Comment · Fri, November 23, 2012
MDMA Neurotoxicity Part 1 Metabolites)
Original post in this thread
MisterYouAreSoDumb · 129 points
This is probably going to be the first in a series of discussions I start about MDMA. There's just too much information for one post. Therefore, I am going to start with one that is very interesting to me: MDMA's metabolites and their role in neurotoxicity. I pre-appologise for the length and terminology used.
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First off, let's discuss how MDMA is metabolized. The human cytochrome CYP450 is responsible for the metabolism of MDMA. The primary enzyme responsible is CYP2D6, using O-demethylation. This process adds two hydrogen atoms to the two open oxygen atoms in MDMA to create HHMA. Let's look at the structure for a minute.
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MDMA is 3,4-methylenedioxy-N-methylamphetamine
HHMA is 3,4-dihydroxy-N-methylamphetamine
So your CYP2D6 enzyme added two hydrogen atoms to the methylenedioxy structure to create a dihydroxy structure. Once it's been o-demethylated to HHMA, it is no longer active like MDMA is. HHMA can then be 0-methylated further to HMMA, or 4-hydroxy-3-methoxy-N-methylamphetamine. Here is an image to help you visualize this process.
This is…
What they were answering
lol_u_so_kawaii · 1 points
In compering levels of MDMA vs MDA neurotoxicity is this corroborated? Because, as you mention, it seems that MDA could hypothetically be around 90% more neurotoxic. Am I understanding this? Thanks
u/MisterYouAreSoDumb
Yes, MDA is much more neurotoxic to 5-HT neurons.
MDMA (5 mg kg-1, i.p.) was without effect on brain 5-HT 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 dosage of MDMA showed no loss in 5-HT in the brain after 7 days. The same dose of MDA showed a 40% loss! It is significantly more neurotoxic.
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Also from another study:
>Indeed,
5-(N-acetylcystein-S-yl)-R-MeDA is more than 2 orders
of magnitude more potent than 5-(glutathion-S-yl)-RMeDA
(14, 15). Intrastriatal administration of 5-(Nacetylcystein-
S-yl)-R-MeDA, **at a dose as low as 7 nmol,
produces a 50% reduction in striatal 5-HT concentrations**,
approximately equivalent to the effects of 23.25 ímol
MDA (93 ímol/kg s.c. in rats weighing 250 g).
5-(Nacetylcystein- S-yl)-R-MeDA is referring to a conjugate of HHA or alpha-methyldopamine. Remember from my post what creates HHA? Metabolism of MDA. If it were the direct metabolite of MDMA, it would be HHMA, not HHA. So a known product of MDA metabolism, at a very low concentration equivalent to .03% of the MDA dose, caused a 50% decrease in 5-HT. See where my theory makes sense?