Alternative pathways of degradation of DMT and their inhibition

[anonenium]

During maps 2013 there was an interesting tidbit i found in the presentation entitled

'Fourteen Years of Clinical Research with Ayahuasca' by Jordi Riba.


At around 18 minutes in we come to a slide about the bioavliability of ayahuasca and a critical piece of information appeared in the following roughly transcribed quote

"...even if mao were 100% inhibited their would be other pathways that dmt could be eliminated from the system."

Now the slide shows that only 10-15% (in those studies) of all the consumed dmt became bioavliable, which in turn shows two fascinating things.

One that +80% of all dmt consumed is destroyed before use.

And two that in oral administration dmt can be fully active at as low as 6mg 0.6mg/kg and 12.75mg at .85mg/kilo (presuming these numbers of administration hold true).

This also means that the aya experience is only a tiny percent of its true power, which begs this question and research of the community.




What other pathways of degradation exist and how could they be inhibited without harming the individual?




I'm just speculating here, but the implications of this question may be among the most important this community could ever pursue. If bioavaliability was raised to just 20%, it would make the experience more than twice as powerful for the low dose, and if 50% could be obtained, I can't even comprehend the implications.


So please, any information about this would be greatly appreciated.

Thank you.

 

[anonenium]

I wanted to add an extra note because this question has been asked repeatedly.

The route of administration is unimportant to the question of bioavailability of dmt.

You can eat it, vape it, snort it, use a brain shunt, iv, suppository, find a way to absorb it through the skin, all of these are means of administration, but the real question is how do we increase and maintain the bioavliability once it is already there.

Now the inhibitors will most likely need to be eaten or possible iv (the latter is worrying for obvious reason) in order for them to reach proper levels, alternatives may appear as the inhibitors are discovered, it's just speculating at this time, but the critical question that must be asked is not one of administration but one of maintaining bioavliability.

One potential that may eventually come out of this as discoveries are made is that one of the inhibitors may be able to be quickly degraded by a secondary chemical, thus allowing for an emergency escape option to present itself in the future that will break a person out of an experience in around the same time it takes for degradation to occur from non inhibited vaporization (~10-15 minutes), but once again, this is just wishful speculation.

If anyone has additional questions please ask.

 

[adam]

I did a search and seemed this hasn't been answered, what about liposomal dmt? Could this increase bioavailability as it does with vitamin C for oral administration?

 

[Infundibulum]

I discussed some of this in this thread

Pharmacokinetics of dmt/Increasing peak experience - DMT Discussion - Welcome to the DMT-Nexus

Internalisation of DMT within the cells (the synapses where it exerts its effects are extracellular space) is a very likely pathway to inhibit its action, or what we generally recognised as its "action". DMT is also detected in the brains of rats up to 7 days after administration according to a recent study, ie much after its psychotropic effects have ceased which is consistent with the idea that after the trip DMT just goes somewhere else where it doesn't primarily act on synapses

 

[Parshvik Chintan]

eh... just eat enough DMT to compensate, imo.

 

[Creo]

The thread Infundibulum linked to is interesting.

One intriguing idea that comes to mind is that there might be obscure admixture plants already being used by shamans in the Amazon which inhibit the enzymes involved in these other pathways. Or it could be that this knowledge is already lost and is waiting to be rediscovered.

It's humbling to realise how little we know about dmt metabolism at present.

 

[anonenium]

hello

Well after going through for a while i finally something interesting.

https://en.wikipedia.org/wiki/Drug_metabolism.

Under the oxidation title are listed the following.


Cytochrome P450 monooxygenase system
Flavin-containing monooxygenase system
Alcohol dehydrogenase and aldehyde dehydrogenase
Monoamine oxidase
Co-oxidation by peroxidases


Now we know the fourth one, but I have tried to look up and down about their are a bunch of novel pharmaceuticals in the line, but then something else jumped out.

Kudzu.

"Pueraria lobata is a known inhibitor of mitochondrial aldehyde dehydrogenase (ALDH2) and increases acetaldehyde." (http://www.alcoholjournal.org/article/S0741-8329(07)00137-1/abstract). What exactly is in it im not sure, but the side effects can be few if any given the prolific nature where it is applied in herbal shops for everything from vertigo to 'liver cleansing'.


I want an option on if it would be worth the risk of trying to hunt down, brew and consume some Kudzu with the next aya in the hopes with it would prove to be a further inhibitor in this department, obviously I dont even know if that is the case though, the mechanisms may be completely unrelated, since i cant even get the name of the compound yet, but any criticism of this plan would be welcomed.

Thank you everyone.

 

[Gone-and-Back]

Is this an herb? If it is, I say go for it and try to do an extraction on it. Once you get an extract, test it out with whatever means available to see what it contains, and then maybe some conclusions can be drawn out if it is safe with an MAOI or not.

 

[anonenium]

hey thanks for the fast reply

kudzu is a herb, or in some peoples minds a plague upon their land which makes all work impossible (given that the root systems for a single plant can be larger then a car) but it has been used in asian for a whole list of things, so i know im not going to die from it (unless it has pesticide on it) but i still want more information before i jump.

if all works out i will follow what you said to the letter, but im still trying to understand

 

[Gone-and-Back]

What better way to understand then to do an analysis test on the extract or the plant itself? I am no chemist and do not know much about these tests, but there are people on here who do.

Maybe you could try to get Benzym's attention on this one? He is one of the chemists of this community and would know better then most how to perform such tests, and maybe has performed them himself on this plant...who knows?

Maybe you could interest him in doing one if you really think that this is a valid way to inhibit more breakdown of DMT in the system.

 

[arcologist]

I'm no molecular biologist/chemist, but wouldn't aldehyde dehydrogenase operate only on aldehydes (which DMT is not)? I think the low bioavailability of oral DMT is probably due to MAO-B, a kind of monoamine oxidase that isn't inhibited by the harmala alkaloids that are part of ayahuasca. The harmalas reversibly inhibit only MAO-A and so leave the MAO-B system unaffected and may not even completely deactivate MAO-A.

If you're trying to make ayahuasca comparable to a DMT breakthrough I think the best approach would be to take an MAOI that inhibits both MAO-A and MAO-B, but there may be additional health risks associated with completely knocking out the MAO system.

 

[Vodsel]

The harmalas reversibly inhibit only MAO-A and so leave the MAO-B system unaffected and may not even completely deactivate MAO-A.

There is research reporting similar inhibitory effects of harmala alkaloids for both MAO-A and MAO-B in vitro. Source.

Harmaline and harmine showed potent in vitro inhibitory activity against recombinant human brain monoamine oxidase (MAO)-A and -B enzymes (IC50 2.5 and 2.0 nM, and 25 and 20 μM, respectively)

Unless for some reason you get different results in vivo, we should assume harmine and harmaline reversibly inhibit both MAO-A and MAO-B in different degrees.

 

[endlessness]

I once asked infundibulum about this and he explained to me that the IC50 values are inversely correlated to inhibition strenght. This means those values show that harmalas are 10,000 times more potent inhibitors of MAO-A than MAO-B. This was done in vivo and so on, so one needs prudency in establishing conclusions, but this, plus the fact that reports show that strict MAOI diet is not necessary, seem to point out pretty clearly IMO that MAO-B inhibition by harmalas is very small to negligible.

As for DMT metabolism, check out this paper:
http://onlinelibrary.wiley.com/doi/10.1002/dta.1344/abstract (attached to post)

Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids
after oral administration of ayahuasca . Riba et al 2012

Basically there is the MAO metabolization of DMT but also CYP-related metabolization. When using MAOIs, the metabolites will show that it is the CYPs which mostly do the work, but when MAOIs are not used, the MAOs are the main enzymes related to DMT metabolization.

And even when inhibiting MAOs, the MAOIs themselves get eventually metabolized by CYP enzymes, so harmine and harmaline turn into harmol and harmalol, which do not have significant MAOI activity and hence the MAOI inhibition is reduced over time.. This means even when MAOIs are consumed, some DMT will still be eventually metabolized by MAO-As


Last note, please be careful with any plans on experimentation. MAOs and CYP enzymes are there in our body for very important reasons. When you start using substances that affect these metabolic pathways, you affect a host of other processes which go on in our bodies. This can be very dangerous if you don't know exactly what you are doing and which exact components are affected by those enzymes. It might be that you start putting yourself in danger. Ayahuasca is strong enough as it is, if you want stronger trip, just take some more, and I'm sure soon enough you'll reach a point where you'll go like "omg why did I ever want it to be stronger?! I never want to take this again, or at least not for a long time"

 

[Vodsel]

those values show that harmalas are 10,000 times more potent inhibitors of MAO-A than MAO-B.

True, I overlooked that nano- prefix there.

One interesting result in Riba's research is the report of DMT N-oxide as a significant metabolic product, associated to the CYP pathway. CYP enzymes appear to be a minority route for DMT degradation when DMT is ingested alone and indole-3 acetic acid is the major metabolite, but when DMT is ingested with MAOIs, the role of CYP enzymes gains importance.

We have many anecdotal reports of the activity of N-oxide, although less potent and perhaps qualitatively different to DMT. Maybe that change in the metabolic pathways of DMT when ingested with harmalas, with a 10-20% of DMT metabolism going through CYP and resulting in N-oxide, is partially responsible for the differences between parenteral DMT and ayahuasca. N-oxide might act as a modulator of the experience, the same way we know NMT to act.

 

[anonenium]

Hello

Where would I look to find out more about CYP enzyme inhibitors?

Also I wanted to mention, the intent here wasn't to have a "stronger" brew, you could consume till swimming, but I think their is something more important which diserves acknowledgment.

If we can find other pathways to oral activation, and ways to decrease the overall degradation, it would mean that we have other ways to control the experience (or maybe even find an "eject button" to quickly bring a person out of trance), the experience could last longer/last as long as you want and you would overall have to consume less for the same experience.

that measure of control I would find invaluable, sure you can drink a gallon of tea, but if you can have a sip last for twelve hours or be able to be pulled out in 15-20 minutes if an emergency happens, or be able to find a compound which inhibits specific receptors so you only have a partial experience, or another compound that would make the receptors fully susceptible, or increase the transportation rate throughout the body, or you get the idea of what im saying, this would be of great importance in my book.

Thus why im curious about the paths less traveled. we have the proverbial door, but we need to find new ways to get the keys to it and put it in the lock.

 

[Sabnock]

anonenium, me and you, you and i, we are both on the same hunt/course my friend. What your last post said, resonates 100% with what i've been trying to figure out ever since i first took Ayahuasca and started researching more into it, last year. I don't have much time right now to explain what i've found so far on my hunt for this kind of information, however i will sum it up as best as i can.

I personally do believe the CYP liver enzymes are important to this "equation", i've tried tracking down herbs/spices that would inhibit these enzymes in an attempt to orally activate DMT without the need for Harmalas, as well as trying to extend the duration of the Harmalas in order to affect the duration of DMT. I've been up and down this road and almost thought i've about hit a dead end, until i saw that you and others are apparently on the same path as me with this. I had read online many reports of people not being able to get DMT orally activated with other natural MAO-A inhibitors, and that even in high amounts they just couldn't get DMT to orally activate, i attribute that to maybe a lack of CYP inhibition with those MAO-A/I's. I heard that Black Seed (Nigella sativa) can inhibit CYP2D6, but i tried a little bit of the seed oil and nothing happened, though it was only one time i tried and there's many variables with this stuff. I think, if anything, the Harmalas have the advantage of inhibiting the CYP enzymes responsible for their metabolization, which means the CYP enzymes obviously stay inhibited for a good maybe 3 to 4 hours until the inhibition lets up enough for the Harmalas to be metabolized out thus ending the experience and taking the DMT with it.

I've taken Moclobemide many times for orally activating Mimosa inner root bark powder capsules, and while it is said Moclobemide's MAO-A inhibition can last anywhere from 8 to 16 hours from a single dose, Moclobemide itself, the pill, is metabolized out in about 4 hours with a pill half life of about 2 hours. And for me, oral DMT with Moclobemide only lasts about 1 to 2 hours, it comes up, stays for maybe 45 minutes to an hour and then just goes away. And i know the MAO-A inhibition from Moclobemide would still be there due to the potentiation of smoked DMT/Changa (even the Changa get's potentiated by oral MAO-A inhibition).

So what does that tell me? Well for one it says the Harmalas are excellent inhibitors of several CYP enzymes, and that so far on my hunt for this information i haven't found anything else that i know can inhibit the CYP enzymes as good and for as long as the Harmalas do. I surely hope we expand on all this and hopefully we can figure this all out, but like i said, i'm on the same quest as you apparently, glad to have you aboard

 

[endlessness]

Sabnock, I'll continue the discussion we were having on the lemon balm thread here since it's more fitting.

Thank you for correcting me there about harmala being a CYP inhibitor! I've looked through the publication though, and it's a bit weird because at no point during the paper, appart from the abstract, do they mention anything about harmala inhibiting CYP 2D6. They just mention harmala is metabolized by it.

It seems that what the logic is (correct me if I'm wrong), is that any substrate to an enzyme is in a way an inhibitor of it, since it temporarily occupies the enzyme and prevents it from working on other. But this is not the same as an actual effective inhibitor of it.

Also, didn't you kinda contradict yourself by first saying moclobemide doesn't work as good as harmalas due to harmalas being CYP 2D6 inhibitors, but then you said that moclobemide is also an inhibitor of CYP 2D6? By the way do you have any other source that mentions harmala being an inhibitor of CYP 2D6, or is the only mention of it in the abstract of that paper (I'm attaching it to this post) ?

Jordi Riba mentions that when one ingests harmalas, the metabolism of DMT shifts a bit to the CYP side (not sure if also 2D6), which is also what happens when one smokes DMT bypassing the first-pass metabolism (info from his talk at a conference, I dont think its published yet). Though MAOs will still eventually metabolize at least part of the DMT, so even if in theory you could totally inhibit CYP enzymes (which could be dangerous, but that's another story), it would still be metabolized by MAOs, so I don't think you can have an orally active DMT without inhibiting MAOs too.

Also you mentioned something in the other thread about how 'moclobemide's DMT activation is only as long as CYP are inhibited by moclobemide', but why are you so sure of that? Do you have any data on how long CYP is inhibited by moclobemide? Also any IC50 values so we know how strong that is?

Anyways, interesting discussion, thanks everybody

 

[Sabnock]

Hey Endlessness, the sources i've come across that mention Harmalas being CYP inhibitors (not just substrates but also inhibitors), are just various sources i had come across by hours and hours of endless searching for answers on the net. I wish i could list all the sources but in order to do that i would have to take the time to re-search and try to find all the sources that talked about the CYP inhibition, which could take some time but later on tonight when i have time i will try my best to find what i can to present to you. The paper i provided the link to talking about it's metabolization was only as an example to show how people metabolize the Harmalas differently due to the CYP enzyme. And yes it does mention in passing that it's an inhibitor, and doesn't go into any detail, so that's not particularly a paper that has any relevant information on the CYP inhibition factor. So when i get the time tonight i will most certainly re-trace my steps and try to find you the paperwork. My computer crashed here recently so i've lost all most backup information for the time being so forgive me for not having this info fresh off the bat for ya, even though it's something i've been wanting to talk to the Nexus community about for awhile now.

And when i say it's an inhibitor of the CYP enzymes, i do mean it inhibits them for a period of time, not just in passing temporarily.

The Harmalas, i believe, inhibit the CYP enzymes the same as they do with MAO-A, it keeps these things inhibited, i'm guessing for as long as the Harmalas themselves are active until they are able to be metabolized. In order for the Harmalas to be metabolized, that would mean their CYP inhibition would have to ease off in order for the CYP enzymes to metabolize them out. This would explain why i personally, feel the DMT for pretty much the entire Ayahuasca session, as if the Harmalas continue to re-cycle the DMT, because if the Harmalas recycle the DMT then it won't go anywhere until the Harmalas start being metabolized. And while i realize many things could play into the recycling of DMT, as the Harmalas inhibit several things like MAO-A, CYP enzymes, even Harmaline inhibits Acetylcholinesterase, in my experience with the Harmalas in the form of Rue (never tried Caapi for Ayahuasca), it seems to me the Harmalas are capable of recycling or keeping around the DMT, whereas the Moclobemide does not, which brings to question what is different?

When i talk about Moclobemide, here's what i mean. Moclobemide is just as good at activating DMT orally as the Harmalas are. The thing though is this. Moclobemide usually takes about an hour to two hours for me to really start feeling the MAO-A inhibition. After 45 minutes to an hour goes by (tried it at different times) i'll take my Mimosa capsules and it generally takes an hour to an hour and a half for the Mimosa to be digested and for the DMT to take effect. On an empty stomach though the Mimosa usually kicks in within 30 minutes after taking it. Anyways, i feel the DMT peak and then it levels out for maybe 30 to 45 minutes maybe even an hour, and then i come back down over the next hour, it doesn't get recycled, it just comes, stays very temporarily, and then goes, def. nowhere near as fulfilling as with the Harmalas. And from what i've read, it's been shown that Moclobemide's MAO-A inhibition lasts anywhere from 8 to 16 hours from a single dose even though Moclobemide's half-life is only 1 to 2 hours. So if the half-life is 1 to 2 hours, then that means action on the CYP enzymes should last only 2 to 4 hours, which to me coincides with the timing and duration of oral DMT with Moclobemide. It's like i take the Moclobemide, i take the DMT, the DMT comes, the DMT goes, though the MAO-A inhibition is still there for a good few more hours as i can feel it and plus smoked Changa is more potentiated with oral MAO-A inhibition so i've tested that out as well.


And i don't have anything showing how long the CYP enzymes are being inhibited for, and so far everything i've talked about comes from an alternate hypothesis i've been thinking about for quite sometime now, due to me wondering, seeking answers, experimenting/experiencing with these substances and i've just really been trying to figure this whole thing out. To me, there is something to all this, and for some odd reason it's very difficult for me to move on or to accept that MAO-A inhibition is the one and only route for DMT activation/metabolization as my experience with these things so far has shown me otherwise.

So in closing, later on tonight i will try my best to search and find any and all information pertaining to this issue and will do my best to present the findings to you. I would really like some opinions on this matter, and maybe even some hardcore answers, because i, like plenty of others i'm sure, am fascinated with all things Ayahuasca/DMT.

 

[Sabnock]

Just by a quick Google search i came across this - Inhibition of human cytochrome P450 enzymes 3A4 and 2D6 by β-carboline alkaloids, harmine derivatives - PubMed, talking about the Harmalas being substrates for and inhibiting, CYP2D6.

And here - Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions - PubMed, they say 5-Meo-DMT is a substrate for 2D6 and that 2D6 metabolizes it into Bufotenine, so there's a good chance nn-DMT also is a substrate for 2D6.

Edit - I've been searching for about 2 to 3 hours now, i seriously can't find alot of the stuff i was able to find last year. And unfortunately i had most of my notes on my computer before it crashed Atleast i was able to find that it inhibits 2D6, even if it is in-vitro.

And now that i look back on it, i am pretty certain there were a good few sources which spoke of CYP inhibition (not just of 2D6), afterall i did spend atleast 4 months of hardcore research and contemplating all of it in my head for this whole "alternate hypothesis" thing based upon all the information i had found. But of course last year Google changed their search engine crap and now everything i search for comes up with like 4 results and then 100's of pages it seems like of purely "related" or shall i say unrelated, results, which i really really hate Google for doing that.

So, i guess there goes a good few months worth of being obcessed with this CYP idea, though if there wasn't anything to it i highly doubt i would have pursued it as much as i did, so atleast for now the CYP2D6 inhibition part still stands, i guess.

Anyways though, if CYP2D6 isn't what is breaking DMT down when MAO-A is inhibited, then what is? And i, like many others, truly do believe DMT has a secondary metabolization process, there has to be, everything points to it.

 

[Sabnock]

Does some happen to have this article? - "Hydroxylation and N-demethylation of N,N-dimethyltryptamine" - Hydroxylation and N-demethylation of N,N-dimethyltryptamine - Cellular and Molecular Life Sciences

I would love to get a copy, preferably with some english translation? Thanks

If DMT is also metabolized by CYP2D6, then CYP2D6 could possibly Hydroxylate DMT into 6-Hydroxy-DMT, which according to this - Comparison of a placebo, N-dimethyltryptamine, and 6-hydroxy-N-dimethyltryptamine in man - Psychopharmacology - 6-Hydroxy-DMT seems to be pretty much inactive. So, what if the Harmalas, by inhibiting MAO-A and CYP2D6, is able to keep DMT around until the Harmalas wear off? Whereas Moclobemide's MAO-A inhibition may last 8 to 16 hours but Moclobemide itself is metabolized out in 4 hours which i would think means it's no longer working on the CYP enzymes since it would already be metabolized out, so CYP2D6 would no longer be inhibited thus causing DMT to be metabolized secondarily by CYP2D6.

Also i found this - New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme - PubMed - saying that "CYP2D6 also metabolizes, indolealkylamines. Moreover, the enzyme utilizes hydroxytryptamines, as endogenous substrates."