Help understanding relative psychedelic 5HT-B2 antagonism risk

[Sir Ron Pib]

Probably many know of the story of fenfluramine and heart valve disease which is linked to 5HT-2B antagonism.
Since such antagonism is common with empathogens and psychedelics I was wondering if any one could help explain the parameters around risk.

Just from looking at wiki we have selective agonists (ex. 6-APB, psilocybin etc) and non selective agonists (MDMA, DMT etc)

Can anyone explain further the risks associated with the two forms
Fenfluramine was seemingly a non selective - although of course the problem was still relatively rare.

Also affinity comes into it - a lot of people have better access to technical papers on the matter and could perhaps explain how to read the figures since they mean little to me currently. Is there a list one could make of relative risk (tentative of course- that there are huge unknows is taken) - is 6-APB worse than 5-APB or are both better or worse than MDMA - how high do classic psychedelics like psilocybin rank etc.

LSD and the like have never classical been linked with any bodily harm so I am guessing the story is rather more complex than 5HT-B2 = heart disease risk but if anyone could help my understanding it wold be good.

 

[Sir Ron Pib]

Just seen on another thread psilocybin and DMT have high affinity so *theoretically* higher risk than the others.

 

[sekio]

I don't think it's as simple as "high affinity for 5ht2B = high risk for heart valvulopathy". Trazodone has affinity for 5ht2b as an antagonist and nobody is concerned about that. It's also pertinent to consider how often the compounds are being administered and at what doses, the half-lives in the body, its accumulation in heart vs other tissues, its ability to activate the receptor vs block it and so on.

The fen-phen disaster had fenfluramine dosed once daily or longer, and the compound responsible for causing the 5ht2b activation was an amphetamine with a long half life (norfenfluramine). So certainly any of the 5ht2b agonist MDMA mimics are something to keep an eye on and not dose daily. (With something like DMT that's eliminated rapidly, it's not worth losing sleep over.)

I don't think heart valve damage is a concern in occasional recreational MDxx users, only heavy ones, though.

For more reading: ref

 

[adder]

Just to make it clear heart valve disease is related to 5-HT2B agonism and not antagonism. 5-HT2B antagonists might thus counteract the negative effects of 5-HT2B agonists which in case of fenfluramine are lasting even after discontinuation of the drug.