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 pharmacodynamicpharmacokinetic (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 D human ¼D animal W human =W animal ð Þ 0:7 (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 ...

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

“…Due to rapid MDMA clearance in rats, repeated s.c. injections of low-dose MDMA in this species might be an acceptable model for po doses administered to humans, but this hypothesis needs to be tested. In any case, the present findings do not support the notion that rats must receive 4-fold-higher doses of MDMA to achieve peak plasma concentrations similar to those observed in humans (Green et al, 2009).…”

“…In two rat studies employing doses of ,10 mg/kg, evidence for MDMA nonlinear accumulation was reported (Chu et al, 1996;), similar to the human situation (Mas et al, 1999;de la Torre et al, 2000;Kolbrich et al, 2008b). By contrast, Green et al (2009) and Hirt et al (2010) suggested linear MDMA kinetics in rat.…”

“…Green et al (2009Green et al ( , 2012 compared literature values for plasma MDMA concentrations following highdose MDMA administration in rats (i.e., 5-20 mg/kg via i.p., s.c., or po routes) to those produced by low-dose administration in humans (i.e., 0.5-2 mg/kg po). From this comparison, the authors concluded that MDMA doses in rats must be 4-fold higher than human doses to achieve similar peak plasma MDMA concentrations and that MDMA pharmacokinetics are linear in rats.…”

Serotonin is involved in the psychostimulant and hypothermic effect of 4-methylamphetamine in rats

“…The only information is from an abuser that self-reported use of 4-MA by oral (160 mg) and intramuscular (80-120 mg) route (EMCDDA, 2012). The human equivalent doses of the range used (2.5 -10 mg/Kg) in the present study, although given subcutaneously, are 30 -120 mg [16], which are in agreement with those reported as psychostimulants.…”

Effects of Dose and Route of Administration on Pharmacokinetics of (±)-3,4-Methylenedioxymethamphetamine in the Rat

“…Perhaps the optimal strategy for relating MDMA data from animals to humans is to compare pharmacokinetic parameters across species (de la Green et al, 2009). Clinical investigations have examined plasma concentrations of MDMA and its metabolites after the administration of psychoactive doses (Mas et al, 1999;de la Torre et al, 2000;Kolbrich et al, 2008b), and comparable low-dose experiments have been performed in monkeys (Banks et al, 2007;Mueller et al, 2008).…”