According to this guy - http://www.youtube.com/watch?v=WdkhTOcMvyQ - With the CYP450 enzyme system, things first become hydroxylated, and then eliminated by one of several processes, which includes, if it's an amine compound, Oxidative Deamination... Ring a bell? So to me it appears that DMT should first rely on CYP2D6 to be inhibited, rather than MAO, so that it survives unscathed, and maybe after that, MAO-A inhibition could be important. But if CYP2D6 isn't inhibited, then the DMT get's metabolized by CYP2D6 and then is eliminated/excreted.

I think this ^ is what is orally activating DMT, not MAO-A inhibition, this makes too much sense to me right now, for it to be MAO-A inhibition. This basically means that if CYP2D6 isn't inhibited, DMT gets hydroxylated to 6-HO-DMT which so far as i know is inactive, and is then eliminated by Oxidative Deamination which, if i'm not mistaken DMT is said to be metabolized by MAO into Indole-3-acetic acid, which is a carboxylic acid which is part of what they call Oxoacids, which comes from the Oxidative Deamination process, which apparently only happens after DMT metabolizes into 6-HO-DMT by CYP2D6, not by MAO. And if this is indeed the case, then that means DMT's oral activation lies within the inhibition of CYP2D6, not MAO. And if that's the case, that would explain why other natural MAO-A inhibitors haven't worked for people trying to orally activate DMT.



Edit: From this page - https://mycotopia.net/fo...inhibitor-maoi-more.html - i found this quote "The relevance of hydroxylation as a metabolic pathway of DMT has received no further attention in the most recent studies and 6-hydroxy derivatives have not been assessed in several experiments on the in vivo and in vitro metabolism of DMT and 5-methoxy-DMT (Sitaram and McLeod, 1990)."

And this "In conclusion, all these studies point out that although oxidative deamination of the side chain by monoamine oxidase appears to be the main metabolic pathway of DMT, the drug can also be degraded by other routes, mainly N-oxidation, but possibly also by N-demethylation, 6-hydroxylation and cyclization. The extent to which these pathways may be active or even predominate when the drug is administered orally concomitantly with selective MAO inhibitors, as is the case in ayahuasca potions, remains to be assessed."

Also from this page - http://www.erowid.org/ar...terio-dmt.synthesis.html - "The dominance of the deamination pathway makes it difficult to study the minor metabolites. Traditionally this difficulty has been surmounted by pre-treating animals with an MAO inhibitor such as pargyline. Inhibition of the major catabolic route leads to "shunting" to the minor metabolic routes, facilitating the study of the minor metabolites. Unfortunately pre-treatment of animals with pargyline can give experimental results which are difficult to interpret since pargyline also inhibits the N-oxidation and demethylation of DMT by 90%." CYP2D6 mediates O-Demethylation as well as Hydroxylation, and both CYP2D6 and CYP3A4 apparently mediates N-Demethylation.

Bump!

Is anyone else going to chime in here? I do feel strongly about this alternate hypothesis for how DMT becomes orally active. And to me, it makes sense because if DMT is smoked or injected, it bypasses CYP2D6 and carries out it's effects until it makes it's way to the liver to be metabolized out by CYP2D6 and then MAO. That's how i'm seeing this.

Cinchona bark contains the alkaloid quinidine which inhibits CYP2D6.

However, my reading of the papers linked to in this thread is that even if you ingest a substance which inhibits CYP enzymes, you will still need to take an MAOI because monoamine oxidase is the main metabolic pathway for DMT. The problem is this could lead to a potentially fatal drug interaction. For example, concomitant use of quinidine and an MAOI could lead to serotonin syndrome.

I'd rather not take quinidine, thanks though. And also, i've learned the whole serotonin syndrome thing is way too overblown, i've had ss before back when i used to be on all sorts of anti-depressants and such, and i know ss isn't pretty in the least bit, but especially when RIMA's are concerned, i've found that ss isn't much of a concern, especially when one doesn't take other pharmaceuticals like SSRI's and such.

But anyways, i'm saying that i believe it's not MAO which destroys DMT upon oral ingestion, instead it is CYP2D6. Because from my current understanding, CYP2D6 first metabolizes DMT and then eliminates it through MAO by Oxidative Deamination. And the reason i believe that is because i find it very hard to believe MAO would seek out this one compound for instant destruction, and besides that i never saw a way for DMT to be deactivated by MAO because it has no way to get to MAO, it must FIRST go through the CYP system for metabolization and THEN is dismantled by MAO and excreted. MAO may breakdown neurotransmitters, but i can assure you my serotonin, dopamine, norepinephrene and so on isn't being broken down by MAO raidly, or else i'd probably be brain-dead in a way without all my neurotransmitters, obviously, so why would DMT? What makes DMT so special that the CYP system, who's main course of action is to activate or deactivate compounds through metabolization, why would it for some odd reason skip the CYP system and head straight for MAO? To me, it just does not make sense, and out of everything i've looked at, MAO dismantling DMT without it first being metabolized, just doesn't make sense.

Oh and Creo, i'm thinking about Black Seed for inhibiting CYP2D6 and CYP3A4- http://www.ncbi.nlm.nih.gov/pubmed/20201775

Care to expand on what you think isn't of concern regarding MAOIs and serotonin syndrome?

I can assure you that there is still a LOT of concern for serotonin syndrome and RIMAs.. There are cases of people dying when mixing moclobemide and MDMA, for example, I can pull the paper for you if you want. Please be careful what you say, you can lead people into considering dangerous actions if you don't explain yourself properly and back up your arguments.

Also I think you are wrong regarding DMT not being metabolized by MAOs. Jordi Riba's paper (and unpublished research) shows this. DMT is primarily metabolized into IAA and then excreted, and this is done by MAO, not by CYP. You say CYP2D6 first metabolizes DMT and then eliminates it through MAO by Oxidative Deamination. So what are you proposing CYP2D6 metabolizes DMT into, which would then be further metabolized by MAOs?

Hey Endlessness, just so you know i know the potential for ss with RIMA's with perhaps something like high doses of Prozac could very well indeed be a cause for concern but i just simply watch what i take, and if i take something that creates the possiblity of ss i approach with caution and responsiblity. Though i've found a couple of studies where combined use of paxil i believe and perhaps even low to regular doses of prozac, along with Moclobemide and it was actually tolerated pretty well apparently. And the sources for those were stored in my bookmarks on my computer before it crashed, but i'm sure you can find it, just search up on Pubmed SSRI and RIMA.

Also about the whole MDMA and RIMA thing, i don't believe it's MAO-inhibition doing that, it's the fact that Moclobemide inhibits CYP2C19 which according to a paper i read last night, that is where the harm comes from as CYP2C19 metabolizes MDMA more than CYP2D6 does, thus the inhibition of CYP2C19 is causing much higher levels of MDMA into the system as well as prolonged exposure to it. Nothing to do with MAO imo.

http://psychedelicresearch.org/?p=78 - Something i just noticed though when re-reading this article, it states that MDMA actually inhibits CYP2D6, so a way one could possibly test my hypothesis is to take some MDMA, no MAOI, and once the timing is right, take same DMT, and see if it might become orally active. Then again MDMA would increase Serotonin, which might mean more DMT is needed. "They estimated that CYP2D6 levels are still only at half-normal 46.6 hours after 1.5 mg/kg MDMA and that it might take roughly a week to return to 90% activity. This estimate seemed a little short compared to an analogous estimate of 70 hours to recover to half-normal when CYP2D6 is inhibited by paroxetine. Given this and some other considerations, they also provided a second estimate (using a biphasic model) that indicated recovery might take even longer: 103 hours to recover to half-normal and roughly two weeks to get back to normal. I wouldn’t regard these as exact numbers, just rough estimates — there are few data points and big error bars."

And with DMT and MAO, i understand it is metabolized into IAA, by Oxidative Deamination. But what i'm saying is i see no way for that to happen, for DMT to be metabolized by MAO, unless it already get's metabolized into something else by the CYP2D6 enzyme, maybe even other CYP enzymes. DMT get's metabolized by the CYP system, maybe to 6-Hydroxy-DMT which is apparently inactive, or it get's metabolized in different metabolites, but either way after it's first metabolized by the CYP system, after it's de-activated, it is then metabolized to IAA through Oxidative Deamination and thus eliminated/excreted from the system.

Not to sound sarcastic , Im really wondering... You're saying all the publications ever written about DMT metabolism, including Jordi Riba's work which was specifically about MAO and CYP metabolism of DMT, are wrong, because 'you don't see it' ? Can you please expand more why 'you don't see it' ?

I'm not saying everyone is wrong, i'm simply saying that i have made the correlation between MAO being inhibited in all studies done, and the MAO-inhibitors all seemed to have inhibited CYP2D6, and possibly other enzymes. I personally haven't come across anything, that mentions MAO being activated by a specific MAO-inhibitor that doesn't also inhibit the CYP system, ya digg? I mean, to me it just seems like an area that people should look at just to make sure, and if my hypothesis is deemed inaccurate and MAO somehow really is what first metabolizes DMT, then i'll accept that. But as of right now, i feel there hasn't been much study in this particular area and would like to see it looked at, if anything to just cross it out.

And like i said, in the video (the first link posted on the first post of the 2nd page here), the guy specifically talks about how after hydroxylation comes elimination, if it's an amine compound, by Oxidative Deamination.

Thanks for expanding your thoughts. I would think that what you mentioned would not have passed unnoticed by the researchers, but I think for the moment, unless some expert can post something we are missing here, we will have to wait for Jordi Riba's unpublished paper to come around. Basically he mentioned the different metabolites of DMT and how use of MAOI shifted the metabolism of DMT towards the CYP side, while without any MAOs, it was clearly the MAO metabolites that were excreted without the CYP action. They tested this with oral DMT+MAOIs, oral DMT without MAOIs and smoked DMT. I do no think he tested a CYP-only inhibition though.

Thanks for understanding Endlessness, it's just been something that has really been on my mind since the middle of last year, and makes more sense to me than MAO does for others, i guess. I'll def. look forward to seeing Jordi Riba's paper when it is published, and maybe that can explain a little more. And while i don't have any concerns about the DMT to IAA metabolization, it's just that CYP issue that has me all wrapped up in confusion because if CYP2D6 (and maybe others) aren't inhibited, i would think it would indeed rapidly metabolize it into something that MAO then comes around and metabolizes that something into IAA, which if i'm not mistaken has been found to be about 50% of the main metabolites recovered in urine.

And i'd really like for someone to study purely the CYP inhibition factor, without MAO being inhibited. I'd do it myself, though i don't know of any good CYP inhibitors except for maybe some Black Seed which i plan on getting soon - http://www.ncbi.nlm.nih.gov/pubmed/20201775

If CYP2D6 is inhibited, say for instance with Harmalas or another MAO inhibitor, DMT doesn't get metabolized and it carries out it's effects, then when the CYP2D6 inhibition frees up a little it's then able to metabolize out the MAOI along with the DMT and the DMT obviously get's metabolized into IAA but i think only after first being metabolized into something else, like 6-Hydroxy-DMT. From there, i further hypothesize that if MAO-inhibition is left out of the picture, DMT still becomes orally active and the inhibition of CYP2D6 (and possibly others) could not only increase the bio-availability of DMT causing a greater intake of the compound IE potency, but also extend the exposure to the compound IE duration, both of which right now MAO-inhibition is attributed to. And that's not to say that MAO couldn't be part of the picture, because it could serve it's role, but i'm looking more towards the CYP angle.

Oh, and CYP2C19 and CYP2D6 are in both the small intestine and liver. Which means that as DMT is being digested, it get's deactivated, but at this time the question is whether it's deactivated by CYP or MAO, and if RIMA's are used to activate DMT orally then how much metabolism shifts to the CYP system?

Btw, while we are at it, anyone know of other natural RIMA's? I read that Quercetin is able to inhibit MAO-A reversibly, has anyone here perhaps tried using it even in high doses or even some other natural MAO-inhibitor besides the Harmalas, to orally activate DMT? The lack of success stories it seems either means Quercetin and other natural compounds that are thought to inhibit MAO-A really doesn't, or it means that something is missing, maybe like CYP inhibition...

I know people, especially here at the nexus, have most likely discussed this kinda stuff alot, but i'm an ask questions kinda guy and it just doesn't make sense to me that there aren't other natural MAO-A inhibitors out there, or something else out there, that can make DMT orally active. But if you ask me, i think there's way more to stuff like DMT/Ayahuasca, and plants we haven't re-discovered, and i think we should really try to work with these things in order to further our knowledge and experience.

Btw, this Ethan McIlhenny guy - http://www.youtube.com/watch?v=pUKW24R9o5U - even talks about how using IAA as a marker for DMT metabolism doesn't seem so complete, picture wise, and he wants to study the pathway for endogenous DMT.

If you had CYP2D6 hydroxylation of dmt prior its oxidative deamination by MAO, then you should end up with 6-OH-IAA, not IAA. In other way, any IAA end-product means that no hydroxylation was involved in the metabolism of dmt. Any 6-OH-IAA presence means that dmt was hydroxylated (presumably by CYP2D6) prior to its oxidative deamination.

Is there evidence of 6-OH-IAA being a dmt metabolite in humans? At least this study, showing that excretion of ayahuasca matebolites, does not mention any hydroxylated IAA derivatives...it does demonstrate that ~50% of dmt is excreted as IAA that argues against any hydroxylation being a major mechanism in dmt deactivation.

Normally you'd need the ration of IAA vs hydroxylated IAA (vs even dmt n-oxide) metabolites in urine and or plasma before even start discussing which is the main pathway(s) of dmt metabolism, no?

(EDIT: also it is worth mentioning that harmine and harmaline are ~1000x better at inhibiting MAO-A than CYP2D6 - worth noting when speculating what get inhibited and what not...)

From my understanding though, 6-HO-DMT wouldn't change into 6-HO-IAA, it would go from 6-HO-DMT to IAA through the CYP system. From what i'm to understand, the CYP system, after hydroxylation, comes Oxidative Deamination by MAO which i would think would go on ahead and convert it to purely IAA without the 6-HO. I didn't even think about the possibility the IAA outcome could be a hydroxylated IAA, because to me it seems that it wouldn't matter about the hydroxylation, that either way the IAA is still the result.

Could you perhaps link me to something that talks about a hydroxylated product turning into a hydroxylated IAA product? I always thought that Oxidative Deamination was supposed to strip everything as it turned the compound into IAA? If you could, since i don't know really that much about chemistry, could you please explain to me why the 6-HO group would still be intact with IAA? That would be a big help in me trying to understand this stuff.

And also, if the Harmalas are better at inhibiting MAO-A than CYP2D6, then how come Ayahuasca inhibits it's own metabolization through the inhibition of CYP2D6 for which it is a substrate for? And also why is it that even though Moclobemide's MAO-A inhibition last's atleast 8 hours, but DMT still gets metabolized out when Moclobemide is metabolized and excereted which would mean it's no longer inhibiting CYP2D6 and CYP2C19 as it's already been metabolized out by the CYP system?

I'm just trying to find out what else is metabolizing DMT, that's what got me started on this whole CYP thing, yes i had some speculation, speculation which could very well be nothing, but if not the CYP system responsible for DMT's destruction even with MAO-A inhibited, then what else is there? Also why don't other natural MAO-A inhibitors work for orally activating DMT?

Or, instead of hydroxylation it could be from demethylation... I just think there's more to all this than we think, and even if it's a dead end i want to figure this out, if anything, just to figure out what's going on with the Moclobemide and why it seems to allow DMT to be degraded, whereas the Harmalas seem to recycle the DMT, so even if i could just extend the Harmala's duration, that would in turn extend the duration of DMT.

It is wrong to think that the result of dmt hydroxylation would end up being IAA, at least without evidence about it. It really makes no sense to add a hydroxyl group just to remove it later on on the pathway.

MAOI makes DMT to IAA

CYP2D6 (as you propose) makes DMT to 6-OH-DMT

And to make IAA from 6-OH-DMT you have to
1. either first remove the hydroxyl group to make DMT again (which would make no sense- why would a pathway add a hydroxyl group just t remove it later??) or

2. deaminate 6-OH-DMT to 6-OH-IAA using the MAO system and then remove the hydroxyl by some unknown mechanism?

So what is the evidence for the latter?


I do not think I follow here. You mix a lot of pharmacokinetical anecdotal observations and speculations?

Harmalas are 1000x times stronger MAOI inhibitors than CYP2D6 inhibitors - this comes from experimental measurements, not "ifs" and "maybes".



It could possibly be that that's all there is to the metabolism of dmt...

Which other (natural) MAOIs do not activate dmt? which experiments established that?


Incorect, see above;

The action of MAO on dmt makes IAA

The action of 6-oh-dmt makes 6-oh-IAA

No action that I am aware of makes IAA from 6-OH-dmt without having to remove the hydroxyl first.

Or, ask yourself, how is 6-OH-dmt broken down to IAA? check the chemical formulas, find the enzymes and tell us how it happens.


Yup!

Well thanks for clearing some stuff up for me there Infundibulum, and of course all that i'm saying is speculation based upon my past experience with things along with as much research as i can do. I just thought that Oxidative Deamination meant that it basically strips everything down and turns it into IAA, so forgive me for sounding like a dummy on that one, at least i'm trying to understand all this.

And alright, so if all this CYP shit is just that, shit, then why is the Moclobemide doing what it's doing? Once again i'm sorry if i sound like a dummy, but it doesn't make sense that if MAO-A is still inhibited by Moclobemide, that DMT can still be broken down even though MAO-A is still inhibited. The Harmalas to me do seem very potent at what they do, and there is probably nothing else out there like them, but i can't help but wonder just what is going on here. And besides that, the placement of MAO in this equation doesn't make sense to me either, if anything, MAO breaking down DMT is a highly random thing if you ask me, afterall, the CYP system is indeed a system of enzymes whose prime responsibility is to activate/deactivate and metabolize/breakdown compounds. To me this really does sound like a freak occurrence with MAO being involved. Am i missing part of the picture when it comes to MAO? Is there something else i'm not aware of MAO being a part of? It just doesn't make sense to have MAO, which breakdown neurotransmitters, to breakdown DMT and maybe PEA and a couple others but nothing else?

And apparently i'm not the only one who thinks there's more metabolization pathways with DMT than just MAO, a lot of the recent studies i'm seeing seems to indicate other metabolic pathways involved with DMT, and of course that is when MAO is inhibited, as Endlessness was pointing out earlier how when MAO is inhibited things shift to the CYP side. So even if MAO still has to be inhibited, what are the chances that we could perhaps inhibit another point in DMT's metabolization, or even the MAOI's metabolization, in order to stretch out the duration more?

And when i talk about other natural MAO inhibitors, i mean things like Resveratrol, Quercetin, Piperine and Curcumin, which have been said to posses MAOI properties for both A and B, i think mostly B though, but if i'm not mistaken they have also used pharmaceutical MAOI's that inhibit B, to orally activate DMT, or did they? And i know DMT is more selective for A, but if some of these MAOI's also inhibit A, then shouldn't it work? And also i know the IC50 values are really weak conpared to the Harmalas, but even at higher doses something should happen, one would think... Back last year when i was really looking into this, as to try to avoid the stomach discomfort that comes with Harmalas due to me already having gut issues and that combined with the Harmalas gut cleansing it just got too much, so i started looking into other alternative MAO-inhibitors, and kept reading reports about how people have tried taking the flavonoids and other compounds, and even in high doses they still couldn't achieve oral DMT success, though now after re-looking up on them i think i'm starting to see why. Anyways does anyone here know of anyone whose perhaps tried and succeeded? I mean surely if DMT IS indeed metabolized by MAO, and these compounds are indeed MAO-inhibitors, then shouldn't these compounds also protect DMT and make it orally active? Though i'd still like to know why Moclobemide's MAO-inhibition would still be there yet DMT gets metabolized out after 1 to 2 hours while the MAOI is still in effect, what's going on there?

Oh well, i guess my "alternate hypothesis" wasn't as i thought it was. Well, atleast there is still Changa, taking Harmalas sublingually as well as smoking them, drinking Lemon Balm or Passion Flower tea for the flavonoid MAOI's to extend the smoked duration. Damn, and i really thought i had something going there, guess not.

Btw, by the "Yup" about demethylation, does that mean you think CYP's demethylation could play into this? Please do expand on that if you can.

Well anyways, i have one more question... Suppose one smoked a bunch of freebased Harmalas for about 30 minutes or so, took some DMT orally and then kept smoking on the Harmalas for another hour or so, could one perhaps achieve oral DMT status, or maybe even try it with sublingual Harmalas? The only "no because..." i've heard about the smoked Harmalas before was because it apparently would take a lot to be smoked in order to inhibit MAO in the gut, then again that's with things like Caapi leaf Changa with no freebased Harmalas.

And is it possible that by inhibiting the CYP enzymes that you can potentiate and possibly lengthen a Harmala dose, thereby increasing the DMT's duration?

No problem Oxidative deamination is, by definition, deamination (removal of amines), not dehydroxylation (removal of hydroxyl groups)


Moclobemide is, just like harmalas, a reversible inhibitor of MAO (abbreviated as RIMA). RIMAs attach to MAO enzymes in an on-and-off action, so obviously when a MAO enzyme is not occupied by a MAOI, it can go and deaminate dmt.

Also, the MAO system is not a highly random thing and most certalnly not a freak occurence. Just as the CYP system is there to neutralise and aid the excretion of xenotoxicants, the MAO system exists to protect you from potentially poisonous amines/alkaloids from the diet. There are numerous (potentially toxic) substances that are broken down by MAO - dietary tyramine is one example.


Surely it is wrong to say that the MAO system is the only one that metabolises dmt. It could be all sorts of other things (CYP included of course). But from what we know so far, the MAO system accounts for over 50% of dmt metabolism, with dmt oxidation to its n-oxide accounting for another ~10%. What happens to the other is a matter of speculation; It could be CYP (but evidence so far is either against or scarce), or it could be that the rest dmt is used by the organism "somehow" (as a building block for other stuff perhaps?) and not metabolised for excretion. Always bear in mind that the MAO and CYP systems motebolise substances to ease their removal from the body and there is no need to assume that EVERYTHING has to be removed from the body.

Also, we could indeed find a CYP inhibitor that blocks another matabolizing pathway of dmt (or even harmalas) to lengthen a trip. The sky is the limit.



Without knowing how much of these other MAO inhibitors those experimenting people took AND the strength of the inbibition, it is very hard to draw any conclusions. I am more inclined to think that these people just didn't take enough.



No, I meant MAO dementhylation