Non‐linear pharmacokinetics of MDMA (‘ecstasy’) in humans

Abstract

Aims 3,4-Methylenedioxymethamphetamine (MDMA, commonly called ecstasy) is a synthetic compound increasingly popular as a recreational drug. Little is known about its pharmacology, including its metabolism and pharmacokinetics, in humans in controlled settings. A clinical trial was designed for the evaluation of MDMA pharmacological effects and pharmacokinetics in healthy volunteers. Methods A total of 14 subjects were included. In the pilot phase six received MDMA at 50 (n=2), 100 (n=2), and 150 mg (n=2). In the second phase eight received MDMA at both 75 and 125 mg (n=8). Subjects were phenotyped for CYP2D6 activity and were classified as extensive metabolizers for substrates, such as MDMA, whose hepatic metabolism is regulated by this enzyme. Plasma and urine samples were collected throughout the study for the evaluation of MDMA pharmacokinetics. Body fluids were analysed for the determination of MDMA and its main metabolites 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HMA). Results As the dose of MDMA administered was increased, volunteers showed rises in MDMA concentrations that did not follow the same proportionality which could be indicative of nonlinearity. In the full range of doses tested the constant recovery of HMMA in the urine combined with the increasing MDMA recovery seems to point towards a saturation or an inhibition of MDMA metabolism (the demethylenation step). These observations are further supported by the fact that urinary clearance was rather constant while nonrenal clearance was dose dependent. Conclusions It has previously been postulated that individuals genetically deficient for the hepatic enzyme CYP2D6 (about 10% of the Caucasian people) were at risk of developing acute toxicity at moderate doses of MDMA because the drug would accumulate in the body instead of being metabolized and inactivated. The lack of linearity of MDMA pharmacokinetics (in a window of doses compatible with its recreational use) is a more general phenomenon as it concerns the whole population independent of their CYP2D6 genotype. It implies that relatively small increases in the dose of MDMA ingested are translated to disproportionate rises in MDMA plasma concentrations and hence subjects are more prone to develop acute toxicity.

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

“…Several studies suggest a non-linear pharmacokinetic response to MDMA in human, monkey and rat (Kolbrich et al, 2008;de la Torre et al, 2000;Chu et al, 1996;Mueller et al, 2008). There have been a few reports regarding the physical or pharmacological effects resulting from interactions caused by MDMA tablet intake or multi-drug abuse.…”

NONLINEAR ORAL PHARMACOKINETICS OF THE Α-Antagonist 4-Amino-5-(4-Fluorophenyl)-6,7-Dimethoxy-2-[4-(Morpholinocarbonyl)-Perhydro-1,4-Diazepin-1-Yl]quinoline IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS

“…Such behavior complicates drug therapy due to extensive variability in exposure, which may lead to variable efficacy and narrow therapeutic window over potential adverse events. Indeed, nonlinear oral pharmacokinetics, within the commonly used dose range, of the recreational drug "ecstasy" are thought to result in cases of acute toxicity (De La Torre et al, 2000). A confident prediction of nonlinear oral pharmacokinetics before clinical studies would substantially reduce the time and research investment involved in getting a drug candidate from discovery through to the market and ultimately contribute to the development of safer drugs.…”

MDMA and MDA Concentrations in Antemortem and Postmortem Specimens in Fatalities Following Hospital Admission

“…The pharmacology of MDMA has been reviewed previously in the literature and indicates MDA concentrations to be significantly lower than the corresponding MDMA concentrations in both plasma and urine (7)(8)(9).…”