Comment · Thu, September 5, 2013
Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 2h apart.
What they were answering
zeekip · 1 points
Following the repeated doses, plasma concentrations of MDMA were higher than those expected by simple dose accumulation (+16.2 % AUC; +12.8 % C max), but those of HMMA and HMA were significantly lower (−29.8 % AUC; −38.2 % C max).
What ? I always though redosing was worse for you. Or am I misreading something here ? Lower plasma concentrations of HMMA and HMA doesn't sound bad at all.
u/MisterYouAreSoDumb
Re-dosing is worse for you, because the N-demethylated metabolites are much more damaging than their N-methylated counterparts. Since MDMA has non-linear pharmacodynamics, the whole re-dosing issue is complicated. The initial dose of MDMA inhibits CYP2D6. This means that more of your initial dose is going to be metabolized by the secondary pathway, CYP3A4. This is going to create MDA. Then once the self-inhibition wears off later in the roll, the MDA will be O-demethylated by CYP2D6 into HHA. HHA will then conjugate with gluthatione, pass the blood brain barrier, and damage 5-HT neurons.
Yes, lower plasma concentrations of HMMA and HMA is ideal, but not if you don't inhibit the secondary pathway, CYP3A4. Ideally you would inhibit all metabolism. However, even if you completely inhibited both CYP2D6 and CYP3A4, you would still have ring-hydroxylation to deal with. Since MDA's ring-hydroxylated metabolite THA is more damaging than THM, at least you would have much less than if you left CYP3A4 intact.
http://www.reddit.com/r/DrugNerds/comments/13lp0b/mdma_neurotoxicity_part_1_metabolites/