Non-linear pharmacokinetics of MDMA ('ecstasy') in humans

Aims 3,4-Methylenedioxymethamphetamine (ME)MA, commonly called ecstasy) is a synthetic compound increasingly popular as a recreational drug. Little is known about its pharmacology, including its metabolism and pharmacokinetic s, 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 receiv ed 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 CY P2D6 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 o f MDMA pharmacokinetics. Body fluids were analysed for the determination of MDMA and its main metabolites 3,4-methylenedioxyamphetamine (MDA), 4-hydro xy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HM A). Results As the dose of MDMA administered was increased, volunteers showed r ises in MDMA concentrations that did not follow the same proportionality wh ich could be indicative of nonlinearity. In the full range of doses tested the constant recovery of HMMA in the urine combined with the increasing ME) MA recovery seems to point towards a saturation or an inhibition of MDMA me tabolism (the demethylenation step). These observations are further support ed by the fact that urinary clearance was rather constant while nonrenal cl earance 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 becaus e the drug would accumulate in the body instead of being metabolized and in activated. The lack of linearity of MDMA pharmacokinetics (in a window of d oses compatible with its recreational use) is a more general phenomenon as it concerns the whole population independent of their CYP2D6 genotype. It i mplies that relatively small increases in the dose of MDMA ingested are tra nslated to disproportionate rises in MDMA plasma concentrations and hence s ubjects are more prone to develop acute toxicity.