 Originally Posted by Ksero
Very interesting posts Alyzarin, in my past I have had experience with time dilation during psychedelics, most notably so with 4-HO-MPT (my friend an analogue clock on his wall, it seemed like it was 4 or 5 seconds, I remember counting 1 Mississippi, 2 Mississippi etc. while waiting for it to tick) although I am not sure of it's method of action, I can say without a doubt that during my experience I had the most clear mind that I have had in my entire life, outside of a lucid dream, coming with was the ability to alter reality at will (look at a metal pole, expect it to bend and it does), which is a stark contrast to other psychedelics where you seem to be "along for the ride." It was almost like having a lucid dream while awake.
This is what I LOVE to hear. Of course it doesn't prove anything pharmacologically, but it sure links to two concepts I've put forward already! The most time dilation, the most lucid control, and a tryptamine? Thank you for this, Ksero!
After I made that last post I went on a receptor research binge. It would seem that there are quite a few serotonin receptors that are directly involved in the control of GABA release in the hippocampus. 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 all seem to increase its release, and 5-HT4 has also been shown to indirectly modulate it with increases in low doses and decreases in high doses when activated alone, but its effect is more variable. With these in mind I start to form an image of psychedelics where the strength of their hallucinations, which seemingly must be activated through 5-HT2A, are dependent on the overall amount of GABA release that the drug causes in the hippocampus, whereas the level of lucidity depends on something else, quite possible the ratio of 5-HT2A receptor affinity and efficacy compared to the other serotonin receptors. I haven't thought quite too deeply in that aspect yet, but I think it could be supported by the fact the bufotenin and psilocin, which are both extremely similar to serotonin in structure, each cause powerful and vivid hallucinations despite the fact that bufotenin is incredibly clearheaded while psilocin is a total mind warp. Bufotenin doesn't seem to display much selectivity between 5-HT2 or 5-HT4, and shows slight selectivity over those for 5-HT3, whereas psilocin seems to be the most selective for 5-HT2 receptors. This same kind of logic seems to hold up well enough when compared to the affinities of other psychedelic compounds for serotonin receptors too, at least as far as I can tell right now.
About the GABA release, I tried to investigate that too. Tryptamines would be the best to look into this for by far both because there's a little more research about them and because they're so similar in structure to serotonin. It's frustratingly difficult to find information about psilocin, but like I said, it seems to be relatively selective for 5-HT2A and 5-HT2C and to a lesser extent 5-HT1A. It could activate other serotonin receptors at higher doses too, but I'm not sure about that, but it's definitely a powerful hallucinogen. However, bufotenin really takes the cake as far as I can tell. In addition to the affinities I mentioned above, it seems to activate 5-HT6 and 5-HT7 as well, but I'm not quite sure to what extent. But what it basically comes down to is that it hits every serotonin receptor that increases GABA levels, that we know of anyway. DMT comes closer to this, but lacks activity is 5-HT3, and a little less importantly, at 5-HT4. LSD is the same but it loses the affinity for 5-HT7 theoretically unless very large doses are taken. I'm not sure if mescaline activates 5-HT6 or 5-HT7 but I would wager it doesn't, but if it does activate 5-HT3 like I speculated before then that would put it on relatively the same level as LSD. All of this would, it seems to me, fit in with the relatively well-accepted idea of bufotenin > DMT > LSD ≈ mescaline > psilocin as far as the structural integrity of their hallucinations go. It also supports the idea that tryptamines will be the most likely to cause lucid dream-like experiences due to the much more variable and widespread activation of serotonin receptors, which is why I was especially happy to hear that your experience involved a tryptamine. However, there are some other factors to consider as well.
Particularly with LSD and mescaline, dopamine receptors may be playing a significant role. Phenethylamines especially are mainly psychedelic due to their similarity to dopamine, rather than serotonin. This involves a favorite neurochemical subject of mine. Mainstream research articles and simplified naming conventions would have you believe that the big three monoamine neurotransmitters, namely serotonin, dopamine, and norepinephrine, have their set of receptors they work through by the same names (except for "adrenergic" receptors for norepinephrine, and epinephrine) that work solely for them, at least within their set of three. But this is not the case. One of my favorite parts of researching is when I come across this particular kind of ligand-receptor overlap in articles, because it's so incredibly rare that you see anyone talking about it. An example of this which I think could be very relevant to scientific research is that the so-called "dopamine" D4 receptor also binds norepinephrine and epinephrine as ligands at nearly the same potency. Evidence here and here, and that first article even says that norepinephrine and epinephrine bind to D2 receptors as well, though at significantly higher and possibly normally irrelevant concentrations. D4 has actually been implicated in the positive symptoms of schizophrenia, like delusions and hallucinations, and I have to wonder if this is the reason that stimulants, which work almost entirely through increasing levels of dopamine and norepinephrine, cause schizophrenic-like symptoms to emerge so well in high doses. Considering all this, if you ask me, D4 at least should actually be considered both a dopamine receptor and an adrenergic receptor. I'm not totally sure on the implications of this one yet either, but while we're discussing dopamine-norepinephrine crossovers, this article here suggests that dopamine itself may also be activating beta-adrenergic receptors.
The interactions that interest me the most though are those between dopamine and serotonin. I'm not sure if serotonin and norepinephrine connect yet... but there's definitely some cool stuff here. For one, dopamine itself is a partial agonist at 5-HT2A receptors (as is serotonin), as stated here. Even more interesting is the fact that its ability to internalize the receptor increases after sensitization with serotonin, but it still can do it by itself. When I originally found that article a long time ago I came across one that said it binds to 5-HT2C as well, but I wasn't as interested in that at the time and unfortunately lost track of it. However, yesterday when I was trying to dig it up again, I came across something even better! Another study that not only includes information about it binding to 5-HT2C, but to 5-HT1A and 5-HT3 as well, located here. This adds a cool extra kick for me too, because I was already going to highlight dopamine's partial agonist effects at 5-HT3 covered here and here. I think these last two articles contribute to what I'm trying to say too, as they talk about how full agonists and partial agonists effect 5-HT3 differently, which means serotonin and dopamine will act differently at it. What it would basically come down to is the idea that all of these receptors at least, 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3, could be considered to be both serotonin and dopamine receptors that play distinct roles in the effects of each. This is first of all, I think, pretty important when you're considering the implications for states of mind which involve very high levels of dopamine and very low levels of serotonin, such as REM sleep dreams, or certain anxious or psychotic states. You also have to wonder how exactly these receptor affinities stack when both serotonin and dopamine are high, especially when it comes to how serotonin primes the 5-HT2A receptor for dopamine.
But what I'm really trying to bring this back to is the relevance for psychedelics. People often think that mescaline, for example, is psychedelic because it's similar to dopamine and dopamine is similar to serotonin, but with this I could suggest that it gets its psychedelic properties solely from dopamine similarities, as the serotonin receptors it's known to bind to bind dopamine as well. In fact, with this in mind, I would say that it's quite possible that mescaline is the closest natural chemical, at least that we know of, in both pharmacology and structure to dopamine, and may create its entire spectrum of effects even more fully than a drug which binds only to the D1 through D5 receptors. In this way I feel that you could almost even separate these two categories of psychedelics into totally different categories, one as serotonergic psychedelics and the other as dopaminergic psychedelics, and that could account for such large differences between tryptamines and phenethylamines, and lysergamides which are actually sort of a combination of the two. But I feel that this also calls for other theories for the clarity of mind than what I mentioned before, which is of course how I got to this point in the first place. When we take these drugs, these "false" neurotransmitters, what we're doing is changing the natural ratio of receptor activity in our brain. Those different ratios that account for different hallucinogen effects have a natural state as set up by our natural neurotransmitters, and the more of a false one we take the more we shift our neural activity in that direction. Given this, and given that bufotenin is the most similar to serotonin in structure and function while mescaline is the most similar to dopamine, is it not entirely possible that they each get their clearheaded mindsets due to the fact that they're the most similar to the states that our brains are used to maintaining for normal functioning of consciousness? That doesn't necessarily rule out what I said before either, but it does make it harder to suggest that GABA release may be one of the only significant factors here. It doesn't deter me, though.
Since my last post I've been trying to tie this all into my last big theory about serotonin, which revolves around causing the hallucinogenic side of near-death experiences. The idea would be both just to try to get a grip on that and to explain why drugs such as DMT are so well-known for creating those kinds of trips. And now that I have this GABA-based dream theory, I think I can begin to pull it all together nicely. Normally, it's bad to raise serotonin too much, as evidenced from things like serotonin syndrome following a MDMA overdose. However, it is known to cause hallucinations despite not causing the normal psychedelic sensory syndrome, and if enough GABA was released then this could logically happen at high enough concentrations anyway, as it would stimulate those GABA(A) receptors enough to cause the dopamine facilitation I mentioned before. You don't normally ever have your serotonin levels this high, except for one situation which would raise them in the brain but not body and ignore these physical hazards: during states of high carbon dioxide detection. To monitor if you need to take a breath (to survive), your body actually keeps track of how much carbon dioxide you have in you rather than how much oxygen you have in you, and these receptors that detect carbon dioxide are called chemoreceptors, or chemosensors if your prefer. Serotonin neurons specifically in the raphe nucleus in the brain, and receptors in some other areas as well, act as carbon dioxide chemoreceptors, and the raphe nucleus is the major source of serotonin neurons in the same way that the ventral tegmental area is the major source of dopamine neurons. Because of this, when carbon dioxide detection is very high serotonin will begin to fire all over the brain, including the hippocampus. This is of course what would happen when you stopped breathing, whether or not you died by suffocation. Interestingly, there's also a quasi-psychedelic mixture known as carbogen which had been used in psychiatric settings to test peoples' reactions to psychedelic states of mind before letting them try LSD, back when it was still spreading to people like Timothy Leary. This is a mixture that contains 30% carbon dioxide and 70% oxygen, which means it gives you more than enough to survive perfectly well, but it also makes your brain think you're suffocating and it begins the same chemical cascade that reasonably could be behind a near-death experience. Accordingly, it is known to cause dissociation which feels sort of similar to nitrous oxide in the way it's administered and begins with an out-of-body experience, but it much more colorful and psychedelic with spiritual and reflective themes and vivid scenes.
I love bringing this all together for my theory because it allows me to categorize each chemical nicely. Dopamine is at the source, more of an imagination-generator than anything. GABA would be the chemical which enhances that imagination circuit to the point of creating the dream world. And serotonin is the chemical which activates that dream world circuit in a way designed specifically to create near-death experiences, while carbon dioxide releases it to start off that whole chain. I think there logically must be another path that eventually leads to GABA for regular dreams too, but that's another issue.... Interestingly, serotonin should also then directly modify the way imagination works at the source through activating some of the same receptors as dopamine, and this could logically play into the different kind of experience. This also fits well with the way you can divide up the different hallucinogens. The dopaminergic psychedelics are more abstract, pure euphoric fantasy, and just chaotic. On the next level up, muscimol, which is really the only natural GABAergic hallucinogen we know of, creates dream-like experiences. Then, you have the serotonergic psychedelics which recreate near-death experiences in high doses. What all of these would come down to is that they activate these same processes in the brain, only with some differences, and that's why they can get so bizarre, but still create experiences which are so similar on various levels. Following this logic, I have to ask myself if it's possible for a serotonergic psychedelic to have the exact right structure to shift the simulated near-death experience to a more lucid level of thought than even serotonin itself, by just having the exact right ratio of receptor activity but taken even a step further than how serotonin achieves it? If this was possible, and if it did so particularly by releasing GABA as I mentioned before, then I think it could reasonably account for an experience that was both spiritual and intense like the near-death experience should be, but had an even more powerful and vivid dreamscape with more of a potential for lucid awareness and control than the natural experience should have. As far as I'm concerned, following this path of activity would be the first step towards creating some of the most incredible states of mind we're possible of reaching and further understanding the intricacies of our minds.
And that's why I'm so excited about tryptamines. Bufotenin seems like it could logically do this to me, but it would be foolish to rule out any tryptamine because you never know when they might have just the right structure to make it happen. So again, thank you so much for the anecdote about 4-HO-MPT! It is very much appreciated! 
 Originally Posted by Ksero
On the role of GABA, my first intentional lucid was after I took a 100mg pill of GABA before a WBTB attempt, I am aware that GABA does not cross the blood-brain barrier when taken orally, but it definitely does something, if taken before bed I have extremely vivid and intense dreams, sometimes becoming lucid without reality checks.
This has played into my suspicions as well, it's definitely something to consider. Thanks for that too, you've been very helpful!
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