Comment · Fri, October 9, 2015
Chiral Pharmacokinetics of MDMA and its Phase I and II Metabolites following Controlled Administration (2015)
What they were answering
MBaggott · 3 points
It's not so much that MDA remains in the system, but that it continues to form. If you were to measure MDA kinetics on its own, it'd have a half life of around 11 h. But here it's still forming from MDMA (probably mostly via 2B6 and 1A2) as it's being eliminated, so it's hard to get a fix on.
I continue to be extremely skeptical of the metabolite theory of toxicity, partly because it's not clear to me how this theory explains the failure of alpha-methyl-dopamine and N-methyl-alpha-methyl-dopamine to have neurotoxicity.
In rats, the oxidative stress begins really quickly after MDMA. For example, we know the extracellular measures of oxidative stress are elevated in rats within 1 hr of MDMA administration. We also know that TPH begins to get oxidatively deactivated within 15 min of subcutaneous MDMA administration to rats. It even happens with infusion of MDMA into the brain, where you expect the MDMA to be draining into the larger peripheral pool as you give it and only minimally metabolizing in the brain. This oxidative stress seems to me unlikely to be entirely due to metabolites. My reading, and that of many other researchers, is that MDMA itself likely produces substantial oxidative stress that, when prolonged, can lead to structural damage and/or changes in gene expression.
u/MisterYouAreSoDumb
How do you explain the studies that show MDMA injected directly into the brains of rats does not show the same level of neurotoxicity as peripherally administered MDMA? The metabolites have to be a major part of it. 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine is a conjugated form of α-Me-DA that has shown to pass the blood brain barrier, and lead to the same neurotoxicity that MDMA shows.