One of the fondest arguments of the MDMA/Ecstasy fan is that the doses used in animal studies are so large as to invalidate predictions or inferences about human health concerns. This most usually comes up in the long standing literature demonstrating lasting reductions in markers for serotonergic neuron function associated with MDMA. In such studies, doses of 5-10 mg/kg (monkeys) or 10-20 mg/kg (rats) are reasonably common; the regimen is often twice per day for 4 days in a row. The chronicity is debatable and indeed shorter regimens can produce significant effects, but that is a topic for another day because the complaints focus on the individual dose levels as well.
But this argument also arises when trying to figure out why three teens have died after consuming Ecstasy tablets, particularly when a medical doctor issues an opinion that it is unlikely to be 3,4-methylenedioxymethamphetamine which is at fault.
It breaks down to "Oh, c'mon! Nobody takes 5 or 10 mg/kg of Ecstasy". The defense is based on a Pharmacology 101 concept that mg of drug per kg of bodyweight is very rough in estimating realistic drug exposure across species. Better to use a complex scaling equation, based on empirical data, that takes into account species-typical differences in drug distribution and metabolism. I overviewed the initial foofraw over the dose-scaling argument that has been subsequently used repeatedly by Ricaurte in defense of his dose selection. Although I also buy the notion that dose-scaling based on species size (mass to surface area, more or less) is important and meaningful... there are caveats to keep in mind.
It is worth recognizing here that most comparisons of dose / exposure to a drug are estimates. Differences in human body size means that human clinical prescriptions (including OTC recommendations) for a fixed mg dose of drug only get in the ballpark. Differences in individual metabolic and other within-species factors mean that using a mg dose per kg bodyweight approach is still only an approximation. Differences in the way two species metabolize different classes of compounds may mean that a dose-scaling equation such as described above holds true for certain types of drugs but not others!
Ultimately, additional data are required to resolve a tight threshold question such as "Is 1.7 mg/kg MDMA likely to cause lasting damage?".
I mentioned the Green et al., 2009 review/synthesis paper which compared MDMA pharmacokinetic (PK) between rat and human here. This was an initial bite on the species scaling question and the data supported the notion that for equivalent mg/kg amounts of drug, humans had much higher peak plasma concentrations compared with rats. There were a lot of limitations to this study including the indirect comparison of previously published data and the differences in route of administration.
A new paper from Mueller et al goes a very long way towards addressing such concerns.
Direct Comparison of (+/-) 3,4-Methylenedioxymethamphetamine ("Ecstasy") Disposition and Metabolism in Squirrel Monkeys and Humans. Mueller M, Kolbrich EA, Peters FT, Maurer HH, McCann UD, Huestis MA, Ricaurte GA. Ther Drug Monit. 2009 Apr 22. [Epub ahead of print]
The paper compared blood levels of MDMA and its major metabolites in humans and squirrel monkeys after oral dosing with MDMA. It is a very comprehensive look at the question, involving multiple doses and a reasonable time-course series as well as the analysis of metabolites.
FIGURE 1. Pharmacokinetic parameters [peak plasma concentration (Cmax), AUC, time of peak plasma concentration (Tmax), and half-life (T1/2)] of MDMA in humans and squirrel monkeys receiving single oral doses of MDMA producing comparable peak concentrations. Dose of MDMA in humans was 1.6 mg/kg; absolute dose of MDMA in the squirrel monkey was 2.8 mg/kg, which translates to a human equivalent dose of 0.8 mg/kg, after interspecies dose scaling (see Materials and Methods for interspecies dose-scaling procedure). Values shown are the mean 6 SD. n = 9 for humans and 6 for squirrel monkeys. *Significant difference between the 2 species (P , 0.05, Student t test).
One of the most important results is here in Figure 1 wherein we see some direct support for the general idea of species-scaling. The peak plasma concentration observed in humans after 1.6 mg/kg (255 ng/ml) was similar (see both stats and the SD error bars) to that observed in squirrel monkeys (313 ng/ml) after 2.8 mg/kg. Wait, but Ricaurte's favored equation suggests an equivalency of 1.6 mg/kg in humans with 5.7 mg/kg in squirrel monkeys...aha, he's proved himself guilty of wild exaggeration!!
Not so fast my friends, the story continues...
Notice that once you get past the time of the human peak (2.4 hrs) concentration of MDMA that levels in human stay higher for much, much longer than in squirrel monkeys? Notice the Area Under the concentration-time Curve value (AUC in the table)? This reminds us that we need to be careful about understanding what pharmacological properties of a drug might be most relevant to our result of interest. The peak concentration might be relevant to one thing (say, subjective 'high') while the relationship between peak and duration of sub-peak exposure may be related to other outcomes (say, liver damage).
Figure 2 of the paper (which I'm not reproducing here) shows that to get an AUC value equivalent to the human one after 1.6 mg/kg you need to give a squirrel monkey 5.7 mg/kg. In which case you get that peak plasma level up to 723.6 ng/ml, in this case significantly higher than the peak plasma seen in the humans after 1.6 mg/kg.
So let us return to our recent discussion on the potential of oral MDMA to cause death in the recreational user. We don't know, of course, which pharmacological parameters might be most important as our rule of thumb because we don't really understand the mechanisms behind various outcomes in humans that clearly. Taking the medical emergency/death outcome, it is very hard to establish the time of crisis relative to original consumption from the case reports. In humans who might show the clearest evidence of lasting serotonin disruptions, it is difficult to go back and ask if it was one or more high-dose long weekends or a single over-the-top day or a sustained history of low-dose consumption that was the critical factor.
For the present data set, however, the predictions go in the same direction it is just a difference of degree. Whether 2.8 or 5.6 mg/kg (peak versus AUC) is our best squirrel monkey equivalent dose to human outcome after 1.6 mg/kg, they are both larger. Let us recall that 1.6 mg/kg translates to a 50 kg (110 lb) woman consuming only 80 mg of MDMA. This is well within a fairly typical (published) range for the content of a street Ecstasy tablet. Put stacking and boosting practices into the equation and the dose estimate only goes up from there.
These are the kinds of data that we need to keep in mind when we are looking at animal data on lethality.
Remember from Hardman et al, 1973 that the LD50 for intravenous administration in monkey is 22 mg/kg (95% CI 17-28) and in dog 14 mg/kg (8-17). Mechan et al. 2006 used much lower numbers, but a repeated oral dosing (at 3 hr intervals) paradigm pointed to a very similar ~25 mg/kg (cumulative) LD50. ... The second issue we need to think about is that LD50 is the dose that is lethal for half of the subject population. But we are not talking detached science here. We are talking about the life of a person here. We are talking outcomes in which the LD10, LD1 or even LD0.01 is important to know.
Also when we are analyzing doses that are being used in human clinical trials of MDMA for PTSD. The 110 lb / 50 kg woman given 125 mg is at a 2.5 mg/kg dose and 3.75 mg/kg cumulative dose if the supplemental is administered. The equivalent numbers for a 220 lb / 100 kg man would be 1.25 and 1.88 mg/kg. The 110 lb / 50 kg woman given 125 mg is at a 2.5 mg/kg dose and 3.75 mg/kg cumulative dose if the supplemental is administered. The equivalent numbers for a 220 lb / 100 kg man would be 1.25 and 1.88 mg/kg.