The ayahuasca effect - The role of MAOI's

[buffachino]

Ok, I thought we could discuss the role of MAOI’s, in combination with DMT and other psychedelics such as psilocin.

Main article by Jonathan Ott.

The general idea is that because of MAO inhibition, levels of endogenous neurotransmitters are increased and could therefore compete with the drug for receptors, thus rendering the exogenous compound less effective.

The benefit is apparently only for oral DMT, in its action of allowing free passage into the brain from the gut.

Other than increasing the absorption of another compound such as psilocin in a similar fashion, use of an MAOI as a potentiator seems counterproductive.

The author commented that the "high 5-HT [serotonin] level" produced by the MAOI blocked the effect of DMT, thought to owe its psychoactivity to serotonin antagonism - with higher background levels of serotonin, higher doses of DMT would be required to produce equivalent effects absent MAOI.

We have seen that MAOI hardly can be said to potentiate DMT; if anything, the reverse obtains, with serotonin antagonism/blockade...

It thus follows that the ayahuasca effect is due to MAO inhibition in the digestive system or blood stream, protecting DMT from metabolism en route to the brain, where the MAOI paradoxically attenuate the DMT effect.

However...

Oral or intramuscularly-injected methysergide (a 5-HT receptor antagonist) was shown to exert a very strong potentiating effect on intramuscularly-injected DMT...

This is consistent with the hypothesis of DMT psychoactivity as a result of serotonin antagonism - MAOI, which elevate brain serotonin, inhibit the DMT effect, and the serotonin antagonist methysergide and serotonin receptor blocker pindolol enhance it.

He also goes on to comment on potentiation (or lack thereof) of psilocybin mushrooms by MAOIs

To be sure, I have heard considerable anecdotal evidence, to the effect that pre-treatment by Syrian rue seeds, B-carboline-rich seeds of Peganum harmala L. used in anahuasca,(5) can potentiate the effects of psilocybian mushrooms, pursuant to this general notion of B-carbolines as all-purpose potentiators of visionary drugs. However, nobody has proffered hard evidence of this, even with the most rudimentary controls. All the anecdotal evidence I have heard concerns vague bioassays involving psilocybian mushrooms as the psilocybin source, sometimes not even weighed doses, but counted, by pairs! Since potency of psilocybian mushrooms is notoriously variable, even in commercially-cultivated Psilocybe cubensis (in commercial-style Mason jar cultures, there was up to a four-fold variation in potency of individual mushrooms from a given jar, even up to nearly three-fold variation in psilocybin content between caps and stems of the same mushroom). Given this gross variation in psilocybin potency, even of cultivated mushrooms, and the fact that, as we have seen, MAOI weaken, rather than potentiate, DMT and LSD, we will need controlled human bioassays with pure B-carbolines and psilocybin in pharmahuasca capsules to establish whether or not MAOI can truly potentiate psilocybin.

So, such a 5-HT receptor blockade resulting from inhibition of enzymatic degradation could possibly decrease the binding potential for exogenous psychoactives. However, this also depends on the relative affinity of the receptors and their subtypes for different ligands and also the extent of the increase in serotonin, which is proportionate to MAO inhibition and individual neurochemistry.

If it is shown that MAOIs do in fact potentiate psilocin’s action in the brain, then the increase in activity is due to:

a) A synergism with the abundant serotonin.

b) An increase in absorption from the digestive tract, leading to more psilocin reaching the brain, in quantities that overwhelm the abundance of competing neurotransmitters.

c) The receptors to which psilocin and other similar psychedelics bind have a higher affinity for such compounds than serotonin.

I find this last option interesting.

If Psilocin is shown to have a higher binding potential than serotonin on specific receptor subtypes, I would think it holds some intriguing possibilities for psilocin’s role in understanding structure/effect relationships in regards to the coding of information through biochemical means.

It would also give credence to T. Mckenna’s stoned ape theory, in that perhaps serotonin emulates psilocin, and that plants shape the human organism, if not all animal life, more than such organisms shape themselves.

What are your thoughts?

 

[Brugmansia]

Interesting. I yet have to experience the MAO factors myself so currently I'm unable to compare this given information with their activity and possible synergy with other psychoactives.

But a question that occupies my mind is how the hell the amazone inhabitants got to know the need for the presence of a MAO in the blood to activate the effects of DMT containing plants...

 

[afer]

A very intriguing question.

c) The receptors to which psilocin and other similar psychedelics bind have a higher affinity for such compounds than serotonin.

I doubt that. It seems more likely to me that the 2nd option has more to it:

An increase in absorption from the digestive tract, leading to more psilocin reaching the brain, in quantities that overwhelm the abundance of competing neurotransmitters.

It's my understanding that serotonin, epinephrine, noradrenaline et al are produced endogenously in very small quantities. Even when their degradation is blocked [which is the case with MAOI], their amounts are negligible compared to exogenously taken ones
Btw, I'dd add the 4th option:

d)The effects of exogenously taken substances overwhelm those of the endogenous ones.

 

[buffachino]

It seems more likely to me that the 2nd option has more to it

I agree option B is the most likely of those I proposed, however we won’t know for sure until tests have been done with pure compounds in vivo/vitro.

Such an undertaking would be complicated because of the differences in individual neurochemistry.

It is also impossible to test exogenous serotonin in vivo for a contrast in potency with psilocin, because of serotonins inability to pass the blood brain barrier.

It's my understanding that serotonin, epinephrine, noradrenaline et al are produced endogenously in very small quantities. Even when their degradation is blocked [which is the case with MAOI], their amounts are negligible compared to exogenously taken ones

It is true that endogenous neurotransmitters are only produced in small quantities and that even with MAO inhibition, their levels in the brain do not parallel the influx of an exogenous psychoactive.

I would think that there would be more enzymatic activity in the gut than in the brain; therefore it would follow that a higher concentration of serotonin in the synapse would fail to parallel the brains inundation by psilocin arriving from the digestive tract.

This would mean that a larger amount of the psychoactive reaches the brain, maintaining dominance over endogenous serotonin which although more concentrated, cannot compete.

Because psilocin exerts its effect in the presence of serotonin without an MAOI, increasing the amount of both serotonin and psilocin would theoretically amount to an amplification of psilocin’s subjective effects, despite there being more serotonin.

It could also be a possibility that when a neuron is stimulated by psilocin, it in turn releases serotonin.

This coupled with MAO inhibition and the ability of the brain to synthesise additional serotonin on demand would increase the amount of serotonin to the extent that it competes more readily with a finite concentration of exogenous psilocin.

It could also be said that, as has been posited of DMT, psilocin acts as an antagonist at the serotonin receptor, preventing the binding of serotonin.
Yet such antagonism, which would result in a decrease in the action potential of serotonergic neurons, does not reflect the excitability that is accountable to psilocin.

So perhaps psilocin and similar psychedelics operate as both an agonist and ‘partial-antagonist’; that is, an agonist which prevents serotonin binding at the receptor. These compounds, although potentially having a lower binding affinity to the receptor than serotonin, once bound to the receptor prevent serotonin from itself binding. This would increase the amount of available serotonin for receptors which are not already occupied by psilocin, meaning that psilocin in the presence of pre-synaptic MAO inhibition would render itself less potent because of its potential action of eliciting serotonin release.

Moreover, psilocin may be subject to reuptake in the same fashion as serotonin, because of the similarity in structure. Thus psilocin could potentially inhibit serotonin reuptake, force serotonin release via the re-uptake transporter as with MDMA (Which is unlikely because of the disparity between the effects of MDMA and those of psilocin), and/or be recycled analogously to serotonin from parasynaptic vesicles upon stimulation of the cell by an action potential. This could also work with stimulation form serotonin, where psilocin is released in cohort with serotonin from activation by either compound on the preceding neuron.

There are many potentialities regarding the mechanism behind psychedelics neuro-pharmacological action, alone and in combination, but because of their regrettable legal status, research in this field is difficult, if not impossible.

All we can do for now is postulate about our own bio-assays in light of what little data is available.

 

[afer]

It's really sad that there's so little data available. I have not yet tried psilocin in conjunction with MAOI, but as far as the DMT goes, there might be something like this[in most of my preparations MAOI was consumed before the DMT concoction, with a 30-minute interval]:
1)MAOIs are absorbed by stomach/duodenum
2)They exert local activity in the gastrointestinal tract and liver, successfully inactivating MAO
3)MAOIs cross the hematoencephalic barrier and act on the MAO present in the brain. As a result, direct psychological symptoms of MAOIs alone are evident [relaxation, giggles, changes in vision etc]
4)DMT, taken 30 minutes after MAOI ingestion, is readily absorbed in the guts, crosses the BBB and binds to 5HT2a receptors. It's my speculation that in may compete with serotonin on those receptors.
Another speculation of mine deals with the bad trips. From my personal exp, as well as from a vast number of others', it's often evident that as the dose goes up, the probability and possibility of a bad trip increases.
It could be explained by the fact that the higher is the DMT [or LSD, psilocine] concentration, the less serotonin can bind to its receptor. And what's the main result of low serotonin? Depression, that's right. Which is strongly amplified by current elevated state and transforms into a bad trip.

And a final note regarding vomiting on MAOI -it could be connected with elevated levels of serotonin in the digestive system, not because of "nasties" whatsoever. Purified extracts cause less nausea though.

 

[buffachino]

It could be explained by the fact that the higher is the DMT [or LSD, psilocine] concentration, the less serotonin can bind to its receptor. And what's the main result of low serotonin? Depression, that's right. Which is strongly amplified by current elevated state and transforms into a bad trip.

I think that difficult or unpleasant experiences from higher doses are not the result of lowered serotonin binding, because the exogenous compounds themselves stimulate the receptor causing the neuron to fire, as does serotonin.

I would posit that difficult experiences from higher doses result from the transcendence of recognised cognitive patterns, which define ones parameters of self reference. Hence, there is usually a great deal of confusion and fear, because the paradigmatic structure of self implicate reflection is overwhelmed by a deluge of inter-neuronal communication elicited by the psychedelic compound.

This is terrifying, especially in those who have a hard time letting go of their self conception.

 

[afer]

Sounds reasonable. I personally find it very difficult to accept ego loss and "let it go". Instead, I often find myself analyzing and trying to logically comprehend what's happening. This, of course, results in even more confusion, as one answer brings tenfold questions, and I ultimately end up suspending in a realm of grotesque and uncertainty, forgetting what I initially started with :)
I'm sure it's all familiar to you though.

This is slightly off topic however, we'd better progress on discussing interaction of MAOI with various substances.
It's interesting to note that traditional Ayahuasca does not seem to cause any tolerance. The brew is often drunk over the course of 2-3 [o even more] consecutive nights. It does not show short-time tolerance either, allowing you to successfully redose if required whilst already under the influence. Which is not the case with most other serotoninergic substances, peyote being an exception to some extent.
I wonder if it's because of the MAO inhibition :?:

 

[GOD]

I`m very interested in this subject but have difficulty in following a lot of what has been said because the english ( not the scientific terms ) is above my head .

So far i think i have understood that no one knows if MAOIs potentiate Psilocybin , that any "evidence" that it does is anecdotal and to find out if it does or not there will have to be scientific tests done . Did i get it right ? If not can someone please explain ?

Another thing that i would like to have clarifyed is that i think J.Ott says that in the quote above......BUT........i`m sure that in a video from the last conference in Basel he said that it definately works ?

 

[afer]

So far i think i have understood that no one knows if MAOIs potentiate Psilocybin

Yep, sadly there's no scientific evidence. From what I've read here and there psilocin is thought to be metabolized by MAO because it's similar in structure to DMT.
I guess the only true way to figure it out is to test it yourself. Let's say, take [1]100g caapi and write down the results. Then, after about 2 weeks, take [2]3 grams of dried shrooms and again carefully observe the effects. After 2 weeks, one should ingest [3]100g of caapi, wait 15 minutes and ingest 3 grams of shrooms. If the exp. [3] will be much stronger than simple exp.[1]+exp.[2],
we can futher talk about some potentiation. Given the same set, setting, and of course batches of MAOI and shrooms. Of course one may use rue instead of caapi, or even moclobemide, for that matter.

Regrettably, all I have now is a ton of caapi, rue, and D.cabrerana [my country is getting more and more strict in its attitude to psychoactive substances, so I stacked myself up in case these would be outlawed], so I can't really test this theory :(

 

[GOD]

But wouldnt that be anecdotal / subjective and not a reliable way of prooveing anything for exactly the reasons mentioned above .

I have 100 grams of capi in front of me now and i think it was a member called endlessness or endless ( sorry ) that said it alone would be hallucinogenic and sugested that i try it . I still didnt do it . Not because it frightens me in any way but because i dont believe it from the scientific evidence that i`ve seen , i dont want to waste it and i cant realy be bothered to take something that might be a waste of my time .

As far as takeing synthetic MAOIs to potentiate DMT or any other drug goes i see no reason to try and wouldnt do it because it hasnt been scientificaly tested and proven that its safe . Another question for me is why try it when P:Harmala is so easy to get , much easyer than chemical MAOIs , and proven to be safe......

But....what about a few of you doing some personal testing as sugested above and letting us know what happens and what you think ? Has anyone here ever tried it ?
.

 

[afer]

As far as takeing synthetic MAOIs to potentiate DMT or any other drug goes i see no reason to try and wouldnt do it because it hasnt been scientificaly tested and proven that its safe

I highly doubt that the safety of Ayahuasca has been proven scientifically. I too, however, wouldn't take synthetic ones, but hey, some pals of mine prefer them to traditional plants, so it's really up to explorer.

 

[GOD]

I think that perhaps 6000 years of human bio-assay is scientific proof . Ask your mates in six thousand years about chemical MAOIs...... and look if their kids , kids have webed feet . Thalidamide was safe.............

 

[afer]

I think that perhaps 6000 years of human bio-assay is scientific proof

No it's not. Christians've been successfully denying scientific postulates for over 2000 years so what :wink:

I agree with you on using established natural sources of MAOIs instead of synthetic ones though.

 

[GOD]

What the fuck has belief got to do with physical proof = the fact that the people in the Amazons dont have webed feet . ( Yes i know thats not well put but if a person thinks about it and trys to understand it they would have to admit what i mean is right ) .

 

[afer]

I was referring to the fact that simply doing something for a long time with success has nothing to do with scientific evidence. YES their experience is credible and important but it was NOT a controlled study and not a study at all.

 

[GOD]

"Au contraire" Quote "Q" .

It is exactly the scientific definition of proof = an experiment that has and can be done with the same results and that for at least 6000 years . How many scientific proofs acepted today can boast that ?

 

[afer]

Oh well. I guess our interpretations of scientific experiment just don't seem to match. I'd rather discuss the topic matter anyway.

 

[GOD]

OK . Me too .

 

[buffachino]

I`m very interested in this subject but have difficulty in following a lot of what has been said because the english is above my head .

Sorry about that. I can get carried away :wink:

I guess the only true way to figure it out is to test it yourself.

Yes, but this needs to be done with pure compounds, not plant material, so that potency is regulated.

Another thing that i would like to have clarifyed is that i think J.Ott says that in the quote above......BUT........i`m sure that in a video from the last conference in Basel he said that it definately works ?

He could have done more testing between when this essay was written and the Basel conference.

But wouldnt that be anecdotal / subjective and not a reliable way of prooveing anything for exactly the reasons mentioned above.

Ultimately the only ‘objective’ way to test for possible potentiation is by taking blood (and perhaps urine) incrementally throughout the sessions and cross referencing the results with dosage and subjective effects over a large span of individual studies, using randomised double blind methods and controls, then come to some kind of statistical average.
Even this isn’t definitive, which I think sheds light on the possibility that initial conditions can never truly be reproduced, results are purely subjective, and psysiological/psychological ‘set’ plays the pivotal role in determining the experience, rather than dose.

Not because it frightens me in any way but because i dont believe it from the scientific evidence that i`ve seen , i dont want to waste it and i cant realy be bothered to take something that might be a waste of my time.

Then you can’t really comment on it can you. It may not be a waste of time, but you won’t know until you try it and find out.
You have to get your hands dirty at some point if you want to learn.

What the fuck has belief got to do with physical proof = the fact that the people in the Amazons dont have webed feet.

The fact remains that there were no scientists around before they started taking ayahuasca to note any possible change in physiology (genetics and so forth) that could have resulted from its intake over a long period of time. This isn’t to say that there have been changes, just that there is no data to inform us either way.

However, I do agree that using plant based psychedelics (including MAOIs) that have been sanctioned by thousands of years of human use are preferable to these synthetic compounds which have a very short history. When dealing with research and pharmaceutical chemicals, one is really playing the guineapig to some extent.

It’s just the risk you take.

All drugs, even plant based ones, must have been tested at some point by people without information about the possible consequences, but it didn’t stop them from doing it and without those first experiments, we wouldn’t know anything at all.
All you can do is work with what you have.

And at the end of the day, when you’re actually on a drug, all that shit goes right out the window, especially regarding psychedelics.
So don’t get too caught up in some kind of need for proof, because truth be told, real proof is hard to come by, perhaps nonexistent.

It's interesting to note that traditional Ayahuasca does not seem to cause any tolerance. The brew is often drunk over the course of 2-3 [o even more] consecutive nights. It does not show short-time tolerance either, allowing you to successfully redose if required whilst already under the influence. Which is not the case with most other serotoninergic substances, peyote being an exception to some extent.
I wonder if it's because of the MAO inhibition?

DMT itself shows little tolerance build-up, so in the presence of MAOIs I would think that repeated dosage would yield equitable results, with at least a small margin of difference.

Here’s a reference from Strassman: http://www.erowid.org/references/refs_view.php?ID=6274.shtml

 

[afer]

I wonder why it does not produce tolerance. Perhaps because it's endogenous?