave parties") may be associated with a potential life-threatening increase in the toxicity of the drug.
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Montgomery, C., Roberts, C. A. · Experimental Neurology (2021)
Mithoefer, M. C., Feduccia, A. A., Jerome, L. et al. · Psychopharmacology (2019)
Baggott, M. J., Garrison, K. J., Coyle, J. R. et al. · Journal of Psychoactive Drugs (2019)
Wagner, A. C., Mithoefer, M. C., Mithoefer, A. T. et al. · Journal of Psychoactive Drugs (2019)
Dunlap, L. E., Andrews, A. M. · ACS Chemical Neuroscience (2018)
Feduccia, A. A., Mithoefer, M. C. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2018)
Papaseit, E., Torrens, M., Pérez-Mañá, C. et al. · Expert Opinion on Drug Metabolism and Toxicology (2018)
Nichols, D. E. · Journal of Psychopharmacology (2017)
Dolder, P. C., Müller, F., Schmid, Y. et al. · Psychopharmacology (2017)
Bershad, A. K., Miller, M. A., De Wit, H. · Psychopharmacology (2017)
Vizeli, P., Liechti, M. E. · Journal of Psychopharmacology (2017)
Papaseit, E., Pérez-Mañá, C., Mateus, J. A. et al. · Neuropsychopharmacology (2016)
Frye, C. G., Wardle, M. C., Norman, G. J. et al. · Pharmacology Biochemistry and Behavior (2014)
Riba, J., Valle, M., Urbano, G. et al. · Journal of Pharmacology and Experimental Therapeutics (2003)