MDMA metabolism and individual enzyme variations

[neurotic]

so i was reading this on reddit, that hypothesized that any damage done and negative post-effects from MDMA was because it was metabolized to an extent to alpha-methyldopamine (neurotoxin) and to 2,4,5-trihydroxy-amphetamine (which drastically lowered enzymes such as tryptophan hydroxylase sometimes up to a week later).

the thread focused on keeping MDMA from being metabolized (by inhibiting CYP3A4) to MDA, because they (a-methyl-DA and 2,4,5-tryhidroxy-amp) were metabolized from it.

but i was wondering, most of MDMA is metabolized by CYP2D6, which is an enzyme that greatly varies from person to person - some people not even having it or something. variations in the expression of 2D6 would mean what?

after MDMA turned into MDA, to be turned into alpha-methyldopamine it would need 2D6. same goes for 2-OH-MDA turning into 2,4,5-trihydroxy-amphetamine. therefore 2D6 is needed to these two unwanted molecules to happen.

if one would have no 2D6 activity, then none of these unwanted molecules would be formed? or if someone had big 2D6 activity, then only little MDMA would be subject to 3A4 metabolism and turned to MDA, therefore less a-methyl-DA and 3,4,5-trihydroxy-amp too, right? because 3A4 is also needed for them to form. its kinda complicated because the paths cross

so, what would individual variations in 2D6 activity mean? do you think it would be better to have less/no 2D6 or more? how would someone without 2D6 activity metabolize MDMA? just ring hydroxylation and N-demethylation into MDA by 3A4?

just wondering

 

[sekio]

MDMA... metabolized to 2,4,5 trihydroxy amphetamine

How? MDMA would go to 2,3,4-trihydroxyamphetamine if anything, I don't see how the hydroxys would migrate around on the ring?

It seems to me if you stop MDMA from being metabolically degraded you'd make it more potent as a toxic substance by increasing its persistence in the body.

 

[neurotic]

How? MDMA would go to 2,3,4-trihydroxyamphetamine if anything, I don't see how the hydroxys would migrate around on the ring?

It seems to me if you stop MDMA from being metabolically degraded you'd make it more potent as a toxic substance by increasing its persistence in the body.

so inhibiting its metabolism would make it exert its effects longer, right? but this study where they inject MDMA directly in the brain concluded it showed no neurotoxicity, therefore any neurotoxicity should come from a metabolite (obviously, a-methyl-DA). and then there's this 2,4,5-THA which inhibits tryptophan hydroxylase and other enzymes.

if that is all correct and MDMA itself isn't neurotoxic, stopping MDMA from being degraded into those nasty metabolites wouldn't be better? it could last longer and deplete more serotonin (?) but that'd be better than what the two mentioned metabolites do, i guess

we don't see as nasty after-effects from other potent serotonin releasers such as mephedrone (which people go way overboard with) so i'm thinking the problem is indeed in these metabolites particular to MDMA/MDA

 

[FnX]

MDMA is something my body doesn't seem to really agree with. Things like butylone and even BZP will give me a better overall experience, but I've had so many bad experiences with these substances I generally steer away from them. I get pretty intense paranoia and psychotic symptoms from MDMA, especially if combined with anything psychedelic. I'm usually aware what's going on in my head and can be like, "ah, I'm starting to feel the paranoia again, gotta ride it out and ignore all this weird shit". But with MDMA, it always seems to catch my by surprise. Everything is all fine and dandy, lovey dovey, then suddenly BOOM it's like I come to somekind of realization and I find myself in the center of some crazy ass conspricay where everyone is out to get me and I gotta play it cool because I'm on to them as well now. I suspect it's some metabolite I really, really don't seem to agree with that's causing this, because the paranoia always hits me with a reasonable delay after the peak has hit me but before any noticeable come down.

I've tried messing with some CYP and MAO enzymes (moclobemide mostly, inhibits MAO-A and CYP2D6 atleast from the top of my head ) before experimenting with drastically reduced MDMA doses, think something like 10-30mg total which felt like atleast 100mg in intensity without any inhibitors. The experience felt quite serotonergic and dreamy for lack of better words and actually less toxic (subjective) as long as regular sized doses were omitted. No noticeable paranoia either. For me, it was definately harm reduction, but it's something that can potentially kill you if you aren't very careful or have something like a bad heart / blood pressure problems you may not be aware of, so I will not recommend this kind of experiment to others. Increased potency means less of a drug in your system for the same intensity of effect, however, the effects profile changes somewhat too because we're getting lesser amounts of (different) metabolites.

https://www.erowid.org/experiences/exp.php?ID=103010 some other dudes experience regarding the matter.

Be careful and don't do anything stupid please, you only have one life. I felt like sharing because I feel there could be potential for harm reduction in this subject too, but again, it's a double edged sword.

 

[neurotic]

^ could this huge potentiation be because of mostly from MAO inhibition and not 2D6 inhibition? MAOIs have side effects alone

the idea is that MDMA itself isn't toxic, but the two metabolites which i pointed out