Comment · Thu, November 22, 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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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.
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What they were answering
assliquorr · 7 points
A minor caveat: the structure of you post seems to suggest the ~10% figure (source?) you cite for CYP3A4 metabolism is complementary to a similarly precise figure for CYP2D6, which AFAIK, is not the case.
While there is good evidence that CYP2D6 is the primary metabolic pathway for MDMA, hydroxlyation is possible at all 3 ring positions. Interestingly, CYP3A4 inhibition would lead to lower levels of ring-hydroxlated MDA metabolites, which I think (largely due to their similarity to 6-hydroxydopamine) are more likely candidates for neurotoxicity than the corresponding MDMA metabolites.
I think I'll buy some grapefruit juice tomorrow. Thanks.
u/MisterYouAreSoDumb
Yes sir, it's much more complicated than my post alluded to. I did not want to completely lose everyone, since I originally posted in /r/Drugs. I have a feeling that some people are already going to just close the post due to it's size.
You are correct to mention ring hydroxylation. Here is a figure I posted on another comment.
I also have a lot of information on why MDMA induces a lowering of TPH, or tryptophan hydroxylase. This is due to the ring hydroxylated metabolites of MDA called 2,4,5-trihydroxyamphetamine (THA) and 2,4,5-trihydroxy-N_methylamphetamine (THM). Here is the study diving into that whole thing. There's a lot in my brain that I want to discuss!
EDIT: And for a source to the ~10% figure, I cannot find one that does not require you to pay. This study I know went into it, but you have to pay to see. I have seen it referenced all over the place as anywhere from 7% to 15%. If you can find a free study that discusses it, please link it. I am going to have to start paying for things if I want to dig fully into it.