Comment · Thu, November 22, 2012
MDMA Neurotoxicity Part 1 (Metabolites)
Original post in this thread
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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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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gnarleycharlie · 2 points
Relatively new here so I'm not sure if this is a dumb question......I see lots of talk about MDMA's neurotoxicity, ways to avoid it, specific biological mechanisms, etc. With that being said I almost never see any mention of other drugs' neurotoxicity. Is there just more research on MDMA neurotoxicity, or are other commonly used drugs not neurotoxic at normal recreational levels?
u/MisterYouAreSoDumb
Ohh no, other drugs are neurotoxic. Some are even significantly more neurotoxic than MDMA. Methamphetamine is one of them, as well as a lot of the research chemicals that come out. It's just that MDMA has been widely used for so long, and has many studies. It's also a very useful compound, that can help a lot of people out in clinical settings. Also, in my opinion, it's worth learning about. It's effects are such that it makes understanding the mechanisms that make it work, worth while.
Here's a simple list:
Methamphetamine- Neurotoxic at recreational doses (Dopamine system, calcium channels)
D-Amphetamine- Can be neurotoxic (Dopamine system, calcium channels)
MDMA- Can be neurotoxic (Serotonin system, calcium channels)
MDA- Neurotoxic (Serotonin system, calcium channels)
LSD- Not neurotoxic (No 5-HT or DA release, binds directly to both receptors)
Psilocybin- Not neurotoxic (No 5-HT or DA release, binds directly to 5-HT receptor only)
Dexromethorophan (DXM)- Can cause Olney's legions (not proven in humans). 5-HT reuptake inhibitor (no observed 5-HT neurotoxicity)
Ketamine- Can be neurotoxic at high doses (aptosis)
4-Fluroamphetamine (4-FA)- Can be neurotoxic (Dopamine system, calcium channels)
4-Para-chloroamphetamine (4-CA)- Very neurotoxic (Dopamine system, calcium channels) **Don't take
Mephedrone (4-MMC)- Not neurotoxic (can cause excitotoxicity at calcium channels, but not damaging to DA system)
Methylenedioxypyrovalerone (MDPV)- Can be neurotoxic (Dopamine system, calcium channels)
Methylone (BK-MDMA)- Can be neurotoxic (Serotonin system, calcium channels)