MDMA Dose Scaling: The PK Data!

May 08 2009 Published by under Drug Abuse Science, MDMA, Neuropharmacology

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.
Mueller09-Fig1-300px.pngFIGURE 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.

8 responses so far

  • Govt. Bureaucrat says:

    Good stuff, Mr. Monkey. Bravo!

  • Anonymous says:

    Thanks for sharing this! I'm going to read it in detail.

  • A handsome treatment of pharmacokinetics, my fine non-human primate friend. I may have said this elsewhere at DM but toxicologists generally start with other species-to-human dose scaling factors of 7 for rats and 12 for mice (e.g. 12 mg/kg in a mouse to approximate a 1 mg/kg human dose). However, these are imperfect and always require that the actual PK experiments be done, as you have illustrated here.
    But this is a terrific example of what PK parameters are most important. That humans and squirrel monkeys have similar peak plasma concentrations is rendered less important by the more than two-fold higher AUC in humans. Here we see that the peak plasma concentrations are influenced primarily by differences in weight vs. surface area whereas the AUC is (probably) influenced primarily by the squirrel monkey's more rapid clearance of the drug, whether hepatic, renal or other local tissue metabolism (it's a dirty combo of demethylenylation, N-dealkylation, deamination, oxidation, methylation by catechol-O-methyltransferase, and glucuronide-, sulfate-, and glycine-conjugation).
    Getting back to other differences even within a given species is that the initial, non-conjugative metabolism of MDMA is mediated by CYP2D6, a notoriously polymorphic enzyme. In humans, there are significant interethnic differences in 2D6 activity: ~75 allelic variations that are grouped into four phenotypes: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). (nice free full-text review, albeit in the oncology setting, by CYP clinical pharm guru David Flockhart and colleagues.)
    So, if there is toxicity in humans, it is important to consider whether the parent MDMA or any number of its metabolites are neurotoxic and whether there are correlations of toxicity with individuals any of the four phenotypes. As if that is not complicated enough, the methylenedioxy group (the MD of MDMA) is notorious for mechanism-based inhibition of P450 activities and I'm having trouble thinking of whether this would be have more or less influence on a poor or ultra-rapid metabolizing individual. This is making my head hurt.
    So, while I'm glad that I don't work in this area, I think there remain tremendously complex questions there for those who do.
    Very nice post, sir.

  • Matt says:

    Every time I see paper like this one, I hope in vain that the researchers will have taken the simple and brave step of modeling a common human MDMA exposure in the animal. Instead of pussyfooting around with interspecies hand waving, it'd be straightforward to determine a dosing regimen for the monkey that imitates both the Cmax and AUC of some oral dose in the human. Then there'd be all kinds of cool studies you could run to compare PD between species. Yeah, there's some issues with metabolites (follow-up studies!), but wouldn't that be much more interesting than repeat presentations of the same ol' human and monkey PK. (Is this paper more than just a re-packaging of their already published data?)

  • John Smith says:

    I’ve been a long time user and fan of MDMA, but I don’t like the negative side effects and health problems that are associated with it; so I was in route for a legal healthier alternative. I tried a lot of legal products on the market, but it was all hype. The closest thing on the market is a product called, "Trip2Night" that can give you similar euphoric effects and lasts around 5 to 6 hours.

  • LetsRoll says:

    What your not putting into the equation is that lab animals are injected with MDMA while humans ingest it, so it loses some of its potency just by stomach ingestion alone. Also why aren't Mercks early reports on their creation available? And what isn't reported is actual cause of death in humans is hyper-hydration. Although true MDMA isn't found too much these days in street level US Distro. You find alot of tabs cut with Meth,MDA etc.

  • TripleG says:

    Because of the non-linear MDMA accumulation and the t1/2 differences it is not 'a simple and brave step of modeling a common human MDMA exposure in the animal'. You also want to keep the stress exposure of the animals to a minimum. The 'ideal' dosis regimen for mimicking human pks in the squirrel monkey is most likely to be far away from that though.
    Lots of animal studies today use per oral administration rather than injection. At least the here mentioned publication by Mueller et al did.
    And DM:
    Did you see that the group found comparable AUCs with 'equivalent' doses (1.6 human and 5.7 in monkey) in both species? Sure, the Cmax was higher in the monkey, but depending on what pk influences the most the pd effect of interest, Ricaurte might not be wildly exaggerating after all....

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