The 5-HT2B receptor, valvulopathy and the apparent safety of psychedelic drugs

[markosheehan]

You probably won't find any, although they could be made. The structure of the 5-HT2A and 5-HT2B receptors are very similar, so they have very similar pharmacology, meaning that ligands tend to show effects at both. It takes some work to design drugs that are selective for one over the other, although it is possible.

so all psychedelics pose the same equal threat as psilocin? surely there are safer ones with less of a risk at least? do you know if LSD, DMT, mescaline,5meo dmt,other lysergamides, other tryptamines and others all pose the same risk.

 

[serotonin2A]

so all psychedelics pose the same equal threat as psilocin? surely there are safer ones with less of a risk at least? do you know if LSD, DMT, mescaline,5meo dmt,other lysergamides, other tryptamines and others all pose the same risk.

25CN-NBOH and DMBMPP are somewhat selective for 5-HT2A vs 5-HT2B. But I don't think there is a reason to really worry about this issue, because the risk is very low with normal use patterns.

 

[markosheehan]

well you said direct 5ht2b is sufficient to produce carditoxic affects which is worrying for heavy users . im trying to minimise the risk by taking less but i would switch to an alternative if it was safer. DMT would be safer maybe because of its very short half life and lower affinity. LSD probably is not as recent assays have said it has a affinity of 1nm even though older ones say its 30nm. mescaline has very little affinity for 2b i think.

psilocin seems to be carditoxic through gq signaling and LSD prefers beta arrestin recruitment. im trying to determine which is more dangerous.

 

[Cotcha Yankinov]

I bet you ideally want a compound that passes the BBB easily, so as to keep good peripheral vs. CNS concentrations.

Just another factor that may come into play.

 

[serotonin2A]

LSD probably is not as recent assays have said it has a affinity of 1nm even though older ones say its 30nm. mescaline has very little affinity for 2b i think.

The results of binding assays depend on the radioligand, species, and expression system, and there is also inherent variability in measurements made in biological systems. If you look across a range of 5-HT2B binding studies, you will see Ki values for LSD of 0.9 nM, 11 nM, 3.7 nM, 30 nM, and 8.9 nM. Some of that variation reflects the use of agonist vs. antagonist radioligands.

Mescaline also has relatively low affinity for 5-HT2A receptors -- that is why it has to be taken in doses of hundreds of mg to produce an effect. Mescaline is not slective for 5-HT2A vs 5-HT2B.

 

[WSH]

I bet you ideally want a compound that passes the BBB easily, so as to keep good peripheral vs. CNS concentrations.

Or alternatively (and even better) use a 5-ht2b antagonist that's very liphophobic!

Some of that variation reflecs the use of agonist vs. antagonist radioligands.

Yes, agonists selectively label the g-protein-coupled receptors, wheras antagonists also bind to the g-protein-uncoupled (non-functional) receptors!

 

[markosheehan]

so would using yohimbine not be worth it or would it help at all?

would i be right to say LSD is less dangerous than psilocin because its ratio of 2a to 2b seems roughly the same or maybe slightly selective for 2a over 2b. however with psilocin 2a affinity is 107 vs 2b affinity 4.6 this suggests psilocin is way more selective over 2b . however psilocin seems to have a lower affinity and lower efficacy so trying to weigh this up against the high selectivity of psilocin for 2b its hard to say which is safer

 

[WSH]

so would using yohimbine not be worth it or would it help at all?

would i be right to say LSD is less dangerous than psilocin because its ratio of 2a to 2b seems roughly the same or maybe slightly selective for 2a over 2b. however with psilocin 2a affinity is 107 vs 2b affinity 4.6 this suggests psilocin is way more selective over 2b . however psilocin seems to have a lower affinity and lower efficacy so trying to weigh this up against the high selectivity of psilocin for 2b its hard to say which is safer

You would have to take such an yohimbine overdose to reach 5-ht2b that you would die.

And psilocin has an 5-ht2a affinity of ~6nm, so if its 5-ht2b is 4.6nm like you said then that's not selective at all.
Your 107nm affinity might come from the use of an inappropriate radioligand, like serotonin2a and I were just talking about.

psilocin 5-ht2a affinity study

 

[markosheehan]

that study is from the 1990s and i dont think it is reliable. it says psilocins affinity for 2b is 410 nm. i doubt thats right. if you go off the PDSP database psilocin affinity is 107 nm for 2a and 4.6 for 2b if this is the case its quite worrying as it means 2b is being stimulated a lot for the dose you are taking compared to lsd which seems to be only slightly selective towards 2b. i think generally the pdsp database is more reliable. ideally it would be best to take the values from the same experiment.

and why would you have to take a overdose of yohimbine. ive also heard ginger is a 2b antagonist so maybe its good to take ginger?

 

[WSH]

that study is from the 1990s and i dont think it is reliable. it says psilocins affinity for 2b is 410 nm. i doubt thats right. if you go off the PDSP database psilocin affinity is 107 nm for 2a and 4.6 for 2b if this is the case its quite worrying as it means 2b is being stimulated a lot for the dose you are taking compared to lsd which seems to be only slightly selective towards 2b. i think generally the pdsp database is more reliable. ideally it would be best to take the values from the same experiment.

and why would you have to take a overdose of yohimbine. ive also heard ginger is a 2b antagonist so maybe its good to take ginger?

I've checked the PDSP database and the only thing that's "unreliable" is that they've used the ridiculous radioligand ketanserin.

The study i posted uses the appropriate radioligand DOI.

The fact that studies are old doesn't necessarily mean they're wrong, we still have wheels on our cars, even though they're were invented very long ago.

The fact that your "evidence" uses a radioligand that does not label the functional 5-ht2a receptor however is relevant.

Another value from the PDSP database with a proper radioligand (DOI) in rat cortex also has a value of 12nm, which is similar to the study that i've posted.

Yohimbine is very selective for alpha2-receptors and they would kill you way before you would reach 5-ht2b.

 

[markosheehan]

it just seems strange in the study that psilocins 2b affinity was 410.

so from the information you know which would be more selective for 2a than 2b psilocin or lsd.
would ginger work do you know?

 

[WSH]

it just seems strange in the study that psilocins 2b affinity was 410.

Yes, that's certainly true, but that's because they labelled the 5-ht2b again with the inappropriate radioligand ketanserin:

By contrast, most derivatives were 2-10 times less potent at the 5-HTb, receptor labelled by [3H]ketanserin in bovine cortex.

The fact that agonists and antagonists label different receptor populations wasn't very much known at that time (actually even today some people don't know about it, yes, i'm looking at you, Thomas S. Ray from the PLOS ONE study) and so they make the most ridiculous comparisons e.g. between 8-oh-dpat-labelled 5-ht1a and ketanserin-labelled 5-ht2a.

Even serotonin itself has hardly any affinity for ketanserin-labelled-5-ht2a, whereas for the functional DOI-labelled-5-ht2a it's approximately as potent as 8-oh-dpat-labelled-5-ht1a:

5-HT2 sites were originally defined by their low affinity for 5-HT (i.e., Ki » 500–1,200 nM); but it is now known, using the appropriate radioligands (e.g., [125I]DOI, [3H]DOB), that 5-HT binds at 5-HT2 sites with high (i.e., Ki <10 nM) affinity

source for quote

So the ketanserin-labelled-5-ht2b value is as irrelevant as your ketanserin-labelled-5-ht2a value.

The 6-12nm DOI-labelled-5-ht2a value is relevant , just like the 4.6nm LSD-labelled-5-ht2b value.
psilo is not selective between 2a and 2b

 

[MocCozmiK]

well how come there have been no studies linking psilocin to being cardiotoxic. we all know so well what drugs are cardiotoxic so why cant we say psilocin is cardiotoxic? ECG is not affected by psilocin administration

I believe there have been studies showing that psilocin has the potential to be cardiotoxic

http://connection.ebscohost.com/c/a...-multiple-intake-resulted-cardiotoxic-effects

https://www.researchgate.net/public...le_intake_resulted_and_in_cardiotoxic_effects

These maybe the same source. And obvious it's from 3 months of daily injections.

 

[markosheehan]

https://thethirdwave.co/microdosing-heart-risk/
They are biased to hell both of them. And by the same group of people.

LSD and I'm confident psilocin is not cardiotoxic in normal usage.
I messaged Dave Nichols a few weeks ago and he told me his son Charles did a study where he chronically gave LSD to mice. They had a pathiolgist come in and look at their hearts. He observed no abnormalities. I can copy the emails if you don't believe me. I would think it would also apply to psilocin's.

Also a recent pharmokinetics study by Paul Hudson gave people psilocybin and they measured ECG no abnormalities were detected. The study is on pubmed I can link it if you want.

These substances are not cardiotoxic in regular doses. I am a paro when it comes to this topic but at this stage I've given up research on it as they are not bad in normal use.

 

[Solipsis]

good for you dude