Comment · Thu, November 22, 2012
MDMA Neurotoxicity Part 1 (Metabolites)
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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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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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Cunnin_Lynguist · 2 points
Wow, fascinating post.
In theory, could CYP2D6 inhibition limit MDA neurotoxicity by reducing the amount of HHA formed, so that less HMA is formed by COMT; ultimately leading to more MDA being excreted in the urine unchanged?
Also remember this thread, where you said CYP3A4 inhibition would potentiate MDMA, correct? Wouldn't CYP3A4 metabolism of MDMA-to-MDA be favourable though (in terms of psychoactivity), because MDMA is being broken down into an active metabolite as opposed to being inactivated by CYP2D6 into HHMA? I understand that 3A4 inhibition should reduce neurotoxicity, but would also possibly somewhat decrease psychoactivity.
Again, great post. Thanks for sharing!
u/MisterYouAreSoDumb
In theory, could CYP2D6 inhibition limit MDA neurotoxicity by reducing the amount of HHA formed, so that less HMA is formed by COMT; ultimately leading to more MDA being excreted in the urine unchanged?
In theory, yes. I am still searching for evidence of this.
CYP3A4 inhibition definitely potentiates MDMA. You only have so much CYP2D6 enzyme, and since this is the primary metabolic pathway, it's totally saturated as it is with MDMA. Inhibiting CYP3A4 will not lead to more CYP2D6 metabolism in the short run. However, it might in the long run, after your roll is over. I take Tums before my roll and at my drop, to increase absorption due to lower stomach acidity. However, I drink Emergen-c and grapefruit juice throughout my roll. This increases stomach and urinary acidity throughout the night. This leads to much of the MDMA being excreted in urine before it can be metabolized too much.