5ht1a vs 5ht2a

[Psyke]

This started out for me as a quick question on how one differentiates the feeling between a 5ht1a dominant psychedelic vs. a 5ht2a dominant one, but if i may i would like to take this thread a step further and also ask why a certain "5htxa leaning psychedelic" might be more favorable as well.

So basically,

what are the differences (subjective or not) between when psychedelics mainly hit one receptor over the other?

What effects arise from each one being antagonized specifically?

Personally, I enjoy DPT exponentially more-so than a vast array of other hallucinogens, and as i understand it antagonizes 5ht2a
exceptionally so. What sort of differences does 5ht2a have vs 5ht1a?

Thanks in advance ladys and gents

~Psyke

 

[sekio]

5ht1a receptor activation is associated with anxiolysis and euphoria, 5ht2a agonism is responsible for "classical" hallucinatory/psychedelic effects.

Compare buspirone (5ht1a) to 25I-NBOMe (5ht2a)

 

[RobotRipping]

what are some 5ht1a dominant psychs though? I can't think of any. The use of such drugs seem to be indicated for plenty of other disorders, like pain relief, anxiolysis and many others but i don't see psychedelia as being a prominent effect of a full agonist. Are you referring to partial agonists? For psychedelics i think the affinity for the 5ht2a receptors would greatly outweight the effects noted from 5ht1a agonism, but i'm no expert on this.

Almost every singe psychedelic (especially the classics) are agonists at 5ht2a receptors. I can't think of a single one that is a full agonist and psychedelic at 5ht1a.

The effects of antagonists aren't particularly pleasant from what i remember. For psychedelics you are looking for agonists.

There are numerous receptor sites for 5ht2 as well, like 5ht2c being correlated with nausea. So a psych that binds less to that receptor and more so to 5ht2a would be a nice one. However i don't know anything about 5ht1a drugs, other than that some psychedlics do hit it but i don't think the effects are appreciable, but perhaps add some anxiolysis to the trip or something.

if you're referring to partial agonist like 5-meo-dmt, aMT then i don't think you can really subjectively figure out what the hell is going on, i imagine the affinity for 5ht2a is the cause of the psychedelia, as 5ht1a agonists have a myriad of effects just from looking at wikipedia.

There are some studies on rats but i can't really find anything about the effects of a partial agonist like 5-meo-dmt that has high affinity for both receptors that can explain how each receptor contributes to the high. I look forward to reading some posts from other members who are better educated on pharmacology though.

 

[kidklmx]

Well, IIRC 2C-B, 5-Meo-MiPT and 5-Meo-DiPT have a high binding rate to 5HT1a so it seems to be linked to euphoria (saw a chart with that the other day)

 

[psood0nym]

Here's a neato chart made by dondante and posted to this ADD thread. (The left side has the highest ratio 5HT2a:1a, and vice versa for the right.):

100,000nM is extremely low affinity - no affinity for practical purposes. Look at what most studies find for affinities to these receptors.

This study did not report any affinities >10,000 nM...I don't know where the 100,000 nM figure came from. Regardless, the functional assay for mescaline at 5-HT2A found an EC50 around 200 nM relative to 5-HT. I'm not sure I understand the discrepancy with the affinity values relative to 3H-ketanserin, but I suppose the results of the binding assay depend on the affinity of the hot ligand.

Anyway, I had some down time last week and made this figure showing 5-HT2A/1A affinity ratios. Obviously, this is the least surprising conclusion of the paper (since there is already evidence regarding the profiles of phens vs. trypts), but I found it satisfying to see it in graph form. It will be interesting to find out what effect other 5-HT receptors have on the phenomenology of the psychedelic experience ... and SERT and DA, alpha2, and sigma receptors too.

*These data points are from published data gathered by the PDSP, not tested by the PDSP.

Also, I left out DOET, because the high 1A affinity doesn't make sense to me. I should ask them to repeat that experiment...

I've read smoked 5-MeO-MiPT and 5-MeO-DMT are similar, and in my experience high dose DPT starts to get 5-MeO-DMT like. If this is because of proportionally high 5HT1a agonism then I'd speculate that subtype receptor has something to do with "pure" ego dissolution effects. That is, 5-MeO-DMT has few classical psychedelic effects but it's a very powerful no-bullshit ego dissolver.

Also, as I recall there may be reasons to question some of the data that the chart is representing.

 

[Psyke]

For psychedelics you are looking for agonists

.

But wikipedia says...
but the modulatory actions of a 5-HT1A receptor antagonist also imply a 5-HT1A-mediated component to the actions of DPT.

or am i missing something?

Also strangely enough, DPT, 5-meo-MiPT, and of course LSD are all my favorite psych's and seem to be highly 5ht1a favored...
I really like this explanation as psoodynm so eloquently puts it:

If this is because of proportionally high 5HT1a agonism then I'd speculate that subtype receptor has something to do with "pure" ego dissolution effects. That is, 5-MeO-DMT has few classical psychedelic effects but it's a very powerful no-bullshit ego dissolver.

I can completely see this with DPT. To me dpt seems very unclassicly psychedelic, which is why i enjoy it so much, it doesn't seem like i am 'tripping' but more-so experiencing a different reality or different perspective on my ego which is very interesting and very calming for me, versus i'm still in the same mindset but frazzled up with visuals as 2c-i may be for example. Hope that makes sense.

P.S Thanks for that table psood...very interesting... wonder why they left out DOET

 

[RobotRipping]

regarding 5ht1a agonism, i don't know about wikipedia but it's clear from that chart at least that agonists are what we are looking at. Go to wiki and look up 5ht1a partial agonists and you'll find some psychedelic friends there. Look at the full agonists and you find some strange medications. Then go look at the antagonists. Risperidone is one of them and is an antipsychotic.

Looking at the chart, there are some noticeable effects from the drugs that hit 5ht1a (tho they are partial agonists and still bind to 5ht2a receptors) and the ones that hit 5ht2 receptors primarily.

I notice dissociative/ego dissolution type qualities of 5-meo-dmt and 5-meo-mipt. if 5-meo-dalt were on that list as well then i'd say there's a notable difference in psychedelics that primarily hit 5ht1a and 5ht2a compared to psychs that hit just 5ht2 receptors. 4-aco-dmt gives me the same type of feeling at high doses. As do most other tryptamines actually.

is it common that tryptamines hit 5ht1a receptors far more so than PEAs? maybe that explains the subjective differences between the two classes, at least a little bit. Wish the chart included other tryptamines then it'd be a lot more clear.

 

[Psyke]

yes it'd be interesting to find out individually which psychedelics influence SERT and DA, alpha2, and sigma receptors, and to see how these play into it all and if there are any running patterns.

@Robotripping: I noticed in the brief paragraph above the chart it does seem to imply a running theme of trypts involving 5ht1a more-so than phens.

An expanded chart would be amazing, I wonder if DOC is similiar to DOB/DOI in it's 5ht2a value's.... for some reason DOC has seemed vastly different than other phenethlamines... i wouldn't be surprised if it had significant 5ht1a binding affinity.

 

[psood0nym]

.
P.S Thanks for that table psood...very interesting... wonder why they left out DOET

The chart was made by Dondante, a Bluelighter, from published data. He says why he left out DOET in the last line in the quote:

Also, I left out DOET, because the high 1A affinity doesn't make sense to me. I should ask them to repeat that experiment...

 

[Psyke]

I know, I saw that and was wondering why dondante didn't think the high 1a affinity didn't make sense to him...too high compared to the rest of the phen's making it an outlier i suppose? seems perfectly possible... like i said i wouldn't be surprised if DOC for some reason or the other has a high a1 affinity as well.

 

[Ziiirp]

Just to add a few obvious ones (that did not get attention in this thread) : DiPT, Mescaline, LSD (and of course 5-Meo-DMT but that was mentioned) all have very high 5HT1a-affinities. The former 2 being special ones, as they seem to lack 2a-affinity significantly*. I heard Mescaline is visual, though. So the linking of the 2a-receptors to visual enhancement is a bit too superficial perhaps. In my view, the visuals are just eye candy anyway. I don't know why in literature the 2a-affinity is always so illuminated, when it is an exquisite orchestration of the whole subgroup-affinities, that makes a profound experience.

 

[zn13bt]

DiPT has a reputation for being a non-visual psychedelic, based on its description in TIHKAL, but it is possible to get visuals on it if you take a high enough dose.

 

[kidklmx]

Where'd you get that Mescaline doesn't bind to 5HT2A? With my limited knowledge, Mescaline doesn't seem to have a high affinity at 5HT2A because that value given is in relation to the ligand used. Just because it shows 0.00 in Psychedelics and the Human Receptorome then it doesn't mean it doesn't bind at all, it just means that the value is above 10,000nM (which explains why the dosages are so high)

 

[Ziiirp]

Okay sorry, that was expressed badly, it binds to 2a (probably every psych. does?), but the <other serotonine receptor>/2a - ratio is so high, that one could consider the 2a-affinity as being not the primary indicator for the entheogenic experience you get from it, contrarily to the hypotheses in other common resources.

 

[Dondante]

Where'd you get that Mescaline doesn't bind to 5HT2A? With my limited knowledge, Mescaline doesn't seem to have a high affinity at 5HT2A because that value given is in relation to the ligand used.

Exactly, though mescaline's relatively low affinity should still put its Ki well under 10,000 nM. The most likely explanation is that the data from that paper is simply incorrect...there is plenty of room for error, and it's not clear that the experiments were repeated to give a mean. As I mentioned above, the same paper cites an EC50 (measure of drug potency by its activity rather than affinity) at 5-HT2A of 200 nM. Another source cites a Ki of 150 nM.

 

[kidklmx]

Yeah I've read a lot of rumbling on psychedelic and the human receptrome not being the most accurate of studies. Luckily I found this old post* in a discussion on mescaline's pharmacology:

The affinity data for 5-HT2A and C given in that article may be somewhat misleading, as the PDSP measurements use antagonist radioligands for these receptors. The Ki's for mescaline given in Bradens thesis are 4142 (5-HT1A, [3H]8-OH-DPAT), 1499 (h5-HT2A, [125I]DOI), 2438 (h5-HT2C, [125I]DOI) and 14,640 (h5-HT2A, [3H]ketanserin).

That's a bit more logical to me, though I'm not going to deny that there's a lot more to psychedelics than just 5HT2A-binding.

*"Limited knowledge" amounts to me lurking ADD and hoping to make some sense of it all :D

 

[Dondante]

^Nice. This paper also found higher affinity for 5-HT2A (Ki 5500 nM) than 5-HT1A (Ki 6900 nM) for mescaline, though it's not the 10-fold to 100-fold selectivity of other phens.

The problem with affinity studies (aside from inconsistencies) is that they only tell you how tightly a compound binds to a receptor...they completely leave out how active a compound is in terms of triggering downstream signaling cascades. You could have two compounds, both agonists, with the exact same affinity for the 5-HT2A receptor, one of which has an maximal activity that is 100% of that caused by serotonin (full agonist) while another could top out at 30% (partial agonist). These differences could result in drastically different effects. Then to add another layer of complexity, one receptor can activate 2 or 3 separate downstream signaling pathways, and these can be preferentially activated by different compounds independently of affinity. Good to keep in mind that it's much more complicated than simple affinity...

 

[electrodevo]

what are some 5ht1a dominant psychs though? I can't think of any.

Using table S2 in this study (Ki values alone), 5-MEO-DMT looks especially dominant at 5-HT1A. 5-MEO-MIPT also looks like it is 5-HT1A dominant. (I'm not counting substances like RR-2B which is an ergoline derivative that I've never heard of.)

Of course, Ki values don't explain everything, and there may be alternate data sets out there. One common thread: neither of these compounds, though, are as visual as strong "classic" 5-HT2A agonists, it seems. Hmm.

5-MEO-MIPT is known to have an "opening up" quality like MDMA, and (though the Ki values here don't indicate so) I've read that one theory behind MDMA "magic" is oxytocin release via 5-HT1A agonism. Hmm.

I cannot conclude anything, and neuropharmacology is more complex than "agonize this receptor = this effect", all I can say is "hmm".

 

[ungelesene_bettlek]

the "psychedelic" phenylpiperazines like pFPP and TFMPP also have high high affinity for the 5HT1A receptor, correct? can we perhaps conclude something from that...?

(sorry for bringing back your memory to drugs of the past which have become forgotten for a reason...)

DiPT has a reputation for being a non-visual psychedelic, based on its description in TIHKAL, but it is possible to get visuals on it if you take a high enough dose.

I have only one experience with DiPT, and in the beginning, its action was indeed almost exclusively acoustic. but later on, I decided to smoke some pot additionally, and this combination was enough to make it also very visual.

 

[electrodevo]

Looks like pFPP is mostly 5-HT1A, yes.

The Wiki for TFMPP seems to indicate that it hits 5HT1A and 5HT2A relatively equally at least, Ki value wise. In action, though, the Wiki indicates that at HT2A is a partial agonist, and a full agonist at HT1A.

I can't remember reading a solo trip report of these compounds though... usually this was taken as "fake ecstasy", eg mixed with a stimulant (BZP, usually).