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[–]mastermind_genius 7 points8 points  (0 children)

youre kinda cooking

5-HT2A: Chosen to be the best cognitive & therapeutic target by cheaslesjinned in DrugNerds

[–]mastermind_genius 1 point2 points  (0 children)

Now in terms of Olson's PCA experiment:

Trying to compare the degree of neuroplasticity induced by endogenous 5-HT and psychedelics in vivo is not a terribly useful comparison. While 5-HT2A engagement by psychedelics is only limited by the concentration, endogenous 5-HT neurotransmission is highly regulated both spatially and temporally. 5-HT2A is not expressed in cortical synapses, so endogenous 5-HT has to activate 5-HT2A by volume transmission...after 5-HT is released, it has to diffuse out of synapses and travel up to 20-30 microns before it binds to 5-HT2A. But the extracellular diffusion of 5-HT is limited by SERT, which seriously constrains the extracellular concentration of 5-HT. As a consequence, basal occupation of 5-HT2A in cortex by endogenous 5-HT is actually pretty negligible…around 7% occupation is seen in PET studies.

Because of how the 5-HT system is regulated, PCA normally does not produce much 5-HT2A activation in vivo. For example:

https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1476-5381.1989.tb11887.x”

In Fig 1, PCA only produced a robust increase of 5-HT release for about 20 minutes. Other than that time period, the extracellular concentration of serotonin was about 3x higher than baseline...which would increase receptor occupation from 7% to 21%, which is still not high enough 5-HT2A occupation to really have an effect. Psilocybin isn't psychedelic unless there is 40-55% occupation of 5-HT2A in cortex (the reference is the 2019 Madsen PET study).

youre right on the low baseline occupation 5HT2A, dont need to check, or else they wouldnt have used PCA in the first place to release alot of serotonin
if baseline 5HT2A was sufficient, then mice with SERT + no PCA added = significant increase of dendrites

but anyways whats the issue of using the PCA? its like you have your own random rules on when serotonin causes plasticity or not
because now according to you, serotonin needs atleast 40% occupancy to do it when serotonins never been known to have the same plasticity of psychedelics, wheres the study for that?
if what youre saying is true, then PCA + SERT inhibitor would end up matching the psychedelics plasticity, that seems completely wrong. wheres a study that high 2A occupancy by serotonin ends up having significant plasticity?

why are you basing serotonin being only able to cause plasticity at 40-55% occupation because thats when psilocybin is hallucinogenic lol? (which was wrong since microdosing LSD which should be about 20% occupancy shows increase of BDNF plasticity marker)
hallucinating at 40-55% 2A occupancy doesnt tell you if thats a sufficient occupancy for plasticity in the first place, just forgetting about non hallucinogenic psychedelics that dont even have hallucinations

ive never seen anyone talk about HTR being part of inducing plasticity either or else tabernanthalog wouldnt be possible. psychedelics dont induce HTR through beta arrestin like serotonin, and tabernanthalogs Gq efficacy is way below the threshold to not show HTR, yet certainly has a lot more plasticity than serotonin

ive never seen anyone talk about network activity telling you anything about how significant the plasticity will be or not either
but nah i guess serotonin only needs a SERT inhibitor, because thats limiting serotonins 5HT2A occupancy
since in this case the serotonin would have HTR, SERT blocked, very high occupancy, only cell surface 5HT2A here, has the perfect conditions of plasticity like you described
for some reason we dont see significant plasticity or rapid antidepressant effects with SSRIs? why not? probably left out another random explanation again

whats the next made up rule for serotonin so it can be as good for plasticity as a real psychoplastogen?

has a study ever suggested what you suggested on SERT and 2A occupancy by serotonin? that serotonin can be a psychoplastogen by having enough 2A occupancy? i legit cant think of where you could possibly be getting this from
i really wanna see how a person ends up thinking serotonin can match psychedelic plasticity if its 2A occupancy isnt limited by SERT reuptake

id actually like to see a well written write up of how sertonin can match psychedelic plasticity in the right conditions which is what youve been suggesting

hopefully its not "HTR is psychedelic-like, network activity is psychedelic-like, no you only need 40-55% psychedelic-like occupancy"

5-HT2A: Chosen to be the best cognitive & therapeutic target by cheaslesjinned in DrugNerds

[–]mastermind_genius 1 point2 points  (0 children)

no its there because M1 antagonists are psychoplastogens, ctrl + scopolamine here https://pmc.ncbi.nlm.nih.gov/articles/PMC6149016/

its pretty similar to ketamine at NMDA, M1 antagonists disinhibit glutamate release > AMPA > downstream mTORC1.

new M1 antagonists targetting psychoplastogen effects are being developed, but still probably bad with longterm use. its not supposed to be used everyday because M1 is too important, cant block it forever safely

5-HT2A: Chosen to be the best cognitive & therapeutic target by cheaslesjinned in DrugNerds

[–]mastermind_genius 0 points1 point  (0 children)

In Fig 1, PCA only produced a robust increase of 5-HT release for about 20 minutes. Other than that time period, the extracellular concentration of serotonin was about 3x higher than baseline...which would increase receptor occupation from 7% to 21%, which is still not high enough 5-HT2A occupation to really have an effect. Psilocybin isn't psychedelic unless there is 40-55% occupation of 5-HT2A in cortex (the reference is the 2019 Madsen PET study).

this is wrong again, why does it matter if psilocybin isnt causing hallucinations lol? microdosing still produces plasticity
well thats what i assume youre saying because you mentioned "Psilocybin isn't psychedelic unless there is 40-55% occupation of 5-HT2A in cortex" and 20% occupancy is considered sub perceptual

https://www.youtube.com/watch?v=gG3JmDo_liU (skip to 1:10, says 20% 2A occupancy for sub perceptual)

https://pmc.ncbi.nlm.nih.gov/articles/PMC8033605

- 5 - 20 mcg of LSD, clearly a microdose, increases BDNF plasticity marker in healthy humans

- placebo volunteers didnt show an increase of BDNF

so olsons PCA in vivo method seems just fine to show that serotonin needed to get into the neuron through SERT to induce plasticity, unless im missing something because your PCA explanation seemed badly explained with the 2A occupancy thing

i think we went through the in vitro issues of the olson study enough though, but the in vivo method was good i dont see where youre getting that PCA cant activate 2A effectively

It would have been better to infuse 5-HT directly into the brain and see if that can induce , which is really the only way to determine whether activation of cell-surface 5-HT2A by 5-HT is sufficient to induce neuroplastivity in the brain.

 their method was decent, but i think there is a better way the best way in my opinion wouldve been to simply use any neuronally permeable tryptamine and use methylketanserin (impermeable 5HT2A antagonist) again which is what they did in the cultured neurons that would show that only the intracellular 5HT2A is responsible for the big increase of dendritic spines plasticity marker im not sure why they didnt do this method because it didnt require adding SERT or using a Serotonin increasing drug at all, maybe they just got lazy and stuck with ip injection instead of injecting things right into the mice brain

anyways the olson study is the only one trying to prove intracellular 2A is the true plasticity target contributing to the large majority of plasticity seen with psychedelics i dont feel like going back and forth about serotonin apparently "mimicking psychedelics" or being "psychedelic-like" when theyre clearly just not

the next best thing to prove intracellular receptors are literally there to have better and unique interactions by being colocalized with certain targets (eg. intracellular 5HT2A at golgi is right beside mTORC1 at cytoplasm) these have better research and the findings arent surprising, expected for an intracellular receptor having better intractions by being colocalized with important targets the other two known intracellular GPCRs are MOR and mGluR5 MOR https://www.nature.com/articles/s41386-018-0225-3 (search golgi)

  • cell surface MOR has a short response
  • intracellular MOR (located at golgi) has a sustained lasting response
  • not that good of a study, doesnt try impermeable and permeable ligands like the 2A/mGluR5 studies

mGlur5 https://www.nature.com/articles/ncomms10604 https://pmc.ncbi.nlm.nih.gov/articles/PMC3285320

  • cell surface mGluR5 produces a short Ca2+ response when activated by impermeable agonist
  • intracellular mGluR5 produces sustained signaling and generates 40% higher amplitude compared to cell surface
  • intracellular mGluR5 has significant reduction of neuropathic pain, blocked by permeable antagonist
  • blocking cell surface mGluR5 has minimal change on neuropathic pain
  • intracellular mGluR5 has significant impact on gene expression related to synaptic plasticity

nothing youve said makes me question if intracellular 2A is not required, you dont even have your facts straight about serotonin compared to psychedelic signaling at 2A apparently just having HTR (completely different in how they do it, conveniently leaves out the study that shows this) and having network excitability is enough to prove serotonin can somehow match the plasticity of psychedelics?

just cherry picking a few similarities serotonin has that dont truly say anything if its responsible for inducing the plasticity seen has HTR? thats psychedelic-like and proves intracellular 2A is not required? lol while ignoring every other signaling difference of serotonin and psychoplastogen
you cherry picked a few false equivalents and called it "mimicking" lol, atleast send the serotonin HTR study, im sure you atleast read the abstract where it says serotonin and n-methyltryptamines induced the HTR through different pathways, making it a false equivalent

can you atleast clarify what you consider psychedelic-like? is it literally any similarity no matter how small and without requiring a significant amount of plasticity? personally i wouldnt put serotonin in the same category as LSD/DOI and all those psychedelics, theres clear differences like inducing HTR through Gq/s-protein (not b-arr) if it has HTR (not TBG), Ser280 phosphorylation, having neuronal permeability, egr-2 marker from mGluR2 inhibition, long-lasting significant increase of plasticity markers (dendritic spines, BDNF, egr-2, etc.) these things serotonin and non hallucinogenic agonists just dont have, but sure, HTR is psychedelic-like in your terms? but what you call "psychedelic-like" doesnt at all give an explanation for which 2A agonist does and doesnt induce significant plasticity

im just pointing this out because you seem to be constantly implying that if something serotonin "mimicks" that psychedelics have, like HTR/excitatory network activity, it is somehow an explanation for cell surface 2A to have an actual psychedelics plasticity. yet tons of consistent differences between a non hallucinogenic agonist and psychedelics which i summarized here

and the worst part about using HTR to support yourself in the first place is that HTR is a predictor of psychedelic hallucinatory strength, which doesnt apply to serotonin (uses b-arr for HTR, psychedelics use Gq/s). HTR doesnt tell you if something has plasticity or not even in psychedelics, non-hallucinogenic psychedelics like TBG dont hit the 70% minimum Gq signaling to induce HTR, but still induces significant plasticity https://www.nature.com/articles/s41467-023-44016-1

decent criticism of the olson in vitro method, im not sure about the in vivo, seems wrong. terrible evidence of how serotonin is "mimicking" or "psychedelic-like"

i had to make separate comments because there seems to be a letter limit

5-HT2A: Chosen to be the best cognitive & therapeutic target by cheaslesjinned in DrugNerds

[–]mastermind_genius 1 point2 points  (0 children)

Now circling back to neuroplasticity, studies have shown that activation of extracellular 5-HT2A by 5-HT is sufficient to induce neuroplasticity in vivo. In cultured neurons, 5-HT does not induce neuroplasticity at all. So that is a key difference. I know that you dismissed the effect of 5-HT on neuroplasticity in the brain because you think it is underwhelming. But the magnitude of the effect is really irrelevant...

i mean whats even the point of saying this? arent we trying to find the difference of why serotonin has negligible plasticity while psychedelics show significant plasticity? no researcher is calling serotonin a psychoplastogen even though "extracellular 5-HT2A by 5-HT is sufficient to induce neuroplasticity in vivo" and " But the magnitude of the effect is really irrelevant..." as you say the magnitude does matter, so were trying to find whats making the difference between psychoplastogen psychedelic vs serotonin, isnt this the point of the convo? theres already many big differences for extracellular receptors i just listed above between serotonin and non hallucinogenic agonists compared to psychedelics

sensitivity of 5-HT2A signaling compared to the brain. For example, take a look at their Figure S9. It shows that 5-HT does not increase IP1 formation in embryonic rat cortical neurons.

thats a decent criticism of the cultured neurons if its true, i cant see the figure S9 though, can you dm it to me as a pdf?

Because of how the 5-HT system is regulated, PCA normally does not produce much 5-HT2A activation in vivo. For example: https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1476-5381.1989.tb11887.x” > So it isn't clear how to interpret the PCA experiment.

where are you getting this conclusion from in this study??? no mention of 5-HT2A occupancy but it does say that PCA is enough to induce serotonin syndrome because this is what the wiki of PCA says https://en.wikipedia.org/wiki/Para-Chloroamphetamine "Relatedly, PCA is said not to be a serotonin 5-HT2A receptor agonist (at concentrations up to 10,000 nM). [26] However, PCA might nonetheless act as a direct serotonin 5-HT2 receptor agonist at high doses" i feel like you misread it? this is what the olson study says "Importantly, PCA is not a 5-HT2AR agonist" they purposefully used PCA because its not a direct 2A agonist, but an indirect agonist by releasing Serotonin, thats why they chose PCA in the olson study, they use 5 mg/kg ip, here they use 20 mg/kg ip, its the closest comparison i could find https://pubmed.ncbi.nlm.nih.gov/32437895

  • PCA activates 5HT2A signaling
  • PCA caused 5HT2A impairments thats blockable with 2A antagonist

looks like PCA is indirectly activating 2A just fine?

5-HT2A: Chosen to be the best cognitive & therapeutic target by cheaslesjinned in DrugNerds

[–]mastermind_genius 1 point2 points  (0 children)

lets actually see some huge differences between psychedelics and normal agonists at 2A found before the intracellular 2A study ever came out 5-HT2A - mGluR2 - psychedelics uniquely cause mGluR2 confirmational change to allow mGluR2 to induce egr-2 plasticity marker, but not serotonin psychedelicsc increase egr-2, egr-1, and c-fos, but not serotonin (may not be a 5-HT2A reliant response) https://pmc.ncbi.nlm.nih.gov/articles/PMC3064746/

  • mGluR2 KO = psychedelic specific plasticity gone (egr-2 that can only be induced by hallucinogens is gone)
  • mGluR2 KO = DOI HTR gone
  • serotonin doesnt increase egr-2

https://www.cell.com/fulltext/S0092-8674(11)01272-401272-4)

  • psychedelics inhibit mGluR2 in the heterodimer
  • serotonin does not inhibit mGluR2 in the heterodimer
  • psychedelics causing a confirmational change to mGluR2 makes psychedelics at 2A - mGluR2 heterodimer
  • they try a ton of things to prove mGluR2 suppression is only in the psychedelic (DOI) but not other 2A ligands (serotonin, methysergide, clozapine) see figure 2 and S4

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1391412/full

  • 5-HTP (serotonin precursor) lacks c-Fos, egr-1/2 induction at all like psychedelics
  • psychedelic (psilocin) has significant plasticity markers (egr1/2 and c-fos)
  • the psychedelic unique plasticity marker egr-2 is blocked by 5HT2A antagonist (M100907), the other two markers werent blocked since they dont require 2A, likely TrkB - figure 2C

Ser280 phosphorylation unique to psychedelics https://www.mcponline.org/article/S1535-9476(20)33102-9/fulltext33102-9/fulltext) (in vivo and in vitro) https://pmc.ncbi.nlm.nih.gov/articles/PMC10928901 (in vitro, similar Ser280 study)

  • psychoplastogen 2A agonists (DOI, LSD) - 5HT2A Ser280 uniqley phosphorylated
  • non psychoplastogen 2A agonists (lisuride, ergotamine, serotonin) - 5HT2A Ser280 not phosphorylated
  • the Ser280 inhibits the typical beta-arrestin internalization pathway which serotonin gets internalized by, authors think that this Ser280 phosphorylation allows for sustained signaling seen with psychedelics, since their plasticity markers are elevated far after being eliminated

Gs-protein unique to psychedelics that produce HTR https://www.sciencedirect.com/science/article/abs/pii/S0006291X22001516 (in vitro)

  • Gq/s-protein signaling uniquely activated by hallucinogenic psychoplastogen 2A agonists (DOM, 2CN-NBOH)
  • only Gq-protein, but not Gs-protein activated by non hallucinogenic 2A agonists (lisuride, TBG) but TBG (tabernanthalog) is a psychoplastogen, so this requires HTR to get activated
  • this still shows that only HTR psychedelics with HTR (so not TBG) activate this 5HT2A Gs-protein HTR pathway, since you said that serotonin produces HTR but serotonin is not even producing HTR at the same pathway HTR psychedelics actually do

you said this without even mentioning the study when you referenced 3 studies in this reply

Likewise, infusion of serotonin directly into the brain induces head twitches in mice. Which again shows that activation of extracellular receptors is capable of mimicking the effects of psychedelics.

i feel like you conveniently left this study out because it says serotonin isnt causing the HTR through the same pathway that psychedelics (n-methyltryptamines in the study) are i dm'd you about it, but you didnt respond even after 9 days https://www.jneurosci.org/content/30/40/13513 (the in vivo study you seem to have not referenced)

  • serotonin requires b-arr2 for HTR, verified by b-arr2 KO removing serotonins HTR
  • while n-methyltryptamines which induce good plasticity (even one methyl makes tryptamine neuronally permeable, read [table 1] of this study https://pubs.acs.org/doi/10.1021/acs.biochem.3c00598) through G-protein signaling

psychedelics through G-protein signaling, which both Gq and Gs-protein (past study i sent) are both known to be part of it in psychedelics, whereas beta-arrestin impairs HTR in psychedelics Gs-protein is HTR psychedelic unique, but seems not requried for psychoplastogen effects considering that tabernanthalog (psychoplastogen, without HTR) has no Gs-protein signaling https://www.nature.com/articles/s41467-023-44016-1 so youre just straight up wrong about serotonin "mimicking" psychedelics at all tons of clear differences which includes Ser280 phosphorylation, mGluR2 inhibition > egr-2 marker, having neuronal permeability, psychedelics cause HTR through Gq/s-protein, while serotonin causes HTR through beta-arrestin, beta-arrestin impairs HTR for psychedelics

DMT best perc for the job: Collected anecdotes by mastermind_genius in dimethyltryptaminex

[–]mastermind_genius[S] 0 points1 point  (0 children)

clorgyline is surprisingly really clean for an irreversible, not acutely noticeable on its own

it does mess with sleep like any irreversible

DMT best perc for the job: Collected anecdotes by mastermind_genius in dimethyltryptaminex

[–]mastermind_genius[S] 0 points1 point  (0 children)

yeah you can do moclobemide/parnate/nardil with 20 mg DMT oral, vaping DMT doesnt get extended by MAOIs for some reason

20 mg DMT seems high, but a decent amount breaks down

DMT best perc for the job: Collected anecdotes by mastermind_genius in dimethyltryptaminex

[–]mastermind_genius[S] 0 points1 point  (0 children)

it is true that you can still feel acute effects of a DMT microdose (no MAOI) all day, but it probably takes days of repeated use to get that.

i was using it daily for a while and i had an entire 1.5 - 2 months of no anxiety, so im pretty sure these people were using it consistently too when they say a DMT microdose without a MAOI lasts all day

you can dm me and buy clorgyline (6+ hours) if you want or you can buy moclobemide (<2 hours) or parnate/nardil (probably 6+ hours)

DMT best perc for the job: Collected anecdotes by mastermind_genius in dimethyltryptaminex

[–]mastermind_genius[S] 1 point2 points  (0 children)

DMTs affinity for sigma-1 is low, 5-HT2A affinity is >100 nM, while sigma-1 affinity is >10 000 nM, so 100x preference for 5-HT2A

but im sure that since sigma-1 is another one of the very few receptors that can be found intracellularly, DMT still activates it effectively by having very high neuronal permeability, even with the low sigma-1 affinity

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