Psychedelics and the Human Receptorome

[any major dude]

Very interesting and quite thorough study on binding affinities and such of 35 different drugs, including many tryptamines & phenethylamines, as well as some ergolines, salvinorin, and morphine. Definitely some surprising results, as some serotonergic psychs showed little or no affinity for the 5ht2a receptor, (mescaline?!? wtf) in this study anyway. the Alpha2 receptors seem to be pretty high on the list of many of what are considered the more "classically" psychedelic substances. The receptor affinities seem to be much more broad than initially thought Anyway, here's the link, discuss amongst yourselves

If I could ever make a statement similar to this quote from the paper in regards to a research project I'd be a very happy man: " DOB, DOET, mescaline, TMA, MDA, MDMA, and psilocin were provided as gifts by the National Institute on Drug Abuse Drug Supply Program. 2C-B, 2C-B-fly, MEM, 4C-T-2, 5-MeO-MIPT, 6-fluoro-DMT, TMA-2, and lisuride were provided as gifts by Dave Nichols. DMT and DOM were provided as gifts by Richard Glennon. 2C-E, 2C-T-2, Aleph-2, DIPT, 5-MeO-DIPT, and DPT were provided as gifts by Alexander Shulgin"

 

[b3576467]

That is simply outstanding, I'm sure everyone will love you for this, and whoever wrote the article.

The detailed affinities (if you scroll down) are incredible. Salvinorin A is interesting. And yeah, it is interesting that the usual thinking of 5HT2A agonistic mechanism of psychedelics is being challenged, and the thinking behind all kinds of receptors really.

Note- I bet not all of the affinities necessarily refer to agonism at that site, but can be an antagonist or partial (weak) agonist.

 

[hamhurricane]

schwing! ive talked to thomas ray years ago the guy is a real eccentric/genius, i had to study his non-psychedelic research during freshman bio its amazing to see a single scientist doing import work on computerized models of evolution and psychedelic pharmacology. i only skimmed the paper but just the fact that it includes DiPT has me salivating.

 

[any major dude]

DiPT had a pretty interesting affinity profile: DIPT: 4.00 5ht1a, 3.53 Imidazoline1, 3.48 5ht2b, 2.98 SERT, 2.83 Sigma1, 2.68 Alpha2C, 2.65 Sigma2, 2.62 Alpha2B, 2.56 D3, 2.55 5ht7, 2.53 H1, 2.51 5ht1d; 0.00: 5ht2a, D4, 5ht5a, D1, D2, Alpha2A, 5ht6, D5, Beta1, Beta2, 5ht2c, DAT, NET, 5ht1b, Alpha1B, 5ht1e, DOR, KOR, MOR, M1, M2, M3, M4, M5, Alpha1A, H2, CB2, CB1, Ca+Channel, NMDA

Also, the most selective for 5ht2a seems to be 2c-e, neither MDA or MDMA had any affinity for SERT or DAT, which i thought was odd... and while mescaline & TMA had no affinity for 5ht2a, TMA-2 did. This study should spawn a lot of really interesting further research

 

[hamhurricane]

holy christ this is a huge deal, so much assumed information just disintegrated. i guess this disproves nuke's theory about the 5HT6 receptor mediating auditory hallucinations, DiPT (my favorite psychedelic) has no affinity for 5ht2a and had a high affinity for imidazole how bizarre! by the looks of this data the 5ht2a receptor is hardly important for psychedelic activity and most of the really desirable drugs (MDMA, DiPT, Mescaline) are potent agonists at the imidazole receptor. TMA is the second after LSD at the 5HT1b yet shulgin hated TMA, my mind is spinning. DOM is almost just as potent a 5ht2b agonist as DOB...

 

[any major dude]

Yeah, its nuts... On another interesting note, the substituted phenethylamines & amphetamines with an ethyl, or ethylthio (in the case of 2 & 4 c-t-2) tend to have higher affinities for the 5ht2a receptor than their halogenated or otherwise alkylated counterparts. Not that I even know what that would mean anymore... ha

 

[cegli]

Wow, no 5HT2a and 5HT2c activity for these at all:

MDMA
Mescaline
DiPT
5-MeO-DiPT

If this study is correct, this should really rewrite a bunch of things we thought we knew about psychedelics...

Look at Mescaline's affinities:

Mescaline: 4.00 Alpha2C, 3.97 5ht2b, 3.61 5ht1a, 3.44 Imidazoline1, 3.16 5ht1e, 2.92 Alpha2A

Have we even suspected any of those receptors to be responsible for psychedelic effects? I feel like we're missing an important receptor in the brain that links these all together... Or maybe the brain can't just be broken down into simple affinities .

 

[vortex30]

Have we even suspected any of those receptors to be responsible for psychedelic effects? I feel like we're missing an important receptor in the brain that links these all together... Or maybe the brain can't just be broken down into simple affinities .

That's what I'm thinking. Abnormal ratios of antagonised/agonised receptors is quite possibly enough to cause the effects of psychedelics, rather than a specific or set of specific receptors. That was very interesting, though a bit advanced for me its cool to see the 5ht-2a theory pretty much being abolished by this (if its accurate, which for now I'll assume, as you'd think they'd have double, triple, quad checked the affinities for mescaline. One possibility that just came to mind though, is a poor sample for those listed drugs with no affinities? For example, completely different, non-psychedelic chems? Who knows...We'll have to wait and see for some more studies like this.

 

[hamhurricane]

and really this study is only the beginning, just look how unexpected the results are: MEM is one of the most selective agonists, 2C-E most potent at 5HT2a? if a full profile of receptor interaction were run for everything in PIHKAL/TIHKAL i would expect the unexpected.

someone is going to have to go through all the wikipedia entries that say "The mechanism of action that produces 2C-x's hallucinogenic and entheogenic effects has not been specifically established, however it is most likely to result from action as a 5-HT2A serotonin receptor agonist in the brain, a mechanism of action shared by all of the hallucinogenic tryptamines and phenethylamines for which the mechanism of action is known." and edit them.

 

[stirfry]

Link to a 2004 study that also seems to cast doubt on the 5-HT2A (partial) agonist theory for the activity of psychedelics.

The present results demonstrate that in X. laevis oocytes, 2C-B, and a series of C(4)-substituted analogs, are 5-HT2A receptor antagonists; they appear to be selective within the 5-HT2 receptor family since no inhibition of the 5-HT-evoked currents was detected at the 5-HT2C receptor. We are fully aware that the present data do not allow us to deduce the nature of the psychostimulant mechanisms of these PEAs; however, the present results demonstrate novel pharmacological properties that might be of interest in the understanding of their psychostimulant properties. Parallel behavioral studies are required to complement the present investigation. Considering that 2C-B, 2C-I and 2C-D are recognized to be hallucinogenic in humans (Shulgin & Shulgin, 1991), the present results cast doubts on the generally accepted notion that the phenylalkylamine hallucinogens act only as full or partial 5-HT2A agonists.

 

[psood0nym]

^Also, the earlier behavioral study, The Paradox of 5-MeO-DMT.

 

[nuke]

i guess this disproves nuke's theory about the 5HT6 receptor mediating auditory hallucinations, DiPT (my favorite psychedelic) has no affinity for 5ht2a and had a high affinity for imidazole how bizarre!

Yes... The mystery continues.

This npKi stuff is kind of weird, though.

 

[Dondante]

Wow, no 5HT2a and 5HT2c activity for these at all:

MDMA
Mescaline
DiPT
5-MeO-DiPT

If this study is correct, this should really rewrite a bunch of things we thought we knew about psychedelics...

Look at Mescaline's affinities:

Mescaline: 4.00 Alpha2C, 3.97 5ht2b, 3.61 5ht1a, 3.44 Imidazoline1, 3.16 5ht1e, 2.92 Alpha2A

Have we even suspected any of those receptors to be responsible for psychedelic effects? I feel like we're missing an important receptor in the brain that links these all together... Or maybe the brain can't just be broken down into simple affinities .

After a taking a brief look at the article, I don't think the results are necessarily paradigm shattering. I could be wrong, but from what I can tell, the results don't demonstrate an absence of 5-HT2A affinity for mescaline. They simply show that the affinity could not be detected, which is not surprising given the low potency of mescaline. If DOM has a Ki of 300 nM for the 5-HT2A receptor, and it is about 50x as potent as mescaline, one would expect that the Ki of mescaline would be >10,000 nM (above detection limit of the binding assay). Also, according to the PDSP database, MDMA (another low potency compound) has a Ki for 5-HT2A of 10,008 nM. I don't have a good explanation for 5-MeO-DIPT.

The paper is very interesting nonetheless. It goes a long way to explain the tremendous qualitative diversity of these drugs.

 

[cegli]

As for 5-MeO-DiPT, seeing as how it's a selective auditory distorter, I think it's possible that a receptor other than 5-HT2A might be mediating its psychedelic effects.

I believe you're thinking of DiPT, which is a somewhat selective auditory distorter. It becomes more psychedelic at higher doses. 5-MeO-DiPT is a somewhat rough typical psychedelic (some say it has slight audio bending qualities at high doses).

 

[seep]

At the risk of sounding like a nerd, what's with all the clunky stats-math in the breadth calculations? Like B(exp) = ln[sigma e^(npKi)]. A little bit of calc turns these equations into simple integrals.

Thanks for posting this!

 

[seep]

* groans *

lol

 

[Hammilton]

This paper is the biggest pile of dogshit I've ever seen. People make stupid comments about Ricaurte all the time, but are calling this guy a genius? LOL

In all of these comments, how is it that no one has commented on the fucked up methodology? That people are accepting really oddball results like MDMA having no detectable SERT affinity when dozens of other studies have found it?

It's like you came across a study that said the sky was orange and just decided to accept it.

Additionally, why the fuck was morphine included in this paper?

Oh god, so many things...

MDMA: 4.00 Imidazoline1, 3.64 5ht2b, 3.26 Ca+Channel, 3.21 Alpha2C, 3.09 Alpha2B, 3.07 M3, 2.94 Alpha2A, 2.54 M5, 2.43 M4; 0.00: 5ht2c, 5ht1d, D2, 5ht1e, 5ht1a, 5ht2a, Alpha1A, Alpha1B, 5ht5a, 5ht6, 5ht7, D1, Beta2, SERT, DAT, NET, 5ht1b, H1, H2, D3, KOR, Beta1, M1, M2, D5, D4, CB1, NMDA, MOR; ND: DOR, Sigma2, CB2, Sigma1

To quote Longimanus, for whom I have the greatest respect:

That is just wrong......
I mean...
Probably the most idiotic article I have seen in a long time. Shows a complete lack of understanding - not only in, hm, "psychedelic" pharmacology but also in the basic ideas of pharmacology.
Of course DOB/DOI will look that bad in terms of selectivity. That happens when one takes the mean of all Ki values for a given compound in the database. The ones that will matter and correlate with "psychedelic" activity, of course, are the ones vs. an agonistic hot ligand, not ketanserin . Not to mention different biological systems....

I'd love to see some really good explanation for why this paper isn't dogshit, and I'm racking my brains trying to come up with something, but I'm drawing a blank. The only explanation I can think of is a woefully incomplete database, which is hardly an excuse.

 

[hamhurricane]

This paper is the biggest pile of dogshit I've ever seen. People make stupid comments about Ricaurte all the time, but are calling this guy a genius? LOL

ah well the voice of reason...

when i called him a genius i was not referring to this specifically but also his work on a computerized model of evolution, ive been hearing about this receptorome project for years from one of his former students and i was very excited to see it come out. unfortunately, i dont fully understand Longimanus's argument if someone could break it down a bit that would be appreciated.

 

[any major dude]

This paper is the biggest pile of dogshit I've ever seen. People make stupid comments about Ricaurte all the time, but are calling this guy a genius? LOL

In all of these comments, how is it that no one has commented on the fucked up methodology? That people are accepting really oddball results like MDMA having no detectable SERT affinity when dozens of other studies have found it?

It's like you came across a study that said the sky was orange and just decided to accept it.

Additionally, why the fuck was morphine included in this paper?

Oh god, so many things...

I'd love to see some really good explanation for why this paper isn't dogshit, and I'm racking my brains trying to come up with something, but I'm drawing a blank. The only explanation I can think of is a woefully incomplete database, which is hardly an excuse.

Well the paper itself said anything above 10,000nM wouldn't be detected, and for lower potency drugs like mescaline, MDMA, etc, it would be expected that they would have a Ki of >10,000 at some receptor sites. What is interesting is the stronger affinity for other receptor sites, and the questions that raises.

Morphine was an active control, IIRC

 

[egor]

I was really excited to read this until I started actually reading it...