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Metabolism of N-isopropylbenzylamine in humans

SelectiveSpeeding

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Hello. I have a few questions regarding the metabolic fate of this compound, which I know is a general answer that can be applied to most phenylalkylamine and alkylbenzylamine related structures. I just want to verify that my research has led me to the correct information and that I understand this enough to be able to explain this properly to others.

From what I can gather, the first step (Phase I), catalyzed by cytochrome P450 enzymes (CYP2D6 and or CYP3A4?) is N-dealkylation as the molecule is a secondary amine, which is essentially removal of the isopropyl moiety through the "carbiniolamine" pathway. The α-carbon is hydroxylated resulting in the primary amine (benzylamine) and a ketone (acetone). From there, benzylamine is metabolized by monoamine oxidases primarily MAO-B, which results in benzaldehyde and an ammonia. There's also a less prevalent pathway of N-oxidation of the original compound which would result in the nitrone because the hydroxylamine formed is not stable. I'm unsure of how big of a factor this would be. Primarily, I am focused on Phase 1 at the moment, and I realize that the specifics of enzyme catalysis is a complex topic on it's own with the metabolites and general mechanisms being what I'm worrying about.

If you're wondering why I'm asking about this, then I'll tell you yes it is because of the fabled use of this compound as a "cut" in commercially available methamphetamine being sold in the USA (and worldwide) that is of Mexican origin. I'm really not of the belief that it is, but the idea has become viral in a few places on the web where this drug is discussed, and it is perpetuated without any proof or verification. In response to this phenomenon, I thought it would be useful to educate myself on the fact that this compound's hydrochloride salt is relatively harmless due to rapid metabolism by P450 enzymes and MAO. I imagine that the half life would not be very long (at least not as long as methamphetamine) but there is no published data on this at all. I'm also pretty sure that it's relatively inactive as a drug molecule, but it still is subject to the human biological environment and want to be able to impress upon people that it's not the cause of life's problems and the center of all evil in the universe.

So if there's anything wrong with the understanding of the mechanisms I outlined in the second paragraph, I would like to hear your input and know if I missed anything. I apologize that this thread has to be about a topic that which the macrocosm of does not belong in this section, but I feel like you that frequent this place would be a good group to ask about the mechanisms and kinetics of this substance's metabolism. Thank you for taking the time to read this, as your time is much appreciated.
 
I'm also pretty sure that it's relatively inactive as a drug molecule, but it still is subject to the human biological environment and want to be able to impress upon people that it's not the cause of life's problems and the center of all evil in the universe.

Having to impress upon users of methamphetamine that the cut of no known adverse etiology shouldn't be a cause to worry. Oh the concessions people will make when it comes to what is known, so long as they romanticize the molecule whose issues they are.

Usually, I've found, this is just scapegoating their own tolerance; which I notice a lot: the longer the exposure the less the returns and the more health issues one is prone to, even if acute exposure is benign.

I do commend you on seeking out the answer despite believing the context itself may be wholly spurious.
 
the first step (Phase I), catalyzed by cytochrome P450 enzymes (CYP2D6
CYP2D6 is involved also in metabolism of methamphetamine and levomethamphetamine + dextro is known to be an CYP2D6 inhibitor (not sure about levo). What interactions could that lead to?
Also, could n-isobenzylamine (NIPB) possibly also be an inhibitor of CYP2D6 at those ridiculous amounts users ingest, to get enough dextrometh into their system?
Also, could it be, that it doesn't make a significant different to majority of population, but for the minority of people who are genetically predisposed to have less CYP2D6 ("poor metabolizers"), it makes a big difference if instead of metabolizing 50mg dextro, they now need to metabolize 50mg of dextro + 100mg of n-isopropylbenzylamine + possibly even 50mg of levomethamphetamine?

(I'm not suggesting anything, I'm not an expert... curious to hear from someone who is.)

Even if it turns out that it does totally nothing, it would be helpful to know that reliably, so the users have one less thing to wonder and worry about.

Anyway, I believe that the bad experiences people describe are caused by racemic meth, which is easier to hide within NIPB... or possibly even pure levo-meth, which is much more common since the decline of manufacturing from enantiopure pseudoephedrine and rise of manufacturing which involves an additional step of resolution... which some may skip, or screw up, or feel bad about throwing away the levo side-product...

I do commend you on seeking out the answer despite believing the context itself may be wholly spurious.
Exactly.

Usually, I've found, this is just scapegoating their own tolerance
Part of it for sure, but it was like that even before n-isopropylbenzylamine (NIPB) started to be a thing, and since then the amount of such reports raised rapidly, which is suspicious.
Also, some such reports were from people who didn't use for like 4-7 years, and then had this experience when they relapsed.
I think that it very likely related not to NIPB, but to Levo-Methamphetamine. Think about it:

1) Racemic became much more common around the same time as NIPB, as it's thanks to NIPB that even shitty racemic formed nice crystals and was possible to sell easily. At the same time sourcing pseudoephedrine became much harder, people were getting gakked. When pseudoephedrine was used, they couldn't include levo even if they wanted. With methods which involve chiral resolution which became more common, levo was just a side product, removing it was an extra step, that extra step could be performed poorly without anyone noticing, or deliberately skipped, or some may even suceed at resolution, but instead of throwing levo away, or trying to racemize and recycle it, they may have sold it. (such samples of pure levo have also been found, although it's not sure if those were leftover side-products of resolution, or if they were sourced from over the counter meds.
What I'm trying to say is that if levo is responsible for what people often report this last decade, then it makes sense that they blame n-iso, which is more obviously visible and became common around the same time as manufacturing methods which produces it as a side-product.

2) Even the users who care and test stuff before using aren't able to notice levo-meth, as all DIY doable tests (reagent tests, even when combined with thin layer chromatography) give same results, for levometh, like if it was (dextro)meth. And even when having it tested in a lab doesn't always help. Most labs aren't using some chirality-sensitive kind of chromatograhy, and for mass spectrometer levometh and meth (and even n-iso) are the same.
Which is another reason why people may tend to blame "n-iso" and not levo-meth, as even after testing the stuff, the levo-meth would usually remain unnoticed, while the NIPD was obvious.

3) The often described effects quite fit the effects of Levo-meth. It is a bit like meth, but with a much weaker dopamine releasing and much stronger norepinephrine releasing effect. Much more of it is needed to get some at least some dopamine rush, but it becomes more of an noradrenaline rush, which is quite different and fits the describtions of having strong physical symptoms of being high, without being much high.
Also the often described effect of "n-iso" building up in the body and it's effects intensifying after few days of using, that also fits, as levo-meth has a significantly longer half-life than meth.
And it's possibly quite unhealthy, considering the longer half-life (more sleep deprivation and its side effects) or considering how strong vasoconstrictior levometh is, as there are multiple known pathways by which it can make various (neuro,hepato,cardio,pancreatic) toxicities of meth much worse, for example weaker bloodblow => more local overheating, and heat is a known factor in both neuro and hepato toxicity...

And I know that levo is an approved and tested med, but it was approved and tested at orders of magnitude lower doses than amounts in which MA is used.

Btw the difference between effects of d-ma and l-ma is actually quite similar to difference between d-amph and l-amph, but is much much bigger. Sorting them by their DA vs NE releasing ratios they go d-meth, d-amph, l-amph, l-meth.
Also interesting (although this is a very wild speculation and possibly just apophenia) that when i was looking at comparative studies, in two of them the data seemed like if effects of levometh and meth weren't just adding up, but like if levometh was possibly even attenuating the effects of dextro... Seemed like if 25mg of d-meth alone worked better than that same dose of d-meth, but combined with additional l-meth.
 
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A recent article in Australia Herald Sun newspaper reported that "crime gangs import legal chemical to make cheap and deadly imitation meth" and specifically named "N Iso" as the substance. This crap is being regularly consumed all over the world there is no denying it
 
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