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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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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empathogen · 8 points
You're amazing and I love this and now you. Can you elaborate on how taking an SSRI (eg Prozac) the following morning might mitigate some of the neurotoxicity? I did a paper on this once in a neuropharm class but haven't researched any of this stuff in years, so I'd like to see what you think. Thanks!
u/MisterYouAreSoDumb
There is great debate as to why this works. The main theory is that the SSRI will bind to your SERT and prevent oxidative substances from being re-uptakes into your serotonin neurons. I do believe this to be the case, but not the whole story. What else are SSRIs potent inhibitors of? CYP450 enzymes. Now most SSRIs are only potent inhibitors of CYP2D6. However, the primary metabolite of fluoxetine, norfluoxetine, also inhibits CYP3A4! So not only does taking fluoxetine bind to your SERT, it also inhibits the metabolism of MDMA to it's toxic metabolites. So my theory still holds up. MDMA induced neurotoxicity arises from the N-Demthylation to MDA, then either O-Demethylation by CYP2D6 to HHA, or ring hyroxylation to THA. Grapefruit juice and fluoxetine both stop this from happening!