Seeming Categorical Toxicity---Serotonergic Stimulants

[AlphaMethylPhenyl]

So maybe this thread has a fast answer. I'm thinking about fenfluramine, of which 5-HT2b is apparently the criminal mechanism. It appears that the classic psychedelics also act on this subtype of the 5-HT receptor, among a giant list (of which at least 15 are natural), but yet there is no talk of heart valve damage from them. Can someone elucidate on how specifically this damage is caused?

But then we have cocaine, which is cardiotoxic. I was under the impression that it's an SNDRI. I guess that the serotonergic mechanism is at least *partly to blame for this toxicity. But does it affect 5-HT2b in a manner similar to fenfluramine? If not, how does it cause this toxicity. Methylphenidate, by contrast, isn't cardiotoxic and some studies suggest that in moderate doses it can improve brain functioning. That said, studies suggest that people can't discriminate between IV cocaine and IV methylphenidate; now I don't know if this is due to some metabolic happenstance or what, but it punches something of a hole in theory.

We know that MDMA is apt to cause destruction of serotonergic neurons due to the acidity of dopamine, which binds to SERT and is treated by the brain as serotonin. Similarly, MDA and cousins. They bind to 5-HT2b, too. What about cardiotoxicity?

Meth needs no introduction. Amp itself in therapeutic doses isn't health food necessarily, but 80+ years of use at even above the recommended max dosage and studies themselves lend credence to relative safety (not saying anyone should take it, though, to be celar).

Mephedrone/Methylone I hazard a guess definitely cause some damage, but they're relatively un-researched.

It just seems that any serotonergic stimulant is damaging in some manner (which isn't to say that a stimulant is otherwise safe).

But the exception seems to be mescaline. I know it has a low therapeutic ratio, but it is otherwise both a substituted phenethylamine and a psychedelic and is without toxicity to brain and heart both.

Maybe I'm trivializing something that's quite complex, but if so, please teach.

 

[LabRat74]

5ht2b activation causes hardening of valves. Serotonin itself is a 5ht2b agonist (funnily enough lol).

"Cardiotoxic" doesnt just mean generally bad for the heart. It is specifically an interference of the electrical signal that controls the rhythm of heart ticks.

Both are bad for the heart but not the same thing.

 

[vecktor]

So maybe this thread has a fast answer. I'm thinking about fenfluramine, of which 5-HT2b is apparently the criminal mechanism. It appears that the classic psychedelics also act on this subtype of the 5-HT receptor, among a giant list (of which at least 15 are natural), but yet there is no talk of heart valve damage from them. Can someone elucidate on how specifically this damage is caused?

The reason the issue hasn't really been seen is that classical psychedelics are not taken daily, for extended periods of time There are lots of other drugs that cause similar valvular damage and plaque formation like fenfluramine, most of them it appears 5ht2b agonism is the mechanism the affinity corelates pretty closely with the level of damage. For example ergot alkaloids like dihydroergotamin and cabergoline taken long term for various conditions show cardiac valve damage, MDMA is also suspect but probably not at normal recreational doses. 6-APB and all the related compounds are highly suspect because they have very high affinity for 5ht2b. The mechanism is probably that 5ht2b activation causes division and proliferation of the fibroblast cells in the valve, and these fibroblasts
The key here is dose and time, a short exposure to a low dose is not going to cause an issue, long term exposure to low and high doses will. I have been going on about this for decades, moderation is the key.

But then we have cocaine, which is cardiotoxic. I was under the impression that it's an SNDRI. I guess that the serotonergic mechanism is at least *partly to blame for this toxicity. But does it affect 5-HT2b in a manner similar to fenfluramine? If not, how does it cause this toxicity. Methylphenidate, by contrast, isn't cardiotoxic and some studies suggest that in moderate doses it can improve brain functioning. That said, studies suggest that people can't discriminate between IV cocaine and IV methylphenidate; now I don't know if this is due to some metabolic happenstance or what, but it punches something of a hole in theory.

cocaine is directly cardiotoxic through an ion channel mechanism, it also causes blood pressure rise which is also indirectly cardiotoxic. I don't think it has much if any affinity for 5ht2b.
Methylphenidate is associated with pulmonary hypertension and valve damage even in children.

We know that MDMA is apt to cause destruction of serotonergic neurons due to the acidity of dopamine, which binds to SERT and is treated by the brain as serotonin. Similarly, MDA and cousins. They bind to 5-HT2b, too. What about cardiotoxicity?

The mechanism for MDMA neurotoxicity is not known with any certainty. It is also not clear whether there is any significant neurotoxicity from recreational exposures, it seems on balance that there is no evidence of neurological harm. the infamous Ricaurte paper on MDMA neurotoxicity was withdrawn many years ago, because it was a complete tissue of lies, and subsequent screening of MDMA users showed no significant cognitive deficits. Everything written by Ricaurte and his collaborating authors is highly suspect, most of the studies are also weak and funded by prohibitionist organizations. Those papers by Ricaurte that haven't been withdrawn (there are lots of them) should be considered interesting but not solid evidence, because Ricaurte went out of his way to cover up the problems with other papers.
There is some evidence that heavy MDMA users show signs of cardiac valvopathy at a rate that is much higher than expected.

Meth needs no introduction. Amp itself in therapeutic doses isn't health food necessarily, but 80+ years of use at even above the recommended max dosage and studies themselves lend credence to relative safety (not saying anyone should take it, though, to be celar).

long term use of either methamphetamine and amphetamine at both medicinal and recreational doses is associated with pulmonary hypertension, cardiomyopathy (heart weakness, high blood pressure. damaged arteries damaged heart muscle)
Methamphetamine is associated with neurological damage and neurotoxicity. Amphetamine has a big question mark over it too.

Methylone is most likely to be cardiotoxic by several mechanisms, 5ht2b agonism possibly but also the metabolite methylenedioxyephedrine is potently cardiotoxic. The related compound Mephedrone showed strong cardiotoxicity.

I wouldn't bet that mescaline is intrinsically safe, but it tends to be used infrequently and therefore is not a problem.