Chiral Pharmacokinetics of MDMA and its Phase I and II Metabolites following Controlled Administration (2015)

Damn, I never thought to consider the stereoselective nature of the metabolism! This is an interesting statement from the paper:

The elimination half-life and AUC could not be determined for R-MDA as the terminal elimination phase was not reached within the 24 hours of sample collection.

So R-MDA remains in the system a lot longer than I even thought.

Median times of first detection for MDMA, DHMA 3-sulfate, DHMA 4-sulfate, HMMA sulfate and HMMA glucuronide were 0.33 h for both R- and S- stereoisomers. Only MDA was detected considerably later with median values of 0.8 and 0.7 h for R- and S-MDA, respective

So so the detection of MDA is considerably later than the other metabolites, as would be expected. As the primary CYP2D6 metabolic pathway is saturated, more gets metabolized by the secondary N-demthylation pathway. This fits with the idea that re-dosing increases the likelihood of damage more than the initial dose, as more of the metabolism will lead to MDA. That is consistent with other studies I have seen.

After 24 h both stereoisomers of MDMA and of all metabolites were still detectable.

That jives with other research I have seen, which is why it is crucial to try an increase urinary acidity at the end of the roll, to excrete as much MDMA unchanged, before it can metabolize.

MDA had the longest tmax of all metabolites analyzed, being significantly shorter for S-MDA compared to R-MDA... These findings are in line with the chiral pharmacokinetic analysis showing higher Cmax for the S-stereoisomer of MDA, DHMA 3-sulfate and HMMA glucuronide, higher Cmax for R-MDMA and R-DHMA 4-sulfate and no significant difference in HMMA sulfate

So R-MDA had the longest time at peak plasma levels than an other metabolite analyzed, but S-MDA had higher peak plasma levels than R-MDA, just for a shorter time period. In contrast, R-MDMA had a higher peak plasma level than S-MDMA, due to a faster metabolism by O-demethylation from CYP2D6.

All this is pretty damn interesting! If my theory is correct, and much of the damage is happening due to the MDA metabolites, that means that most of the oxidative damage is happening after the roll is already finished. Since it takes time for the MDA levels to reach peak levels, the damaging N-demethylated metabolites are being formed well into the next day and longer. Of course I could be wrong about everything. However, we know a dose of MDA leads to much more damage than the same dose of MDMA. Since we are pretty sure the damage is metabolite related, then it would stand to reason that much of the damage from MDMA is a delayed metabolic effect from MDA. I would love to see another study looking into just the N-demethylated metabolites of MDA, and see how long those are in the body.