Does LSD really have a bad tolerance issue?

[red22]

What other psychedelics have this tolerance issue? Is there any reason to believe that intriguing analogs of LSD, like lysergic acid ethylamide and lysergic acid butylamide have this tolerance issue?


LSD has a unique mechanism that causes tolerance to spike massively after a single dose, that being that the molecules effectively bind permanently to the 5ht2a receptors which forces the brain to destroy them and replace them over the course of a week.

magistrate101, Feb 11, 2024, https://www.reddit.com/r/RationalPsychonaut/s/MnRxPGV6K5


I recently read that scientists were able to actually see and capture what LSD looks like when binding to a serotonin receptor. Apparently the binding is so strong and permanent, that ultimately the brain has to recycle that particular serotonin receptor.

cryptix420, Aug 30, 2019, https://www.bluelight.org/community...thing-you-know-about-lsd.878236/post-14622083

AFAIK LSD takes a bit to lock itself to the receptor and stays there while you are high but it does eventually leave the binding site.
Phenethylamines and Tryptamines just go in and out quickly, and they can be metabolised/eliminated when they are not bound.
I think this is what causes the LSD peak to last longer compared to total duration of the effects, while Phenethylamines and Tryptamines have relatively shorter peaks and longer tails.

Phobos, Aug 31, 2019, https://www.bluelight.org/community...thing-you-know-about-lsd.878236/post-14622354


I'll include this link, as it's relevant, but I didn't want to look at it cuz it's lengthy:

FAQ/Tip 020: What Causes Tolerance? Functional Selectivity & GPCR Downregulation; The LSD Tolerance Graph ; Back to the Baseline; Tolerance Calculators (Do not Apply); Further Research: Gq & β-Arrestin Pathways; Other Research: Non-responders. NeuronsToNirvana, reddit, Jul 8, 2022

 

[foodcrisis]

for me mdma and mda are probably the drugs i notice with most tolerence issues.. it takes me months with out using to be able to get the same feeling from a roll.

with lsd it takes me like 4 days to get my tolerance back to normal.. most people say it takes at least a week or two... shrooms take me about a week until i can trip the same again.

most uppers and downers i will get a tolerance to, but it's not like psychedelics and E where they just won't work at all if i did them the day before.. like with adderall i can do it for like a few weeks with out getting a whole lot of tolerance issues. same thing with opiates...

cool article though about the receptors having to recycle themself. sounds interesting. wish i understoond it more.

 

[red22]

Another Bluelighter said that "simple short acting tryp's" have the least tolerance build-up. Presumably, by this, he means base tryptamines (the ones with only three or four letters and no dashes, like DMT and DALT). This makes sense, as DMT is well known to have little to no tolerance build-up.


Also simple short acting tryp's don't really form tolerance like normal long duration ones.

@Help?!?!, Sep 25, 2013, https://bluelight.org/xf/threads/the-big-dandy-met-thread.255405/post-11849534


A study of repeated administrations of dosages of 16 mg i.v., at half-hour intervals, were made to explore the possible development of short-term tolerance and none was observed.

In the definition of DMT either as an endogenous psychotogen or, equally appealing, as a natural neurotransmitter,[*] it would be desirable to show that the body does not build up tolerance to it (otherwise the psychotic would spontaneously repair, and the brain would spontaneously shut down). To address this, four subjects were given some 50 mg of DMT intramuscularly, twice daily, for 5 days. The blood levels that were achieved, and the picture of autonomic effects (both in mydriasis and in cardiovascular function) were not changed. No tolerance was seen. The psychological conclusions were a little bit less convincing. Several said that the “high” was diminished, but others seemed to feel a maintenance of subjective responses. The jury is still out on this one.

Alexander Shulgin. TiHKAL. Shulgin A, Shulgin A. 1997 (Part 2, #6 DMT, EXTENSIONS AND COMMENTARY)


Why DMT works all the time and LSD won't - Tobias Buckborn. OPEN Foundation, Jun 6, 2016


DMT has 0 tolerance build-up I smoke it daily atleast 3 times a day FFS. Mate.

Superb-Preference-83, May 3, 2024, https://old.reddit.com/r/Ayahuasca/comments/1cht1qg/restarting_psilocybin_microdosing_after_an/l2eceyu/

This is a comment about DET that reaffirms what Help said:

I know that all psychedelics present cross tolerance but DET is probably the best choice since it’s a 3-4 hour trip so not insanely short like DMT and the tolerance issue isn’t even half as big as other psychs.

...

Shrooms do definitely ramp up my tolerance to the max, I once tried shrooms on day 1 and my usual dose of DET the following day and all the DET did was keep me awake for a few good hours,

MrCorruptor, Feb 7, 2024, https://www.reddit.com/r/Psychedelics/s/3LVAcpX0sc


*Current state of knowledge about endogenous DMT

 

[JackARoe]

What other psychedelics have this tolerance issue? Is there any reason to believe that intriguing analogs of LSD, like lysergic acid ethylamide and lysergic acid butylamide have this tolerance issue?

Large questions red. What always amazed me is how while LSD causes a tolerance to where you have to double each day, something like DMT is said to not have that tolerance. I have only blasted off on DMT twice in a row once in my career. Both trips were strong. First one very refreshing and beautiful. The second one very weird as if to say we gave you stuff to think about, don't steamroll over the wisdom with another trip so quick. (at least my own thoughts say that). But people say they can blast off many times in a row until a "lock out". (also something I never experienced and probably due a lot of space between trips) But lock out seems similar yet outside the bounds of what tolerance is.

I suspect most psychedelics have a strong tolerance. Some much stronger like LSD. Mushrooms a bit less. DMT seems not at all.

For sure someone here at BL will come in an list each substance and the different receptors being affected. All the who, what, where, why, when and how. (no pressure lol)

 

[specialrelativity]

No, not really, no tolerance in my experience travelling on LSD -25s day after day after day after night after night. Sleeping too on it, every once in a while *winks*.

 

[jasperkent]

It has been my experience that tolerance builds pretty quickly from day to day. Like 1 hit today means I'll need 2 hits tomorrow for the same effect-- and 3 the day after that.

But it only takes a few days of abstinence to bring it back down to baseline.

 

[pupnik]

the spectacular visual high from smoked DMT disappeared with daily use, but returned spectacularly with a 3 month break and then diminished again.
the body high, heart rate, BP, flush continued so as a dopamine activating narcotic it is not really producing much tolerance, but as a psychedelic it definitely does produce tolerance.

many psychedelic drugs produce multiple effects, but the spectacular visual stuff is very much tolerance affected when doses are not spaced out reliably for those receptors to be replenished.
Dopamine receptors have different affinity and regeneration profiles than serotonin receptors.

 

[3DQSAR]

the spectacular visual high from smoked DMT disappeared with daily use, but returned spectacularly with a 3 month break and then diminished again.
the body high, heart rate, BP, flush continued so as a dopamine activating narcotic it is not really producing much tolerance, but as a psychedelic it definitely does produce tolerance.

many psychedelic drugs produce multiple effects, but the spectacular visual stuff is very much tolerance affected when doses are not spaced out reliably for those receptors to be replenished.
Dopamine receptors have different affinity and regeneration profiles than serotonin receptors.

DMT gives you a VERY clear message that it's time to take a break. I noted that if I just sat and smoked the entire gram in one sitting, over the day I needed more per dose BUT it still worked.

I didn't smoke the last bowl or remelt the stuff in the stem back into the crook so next morning I thought '80mg or so - let's see' and it did next to nothing.

I did trials every month or so and I concur that you need a 3 month gap.

 

[pupnik]

right, but even if every smoke is not psychedelic, it is stimulating enough to be more-ish and more-ish again.
not quite addictive, as the yearning for more is more like curiosity or appetite than need.

 

[Just A Guy]

A good friend offered me the opportunity to try DMT last Friday. (My first time.)

The goal was ego-death, and while the first hit of vaporized DMT was truly remarkable, it didn't quite make it there. So when it became obvious that I was coherent again after the first try, a second, much larger (perhaps twice as large) hit was provided. There may have been tolerance, but it didn't matter. We believe I achieved ego loss, even if it was only for 20 seconds or so. Trip report to come after I've processed the experience more.

 

[pupnik]

@Just A Guy
that is consistent with my findings, the first day in a month or so, I can blast into psychedelic wonderment several times...