I'm glad you're back Kaleida.
I'll have to digest this post tomorrow as currently I am rather mush-brained...
I'm definitely glad to be back.
I really missed having all these kinds of discussions and having a good place to bounce my thoughts of others who can actually relate to the kinds of things I'm talking about. If anything significant comes to mind after you really take it all in related to those theories and such I'd love to hear what you've got to say about it! With as much experience with these chemicals as you've got your opinions on these things surely would stand out at least among the rest of the anecdotal evidence.
I typically use cannabis only to control side-effects, but since the 4-HO-EPT was virtually body-load free, I never ended up smoking any. Smoked 4-HO-EPT might be interesting, but I wonder if the best route into 4-HO-EPT-land will be EPT itself, as the base tryptamines seem to be qualitatively similar their 4-substituted cousins but with more hyperspatial oomph.
Ah, I gotcha. Yeah, it has been remarkably clean feeling for me so far, I just pretty much always smoke cannabis if I can heh.
EPT does sound really interesting to me, at least based on the couple really positive reports out there. I'm very interested to see what it will be like, but also what qualities will or won't survive the reversion from 4-substituted to base; by that I mean, for instance, while MiPT definitely shares certain qualities with 4-HO-MiPT for me, there are also interestingly quite a few things that it shares with 4-HO-MET for me that 4-HO-MiPT does not, almost like in some way they have their own sort of equivalence. I am beginning to suspect that there might be another sort of "distortion away from DMT" structure-activity relationship going on actually, because I also smoked MET this morning and in certain ways actually found the experience more like psilocin than like 4-HO-MET, and they should be on that same level of distortion as well. So, if there is something like that going on, I wonder if perhaps it might actually end up being somewhere between both 4-HO-EPT and 4-HO-MPT? I hadn't actually thought of that until now but that sure would be interesting if true.... Ahh, there are so many potential relationships among these molecules to explore!
Anyway though, regardless of any similarities and differences between this and that, I have definitely noticed that the base tryptamines are often more visionary and lively too. The 4-substituted tryptamines can definitely show me other worlds as well, but it seems like there is more often some sort of detachment from it, whether it is because it's clearly just reflective of myself and more of just a personal trip rather than an interactive one, or because it's just sort of detached in general like watching some sort of visionary movie. I must say though that I am still quite intrigued in what those worlds hold, and these N-propyl-4-substituted tryptamines in particular I think really might have some promise there given that I personally at least find them to already be very hedonistic and visionary to begin with, I suspect that they might really be able to reach their maximum potential in that kind of state. But, further testing will reveal whether or not there is truth to that....
Really cool you made that list Kaleida. If you take requests, I'd love to see how 5-MEO-DMT fits in on that list
Is the number the ratio of measured 5ht2a:5ht2b affinity?
I worry a little about the 5ht2b agonism and heart valve thing a little.
edit: oh.. you couldn't find numbers for 5-MEO-DMT.. I might have data on that tucked away somewhere, I'll try to find it and see if I do.
Thanks, I'm glad you like it.
Here, I'll explain it all a little more....
First, this is the study that contains the data on the 2Cs, mescaline, their NBOMe counterparts, and LSD:
Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs).
Next, here is the one that contains the data on the tryptamines:
Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens.
Finally, here is the one that contains the data on the benzofurans, MDMA, MDA, and 2C-B-FLY:
Pharmacological profile of novel psychoactive benzofurans.
If you will look closely, you will see that the names Anna Rickli, Marius C. Hoener, and Matthias E. Liechti appear in the authors section of all three papers. This is what I mean when I say that I prefer data that comes from the same research teams, because if there is one thing I have learned from years of reading receptor data it's that the numbers for the same drugs at the same sites can vary wildly depending on the protocol, but if you have the same people doing the same kinds of studies over and over again with the intent of creating a universally comparable data set then that seems like the best possible scenario to go with to me. So, I do have plenty of binding data for 5-MeO-DMT, but not by these people. I have seen a couple other things that I believe were by them, with data presented the same way, but it was for things like the cathinones and fluorinated amphetamines, which I didn't think that relevant to this (or to my interests in general). If however you do manage to come across data for 5-MeO-DMT or other psychedelics I don't have listed there by this team, I would love to see it!
As for how the list itself was made, I know you might not be able to see the full versions of all of those studies right now, but look at least at the last one which should be the full version in HTML form. If you scroll down to the binding data, you can see that they tested many receptors, but specifically for 5-HT2A they tested for receptor binding Ki, activation potency EC50, and activation efficacy %, whereas for 5-HT2B they only tested for the last two of those. The data included in all three of the studies is like this, so given that the activation potency EC50 was the best equivalency I could get that was what I used, I just divided the 5-HT2B values by the 5-HT2A values. It would be nice to have direct binding Ki too, but I'll take what I can get. Something I'd consider an important takeaway from this though is that the list probably shouldn't be considered completely exact in its distribution of individual drugs, but the relative flow of different chemical classes and certain outliers probably do have some merit.
And yeah, I worry about the heart valve thing too. If it's any consolation, I know that while Dr. Shulgin did have to have a heart surgery related to this kind of issue late in life, it's worth considering that he favored the phenethylamines which apparently bind about as strongly there as MDMA, and he used them for his entire life and only had that one consequence from it after already making it into old age. This would seem to suggest to me at least that if damage is being done, it might be at least slow enough, especially if you favor indoles, that it's still something you could consider a fair trade for a lifetime's worth of the good psychedelics can do for you. Anyway, those are my feelings about it for right now.
Sweet jesus, very nice post..
Isn't something like 4-HO-MET a demonstration though that we don't really require the 5-HT2B receptor for good and full effects?
Also the possibility of some correlation may be noted: it may be quite hard to make a drug that has nice monoamine effects but no affinity for 5-HT2B because of certain similarities regarding binding sites but that doesn't mean you need 5-HT2B. Interesting that it's necessary for SSRI's but aren't those a very different animal altogether, with the whole blood level build-up super slow onset of efficacy? It's curious, but I don't think it is a sign that 2B may be necessary for the activity of certain recreational drugs based on this, but you could be on to something.
I didn't find 4-HO-MiPT empathogenic but maybe I could see MiPT being considered that way. Probably DiPT a lot more. What do they do on SERT anyway?
I wonder if there are different polymorphs of 5-HT2A in the same individual and that those in the auditory cortex are among the few ones that are forgiving of the bulky di isoprop substitution, I mean possibly DiPT does still bind to other 5-HT2A throughout the brain and may even activate them, but perhaps the specific conformational changes don't tend to lead to the correct downstream pathways (iirc ip3 / plc etc). So could be that it is not even necessarily polymorphism but just a different GPRC complex coupling in say the auditory cortex.
It does appear that the conformation change upon activation just being a bit different can make the difference between producing effect, producing tolerance, etc.
I'm asking a very related question in NSP about why drugs in the same class like this still can have various effect profiles despite not really being known to bind to a different set of receptors.
Not really sure where you went kaleida or that you went away, but thats cause ive been very busy. Good to see all you guys and good to be here.
Haha, thanks, I'm glad you think so!
First, about the 4-HO-MET. Oh yeah, I don't think the 5-HT2B receptor is necessary for the effects of psychedelics at all, including the serotonin release (at least not necessarily). If the old research I recall reading that claims that there is a 5-HT2A receptor involvement in psychedelic serotonin release is correct then I think that could be all that's required to explain why even a selective agonist there could have more nonselective serotonergic empathogenic effects as well. The significance of what I am trying to say though is not just that 5-HT2B receptors could make psychedelics empathogenic, but that they could make them
more empathogenic, the simplest example as highlighted by the list being for instance what people expect from typical phenethylamines vs most tryptamines. When it comes to 4-HO-MET for me for example, I could definitely see it having some of that relaxing euphoria and glow, but compared to something like 4-HO-MiPT I honestly don't find it very empathogenic at all. I've taken 4-HO-MET with some of my closest friends multiple times and each trip I spent most of it wishing I had taken something else and that I could just retreat into solitude and enjoy the trip and introspection. In contrast, I took 4-HO-MiPT for the first time with total strangers and spent the night hugging them and talking about how happy I was to make new friends. As for as I'm concerned, those are in two entirely different categories of experiences! Not to get too heavy into the theorizing either, but if I had to guess, I think I would honestly say that if 4-HO-MiPT does involve more serotonin, 4-HO-MET might involve more dopamine instead, something that seems a lot more fitting with the very different type of euphoria it gives me.
About the SSRIs, it's very true indeed that anything that can be identified as their mechanism of action certainly should not necessarily be immediately thought of as capable of producing immediate recreational effects, if their extremely low abuse potential is anything to go on, but it must also be considered that by those same and other easily found studies it would appear that 5-HT2B receptors are also responsible for the serotonin release and subjective effects in animals of MDMA, which is far more obvious and fast-acting in effect. I think it may be worth considering as well that the therapeutic efficacy of SSRIs which is known to have a slow onset may have much less to do with any level of acute serotonin release than it does with a re-organization of serotonin receptor circuitry, which also according to those studies 5-HT2B agonists appear to cause as well, but that doesn't mean that that serotonin wouldn't be able to cause recreational effects if it were further increased at one time in the right way. I have also seen a few animal studies on 5-HT2B agonists specifically that have noted them to have immediate anxiolytic effects as well, which would appear to further support that notion. I definitely think that it must be a complicated picture overall, but I do truly think there at least could be something real and significant going on here.
I think it's pretty interesting as well that you didn't find 4-HO-MiPT empathogenic, but that you do feel that way about MiPT and DiPT. This seems like it could still be perfectly explainable by this theory to me, but that for instance you might just been in a different baseline level than some of us, making it so that your perfect range of empathogenic to psychedelic effects based on the receptor activities is just not quite reached by 4-HO-MiPT, but on the flip side that could also make it easier for you to get such effects from DiPT than it might be for others, if there is also a ceiling to the range within relatively easy reach. At least, I think that all makes sense, if you get what I'm saying.... I feel that it would be similar to how many people describe 4-HO-MiPT as causing all these beautiful and intense visuals, but I honestly just don't get that many out of it, I find that the other, non-hallucinogenic subjective and physical effects become just too much for me to want to push further at a dose where my visuals and such are becoming strong but still just aren't that interesting yet. It would just be another example of how, in addition to all these molecules being a collage of frequencies all tuned in their own unique ratios, we humans each also begin with our own unique ratios that serve as the basis for how each molecule's alterations build up to subjective experiences in us.
As for the SERT, I'm fairly certain that almost every tryptamine and phenethylamine I've ever seen tested for it has bound to it at some dose, though whether these generally act as inhibitors to any significant degree I can't really say. I'm afraid I am not as familiar with reuptake inhibitor research as I am with psychedelic stuff either, especially without having much personal experience with them I usually don't consider myself to be able to glean much insight from that sort of research.
I definitely get what you mean about the DiPT binding and polymorphisms and all that too, very interesting thoughts. I have thought quite a lot before about what might allow the DiPT molecules to behave that way, and if there are any differences between the receptors in different parts of the brain like that.... It really would be quite fascinating to see more research done on those auditory effects, though I'm sure there are some underway somewhere. Do we actually know for sure yet if they even have anything to with 5-HT2A at all? It really wouldn't surprise me to learn that they do, but just out of curiosity. Also, I'm wondering, do you get those audio effects on any other psychedelics as well? I seem to be one of the more sensitive ones to it, as I have definitely gotten it on DiPT, 4-HO-DiPT, and 4-HO-MiPT, and in retrospect I think I actually had it on the peak of my MiPT trip as well. I find this particularly interesting given the fact that I know there are at least one or two anecdotes of alpha,N,N-trimethyltryptamine having audio distorter effects, and that tail shape overall is obviously quite similar to the MiPTs. I think it would be quite fascinating, especially if it is proven that 5-HT2A is responsible for the audio to effects, to see a broad signalling pathway functional test on a range of alpha-methyl-N,N-dialkyltryptamines and their corresponding derivatives of MiPT with both the free isopropyl carbons expanded much like the alkyls on the nitrogen usually are, and, on the other hand the alpha-methyl group then expanded further to mimic the tail of the regular tryptamines like for the diisopropyl structure. I feel like if nothing else that could definitely provide some unique insight into all of this....
And yeah, I was actually gone after you were talking about becoming busy with life earlier this year and came back I guess just before you started getting back into things here again, so it doesn't surprise me that you missed it. I disappeared while dealing with some unexpected psychological issues that I believe were caused by a convergence of a bunch of different stressful life factors at the time.... It left me feeling a bit manic for a while and really shook me up about a lot of things that were going on in my life, including in multiple ways my substance use. I'm beyond it now, but it took a while to work through all of that.... I'm definitely glad to be back here now and in this again and discussing these things with all you wonderful people.
Very interesting post Kaleida, that's a good amount of thought and insight.
I would just like to say, anyway, that this hypothesis of yours:
"If what this study is saying is true, then the reason that 5-HT2B has appeared to be necessary for the serotonin-increasing effects of drugs is not just because of some regulatory mechanism or whatever, but because it literally is just being activated directly by these drugs and is directly responsible for serotonin release,"
Is already addressed in one of the papers you linked, "
5-HT2B receptors are required for serotonin-selective antidepressant actions" :
"the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT2B receptors, and (iii) a selective 5-HT2B agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT2B receptors. The 5-HT2B receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT2B receptor should be considered as a new tractable target in the combat against depression."
They literally show how genic or pharmacological inactivation of 5HT2B receptors abolishes the effect of SSRIs, and also how a selective 5HT2B can mimic SSRI effects, so it is indeed directly involved in whatever process is going on in the brain leading to increase extracellular serotonin.
From the discussion:
"Based on the results presented herein, the activation of 5-HT2B receptors is necessary for acute and chronic SSRI actions, and chronic stimulation with a 5-HT2B receptor agonist is sufficient to mimic SSRI effects in WT mice. Furthermore, the moderate increase in extracellular 5-HT levels induced by SSRIs in the absence of functional 5-HT2B receptors might be insufficient to trigger behavioral and neurogenic actions. These data, together with the single-cell RT-PCR results showing expression of 5-HT2B receptors in raphe serotonergic neurons, are consistent with a presynaptic action of 5-HT2B receptors mediating the acute and chronic SSRI effects."
Ah, you are very right! Awesome catch, I guess I should read my sources more thoroughly haha. I know I read some of these papers more a while ago, probably not all of them, but even the ones I did were a few years ago now, I really should read up on them again and get some perspective with this newer information.
Yeah, I still had the thought in my head that 5-HT2B agonists were producing SSRI-like effects at least in the moment, but it seems they really do go much deeper into it.... The fact that they show that they can also mimic the chronic effects and even mention how the SSRIs do have SERT-related serotonergic effects that might just not be enough on their own, it really brings everything together.... Man, this is some heavy stuff, I love finding new mysteries of neuropharmacology.
Also, thanks! I'm glad you found it all interesting. :D
While we are on the subject, anyone heard of 4-HO-EPT or 4-HO-MCPT? They popped up and curious to know anything about them...Edit, nevermind, I just found Small & Handy threads for each one. They are novel for sure at this point in time.
Oh yeah, definitely join those discussions if you're interested!
We'd love to have your perspective on these new molecules! I haven't tried the 4-HO-McPT yet, but I am thinking that there's a very strong possibility that I will next weekend now. I have tried 4-HO-EPT twice, and I personally found it quite promising so far.
They make me excited like a 5 year old boy looking at a new BMX, Dyno or GT, way back when they were all the rage in elementary school. Definitely catch you in the Small & Handies for these novelty delights mi amigo!
Not my personal example, but definitely this ^ haha.
4-HO-MiPT gave me one of the best trips I've ever had, I took 30mg of it on the tail end of a DOC trip, after a day spent climbing up a mountain stream over boulders and waterfalls with my good friend. I still intend on writing a trip report about it but it's really hard to explain. It was centered around me, this human iteration, and it was an coalescing of a lot of stuff I had been working on regarding being mindful and as fully conscious of my thought processes as possible. I experienced so many tests of myself that night, so much so that it felt like the universe was guiding me. I have actually applied much of what I experienced/learned on that trip into my daily life, it marked a turning point for me, or rather a level-up I should say as my direction has stayed the same. It was also among the most euphoric and loving I have ever felt. My friends told me I was just radiating peace and bliss and was awesome to be around, that the look on my face was wonderful.
Damn I might spend the evening writing that thing finally, it happened well over a year ago now, I don't want to totally lose it.
Do it! I'd love to read that.
I'll be writing a report tonight too, hehe.... I smoked 35 mg of MET this morning and it was actually pretty darn interesting.
