Booster Doses of Only MAOI

[PowerfulMedicine]

It's often suggested that if a person wishes to keep an Ayahuasca experience going for a longer period of time, they should redose with both the DMT and MAOI brews.

Will a booster dose of only the MAOI prolong the effects of the initial DMT dose? For instance if you were to take an initial dose of Acacia confusa and Peganum harmala brews and then take a booster dose of Peganum harmala brew 3-4 hours later, would it intensify the DMT effects further or just add increased psychoactive effects from the syrian rue?

I'm not sure whether or not this is worth trying. The reasoning behind my question is that at some point the MAOI effects of the initial syrian rue dose will decrease. Hopefully the booster dose would increase the inhibition, slowing down the metabolism of the DMT and prolonging the effects of the DMT.

Would it work like this? Or do the MAOI effects only extend to the digestive tract? Would the MAOI booster slow the break down of DMT already in the blood stream?

On a related dose, how is DMT metabolized once it reaches the blood stream?

 

[Sabnock]

I could be wrong, but i do believe redosing the Harmalas will prolong the DMT experience. One time i did redose some Rue seed 2 hours after i had taken some Rue/Mimosa and it made the experience last about 8 hours compared to the usual 4 hours.

I actually have an idea where instead of redosing the Harmalas/Rue, i'd take my Rue and Acacia/Mimosa like usual but also take 2.5 grams of Nigella Sativa aka Black Cumin seed which is said to inhibit the CYP3A4 and CYP2D6 liver enzymes which are responsible for the metabolism of the Harmalas, that way i could very possibly slow down the metabolism of the Harmalas thus causing an extension in the duration of the experience and that should prolong the DMT part. But simply redosing the Harmalas will work just as well, apparently in the jungle they sometimes drink Ayahuasca multiple times and have it last over 12 hours or so.

 

[downwardsfromzero]

I could be wrong, but i do believe redosing the Harmalas will prolong the DMT experience. One time i did redose some Rue seed 2 hours after i had taken some Rue/Mimosa and it made the experience last about 8 hours compared to the usual 4 hours.
[...] apparently in the jungle they sometimes drink Ayahuasca multiple times and have it last over 12 hours or so.

From a purely theoretical viewpoint, I would say this sounds unlikely. Why? Because diminishing DMT effects strongly implies that the DMT has been metabolised (i.e. destroyed) and merely adding more MAO inhibitor won't make it magically reform again.

As regards drinking multiple ayahuasca doses in one session, this does work and if it is from the same batch (which it usually will be) then it means drinking more DMT along with your caapi.

This is in no way belittling the beneficial effects of the harmaloids themselves...

 

[universecannon]

It depends. The amounts, time between doses, and individual differences all factor in. And sometimes the DMT only seems active for a very short period, with the harmalas dominating most of the experience... other times it doesn't seem to stop for hours on end.

Just trust your gut and experiment. But be careful of redosing too much too quickly. Years ago I took 50g caapi with 8g mimosa...It didn't really kick in for whatever reason, so I took another 50g caapi and 8g mimosa....Big mistake lol

 

[Sabnock]

downwardsfromzero, the thing is though, when re-dosing Harmalas, one needs to time it just right. I myself, like to take more Harmalas just as Ayahuasca kicks in 2 hours after ingestion. That way, by the time the experience from the first Harmala dose ends, the second dose will have kicked in beforehand, allowing the DMT to stay around longer (as long as the second Harmala dose kicks in before the DMT is metabolized out).

Also, if DMT diminishes before the Harmalas are metabolized out, then that means there's a secondary metabolism of DMT that is not MAO-A/I dependent, which has been my thought for quite some time, and i think it's the CYP enzyme system that is responsible for the secondary metabolism of DMT, perferably CYP2D6, just like with 5-MEO-DMT - Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions - PubMed

And if that's the case, then taking something like say, 2.5 grams of Nigella Sativa seed, should inhibit CYP3A4 and CYP2D6, which are responsible for the metabolization of the Harmalas, which not only would extend the duration of the Harmalas as well as how much Harmalas are absorbed in the gut, but would in turn ALSO extend DMT's duration.

Or, one could simply re-dose Ayahuasca (both Harmalas and DMT) if they wanna be sure. But i myself, i want to try my best to use as little DMT as possible and use the Harmalas to keep the DMT around. Which, if MAO-A inhibition doesn't prevent DMT from being broken down, then i think people should be trying to figure out what DOES break it down, which is why i eventually want to test out my CYP hypothesis.

 

[PowerfulMedicine]

Because diminishing DMT effects strongly implies that the DMT has been metabolised (i.e. destroyed) and merely adding more MAO inhibitor won't make it magically reform again.

The diminishing effects would imply that some of the DMT has been metabolized, but not all of it. When all the DMT is metabolized, its effects will be over (although any afterglow is probably due to residual neurochemical changes and not the DMT itself).

As the harmalas are themselves metabolized, the inhibition of MAO decreases. Assuming that MAO still plays a role in DMT metabolism once it reaches the bloodstream, redosing with harmalas would inhibit more MAO and slow any subsequent DMT metabolism.

So as long as MAO metabolizes DMT to a significant extent in other parts of the body, a booster dose of harmalas should lengthen the effects.

 

[PowerfulMedicine]

Also, if DMT diminishes before the Harmalas are metabolized out, then that means there's a secondary metabolism of DMT that is not MAO-A/I dependent, which has been my thought for quite some time, and i think it's the CYP enzyme system that is responsible for the secondary metabolism of DMT, perferably CYP2D6, just like with 5-MEO-DMT - Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions - PubMed

And if that's the case, then taking something like say, 2.5 grams of Nigella Sativa seed, should inhibit CYP3A4 and CYP2D6, which are responsible for the metabolization of the Harmalas, which not only would extend the duration of the Harmalas as well as how much Harmalas are absorbed in the gut, but would in turn ALSO extend DMT's duration.

I was thinking about Cytochrome P450 enzymes (CYP) being a possibility as well. I looked at that abstract you linked. I wish I could access the paper, but I'll have to wait until the next semester starts up to see if I can.

According to the abstract, CYP2D6 O-demethylates 5-MeO-DMT. This is also what CYP2D6 dose to other drugs like DXM. N,N-DMT doesn't have any methoxy groups to demethylate, so this enzyme probably doesn't do anything to DMT. But inhibiting CYP2D6 would potentiate and lengthen the duration of the harmalas, which would be helpful.

What we need to find is the enzyme that N-demethylates DMT, since that is the only other enzymatic activity that isn't deamination that could metabolize DMT.

I'm surprised that there hasn't been much interest in using other enzyme inhibitors besides MAOI's to potentiate DMT. DMT is a precious resource that I personally would like to conserve as much as possible.

 

[downwardsfromzero]

I was just pondering whether unmetabolised DMT might get displaced from the enzyme active site or from associated binding and transport sites by harmaloid redosing.

Interesting thoughts there on the other metabolic pathways, certainly worth looking into.

Now I ponder the notion that enzymes facilitate reaction equilibria and might under certain conditions work backwards, e.g. methylating enzyme(s) might then demethylate if there's a low concentration of SAME or other methylating agent (?).

 

[PowerfulMedicine]

I was just pondering whether unmetabolised DMT might get displaced from the enzyme active site or from associated binding and transport sites by harmaloid redosing.

This is what I was thinking, and the reason for this thread. It seems reasonable to think this would be true since, as you previously mentioned, enzymatic reactions operate under the processes of equilibrium chemistry just like all other aqueous reactions.

Now I ponder the notion that enzymes facilitate reaction equilibria and might under certain conditions work backwards, e.g. methylating enzyme(s) might then demethylate if there's a low concentration of SAME or other methylating agent (?).

I hadn't really thought of that. I usually imagine enzymes as catalyzing irreversible reactions for the sake of simplicity. The point of the enzymes in the case of drugs is to change them to a form that is more easily removed by the body. It doesn't make sense for an enzyme to catalyze one reaction back and forth. That would be like doing nothing. Its a waste of energy.

That isn't to say that this isn't possible or that it doesn't happen on a small scale. Life doesn't evolve along totally logical pathways and is never perfectly efficient. I'm sure that under some circumstances there are enzymes that do this, but only when it's thermodynamically favorable. And my guess is that this is only favorable under unstable conditions and with some specific enzymes.

I think you'd have to look into the chemistry behind each specific enzyme if you wanted see if the reverse reaction occurs enough to be significant or if it's even possible. But this could be an interesting hypothesis to explain some of the differences from one trip to the next.

For instance, maybe during one trip the conditions in your body could be slightly more favorable to allow the reverse reaction of some dehydroxylating enzyme, thereby creating small amounts of psilocin or bufotenine and leading to slightly different effects compared to another time when the conditions were less favorable.

This is all just speculation, but it does seem that differences in the production of trace metabolites could play a role in the difference from one trip to the next using the same substance.

 

[downwardsfromzero]

[...]I think you'd have to look into the chemistry behind each specific enzyme if you wanted see if the reverse reaction occurs enough to be significant or if it's even possible. But this could be an interesting hypothesis to explain some of the differences from one trip to the next.

For instance, maybe during one trip the conditions in your body could be slightly more favorable to allow the reverse reaction of some dehydroxylating enzyme, thereby creating small amounts of psilocin or bufotenine and leading to slightly different effects compared to another time when the conditions were less favorable.

This is all just speculation, but it does seem that differences in the production of trace metabolites could play a role in the difference from one trip to the next using the same substance.

Yes, I'm certainly not suggesting that this idea applies to all enzymes. It will also vary between different substrates for the same enzymes. Equilibrium reactions would be more likely where the reactants and products are at a similar energy level - like methyl group transfer - rather than something like an oxidation/hydroxylation at carbon where the products are energetically more favourable than the reactants.

Our bodies are indeed dynamic systems and normally we vary our inputs quite a lot on a day-to-day basis. Our metabolic systems then respond to these variations - "you can never step into the same river twice"!

It occurs to me that the dietary monotony of shamanic apprenticeship, as well as the social isolation often used, may serve to minimise these random daily variations and thus give a clearer picture of what it is being learned. The apprentice will be starting from a clear baseline, so to speak.

 

[Infundibulum]

@downwardsfromzero and PowerfulMedicine

Some enzymatic reactions are not reversible by the same enzyme, such as those that have an energetically unfavourable barrier; e.g. amination of dmt after its deamination by MAO enzymes or other enzymatic reaction that involve hydrolysis.

I also feel that demethylation of dmt to NMT and then tryptamine is a bit unlikely mechanism to stop dmt action - If I remember correctly, in ayahuasca studies where humans ingested the decoction, the only metabolites of dmt detected were indoloacetic acid and dmt-n-oxide. INMT, the enzyme that methylates tryptamine and NMT to NMT and DMT respectively could theoretically do the reverse reaction (i.e. demethylation) but the reverse reaction is energetically unfavourable since charging back s-adenosyl methionine with a methyl group requires quite a bit of energy.

I personally think that it is sequestering of dmt out of where it normally acts that is responsible for the trip slowly ceasing, plus its conversion to IAA and n-oxide (at least that's what human studies tell us re dmt metabolites....) See this (a bit outdated) thread for more. Let's also not forget that dmt is detected in rabbits up to 7 days after injection.

Finally, CYP2D6 may not O-demethylate dmt (for the obvious reasons) but can O-demethylate harmine and harmaline to harmol and harmalol, and both of the latter metabolites are found in ayahuasca drinkers.