Comment · Wed, November 28, 2012
Research Suggests no Neurotoxicity in MDMA
Original post in this thread
PuffyCheek · 194 points
In partial response to what I've been reading in the bestof'd thread here at /drugs, I think it would be good to start a discussion about the neurotoxicity in MDMA.
I feel as if the harmful effects discussed in the thread were overblown. According to a research done by the Harvard Medical School last year in 2011, users who were asked to use MDMA under a controlled setting over a certain period of time showed no signs of cognitive impairment nor decreased mental ability.
So the question remains, why do we have so much evidence from past research studies that show otherwise? The researchers at Harvard Medical School responded by saying that past research studies lacked a proper control environment. What that means is that past research studies did not control their test group to make sure they didn't engage in unhealthy activities after ingesting MDMA (i.e. going to a rave and dancing for 8 hours straight).
No research since 2011 has proved Harvard Medical School's conclusion wrong, that MDMA is actually harmful to your brain. No other research studies that I could personally find had settings as controlled as the one conducted by HMS.
That being said, research was done…
What they were answering
engjosh88 · 2 points
I just re-read my reply and it sounded a little snarky and I apologize for that because I'm interested in maintaining an intelligent discussion.
I read your post on /r/DrugNerds and while interesting, it refered mostly to 10-15 year old studies with only one semi-relevent 2009 abstract that spoke nothing of core body temperature.
Can you please link one or two relevant studies in the past year or two. I'm sure you realize as well as I do that even today we are just scratching the surface of understanding this drug. It has only recently become interesting due to its new recreational use.
I certainly urge you to pursue information, but I humbly suggest you be careful with where you are posting information that can be easily misinterpreted by people looking for "drug advice" such as in /r/Drugs. A lot of readers are just looking for an excuse to say "this drug is probably safe, especially the way I'm doing it" and don't really understand if and how they're wrong.
u/MisterYouAreSoDumb
No problem. I understand your hesitation. Most of my proof was written via private message between myself and the Redditor that got me the studies.
http://www.ncbi.nlm.nih.gov/pubmed/18074122
http://www.ncbi.nlm.nih.gov/pubmed/19628751
http://www.ncbi.nlm.nih.gov/pubmed/17640955
http://www.ncbi.nlm.nih.gov/pubmed/11351932
http://www.ncbi.nlm.nih.gov/pubmed/15212815
http://www.ncbi.nlm.nih.gov/pubmed/15380932
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I'm going to copy what I said in the PMs so that you can pick apart my theory as well. Forgive the writing style, but that is how I make sense of what's in my head. Writing it out helps.
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Ohh man, these are good! It's looking more and more like my theory is correct. The study below pretty much proves it, but they stopped short of postulating that it was HHA. They did say that it was likely the conjugates of HHA and HHMA though. They could have proven my theory with one extra test, inhibiting the metabolism of MDMA to MDA. However, one little tidbit stands out differentiating HHMA from HHA.
They used entacapone to inhibit the COMPT from methylating HHMA and HHA to HMMA and HMA respectively, which caused greater neurotoxicity. This drastically lowered both HMMA and HMA as expected, and raised HHMA, but did NOT change HHA serum levels. So where did it go? Preventing the metabolism of HHA to HMA, while still keeping the metabolism of MDA to HHA the same, should have raised levels. It didn't! There are only a couple other paths for it to go. Two of them would be 5-(glutathion-S-yl)-alpha-methyldopamine and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine. However, those have been shown to not cause neurotoxicity. What is the only path left? HHA had to be conjugated by glutathione to 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, the neurotoxin that has been shown to cause the exact same toxicity observed in MDMA use.
So this is pretty certain now. My only loose end here is HHMA, N-methyl-alpha-methyldopamine causing hepatic toxicity. Why is HHMA toxic there but not in the brain as I postulate? Perhaps it is, but it simply lacks the transporter to cross the blood-brain-barrier. This is why it has been show to be hepatotoxic, but not toxic to 5-HT neurons.
And guess what I just found?!? This study proved that neither HHMA, HMMA, nor their sulfate or glucuronic conjugates are found in the brain after MDMA use! So that proves it!
The MDMA metabolite HHMA, being conjugated with glutathione causes hepatotoxicity. However, it is NOT found in the brain after MDMA use (due to lack of transporter across the BBB). Meaning that the direct metabolites of MDMA via CYP2D6 are NOT neurotoxic.
However, a portion of your MDMA dose is N-Demethylated to MDA by CYP3A4. It is then O-Demethylated by CYP2D6 into HHA. HHA is then conjugated by glutathione into 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, which is then transported across your blood-brain-barrier, where it causes a release of oxidative molecules. This damages the 5-HT neurons!
This explains everything! It explains why MDMA and MDA are both non-neurotoxic when injected directly into the brain, even though dopamine levels rise drastically with MDA. It explains why MDA is much more neurotoxic than MDMA when orally administered. It explains why temperature increases cause greater neurotoxicity (I did not explicitly tell you why yet, but it does). Holy hell, this is good stuff!
Sorry for the large wall of text, writing like this helps me get my ideas out and visualize the mechanisms. I am going to keep verifying my findings, but I think I am on to it. Would you be able to get me the full studies that I linked above?
This is the study I was referring to mostly- Relationship between core body temperature and MDMA metabolism in rats - Goni-Allo et al
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After reading the two new studies, it just confirms my theory even more. HHMA, HMMA, nor it's conjugates were found in the brain after MDMA dosage; even after extremely high doses and very high HHMA and HMMA plasma levels. This means they do not cross the blood brain barrier. However, they even went one further and injected them directly into the brain. This did not cause 5-HT deficits either. So they proved that HHMA, HMMA, nor it's conjugates are the cause of neurotoxicity. Sweet!
They do postulate that HHA is not the cause, but I do not see any scientific reasoning. They cite another study from 1991 as evidence. However, I just read through that one and I disagree with their findings. They think that because the levels of HHA and HMA detectible in urine are very low, that they cannot be the cause of the neurotoxicity. However, I think that is precisely the evidence FOR HHA being the cause. It does not stay as HHA. It immediately reacts with glutathione to form 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine. That's why HHA, and consequently HMA, levels are low in urine. That, along with the more recent studies showing 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine does in fact produce the same type of neurotoxicity seen in MDMA when administered alone, proves to me that this is the cause.
I am very confident that my theory holds up. Now we just need to find someone to validate it in the lab.
As far as inhibiting CYP2D6 to decrease the O-Demethylation to HHMA, I do not see it as being super dangerous like an MAOI. It will increase your serum levels of MDMA, possibly making serotonin syndrome happen at a lower dose. So you will just need to take less MDMA for the same effect.
I will say that HHMA has been shown to still be hepatotoxic. So inhibiting that will still help protect your liver, even if it's not causing the neurotoxicity. The last study you got me proved that vitamin C prevented the hepatotoxicity though. So just make sure you take Emergen-C with your MDMA, and your liver should be all good.