Bluelight

Thread: Why can't we build tolerance to DMT?

Results 1 to 18 of 18
  1. Collapse Details
    Why can't we build tolerance to DMT? 
    #1
    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.
     

  2. Collapse Details
     
    #2
    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.

    ~snr
     

  3. Collapse Details
     
    #3
    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?
     

  4. Collapse Details
     
    #4
    Bluelighter atrollappears's Avatar
    Join Date
    Oct 2011
    Location
    Philadelphia
    Posts
    396
    Quote Originally Posted by ProducedRaw View Post
    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?
    I don't see why dopamine would cause any less tolerance than any other dopamine agonist; similarly, I don't see why DMT would cause anything that different than a synthetic agent that acts like DMT. An example of this is GHB, which exists in the brain naturally, but causes tolerance. So SNR's logic is right, it should be explained by whatever peculiar actions DMT has.
     

  5. Collapse Details
     
    #5
    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.
    http://www.sciencedirect.com/science...66432896000812

    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.
    Best
    EA
     

  6. Collapse Details
     
    #6
    Edit: Ignore.
     

  7. Collapse Details
     
    #7
    Bluelighter MeDieViL's Avatar
    Join Date
    Feb 2007
    Location
    Belguim
    Posts
    3,113
    Quote Originally Posted by Epsilon Alpha View Post
    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.
    http://www.sciencedirect.com/science...66432896000812

    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.
    Best
    EA
    Many psychedelics also act on 5HT2A; id be very interested in the mechanism behind this.
     

  8. Collapse Details
     
    #8
    Bluelighter Nagelfar's Avatar
    Join Date
    Nov 2007
    Location
    Vancouver, Washington USA
    Posts
    1,132
    Quote Originally Posted by Epsilon Alpha View Post
    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.
    And quite quickly too, if I am not mistaken. Psilocin seems to require many multiples of the dose in not very long of a succession of ingestions. Might environment play a factor? Mushrooms of the sort that are a pro-drug to psilocin are readily available as a foodstuff, might it be as simple as an evolutionary trait for survival? Meaning, might it not be DMT that prevents endocytosis, but that extra hydroxyl that is able to cause it by means of an atavistic genetic programming?
     

  9. Collapse Details
     
    #9
    Bluelight Crew Cloudy's Avatar
    Join Date
    Aug 2005
    Location
    In house of a smoke
    Posts
    5,647
    ... 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
    action
    http://www.maps.org/w3pb/new/2004/20...ls_22684_1.pdf (pg 142, 12 on the pdf file)

    Nichols has a paper on the action/pharmacological properties of hallucinogens
     

  10. Collapse Details
     
    #10
    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 10:33.
     

  11. Collapse Details
     
    #11
    Quote Originally Posted by skillet View Post
    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?
    I have the pdf if you would like, not sure how to post it though... Not yet had the time to have a look at it either, does sound interesting.
     

  12. Collapse Details
     
    #12
    I usually use www.sendspace.com
     

  13. Collapse Details
     
    #13
    Senior Moderator
    Neuroscience and Pharmacology Discussion
    Philosophy and Spirituality
    ebola?'s Avatar
    Join Date
    Sep 2001
    Location
    Norfair, Zebes
    Posts
    19,840
    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?

    ebola

    Getting high? RTFM: Bluelight Drug FAQs | Bluelight WIKI
     

  14. Collapse Details
     
    #14
    http://www.sendspace.com/file/izwxjn

    Hope that works and you find it useful
     

  15. Collapse Details
     
    #15
    Bluelight Crew Cloudy's Avatar
    Join Date
    Aug 2005
    Location
    In house of a smoke
    Posts
    5,647
    Quote Originally Posted by ebola? View Post
    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?

    ebola
    I don't know about that. My favorite way of ingesting dmt goes as follows

    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.
     

  16. Collapse Details
     
    #16
    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
     

  17. Collapse Details
     
    #17
    Quote Originally Posted by bleh123 View Post
    The way I see it, everything agonized should be downregulated by 5-HT agonists over time. The most notable reason why this may not be *noticable* is that DMT is so short lasting due to MAO that some NT receptors may require longer periods of overstimulation to appreciably downregulate. The relative duration of 4-AcO-DMT vs DMT is roughly 50-fold, so less tolerance does intuitively make sense.
    From my personal experience, I've taken oral dmg with a MAO inhibitor in the past on two successive days where both of the experiences lasted 6 or so hours. The one on the second day was much more intense, this could have been due to a buildup of harmaline compounds too, but definately no noticeable tolerance buildup. Sadly though, although the dosages were supposedly the same, because of the nature of ayahuasca brewing you never know what kind of a dosage you manage to extract presicely (we made different brew on both days).
     

  18. Collapse Details
     
    #18
    Bluelighter MeDieViL's Avatar
    Join Date
    Feb 2007
    Location
    Belguim
    Posts
    3,113
    I havent read the whole thread apologize if this has been posted before but this paper provides some insights.
    http://www.mimosahostilis.com/files/...0subjectiv.pdf
     

Posting Permissions

  • You may not post new threads
  • You may not post replies
  • You may not post attachments
  • You may not edit your posts
  •