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What IS Psychedelic Tolerance, chemically?

RhythmSpring

RhythmSpring

Bluelighter
Joined
Jun 19, 2008
Messages
2,256
I UTFSE, but couldn't find anything on this. Basically, I'm wondering why, neurologically, a dose of psilocybin, for example, will be less effective after a recent dose of it.

And would taking an MAOI, in between trips or during the next trip, "reset" tolerance to any degree?

I mean, Ayahuasca, which includes an MAOI, builds up virtually no tolerance, from what I hear. People can take it multiple nights in a row without any decrease in effects.
 
RhythmSpring said:
I UTFSE, but couldn't find anything on this. Basically, I'm wondering why, neurologically, a dose of psilocybin, for example, will be less effective after a recent dose of it.

And would taking an MAOI, in between trips or during the next trip, "reset" tolerance to any degree?

I mean, Ayahuasca, which includes an MAOI, builds up virtually no tolerance, from what I hear. People can take it multiple nights in a row without any decrease in effects.
Click to expand...

When the serotonin receptors on a neuron are occupied by agonists, the cell is stimulated, and it responds by internalizing the receptors in an attempt to reduce the response back to a basal level. That means that the number of serotonin receptors on the surface of the cell is decreased. The longer and stronger the stimulus, the more receptors are internalized, and the more receptors are removed from the cell surface. With fewer serotonin receptors on the cell surface, subsequent exposure to an agonist causes a weaker response. The receptors are replaced as new protein is synthesized, which occurs with a half-time of several days up to a week. Thus, it takes 2-4 weeks for neurons to fully replace serotonin receptors after repeated exposure to strong agonists. MAOIs have nothing to do with it. It is a bit of a mystery why DMT does not seem to induce tolerance. It must not trigger receptor internalization.
 
^This, taking more (or MAOI in your case) never works out because your receptors need to come back to appreciable levels. Or at least for the first few days, after a while (tolerance is a tricky situation, sometimes I do get effects other times I don't, so I can't really specify, but let's say 3 days) you just need more.

If you need any real-world examples, I believe there's a B&D on tolerance and cross-tolerance.

P.s Anyone knows the science behind cross-tolerance between Phenethylamines and Tryptamines? The "cool down"-period is apparently shorter if you switch between the 2
 
^AFAIK they act at different sites on the 5-HT receptors, which apparently causes only partial cross tolerance.
 
I've heard "theres no tolerance" about ayahuasca too but I notice a very definate drop in psychedelic effects if you take oral DMT and moclobemide regularly - once a month is about the most I can take it and still get good psychedelic effects.

I always tend to think the more psychedelic the effects the more time your brain will need to recover. Perhaps if you're taking small doses of oral DMT you can take it regularly - a lot of the guys taking it 40 days in a row in the rainforest would have been taking it because they had worms rather than for the psychedelic effects. They often take very, very low dose DMT brews.

That's my experience anyway - some people claim they can take big doses of oral DMT and see no tolerance but I definately do. I do take enough DMT to stun a charging gorilla tho.
 
NMDA antagonists have been reported to reduce tolerance to many other classes of drug, though I'm not sure if this is true regarding 5HT2a agonists. Ibogaine is also reported to reduce tolerance to other classes of drug, with fatal overdoses sometimes reportedly resulting from users who take large doses not realizing their tolerance has been reduced. There are drugs, like salvinorin A, for which tolerance reduces the more a user takes it. This is called sensitization. I believe there are a number of mechanisms for HOW a drug produces tolerance or sensitization, and probably many more mechanisms totally unknown. I don't think any THOROUGH mechanism is known for how some drugs reduce tolerance to numerous drug classes at the same time, though if anybody knows better I'd enjoy an explanation. The pervasive ignorance of the "hows" and "whys" of drug workings is why FDA approval of drugs more or less simply involves enough people having reactions to the drug in clinical trials that aren't severe enough to justify denying people its benefits.

It's funny, even though FDA approval or rejection of a new drug is a hell of a lot more controlled than the RC market's rejection of a new designer high, it's often fundamentally not that different as, in the final analysis, it's still largely relying on subjective user reports to approve or reject a drug. There are certainly cases where, for instance, a theory exists for how the metabolism of a particular drug will produce a known toxic metabolite, or where instrumental tests (blood pressure, EKG, etc.) indicate unacceptable reactions to a new drug, and these are cases where "deeper knowledge" is informing a new drug's acceptance or rejection, but ultimately our knowledge of the "hows" and "whys" of drug workings only goes so deep because we, for instance, don't know how the neural correlates of consciousness produce subjective effects. I think a lot of people read or hear highly technical talk of the workings of drugs and imagine in all they don't follow in that fancy talk that much more is being explained than actually is. But the truth, at least as far as I can discern, is that investigating how drugs do what they do is, intellectually, currently extremely dissatisfying. I know you didn't ask for this explanation but, for me at least, this is the sort of answer that this line in inquiry ultimately leads to. There are undoubtedly more informed responses than I've given, though arguably these sorts of responses require many books to flesh out so it's difficult to gauge the degree of detail appropriate for an online post.
 
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^I may have read something about dissociatives/ketamine doing something to neurons, which psychedelics in turn reverse. Could be related to psychedelics tolerance? I seriously need to get a deeper understanding of the brain..
 
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Moving this to ADD should allow us to get to the bottom of it sooner rather than later. :)
 
^I agree, though tryp2fun already offered some of what the OP was looking for. Now if only some moderator would do what they say instead of just posting about it [insert smiley winky face].

Also, I think a lot of this is covered in the Erowid/Bluelight neuropharmacology text (granted, if everybody was able to quickly find information that has already been covered here and on Erowid there would be far less activity in these forums and nobody would visit, heh).
 
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I'll just add that acute downregulation of 5ht2a receptors appears to be particularly rapid (an anecdotal reports of regular use of psychedelics suggest upregulation rapid too).

ebola
 
Isn't it also true that this downregulation is directly related to potency? Not sure how that is translated from affinity or efficacy but I'd bet on the latter...

It would be nice to learn how tachyphylaxis fits in exactly, I have been wondering about that for a while and have posted questions about it repeatedly.

I wonder how a trip from a full dose of a moderately potent psychedelic is qualitatively different from a full dose of an extremely potent psychedelic, by that I mean: is it true that although both hypothetical drugs can cause a +++ experience, the more potent drug causes more tolerance? Is that compensated by getting effects that are just qualitatively more intense? It is hard to make such claims but still, the N-benzylated phens suggest something like that.

From what I read so far the better a ligand is at either activating a receptor or causing the actual signal transduction from the actual neuron, the stronger and faster the downregulation. I take from this that if a drug is to act with considerable potency, it had better all arrive quickly in the brain before this downregulation which is set in motion prevents its action. Though what I don't understand is why a drug is able to overcome this by 'overwhelming' the system? Why doesn't this tachyphylaxis / fast downregulation cause the trip from a potent psychedelic to be quenched say after 30 minutes regardless of the drug's absorption / delivery?

Is this related to the concept that psychedelics can set in motion a sort of chain reaction that can go on for hours, like LSD can cause a trip that has a peak that is longer or has a different intensity timeframe than the half-life should allow? Can superpotent psychedelics overwhelm the system if they are quick enough to start a signal cascade that itself is not nullified by downregulation? If so, is this because downstream effects are not as simply affected by downregulation as the 5-HT2A pharmacokinetics of the drug?

@Ps00donym: I hope you find getting to the bottom of something still as valuable if that bottom turns out to be the lid of a can of worms?
 
From what I read so far the better a ligand is at either activating a receptor or causing the actual signal transduction from the actual neuron, the stronger and faster the downregulation.
Click to expand...

I think that this follows, as intracellular processes undergird the cascade eliciting most cases of receptor downregulation.

Why doesn't this tachyphylaxis / fast downregulation cause the trip from a potent psychedelic to be quenched say after 30 minutes regardless of the drug's absorption / delivery?
Click to expand...

I think that this is just because intracellular processes and downstream transmission take time, and "high efficacy" ligands aren't so overwhelmingly effective as to cause downregulation with but a single interaction with the receptor (this would be very odd in a system 'designed' to maintain homeostasis with varying function of endogenous ligands with full efficacy).

Is this related to the concept that psychedelics can set in motion a sort of chain reaction that can go on for hours, like LSD can cause a trip that has a peak that is longer or has a different intensity timeframe than the half-life should allow?
Click to expand...

LSD's time-course actually runs pretty close to what its half life suggests, and its first-order metabolite is reasonably active. It's just that early studies of the compound used diagnostics insufficiently sensitive to detect such tiny concentrations of the compound. I'm actually not thinking of any lengthy activity, brief half-life compounds off-hand (but rather only the converse, as with MDMA), with the exception of irreversible enzyme-inhibitors.

ebola
 
I've got that same general sense of it (regarding potency), but it's not substantiated. The other (also unsubstantiated) factors I've heard linked to a higher relative degree of tolerance development are selectivity (e.g. NBOMes) and duration of action. These latter two factors make sense to me intuitively, as I imagine a more selective drug will result in less signals from other receptors being activated to that might potentially compete with those being sent by the selected-for receptor, and the longer the duration (and duration of active metabolites) the more time those signals will be sent for. Any truth to this?
 
The thing that has always confused me is that long lasting psychedelics like 2c-p or doc can result in tripping for many hours but redosing of a short acting psychedelic like mushrooms or 2c-c cannot. even if you had two people, one on doc and the other on 2c-c and timed it so they peaked at the same time, the 2c-c person would be back to baseline and unable to get back up way before the doc person. Is it just that things like doc bind the actual receptors for longer and that they can't be desensitized whilst actually bound? Or is it that duration has more to do with how quickly a drug induces desensitization and internalization rather than metabolism. So even if you had a psychedelic that lasted days in the system but induced desensitization in an hour it would still only last an hour. This is likely at least partly why mdma doesn't last long. SERT is internalized pretty quickly.
 
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tryp2fun said:
When the serotonin receptors on a neuron are occupied by agonists, the cell is stimulated, and it responds by internalizing the receptors in an attempt to reduce the response back to a basal level. That means that the number of serotonin receptors on the surface of the cell is decreased. The longer and stronger the stimulus, the more receptors are internalized, and the more receptors are removed from the cell surface. With fewer serotonin receptors on the cell surface, subsequent exposure to an agonist causes a weaker response. The receptors are replaced as new protein is synthesized, which occurs with a half-time of several days up to a week. Thus, it takes 2-4 weeks for neurons to fully replace serotonin receptors after repeated exposure to strong agonists. MAOIs have nothing to do with it. It is a bit of a mystery why DMT does not seem to induce tolerance. It must not trigger receptor internalization.
Click to expand...

Regarding the lack of tolerance to DMT, it seems this only happens with smoked doses. I've not really heard of many people seeing the same with Ayahuasca/Pharmahuasca - but with smoked doses it's kind of understandable, when the drug is only in effect for a matter of minutes maybe it's simply eliminated too quickly for the brain to begin its normal reaction.

That would also explain why the same isn't true for Ayahuasca.
 
Of course agonization of the receptors only for a couple of minutes is not enough to cause downregulation or whatever mechanism it is that causes the tolerance. The longer the agonization, the greater the downregulation. The longer the half-life, the more tolerance a single administration causes. Not sure if this is true for every scenario, but it certainly appears obvious for most cases.
 
I would imagine that DMT doesn't cause downregulation when smoked as it's in the body for such a short amount of time, but I might be totally off there. As for other psychedelics, 4-HO-MET definitely caused some downregulation for me (redosing gave me diminishing returns) and LSD is known to cause rapid downregulation.
 
Hey, thanks everyone for such in detail answers/discussion.

I have a follow-up question: Ibogaine resets opiate tolerance. Might it reset psychedelic tolerance, too? Perhaps an iboga microdose makes one more sensitive to the effects of other psychedelics?
 
I'd like to know whether using 5-HT antagonists causes 5-HT upregulation, and if this provides means for reseting psychedelic tolerance or potentiating psychedelics. One of my friends has used mirtazapine and before we trip together he ceases to use it for a couple of days. He tends to get more high from similar amounts of psychedelics than the rest of us. Might this be an example of 5-HT antagonist inspired upregulation?
 
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