Clinical MDMA Brief (23 Jan 2009)

An interesting contribution to the debate over comparing human MDMA doses to the animal literature (I overviewed part of it here) has been recently supplied by Green and colleagues.

Green AR, Gabrielsson J, Marsden CA, Fone KC. MDMA: On the translation from rodent to human dosing. Psychopharmacology (Berl). 2009 Jan 13. [Epub ahead of print]; DOI: 10.1007/s00213-008-1453-8

For some background on why this is important as a topic of discussion, see these posts and especially this one.

Figure 1 from the Commentary draws from previously published data to compare peak blood levels of MDMA observed after a given dose (represented in milligrams of drug to kilograms of bodyweight; mg/kg) in humans and several rat species. The inset is a blowup of the human data all from oral administration studies. The rat data were more varied:

The rat studies used oral, intraperitoneal and subcutaneous routes of administration and three different strains (Wistar, Sprague-Dawley, and Dark Agouti). However, despite the varied routes of administration and various strains of rat used, the peak plasma concentration (taken as occurring within 1-3 h postadministration) at any one dose was similar across the studies, and it was, therefore, considered reasonable to use a mean value obtained from all studies that used the same administered dose.

The authors suggest that these direct pharmacokinetic data are supportive* more of the species-scaling approach then they are of the simplistic mg/kg approach when it comes to comparing approximately equivalent exposure to drug between the species. (An accompanying letter from the de la Torre group that has generated most of the available human MDMA pharmacokinetic data endorsed the conclusions.)
Yup, too true.
Now this does not in and of itself say much about any particular toxic endpoint of interest, from serotonin disruptions to emergency medical problems and death. This comparison does, however, give a bit more of a flavor for why I disagree with those nutters who try to dismiss the animal science by talking about the mg/kg doses as if they were directly comparable between rats and humans. As the authors put it, such a positions “is naive and with no credibility”. A nicer, albeit considerably less entertaining, way to make the point than putting in a picture of a teddy bear on a bathroom fixture, don’t you think?
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*It’s a short Commentary so, really, I’d feel like I was flirting with the line on fair use if I gave away their line of explanation.