bloodshed344
Bluelighter
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By IA I meant the number for how much it activates the receptor... IA may not be the correct set of two letters.
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N&PD Moderators: Skorpio
Does 5-HT2B activation add delirium to 5-HT2A psychedelia?
- Thread starter Wandering Girl
- Start date
chaosbydesign
Bluelighter
I love this thread, first off... It has a lot of material compiled that I've discussed with two of my best friends (you know who you both are in this thread
), and as you both know, I am extremely interested in the topic but don't have any more sources to add. I do, however, offer you my subjective experiences... As I love to share those anyway!
So I'll start by stating that I've never used any deliriants in the past.. My first time will be next month (again, thank you for willing to be my guide- you know who you are)
So one thing that particularly caught my attention that you mentioned, wandering girl, is the fact that your friends used to see who would experience delirium with MDMA and/or MDA. This reminds me of some experiences I've had with MDMA where I kept trying to hold conversations (as I love to talk and connect with others on MDMA), but I couldn't seem to finish a sentence without forgetting what I was speaking of and where I was, to the point where I might start off a sentence response like, "Yeah... I know what you mean..." But then I would trail off... "About the boats and lakes over there.. We should swim over to that island.." XD this is a real example of something I said exactly word for word pretty much, and it's because I kept forgetting where I was and switching over to thinking I was still staying in a cabin in Tennessee that I had visited a couple months earlier with my family. These doses of MDMA weren't huge, either (probably were close to 200mg-- then again, I weigh less than 100lbs and am quite sensitive and usually 120mg is the highest I feel I need to go on MDMA). I've also noticed other people, especially when relaxed or sleepy on MDMA, starting sentences and trailing off in ways that make absolutely no sense given the shared situation... Because they finish the sentence with their own "dream thoughts".
This phenomenon is something that seems like it would be normal on MDMA + ketamine (a combination I happen to really enjoy), but I've seen it happen from MDMA by itself a handful of times too! Makes a lot of sense given the ideas and studies discussed here about the 5ht2b receptor, delirium-like effects due to serotonin, etc....
Forgive me if this is off topic here, not trying to cause a huge branch-off or anything... But, though not a psychedelic drug, did any of you ever happen to theorize about why the sleeping medication Ambien tends to cause such deliriant-like effects in some people? I have tried searching online, but haven't even found much good or detailed info on the mechanisms of how it works. To be honest, Ambien was the first (unintentional) trip I ever had! I was pretty taken aback at what happened, for I was expecting *nothing* like it, and at the age of 16, had never even tried weed before the first time I got this effect with the Ambien that my mom gave me (hehe). The delirium I experienced on it was always on par with the kind I might get from a high fever... (Things like having conversations with objects that had developed personalities and intentions, pondering what the past lives might be of a certain corner of the room I was in, etc...) What a strange drug Ambien is... Again, ignore this portion of my post if it's too off-topic.
Just wanted to share, if nothing else.
Wandering Girl
Bluelighter
This post is already really long, so I'm putting my responses to bloodshed344 and chaosbydesign in here.
Oh, like intrinsic activity? (That's the first thing that comes to mind for those letters....)
I love this thread, first off... It has a lot of material compiled that I've discussed with two of my best friends (you know who you both are in this thread), and as you both know, I am extremely interested in the topic but don't have any more sources to add. I do, however, offer you my subjective experiences... As I love to share those anyway!
So I'll start by stating that I've never used any deliriants in the past.. My first time will be next month (again, thank you for willing to be my guide- you know who you are)
So one thing that particularly caught my attention that you mentioned, wandering girl, is the fact that your friends used to see who would experience delirium with MDMA and/or MDA. This reminds me of some experiences I've had with MDMA where I kept trying to hold conversations (as I love to talk and connect with others on MDMA), but I couldn't seem to finish a sentence without forgetting what I was speaking of and where I was, to the point where I might start off a sentence response like, "Yeah... I know what you mean..." But then I would trail off... "About the boats and lakes over there.. We should swim over to that island.." XD this is a real example of something I said exactly word for word pretty much, and it's because I kept forgetting where I was and switching over to thinking I was still staying in a cabin in Tennessee that I had visited a couple months earlier with my family. These doses of MDMA weren't huge, either (probably were close to 200mg-- then again, I weigh less than 100lbs and am quite sensitive and usually 120mg is the highest I feel I need to go on MDMA). I've also noticed other people, especially when relaxed or sleepy on MDMA, starting sentences and trailing off in ways that make absolutely no sense given the shared situation... Because they finish the sentence with their own "dream thoughts".
This phenomenon is something that seems like it would be normal on MDMA + ketamine (a combination I happen to really enjoy), but I've seen it happen from MDMA by itself a handful of times too! Makes a lot of sense given the ideas and studies discussed here about the 5ht2b receptor, delirium-like effects due to serotonin, etc....
That is a very helpful anecdote, thanks so much for the contribution! ^_^ And it's pretty hilarious too. XD But the thing about you suddenly thinking you were in Tennessee especially is a wonderful example of what I'm trying to get at.... That's exactly the kind of thing that can happen commonly when you slip into delirium on anticholinergics, and it's exactly what happened to me and my friends on our MDMA experiences too. It's really one of the first things that made me start to think about how incredibly similar they can be. I'm jealous that you were able to get them from MDMA alone too! Haha. I've only known one other person who was as sensitive to MDMA as that, and actually I would say more so.... He said whenever he would take a normal dose he could close his eyes and be flying through outer space. O.O But he also reports full-bodied entity contact hallucinations just from smoking too much weed.... I don't know if that's a blessing or a curse. >.>
Forgive me if this is off topic here, not trying to cause a huge branch-off or anything... But, though not a psychedelic drug, did any of you ever happen to theorize about why the sleeping medication Ambien tends to cause such deliriant-like effects in some people? I have tried searching online, but haven't even found much good or detailed info on the mechanisms of how it works. To be honest, Ambien was the first (unintentional) trip I ever had! I was pretty taken aback at what happened, for I was expecting *nothing* like it, and at the age of 16, had never even tried weed before the first time I got this effect with the Ambien that my mom gave me (hehe). The delirium I experienced on it was always on par with the kind I might get from a high fever... (Things like having conversations with objects that had developed personalities and intentions, pondering what the past lives might be of a certain corner of the room I was in, etc...) What a strange drug Ambien is... Again, ignore this portion of my post if it's too off-topic. Just wanted to share, if nothing else.
I'm afraid I can't help you too much here, but it has always been a subject of much interest to me. From all accounts I've heard (and the one time I used zolpidem myself, though not at a high enough dose for very much hallucination) it does seem delirious in a way similar to alprazolam or alcohol but with a little more psychedelia involved, though I wouldn't quite say it was exactly like a deliriant. All the reports I've ever read put it more on the level of an upper psychosis but with a downer mindset and some visuals thrown in, but I would like to experiment more with it to be sure.... I think the place to start would be asking how does muscimol cause hallucinations? Do you have any experience with amanitas?
Alright, I've been thinking a lot about the ways in which serotonin syndrome and anticholinergic hallucinations could be linked. Let me know what you guys think about this.
If 5-HT2B is releasing serotonin in the brain then obviously plenty of serotonin receptors are being stimulated as a result of it, and part of what I was saying before was that since 5-HT2B seems to be protective against serotonin syndrome and its effect could possibly even be localized (just based on some other tidbits I've found), it might be able to achieve serotonergic effects stronger than what would normally be physically safe from a widespread serotonin releasing agent, similarly to how direct agonists like psychedelics work but without the psychedelia on its own. With that in mind I've been trying to think of what other serotonin receptors might do at levels of activity above where we normally see them... and that led me to 5-HT3.
Widespread activation of 5-HT3 by agonists causes nausea and anxiety. If 5-HT3 plays an important role in the effects of psychedelics then it sure would be nice to find some way to activate it while still getting around that... like by activating 5-HT2B, which should logically lead to 5-HT3 activation in areas where it releases serotonin while still causing anxiolysis as one of its own widespread activation effects instead. As far as I can tell there is frustratingly little research on the activation of 5-HT3 by psychedelics, but at least a couple of different sources I've read claimed that psilocin and LSD do not activate it. It's possible that some phenethylamines might I suppose since they do cause nausea, but that could also result from binding to dopamine receptors. I think the only thing I could really point out here and feel would really be significant is bufotenin, which is known to cause significant nausea, and is also said to have very powerful hallucinations, and I've ever heard people describe a "phase" of it where they would slip into a dream-like state with realistic out-of-body experiences... sounding very similar to deliriants.
So why am I talking about 5-HT3? Well, chew on these:
Interactions between 5-HT3 receptors and cerebral dopamine function: implications for the treatment of schizophrenia and psychoactive substance abuse.
Psychosis in advanced Parkinson's disease: treatment with ondansetron, a 5-HT3 receptor antagonist.
There's just a couple of things for you to think about which led me down this path. But there's more to it than that.... We already know that 5-HT2B is involved or at least required for the release of serotonin in the nucleus accumbens, in the striatum, as part of the effects of MDMA. So what exactly is going on with 5-HT3 in the striatum? How about this:
Nicotinic receptors co-localize with 5-HT(3) serotonin receptors on striatal nerve terminals.
As that last sentence states, this implies activity shared by both cholinergic and serotonergic activation, specifically about regulation of dopamine, which is implicated in psychosis including in relation to 5-HT3. Nicotinic acetylcholine receptor activity causing hallucinations is not news either; pure nicotine overdoses have been documented with it a la Arnold Schwarzenegger and his nicotine gum. Varenicline, a smoking cessation aid which is an agonist at both alpha4beta2 nicotinic and 5-HT3 receptors, has also been known to cause hallucinations. It's notable that high acetylcholine and dopamine activity in brain areas such as this are also associated with dreaming, and cholinergic drugs are known to enhance dream vividness. Nicotine patches are said to make dreams extremely clear and involving all five senses, and acetylcholinesterase inhibitors such as galantamine are often used by lucid dreaming communities. Intriguingly, there's also a chemical called scopoletin, already mentioned in this thread actually, that is found in several plants currently known to drastically enhance the hallucinations caused by anticholinergics, and it's becoming an increasingly common practice in some entheogenic communities to combine them. However, scopoletin is also an acetylcholinesterase inhibitor like galantamine. So how could this possibly make sense, you ask?
Like I said, I've been trying to think of a way to bring together the hallucinations of serotonin syndrome and anticholinergics.... What if blocking muscarinic receptors is more like a decoy than anything? We call them "anticholinergics"... but how do you explain the fact that scopolamine itself increases acetylcholine concentrations in the nucleus accumbens? Oh yes.
Different effects of scopolamine on extracellular acetylcholine levels in neostriatum and nucleus accumbens measured in vivo: possible interaction with aversive stimulation.
It's known that anticholinersterase inhibitors are useful in combating anticholinergic overdose, but what if they're only taken in small enough amounts that they don't overpower the antimuscarinic effects but do increase the lifespan of acetylcholine released by them? Could that not account for the increase in effects of tropanes noted by the addition of scopoletin-containing plants? And if that was the case, could this convergence of alpha4 nicotinic subunits and 5-HT3 receptors not account for at least some of the psychotic/deliriant effects that serotonin syndrome, anticholinergics, and possibly direct 5-HT3 or 5-HT2B agonists share?
Morninggloryseed
Bluelight Crew
Astounding. I cannot wait till my mind has returned to a place where I can contribute to material like this. /me looks up to great scientists and neurophilosophers and can't wait to be a peer with you good folks again.
immad
Bluelighter
- Joined
- Feb 6, 2007
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- 506
Could brain temperature be involved? Large increases in serotonin levels turn up the central thermostat, while anticholinergics block peripheral temperature control by inhibiting sweating, which could also increase brain temperature. Since delirium is also involved in high fever, could there be a connection? Do anticholinergics and serotonin releasers still cause hallucinations when the subject is rigorously cooled?
Wandering Girl
Bluelighter
I'm happy that you think so. :D I look forward to any future contributions you may have!
I get where you're coming from, and I'm sure such things could contribute to the hallucinations, but I don't think it's really enough to explain it. I say this even just because I've hallucinated my head off from deliriants and serotonin releasers and definitely never come close to being as heated up as I have been from fevers; it's pretty noticeable and you feel pretty crappy when your temperature is that high. In addition to that, I've had high fevers and never once hallucinated from them. I just have a hard time believing that someone on datura would suddenly sober up if you helped cool them off.
The first thing that comes to mind is this case report: Diphenhydramine overdose mimicking serotonin syndrome. Diphenhydramine is both an anticholinergic deliriant and a SSRI, so it doesn't get much better than this for this kind of example. This girl took 1800 mg, far above the required amount for complete delirium, and was hallucinating heavily while showing symptoms both of anticholinergic overdose and serotonin syndrome. Her temperature at the time however was 37.9°C, or around 100.22°F. There's no way that that's enough to cause the level of hallucination she was surely submerged in, and I think the fact that she could even take that much and still just be at that level implies that she would not need to be overheating to hallucinate. They claim that her temperature went up more after they measured it, but she was already completely gone by then, and it went back down by the end of the first day. She didn't sober up until the third day.
We also just know so much about how these drugs work in the brain, there's plenty to suggest that their effects are more neurochemical in nature than simply related to temperature. An extremely extensive amount of research has been done on scopolamine in particular.
atara
Bluelighter
http://en.wikipedia.org/wiki/6-APB
http://www.sciencedirect.com/science/article/pii/S0014299912010114
That affinity is nothing to sneeze at! 6-APB may be the most potent and selective 5-ht2b agonist known. However, it doesn't seem to produce much in the way of delirium. I'd nonetheless be very careful with respect to regular use of this compound, considering the known long-term side effects of 5-ht2b receptor activation. I wouldn't use it any more often than typical MDMA rules (twice a month/15 times a year).
Also perhaps 5-ht2b is more responsible for the primary effects of 6-APB than we thought, considering that its affinity for SERT is basically irrelevant at normal dosages: the primary thing separating 6-APB from Ritalin is 5-ht2b!Last edited:
zn13bt
Bluelighter
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Wandering Girl pointed me to this thread and asked me to contribute as an experienced user of NBOMes. I don't know how well this fits in with her theory, but I will say that NBOMes (especially 25I) are easily the most visual of the dozens of psychs I've tried, and this seems to be a common opinion among other users.
One experience I had in particular was a little over a year ago on a relatively high dose of 25I (1.2mg buccal). I had my eyes closed and started to see flashes of various bits of faces, eyes and mouths mostly, but instead of the more cartoony flat-looking visuals that I was used to seeing on other substances, I was astonished to be viewing highly detailed 3D flash snapshots with vivid colors and lighting. I could even see the glisten of tears on the eyeballs and saliva on the teeth in the mouths. The visuals converged into a series of shifting and completely realistic still images of a gorgeous young woman (resembling Megan Fox, only way hotter because she wasn't trying so hard to be agressively sexy :D) wearing a gray tank top and blue cutoff shorts and green flip-flops, standing outside in the warm summer sun on a grassy lawn looking back at me impishly. The images weren't completely stable and kept rhythmically shifting in zoom and perspective about once a second, but at the same time they were highly synesthetic and combined multiple sensory modalities in a unified whole. I could practically feel the softness of the woman's skin and the warmth of the sun on her body, as well as very definite qualities of temperature, time of day, the smell of the atmosphere, and location of the environment all present with the image. I was amazed at how completely realistic it looked and felt (except for at the edges of the visual where it was shifting), and yet I was completely aware the whole time that it was all a mental fabrication and I was really stuck inside my bedroom with pouring rain outside. The expression on her face changed from impish curiosity, to lust, then to annoyance when I didn't really respond to her advances (I was still too surprised to really react), then to anger and even fury. Her eyeballs bulged out and she bared her teeth, and then the sense of place and time went away and the scene flattened and transformed into a grotesque monster with dozens of eyeballs all piled up in a pyramid staring at me. Somehow I managed to not freak out, and I beheld it all from within a state of serene acceptance. The visuals decohered back into innumerable flashing disembodied eyeballs and gnashing teeth, and I simply smiled and even said "smile!" out loud to get them to smile too. Gradually their expressions changed from fear and anger to amazement, and some of them seemed to be laughing. I tried to recall the summer day woman in my imagination, but it didn't have any effect on the visuals. Eventually I opened my eyes and saw the same faces popping out of the walls everywhere.
Ever since that one trip, it seems like something got rewired in my brain and the face-recognition part of my mind is on a hair-trigger and I can see faces in all kinds of visuals nowadays (which can be a little creepy, and has definitely contributed to my slowing down my usage of psychs over the past year). I pretty much always get glistening 3D eyeballs looking back at me on a good dose of any NBOMe, and I'll even get glimpses of them on what were once relatively mild substances like 4-HO-MET or 2C-C. The only exception is allylescaline, which still gives me cartoony Picasso-esque faces like it always has (and like mescaline gave me the two times I tried it); somehow its style of visuals haven't been affected. I've also noticed that the CEV faces I see nowadays are a lot more emotionally expressive, almost to the point of being caricatures, and they seem to smoothly progress through various distinct emotional states as I watch them. When this happens I often wonder if I'm consciously witnessing the spreading activation of neural networks in my brain progressing through their phase spaces of emotional representations, triggering downstream areas in the visual cortex to create the visuals I'm seeing.
Edited to add: I think it'd be interesting to look at melatonin too, I take it for insomnia and in high enough doses it makes my dreaming a lot more vivid than usual. A few times I've woken up in the middle of the night while on melatonin to see complex kaleidoscopic patterns (such as arrays of multicolored diamonds, or five-pointed stars), which makes me think it's something similar going on to what WG was talking about in the first post about how deliriants at low doses have low-level visuals which combine to form panoramic scenes at higher doses.Last edited:
immad
Bluelighter
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Fair enough, I already thought there would be more to it, but it can be quite easy to forget about certain simple principles that might fit the data as well (Occam's razor and such).
atara
Bluelighter
This is quite a series of jumps-to-conclusions. MMDA CEVs are prominent, but if it exhibited deliriant activity one would have expected to see more mention of this in the literature! MMDA is one of the oldest of the amphetamine psychedelics; it was introduced by Shulgin in 1964 as a "new psychotomimetic". It was subsequently found to be useful in therapy as it lacked the stimulant properties of its cousin MDA -- MDMA, 2C-X et al were not known at this time. As such, there is an extensive report on the use of MMDA in psychotherapy dating from 1973:
http://www.drugs-forum.com/chemistry/chemistry/mmda.pharmacology.shulgin.html
This is probably a better source than morninggloryseed's trip report, no offense to him, but he's only one person, and the first-person is the worst-person with regard to understanding the effects of something.
"Visual phenomena with open eyes, such as enhancement of color or distortion of facial expressions or objects, were observed with MMDA in only three instances, in all three cases at the large dosages. Phenomena such as imagery filling the visual world, illusions or hallucinations frequently reported with LSD5 were not observed here."
"True depersonalization was not observed at all."
A lack of OEVs is a pretty strong case against deliriant activity; after all, the anticholinergics are most famous for these. In general, the report paints a picture of a mild-mannered psychedelic-entactogen with some therapeutic potential, certainly not a deliriant by any measure. The problematic aspect of MMDA seems to be some anxiogenic effect, which could also influence a user to misreport an experience as more realistic and/or intimidating than it really was.
Of course, there is also no reason to believe MMDA has much affinity for 5-ht2b, especially if mescaline lacks this affinity. MMDA after all has oxygens in the same place as mescaline. So I don't think MMDA, which has no published binding profile, is terrifically relevant to the question.
Closest thing I can find to mescaline-binding-5-ht2b is this:
http://chemistry.mdma.ch/hiveboard/rhodium/pdf/nichols/nichols-subst.amph.5-ht2abc.affinities.pdf [1]
TMA has relatively low affinity for 5-ht2b, which suggests a similar story for mescaline. Story checks out. In fact, most of these amphetamines have pretty low 5-ht2b affinity!
But can we really call the differences between psilocin and LSD "delirium"? Certainly, psilocin seems to be more entheogenic, DMT much more so. But compare with the NBOMe drugs 25C-NBOMe and 25I-NBOMe:
http://www.bluelight.ru/vb/threads/670462-N-benzyl-phens-may-not-be-as-selective-as-we-once-believed
These have significant 5-ht2b affinity, approaching their 5-ht2a affinity. But the trips take place "in reality", and are decidedly less immersive than LSD. I did find 25C to be sort of empathy/socially-promoting, and so I agree that 5-ht2b probably contributes to entactogenic properties and may have some psychedelic potential. Add 6-APB to the mix: it may show that 5-ht2b alone is enough for visual effects and psychedelic, even entactogenic activity. But the effects of 6-APB are considered to be mildly psychedelic, easily controllable, and even pro-social.
Delirium? I'm not convinced. Psilocin adds 5-ht1a to 5-ht2a and 5-ht2b, and indeed I've heard many suggestions that this receptor is responsible for some important entheogenic effects; 5-ht1a agonists alone are serenic (anti aggressive), and of course learning not to be aggressive can be an important point of emotional growth for people who take these drugs. But I digress.
Once enough receptors have been tickled, we do see a lot more "immersive" experiences -- but LSD does this, hitting 5-ht1a/2a/2c/5a/6 with very high potency and 5-ht1b/1d/2b/D2/D3 with somewhat less. I'd suggest that with psilocin and DMT the powerful nature of the experience is brought on simply by the many effects of these unselective ligands.
See previous notes about 6-APB, I guess. Reasonable.
Nope! See the link above [1]: DOx have a 5-ht2b/5-ht2a ratio similar to that of LSD, and their action at 5-ht2b probably isn't clinically relevant at ordinary doses.
NBOMes are often considered mild at "ordinary" doses: 200-500 µg for 25C, 300-700 µg for 25B, 500-1000 µg for 25I. Their reputation as very powerful drugs comes from a disappointing tendency of users to take the drugs far above recommended doses (I've heard reports of 4000 µg 25I, which is a terrible idea) due to their easy availability and the difficulty of working with small amounts of the compound.
Then why did I find so many? If you have time to type 4000 words, you have time to run searches in Google Scholar, SciFinder, Wikipedia, Erowid and other wonderful sources of information. Understanding how you know things is a primary goal of science: science is the knowledge-justification par excellence, and keeping track of why you believe the things you do is one of the best ways to keep yourself honest.
With that said: one published binding profile usually isn't enough to get a good idea of how a compound works. In order to state any of this with any confidence I'd want to see replication of all the numbers. Unfortunately, since the government (may they rot in hell) really hates it when people do honest research on these compounds, such replication is not likely forthcoming.
EDIT: Let's go back to the beginning:
I'd figure this is substantially dopamine mediated, cf stimulant psychosis, schizophrenia, etc. D2-mediated hallucinations are generally indistinguishable from reality. Obviously ketamine produces powerful hallucinations in combination with MDMA, as it does with anything. Similar effects (in fact stronger ones) are had combining psychedelics with cocaine, which has no 5-htR affinity:
http://www.erowid.org/experiences/exp.php?ID=33540
http://www.erowid.org/experiences/exp.php?ID=61697
and have also been reported with modafinil, everyone's favorite DRI/D2-partial-agonist:
http://www.erowid.org/experiences/exp.php?ID=77413Last edited:
Wandering Girl
Bluelighter
Well, just as a disclaimer I've never tried 6-APB personally... but I would tend to disagree. Everything I've ever read would suggest that full visual doses of 6-APB can be extremely powerful. And if you're talking about less than full visual doses then it doesn't matter anyway because my theory only relates to how 5-HT2B effects 5-HT2A. Something to consider in relation to compounds like MDMA and MDA is that a lower affinity for monoamine transporters would mean less things like dopamine release for the same level of roll (if 5-HT2B is truly responsible for the core of its effects) and more serotonin selectivity, which could lead to 6-APB's hallucinations being less "overt". However, the main marker I use for delirium in this case is the realism of closed-eye visuals or very high doses, and since the latter doesn't really apply here by relation to what would be considered a high dose on something like a tryptamine (unless someone wants to take that heroic of a dose of 6-APB to try it, be my guest... but seriously don't) it's the former that will be really telling. It's the same scenario with 2C-B-Fly and the "lower" doses of tryptamines.
On that note, this is what I always think of from an Erowid report on 200 mg of 6-APB: My Favorite Drug of All Time.
That sounds about right to me. Of course, I would want to try it for myself before making any final decisions. Have you used fully visual doses of 6-APB before?
Wandering Girl pointed me to this thread and asked me to contribute as an experienced user of NBOMes. I don't know how well this fits in with her theory, but I will say that NBOMes (especially 25I) are easily the most visual of the dozens of psychs I've tried, and this seems to be a common opinion among other users.
Thanks so much for stopping by! ^_^ My ideas about this are constantly growing and changing and now I'm trying to incorporate every serotonin receptor I can into it, so all anecdotes with newer psychedelics (particularly those such as this where we have binding data) are appreciated!
I don't think I've ever read a trip report that made me want to try a drug as much as that does.
That sounds really incredible! And so does she. >w< I'm super jealous!! You weren't kidding when you said you have strong experiences from 25I-NBOMe. I'm actually thinking about some other receptors in relation to this particular drug now, but I'll mention that in a bit.... But I would recommend checking out what I have to say about 5-HT5A! It's kind of an obscure one, but I think there's definitely something interesting here....
This actually happens to me after nearly every psychedelic experience I have. Remember how I was talking about how often I see entities in my visuals? Yeah, it started like that.... They started out cartoony and faint, then got to like cave and temple drawing kind of things, then progressed to seeming like they were computer generated or in virtual reality, and then finally after the highest dose of DMT I took they started looking extremely detailed all the time. Even once after that on one hit of LSD when it still wasn't super vivid or superimposed on reality or anything, a female I saw as part of my patterns was still fully rendered within that structure. I love it, it's one of my favorite parts about tripping.
I get it, and I appreciate the contribution. I do think though that Occam's razor is relevant but somewhat limited when it comes to theorizing about the brain, especially in relation to the effects of psychedelics. Even the theory with the least amount of assumptions will still have a pretty large amount of them, since there's still so much we don't understand about the brain and all we're doing here is hypothesizing. We would need some pretty extensive and specific research studies to get any of this down for sure.
I'm going to have to look into that because I really do find MMDA regardless of any of this!
As I said in my response above, I don't believe that OEVs are completely necessary for what I'm saying, especially not with drugs you can only dose so high on. I also feel like you're confusing what I'm saying a bit.... I never claimed that they were actually anticholinergic, but just that the way their hallucinations form can be similar. There's no reason they would have to share every aspect of deliriants just because they had some hallucinogenic qualities in common. As I stated before, I only called it delirium because of the similarities.
There has also been a lot of challenging mescaline's lack of 5-HT2B activity in this thread already. The Psychedelics and the Human Receptorome study that keeps being pushed on me suggests that mescaline and the amphetamines do have significant affinity for 5-HT2B. And I do feel that it's relevant, because it still works through empathogenic means.... No one is trying to say anything for sure here, I'm just trying to draw connections.
I'm going to be discussing more of this later on, I was hoping to finish it before more responses such as yours but it's been taking longer than expected. I don't know how much of the thread you've read but I've moved on to considering the other serotonin receptors more heavily too, not just 5-HT2B.
The study bugs me too... this is why I was opposed to the PLOS ONE study but people keep saying it's right. Data doesn't match up from one source to the next. How is one supposed to know what's right? I have to say though that with further research into this stuff and just going by the body highs of the drugs alone, that study does seem believable....
Again, if you are basing this off of mildly psychedelic doses of 6-APB then you aren't considering what I said correctly. I never claimed that 5-HT2B could cause delirium, only that it could make 5-HT2A hallucinations more delirious than normal. It would still require full 5-HT2A activity to take effect.
What exactly is the level of activity you're considering "mild" then? Does that include the visuals?
Then why did I find so many? If you have time to type 4000 words, you have time to run searches in Google Scholar, SciFinder, Wikipedia, Erowid and other wonderful sources of information. Understanding how you know things is a primary goal of science: science is the knowledge-justification par excellence, and keeping track of why you believe the things you do is one of the best ways to keep yourself honest.
With that said: one published binding profile usually isn't enough to get a good idea of how a compound works. In order to state any of this with any confidence I'd want to see replication of all the numbers. Unfortunately, since the government (may they rot in hell) really hates it when people do honest research on these compounds, such replication is not likely forthcoming.
You misunderstood me. I didn't mean there weren't sources to back it up, I meant that I hadn't linked to any in my post. I read studies and archive the links like it's nobody's business.
So I'm starting to get really into researching all of these different serotonin receptors and the relationships between them... it's really crazy stuff! There's so much to learn that it's hard to know where to start, but for the sake of furthering the ideas of the this thread I've been trying to stick to their effects in relation to the nucleus accumbens, or if that information isn't available, at least as they relate to schizophrenia. There are surely multiple mechanisms of action going on with some of these that could alter hallucinations, but I'm trying to stick to the delirium/well-structured hallucination theme here.
Before I get started, 5-HT2B and 5-HT3 still won't be discussed here... I've pretty much already covered what I can. I'd like to preface this with this thought: 5-HT3 interests me so much mostly because of its colocalization with nicotinic acetylcholine receptors. It's important to remember that two dopamine releases in the same part of the brain are not necessarily equal; if they come from different sources then they can have different effects. The connection of 5-HT3 with nicotinic receptors intrigues me so much because of my theory about how it ties into the downstream effects of scopolamine, specifically relating to the similarities between serotonin syndrome and anticholinergics. However, it's possible that many other dopamine releases are also playing a role and/or modulating these effects, and that's why I've taken the time to look up all of this as well.
So, let's get on with it!
5-HT1A
To be honest, I'm having some trouble finding information about what exactly 5-HT1A does to dopamine in the nucleus accumbens.... It doesn't make it any easier than the research drugs previously though to be selective 5-HT1A agonists were found to have dopamine agonist properties instead, and I've found reports claiming that they could go either way with this. There is an angle that I feel is worth considering, though. We've been talking a lot about serotonin release in the nucleus accumbens here. In relation to individual serotonin receptor activation, aside from how I've already talked about 5-HT3 due to most psychedelics' apparent lack of affinity there, I think it's best if we don't dig too deeply into this serotonin release for now. It's only going to make things much more complicated if we try to compare it to what all of these direct agonists do as well. But what we do already know from that study from before is that serotonin positively influences dopamine and negatively influences acetylcholine here. This is very useful to us, as the entire point of this is to try to determine how much these psychedelics influence dopamine concentrations due to receptor activity ratios, so what it basically comes down to is that this has already been solved for us with serotonin, at least enough for now.... So for the sake of the discussion here, I feel that we can use a psychedelic's overall effects on serotonin release in the nucleus accumbens as just another measure of potential dopaminergic activity similarly to how we are considering direct effects through various receptors. Make enough sense?
So what it comes down to is this.... 5-HT1A receptors act as negative autoreceptors in the raphe nucleus, the major source of serotonin projections in the brain. This means that they inhibit the release of serotonin. This is important because of how we've been talking about 5-HT2B receptors positively influencing serotonin release. With this in mind, a psychedelic which has a high ratio of 5-HT1A to 5-HT2B activity should keep much lower serotonin concentrations levels than one which has a high ratio of 5-HT2B to 5-HT1A. This doesn't mean that it's completely insignificant in those cases, though; for example, if that downstream 5-HT3 activation does influence 5-HT2A hallucinations then even a 1A:2B ratio which keeps serotonin levels at relatively the same place as sobriety will have more of that influence than one which makes them lower than normal. I think this is important to remember when it comes to what we've been talking about so far.
Psychedelics with moderate or considerable affinity for 5-HT1A over 5-HT2A include DPT, LSD, 5-MeO-MiPT, psilocin, 5-MeO-DiPT, DOET, 5-MeO-DMT, mescaline, and MDA. This receptor is often thought to contribute to feelings of love and peace in low doses and ego death in high doses. I can't say how that effects the nucleus accumbens, but it seems like a strong enough argument given the drugs that activate it most strongly. I'll stop that here for now, though.
5-HT1B
This is a receptor that has really caught my attention. Check these out:
Dopamine release in the nucleus accumbens and latent inhibition in the rat following microinjections of a 5-HT1B agonist into the dorsal subiculum: implications for schizophrenia.
Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway.
So in case that got past you, let me highlight it: activating 5-HT1B increases dopamine in the nucleus accumbens for a long period of time. I would LOVE to read these full articles because this doesn't say exactly how long, but it certainly makes me wonder considering that they listed the time that it had returned to normal for sure as three weeks.... I'm thinking about just buying them so I can check it out. And according to the first study, this effect occurs as a function of the hippocampus through glutamate receptors, and it can be reproduced by NMDA antagonists. I have to wonder... is this why psychedelics, empathogens, dissociatives, and cannabinoids (when used sparingly) can have long-lasting afterglows that make the world seem new and brighter? That would make perfect sense, wouldn't it?
I also have to wonder if this mechanism is part of how dissociatives cause their hallucinations/psychosis, because if so one could presume that 5-HT1B activation might cause similar effects as well.... Psychedelics that seem to bind to 5-HT1B more strongly than or relatively equally to 5-HT2A are DPT, LSD, 2C-E, 2C-B, 5-MeO-MiPT, psilocin, and 5-MeO-DMT. A good batch of powerful psychedelics there, except for maybe the 2C-B which people generally don't take in huge doses anyway.... Food for thought?
5-HT1D
I honestly couldn't find much about 5-HT1D in relation to this subject.... That doesn't mean I'm not interested in it, but I won't go into it much for now. Has anyone heard anything about 5-HT1D in relation to the nucleus accumbens of schizophrenia?
5-HT1E
This one seems even harder to find than 5-HT1D, but that might be because of the lack of selective ligands.... As with 1D, a lot of psychedelics seem to bind to it. Anyone have any ideas?
5-HT2A
Ah, 5-HT2A.... I could go on and on about this one, but I'll try to keep it simple for now. (I'm honestly kind of rushed to finish this post at the moment, I've been working on it for a while and I have a lot of things to do today.)
I've always heard that 5-HT2A and 5-HT2C counterbalance each others' dopamine release, with the former facilitating it and the latter inhibiting it. I'm trying to find evidence for this directly in the nucleus accumbens right now, but like I said I'm a bit rushed.... I know that 5-HT2C lowers dopamine there though, and I think this is worth considering:
Opposing Roles for 5-HT2A and 5-HT2C Receptors in the Nucleus Accumbens on Inhibitory Response Control in the 5-Choice Serial Reaction Time Task.
So it seems that they do oppose each other in at least some way there....
One thing I just want to say about this is how I think it would relate directly to what I'm trying to say here. 5-HT2A causes multiple types of hallucinogenic effects on its own, but if nucleus accumbens dopamine release is one specific aspect of that then it would make sense that other serotonin receptors that increase dopamine release would specifically enhance that one aspect of those hallucinations, right? That's a big part of what I'm trying to get at here, it would shift the balance of 5-HT2A effects toward the fully-structured hallucinations.
5-HT2C
Like I said before, this is a receptor that's known for supposedly reducing dopamine levels. Here's a study on its constitutive activity that claims that it does so in the nucleus accumbens:
Constitutive Activity of the Serotonin2C Receptor Inhibits In Vivo Dopamine Release in the Rat Striatum and Nucleus Accumbens.
Here's one on the selectivity of effect in how it reduces dopamine as well, though I wish they could have used a selective agonist. Still, it's interesting:
In vivo evidence that 5-HT2C receptor antagonist but not agonist modulates cocaine-induced dopamine outflow in the rat nucleus accumbens and striatum.
And here's one more related to the efficacy of antidepressant treatment:
Hyperfunctionality of serotonin-2C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment.
So, I'm starting to wonder if there's really any reason at all to activate this receptor.... If it lowers dopamine then it's kind of hurting our cause, right?
Anyone some psychedelics that bind to it more significantly than to 5-HT2A are DMT, DPT, DOI, psilocin, and 5-MeO-DMT. Interestingly, LSD, phenethylamines, amphetamines, and some research chemical 5-MeO-tryptamines seem to bind to 5-HT2A and 5-HT2C either relatively equally or to the former more than the latter. I've heard the idea proposed before that stronger 5-HT2C activation than 5-HT2A leads to a more potent inhibition of proper movement, aka becoming physically overwhelmed and unable to move properly on psychedelics.... That doesn't seem too far out from believable based on that binding data, I'd say. I wonder if that same dopamine release could also be somewhat related to some of the more stimulant psychosis-y effects of high doses of some phenethylamine psychedelics?
5-HT4
This one seems to be ignored a lot in binding studies like 5-HT3.... Does anyone know why?
This doesn't specifically relate to the nucleus accumbens, but it is in the striatum. Keep in mind that it may not be in the same area though - they found 5-HT2 and 5-HT3 receptors to not be important for dopamine release in the tested area, at least in this experiment. Still, it's interesting to look into... I'm going to keep looking for more defining studies though. Anyway, here it is:
Evidence for 5-HT4 receptor subtype involvement in the enhancement of striatal dopamine release induced by serotonin: a microdialysis study in the halothane-anesthetized rat
5-HT5A
This is another one of those ones that's hard to find much information on.... I've seen studies trying to link it to schizophrenia, but the results always seem varied. Here are a couple of studies on that, though:
Family-based association studies between 5-HT5A receptor gene and schizophrenia.
Association of a 5-HT5A receptor polymorphism, Pro15Ser, to schizophrenia.
This is all interesting stuff, but what really stands out to me is the mention of a loss of some motor activity from LSD in 5-HT5A knockout mice.... Even if that doesn't necessarily signal some kind of psychosis, it does imply that something is going on there. The neurochemical bases of motor activity and psychosis are often not far removed from each other, though that doesn't necessarily prove anything of course....
Speaking of not necessarily proving anything, one of the real reasons I've always been interested in this receptor is the fact that some people report mild psychedelic effects from large doses of valerian root, and valerenic acid, one of its main constituents, is a partial agonist at 5-HT5A. Does anyone know if it acts anywhere else as well? The only times I've heard of this being done at doses above what were just enough for some mild open-eye distortions came with some very interesting descriptions: one was from a friend who said that they had some "DMT-like" closed-eye visuals, though I never got any more information than that, and the other was from an online report where the tripper reported seeing vivid and realistic scenes behind closed eyes, though without too much color in them. That last one really interests me.... Psychedelics that apparently bind strongly or at least equally compared to 5-HT2A include DMT, LSD, psilocin, 5-MeO-DMT, and interestingly, 25I-NBOMe, but not 25B or 25C. Given the visionary power of those first four compounds (especially the 5-MeO-DMT, despite very few "regular" psychedelic hallucinations by comparison), I can't help but wonder.... Some of the ways that zn13bt describes his vivid closed-eye imagery on 25I-NBOMe even remind me of that valerian root report. I don't know, but I'm certainly going to be reading more NBOMe reports now to compare things!
5-HT6
I honestly don't know too much about 5-HT6, but I was able to find something interesting on it. Check this out:
Evidence for a role of a dopamine/5-HT6 receptor interaction in cocaine reinforcement.
This is a pretty new study, and a very interesting one I think. I'm certainly going to be looking more into 5-HT6... it could lead down an interesting path!
Psychedelics with significant 5-HT6 affinity over 5-HT2A seem to include DMT, LSD, 5-MeO-MiPT, psilocin, and 5-MeO-DMT. Not a bad list if I do say so myself!
5-HT7
I had trouble linking this one to the nucleus accumbens as well, but since I posted some 5-HT5A information I'll cover this too. There are a couple links between 5-HT7 and schizophrenia and using 5-HT7 antagonists as antipsychotics, though it related to the hippocampus. Here they are:
Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population.
Serotonin 5-HT(7) receptor blockade reverses behavioral abnormalities in PACAP-deficient mice and receptor activation promotes neurite extension in primary embryonic hippocampal neurons: therapeutic implications for psychiatric disorders.
I'd be very interested in learning more about this too, if anyone would know where to look....
Psychedelics with significant 5-HT7 activity appear to include DMT, DPT, LSD, 5-MeO-MiPT, psilocin, 5-MeO-DiPT, and 5-MeO-DMT. Again, an interesting batch.
So that's all I have to say for now.... I have a headache from staring at the computer so much and have other stuff to go do now. @_@ I might say more much later tonight, but that's it for now! Does anyone have anything to add? If you know good places to research serotonin receptors or even if you just have any theories about these in relation to some psychedelics I'd love to hear it!
atara
Bluelighter
Wandering Girl said:
Of course! 200-500 µg was my primary dosing range with 25C; it led to many very visual experiences, but nothing delirious.
Wandering Girl said:
"Psychedelics and the human receptorome" is generally considered to be discredited; you're right to ignore it. I would trust rather the data published in peer-reviewed journals; when citing from PLoS One it is important to consider the reputation of the authors, since here it will be your only clue to reliability. Another simple test is the degree of excitement versus the degree of exciting: if that PLoS One paper had really mapped out the binding profiles of all of these drugs, you'd expect they could publish it somewhere better than PLoS One!
I guess the real problem is this just plain isn't delirium. If you phrase the question as "do 5-ht2b agonists produce more realistic CEVs", then maybe the discussion goes a little easier. But anticholinergics are known for open-eye visuals! I.e. not like that's an effect: that's the reason they're called deliriants!
Wandering Girl said:
That doesn't sound like delirium at all. This is delirium:
http://www.erowid.org/experiences/exp.php?ID=56930
Delirium isn't realistic visuals. Delirium means that your mind-set has been so fucked you can no longer tell visual from vision. In fact, delirious hallucinations might not be realistic at all: it's not whether it's realistic, it's whether you think it's real. Case in point:
http://www.erowid.org/experiences/exp.php?ID=56136
Now, are 5-ht2b agonists more likely to produce realistic CEVs? I dunno. I suspect -- by analogy to similar compounds -- MMDA-1 (aka MMDA) has no clinically relevant 5-ht2b affinity, ditto 2C-T-2, and these are both infamous for their CEVs. In particular, MMDA-1 is a close structural analogue of TMA-1, which has low 5-ht2b affinity, and 2C-T-2 derives from a class with categorically low affinity for the same -- none of the DOx analogs in Nichols' study had 5-ht2b affinity close to their 5-ht2a affinity.
Are 5-ht2b agonists entactogenic? I think there's a case to be made here. 6-APB is a good example. Are they entheogens? DMT is a good argument, but it touches everything.
I'm not really sure what this means?
Due to its location in the temporal lobe, and binding to this receptor by DiPT and 2-methylated tryptamines, it has been suggested that this receptor may be responsible for auditory hallucinations.Last edited:
zn13bt
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Maybe hypnagogia would be a better term for the kinds of panoramic visuals that Wandering Girl is interested in, rather than delirium (which implies that they're being mistaken for reality). I don't think I've ever had an episode of outright delirium on any psychedelic, but I have had brief moments of hypnagogic dreaming, like the 25I experience I described before.
specialspack
Bluelighter
I think a lot of time could be saved here by everyone, by judicious use of the handy PDSP database - http://pdsp.med.unc.edu/pdsp.php
You can also download the full database as a text file. It makes the finding of relevant binding affinities much easier...!*
Well - psilocin? Psilocin has an affinity of 4.6 nM (vs 3H-LSD, human cloned receptor). Which puts it a couple of orders of magnitude above MDMA, at 700 nM on the same assay.
Given that the APBs have high 2B affinity as well, yet their dosages are of the same magnitude as MDMA, there's clearly something else going on. I would assume it might have something to do with MDMA having more effects at VMAT than APB (or indeed, psilocin)?
@Wandering girl - there's just waaay too much information in your posts to try and respond to anything but a small part of it. While I'm completely in agreement that multiple receptor effects modify the psychedelic experience, and I'm sure contribute to the differential effects of different substances - trying to pin down the causal relations, without a heavily funded research base to test some hypotheses, isn't going to get us very far...
I think in general, there are quite a few places where you're skating over logical jumps from one thing to another, and attempting to do line-by-line responses is not practical (or conducive to useful debate). There's one rather large hole in all of this - efficacy. You make a few brief comments about the lack of efficacy of 2C-xs, which I certainly don't think the literature supports, and more general comments about how like serotonin psychedelics are. It's becoming clear that functional selectivity / agonist trafficking is going to emerge as another layer of modulatory complexity. So assumptions that just because a drug has high binding affinity, therefore it activates that receptor are false and overly simplistic. Especially looking at the less-researched serotonin receptors in your last post - without any functional assays, how do we know what effects psychedelics are having?
Here's a recent paper on functional selectivity of LSD at 5HT2B, for instance - literally the tip of the iceberg:
http://www.ncbi.nlm.nih.gov/pubmed/23519215
Oh, and of course don't forget that we are only just starting to look at how different drugs produce whole brain, systems level changes. Mapping the relationship of receptor profile binding & efficacy to changes in brain activations and functional connectivity is an enormous undertaking :D
http://www.pnas.org/content/109/6/2138
*NB, however - the recepterome thread http://www.bluelight.ru/vb/threads/487865-Psychedelics-and-the-Human-Receptorome/page2 - contains some discussion about Roth's apparent distrust of the Ray results, yet they are reported in the database as "PDSP certified data". Or at least they mostly are. I have noticed a few discrepancies here and there between the values in Rays paper and PDSP data. Why this is the case is mysterious to me.
atara
Bluelighter
Aminorex (870 nM), 6-APB*, 25x-NBOMe, ...psilocin?
*5-ht-reuptake Ki ~2600 nM, probably not too relevant at normal doses.
The funny thing is that 6-APB has now been suggested as a research ligand for the receptor, because even the medical community was having trouble finding a selective compound. Who says the RC scene is bad for science?
endotropic
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Aminorex (870 nM), 6-APB*, 25x-NBOMe, ...psilocin?
*5-ht-reuptake Ki ~2600 nM, probably not too relevant at normal doses.
The funny thing is that 6-APB has now been suggested as a research ligand for the receptor, because even the medical community was having trouble finding a selective compound. Who says the RC scene is bad for science?
Are we sure those are all agonists or are those just based on Ki?
Who says the RC scene is bad for science? Pretty much just politicians and the feds.
specialspack
Bluelighter
Yep:
Iversen (2012) Neurochemical profiles of some novel psychoactive substances. Eur J Pharmacol.
Plot available to view here - http://www.sciencedirect.com/science/article/pii/S0014299912010114
Wandering Girl
Bluelighter
What were the visuals like though?
Alright, that's what I thought.... Guess I'll be switching back to my old ideas about the binding data then.
Have you done deliriants before? I have, several times. In full delirium doses they are known for open-eye hallucinations. In lower doses they actually can create some pretty significant CEV, generally extremely realistic stuff. They also have more "regular" OEVs comparable to psychedelics like patterns and distortions in those low doses.
Alright, let me rephrase myself because we're not talking about the same thing here. zn13bt puts it well. The only reason I said delirium is because I was referring to the hallucinations caused by deliriants. But I specifically mean the hallucinations, not necessarily the inability to differentiate between them (though I know that that can happen on psychedelics too). This is another reason why I think that the whole 5-HT3/nicotinic receptor connection is interesting. By comparing these hallucinations to those generated in dreams I clearly can't be claiming that you must be delirious to experience them, or lucid dreaming wouldn't be possible. The thing I was thinking about by mentioning that scopolamine increases acetylcholine release in the nucleus accumbens was that it could be something along the lines of nicotinic activation causes hallucinations but muscarinic inactivation causes disturbances in consciousness leading to delirium. In that way, if just for example the 5-HT3 thing had some backing, it would make perfect sense that a serotonergic could cause the same types of well-structured hallucinations without necessarily leading to the delirious mindset.
I don't think that logic really holds up.... There's hardly much of a difference in the change between MMDA and TMA-1 and the change between MMDA and MDA. And TMA-1 lacks a methylenedioxy ring and so it's not crazy to think that it could have low 5-HT2B affinity like you say that the DOx compounds, which also lack that, have. On the other hand, every tested drug that I know that has it, or some modification of it a la 5/6-APB, does have 5-HT2B affinity, and MMDA has it. I think it would be pretty unfair to jump to the conclusion that MMDA lacks that affinity.
I would also have to argue the same for 2C-T-2. As far as I can see, Nichols' study didn't test for Aleph-2, and even aside from that, the change from phenethylamine to amphetamine can make for some pretty big pharmacological changes in many substances. I would have to counter-suggest that 2C-T-2 is more likely to have a similar binding affinities to other 2C-x chemicals than the DOx family, and the binding data for 2C-I listed in the picture alongside NBOMes in the thread that you started lists non-selective binding for all 5-HT2 receptors, including 5-HT2B. Again, I don't think it's quite as simple as you say.
My point was just because I'm saying they're similar in some ways doesn't mean they have to have every single thing in common, like how I talked about the muscarinic/nicotinic ratio with scopolamine.
That's really interesting! I'm going to have to look more into that for sure. Thanks for that.
This is probably a better way to think about it, and that would lead to the full dream sequences in high doses of thinks like DMT and psilocin.
This is seriously not loading for me in any manageable manner. Is anyone else having this problem?
Without a doubt. Again, this is why I just felt like starting a discussion to get ideas flowing. I just like thinking about this stuff in my spare time, it's not like I'm really intending to prove anything.
I've never had any problems with line-by-line responses.... What's wrong with it?
I'm aware that it just gets more and more complex like that - and that's a very interesting study on LSD by the way! - but that's always how the brain is. I don't think it's wrong to work with things on a larger scale and then move downward from there when you have some ideas floating around. I've also generally tried to avoid claiming that anything that binds to a specific receptor activates, I've just been trying to point out that they do bind to it. Mostly, anyway. Again, it's about getting ideas flowing.... I made this thread with a totally casual mood, I just like thinking about this stuff.
This is a different paper than the one I first read it in (that one also covered 2C-C):
Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT2A and 5-HT2C receptors
Comparison of the agonist potencies and efficacies of PIA/PEA pairs said:At the 5-HT2A receptor, the efficacies of all the PIAs were significantly greater than those of their corresponding PEAs; in contrast, the efficacies were not significantly different at the 5-HT2C receptor, with the exception of the DOI/2C-I pair. Each PEA was much less efficacious at the 5-HT2A than at the 5-HT2C receptor. However, the PIAs did not show very marked differences in efficacy between both receptor subtypes. Only DOI and DOM were almost full agonists at the 5-HT2C subtype, while their efficacies at the 5-HT2A receptor relative to 5-HT were about 50%, like DOB and 2,5-DMA (but not the less efficacious DON). The EC50 values and the relative Imax for all these compounds are summarized in Table 3. In contrast to the practically full agonism of DOI at the 5-HT2C receptor, 2C-I was a partial agonist at both subtypes, showing a significantly lower efficacy at the 5-HT2A receptor (Table 3 and Figure 4). Representative tracings showing the partial agonism of DOI at the 5-HT2A receptor and full agonism at the 5-HT2C receptor are shown in Figure 4A,C.
So there's at least two papers that support it.
Yes, I am very interested in seeing more studies like this!
Yeah, that's why I generally avoid this paper.... Too much apparent uncertainty. >.>
specialspack
Bluelighter
When the topic is so far-ranging as this thread has become, line-by-line reviews quickly become enormous, unwieldy posts that are difficult to read.
Personally I think it's important to note the methodology of the assay in question. So this paper, Acuna-Castillo (2002) uses cloned rat receptors expressed in Xenopus oocytes, and measures efficacy by single cell current. On the other hand, the same group produced another paper more recently - Moya (2007) - that used human cloned cells and measured AA and IP accumulation in their functional assays, and have quite different numbers. The Nichol's group's results are also quite different - Parrish's dissertation thesis quotes IAs around 30-40% for the 2Cxs (human receptors, IP accumulation) and EC50s around 10-20nM.
Moya et al (2007) "Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)2A and 5-HT2C Receptors"
http://www.ncbi.nlm.nih.gov/pubmed/17337633
Wandering Girl
Bluelighter
Well, I've never personally had any problem with them and I've gotten into discussions much longer than this one... but for what it's worth, I'm going to stop doing those long posts for now anyway. After the last few ones I had migraines just from staring at the screen for so long. @_@
That's interesting that they followed it up with more, but... correct me if I'm wrong, but aren't head shakes correlated to 5-HT2A hallucinogenic activity? That 2007 study still lists the phenethylamines as only weak head shake inducers. Does the full paper have tables of values? I only have access to the abstract.