Deinonychus
Bluelighter
- Joined
- Oct 20, 2012
- Messages
- 401
I saw thizzkid's thread and started writing up a reply I've been mulling over but haven't put to paper yet for a while. The post kinda outgrew its holding cage, so I figured I'd post it as its own thread.
---
In response to thizzkid's experience, I said: I think this emphasizes a potential wrinkle in the ongoing clusterfuck that is the NBOMe overdose saga.
I have been suspecting for a while that these compounds may have some of the unpredictable dose/response curve that the Aleph series exhibits. As a caveat, this is not to say that all overdoses are explained by this theory, that it isn't important to be safe with your measurements and dosages, etc. Or, it is possible that the full-on agonism of these compounds may interact with differences in receptor structure amongst the general population. Bear with me..
If you care to, take a minute some time and take a good look over the BnD threads for the 25x series. Pay attention to doses, in particular people's average or 'favorite' dose, their sweet spot. I have seen people give doses of between 400 micrograms and 4 milligrams, varying by compound. I personally do not take any less than 1.5 to 2 mg of 25I or C, and 2 to 3 of 25B, in combination with other substances most of the time.
I'm no neuroscientist or biochemist, but I read and enjoy all types of science, those subjects included. As such I would be willing to provisionally postulate one possible mechanism for such dose sensitivity. It is possible that some people may exhibit modifications in the generic code for specific 5-HT receptors. This would have to be something small, were not talking deletion or accidental stop codons or van transposition, more likely would be a single-nucleotide polymorphism, or SNP. These SNPs are what are measured when you take one of those mail-in 'what's my ancestry' DNA kits, as full sequencing would be financially infeasible. The SNP variations are correlated in theory with genetic population groups, and thus can be used to determine in broad terms where your ancestors came from. These variations don't usually affect people's health, which again would point to a very small and likely mostly harmless type of modification in the protein that the altered gene codes for, in this case one of the 5-HT receptors.
If this is the case (and Wikipedia says it is, so yeah, so there!) I would further speculate that this modification would likely be located somewhere that is not the binding location, but is close enough to change the conformation of that area slightly. Remember, when we are talking about chemical agonism or partial agonism we are not talking about (relatively) strong connections like covalent (except for compounds that do, and fuck up the receptor's ability to unbind itself) or even ionic bonds between the compound and the receptor, we're talking hydrophobic/philic stuff, steric bulk, floppy alkyl moieties, hydrogen bonding, and van der Walls and electrostatic interactions, so a small change in either the drug – see difference between various alkyl or halogen substituents at 4-position of PEAs – or in the receptor – like small conformational changes in the makeup of the protein(s) that make up the receptor structure – can have a proportionally large effect on the effect produced by the receptor-substrate complex.
An analogy would be a compound that acts on a receptor in an allosteric fashion – that is to say that the compound doesn't actually sit in the location where the normal substrate binds, instead it attaches elsewhere, slightly altering the shape of the receptor and producing changes from the natural state in this fashion. Except that in this theory it is an SNP that changes a single codon and thus swaps out one amino acid for a very similar but different one, thus also changing the receptor shape and thus how the receptor handles agonist or partial agonist substrates.
Keep in mind though, besides the fact that I'm theorizing out of my admittedly somewhat well-informed ass, there are a hundred and one other things it could be. And even if it is a change in SNP fashion, there's epigenetic effects, intron and exon action, positive and negative feedback loops of every imaginable complexity and depth, the environment around the receptor, natural differences in brain chemistry, electrochemical interactions between neurons, the non-neuron cell population in the brain, etc etc all the way through the orders of magnitude and through the boundary between generally known in a semi-mechanistic fashion (like receptor binding and neurochemical structure) and unknown (consciousness and its subsystems).
Heh way to shoot down my own theory, right? Except that my point is exactly that: there's so much shit going on in out heads all damn day! And even when were tripping its *still all going on in there*, and we have generally no idea how much of it works or fits together. I mean we haven't even yet elucidated the structure of any of the 5-HT receptors yet!
We *have* located their genes however. And the 5-HT2A has two hundred and fucking fifty fucking five *known* SNPs (citation)! 255! My thinking is that there is more than slight probability that at least one of them may change the conformation of the receptor binding area enough to modify the reaction to agonists... and what strong agonists the NBOMe series are! On the tenth of nanomolar level at that... enough so that these chemicals can be used as fully-agonistic ligands to map the distribution of 5-HT2A receptors when labelled with a radioisotope using a PET scan. Besides that, it also targets the 5-HT1A, D3, H2, 5-HT1D, α1A adrenergic, δ opioid, serotonin uptake transporter, 5-HT5A, 5-HT1B, D2, 5-HT7, D1, 5-HT3, 5-HT1E, D5, muscarinic M1-M5, H3, and the dopamine uptake transporter at >500 nanomolar levels.
So not only is there a possibility that one of the 255 different 5-HT2A variants will change binding affinities, each SNP can be combined with multiple others, so using the party handshake equation of x(x-1)/2, we get 32,385 possible combinations with the *known* extant SNPs for the single receptor variant subtype. Gee, I wonder how many SNPs there are for each target listed above, no? Very fucking many handshakes, is the droid you're looking for.
---
Getting down to the point past the walls of text, I would be highly surprised if there weren't geometrical differences between various individuals when it comes to serotonin receptor structures, as a result of various changes in receptor protein structure. Psychedelic users have always known that some people are 'hardheaded', and others are extra-susceptible.
The thing is though, that this is the first time that we have such ridiculously wickedly strong full agonists in circulation amongst the drug-eating/sniffing/shooting/plugging public. But what about acid you say? Well, LSD is only a strong partial-agonist. That's not to say that biological permutations may not also affect its binding affinity and effects – indeed, of the classical psychedelics there is hardly such a variable subjective experience as that produced from acid.
So, having established that there are variants in the genetic code for the various receptor subtypes, and understanding that small changes in the code can mean small changes in the protein, it only follows that we understand that once we are in the realm of concrete, physical things like proteins as opposed to the information coded within an albeit concrete chemical like DNA, the effects compound one another, because the interactions between amino acids within a folded protein are legion, complicated, and not fully understood. This is why four fucking values, a simple base four / quaternary numeral code like DNA, produces such an absurd profusion of dissimilar things.
---
It is a total fucking tragedy that people have died from these compounds. There is seriously no excuse for being unsafe with these violently powerful tools. But the key there is the word tool. What if you picked up a hammer to nail something together and found yourself using a sledgehammer on a penny nail, or a ball-peen hammer? You'd be pretty confused, no? Now imagine if the result was that the hammer still *looked* like a normal carpenters' hammer, but applied the force of a sledge/ball-peen/ordinary hammer based on who was holding it? It might follow that some people were simply hitting the nail way too hard, and others too softly, instead of that something unseen was taking place. Occam's razor, but without all the information and with an incomplete picture of things, and thus unhelpful.
This is a contrived analogy, but it is designed for people to easily understand when SNPs and receptor binding affinities are not known quantities. That's just fine too, I started reading on Erowid back in '01, and it's required constant leisure-time studying until now to grasp as much about drugs' effects in the brain as I do as somebody not in that field as a career – and there's still infinitely more to know.
Basically, there are two effects that I'be unfortunately mixed and blended together here into this post now that I re-read it, into an inextricable mess. There is:
1. the natural variation in binding affinities that SNPs themselves may probably cause
2. the unpredictable dose/response curve of the Aleph series
Now it is possible that the mechanism for the Aleph thing has to do with conformational differences between different people's receptor types. But I expect it to be either more metabolic, or more organic chem-oriented. And despite my having just done so throughout the post, it is important not to conflate the effects of theoretical causes 1 and 2. Do as I say, not as I do!
Both however may produce the same statistical pattern: a variation in mean dose over the population that is wider than should be expected. I mean we have had people die from under 10mg, and live from 20-30mg if that nutsack-crazy report on erowid is true. And we have people taking a milligram and freaking, and taking a milligram and getting almost nothing (me!).
The two mechanism are different though. Aleph unpredictability in dose/response is some mechanism I don't have enough information to conjecture about, whereas my SNP idea relies on the full-agonist nature of the NBOMes and the fact that at that potency differences in binding affinity that result from differently structured receptors may make a huge difference in effect, instead of merely resulting in 'hard/soft' heads.
So if it is true that these drugs do have an Aleph-y nature to them, it is critical to figure that out, and soon, since elucidating receptor structures is beyond the abilities of even Bluelight. In an ideal world we would have real statisticians to measure these things, but we don't. In this case, perhaps a stickied thread somewhere asking about dose would be better than nothing. We already have the 'have you heard about NBOMes and if so where' thread in PD, so the idea of gathering as much information with the largest sample size we amateurs can is not an alien idea.
With the Alephs, we had Shulgin to watch out for our collective asses. There is no such luxury here. Think about how often we have seen psychedelic phenisopropylamines around: DOX shit ain't hard to track down. Ditto for 4-thio PEAs. But how often have we seen Alephs? To my knowledge I have seen them on offer in a group buy that got scammed by the lab a grand total of one time. It isn't like they don't have interesting properties, or aren't easy to synthesize. But there's a degree of risk in letting them out into the world without supervision.
Unfortunately with these N-benzyl PEAs it is too late for that. So damage control and mitigation must be implemented, and acting without information isn't a useful thing. We need to know whether these compound have Aleph-action, and soon.
Besides that, anybody have stuff to add or take issue with? I'd love some input on this idea, whether NBOMe related, Aleph related, receptor/gene related, whatevs. Have at it!
---
In response to thizzkid's experience, I said: I think this emphasizes a potential wrinkle in the ongoing clusterfuck that is the NBOMe overdose saga.
I have been suspecting for a while that these compounds may have some of the unpredictable dose/response curve that the Aleph series exhibits. As a caveat, this is not to say that all overdoses are explained by this theory, that it isn't important to be safe with your measurements and dosages, etc. Or, it is possible that the full-on agonism of these compounds may interact with differences in receptor structure amongst the general population. Bear with me..
If you care to, take a minute some time and take a good look over the BnD threads for the 25x series. Pay attention to doses, in particular people's average or 'favorite' dose, their sweet spot. I have seen people give doses of between 400 micrograms and 4 milligrams, varying by compound. I personally do not take any less than 1.5 to 2 mg of 25I or C, and 2 to 3 of 25B, in combination with other substances most of the time.
I'm no neuroscientist or biochemist, but I read and enjoy all types of science, those subjects included. As such I would be willing to provisionally postulate one possible mechanism for such dose sensitivity. It is possible that some people may exhibit modifications in the generic code for specific 5-HT receptors. This would have to be something small, were not talking deletion or accidental stop codons or van transposition, more likely would be a single-nucleotide polymorphism, or SNP. These SNPs are what are measured when you take one of those mail-in 'what's my ancestry' DNA kits, as full sequencing would be financially infeasible. The SNP variations are correlated in theory with genetic population groups, and thus can be used to determine in broad terms where your ancestors came from. These variations don't usually affect people's health, which again would point to a very small and likely mostly harmless type of modification in the protein that the altered gene codes for, in this case one of the 5-HT receptors.
If this is the case (and Wikipedia says it is, so yeah, so there!) I would further speculate that this modification would likely be located somewhere that is not the binding location, but is close enough to change the conformation of that area slightly. Remember, when we are talking about chemical agonism or partial agonism we are not talking about (relatively) strong connections like covalent (except for compounds that do, and fuck up the receptor's ability to unbind itself) or even ionic bonds between the compound and the receptor, we're talking hydrophobic/philic stuff, steric bulk, floppy alkyl moieties, hydrogen bonding, and van der Walls and electrostatic interactions, so a small change in either the drug – see difference between various alkyl or halogen substituents at 4-position of PEAs – or in the receptor – like small conformational changes in the makeup of the protein(s) that make up the receptor structure – can have a proportionally large effect on the effect produced by the receptor-substrate complex.
An analogy would be a compound that acts on a receptor in an allosteric fashion – that is to say that the compound doesn't actually sit in the location where the normal substrate binds, instead it attaches elsewhere, slightly altering the shape of the receptor and producing changes from the natural state in this fashion. Except that in this theory it is an SNP that changes a single codon and thus swaps out one amino acid for a very similar but different one, thus also changing the receptor shape and thus how the receptor handles agonist or partial agonist substrates.
Keep in mind though, besides the fact that I'm theorizing out of my admittedly somewhat well-informed ass, there are a hundred and one other things it could be. And even if it is a change in SNP fashion, there's epigenetic effects, intron and exon action, positive and negative feedback loops of every imaginable complexity and depth, the environment around the receptor, natural differences in brain chemistry, electrochemical interactions between neurons, the non-neuron cell population in the brain, etc etc all the way through the orders of magnitude and through the boundary between generally known in a semi-mechanistic fashion (like receptor binding and neurochemical structure) and unknown (consciousness and its subsystems).
Heh way to shoot down my own theory, right? Except that my point is exactly that: there's so much shit going on in out heads all damn day! And even when were tripping its *still all going on in there*, and we have generally no idea how much of it works or fits together. I mean we haven't even yet elucidated the structure of any of the 5-HT receptors yet!
We *have* located their genes however. And the 5-HT2A has two hundred and fucking fifty fucking five *known* SNPs (citation)! 255! My thinking is that there is more than slight probability that at least one of them may change the conformation of the receptor binding area enough to modify the reaction to agonists... and what strong agonists the NBOMe series are! On the tenth of nanomolar level at that... enough so that these chemicals can be used as fully-agonistic ligands to map the distribution of 5-HT2A receptors when labelled with a radioisotope using a PET scan. Besides that, it also targets the 5-HT1A, D3, H2, 5-HT1D, α1A adrenergic, δ opioid, serotonin uptake transporter, 5-HT5A, 5-HT1B, D2, 5-HT7, D1, 5-HT3, 5-HT1E, D5, muscarinic M1-M5, H3, and the dopamine uptake transporter at >500 nanomolar levels.
So not only is there a possibility that one of the 255 different 5-HT2A variants will change binding affinities, each SNP can be combined with multiple others, so using the party handshake equation of x(x-1)/2, we get 32,385 possible combinations with the *known* extant SNPs for the single receptor variant subtype. Gee, I wonder how many SNPs there are for each target listed above, no? Very fucking many handshakes, is the droid you're looking for.
---
Getting down to the point past the walls of text, I would be highly surprised if there weren't geometrical differences between various individuals when it comes to serotonin receptor structures, as a result of various changes in receptor protein structure. Psychedelic users have always known that some people are 'hardheaded', and others are extra-susceptible.
The thing is though, that this is the first time that we have such ridiculously wickedly strong full agonists in circulation amongst the drug-eating/sniffing/shooting/plugging public. But what about acid you say? Well, LSD is only a strong partial-agonist. That's not to say that biological permutations may not also affect its binding affinity and effects – indeed, of the classical psychedelics there is hardly such a variable subjective experience as that produced from acid.
So, having established that there are variants in the genetic code for the various receptor subtypes, and understanding that small changes in the code can mean small changes in the protein, it only follows that we understand that once we are in the realm of concrete, physical things like proteins as opposed to the information coded within an albeit concrete chemical like DNA, the effects compound one another, because the interactions between amino acids within a folded protein are legion, complicated, and not fully understood. This is why four fucking values, a simple base four / quaternary numeral code like DNA, produces such an absurd profusion of dissimilar things.
---
It is a total fucking tragedy that people have died from these compounds. There is seriously no excuse for being unsafe with these violently powerful tools. But the key there is the word tool. What if you picked up a hammer to nail something together and found yourself using a sledgehammer on a penny nail, or a ball-peen hammer? You'd be pretty confused, no? Now imagine if the result was that the hammer still *looked* like a normal carpenters' hammer, but applied the force of a sledge/ball-peen/ordinary hammer based on who was holding it? It might follow that some people were simply hitting the nail way too hard, and others too softly, instead of that something unseen was taking place. Occam's razor, but without all the information and with an incomplete picture of things, and thus unhelpful.
This is a contrived analogy, but it is designed for people to easily understand when SNPs and receptor binding affinities are not known quantities. That's just fine too, I started reading on Erowid back in '01, and it's required constant leisure-time studying until now to grasp as much about drugs' effects in the brain as I do as somebody not in that field as a career – and there's still infinitely more to know.
Basically, there are two effects that I'be unfortunately mixed and blended together here into this post now that I re-read it, into an inextricable mess. There is:
1. the natural variation in binding affinities that SNPs themselves may probably cause
2. the unpredictable dose/response curve of the Aleph series
Now it is possible that the mechanism for the Aleph thing has to do with conformational differences between different people's receptor types. But I expect it to be either more metabolic, or more organic chem-oriented. And despite my having just done so throughout the post, it is important not to conflate the effects of theoretical causes 1 and 2. Do as I say, not as I do!
Both however may produce the same statistical pattern: a variation in mean dose over the population that is wider than should be expected. I mean we have had people die from under 10mg, and live from 20-30mg if that nutsack-crazy report on erowid is true. And we have people taking a milligram and freaking, and taking a milligram and getting almost nothing (me!).
The two mechanism are different though. Aleph unpredictability in dose/response is some mechanism I don't have enough information to conjecture about, whereas my SNP idea relies on the full-agonist nature of the NBOMes and the fact that at that potency differences in binding affinity that result from differently structured receptors may make a huge difference in effect, instead of merely resulting in 'hard/soft' heads.
So if it is true that these drugs do have an Aleph-y nature to them, it is critical to figure that out, and soon, since elucidating receptor structures is beyond the abilities of even Bluelight. In an ideal world we would have real statisticians to measure these things, but we don't. In this case, perhaps a stickied thread somewhere asking about dose would be better than nothing. We already have the 'have you heard about NBOMes and if so where' thread in PD, so the idea of gathering as much information with the largest sample size we amateurs can is not an alien idea.
With the Alephs, we had Shulgin to watch out for our collective asses. There is no such luxury here. Think about how often we have seen psychedelic phenisopropylamines around: DOX shit ain't hard to track down. Ditto for 4-thio PEAs. But how often have we seen Alephs? To my knowledge I have seen them on offer in a group buy that got scammed by the lab a grand total of one time. It isn't like they don't have interesting properties, or aren't easy to synthesize. But there's a degree of risk in letting them out into the world without supervision.
Unfortunately with these N-benzyl PEAs it is too late for that. So damage control and mitigation must be implemented, and acting without information isn't a useful thing. We need to know whether these compound have Aleph-action, and soon.
Besides that, anybody have stuff to add or take issue with? I'd love some input on this idea, whether NBOMe related, Aleph related, receptor/gene related, whatevs. Have at it!
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