Comment · Sat, November 24, 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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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 · 2 points
Hey there, might be arriving a little late to the party, but here's something you might want to know. My dissertation at university was investigating MDMA and mephedrone. Something that interested me at the time was that a lot of the thoughts about the neurotoxicity of MDMA was based off of research carried out in other animals, which could be problematic for a few reasons... Sorry for the wall of text that's coming, It's just the relevant section copied out of a draft of the work.
"the proportion of metabolites formed in normal metabolism of MDMA by rats and humans varies. Humans produce ≈2-3 times less (10% vs 30%) MDA (3, 4-methylenedioxyamphetamine) than rats. MDA is recognised as the principle metabolite responsible for neurotoxic damage. Figure 3, attached in supplementary material is a schematic showing proposed pathways of metabolism of MDMA to MDA (Capela et al 2006). An additional consideration is the absence of the auto-inhibitory effects of CYPD26, a cytochrome enzyme largely responsible for processing xenobiotics, including metabolism of MDMA. (Green et al. 2012) Rats instead have a homologous but functionally distinct enzyme – CYPP2D1, which displays no auto-inhibition. (Malpass et al. 1999) (Maurer et al. 2000) This dual metabolism and inhibition by CYP2D6 in humans means the associated kinetics are non-linear. This is not true for rats, where the relationship…
u/MisterYouAreSoDumb
After I wrote this post, a gracious Redditor with full access got me all the studies in full, so that I could go through them. I had just been reading the abstracts, and those papers I could find for free online before. Now I have read through them all in full, as well as the one you are speaking to. The non-linear kinetics in humans still fits within my theory. Included with the rat studies, I read through primate and even a human study. The more I read, the more my theory keeps falling into place. It has also clarified some things for me. I postulated that rats showed greater 5-HT damage because they had less efficient delivery systems for antioxidants. I now believe that still may be the case, but it is more to do with their CYP2D1 enzyme being the primary metabolic pathway for MDMA to MDA. Not only that, but we always thought that temperature increases led to greater 5-HT neurotoxicoty because it reduced the efficiency of our antioxidants systems. However, after reading the full study (Banks et al. 2007), temperature increases led to greater metabolism to MDA. Also, re-dosing has been a known path to neurotoxicity. The study (Torre Farre 2004) showed that re-dosing in primates led to a 200% increase in MDA levels, up to 18% of the total MDMA dose. This proves that the metabolic pathway to MDA is there in primates, as well as providing reasoning for the higher neurotoxicicty observed when re-dosing. It all fits perfectly within my theory! I've been going back and forth with the Redditor who is getting me the studies via private message. In that time I have gathered much more evidence that MDA is the cause. I am going to write a huge post in /r/DrugNerds with explanations and citations. But below is what I believe to be the cause of MDMA induced neurotoxicity.
MDMA is N-Demethylated by the human enzyme CYP3A4 to MDA. Temperature increases, as well as re-dosing intervals, increase this metabolic pathway, leading to as much as 18% of total MDMA dosage becoming MDA in primates. MDA is then either O-Demethylated to 3,4-dihydroxyamphetamine (HHA) via the human enzyme CYP2D6, or ring-hydroxylated to 2,4,5-trihydroxyamphetamine (THA).
HHA is very unstable, and rapidly conjugates with glutathione into 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine. This is the substance that causes 5-HT neurotoxicity in the brain. Even if COMPT is inhibited, causing less HHA to be metabolized to HMA, HHA levels DO NOT rise. This also leads to incresed 5-HT damage. This proves that HHA is unstable, and is rapidly conjugated by glutathione. If it was not being conjugated, an inhibition of COMPT would lead to an increase in HHA serum levels, as well as an increase in HHA in the urine. It does not.
The other piece of this puzzle is THA. The ring-hydroylated metabolite of MDA, administered by itself, led to a 92% decrease in tryptophan hydroxylase (TPH) after 7 days. This explains MDMA's reduction in TPH the 2 weeks following use, consequently causing serotonin stores to not replenish in a timely manner. That does not mean that MDMA itself is not to blame as well. The ring-hyroxylated metabolite of MDMA, 2,4,5-trihydroxy-N-methylamphetamine (THM), also reduced TPH. However, it only reduced it by 48%. There is no doubt, MDA is much more damaging to the serotonin system.
Now you may be thinking, what about HHMA, HMMA, and their conjugates? They are probably leading to toxicity as well, right? NOPE! The study (Mueller et al. 2004) proved that neither HHMA, HMMA, nor any of their conjugates pass the blood brain barrier. Furthermore, they injected them directly into the brain, causing ZERO elevation in 5-HT damage. This proves that the N-methylated metabolites of MDMA directly ARE NOT neurotoxic. However, the study (Carvalho et al.) did prove that HHMA is hepatotoxic. They also proved that abscorbic acid prevents this hepatoxicity. So the N-methylated metabolites are still toxic, but damage is limited to the periphery.
Take this information, along with the fact that MDMA nor MDA are neurotoxic when directly injected in the brain, and my theory is the only thing left. 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine and 2,4,5-trihydroxyamphetamine (THA) are the two substances that are solely responsible for MDMA induced neurotoxicity. They also happen to only be possible if MDMA is N-demethylated to MDA. This is why MDA is much more neurotoxic than MDMA when administered alone. It's also why re-dosing and temperature increases lead to more 5-HT system damage. MDA is the asshole in the room. Inhibit CYP3A4 to prevent the neurotoxic metabolites from being created!
p.s. I will provide many more sources and quotes for proof, once I write my full post. This was just an informal explanation to you in the interim.
So I am excited as hell about this. How about you?