Pharmacology What are the mechanisms behind the hypertension/vasoconstriction caused by serotonergic psychedelics?

[dydst]

*I am new to pharmacology, so I apologize if I get any terminology/concepts wrong*

Hi all,

I got an opportunity to try 5-MeO-MiPT last weekend (fantastic drug, btw), but was badly bothered by intense vasoconstriction and high blood pressure. It got me wondering, what is/are the mechanism(s) behind such effects, which seems to be common to all serotonergic (“classic”) psychedelics I’ve tried?

For instance, this paper lists the binding potency of several dozen major psychedelics. 5-MeO-MiPT binds most strongly to 5ht1a (Ki=12.3 nm), 5ht7 (Ki=19.8 nm), 5ht1d (Ki=22.5 nm), 5ht2b (Ki=58.5nm), as well as 5ht6, Alpha2A, 5ht1b, 5ht2a and Alpha2C, and a number of other different receptors with varying degrees of potency (in that order).

Are the physical symptoms I experienced due to activation of one or more of the serotonin receptors? It also binds to Alpha 2A, 2B and 2C with relatively weak potency, but as I understand it, activation of those receptors by agonists tends to result in vasodilation, not vasoconstriction. I read several papers about the influence of serotonin receptors on hypertension and vasoconstriction, but there didn’t seem to be a consensus on which receptor(s) is/are responsible for these symptoms in psychedelics.

Does anyone know, or have any thoughts?

 

[Juicewrldfan]

Not certain but I’m pretty sure activation of alpha 2 by agonists causes vasoconstriction not dilation.

 

[Juicewrldfan]

*I am new to pharmacology, so I apologize if I get any terminology/concepts wrong*

Hi all,

I got an opportunity to try 5-MeO-MiPT last weekend (fantastic drug, btw), but was badly bothered by intense vasoconstriction and high blood pressure. It got me wondering, what is/are the mechanism(s) behind such effects, which seems to be common to all serotonergic (“classic”) psychedelics I’ve tried?

For instance, this paper lists the binding potency of several dozen major psychedelics. 5-MeO-MiPT binds most strongly to 5ht1a (Ki=12.3 nm), 5ht7 (Ki=19.8 nm), 5ht1d (Ki=22.5 nm), 5ht2b (Ki=58.5nm), as well as 5ht6, Alpha2A, 5ht1b, 5ht2a and Alpha2C, and a number of other different receptors with varying degrees of potency (in that order).

Are the physical symptoms I experienced due to activation of one or more of the serotonin receptors? It also binds to Alpha 2A, 2B and 2C with relatively weak potency, but as I understand it, activation of those receptors by agonists tends to result in vasodilation, not vasoconstriction. I read several papers about the influence of serotonin receptors on hypertension and vasoconstriction, but there didn’t seem to be a consensus on which receptor(s) is/are responsible for these symptoms in psychedelics.

Does anyone know, or have any thoughts?

Quick google search

https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/alpha-2-adrenergic-receptor#:~:text=The%20cardiovascular%20effects%20of%20alpha,smooth%20muscle%2C%20resulting%20in%20vasoconstriction.

 

[dydst]

See, now, I’m just really really confused. You’re right; the writings in that link seem to indicate that the activation of alpha-2 by agonists causes vasoconstriction.

But then I see information that says exactly the opposite: for instance, clonidine is an alpha-2 agonist which causes vasodilation. Does anyone know what’s going on?

 

[SpiralusSancti]

Well, it’s far from well understood. If it was understood better we would be able to figure out much more accurately in advance which substances are bound to causes harm via this mechanism.

Are BDF and nbome’s extremely high affinities for 5ht receptors sole reason for them being so dangerous. I don’t think so. We are far from something like scale connecting oil solubility of anesthetics to their potency (and even with that there are exceptions).

 

[Juicewrldfan]

See, now, I’m just really really confused. You’re right; the writings in that link seem to indicate that the activation of alpha-2 by agonists causes vasoconstriction.

But then I see information that says exactly the opposite: for instance, clonidine is an alpha-2 agonist which causes vasodilation. Does anyone know what’s going on?

Well it’s complicated. It seems certain doses cause dilation and certain doses cause construction or maybe it causes constriction in certain systems but dilation in others as is often the case. I found many articles that talk about dilation effects of clonidine and I also found this one talking about constriction. Lead me to believe my above mentioned theory



“V clonidine, at doses that decrease blood pressure, causes arterial vasoconstriction in awake subjects.”

Clonidine-induced vasoconstriction in awake volunteers - PubMed

IV clonidine, at doses that decrease blood pressure, causes arterial vasoconstriction in awake subjects. These data suggest that an alpha-2 agonist with a high alpha-2a/alpha-2b selectivity should provide more profound sedative and analgesic effects with less undesirable vasoconstrictive effects.

pubmed.ncbi.nlm.nih.gov

 

[dydst]

Well, it’s far from well understood. If it was understood better we would be able to figure out much more accurately in advance which substances are bound to causes harm via this mechanism.

Are BDF and nbome’s extremely high affinities for 5ht receptors sole reason for them being so dangerous. I don’t think so. We are far from something like scale connecting oil solubility of anesthetics to their potency (and even with that there are exceptions).

Interesting point. I went into it, thinking that it was settled science, and that’s why I came out so confused.

BTW, What do you think accounts for the toxic potential of NBOMes? And what is BDF? (edit: you must be talking about brono-dragonfly)

 

[dydst]

Well it’s complicated. It seems certain doses cause dilation and certain doses cause construction or maybe it causes constriction in certain systems but dilation in others as is often the case. I found many articles that talk about dilation effects of clonidine and I also found this one talking about constriction. Lead me to believe my above mentioned theory



“V clonidine, at doses that decrease blood pressure, causes arterial vasoconstriction in awake subjects.”

Clonidine-induced vasoconstriction in awake volunteers - PubMed

IV clonidine, at doses that decrease blood pressure, causes arterial vasoconstriction in awake subjects. These data suggest that an alpha-2 agonist with a high alpha-2a/alpha-2b selectivity should provide more profound sedative and analgesic effects with less undesirable vasoconstrictive effects.

pubmed.ncbi.nlm.nih.gov

I didn’t read that article, but I saw one that referenced the fact that doses of clonidine above 0.7 µg cause paradoxical vasoconstriction due to the poor selectivity of the drug and it’s additional activation of alpha-1 receptors.

It’s all fascinating to me

 

[Juicewrldfan]

I didn’t read that article, but I saw one that referenced the fact that doses of clonidine above 0.7 µg cause paradoxical vasoconstriction due to the poor selectivity of the drug and it’s additional activation of alpha-1 receptors.

It’s all fascinating to me

Interesting…

 

[SpiralusSancti]

BTW, What do you think accounts for the toxic potential of NBOMes? And what is BDF? (edit: you must be talking about brono-dragonfly)

Well imo with nbome’s the thing is that I’m not exactly sure they are indeed as toxic as it might seem at first, even tho I was one of the first pointing to dangers of same, to weird and fucked up reactions to be precise. For a start, wide market is simply not for microgram range substances. So none of it should have flood the market in a powder form. Than that using blotters for sublingual dosing is not either precise or consistent with different types of paper. Also those blotters were dosed too high. Like I had 1.2mg tabs, but with 25c I was tripping quite hard with only or even less than 400µ. Possibly biggest problem was STRONG AND LONG LASTING TOLERANCE, to effects but very unlikely to toxicity. Nbome doses should be spread more like a MDMA not acid as most people did. All in all when I consider that I had very unpleasant body load at about 3mg (1 c, 1 b, 1i) but still comparable to strong does of 2c-b in form of HBr salt and that without addicng stimulants or other potentially dangerous combos about 10x bigger dose than was certainly active was still fine doesn’t sound impressive compared to LSD T.I. but it is possibly better than with 2c-t-x for example. People ignored that nbome’s are developed from group of drugs that isn’t most mind bending but still went for those doses and that was just ODs. Nbome’s were on light side of psychedelics but both dosed too high, too often and often by people looking for acid like mindfuck with group that simply isn’t for that.

As for bromo-dragonfly idk. I really liked it. Much more than nbomes. Hell even more than 2c-x. On par with DOx. Wouldn’t want to play with that one at 10x of really active dose. I had virtually none body load at dose and with isomer I tried and it was comparable to a much better, much longer lasting 2c-b in some ways. But this one really does get really vasoconstricting in high doses and ODs but I’m confident it wouldn’t ever killed anyone if it was not sold as acid, in powder form or to people without common sense for trying new, potentially deadly substances. Thing with BDF is that while it is very vasoconstricting, it’ll get really uncomfortable long before it gets really dangerous. I think reason for that is, maybe in most part it’s subjectively strong substance and as on LSD, body load, even tiny feels rather alarming.

Probably not the answer you were looking for but might put some perspective on nbomes and BDF.

 

[dydst]

Spiralus,
You said: “Thing with BDF is that while it is very vasoconstricting, it’ll get really uncomfortable long before it gets really dangerous”

Could you expound on that?

 

[MBaggott]

For instance, this paper lists the binding potency of several dozen major psychedelics. 5-MeO-MiPT binds most strongly to 5ht1a (Ki=12.3 nm), 5ht7 (Ki=19.8 nm), 5ht1d (Ki=22.5 nm), 5ht2b (Ki=58.5nm), as well as 5ht6, Alpha2A, 5ht1b, 5ht2a and Alpha2C, and a number of other different receptors with varying degrees of potency (in that order).

Are the physical symptoms I experienced due to activation of one or more of the serotonin receptors?

I tend to think so. Most serotonin receptors have some effect on the cardiovascular system, especially 1B and 2A. I separately screened 5-MeO-MIPT for agonist and antagonist effects and got a somewhat different profile than that paper with 1B and 2A among the higher potency sites. I would guess the adrenergic receptors don't come into play at typical doses.

 

[ecstacylover]

5-HT's effect on smooth muscle cells (which envelop blood vessels and thus in part govern blood pressure) was studied in the context of pulmonary hypertension, which is associated with increased 5-HT receptor expression in the smooth muscle layer of the pulmonary artery. Probably not a bad guess that smooth muscle cell contractility along the rest of the vascular system is regulated by 5-HT in a similar manner.

In general, smooth muscle contraction occurs via calcium-mediated activation of myosin light chain kinase, so you might expect that 2A is one of the main contributors—and indeed it is. However, it doesn't appear that the calcium increase proceeds via IP3R activation. Rather, it proceed via DAG-sensitive PKC modulation of Kv1.5-containing potassium channel expression, which in turn activates L-type calcium channels. 2A activation of tyrosine kinases (e.g. Src) might also contribute.

Not sure if the mechanism by which 1B-like receptors alter smooth muscle contraction is known, and ofc 5-HT receptors might also govern blood pressure by modulating cardiac output.

Relevant papers here, here, and here.

I separately screened 5-MeO-MIPT for agonist and antagonist effects and got a somewhat different profile than that paper with 1B and 2A among the higher potency sites.

Maybe I'm missing something, but the efficacy data from that paper makes no sense. Their method was supposedly to perform 4 single functional assays with each compound to obtain an average measure of efficacy, yet the attached data contains anywhere from 1-4 data points for each compound (with wildly varying efficacies). Or for example they found DiPT had negligible 2A affinity yet their data suggests it had 2A efficacy (344nM or 1411nM like which is it...).

 

[chicken hoagie]

This is very simple guys.


Let me break down how blood pressure works.


We have beta agonists, which when agonized, will cause alpha-2 antagonism, causing a reverse feedback loop which looks to shut down the agonism. Your body wants balance, at all times. Alpha-2 agonists, will in turn do exactly the opposite. That is why when you build tolerance to drugs like clonidine, it is extremely dangerous to go cold turkey because recruitment of new beta receptors is what your body does to balance out lowered diastolic or systolic pressure. When you make your diastolic and systolic numbers very far close together, or too far apart, or both become too high or low, it becomes dangerous.

You have to be careful with these drugs, but used properly can help you lose weight, help with many mental health issues, or help you gain weight as well, and also stabilize any heart condition you may have for at least some time.

 

[chicken hoagie]

These cells also reside in fat cells, where they will be antagonised by alpha-2 receptors to be signalled to burn, or by beta agonists, signalling to be burned. But beware when coming off, as you may gain the fat right back if you dont re-balance things out beforehand.

 

[MBaggott]

Maybe I'm missing something, but the efficacy data from that paper makes no sense. Their method was supposedly to perform 4 single functional assays with each compound to obtain an average measure of efficacy, yet the attached data contains anywhere from 1-4 data points for each compound (with wildly varying efficacies). Or for example they found DiPT had negligible 2A affinity yet their data suggests it had 2A efficacy (344nM or 1411nM like which is it...).

Yes, the data in that paper are unreliable. The lab doing the assays and the author had a falling out before the data were fully collected and validated. The author went ahead with publishing despite the lab's protests that these were unreliable preliminary numbers.