Psilocin pharmacology

[markosheehan]

does psilocin increase serotonin levels by being a reuptake inhibitor.

https://pdfs.semanticscholar.org/5fb0/009cfe34bb404782b1479dacdfe21a1fceeb.pdf

in this study psilocin has a ki value of 6 for sert.

the impression i got from most people was psilocin and no affect on serotonin however even though its value is not that high its not that low either when compared to others.

on the other hand lsd and mescaline had very little affinity for sert

 

[Solipsis]

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009019 in this study it says it has affinity for sert

SERT: 3.57 ibogaine, 3.31 DPT, 3.25 6-F-DMT, 2.98 DIPT, 2.83 DOI, 2.72 5-MeO-DIPT, 2.37 DMT, 1.74 psilocin, 1.28 5-MeO-MIPT, 1.08 Aleph-2, 0.97 5-MeO-DMT, 0.66 DOB; 0.00: 2C-E, MDA, 2C-B, mescaline, 4C-T-2, 2C-T-2, lisuride, MEM, 2C-B-fly, DOM, TMA, MDMA, TMA-2, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, DOET, salvinorin A; ND: morphine, THC

https://pdfs.semanticscholar.org/5fb0/009cfe34bb404782b1479dacdfe21a1fceeb.pdf

it also says in this psilocin has a ki value of 6 to sert

Above are npKi values though, the ki Ray measured was 851.6 nM while in literature there was PDSP 3801 (3H-CITALOPRAM/Human)... this is quite low, I don't think serotonin levels should be affected with great significance.

Moving this finally to the NSP forum. Markosheehan has made it clear all pharmacology data about psilocin is requested and if possible explained. PD and I cannot provide sufficient answers.

He should do his own talking but it seems topics of interest are whether there is elevation of brain serotonin levels (I should add, the question should include whether this is significant or not), and also about 5HT2B efficacy and selectivity, and whether it is a full agonist at that receptor or not.

It seems fair to reveal what the underlying concerns are, so that less time and energy is wasted on debating analytical values before significance is made clear.

 

[serotonin2A]

Psilocybin/psilocin do not increase synaptic 5-HT levels. Psilocin is a potent agonist at 5-HT1A autoreceptors, which completely inhibits the firing of serotonergic neurons.

In terms of direct effects on SERT, psilocin binds with affinity in the low micromolar range. Affinity in that range has questionable relevance to the behavioral effects of psilocin (because CNS levels are probably an order of magnitude lower). Also, there is also some evidence that psilocin is a substrate rather than an inhibitor. Nevertheless, even if psilocin is an uptake inhibitor and such interactions occur in vivo, psilocin would lave little effect on synaptic 5-HT due to autoreceptor activation.

 

[Solipsis]

Does it? Is there a fitting model or explanation for the extremely intense psychedelic trips other 5-HT1A agonists are known for like 5-MeO-DMT?
Are you saying this inhibition also affects firing of 5-HT2A activated neurons, and also does the inhibition actually preclude things like reuptake inhibition increasing synaptic serotonin a very little bit?

 

[serotonin2A]

Does it? Is there a fitting model or explanation for the extremely intense psychedelic trips other 5-HT1A agonists are known for like 5-MeO-DMT?
Are you saying this inhibition also affects firing of 5-HT2A activated neurons, and also does the inhibition actually preclude things like reuptake inhibition increasing synaptic serotonin a very little bit?

There are two things to consider. First, the action of tryptamines on presynaptic 5-HT1A and 5-HT1B receptors would tend to potentiate their psychedelic effects by reducing synaptic 5-HT, which in turn reduces competition for 5-HT2A binding.

Second, potent 5-HT1A agonists like 5-MeO-DMT can activate postsynaptic 5-HT1A receptors, an action that can produce psychoactive (albeit not psychedelic) effects.

So with 5-MeO-DMT, you are taking a 5-HT2A agonist, potentiating that effect by activating presynaptic 5-HT1A receptors, and then adding to that an unusually strong postsynaptic 5-HT1A receptor-mediated behavioral component.

There may be additional complexities with 5-MeO-DMT because it is a potent agonist at certain other 5-HT receptors that are not usually associated with hallucinogen action, such as 5-HT7.

Psilocin et al completely inhibit the firing of serotonergic neurons in the raphe, so there would not be any synaptic serotonin to be taken up by SERT.

 

[Solipsis]

That's very comprehensive Understood.

I wonder if it is significant that this inhibition of serotonergic firing impairs your 'baseline' much more apart from the 5-HT2A activity? Could that say something about tendencies in the psilocin experience?

 

[TheChin]

Interestingly, in humans, 5-HT1A agonists blunt the psychedelic effects of psilocybin:

Eur Neuropsychopharmacol. 2016 Apr;26(4):756-66. doi: 10.1016/j.euroneuro.2016.01.005. Epub 2016 Jan 22.

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

Abstract

The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases.


Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

 

[serotonin2A]

Interestingly, in humans, 5-HT1A agonists blunt the psychedelic effects of psilocybin

That is pretty much what one would predict. Psilocybin/psilocin is a potent agonist at presynaptic 5-HT1A receptors but is only weakly active at posysynaptic 5-HT1A receptors. Note that postsynaptic 5-HT1A receptors in pyramidal neurons tend to oppose the response to 5-HT2A activation. So combining psilocin with another 5-HT1A agonist would potentially augment its effects on postsynaptic 5-HT1A receptors, dampening the 5-HT2A-mediated response to psilocin, without influencing the action of psilocin at presynaptic 5-HT1A receptors (because psilocybin/psilocin is already fully activating that subpopulation).

 

[Cotcha Yankinov]

There may be additional complexities with 5-MeO-DMT because it is a potent agonist at certain other 5-HT receptors that are not usually associated with hallucinogen action, such as 5-HT7.

Do you think functional selectivity at other non 5-HT2 receptors could explain the auditory effects of DiPT?

 

[TheChin]

That is pretty much what one would predict. Psilocybin/psilocin is a potent agonist at presynaptic 5-HT1A receptors but is only weakly active at posysynaptic 5-HT1A receptors. Note that postsynaptic 5-HT1A receptors in pyramidal neurons tend to oppose the response to 5-HT2A activation. So combining psilocin with another 5-HT1A agonist would potentially augment its effects on postsynaptic 5-HT1A receptors, dampening the 5-HT2A-mediated response to psilocin, without influencing the action of psilocin at presynaptic 5-HT1A receptors (because psilocybin/psilocin is already fully activating that subpopulation).

It seems to me that the presence of an additional 5-HT1A agonist (assuming decent potency and appropriate concentration) would result in two things: less competitive substrate (serotonin) and increased psilocin concentration (because less of it binds to the 1A receptor). This would imply greater activity of psilocin at 2A receptors (the result being, you trip harder). Even if some of the extra psilocin activated postsynaptic 1A receptors, it would seem that, at a minimum, it would be offset by the increased 2A activity. In other words, the addition of a 5-HT1A agonist shouldn't really sway a psilocybin trip too much either way...but this study shows that it does. It appears there's a lot more going on here...or that I don't understand this well enough. Feedback welcome.

 

[serotonin2A]

It seems to me that the presence of an additional 5-HT1A agonist (assuming decent potency and appropriate concentration) would result in two things: less competitive substrate (serotonin) and increased psilocin concentration (because less of it binds to the 1A receptor). This would imply greater activity of psilocin at 2A receptors (the result being, you trip harder). Even if some of the extra psilocin activated postsynaptic 1A receptors, it would seem that, at a minimum, it would be offset by the increased 2A activity. In other words, the addition of a 5-HT1A agonist shouldn't really sway a psilocybin trip too much either way...but this study shows that it does. It appears there's a lot more going on here...or that I don't understand this well enough. Feedback welcome.

You are overlooking two issues.

First, compared to the number of molecules in typical drug doses, the number of receptors in the body is lower by orders of magnitude. So preventing psilocin from binding to 5-HT1A doesn't appreciably alter its concentration in the body.

Second, activation of postsynaptic 5-HT1A receptors blocks the physiological response to 5-HT2A activation. There are many studies that have shown this, but here are a few:

https://www.ncbi.nlm.nih.gov/pubmed/14754868
https://www.ncbi.nlm.nih.gov/pubmed/1851255

 

[TheChin]

You are overlooking two issues.

First, compared to the number of molecules in typical drug doses, the number of receptors in the body is lower by orders of magnitude. So preventing psilocin from binding to 5-HT1A doesn't appreciably alter its concentration in the body.

It may not alter its absolute concentration, but it leaves more psilocin to bind to other receptors (e.g. 2A, which it binds to with high affinity).

Second, activation of postsynaptic 5-HT1A receptors blocks the physiological response to 5-HT2A activation. There are many studies that have shown this, but here are a few:

https://www.ncbi.nlm.nih.gov/pubmed/14754868
https://www.ncbi.nlm.nih.gov/pubmed/1851255

I will read these references tomorrow, thanks. But, the more 5-HT2A activation, the more 1A activation needs to take place to offset it. Since psilocin binds 2A more potently, the balance should swing in favor of 2A receptor activity, all else being equal.

 

[serotonin2A]

It may not alter its absolute concentration, but it leaves more psilocin to bind to other receptors (e.g. 2A, which it binds to with high affinity).

^That statement does not make any sense. If binding to 5-HT1A takes up so much psilocin that there is less available to bind to other sites, then you are describing a change in concentration. Receptor occupation by a ligand is dependent on the concentration, so if there is no change in the concentration then there can not be a change in the interaction of psilocin with other receptors.

The formula for occupation is as follows: % = ( [L] / ([L] + Kd))*100

where [L] is the ligand concentration. If neither the concentration nor the affinity (Kd) of psilocin changes, then the level of receptor occupation and the cellular response induced by psilocin will not change either.


The situation you are describing ("ligand depletion") never happens in the body. There are so many more drug molecules in the body than there are receptors that there is effectively no shortage of free drug due to binding.

 

[Abject]

Serotonin2A I fucking love you you're my favourite poster since Mr B left
Thanks for the info, much appreciated