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

All said and done, I think the possible role of metabolites is an interesting possibility, but it's just a possibility. If it is wrong, speculative harm reduction attempts to decrease metabolites may be instead increasing neurotoxicity.

Taking out the grapefruit juice from the supplementation equation leaves us with antioxidants, flavonoids, membrane stabilizers, and magnesium. Even leaving it in, GFJ is a fairly poor CYP inhibitor, and mostly limited to the GI tract, rather than liver. The bulk of the supplementation is dealing with antioxidants to bind to any of the oxidative substances, whether they be metabolites or other compounds, and magnesium to help curb excitotoxicity. The GFJ can be left out of the equation entirely, and the regimen would still provide protection, regardless of the metabolite theory being correct or not. I think that anyone can agree that taking antioxidants and magnesium is probably a good idea when taking a substance that is known to cause oxidative stress and excitotoxicity.

Not sure why you're arguing with me about the second paper you cited. I said it doesn't compare neurotoxicity of MDA and MDMA and it doesn't. You lose credibility when you counter factual statements (about whether neurotoxicity was compared with irrelevant ones (about whether MDMA was used in the paper).

I brought it up simply for the following statement:

As a positive control, another group of animals received MDA, but a slightly lower dose was used (2 x 3 mg/kg/day, 4 consecutive days) due to a high rate of mortality among the MDA-treated animals given the higher dose.

You are right that it does not directly compare MDA's neurotoxicity to MDMA. It actually does not directly measure the neurotoxicity of any of the compounds. They are testing for 5-HT and DA release, and comparing the results. However, it does have some good discussion on it. I also found the high mortality rate among MDA-treated rats to be relevant to the point I was making about MDA being more toxic in general.

Here's an argument for a lack of importance of MDA formation: MDA has kinetics that are fairly similar to MDMA. A psychoactive MDA dose in a human or rat (say 1.4 mg/kg) would produce plasma concentrations that are ballpark ~200 ng/mL not the ~15 ng/mL we're seeing here. And that ~200 ng/mL exposure isn't neurotoxic in a rat. Science has tons of experience giving rats MDA doses of ~2.5 mg/kg without toxicity (Ricaurte's first paper gave it repeatedly without any toxicity).

5mg/kg in rats was where they started seeing 5-HT system damage. Would we not then correct it for allometric scaling to humans, to get a more accurate picture? That would be roughly .8mg/kg in humans, or a 65mg dose for my body weight, if we used the 5x6/37 basic scaling equation.

You and I are both in agreement that more research is necessary to determine the exact cause of 5-HT system damage after MDMA use. However, I know that people are going to use MDMA regardless, and there was a notion that it was not neurotoxic at all. People were constantly saying that MDMA was perfectly safe in humans, which benefited nobody. The supplement regimen that I promote is based around things that have been proven to help mitigate MDMA-induced neurotoxicity, like Alpha Lipoic Acid, Acetyl-L-Carnitine, Vitamin C, CoQ10. The GFJ is ancillary, and can be dropped. Most people are deficient in magnesium as it is. So it is good to have that in there, to help regulate the NMDA channels.