Hi all,

SWIM'd like to start a theoretical discussion about the pharmacokinetics of dmt. What he is aiming for is a way to prolong the peak of a smoked dmt experience, which in itself can be unrewardingly fast. He hopes that the discussion will bring valuable testable points that will possibly lead to longer peak experiences.

As with every drugs, so dmt to be effective has to enter the body somehow, then exert its actions and finally be cleared off by some mechanism. We already know that MAO-A enzymes break down dmt in the digestive tract; inhibition of these enzymes is the key to oral dmt administration. Oral dmt can be quite long (3+) hours but less intense than smoked dmt.

What happens when dmt is smoked? The freebase travels from the lungs, to the bloodstream then through the BBB into the brain and straight on its cognate receptors. There it exerts it effects and after 5-10 min the effect starts fading away leaving an afterglow of 20-30 min.

SWIM questions; what is the determining factor for the quick cessation of the peak experience? He can think of 3 possible mechanisms, not mutually exclusive of course:

1. rapid turnover of dmt in the brain
2. quick tolerance build-up (receptor downregulation?)
3. exit of dmt from the brain/areas of action


1. Rapid Turnover

We already have anecdotal data about disrupting the turnover of dmt but certainly not the whole story. Inhibition of MAO enzymes in the body (oral/sublingual/smoked harmalas) followed by dmt smoking does affect the experience albeit slightly. The peak becomes slightly longer (2-3min?) and yet the after-peak appears to be definitely longer. Visuals may last up to 1 hour. So inhibiting enzymes involved in the turnover does have an effect on the duration.

Sadly however, the peak experience is not greatly lengthened. Could there be another pathway of dmt clearance in the brain other than MAO-As? Or could it be that the brain contains different isozymes (enzymes with same core function but different in details) of MAOs that are not strongly inhibited by harmala MAOIs???

2. Rapid tolerance

The rapid tolerance build-up appears an attractive mechanism for explaining the quick termination of the peak. But this is crazy, there are not many substances in general that evoke such a quick tolerance! And how this tolerance is expressed at the molecular level? One of the most common ways of tolerance build-up is the degradation/internalisation/deactivation etc of the receptors the dmt acts upon. But this is really too fast a mechanism to account for such a quick tolerance build-up. If tolerance accounts for dmt peac cessation then it must be some pretty sleek mechanism. Tolerance does not only build up quickly but it is reversed quite quick as well; 30 min after smoking dmt there is litte if any tolerance left. What molecular mechanism could account for such a response?

Should quick tolerance be responsible for the short effects, then the question is; is there some pharmacological intervention that would stop receptors from becoming unavailable to dmt? Is there a pharmacological agent that has been shown to, say stop the tolerance build-up for other psychedelics such as LSD or psilocin or even other fast-acting ones like 5-meO?

Another mechanism for peak cessation may be the rapid uptake of dmt intracellularly. This means that it is no longer able to act on its receptors and the peak experience fades. This point has actually been demonstrated; dmt is a substrate for both SERT and VMAT2, the transporters responsible for reuptake of neurotransmiters like serotonin. Should SERT and VMAT2 rapidly clear off the dmt from the synapses, then the peak experience ceases and a little dmt is left to act on the synapses thus making the post-peak experience. The fact that dmt also activates the intracellular sigma-1 receptor also fits nicely with this theory; after the peak, the internalised dmt assumes different targets to exerts its afterglow effects.

Should this be true, would inhibitors of SERT or VMAT like SSRIs increase the peak experience? Have people who take SSRI's noted an increase in the peak experience?

(Also guys, am I missing any other tolerance build-up mechanisms here?)

3. exit of dmt from the brain/areas of action

Well, for this last one SWIM really has no clue; but has anyone ever heard of such a strategy, i.e. quickly go in the brain, do the deed and quickly move out of the brain. Guerilla attack?

Please share your thought, of course SWIM's missing an awful lot of things but he believes that people may come with valuable information and discourse that may help (theoretically always) to increase the duration of a smoked dmt peak.

I think Antrocles' post "reconstruction" in DMT Experiences is relevant to this thread. Worth a read for sure!

Seems like with enough MAOI on board one can have a pretty long peak.

Pokey

Before we get started I'd like to add that messing with the pharmacokinetics of drugs can be a very very risky thing to do. So lets make sure everyone knows this is theoretical before thinking about taking weird drug combinations. Anyway since I find pharmacokinetics of drugs interesting I have some input.



There is enough evidence to suggest that indolealkyleamines like dmt bufotenine 5-meo-dmt etc are metabolized by other enzymes other then MAO although MAO certainly seems to be the most important. Mechanisms reported that dmt and 5-meo-dmt are metabolized by deamination (probably by MAO), O-demethylation (for 5-meo-dmt via CYP2D6), and N-oxygenation which makes n-oxides. N-oxides are actually major metabolites in rat tissue. Anyway there are other pathways.

More info on pharmakinetics of these compounds can be found on this paper where I got the above:

Indolealkylamines: biotransformation and potential drug-drug interactions. 2008 Ai-Ming Yu American Associations of Pharmaceutical Sciences.

But if they are metabolized by cytochrome p450 enzymes perhaps this is predominantly taking place in the liver. I never heard of cytochrome p450 enzymes being in the brain but I really don't know.

Taking cytochrome p450 inhibitors is super risky with other substances. Plus so many of them its important to know which one to inhibit. More needs to known and learned.



These are good questions. Although I do not recommend anyone combine SSRI's with DMT because of the potential for a kind of seretonin syndrome to develop is there. But it would be interesting to hear from anyone who has gone against the advice of their doctors and took something like dmt 5meodmt or bufotenin while taking an ssri. I have heard that being on SSRI and taking something like lsd dulls the experience. Which I guess is odd because you would think it enhances it?



Also a good question. Its possible that something like what goes on with cannabinoid receptors is going on. Endocannabinoids act as retrograde signals. They get released from postsynaptic neuron and bind to CB1 receptor on presynatic neuron which can have an inhibitory or stimulatory effect depending on the neurons they are on and other factors. It might be something like this. Might not be CB1 receptors but something that has similar functions for the receptors dmt is active on? Something like this could explain why smoking weed enhances tripping on lsd or shrooms. But tolerance I am not sure? LSD and weed certainly leads to greater effects but many people find dmt dulled by cannabis so there must be more mechanisms involved other then 5-HT2a for dmt anyway.



I guess this depends on the question of whether or not drugs circulate the body after going to the brain and before being deactivated. This is tough pharmakinetics to measure but possible. Some stuff on this must have been tested with other drugs. The rate of turnover in the brain and liver for examples. How inhibitors effects levels etc.

i have a friend who would eat lots of rue(hes a tough nut) and then smoke large amounts of dmt...and be gone for 6 hours at a time...id have to say..that with enough harmalas in the system that if the dmt was ejected from the brain..the harmalas keep it circulating..

also i have had pharma experiences that have totally surpassed any smoking experience that i have had..with the peak lasting 3 hours..even with massive purging...if i had been alone..and been able to sink into it smoother..i would have been in hyperspace for a loooong time...


but by adding harmalas to my smoking mixture..it does lengthen the peak..but as you said...not by much...but also...im guessing i only get a few mg of harmalas from a smoked dose of changa...im sure if i took enough for full mao inhibition...that the peak would last hours...

Agreed good pharma dose can surpass smoking and last a long time. Wouldn't even want to potentiate that kind of experience with any other substances as harmaloids and dmt get really strong orally.

Either way pharmacokinetics is interesting.

Beside MAOI's, there might be some other ways to increase the intensity and duration of a DMT-peak.

I have no experience with a datura/smoked DMT combo, but i know from experience that it can make oral psychedelics more intense and last a little longer (although this is mostly the afterglow effects).

Another thing is that some psychedelics have synergistic effects with DMT. They can not only potentiate the DMT effects, but also increase it's duration because the threshold for DMT becomes lower, so when the DMT level in the blood sinks below the normal threshold level, effects can still be felt and because the brain activity that's generated by DMT is simmilar to the brain activity generated by these synergistic substances so that the brain seems to keep hanging longer into this 'psychedelic-mode' state, or makes no longer a switch between DMT-state and sober but a smoother and thus slower switch.
Experience from me and others confirms that synsegistic substances can increase duration, but how that works is ofcourse nothing but speculation.

I have quitted cannabis, but i remember that it could bring back LSD effects when smoked very shortly after an LSD experience, and that it could stretch the effects of LSD for a few hours. Since LSD has simmilar mechanisms of action as DMT, this might be true for DMT as well.

Another thing that might work is sleep deprivation. When the brain is tired, it might take more time to 'restore' the normal functioning-mode.
I have never timed it, but i belief that oral psychedelics always last a little longer for me, when i take them at night and stay awake for that night.

i noticed that with mixing bufotenine and dmt..the effects of both increased dramatically..and also increased the duration A LOT...like...still having visuals the next day after a 4-5 hour journey on a bufotenine and dmt changa mix..

so i wonder if smoking a few milligrams of bufotenine right before a dmt blast off would increase the duration..perhaps ill try this next time

Thanks for the input everyone!

SWIM was thinking make a small experiment with kanna and smoked dmt. Kanna is anecdotally reported to have SSRI activity that may increase the action of dmt by allowing it to act longer on its target neurons. Or combine kanna with, say, harmine and then smoke dmt.

SWIM's planning to chew 1g of kanna for 15 min before blasting off. Has anyone tried this combination? He's tried smoking dmt along with kanna in the past but he didn't really like the experience. It became too dark red in colours, too robotic and too insect-dominated. It was a single try though, he's not saying that this is the consensus alteration of experience when dmt is combined with kanna!

The user ms_manic_minxx asked me to post this info here since he's in the nursery and cannot post on these sections:


SWIM thanks for the info and wants to ask whether anyone has similar experiences.

^^probably seretonin syndrome developing. serious and potentially fatal.

That's what I think. SWIM was thinking to start with chewing a small amount of kanna (250mg) and smoke dmt 30-40min later.

This is different from combning MAOI with Kanna's speculative SSRIs but still it's safe to start low and increase the dose steadily.

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Once, some rue seeds were consumed as a tea. About two hours later some secret ingredient was vaporized to no effect. No immediate effect that is. About five minutes later, one was in a place they'd never been in before. Beware that rue can offset the onset( ) by a few minutes. Be careful. Also, you are in the zone for a good bit longer than vaped alone.

Try sublingual FB with predosed sublingual harmala. It burns but it is OH SO NICE!! Easier onset, longer lasting than vaped, very little harmala is needed.


Also, one had tried Kanna before sublingual FB and found it more euphoric. This was a single session only so more research needs to be done. ~40 mg Kanna followed by ~40 mg FB. No ill after effects.



Espiridion

Hey Infundibulum did you ever try this combo out ?

Has anyone looked into piperine which is easily extracted more or less from common black/white pepper?

It has some CYP450 inhibiting properties but..thats NOT the interesting part. The interesting part is that it is a P-glycoprotein inhibitor.It goes without saying,but lets say it : be very very careful. Still, look into it in wikipedia and over at google to see what it can do.

I propose it more or less as a method of targeting Infundibulum's 3rd proposed mechanism of action.

I asked my friend and he told me that he can't imagine taking Freebase sublingual....it feels like it destroys your mouth...how does fumarate feels like?

SWIM tried kanna (250-500 mg) before smoking without feeling any change in the peak duration. However, that dose is quite small and kanna may require more than one hour to be fully assimilated.

I’m resurrecting an old thread rather than starting a new one since I have questions and observations regarding pharmacokinetics of DMT.

So far, this thread mainly discusses how to extend the duration of an experience, but what I’m more interested in is extending the depth of the experience without blackout or memory loss. It seems it can be done by taking a dose very quickly.

Let’s say you normally take a 30mg dose in 3 slow hits. How long does it take to get the full dose into your body? Here’s an example:

1st hit: 20 sec. inhalation, 15 sec. hold = 35 sec.
2nd hit: 20 sec. inhalation, 15 sec. hold = 35 sec.
3rd hit: 20 sec. inhalation

So from the start of the 1st inhalation to the end of the 3rd inhalation is 90 seconds.

If this dose is inhaled in a single quick inhalation, the start to finish time is 10 to 15 seconds.

My observation has been that a single quick inhalation produces an experience of much greater intensity than the same dose taken in 2 or 3 hits. And it seems that memory is not affected as much either.

What do you all think?

(With the proper equipment and technique, it’s relatively easy to inhale a 30mg dose in 10-15 seconds. I have average lung capacity at best, and can do it without difficulty.)