Is DMT the only psychedelic that tolerance cannot develop with? From my experience 5-meo-DMT seems to have this property as well.
Does this happen with MET, DET, DPT or DiPT?
I know tolerance doesn't develop with oral DMT, would this be the same for other tryptamines + MAOI? Are there any other drugs that do not develop tolerance at all? Maybe salvia?
And lastly, how does this work? Is it dependent on the metabolism of the drug or does it have to do with 5HT-2a receptors?
I know this is more than one topic, but it seems very odd and unique to me, seems like a worthwhile discussion.
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I didn't know that you couldn't build a tolerance to DMT. I recall reading that DMT causes cross tolerance with other psychedelic tryptamines, but Rick Strassman's work suggests otherwise..
Anyways. IF it was true that you could not build a tolerance to DMT, I would think that it may have something to do with the agonistic actions of DMT at the Sigma receptor. While not much is really understood about the sigma receptor, there is information about σ1R's and their actions with various ion channels..
Also worth looking at: Imidazoline receptor - can affect NMDAR's; Trace Amine Associated Receptor 1
Hope this wasn't too disorganized.
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- Dec 2006
This is more of a question than an answer but could it be because DMT might be an endogenous sigma-1 ligand and is well tolerated by the body? In other words, if we had a way of forcing, for example, dopamine through the BBB, would that cause a buildup of tolerance or would it be tolerated too?
Excellent question, now one thing that is to be considered is how we define tolerance. I know several people that have gone on DMT binges (yeah I know...) and apparently over the course of a week there is some tolerance that can build up be it from NT depletion or whatever that case. DMT does not downregulate 5HT2A receptors, which in itself is an interesting effect but compounds only differing by the addition of a hydroxyl on the 4 or 5 position do produce tolerance.
Mind posting the Rick Strassman paper where he mentions tolerance? I'd like to see what he says on the cellular side of things. A pet theory is that DMT being the oily motherf*cker it is binds 5HT2A in a way which prevents the endocytosis of the receptor, while having some negative modulatory actions on various cation channels. That would prevent the tolerance seen in most other classical hallucinogens while at the same time
It also involves 5HT1A agonism so perhaps that helps prevent the body from "feeling" excessive 5HT2A agonism.
I'm doing a term paper on the history of 5HT receptor subtypes and signalling so that paper might actually help me out on the paper and provide a more satisfying answer.
14-03-2012 04:35... these workers found that the 5-HT2C but not
the 5-HT2A receptor showed profound desensitization to
DMT over time. Although these findings were unexpected,
Strassman et al. (1996) have shown that in humans
repeated dosing with DMT did not lead to tolerance.
Therefore, if 5-HT2C desensitization is also occurring in
humans in response to repeated DMT administration, the
failure to observe tolerance to the behavioral effects would
be consistent with a 5-HT2A-mediated mechanism of
Nichols has a paper on the action/pharmacological properties of hallucinogens
That makes the most sense to me too, I bet if you were to keep a DMT trip going for 5-6 hrs by continuous infusion or ayahuasca or something you'd get a similar degree of tolerance as you would from a mushroom trip.
But I don't know, would be interesting to read this if someone can get it?
Last edited by skillet; 14-03-2012 at 11:33.
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- Jul 2010
Neuroscience and Pharmacology Discussion
Philosophy and Spirituality
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- Sep 2001
- Norfair, Zebes
Anecdotally, I thought that DMT induced profound tolerance, manifesting in a couple tens of seconds following ingestion (eg, smoke that shit quickly if you want to 'break through'), but dissipating in an hour or two. This is in line with the particular time-course of the effects with vaporization or injection of the compound. What is the time course of tolerance to 5-meo-dmt like?
- Join Date
- Jul 2010
Hope that works and you find it useful
35-40mg smoked @ 0:00
20mg smoked @ 0:05
70-80mg smoked @ 0:15
I get a pretty solid trip off the first, with a small little bumper to keep the experience going for a little while, then I end up blasting off in a breakthrough experience on the last bowl. I love doing this so my body and mind get adjusted to being in the world so when I fully launch myself out there the experience isn't as hard to come up into.
actually you CAN develop tolerance to DMT, but it's just not very long lasting, try smoking the same dose constantly throughout the day, and you'll find you won't get as much of a trip as you did when you started. i believe some study found that tolerance resets in ~30 minutes, but i can't remember it so i may be wrong.
doesn't salvia also lack significant tolerance-inducing properties? i suppose some chemicals our body doesn't seem to upregulate to, i believe some studies should be conducted on this
I havent read the whole thread apologize if this has been posted before but this paper provides some insights.