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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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
lol_u_so_kawaii · 6 points
Wow. Thank you so much, I don't think I've seen such a artful and intriguing post in a long time. Greatly appreciated. We need more people like you!
Can I ask you a favor? Would you mind linking what you view as the most accurate "overview" of MDMA. I know many people point twords Dancesafe's overview, The Dea.org's and "Ecstasy: The Complete Guide's Does MDMA Cause Brain Damage?" but I am very curious on your pick. Thanks!
u/MisterYouAreSoDumb
Ohh man, my theory is very complex, and involves many different systems and mechanisms. There is no one place that explains it in full. I have spent thousands of hours researching and testing (on myself) my postulations. I will give you a very very basic idea of it.
MDMA induced 5-HT neurotoxicity arises from the metabolites I mentioned in my post.
Oxidative stress is exacerbated by increasing body temperatures due to a lowering of effectiveness of your body's natural mechanism for protection, antioxidants. Dopaminergic drugs increase body temperature even more. THC helps lower your temps.
Excitotoxicity and tolerance arises from MDMA induced extracellular glutamate release. This binds to your NMDA receptors, opening your ion channels, and allowing calcium to enter your neurons in too high a concentrations. This lowers the effectiveness of your calcium channels, and can even lead to neuronal death if the Ca levels get too high. Magnesium supplementation is needed.
Dopamine toxicity is a whole different ballgame. Similar mechanisms, but different compounds. It will take time to explain all that.
Water retention is due to release of vassopressin. Green tea extract can help with this.
The reason your serotonin levels take so long to replenish after use is due to an MDMA induced lowering of tryptophan hydroxylase. This is due to the ring hydroxylated metabolites of MDMA, 2,4,5-trihydroxyamphetamine (THA) and 2,4,5-trihydroxy-N-methylamphetamine (THM).
There is more, but you get the idea. I will eventually do a very large write up about how to protect yourself from everything, with citations.