MDMA is MDMA but CYP enzymes are enantio-selective -- explanation for 'monginess'

[Jabberwocky]

Apparently there are actually a lot of CYP enzymes that contribute to the metabolism of MDMA:

CYP1A2
CYP2B6 (n-demethylation)
CYP2D6 (clearance)
CYP2D19
CYP3A4

And apparently all but 1A2 and 3A4 are enantioselective in metabolizing MDMA (they metabolize one isomer preferentially)

https://www.ncbi.nlm.nih.gov/pubmed/18725511


There are multiple polymorphisms in CYP in humans, as the dose increases, the effect of:

individual polymorphisms,

enantioselective CYP enzymes,

CYP inhibitors (fluconazole all but 1A2 and 2B6) not expected to impact MDXX metabolism


-- could easily lead to an enantiomeric excess even though the original substance is a (50/50) racemic mix

 

[TheDEA.org]

Nice catch!

Yes, you are correct; metabolisms vary, and many enzymes are stereoselective, so over the course of the high the balance of S(+) to R(-) isomers will shift, and shift in ways that are not entirely consistent from person to person. If memory serves, the more potent S(+) isomer is broken down more quickly, which could certainly be a factor in how you feel differently later in the high (and during the recovery) than you do early on.

Another interesting possibility is that the two isomers are being transported past the blood-brain barrier at different rates; I don't recall if I've seen research that covers that....

For everybody scratching their heads and saying 'the heck?', there are actually two kinds of MDMA molecules. They have the same parts, connected in the same places, but in a slightly different way. The two are mirror images of each other, a bit like your reflection in a mirror is more-or-less you, but reversed.

These two mirror forms are called isomers, which the chemists label (with complicated rules) as either 'R' or 'S'. The 'S' version is a bit stronger, and is the main dopamine releaser; you might think of it as the 'fire' of the MDMA high. The 'R' version is mostly a serotonin releaser, and might be thought of as more the 'glow' and calm of the high.

Both isomers together give MDMA it's classical effects; if you could get just one isomer or the other, it would feel significantly different from the mixed ('racemic') form.

MDMA sold on the black market has always been racemic (a 50-50 mix of both forms.) It's what people expect, and it adds extra steps to the process to separate out the two isomers so there's no motive for chemists to bother. There's been some speculation that some newer methods for producing MDMA are accidentally producing a different ratio of the isomers, but I think it's quite unlikely.

 

[Brenner]

Nice catch!

Yes, you are correct; metabolisms vary, and many enzymes are stereoselective, so over the course of the high the balance of S(+) to R(-) isomers will shift, and shift in ways that are not entirely consistent from person to person. If memory serves, the more potent S(+) isomer is broken down more quickly, which could certainly be a factor in how you feel differently later in the high (and during the recovery) than you do early on.

Another interesting possibility is that the two isomers are being transported past the blood-brain barrier at different rates; I don't recall if I've seen research that covers that....

For everybody scratching their heads and saying 'the heck?', there are actually two kinds of MDMA molecules. They have the same parts, connected in the same places, but in a slightly different way. The two are mirror images of each other, a bit like your reflection in a mirror is more-or-less you, but reversed.

These two mirror forms are called isomers, which the chemists label (with complicated rules) as either 'R' or 'S'. The 'S' version is a bit stronger, and is the main dopamine releaser; you might think of it as the 'fire' of the MDMA high. The 'R' version is mostly a serotonin releaser, and might be thought of as more the 'glow' and calm of the high.

Both isomers together give MDMA it's classical effects; if you could get just one isomer or the other, it would feel significantly different from the mixed ('racemic') form.

MDMA sold on the black market has always been racemic (a 50-50 mix of both forms.) It's what people expect, and it adds extra steps to the process to separate out the two isomers so there's no motive for chemists to bother. There's been some speculation that some newer methods for producing MDMA are accidentally producing a different ratio of the isomers, but I think it's quite unlikely.

I've been following the isomer talk for some time. Yes, all well known synth routes produce a 50/50 racemic product, but how do you know all the black market chemists (assuming there is more than one) are following these specific routes to the letter? Do you personally know them all and have observed their process?

There are a heck of a lot of variables in any of those synth routes, some of them obvious, some probably not even properly documented. Anything could be possible here with the clandestine chemist. Until someone can confirm by testing some of this apparent "mongy" MDMA by chiral column or similar method, i'd say this argument remains firmly valid.

 

[TheDEA.org]

but how do you know all the black market chemists (assuming there is more than one) are following these specific routes to the letter? Do you personally know them all and have observed their process?

There are a couple reasons I don't think the 'different isomer mix' theory has credibility.

1. Stereoselective chemistry is relatively hard. Standard MDMA synths are cheap and easy. To go from a conventional synth to a stereoselective synth is not a simple thing; it's a lot more than just 'not following tradition to the letter'. It only happens deliberately, methodically. It's not an accident or a glitch in the process. You do NOT unintentionally get from racemic to stereoselective.

2. Drug labs get caught. Pills get analyzed (which tells stories about the methods used to synth the drug.) When a lab or pill that shows signs of a novel synth shows up, it gets reported. To a drug forensics lab, a pill taken from a teenager's pocket tells them as much about the way it was made as kicking in the door of the lab would; each synth comes with its own fingerprint of byproducts. So far as I know, there are no researcher or government reports to back up this notion.

3. Because weak pills would not be the result of a breakthrough in stereoselective MDMA synths. If the cooks had adopted a stereoselective process, they would be choosing the stronger isomer, not the weaker one. People would be asking 'why did this 100 mg pill kick my ass?!?', not 'why is stuff lame these days?'

This idea of weak 'molly'/pills being the result of a new stereoselective method is essentially a theory that cooks are going to extra trouble and expense to create weaker pills (by synthing mostly the R isomer) when less effort would give a better (racemic) product, and the same amount of effort could give them exceptionally strong, fiery pills (by synthing the S isomer.)