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N-benzyl phens may not be as selective as we once believed.

atara

atara

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Apr 1, 2010
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New binding data seems to indicate that N-benzyl phenethylamine psychedelics may not in fact be highly selective 5-ht2a agonists. Worse yet: the most popular members of the 25x series all seem to have significant affinity at 5-ht2b.

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This is the first molecular evidence that these drugs don't share the wide safety margin of the ergolines and psilocinoids. We've known that for a while now from the, uh, reports of people dying, ofc.

The moral of this story is that untested means untested, published receptor affinities or no. Please don't be a hero.

Also note that these numbers aren't necessarily perfect either. Published does not mean true.
 
Thank you, thank you, thank you. That is great information it is just a start but a beautiful start!

DONT BE A HERO!!! Love it. Very true

Lets all just stay safe and party safe!
 
It's always too easy to say this in retrospect but I knew they were not really to be trusted so much as they were by some people.

'Was already having doubts if I would want to choose to further experiment with the range of NBOMe compounds I have, but they have just been pushed down the list even a bit more. Not saying that I am not interested in getting a feel of 25I-NBOMe once or twice but for now I prefer the psychedelics that are not as dubious.

Can someone put into perspective how typical 2C-X compounds and DOX compounds agonize 5HT2B?

And how come we are just hearing about this now, i.e. I thought these affinities were already checked in earlier panels? Weren't they or did other values come out? (Obviously I can't be bothered to see for myself at the moment but I just might at a less inconvenient time :) )
 
It tends to play a role in causing nausea. A high Ki number means a low affinity, so they should not be too nauseating. And from reports I think they aren't, at least not like some other psychedelics.
 
Cface said:
Can someone explain the role of 5-HT3?
Click to expand...

Sure. First: the >10000 actually means the compound has extremely low affinity. None of the NBOMe compounds bind 5-ht3, and that's a good thing, because...

5-ht3 is actually sort of interesting: it's actually not a guanine-linked protein-coupled receptor like all of the other monoamines, it's an ion channel like GABA-A, NMDA, etc. That is to say, it actually initiates neural signaling. And that leads to...

When the receptor is activated to open the ion channel by agonists, the following effects are observed:
CNS: nausea and vomiting center in brain stem, anxiety,[15] seizure propensity [16]
PNS: neuronal excitation (in autonomic, nociceptive neurons), emesis[15]
Click to expand...

Yeah, not fun.
 
Wait. So the higher the number the lower the affinity? Does this apply to all receptors in the chart?
 
atara said:
New binding data seems to indicate that N-benzyl phenethylamine psychedelics may not in fact be highly selective 5-ht2a agonists. Worse yet: the most popular members of the 25x series all seem to have significant affinity at 5-ht2b.
Click to expand...

MDMA has an affinity of 0.5 - 0.7 at 5-ht2b according to this paper http://www.maps.org/mdma/mt1_docs/ib_mdma_12_07_final.pdf

So I don't think it's anything to worry about as long as you don't trip very often.
 
^I think there's more to it than affinity, though, like high efficacy (not reported here) -- or the ability to provoke a response from the receptor. DMT has high affinity for 2b as well yet it's physiologically quite safe, I assume because it has low efficacy. DOB-dragonfly is non-subtype 5HT2 selective yet overdoes can cause vasoconstriction so severe amputations have resulted in some cases. I assume since it's 5HT2 selective and much more selective for 2b over c or a it's vasoconstrictive effects are mediated largely by 5HT2b, suggesting a drug with high efficacy and affinity there may be dangerous.

It is weird that this is the first time we're hearing this about the NBOMes, though if true it could help explain a major cause of the reported medical emergencies and deaths (and perhaps treatment using 5HT2b antagonists?) However, there could be something more going on than 5HT2b agonism (though I'm no expert). I'm not sure how fair an analogy ergotamine is here, but like NBOMes it's active at 1 mg, is nearly a full agonist at 2b, and has an extremely high affinity for it, yet it's LD50 in rats is 80mg/Kg (much much higher than the supposed NBOMe medical emergency doses). Maybe someone better informed can explain why this is a disanalogy. Regarding long term damage to the heart, and given how infrequent people dose NBOMes relative to 5HT2b agonist problem drugs like fenfluramine that were taken daily for months to years, I'm not sure how strong a threat they pose.

I personally will continue to use 25c and 25I like I have been, a few times per year, as they do make for great experiences. However, due to the seeming hypersensitivity of some users (and medical emergencies purportedly resulting in a few cases from doses close to the normal range), I don't think I'll ever share an NBOMe with friends unless they've figured out their sensitivity beforehand on their own plus they use from a solution they've mixed themselves and have used before.
 
I agree: with MDMA even at very high doses (I have abused it a while back and am amazed that I did not kill or damage myself noticeably) I don't get vasoconstriction but I did with very low doses of NBOMe compounds. I think with MDMA deaths it is often hyperthermia and dehydration and things like that as cause of death IIRC and these are preventable, although I still think that you should not OD on MDMA if you value your health and life.
With NBOMe compounds however the danger seems more acute and the added fact that we still don't know a lot about them is good reason for me to avoid them as much as 'possible'.
 
So THAT'S why 25b seems to be ridiculously chronic. On this chart I've only tried 2c-I and 25-i(2C-I and 25-B I have most experience with, 25-I seemed weak to me), but thinking about the experiences and actually looking at the data, it seems like the others are pathetic compared to 25-b. Not pathetic obviously, they're still powerful, just in different areas. 25-b just seems to be overall very strong and balanced. Which can be great, but obviously all that receptor activity can easily be overwhelming and deadly. Be seriously careful with these drugs, as they are no joke.
 
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Very scary/interesting. Any data on potency at 5ht2b though? And what about tryptamines?
 
Can anyone elaborate on how it could happen that these numbers are so different than the other ones?


Older values for 25i-NBOME:
"The ligand (25i-Nbome[this word was edited by person copied from]) had low affinity for most receptors, with the following reported Ki values (nM) for receptors where it had significant affinity: (remember the lower the number, the greater the binding):

5-HT2a (0.044)
5-HT2c (2)
5-HT6 (73, +/-12)
5-HT2B (231, +/-73)

u opiate (82, +/-14)
H1 (189, +/-35)
kappa opiate (288 +/-50)"

http://www.pubmedcentral.nih.gov/art...&artid=2719953"

Also, what is so significant about the broad/high affinity? You guys are smart people, and the response has been quite shocking. Would like to know why? Isn't affinity just how fast a chem produces an effect at a receptor site?

Though, I am putting my NBOMe usage on hold indefinitely. Doesn't appear to be the safest thing I've ever done
 
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Atara, can you please provide the link to the information that you posted (i.e. the paper)?
 
Yup, I won't be fucking with any of those any time soon. I get bad vibes from RCs that are that potent in general.
 
Hello, can someone in simple words explain what are the implications of this new discovery. Is it bad because nbomes are to harsh just to one group of receptors? What is the difference with acting of LSD for instance? Is it less aggressive on some receptors or is it as harsh on some ones (5HT-Ax) in the same way as nbomes on 5HT-2x?
 
I think the problem is that NBOMes target more receptors than LSD, which increases the odds of adverse reactions. Statistically, the molecule could bind in different ratios every time you dose, and some ratios may be more harmful than others.

Hope that's clear...
 
Well this graph shows LSD's affinities if you want to compare...

There are a few receptor binding affinities to note here, they involve the following subtypes of 5-HT (serotonin) receptor:

5-HT1A: Involved with many functions, agonists of this receptor seem to have mostly positive effects on anxiety and depression, and they lower heart rate and blood pressure rather than increasing them, so not immediately worrisome.
5-HT2A: Functions involved: neuronal excitation, behavioural effects, learning, anxiety Responsible for psychedelic effects the most (significant agonism is necessary for the effect of classic psychedelics). Note that vasoconstriction is also partially regulated by it.
5-HT2B: Functions involved: behavioural effects, vascular: pulmonary vasoconstriction, Cardiac: The 5-HT2B receptor regulates cardiac structure.
5-HT2C: 5-HT2C receptors significantly regulate mood, anxiety, feeding, and reproductive behavior.
5-HT5A: May have vasodilatory and vasoconstrictive effects among other things. Probably of less importance here.



LSD at typical doses significantly affects 1A, 2A, 2C and 5A but much 2B less so.
These new results show that 25I-NBOMe may significantly affect 2A, 2B, 5A and - moderately - 2C but 1A less so.

Considering there have been deaths from 25I-NBOMe and possibly other 25X-NBOMe compounds at doses that were not even that insane, we may ask ourselves if the victims had unusually high densities of a certain receptor for which these NBOMe compounds have enough affinity and efficacy to kill, possibly mediated by cardiac and (vaso)pulmonary complications.

If we compare these values, we see that 2B is the receptor subtype that could make a difference. It is involved with functions that may be related to the complications and it could explain why NBOMe compounds can be dangerous if especially if you are unlucky (with 5-HT2B densities for example), while LSD is relatively a very safe drug.
Not only may these NBOMe compounds have the affinity to affect 2B significantly but if they also have an efficacy that LSD lacks then this could explain why LSD does not even tend to be lethal at incredibly high doses at which even LSD binds to 2B significantly. Because even if it binds at that point, lack of efficacy would still mean a lack of activation that would otherwise lead to potentially dangerous complications.
However it seems 2B issues would mostly promote chronic toxicity and not acute toxicity.

A lot of this is speculation, as we do not know the efficacies as is already mentioned, and there may be far more complex pharmacodynamics going on. LSD is -IIRC - unusual because it sets in motion a signal cascade that causes the trip, even though levels of LSD dwindle from breakdown. Maybe NBOMe compounds have similar qualities to LSD regarding the way they affect receptors but they might be more persistent and this could be dangerous on your system. I might be talking out of my ass and I might not even be the ADDer to ask these questions to begin with, but we might be onto something.

Hopefully this offers a nuanced explanation of how these drugs are 'harsh' with regard to how strongly they bind to receptor subtypes. I expect others to step in if I made mistakes or oversimplifications that give you the wrong impression.
 
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