Comment · Thu, November 22, 2012
MDMA Neurotoxicity Part 1 (Metabolites)
Original post in this thread
MisterYouAreSoDumb · 77 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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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.
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What they were answering
Toodlum · 3 points
Good post.
Not sure if you were trying to put it in layman's terms, but alpha-methyldopamine itself is not implicated in neurotoxicity.¹ Rather, it is alpha-methyldopamine's conjugation with glutathione that produces the neurotoxic 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine. This was mentioned in one of the studies you linked, but I didn't see it mentioned in your write-up.
I look forward to reading your future posts.
u/MisterYouAreSoDumb
I thought digging deeper into the exact mechanism of HHA's involvement in neurotoxocity would confuse some people, as well as make my wall of text even larger. I figured those interested enough would find that info very quickly using my sources. It was in a few of them I believe. There are also other sources for reactive oxygen species, as well as conditions that exacerbate the issue that I did not mention.
There is also a whole other mechanism for metabolism, ring hydroxylation, that I did not discuss.
There are implications to this as well.