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 Once it's been o-demethylated to HHMA, it is no longer active like MDMA is.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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What they were answering
ActuallyNotRetarded · 1 points
Are you saying that piracetam can potentially be toxic?
u/MisterYouAreSoDumb
No, I'll copy a post I made the other day.
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Piracetam is known to increase the density and permeability of NMDA receptors in the hippocampus and acetyl-choline receptors in the frontal cortex. This potentiates the activity of glutamate, potentially causing a sate of excitability. I stop short of excitotoxicity due to it's function as an allosteric modulator. However, that does not mean it's effects are all wanted. There is no doubt in my mind that piracetam potentiates MDMA and amphetamine based stimulants, as I have personally experimented with many combinations. However, with primarily dopaminergic stimulants like amphetamine, it causes a state of irritability with me. This anecdotal result fits perfectly within the studies that show increased glutamate activity at the NMDA receptors. So yes, it definitely potentiates it, but I do not personally like the feeling. Now on to MDMA. Since MDMA has a much lower affinity for DA and much higher affinity for 5-HT, piracetam's effects are slightly different. It still potentiates MDMA's activity. However, it does not cause the same irritability shown in the more dopaminergic drugs. It makes your roll slightly more lucid, which can be enjoyable to some, and annoying to others. I find that it slightly kills the empaty of the experience. I've settled on not taking any nootropics before my roll, then taking some before bed and the following week. This seems to be the best results for me. You also have to take into consideration whether this is an attack dose before the roll, or if you have been taking piracetam long term ahead of your roll. Long term administration of piracetam will be more likely to increase your NMDA receptor density than an attack does would. An attack does will have mostly a positive allosteric modulation effect at your AMPA and NMDA receptor sites.
Some more reading:
http://www.sciencedirect.com/science/article/pii/S0006295298002950
http://www.ncbi.nlm.nih.gov/pubmed/9121626
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872987/
This is why there is great debate as to whether or not piracetam increases excitotoxicity when administered with dopaminiergic drugs. It most definitely increases the effectiveness of dopamine in various areas of the brain. However, it's effects on NMDA and AMPA receptors are my obvious focus. Piracetam absolutely shows increased calcium influx into neurons, which is a main cause of excitotoxicity and tolerance. However, there is not currently conclusive evidence that it's voltage-dependent actions on those ion channels cause any damage, or if they in fact help modulate the transmission. Those people who have formed a tolerance to MDMA and amphetamines find that piracetam definitely brings back some of the magic. Since MDMA's and amphetamine's tolerance stems from a lowering of effectiveness at your gated calcium channels, and piracetam has been shown to increase influx of calcium through said channels, one can see the pharmacological reasoning for the anecdotes. What we need to figure out now is if this added influx of calcium has a limit. Does piracetam being an allosteric modulator give it the ability to close the calcium channel once a certain voltage has been reached, and is that voltage at a level before excitotoxicity comes into play? If so, then we should get potentiation without damage.