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 TurnoverWe 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 toleranceThe 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 actionWell, 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.
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