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 · 1 points
Most studies putting MDMA into the brain have kinetic difficulties. The brain is a small compartment compared to the rest of the body and the drug will distribute into the body. So you get higher concentrations where you administer the drug into the ventricles (or wherever), but they drop in space and time. The oxidative stress theory predicts long term changes only after the animal's antioxidant defenses are exhausted. This takes hours with a peripheral dose (and is helped by hyperthermia) and probably takes much longer with a central infusion, since you're not causing as widely distributed a stressor. My guess is you would eventually get toxicity with longer icv infusions.
Metabolites might still play a role of course. And even if metabolites played no direct role in toxicity, one would predict that their presence would prolong the presence of MDMA.
On the other hand, with the toxic metabolite theory, one would predict that presence of the parent drug and other metabolites would tend to be protective. Has anyone shown that conjugate still gets into the brain and is still toxic in the presence of much higher concentrations of these other compounds? I don't think so.
Now it's your turn to answer my previous question. Why isn't alpha-methyl-dopamine neurotoxic or, for that matter, the prescription drug Aldomet (methyl-dopa), which has alpha-methyl-dopamine as a metab…
u/MisterYouAreSoDumb
Why isn't alpha-methyl-dopamine neurotoxic or, for that matter, the prescription drug Aldomet (methyl-dopa), which has alpha-methyl-dopamine as a metabolite?
That I don't know. We know the glutathione conjugate of it is. As to why that conjugate does not form when you take alpha-methyl-dopamine or Aldomet directly, I have no answer.
So your theory is that MDMA itself is neurotoxic, and that the metabolites are ancillary to the damage? So in that case, MDA itself is directly neurotoxic as well, since it shows even more damage dose-for-dose than MDMA. To prove that, I suppose you would need to do longer icv infusions, and perhaps raise their body temperatures.