Can select 5-HT2b agonism cause death (NBOMes)? What antagonists might combat it?

[psood0nym]

The recent thread in the Psychedelic Drugs forum, N benzyl phens may be as selective as we once believed, has me wondering about the dangers of 5HT2b and c agonism. Many of you probably remember an incident a few years ago where DOB-dragonfly sold as 2C-B-Fly resulted in a number of deaths and cases of vasoconstriction so severe and long lasting a few victim's limbs needed amputating.

According to two sources on its Wiki page, DOB-Dragonfly "is most accurately described as a non-subtype selective 5-HT2 agonist, as it is actually twice as potent an agonist for 5-HT2C receptors as for 5-HT2A, as well as being less than 5x selective for 5-HT2A over 5-HT2B.[4][5]". (Ki = 0.04, 0.19, and 0.02 nM for 5-HT2A, 5-HT2B, and 5-HT2C) This suggests that the deaths and injuries that resulted from the aforementioned overdoses overwhelmingly owe to 5-HT2b mediated effects, particularly vasoconstriction I assume, and little else directly speaking, doesn't it? Perhaps I'm overlooking a key detail as I'm not well versed in pharmacology, but given the high affinities and efficacies of popular NBOMes and DOB-Dragonfly at 5-HT2b, and the 5-HT2 selectivity of DOB-Dragonfly, it seems as though strong 5-HT2b potency may be what's chiefly leading to deaths/emergencies.

Has anybody compared medical reports or other documentation between cases of NBOMe and DOB-Dragonfly hospital emergencies and/or autopsies to see if the NBOMe cases indicate signs of severe vasoconstriction like those for DOB-Dragonfly? Such reports might be found by those with full-text access to medical journals, maybe as short accounts by emergency room staff, etc., in the letters to the editor section.

Is it feasible that some 5-HT2b antagonists could be used in a relatively safe way in emergency rooms to knock NBOMes off the receptor and save lives? Which ones, and have they been reported to the medical community? I know such drugs have been used in patients recovering from long term cardiac damage from fenfluramine but that's clearly a very different situation than what I'm asking about.

If the 5-HT2b vasoconstriction idea is unfeasible, what do you think is causing the deaths?

Apologies if this has been covered before.

 

[Anon0631]

given the high affinities and efficacies of popular NBOMes and DOB-Dragonfly at 5-HT2b/c, and the 5-HT2 selectivity of DOB-Dragonfly, it seems as though strong 5-HT2b/c potency may be what's chiefly leading to deaths/emergencies.

I haven't seen any data for high efficacy at 5HT2b, can you point me in the right direction?

 

[sekio]

Do we really know that 5ht2b is what is causing vasoconstriction? The "classical" worry about 5ht2b agonists came about after the whole Fen-Phen fuckaround in which it was discovered that regular usage of fenfluramine caused the generation of a significant amount of norfenfluramine, a 1' metabolite with strong agonist activity at 5ht2b, and this eventually causes heart valve cells to overproliferate and cause valvular defects. I don't think vasoconstriction was the worry at the time. These cmpds were used as diet pills semi-successfully before they got shitcanned due to the heart valve thing; I also don't recall many people dying from phenteramine overdoses due to vasoconstriction.

5ht2b receptor activation is associated with the development of pulmonary hypertension, but I don't think it produces it in acute dosage.

There are other psychedelics in common use that are 5ht2b agonists.

Non-selective
MDMA (Ecstasy)[15]
MDA[15]
[...]
DMT
5-MeO-DMT

I am pretty sure a good collection of the 2c-x drugs, and some of the tryptamines, also have moderate affinity for 5ht2b. Some of the ergolines used as non-psychedelic medicine are also 2b agonists.

So the long and short of it is: maybe. But I would be just as quick to blame the rather potent 5ht2 activation in general, than any one receptor.

 

[psood0nym]

^I'm aware of the other psychedelics that are 5-HT2b agonists, but was working on the possibility that the uniquely high potency of NBOMes and DOB-dragonfly could be a critical factor (though if this is true I'm confused by the relatively high LD50 of ergotamine, which appears to be very potent at 2b). If the claim about DOB-dragonfly stating it ""is most accurately described as a non-subtype selective 5-HT2 agonist" is actually true, and overdoses have truly caused death via vasoconstriction as looks to be the case given the amputations, then if receptor activation is the cause of problems isn't it likely it's either 5-HT2a or b? These are the only subtypes of 5-HT2 I know of for which there is evidence of mediating vasoconstriction. In what other way might it cause such extreme vasoconstriction, or are other possibilities just unknown?

So to answer you're question: no, not really -- it could be 2a, 2a and 2b, some unknown interaction, or a known interaction I'm not aware of (of which there are plenty). I'm just putting this out there on the off chance it could eventually inform some sort of treatment since I don't know of any that exist that directly responds to NBOMes. I did find this and this though:

"Increases in plasma 5-HT initiate rapid and sustained increases in pulmonary vascular resistance, reflecting acute vasoconstriction followed by structural remodeling associated with smooth muscle cell proliferation. Pulmonary vasoconstriction is mediated by 5-HT2a, 5-HT1b/1d and 5-HT2b receptors expressed on vascular smooth muscle cells. (McGoon and Vanhoutee, 1984; Choi and Maroteaux, 1996; MacLean et al., 1996; Keegan et al., 2001), although 5-HT2b is also implicated in the mitogenic action of 5-HT ... The 5-HT2b receptor has also been implicated in causing vasoconstriction in humans and mammals ... (Launay et al., 2002)

One of the important vascular effects of 5-HT is its ability to act as a vasoconstrictor. The 5-HT2A, 5-HT2B and 5-HT1B receptors have been implicated as mediators of 5-HT-induced contraction in vascular smooth muscle. 5-HT2A receptors mediate contraction in many arteries including the rat thoracic aorta [1] and pulmonary arteries [2]. 5-HT2B receptors mediate 5-HT-induced contraction in the rat stomach fundus, the aorta and mesenteric arteries from hypertensive deoxycorticosterone acetate (DOCA)-salt rats [3-5] ...

... In isolated-tissue baths, DOCA-high salt aorta contracted to the 5-HT2B receptor agonist BW723C86 on day 1; Sham aorta did not contract. The 5-HT1B receptor agonist CP93129 had no effect in arteries from any group. On days 3, 5 and 7 CP93129 and BW723C86 contracted DOCA-high salt and Sham-high salt aorta; Sham and DOCA-low salt aorta did not respond. Western analysis of DOCA-high salt aortic homogenates revealed increased 5-HT2B receptor levels by day 3; 5-HT1B receptor density was unchanged. Aortic homogenates from the other groups showed unchanged 5-HT2B and 5-HT1B receptor levels. ....

... there was an increased contractile response to the 5-HT2B receptor agonist BW723C86 prior to an increase in blood pressure in the DOCA-high salt and Sham-high salt treated rats

Granted, the effects in the second quote were only recorded in these special high salt rats, but perhaps in humans the results would be different. The implication from these studies that 5-HT2b agonism causes acute vasoconstiction in the lungs and heart makes extremely potent 5-HT2b agonists sound pretty dangerous, especially for those who just happen to have or have developed higher receptor densities.

 

[Solipsis]

A very interesting subject, but we should not overreact.

Even if we were to investigate how acute 5-HT2B's effects on the cardiovascular system could be if pushed hard enough, if we compare the scarce data on the circumstances of causes of death from 25I-NBOMe (here) it seems that these victims suffered fatal seizures. AFAIK no exploding or acutely engorged hypertrophic hearts killed these people.
If we focus on the cardiovascular system and the CNS, even cerebrovascular constriction would result in things like strokes, not seizures, correct? And in the case of DOX or Bromo-Dragonfly overdose did they slip into a coma? I'm not sure what kind of 'overload' would cause that...

But if we focus on the seizures, defined as excessive or anomalous nervous activity, a fatality from a superpotent psychedelic like that reads like some kind of massive electrochemical overload i.e. status epilepticus.

I realize that this does not explain why LSD does not kill people that way, but there might be a significant difference between the way LSD agonizes 5-HT1A, 5-HT2A, 5-HT2B and/or 5-HT2C and the action of 25X-NBOMe compounds. Somehow with LSD there is a saturation effect observed (which I believe happens in stages considering LSD's promiscuous pharmacology) that may not be there with the NBOMe compounds.
I am not sure if this analogy holds up, but there are other compounds like L-theanine that are self-limiting and show an effect ceiling, while there are other drugs acting on the same receptors that lack this, giving them the potential to cause complications (i.e. overdose). Some of these compounds may be mixed agonists, there can be a variety of reasons why some drugs have a much more pronounced ceiling than others...

I was initially taken aback reading about NBOMe compounds not being as selective as once believed. And 5-HT2B seemed like a good culprit to fixate on for a little while. It still very well might be what is causing these deaths, my expertise is too limited to feel quite confident... But maybe the Bromo-Dragonfly OD syndrome is obscuring the truth with these other compounds here? And it seems too 'experimental' to consider administering a selective 5-HT2B antagonist in case of an NBOMe-related emergency, we are not Dr. House and such a victim is not our guinea pig...

Anyway if we could experiment, perhaps if someone is approaching the supposed status epilepticus stage it is best to just administer a serotonin antagonist, could be an antipsychotic to antagonize 5-HT2A or one that is not even that selective (maybe better chance of success but less diagnostic value), I don't know if they tried to administer status epilepticus treatments to save the 25I-NBOMe victims, but as the Dutch proverb more or less goes, that would be 'mopping with the water running', and it may not have been enough to stop it... negating the primary action/cause might?

Don't take my word for it, seriously I am basically thinking out loud.

 

[Black]

i don't think that 5-ht2b is the culprit here. mdma and the apb's also have quite an affinity (and efficacy, the apb's are full agonists) at this receptor and we don't see people dropping dead from the 100-200mg doses these comounds are usually taken at. but i don't have a better idea either.

 

[psood0nym]

^Perhaps it's some transduction pathway that 5 and 6-APB do not act through. Or maybe it's 2a? From wiki's page on functional selectivity:

One notable example of functional selectivity occurs with the 5-HT2A receptor, as well as the 5-HT2C receptor. Serotonin, the main endogenous ligand of 5-HT receptors, is a functionally selective agonist at this receptor, activating phospholipase C (which leads to inositol triphosphate accumulation), but does not activate phospholipase A2, which would result in arachidonic acid signalling. However, the other endogenous compound Dimethyltryptamine activates arachidonic acid signalling at the 5-HT2A receptor, as do many exogenous hallucinogens such as DOB and LSD. Notably, LSD does not activate IP3 signalling through this receptor to any significant extent. This may explain why direct 5-HT2 agonists have psychedelic effects, whereas compounds that indirectly increase serotonin signalling at the 5-HT2 receptors, such as SSRIs, generally do not.[2]

It seems as though the effects of the 5-HT2 family are highly complicated even at the level of the neuron. If death is caused by NBOMes and/or DOB-Dragonfly via effects mediated by 5-HT2a/b agonism through some mechanism we're not yet aware of then relatively safe potent antagonists for these receptors could nevertheless still prove themselves life savers in medical emergencies involving the compounds even if we don't know why they're effective. I'm stretching here, of course, but what if it's true?

 

[endotropic]

What evidence is there right now that something other than strong 5-HT2a agonism is to blame? 5-HT2a agonists all cause peripheral vasoconstriction to some degree, why is it so hard to believe that this receptor is the culprit?

Assuming that 5-HT2a is to blame, there have recently been other threads on this board discussing antagonists that are currently used by medical professionals for psychedelic overdose, as well as theoretically useful compounds.

 

[psood0nym]

^It's not that hard to believe, which is why I ask "maybe it's 2a?" above. If these other 5-HT2 antagonists are currently used effectively by medical professionals I wonder why tolazoline was used instead of them to treat DOB-Dragonfly vasoconstriction.

 

[Black]

^Perhaps it's some transduction pathway that 5 and 6-APB do not act through. Or maybe it's 2a? From wiki's page on functional selectivity:

It seems as though the effects of the 5-HT2 family are highly complicated even at the level of the neuron. If death is caused by NBOMes and/or DOB-Dragonfly via effects mediated by 5-HT2a/b agonism through some mechanism we're not yet aware of then relatively safe potent antagonists for these receptors could nevertheless still prove themselves life savers in medical emergencies involving the compounds even if we don't know why they're effective. I'm stretching here, of course, but what if it's true?

good point. the signalling after 5-HT2B activation is definitely complex compared to quite a lot of other receptors; more complex than 2A for sure. 2B activation can also lead to production of NO, so agonists should be more vasodilatory than vasoconstrictive (at least in the brain (?) and of course if they indeed induce NO synthesis, which is not a sure thing as we know). serotonin and its receptors have been studied for so long and we still know so little...

 

[electric wizard]

i did 25i-nbome with 2c-b, kava kava a few days ago and was almost paraletic my toes were purple and my head was red and i couldnt walk suprised im still alive :D

 

[al-laddin]

I hope Im not digging up too old of a thread but I feel I have something to add

I took 25c -nbome at just under 1ml dose(first and last time ever). The effects where extreme to say the least. During my peak I smoked some cannibas....maybe two hits and what happened next was full on panic and delirium. Absolute terror , mixed and jumbled thoughts. My mind was playing word association with extremely random words/thoughts...."the hotdog was an equilibrium desktop" and things like that. Whatever function it is in you consciousness that justifies what you are saying and or doing is correct was giving me the green light so to speak. As in my mind was not filtering or incapable of stopping this word association game. This made my panic worse, it felt like my heart was going to jump out of my chest and started having severe chest pain. I remembered I had stored one mg of alpraz for just this type of scenario and quickly munched it. I soon found myself calm, serene and almost able to laugh about what I had just gone through. What is the action of benzos in this regard. Do they block these serotonin receptrs in anyway. I also found that the effects of the nbome quickly decreased after the benzo administration

 

[blueberries]

Everyone probably knows this already but here are my notes on HT2 agonists, I hope this helps in some way:

HT2 FUNCTIONS

HT2A:
HT2A agonism doesn't automatically mean the compound will be psychedelic. 6-Fl-DET is inactive as a psychedelic despite agonising HT2a. The same occurs in Lisuride, an ergoloid derivative. Lisuride has high affinity for D2,3&4, HT1a,2a&c but lacks psychedelic affect. This suggests that there are various genes (GPCR oligomers) encoded into the HT2a receptor and while a less selective ligand such as LSD can connect with these receptors (specifically MGluR-2), some cannot and display no psychedelic effects. This suggests that in future, compounds will be able to access these more selective sites to shape the affect of the drug.



HT2B:
- CNS Presynaptic Inhibition - meaning agonism causes serotonin to be released. HT2B inhibited mice were void of MDMA-induced hyperlocomotion and 5-HT release.
- Pulmonary vasoconstriction - agonism caused
- HT2B regulates cardiac function. In failing human heart conditions, HT2B receptors were way overexpressed than usual.
- Modulates serotonin release and protects against serotonin syndrome even if agonised.



HT2C:
Significantly regulate mood, anxiety, feeding and reproducing by regulating dopamine release in multiple areas of the brain. Antagonism increases dopamine release however. Therefore the agonism of HT2C contributes to depression and anxiety. In fact suicide victims usually have an abnormally high amount of HT2C receptors present in the prefrontal cortex.

 

[Black]

i thought 5-ht2c agonism was also needed for a compound to be psychedelic?

 

[nickfurry]

So 5HT2c agonism causes depression, and MDMA and similar drugs are dirty in the sense that they are not that receptor specific. Is that why a too low dose of MDMA makes you feel miserable?

Further, is valvular hypertrophy caused directly by 5HT2b agonists, or do they simply cause the blood pressure to rise, whereupon the body responds by strengthening the valves? Or does 5HT2b agonists cause cells with 5HT2b to release other hormones or signals that then causes hypertrophy in valve muscles?

 

[Black]

Further, is valvular hypertrophy caused directly by 5HT2b agonists, or do they simply cause the blood pressure to rise, whereupon the body responds by strengthening the valves? Or does 5HT2b agonists cause cells with 5HT2b to release other hormones or signals that then causes hypertrophy in valve muscles?

5-ht2b agonism specifically induces growth in the valves. otherwise you'd see valvulopathy in all those hypertension patents, who have higher blood pressures for longer peroids of time than anyone taking full-agonist-entactogens or fenfluramine. mdma itself doesn't seem to be that bad in this respect; we haven't seen a valvulopathy-epidemic in the uk or in the nederlands yet, which are both hotspots for mdma (ab)use.

 

[Euphorogenesis]

i thought 5-ht2c agonism was also needed for a compound to be psychedelic?

No, 5-HT2_A agonism is required for psychedelia. It so happens that psychedelic phenethylamines usually antagonise 5-HT2_C which causes them to be more stimulant like in nature than anything due to an increase in striatal and mesolimbic dopamine function.

 

[BallsStapledToLeg]

So my thinking on this issue is that the NBOMe class exerts its cardiovascular effects via the 5HT2A receptor via several signalling pathways. Human 5HT2A receptors have been shown to be involved in vasoconstriction. And, agonism of hypothalmic 5HT2AR by DOI has also been shown to increase secretion of several hormones involved in fluid balance/vascular tone (renin and oxytocin).

Keep in mind that the NBOMe's are full agonists that preferentially activates phosphoinositide turnover over production of eicosanoids . Classical psychedelics are typically thought of as partial agonists as well which preferentially activate at least the PLA2 pathway over the PLC pathway. While it is a bit of a stretch based on the evidence I've seen in the half hour I put into this post it appears that the increased phosphoinositide production relative to arachidonic acid production (possibly explaining the alleged less "trippy" quality these drugs have to classical psychedelics) it may results in greater smooth muscle vasospasm. This is supported by the fact that phospholipase C activation (which cleaves phosphoinositide) is involved in producing vasoconstriction with 5HT2A agonists.

This hypothesis of mine isn't perfect and doesn't address all the signalling modalities of the 5HT2A receptor in human vascular smooth muscle, but it does offer and explanation of why we see more severe vasospasms with this class of drug
http://molpharm.aspetjournals.org/content/70/6/1956.full


TL;DR: NBOMe's preferentially activate different 5HT2A signalling pathways than classical psychedelics, this may explain the greater vascular activity they have in vivo. Activation of other 5HT receptors may also produce effect to some of these processes but I'm cutting off the pubmed binge here.

 

[serotonin2A]

So my thinking on this issue is that the NBOMe class exerts its cardiovascular effects via the 5HT2A receptor via several signalling pathways. Human 5HT2A receptors have been shown to be involved in vasoconstriction. And, agonism of hypothalmic 5HT2AR by DOI has also been shown to increase secretion of several hormones involved in fluid balance/vascular tone (renin and oxytocin).

Keep in mind that the NBOMe's are full agonists that preferentially activates phosphoinositide turnover over production of eicosanoids . Classical psychedelics are typically thought of as partial agonists as well which preferentially activate at least the PLA2 pathway over the PLC pathway. While it is a bit of a stretch based on the evidence I've seen in the half hour I put into this post it appears that the increased phosphoinositide production relative to arachidonic acid production (possibly explaining the alleged less "trippy" quality these drugs have to classical psychedelics) it may results in greater smooth muscle vasospasm. This is supported by the fact that phospholipase C activation (which cleaves phosphoinositide) is involved in producing vasoconstriction with 5HT2A agonists.

This hypothesis of mine isn't perfect and doesn't address all the signalling modalities of the 5HT2A receptor in human vascular smooth muscle, but it does offer and explanation of why we see more severe vasospasms with this class of drug
http://molpharm.aspetjournals.org/content/70/6/1956.full


TL;DR: NBOMe's preferentially activate different 5HT2A signalling pathways than classical psychedelics, this may explain the greater vascular activity they have in vivo. Activation of other 5HT receptors may also produce effect to some of these processes but I'm cutting off the pubmed binge here.

The PLA2 versus PLC hypothesis never really panned out. One of the key findings was that TCB-2, which preferentially activated the "non-hallucinogenic" cascade, was found to be hallucinogenic in humans.

I don't think it makes sense to try to apply this argument to the NBOMes. Nichols et al. were proposing that the PLC pathway isn't responsible for hallucinogenic effects. So if the NBOMes are PLC-selective then it argues that 25I-NBOMe shouldn't be hallucinogenic. The fact that it is hallucinogenic indicates that this functional selectivity story needs to be revised.

The reason why the PLA2 story was so interesting is that it was thought at one time that hallucinogen effects in cortex depend on a retrograde messenger. Arachidonic acid, which can be generated via PLA2, would have fit that role perfectly. But further work showed that a retrograde messenger probably isn't involved.

 

[BallsStapledToLeg]

The PLA2 versus PLC hypothesis never really panned out. One of the key findings was that TCB-2, which preferentially activated the "non-hallucinogenic" cascade, was found to be hallucinogenic in humans.

I don't think it makes sense to try to apply this argument to the NBOMes. Nichols et al. were proposing that the PLC pathway isn't responsible for hallucinogenic effects. So if the NBOMes are PLC-selective then it argues that 25I-NBOMe shouldn't be hallucinogenic. The fact that it is hallucinogenic indicates that this functional selectivity story needs to be revised.

The reason why the PLA2 story was so interesting is that it was thought at one time that hallucinogen effects in cortex depend on a retrograde messenger. Arachidonic acid, which can be generated via PLA2, would have fit that role perfectly. But further work showed that a retrograde messenger probably isn't involved.

Interesting, hadn't heard that the PLC/PLA2 theory didn't work out. Mind pointing me in the direction of some literature on it, I haven't done any current reading on 5HT2A in ages.

My point however is that the greater PLC activity seen in the NBOMe series (one was quoted at 65x PLA2 activity) could explain the vasospasm seen in humans. 5HT2A is known to mediate vasoconstriction via a PLC pathway that NBOMe's are known to selectively activate. 5HT2A is known to be the main vasoconstriting 5HT receptor in rats.

What do you think?