MDMA: On the translation from rodent to human dosing

Abstract

The recent paper in this journal by Goni-Allo et al. (2008) was a welcome addition to the literature on the effects of MDMA in rodents because it examined functional changes and related them to the systemic exposure (e.g., plasma concentrations) of the drug. Such pharmacodynamic– pharmacokinetic (or quantitative pharmacology) studies are vital if we are to attempt to relate preclinical findings to the possible acute and long-term consequences of human ingestion of MDMA. The debate on whether preclinical findings on the serotonergic neurotoxicity induced by MDMA in the rodent brain can be extrapolated to human recreational usage has engaged scientists’ minds for around 20 years. Concerns have been raised as to whether the administered dose of MDMA typically used to cause neurotoxicity in rats allows any translational projections to be made as to the doses required to produce similar damage in the brains of humans following recreational use of the drug. These concerns are discussed in this short article. In order to extrapolate doses used in animal studies to those in man it has been suggested by some (McCann and Ricaurte 2001) that the technique of interspecies scaling (Mordenti and Chappell 1989) should be used. Based on similar exposure (AUC, Css) to MDMA in rats and humans, this proposes that using the equation Dhuman1⁄4Danimal Whuman=Wanimal ð Þ (where D is dose in milligram and W is weight in kilogram) allows calculation of equivalent doses in animals and humans. Accordingly, the dose of 20 mg/kg in rats becomes equivalent to a human dose of 280 mg (4 mg/kg) or somewhat over three ecstasy tablets. Other investigators (Sessa and Nutt 2008) have intimated that a dose of (for example) 20 mg/kg given by intraperitoneal injection to rats can be directly extrapolated and therefore proposed that a similar oral dose is required by human users to achieve a similar effect. So, a 20 mg/kg dose in rats is deemed “equivalent” to a 1,400 mg dose (20 mg/kg× 70 kg body weight) which is around 20 ecstasy tablets. Of course, neither of these approaches has been shown to be valid for MDMA. Furthermore, the common practice of relating the pharmacological response directly to the administered dose is basically flawed. In examining the pharmacodynamics of a specific compound, factors like bioavailability, active metabolites, plasma protein binding differences, and pattern of systemic exposure can all play a major role in determining the onset, intensity, and duration of final effect. Since the exposure patterns of MDMA and active metabolite(s) can vary markedly between species, they confound any simple interpretation on a drug effect at any specific dose in one species producing a quantitatively similar effect in another, since it is impossible for all of the administered substance (at any stated dose) to be responsible for the observed pharmacological effect. For intelligent interpretation of any data collected, it is important at the very least to have a measurement of “exposure” of parent and potentially active metabolites and by that we mean the AUC or average concentration within a dosing interval or the peak plasma concentration that occurs following drug administration. Ideally, this means the unbound plasma concentration. This still fails to take into account the half-life of the drug, plasma protein binding (which can even change with plasma drug concentration in the same species), and the pharmacological action of active Psychopharmacology (2009) 204:375–378 DOI 10.1007/s00213-008-1453-8