Comment · Sat, October 10, 2015
Chiral Pharmacokinetics of MDMA and its Phase I and II Metabolites following Controlled Administration (2015)
What they were answering
MBaggott · 1 points
Yes, we have strong reasons to think that both MDMA and MDA are bioenergetic stressors and I find it plausible that this stress becomes directly toxic with high exposures.
I don't have a strong opinion on the relative toxicity of MDMA vs MDA (haven't reviewed the small literature recently, but mg doses would be an unfair comparison, and greater toxicity from MDA could be driven by greater hyperthermia, which isn't relevant in all human settings). I also don't think there's evidence typical human doses of MDMA lead to toxicologically relevant exposures to MDA.
I do think dihydroxy metabolites of MDMA and MDA are reactive and thus potentially toxic. And I accept that specific conjugates may be particularly toxic (tho Melanie Mueller didn't see much toxicity from 5-NAC-HHMA and what she did see was not blockable with fluoxetine).
But I don't see strong evidence the dihydroxy metabolites or their conjugates play a major role in MDMA's serotonergic toxicity. MDMA neurotoxicity is dose-dependent in the rat, while DHMA formation seems relatively dose-independent (Conchiero et al 2014, suggesting DHA would be too). MDMA neurotoxicity has been correlated with MDMA plasma levels but not DHMA.
I'd be happy to have my skepticism resolved, even if I am wrong about all this. Here's what would convince me: if someone injected a low neurotoxic dose of MDMA both with and without th…
u/MisterYouAreSoDumb
That would be a very interesting study to see. I am certainly willing to consider my theory is incorrect as well.
This is the study that showed MDA was significantly more neurotoxic than MDMA. It's not in humans, though.
MDMA (5 mg kg-1, i.p.) was without effect on brain 5-HT content. content. A single dose of MDA (5 mg kg-1, i.p.) produced a major (approximately 40%) loss of 5-HT content of cortex and hippocampus 7 days later.
So a 5mg/kg dose of MDMA did not lead to a loss of 5-HT content, but a 5mg/kg dose of MDA caused a 40% loss.
Here is another study that had to lower the MDA dose compared to MDMA and other metabolites, because the mortality rate of the rats was too high. They postulate that is because of the higher dopamine release, though.
Taken together, MDMA, N-Me-Alpha-MeDA, and Alpha-MeDA were shown to be neurotoxic in a concentration-, temperature-, and time-dependent manner. These metabolites are more neurotoxic than the parent compound MDMA, with 5-GSH-Alpha-MeDA being the most toxic.
So they showed the glutathione conjugated metabolite of MDA to be the most neurotoxic of the bunch. That would jive with my theory that MDA metabolism is the biggest cause of 5-HT system damage, and explain why studies have shown equivalent dosages of MDA to be more neurotoxic than MDMA.
Just look at how much lower the 5-HT content is after exposure to the metabolites than MDMA.
This study shows that 8-9% of an MDMA dose is metabolized to MDA in humans. Given the other study showing 40% loss in 5-HT content after exposure to MDA, but none when exposed to the same amount of MDMA, it would seem that 8-9% could be enough to be leading to the bulk of the serotonin system damage seen after MDMA exposure.
What are your thoughts?