Author Topic: Trip Tolerance: Neurons Swallowing own Receptors  (Read 4041 times)

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Trip Tolerance: Neurons Swallowing own Receptors
« on: June 17, 2003, 08:05:00 PM »
When you first ingest a psychedelic drug, you soon discover that you develop tolerance to its effects very quickly, a single dose of a tryptamine or phenethylamine can block almost all the effects of any psychedelic for a day or two, as well as attenuating the effect of any taken within 1-2 weeks. Why is that? Why is it so effective? Was D.A.R.E. right after all, and you really did etch away the braincells with that Acid blotter? Nope, not by far - read on...

The effects of the "classical hallucinogens" (largely the Phenethylamines and the Tryptamines) are all chiefly mediated by them binding to and activating the 5-HT2A receptor (they are 5-HT2A agonists), which is a member of the neurotransmitter receptors in the body and brain which binds Serotonin (or 5-HT, from its chemical name 5-Hydroxy-Tryptamine). This receptor is very easily deactivated, probably because it is not used to a large extent (to the best of my knowledge) during everyday brain-activity, something that for simplicitys sake can be verified by the fact that you usually never get religious experiences while standing in line in the store, nor are the clouds constantly on the morph.

When the 5-HT2A receptor becomes more stimulated than it is used to (as in you ingesting ANY active amount of a psychedelic drug), the neurons on the recieving end of the synapse responds to this with "receptor internalization", the nerve cell actually drawing the receptor into the cell membrane, so that all its contact with the surface is lost.

You can draw an analogy with the eyes of a snail - when its eye is poked or otherwise disturbed, it almost instantly retracts the telescopic eye and turns the eye tube inside out, so that it becomes buried inside the head, safe from eye-poking scientists. In the same way the serotonin neurons become stressed by being poked with 5-HT2A agonists and retracts its receptors so that any further poking does not lead to the activation of the receptor, which would otherwise force the neuron to fire repeatedly, sending away an electrical pulse of a few tens of millivolts - it doesn't sound like much, but for a cell which  may have a diameter of only 0.05-0.1 millimeter (that's 1/2500 to 1/5000 of an inch), that is hard work. If you had to make 20 push-ups every time the phone rang, you would also soon disconnect the phone if you got a series of prank calls (which is very close to what serotonin neurons would consider 5-HT2A agonist drugs to be). They are small, but very clever - after all, they are brain cells by profession.

When the receptors internalized, the nerve cell cannot become activated by any 5-HT2A agonists, regardless of how much of it you ingest - the drug cannot reach, and thus not activate the receptor. That you still feel something even if you would take a trip every day for a week is because not 100% of the receptors are internalized, and that most drugs affect a whole range of other receptors, but to a lesser extent. There are also a few other mechanisms contributing to the development of tolerance to psychedelics, but this is by far the most important one, and the most fantastic of them all. A short period after the drug has left the body, the 5-HT2A receptors either return to the surface, or if the repair machinery in the neuron determines that any of them were damaged, they are broken down to their constituents again and are thus salvaged for spare parts, so that new 5-HT2A receptors can be built and re-installed, allowing the serotonergic neuron to return to exactly the same pristine state it was before the weekend.

To study this more in-depth, I have linked a few articles of interest below - most (if not all?) of them should be free to download, otherwise just tell me, and I'll upload them to my page.

Further Reading on 5-HT2A Desensitization:

Mechanisms of Ligand-Induced Desensitization of the 5-HT2A Receptor

J. Pharm. Exp. Ther. Vol. 300, Issue 2, 468-477, February 2002


Differences in Rapid Desensitization of 5-HT2A and 5-HT2C

J. Pharm. Exp. Ther. Vol. 299, Issue 2, 593-602, November 2001


Dynamin-dependent, Arrestin-independent Internalization of 5-Hydroxytryptamine 2A (5-HT2A) Serotonin Receptors

J Biol Chem. 2001 Mar 16;276(11):8269-77


The Interaction of a Constitutively Active Arrestin with the Arrestin-Insensitive 5-HT2A Receptor Induces Agonist-Independent Internalization

Mol. Pharmacol., May 1, 2003; 63(5): 961-972.


Cell-Type Specific Effects of Endocytosis Inhibitors on 5-HT2A Receptor Desensitization and Resensitization

Mol. Pharmacol., Vol. 60, Issue 5, 1020-1030, November 2001


Receptor Internalization Process

Roth Lab: Functional Studies of 5-HT Receptors



  • Guest
Thank you!
« Reply #1 on: June 18, 2003, 02:21:00 PM »
Thank you for an enlightening post. Made some things much more clear to me.  :)  Love your very fitting analogies.


  • Guest
Receptor internalization that you speak of is...
« Reply #2 on: June 18, 2003, 09:59:00 PM »
Receptor internalization that you speak of is referred to as Endocytosis. The receptors are disposable so to speak. After endocytosis, it is taken into a lysosome where it is hydrolytically digested, and a new receptor is built in the endoplasmic reticulum (ER), folded in the golgi, and transported to the cell membrane.


  • Guest
Degradation is usually a minor pathway, most...
« Reply #3 on: June 18, 2003, 10:39:00 PM »
Degradation is usually a minor pathway, most of the receptors are continously recycling between inner compartments and the surface. Binding of ligands just changes the rate of internalization and thereby shifts the equilibrium to higher intracellular concentrations.


  • Guest
So, is there a possibility to make trips more...
« Reply #4 on: June 18, 2003, 11:10:00 PM »
So, is there a possibility to make trips more 'first-time-like' by taking 5ht2a-antagonists?


  • Guest
Wouldn't it be a bit naïve to think that what...
« Reply #5 on: June 19, 2003, 12:29:00 AM »
Wouldn't it be a bit naïve to think that what a trip feels like is only based on the sensitivity of the neuron? After tripping ten times you already have some kind of an idea what it's like and there's no turning back. No, you didn't say that... just happened to cross my mind. I agree that creating a tolerance for 5-HT2A antagonists would be interesting to play with before ingestin the agonists.


  • Guest
Slappy: I thought that the definition of ...
« Reply #6 on: June 19, 2003, 12:40:00 AM »
Slappy: I thought that the definition of endocytosis was a cell "ingesting" something from the outside of the membrane, allowing it to end up in an endosome in the cytosole. This being different from this receptor internalization, always being labeled as that in the literature, as well as not being digested, but rather recycled.

Yellium: Trips does not appear "first-time" the first times just because you have a full set of 5-HT2A as a trip virgin. That effect is much more complex and involves you becoming familiar with the feelings - I don't think that "familiarity" has a neurochemical counterpart, only a psychologic (quite a few abstraction layers higher).

The tolerance which is due to 5-HT2A receptor internalization hasn't got anything to do with the subjective quality of the effects from 5-HT2A agonists (i.e. psychedelics), only the quantitative effects you are able to attain with a specific dose.


  • Guest
I can't thank you enough.
« Reply #7 on: June 19, 2003, 09:48:00 AM »
Rhodium, it's clear why you're the Chief Bee.

Is it the case whether similar behaviour is exhibited in other receptor types from differnt agonists? Does it follow (as it would seem) that the reverse occurs when antagonists are acting?


  • Guest
Different mechanisms for different receptors
« Reply #8 on: June 19, 2003, 03:58:00 PM »
This is only fully valid for the 5-HT2A receptor (the one responsible for the great majority of all psychedelic action), and not the universal tolerance-producing mechanism for all receptors, it even differs between different 5-HT2x receptors, see the following article at

Medline (PMID=11602671)

for example:

Differences in rapid desensitization of 5-HT2A and 5-HT2C receptor-mediated phospholipase C activation.
J Pharmacol Exp Ther. 2001 Nov;299(2):593-602.


The serotonin (5-HT)2A and 5-HT2C receptors share a high degree of sequence homology and have very similar pharmacological profiles. Although it is generally believed that the cellular signal transduction mechanisms activated by these receptors are indistinguishable, recent data suggest significant differences in their signaling cascades. In this study we explored differences in the characteristics and mechanisms of rapid desensitization between the 5-HT2A and 5-HT2C receptor systems. For both receptor systems, pretreatment with 5-HT reduced the ability of a maximal concentration of 5-HT to stimulate phospholipase C-mediated inositol phosphate accumulation by about 65%, although the 5-HT2C receptor system was more sensitive to the desensitizing stimulus. Differences in the concentration dependence of the rate constant for desensitization (k(des)) suggested different mechanisms of desensitization for the 5-HT2A and 5-HT2C receptor systems. At very high receptor occupancy (>99%), the responsiveness of the 5-HT2A, but not the 5-HT2C, receptor system returned to control levels despite the continued presence of the agonist. This resensitization was dependent upon the activity of protein kinase C (PKC). Agonist-induced desensitization of the 5-HT2A, but not the 5-HT2C, receptor system was reduced by the PKC inhibitors staurosporine and bisindolylmaleimide, and by down-regulation of PKC. In addition, inhibitors of calmodulin (W-7) or of calmodulin-dependent protein kinase II, reduced 5-HT2A, but not 5-HT2C, desensitization. Desensitization of the 5-HT2C, but not the 5-HT2A, receptor system was dependent on G protein receptor kinase activity. These data further emphasize the major differences in the signaling systems coupled to 5-HT2A/2C receptors.


  • Guest
Any opinions on whether the 5-HT2A antagonists
« Reply #9 on: April 04, 2004, 11:51:00 PM »
Any opinions on whether the 5-HT2A antagonists (refered to here:

Post 440879

(yellium: "So, is there a possibility to make trips more...", Serious Chemistry)
) would cause the same desensitization as the agonists. After all the antagonist binds to the receptor also.


  • Guest
That theory sounds funny
« Reply #10 on: April 05, 2004, 02:21:00 PM »
If I told you that DMT produce to no tolerance whatsoever (duh, the brain would stop function if that was the case) I relize that I would be telling you an old story. DMT and 5-MeO-DMT are, of course, non-selective 5-HT2A agonists, they also agonize other subtypes such as 5-HT1A, 5-HT2B et al. However, if the above explanation would hold true - there would be at least some change in activity noted when repetadley smoking DMT/5-MeO-DMT. These compounds are very potent 5-HT2A agonists and 5-HT2A agonism plays an importnant role in the DMT intoxication. You can smoke (5-MeO-)DMT over and over again and get as magnificant mind-expantion every time, with no loss of intensity whatsoever.


  • Guest
Too short-acting to matter
« Reply #11 on: April 05, 2004, 05:03:00 PM »
My opinion on that matter is that DMT and 5-MeO-DMT are too short-acting to affect the receptor down-regulation, which only comes into play when the receptors are stimulated for longer time-periods. I assume that it is evolutionary advantageous for an organism (such as humans) to pull 5-HT2A receptors out of circulation if they are "switched on" for extended periods of time. The neurons can probably not differentiate between a receptor being activated due to an agonist or damage to the receptor itself.


  • Guest
Not long ago we had alot of material on a...
« Reply #12 on: April 05, 2004, 10:11:00 PM »
Not long ago we had alot of material on a supoused DMT tachyphylaxis on the net. Now I can't find any. Is it possible that it does actually happen, but that the psychotropic effects appear partially via other mechanism or chain mechanisms?


  • Guest
Antagonists cause downregulation as well
« Reply #13 on: April 06, 2004, 04:11:00 PM »
Yellium and Jsorex: Antagonists cause downregulation of the 5-HT2A receptors as well. Read the papers that Rhodium cited as well as the second abstract bellow. This is quite unique to these receptors. So a pretreatment with 5-HT2A R antagonists should produce tolerance to agonists instead of making the response stronger like suggested by Yellium’s post.

Here are two older reviews dealing with 5-HT2A R regulation.
(I can't find the PDF's on my computer anymore. Maybe somebody with access can upload them for interested bees to read.)

Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists.
John A. Gray and Bryan L. Roth
Brain Research Bulletin 56 (2001) 441-451.


Abstract: 5-Hydroxytryptamine2A (serotonin2A, 5-HT2A) receptors are important for many physiologic processes including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. A large number of pharmaceutical agents mediate their actions, at least in part, by modulating the number and/or activity of 5-HT2A receptors. Drugs with action at 5-HT2A receptors are used in the treatment of many disorders, including schizophrenia, depression, and anxiety disorders. This review summarizes over two decades of research on the regulation of 5-HT2A receptors and provides a comprehensive review of numerous in vivo studies describing the paradoxical phenomenon of 5-HT2A receptor down-regulation by chronic treatment with antidepressants and antipsychotics. In addition, studies reporting antagonist-induced internalization of 5-HT2A receptors and other G protein-coupled receptors will be highlighted as a possible mechanism to explain this paradoxical down-regulation. Finally, a review of the cellular and molecular mechanisms that may be responsible for agonist-mediated desensitization and internalization of 5-HT2A receptors will be presented.

Regulation of central 5-HT2A receptors: a review of in vivo studies.
Arlene S. Eison and U. Lena Mullins
Behavioural Brain Research 73 (1995) 177-181.


Abstract: Numerous investigations have studied in vivo regulation of central 5-HT2A receptors. The majority of pharmacological studies point to non-classical regulation of this site. Serotonergic denervation does not modify 5-HT2A receptor density or second messenger responses (phosphoinositide hydrolysis). 5-HT2A receptor downregulation is produced by the chronic administration of 5-HT2A receptor agonists and uniquely among monoamine receptors by antagonists. Several classes of psychotherapeutic agents also downregulate 5-HT2A receptors with chronic administration including classical antidepressants and antipsychotics. 5-HT2A receptor downregulation produced by 5-HT2A antagonists and antidepressants occurs after presynaptic 5-HT denervation, suggesting that 5-HT2A receptors are postsynaptically localized and emphasizing that they are regulated differently than traditional monoaminergic receptors. Interestingly, the behavioral and biochemical effects of 5-HT2A receptor activation are modulated by activity at other 5-HT receptor subtypes (5-HT1A), as well as by stimulation of receptors for other neurotransmitters and hormones such as norepinephrine (beta-adrenergic) and melatonin. It is suggested that these diverse modulatory influences on 5-HT2A receptor regulation and function may meaningfully impact the therapeutic actions of drugs, including pharmacologically distinct antidepressants.

Note that both issues of the two journals containing these two papers are solely devoted to serotonin, its receptors and transporters and other related stuff:
Behavioural Brain Research 73, Issues 1-2 (15 December 1995) (many papers in here are very interesting!)
Brain Research Bulletin 56, Issue 5 (15 November 2001) (pages 495-507 might bee interesting)

Edit: The wrong DOI number and the reference has been corrected.


  • Guest
DMT tachyphylaxis
« Reply #14 on: April 06, 2004, 07:15:00 PM »
A competative or non-competative antagonist binds to the site, just like the agonist, but without the physiological effect.  "Antagonist" does not refer to a drug that give the opposite pharmacological response. There is a term for that also, which is used occasionally. I don't know what it is in english, though. Anybody?

So does DMT tachyphylaxis occur or not? There used to be material on the net suggesting that earlier.


  • Guest
Rhodium: Slappy: I thought that the definition
« Reply #15 on: April 06, 2004, 07:32:00 PM »

Slappy: I thought that the definition of endocytosis was a cell "ingesting" something from the outside of the membrane, allowing it to end up in an endosome in the cytosole. This being different from this receptor internalization, always being labeled as that in the literature, as well as not being digested, but rather recycled.

Not necessarily, it can refer to cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles, where endosomes play a central role in the endocytosis, but by no means limited to ingestion or any metabolism. Endo-cytosis = entering the cytoplasm


The articles you posted have the same DOI? Some mistake?


  • Guest
Inverse agonist
« Reply #16 on: April 06, 2004, 07:52:00 PM »
A competative or non-competative antagonist binds to the site, just like the agonist, but without the physiological effect. 

Did anyone say otherwise? Then isn't it rather remarkable that antagonists also cause receptor downregulation?

"Antagonist" does not refer to a drug that give the opposite pharmacological response. There is a term for that also, which is used occasionally. I don't know what it is in english, though. Anybody?

The term you are looking for is

'Inverse agonist'



  • Guest
DMT Tachyphylaxis (Tolerance)
« Reply #17 on: April 06, 2004, 08:12:00 PM »
Human psychopharmacology of N,N-dimethyltryptamine.
Strassman RJ.
Behav Brain Res. 1996;73(1-2):121-4.

Medline (PMID=8788488)

We generated dose-response data for the endogenous and ultra-short-acting hallucinogen, N,N-dimethyltryptamine (DMT), in a cohort of experienced hallucinogen users, measuring multiple biological and psychological outcome measures. Subjective responses were quantified with a new rating scale, the HRS, which provided better resolution of dose effects than did the biological variables. A tolerance study then was performed, in which volunteers received four closely spaced hallucinogenic doses of DMT. Subjective responses demonstrated no tolerance, while biological measures were inconsistently reduced over the course of the sessions. Thus, DMT remains unique among classic hallucinogens in its inability to induce tolerance to its psychological effects. To assess the role of the 5-HT1A site in mediating DMT's effects, a pindolol pre-treatment study was performed. Pindolol significantly increased psychological responses to DMT, suggesting a buffering effect of 5-HT1A agonism on 5-HT2-mediated psychedelic effects. These data are opposite to those described in lower animal models of hallucinogens' mechanisms of action.
____ ___ __ _

Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans.
Strassman RJ, Qualls CR, Berg LM.
Biol Psychiatry. 1996 May 1;39(9):784-95.

Medline (PMID=8731519)

Tolerance of the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received intravenous 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 separate days, in a randomized, double-blind, design. Tolerance to "psychedelic" subjective effects did not occur according to either clinical interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.


  • Guest
Paradoxical trafficking and regulation of 5-HT2A r
« Reply #18 on: April 06, 2004, 08:19:00 PM »

Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists
Brain Research Bulletin
Volume 56, Issue 5 , 15 November 2001, Pages 441-451


  • Guest
Then isn't it rather remarkable that ...
« Reply #19 on: April 06, 2004, 09:00:00 PM »
Then isn't it rather remarkable that antagonists also cause receptor downregulation?

Yes that is indeed remarkable and puzzled me too. I was convinced that antagonists don't do any alosteric changes to the receptor protein. So how can the information of the site being occupied by an antagonist tranfer to the internal side of the membrane and activate the internalization process?
Is it possible that there are four (or more) alosteric structures of the 5-HT2A receptor?
-one that tightly binds the Gq-protein (inverse agonist binding)
-one normal (no ligand)
-one that dissociate the complex with the Gq-protein and also activate iternalization (agonist binding)
-and one that does not dissociate the Gq-protein but nevertheless activate a mechanism for internalization (antagonist binding)