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

[Anon0631]

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.

That, my friend is utter nonsense!

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?

It has been widely publicised that NBOMe's only had significant action at one particular kind of receptor, the one associated with psychedelic action. This would have meant that it makes you trip without affecting any other brain systems. This is unlike LSD which sticks to a whole host of receptors leading to 'rich' pharmacology (ie. unexpected effects).

This is incomplete data but shows that at least some NBOMe's aren't as selective as previously thought. However without another set of numbers (efficacy data) no real conclusions can be drawn. All the rest is speculation from advocates of the 'LSD is good, everything else is bad' religion.

Presumably, judging by the numbers in this chart, if 25i-NBOMe is highly dangerous (which IF people are getting into trouble on REASONABLE doses, it is) and if it's because of the compounds 5HT2b affinity, then 2c-i is just as bad. The thing is, the 2c compounds are respected by the psychedelic community and although people have died or been hospitalised due to large overdoses, they mostly seem well tolerated at reasonable doses.

 

[Solipsis]

Well it is never that black and white, but LSD does have the advantage of having been more extensively studied and having the reputation of having a fantastic therapeutic index.
While the 25X-N-Benzyls show(ed) much promise as selective agents the factor of the unknown means there are more risks involved, most of all ones we do not really understand. So they might not be bad, but the factor of the unknown is certainly not good IMO. And that is why I have had mixed feelings from the start... very interested in trying some but apprehensive about the potential dangers.

I think I have 25I-NBF, which seems to have a more favorable binding profile (or does it?). Maybe I should try that instead of the NBOMe compounds. Although it is quite possible that I might die extra hard with that which would of course be super ironic and everything.

My previous post was speculation, absolutely, and coming from someone who is still learning the ropes at that. But I tried to be objective and am not especially biased favoring LSD for reasons that I think are any less objective.

 

[Anon0631]

^ Agreed. The danger related to taking NBOMe's is that we don't know the long term effects, etc. then again if everybody waits until they are known, there will never be any data available. The key as always is use with maximum responsibility.

 

[dingophone]

^ Agreed. The danger related to taking NBOMe's is that we don't know the long term effects, etc. then again if everybody waits until they are known, there will never be any data available. The key as always is use with maximum responsibility.

Nail on the fucking head.

 

[psood0nym]

... especially if you are unlucky (with 5-HT2B densities for example)

That's what I was speculating, too. Early on I was convinced it was people screwing up decimal points or using crude methods to measure, and I'm sure that is still happening, but at this point it really does seem like NBOMes can be dangerous at near normal doses, and high 5HT2b densities in the wrong places might just be why (I'm also not that knowledgeable, though).

I think one way to gather some evidence as to whether 5HT2B agonism is the biggest culprit is to compare NBOMe emergency medical records with the DOB-Dragonfly medical records. If you recall, from my first post:

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

Assuming the DOB-dragonfly people got their affinities in the right neighborhood, as well as that this paper has, if 2b-mediated vasoconstriction is the culprit we'd expect signs of severe vasoconstriction to be reported in NBOMe cases as well (esp. in cases that resulted in death or medically confirmed life-threatening situations). I think some of the DOB-dragonfly amputation cases probably owed to the enormous duration of its vasoconstrictive effects, so evidence of such for the shorter duration NBOMe emergencies may not exist.

Does anybody have links to both types of records or some other documented evidence that suggests similar, or different?

Presumably, judging by the numbers in this chart, if 25i-NBOMe is highly dangerous (which IF people are getting into trouble on REASONABLE doses, it is) and if it's because of the compounds 5HT2b affinity, then 2c-i is just as bad.

2C-I's says 9.3, 25I = 2.3, and at 0.5 25B has the strongest affinity of the more common NBOMes, plus we don't know efficacies, so I wouldn't say that. See here about potency:

Affinity is the ability of the drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.

The common measure that would be really informative is EC50.

Anybody know a 5HT2b antagonist that might help in an NBOMe emergency?

 

[psood0nym]

Atara, can you please provide the link to the information that you posted (i.e. the paper)?

It's a 2010 Ph.D thesis that probably only recently got published.

 

[dingophone]

Anybody know a 5HT2b antagonist that might help in an NBOMe emergency?

Quick search reveals only 2 that aren't obscure research chemicals or dangerous; http://en.wikipedia.org/wiki/Lisuride, http://en.wikipedia.org/wiki/Sarpogrelate. Though these compounds certainly seem like good candidates: http://en.wikipedia.org/wiki/RS-127,445, http://en.wikipedia.org/wiki/PRX-08066, http://en.wikipedia.org/wiki/SB-204,741

 

[Cortexiphan]

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

The 5-HT2A value in this case is for an agonist labelled receptor (from the earlier Braden-paper). The other values are from PDSP who AFAIK uses antagonist labelled receptors. Affinities measured with mixed agonists/antagonists can never be compared because the percentage of receptors in the high-affinity state vary from receptor to receptor. Agonist labelled assays can give anywhere between 1 and 100 times better affinites than the antagonist labelled assays. Take a look at Michael Bradens thesis, there are lots of compounds with both agonist and antagonist labelled 5-HT2A assays.


The values from the Ettrup-paper are also from PDSP and seems to in accord with Nichols numbers although it looks like there is a typo in the 5-HT2B value, 2.3 nM and 231 nM for the same compound seems suspicious when the closely related compounds in the Ettrup-paper are all in the same ballpark.

 

[Anon0631]

Ok! It's been less than 48 hours since this thread was posted and already people are linking to it from all over the place, citing it as a proof that NBOMe's are dangerous due to 5HT2b agonism. This is simply misinformation as absolutely no conclusions can be drawn without efficacy information to match the affinity data.

The data cited taken on its own would suggest that 25i-NBOMe and 25i-NBF have similar potency whereas we know from the Ettrup paper 25I-NBF have 50 fold lower functional potency (source).

Please everyone, stop spreading misinformation. The data above is incomplete and not adequate to support the conclusions drawn.

 

[lamanogaucha]

Thank you for the link, Psood0nym.

 

[Seemingly]

Is there any data in comparison to other 2C-X compounds, especially 2C-B?

 

[specialspack]

It's a 2010 Ph.D thesis that probably only recently got published.

The table in the OP was also published as part of the supplementary data from the Ettrup paper, and is freely available from the journal:

http://link.springer.com/article/10.1007/s00259-010-1686-8

The 5-HT2A value in this case is for an agonist labelled receptor (from the earlier Braden-paper). The other values are from PDSP who AFAIK uses antagonist labelled receptors. Affinities measured with mixed agonists/antagonists can never be compared because the percentage of receptors in the high-affinity state vary from receptor to receptor. Agonist labelled assays can give anywhere between 1 and 100 times better affinites than the antagonist labelled assays. Take a look at Michael Bradens thesis, there are lots of compounds with both agonist and antagonist labelled 5-HT2A assays.


The values from the Ettrup-paper are also from PDSP and seems to in accord with Nichols numbers although it looks like there is a typo in the 5-HT2B value, 2.3 nM and 231 nM for the same compound seems suspicious when the closely related compounds in the Ettrup-paper are all in the same ballpark.

A crucial point to note is that in the table, the notes "b" and "c" next to the 5HT2A rows indicate that the hot ligand in the PDSP screening was:

b - ketanserin
c - LSD

Thus the values in the second row are agonist labeled affinities, and in the cases where both are presented it seems like the values are pretty close. However, I don't know why they've chosen LSD as the hot ligand in these studies and whether it can be directly compared to the results in Braden's thesis etc, where the hot ligand is DOI.

Ok! It's been less than 48 hours since this thread was posted and already people are linking to it from all over the place, citing it as a proof that NBOMe's are dangerous due to 5HT2b agonism. This is simply misinformation as absolutely no conclusions can be drawn without efficacy information to match the affinity data.

Very true. It's also useful to point out that PDSP certified screening of psilocin showed 5HT2B affinity of 4.6 nM. And no one is screaming about how dangerous psilocin is...

 

[Dondante]

Very true. It's also useful to point out that PDSP certified screening of psilocin showed 5HT2B affinity of 4.6 nM. And no one is screaming about how dangerous psilocin is...

Exactly...because 5-HT2B agonism is not acutely cardiotoxic! Chronic stimulation of 5-HT2B receptors, OTOH, can lead to fibrosis of the heart valves.

NBOMe series still looks fairly selective to me...lack of high 2A>2C selectivity is no big surprise since the two receptors seem to have a very similar pharmacophore. 25D-NBOMe stands out with >20-fold selectivity for 2A>2C. Also, it's important to note that affinity is only part of the picture...two drugs with similar affinity can have vastly different effects depending on intrinsic efficacy (functional response) and functional selectivity (preferential activation of certain downstream signaling cascades), e.g. lisuride vs. LSD.

 

[Anon0631]

So, can we agree that no valid conclusions can be drawn from the provided data?

I'm still concerned by the medical emergencys caused by 25i-NBOMe obviously and would love to see more research to answer the following questions.

Were these all overdoses? If so how many multiples of a reasonable dose are we talking? What's the therapeutic index of 25i approximately? How does this compare to the therapeutic index of the 2c-x and DOx compounds? Do we consider this ratio acceptable?

And finally the really important question: is 25i unique in its ability to cause these emergencys or do the other NBOMe's share the same property?

 

[kidklmx]

^No way to tell for sure, but the general consensus seems to be that they most likely are ODs. Luckily for those trying the drug, the media is really vague with these reports, so there is little to no information. Even one time they reported it as "smiles", which to the best of my knowledge was the brand name for 2C-I in smart shops. Wish more people would come on here to talk about what went wrong, so we can actually form a real opinion on the safety of these.

There have only been reports of 25i-NBOMe, but how much of that actually was 25i and not something else we do not know either. I think it's likely that when someone says "NBOMe" a reporter takes that as 25i-NBOMe because of all the bad news.

In the end I don't really see the big issues with the NBOMe deaths, apart from that they're deaths. It seems to me that the media are just trying to bring down the RC scene. In severity for your body I still think this is relatively safe compared to other RCs, but maybe not compared to psychedelics. Some people seem to experience a nasty bodyload, but I've never seen that with the people I tried this with and it's not like the 2C-Ts are benign on your body either.

 

[sekio]

As far as I can tell, there have been deaths blamed on almost every single psychedelic, designer and non, so it's hard to tell. Even things like 2ce, 2ci, MDMA, LSD, ketamine, ayahuasca/DMT, I'm sure someone has blamed mescaline for a death or two too. I guess it boils down to relative safety, deaths per number of users. There just need to be more comprehensive reviews of this kind of shit.

 

[kidklmx]

Maybe with New Zealand's new RC policy? Not that I'm hopeful that that is going to change things. Though, more and more research is being done these days so who knows what will happen?

P.S Some people report the NBOMes as being much worse for things like HPPD, visual artifacts, etc. Could at least that be blamed on the high affinities or should they just look more closely at their own drug usage?

 

[psood0nym]

Were these all overdoses? If so how many multiples of a reasonable dose are we talking? What's the therapeutic index of 25i approximately? How does this compare to the therapeutic index of the 2c-x and DOx compounds? Do we consider this ratio acceptable?

And finally the really important question: is 25i unique in its ability to cause these emergencys or do the other NBOMe's share the same property?

Erny reported a woman who stopped breathing on a dose of 25B-NBOMe at under 3 mgs I believe (later revived at the hospital). I found the post recently and re-posted it, and in that same thread another low dose medical emergency was reported, but I don't remember the tread title. The fact that DOB-Dragonfly is a non-subtype selective at 5-HT2 that has killed and has caused vasoconstriction so severe amputations resulted at 2C-B-Fly doses (~10 mg) indicates agonism at 5HT2 is capable of killing, most likely through vasoconstrictive effects. That must be true unless DOB-Dragonfly is in fact NOT non-subtype selective at 5-HT2 and causes the severe vasoconstriction by some still unknown means. If the NBOMes do have greater efficacy than DOB-Dragonfly at whichever receptor subtype(s) is the culprit then they could theoretically kill at doses high in the "normal" range. I've read that a lot of what are termed "full agonists" are in fact partial agonists with high efficacy, so it's possible two drugs both termed "full agonists" at a receptor may nevertheless differ in the magnitude of their effects there.

I started a thread in ADD asking if powerful enough agonism at 5-HT2b could kill. It was pointed out that 5 and 6 APB have high affinity at 2b and are full agonists there but don't seem to be killing people. At this point it looks like powerful agonism at 5-HT2a might be all that's needed to cause lethal vasoconstriction -- or there's some difference in functional selectivity at 2b between the NBOMEs and the APBs that explains how NBOMes could kill via agonsim there but not the APBs (or we haven't the first clue at all how they're killing because some mystery factor is to blame).

 

[Dondante]

The fact that DOB-Dragonfly is a non-subtype selective at 5-HT2 that has killed and has caused vasoconstriction so severe amputations resulted at 2C-B-Fly doses (~10 mg) indicates agonism at 5HT2 is capable of killing, most likely through vasoconstrictive effects. That must be true unless DOB-Dragonfly is in fact NOT non-subtype selective at 5-HT2 and causes the severe vasoconstriction by some still unknown means.

I think there's something else going on with DOB-Dfly. Vasoconstriction could be due to alpha-adrenergic stimulation or some other unknown mechanism. Remember, ergotamine and other ergot alkaloids (structurally similar to many psychedelics) were responsible for ergotism, which seems to be essentially what we've seen with overdoses of DOB-Dfly...severe vasoconstriction leading to dry gangrene. Ergot fungus extracts have been used for centuries to treat post-partum hemorrhage due to strong vasoconstrictive properties.

 

[psood0nym]

... so DOB-Dragonfly is nonsubtype selective at 5HT2 and has some other mystery killer property? If that's true it leaves us with no practical recourse for prospective treatments, helpless as we began, though feeling stupider for going through the journey of discovery. Well, g'night everybody!