Comment · Sun, November 25, 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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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
MedullaOblongAwesome · 1 points
I've got to say, my work in the area was restricted largely to investigating the way that the two drugs interacted with each other (whether or not taking MDMA in adolescence could lead to a sensitised response to mephedrone in adulthood [short answer: probably not] so I'm not so hot on the metabolism and toxicity stuff having touched on it in only around as much depth as we're discussing here, and often less, but you seem to be pretty much on the money with what you've written so far. What stuck with me was the same conclusion you've drawn - MDA is the bastard you want to be minimising (gastrointestinal and hepatic damage, dehydration related ischemia's and whatnot aside). One thing I will say though, you have to remember to not get tunnel-vision: focusing solely on serotonergic neurotoxicity in "ideal" conditions mightn't be the best way to reach the best conclusions - most drug users are polydrug users, and taking them recreationally in a far from "normal" environment - intense physical activity, etc. The thermogenic effects in particular are a real ballache - If I recall, they have opposite effects at doses used in a "therapeutic" session than the effects they have recreationally. As for drawing conclusions about central toxicity of certain compounds, or anything really, there's been some pretty furious exchanges of critiques between lab groups on both sides of the debate…
u/MisterYouAreSoDumb
Thanks! My professional career has absolutely nothing to do with neurochemisty. I actually started my own telecommunications company. In the future I may look into organic chemistry, though.
As far as your other concerns, I have definitely considered them. I mentioned at the bottom of my post that it was simply speaking to 5-HT system damage. There is a lot more I have to say about increased extracellular glutamate, NMDA and AMPA receptors, as well as dopamine toxicity. Also, my findings here are aggregated from many studies, by many different labs, from many different perspectives, over the last 30 years. When an issue would arise in one study, I would look to other studies to find possible clarifications. I did not go into this with any preconceptions, but rather an open mind to try and find the truth. I made every attempt to eliminate selections bias, and I have nothing to gain professionally from my theory. If I ended up finding that there was no way to mitigate neurotoxicity, then c'est la vie.
MDMA is not my only focus, though. It is simply the one that got me interested. I've been doing a lot of research into other areas as well. Nootropics is a big one at the moment. The different receptor sub-types and their functions. Nerve growth factor, brain derived neurotophic factor, and how they are used to rebuild axon terminals. The function of histamine in the central nervous system, and how it can affect cognition. Acetyl-choline and it's role in depression. My brain just wants to learn it all!
Now I just need to find someone with access to a research lab to verify my theory in practice. It will not be hard, and I already have an idea how to do it. It would require primate testing though, and I am not sure how I feel about that. I'm not sure if I could personally be involved in it. I've tested my theories on myself many times, and I'm fine with that. However, my results are only going to be anecdotal unless we can get brain samples. Given the information that's out there right now, I am 99% sure my theory is correct. Is the killing of some monkeys worth bridging that 1% to certainty? Ehh, I'm not sure. I like monkeys, and I would feel like shit being involved in their death. Perhaps I am not a true researcher at heart...