Comment · Sat, October 10, 2015
Chiral Pharmacokinetics of MDMA and its Phase I and II Metabolites following Controlled Administration (2015)
What they were answering
MBaggott · 1 points
You seem to be mixing three issues: serotonergic neurotoxicity, acute lethality, and classical neurotoxicity. However, the first issue is the one we were discussing.
The first study is relevant to serotonergic toxicity, although Dark Agouti are an odd rat strain. We should collect more of those studies and look at them together. Another one would be Donna Stone's paper that found MDMA and MDA to be pretty comparable.
The second study doesn't compare the neurotoxicity of MDMA to MDA. It compares MDA to some other analogs. So it isn't really relevant for the MDMA vs MDA serotonergic neurotoxicity issue.
The third study is one of cell death in vitro and again isn't relevant because it isn't studying the serotonergic neurotoxicity we're concerned about. Also those concentrations are really high and aren't reached in vivo.
The fourth review paper doesn't show 8-9% of the MDMA is metabolized to MDA; it states the exposure in the blood to MDA is 8-9% of the exposure in the blood to MDMA. But that exposure to MDMA does not represent the full administered dose since some is already metabolized and not all is necessarily absorbed. It is probably closer to 3% of the administered dose becoming MDA in this dataset (they recover 2.85% of the dose in urine as MDA + DHA). And an AUC comparison ignores the absolute concentrations…
u/MisterYouAreSoDumb
True, I was kind of jumping back and forth between 5-HT system damage and apoptotic death. They do seem closely linked, though. That study showed that the apoptosis was dependent on 5-HT2A activation. Perhaps I am making connections where there are none.
The second study certainly does investigate both enantiomers of MDMA, along with MDA and the other analogs. MDMA is in their materials and methods.
(+)DOM, (-)DOM,( - )MDA, ( + )MDA, ( + )MDMA, ( - )MDMA, (~ )MDE, d-methamphetamine, (+-)fenfluramine, (+-)para-chloroamphetamine
The third study is investigating cell death. It still seems relevant to the overall picture of toxicity, and the relative damage each compound causes. It might not be useful for finding the exact cause of 5-HT system damage. However, it does show that the metabolites are more neurotoxic when looking at direct exposure.
Yeah, the 4th study does not say 8-9% of the dose is metabolized to MDA. However, the AUC being 8-9% of the AUC of MDMA still seems relevant, doesn't it? If the bulk of the damage is being caused by the toxic metabolites of MDA, that study shows in humans that pathway is leading to measureable amounts of it.