Strongest and weakest cognitive effects?

[bindingaffinity]

I'm curious about which (classical/serotonergic/5-HT2A agonist) psychedelics produce the strongest array of cognitive effects (a.k.a. "headspace" or "mindfuck") when taken in safe dosages. From what I've gathered (by reading a whole lot of threads on Bluelight and elsewhere), LSD and mushrooms are generally agreed to have very strong, and possibly the strongest, cognitive effects (outside of substances like DMT and 5-MeO-DMT that usually entail a complete breakthrough experience). Notably, whole mushrooms are reported to have stronger cognitive effects than synthetic psilocin, psilocybin, or psilacetin (there seems to be some speculation that this is due to other mushroom alkaloids), and LSD is reported to have stronger cognitive effects than most other lysergamides.

On the other hand, it seems like the weakest cognitive effects come from the NBOMe and NBOH series, especially the 4-halogenated series. I find this very intriguing in the light of the high selectivity for 5-HT2A of the N-benzyl-phenethylamines, especially 25I-NBOH, which is extremely selective for 5-HT2A over even the very similar 5-HT2C. (Although I've also read plenty of trip reports on NBOMes and NBOHs where there was a strong mindfuck component, these tended to be in the strong to unsafe dose range.) Similarly, the relatively selective phenethylamines are typically described as having weaker cognitive effects than the comparatively promiscuously binding tryptamines.

So my question for you all is, which psychedelics have the strongest or weakest (or just notably strong/notably weak) cognitive effects? Are there any RCs that are noted for uncommonly strong cognitive effects, or any naturally occurring psychedelics with uncommonly weak cognitive effects?

(By cognitive effects, I'm thinking of things like thought loops, time distortions, altered memory, altered thought patterns, analytical or introspective thoughts, existential realizations a la William James on nitrous oxide, delusions, insights, confusion, and acute mental hyperclarity. Of course, it's also possible that by shoving a whole spectrum of effects under one rubric I'm oversimplifying this greatly...)

 

[Volsam]

Yes, it seems that the more you move from "classical" psychedelic structures of Mescaline, Psilocybin and LSD, the more narrow resulting effects will be.

There are few exceptions: 4 subs MiPTs, METs and DETs for tryptamines, as well as ETH-LAD for lysergamides and 2C-P (and 2C-E which I have not tried yet) and DOC for phenethylamines - all may be considered just as wholesome, deep and unique as classic ones, at least in my opinion. :D

I totally agree on 25I-NBOH - it felt just bizzare compared to everything else I have ever tried, felt more like a strict lab research tool, not something humans should be taking for fun or mystical revelations.

 

[Pfafffed]

I've only explored around forty different psychedelics, so there are others here that can probably give you a better idea.

I'd say that 4-HO-DMT has the strongest headspace of the natural psychedelics, but 4-AcO-DMT is a quite comparable synthetic. 5-HO-DMT, however, has one of the lightest headspaces I've ever experienced, and it's natural.

The second strongest headpiece I've come across is 2C-E, and the weakest I've come across is 4-MeO-MiPT, both synthetic. I've never ventured into NBOxs, so I can't comment there

 

[Hexagon Sun]

Interesting question. I fail to see the natural/synthetic opposition, thought. We could find a new plant/cactus or funghi that have 2c-e or a nbome. So the diference is merely academic.

 

[bindingaffinity]

I don't see any compelling reason why natural psychedelics would have different effects, as a class. It's possible that (the currently known) naturally occuring compounds in the phenethylamine and tryptamine classes are constrained to look more like naturally occuring monoamine neurotransmitters, given that their biosynthesis is similar (start with one of three basic amino acids---phenylalanine, tyrosine, tryptophan---and go through a series of hydroxylation, O-methylation, and decarboxylation steps). As a result, they might bind more promiscuously to monoamine receptors, creating a deeper range of effects. This is all total speculation though, which I don't really believe. The other hypothesis I have is that congeners of psilocin/psilocybin or mescaline add to the mushroom or cactus experience in a way that's not experienced with pure psilocin/psilocybin or mescaline, respectively. This is also pure speculation but at least it's pure speculation that follows Shulgin's own reluctance in grouping pure psilocin/psilocybin/psilacetin with whole mushrooms.

I think a much better explanation for why natural psychedelics are believed to have qualitatively different effects than synthetics lies entirely in the eye of the beholder. A lot of effects of psychoactive substances may be socially mediated (although most of the research I've read about this focused on socially mediated effects of alcohol specifically), and the way our culture in particular views nature and natural substances might lend itself to deeper or more spiritual trips when taking a psychedelic of known natural origin. It's striking that many people who don't seem to have this bias rate mescaline a lot lower in overall strength of cognitive effects (c.f. the old "psychedelic scale" thread where some users rated it on par with 2C-C or 2C-D). 5-HO-DMT is also another very striking counterexample.

Of course, plenty of compounds previously believed to be synthetic have turned out to occur in nature as well. Tarragon produces (very low concentrations of) temazepam, potato plants synthesize (similarly low amounts of) diazepam, and the millipede Glomeris marginata uses methaqualone-based compounds as a chemical defense against predators.

 

[pupnik]

too general a question.
every sensation is already a cognitive effect
every perception is subject to a cognitive effect,
every contextual cue is subject to a cognitive effect,
every memory is subject to a cognitive effect,
every focused idea is subject to a cognitive effect.
every attitude is subject to a cognitive effect, anxious or calm
every feeling, every reflex, every mood,

various parts of the brain deal with senses
various parts of the brain deal with mood
many of the other mental factors are spread through multiple regions of the brain.

the various 5HT1a,1b,2a,2b etc. receptors are also positioned in multiple locations of the brain, so agonists to these will introduce, the psychedelic effects to these regions with more or less general sympathomimetic stimulation effects.

SO we should find variance in the quality of trips from different substances, but the basics have not yet been studied and compared in dose response testing:
eg we could use a dose response curve for the following for each substance:

• Audio enhancement magnification and extension of sounds (I found NBOMES most extreme here> shrooms > LSD > Weed)
• Visual enhancement distortion and elaboration (hallucination) (I found SALVIA > LSD > Shrooms > Weed > NBOME)
• MOOD anxiety vs tranquility (NBOME most anxious then Weed > SALVIA > LSD > SHROOM which was the most calm)
• Ideation extension (SALVIA>WEED>SHROOM>LSD>NBOME)
• Perception extension -increased alacrity (LSD>SHROOM>NBOME>WEED>SALVIA)
• Perceptual distortion -increased disruption (Salvia>shroom>NBOME>LSD>WEED)
• Poetic synthesis of ideas (spirituality?) (salvia>shroom>LSD>weed>NBOME)

I am sure that this may vary between people as well as by dosage since we may have different distributions and densities of receptors.

 

[bindingaffinity]

You're definitely right, trying to separate out several loosely related spectra of cognition into a single box and labeling it "cognitive effects" was a mistake. Thanks for providing those scales, I have to comment that I'm surprised how low you have ranked NBOMes in the visual dimension because most reports I've read say they're highly visual. But of course everyone's experience is different. I'm curious how you'd locate 5-MeO-DMT, mescaline, and MDA on the above scales (choosing those 3 in particular because they are psychedelics whose binding affinities I have on hand, which all have relatively low binding to 5-HT2A relative to other targets). I'm also wondering if you have a scale for, for instance: degree/occurrence of time dilation, propensity for thought loops, potential for ego death, potential for psychotherapeutic use (ok that one also may be too broad), or changes in thought patterns similar to the formal thought disorder of schizophrenia or schizoaffective disorder (that may also be a couple dozen phenomena jammed into a single label).

 

[pupnik]

As for NBOME's and visual, they do have a strong visual effect, but it is like looking through a broken lens or fractured prism, which is nice but not significantly more impressive to me than similar effects from lsd etc. while the auditory effects were shocking, and I did hear loud mechanical sounds on it which have no foundation IRL - so completely hallucinatory on moderate dosages.
I never went higher than one tab 1000 mics of nbome of any kind.

So - since I don't have first hand experience with Mescaline or 5-MeO anything I cannot really put them into any of my "scales" and my MDA experience is too limited, I liked it the way I would like an amphetamine, and feared it and my heart rate the same as well.

Time Dilation: all of the psychedelics are doing time dilation AFAIK in a dose dependent way - this is the primary effect, but we do not notice the clock going backward or jumping like deja vue untill the effect is quite extreme however, each hallucinatory experience or even color enhancement itself is actually a time dilation: e.g. the color of one image in a moment is overlaid into the color of the next momentary image, and they add together in chroma and intensity. All aspects of frame stacking, and time looping relate to this primary effect of slower fading signal pulse trains due to psychedelic dose.

Ego death: this term is defunct. not even worth arguing about.

Derealization: may relate to ego loss but directly refers to the disappearance of reality on all channels - the intensification of dream like states - and the onset of black out or white out. Extreme Time Dilation or frame stacking will cause this.

Loops: are interesting but they are also largely TD or FS triggered and sustained, but they involve habits engaging as response to a perceived event, and then often agonizingly re-triggered as the trigger signal has not yet fully faded, and then the trigger signal becomes bound to the onset of the response cycle and this itself re-triggers the response, and it seems endless due to the reverberant time dilation.

I think lsd particularly can be accurately dosed and if the psychiatric guide is familiar with it large doses and courses of micro doses as follow up can be excellent for a variety of anxiety or depressed cases that need relief from painful cycles. (just me talking, no evidence to back up my statement except personal experience)

 

[Ziiirp]

There is a book "Psychedelic information theory". It is quite metaphysical but pretty interesting and contains data for the distinct perceptive effects for targeting of each of the 5ht-receptors (and others). I lost the book.

Ah the ebook is now free :

http://psychedelic-information-theory.com/pdf/PIT-Print-Web.pdf

Page 63 following should address the topic.

 

[TheAppleCore]

Difficult and somewhat vague question, as others have pointed out, but I'll answer just for fun. I'm far more experienced with tryptamines than any other class, so I'll just circumscribe my answer within that category for now.

* 4-AcO-DMT is the first that comes to mind, for the strongest cognitive effects; it's very disorienting, somewhat like dissociatives, which is why it's one of my least favorite psychedelics.
* 4-AcO-DET is quite powerful as well, but in a different and more enjoyable way for me, causing things like strong synesthesia, and classical religious awakening type experiences, but in a way that feels somewhat depersonalized and "dreamy" compared to other psychedelics.
* MiPT is at the weaker end of the spectrum for me, feeling almost like a cross between a psychedelic and a stimulant.

I should also note that I have tried 25I- and 25C-NBOMe, and they were cognitively "light" in much the same way as MiPT. I suspect that both MiPT and the NBOMe phenethylamines are selective for some of the same pharmacological targets. But then again, MiPT was totally devoid of visuals.

 

[bindingaffinity]

Thanks all for sharing your experiences and information and indulging this very poorly-defined question.

TheAppleCore, did you ever write a TR on MiPT? Your description sounds familiar to me for some reason, but if you did I can't find it.

I ask this question because in part I'm trying to figure out what targets and structures might make different psychedelics subjectively prone to more "deep" or "shallow" experiences. Obviously I'll have to refine the questions I'm asking a lot more before even being able to collect enough data on the subjective effects to start looking for patterns.

 

[TheAppleCore]

Thanks all for sharing your experiences and information and indulging this very poorly-defined question.

TheAppleCore, did you ever write a TR on MiPT? Your description sounds familiar to me for some reason, but if you did I can't find it.

You're welcome! You're probably thinking of this post. I never wrote a proper trip report for MiPT.

I ask this question because in part I'm trying to figure out what targets and structures might make different psychedelics subjectively prone to more "deep" or "shallow" experiences. Obviously I'll have to refine the questions I'm asking a lot more before even being able to collect enough data on the subjective effects to start looking for patterns.

Kaleida and I have been bandying around a pet theory that the heavily cognitive effects of psychedelics are largely triggered by 5-HT2A signaling through phospholipase A2, whereas phospholipase C pathway is responsible for stimulant-type effects, including things like increased reward salience, and when pushed far enough, hallucinogenic effects resembling stimulant psychosis. The latter are what I ascribe to MiPT and the NBOMes. She's the one who's done most of the research behind this, but based on the data she's shared with me, this seems to hold up with my experience so far.

Of course, that's just one piece of the puzzle, and things like binding affinities to all the various 5-HT receptor subtypes would also play a role...

 

[bindingaffinity]

Kaleida and I have been bandying around a pet theory that the heavily cognitive effects of psychedelics are largely triggered by 5-HT2A signaling through phospholipase A2, whereas phospholipase C pathway is responsible for stimulant-type effects, including things like increased reward salience, and when pushed far enough, hallucinogenic effects resembling stimulant psychosis. The latter are what I ascribe to MiPT and the NBOMes. She's the one who's done most of the research behind this, but based on the data she's shared with me, this seems to hold up with my experience so far.

Of course, that's just one piece of the puzzle, and things like binding affinities to all the various 5-HT receptor subtypes would also play a role...

Fascinating! Do you have data you can share about the functional selectivity of different psychedelics for these two pathways? I admit it would surprise me a little of the NBOMes were entirely recruiting PLC, because of the old data about lisuride having strong 5-HT2A agonist activity through the PLC pathway.

I'm also wondering how much dopamine receptor agonism plays a role specifically in lysergamide effects. I've seen several drug discrimination studies in rats where selective D4-agonists substitute partially or completely for LSD, especially if the training was done after some delay after administering the LSD. Similarly, there seems to be a robust result that 5-MeO-DMT stimulus in animal studies is related to 5-HT1A agonism. But it's hard to tell how much animal studies about subjective effects will ever carry over to humans.

 

[Kaleida]

Fascinating! Do you have data you can share about the functional selectivity of different psychedelics for these two pathways? I admit it would surprise me a little of the NBOMes were entirely recruiting PLC, because of the old data about lisuride having strong 5-HT2A agonist activity through the PLC pathway.

The psychedelics currently in existence and used by humans, incuding the NBOMes, are generally not that selective; it's not a question of whether or not they entirely recruit PLC or PLA2, but of how much they recruit both relative to one another.

For example, this study shows the following ratios of arachidonic acid (PLA2 signaling) to inositol phosphate (PLC signaling) release after this given set of psychedelic substances:

AA/IP

2C-E (0.0845)
DOC (0.2771)
2C-T-2 (0.2911)
2C-C (0.3466)
DMT (0.9665)
2C-D (1.0552)
LSD (3.8258)

It also claims that 2C-I was found to activate IP release strongly like the other psychedelics, but only did AA release very weakly, so much so that they didn't even measure its binding affinity. In addition, before considering this all this, you also have to note that serotonin is also on the list, with a value of 1.8140. How could this be? Well, it must be noted that there are actually multiple 5-HT2A receptor pathways tied to PLA2 activation, one being by Gα12/13 proteins and the other being by Gαi/o proteins, the latter of which has already been shown to be activated by LSD but not lisuride. For me, there are two important implications to consider here because of this: first of all, if serotonin is truly "non-psychedelic" in the way that lisuride seems to be, it's possible that it also does not work through the Gαi/o pathway and is instead producing its arachidonic acid release primarily via the Gα12/13 pathway, and second, if that's the case, it means that even though all these psychedelic pathways may indeed work through Gαi/o, they may also work through Gα12/13, and therefore their arachidonic acid release must be taken with a grain of salt, because theoretically only part of it may actually relate to the more truly psychedelic effects of 5-HT2A receptor activation. Of course, this is on top of the fact that other variables, such as the efficacy at activating each pathway, also come into effect on top of the affinity ratios and such, so really the whole thing should be taken with a grain of salt anyway, but with that all in mind, I don't think it hurts to theorize a bit.

So, what we're theoretically looking at here seems to be a spectrum that defines 2C-E as being the most heavily mentally psychedelic compared to any stimulating effects, followed DOC, 2C-T-2, and 2C-C being a bit more stimulating than 2C-E and therefore less mental but still closer to its end of the spectrum, then DMT and 2C-D being about in the middle, followed by LSD being particularly stimulating, but, remember that, with the possible exception of 2C-I due to its low PLA2 efficacy, all of these molecules have the full potential to be both very mentally psychedelic and very stimulating, it's just about the ratios of effects from another, so you can't say "Oh, well I get lots of stimulation from 2C-E, and lots of mental effects from LSD...." Of course you do, because all of these drugs work through both pathways. But isn't 2C-E known to be a particularly heavy and often neutral trip, whereas LSD is particularly rewarding and cognitively stimulating compared to many psychedelics? I think there's some observable order to it. Likewise, I think it makes sense that DMT might be particularly intense due to it having a nice balance of both effects for the tryptamine world, but then you've also got 2C-D in the same category, which may be a hard to grasp for some, but I honestly think that makes perfect sense in the phenethylamine world since it is known to be a particularly cognitively stimulating 2C as well; this to say again, that, we're obviously missing a lot of information and this should all be taken with a grain of salt, but yet, there does seem to be at least some logic to it that does correspond to commonly achieved recreational effects of these psychedelics, so I think it's a useful preliminary model at the least.

Also, for the record, while I'm having a little trouble digging up the old studies right now, everything I've seen suggested to me that psilocin is likely pretty strongly selective for PLA2, even more so than 2C-E, which I also think fits, whereas many synthetic tryptamines seem to be much less selective in their actions, which I tend to think is a plausible reason for why many synthetic tryptamines feel more LSD-like than psilocin does, or, alternatively, why they feel more phenethylamine-like for the same sort of reason that LSD is often said to combine both tryptamine and phenethylamine elements. And I could go more into that but I don't really have too much time right now.... If you have any questions feel free to ask though, I can try to dig up more sources and examples later when I've got a better opportunity.

So, as for the NBOMes, assume that they activate both pathways at relevant dosages, because most psychedelics do. Furthermore, assume that they're all different from one another, and you can't just say "this is what NBOMes do" as a blanket statement. Nonetheless, based on what I've read so far, I wouldn't be surprised if they're somewhat biased towards PLC as many phenethylamines seem to be at least a bit relative to the classic tryptamines, possibly producing their more readily achievable stimulant and psychotic effects, whereas the more classically mental headspace some people get with much larger dosages of them could probably relate to the PLA2 pathway starting to make more of an appearance. That's just one idea, anyway. I haven't actually taken any NBOMes myself so I can't really theorize about them beyond that.

I'm also wondering how much dopamine receptor agonism plays a role specifically in lysergamide effects. I've seen several drug discrimination studies in rats where selective D4-agonists substitute partially or completely for LSD, especially if the training was done after some delay after administering the LSD. Similarly, there seems to be a robust result that 5-MeO-DMT stimulus in animal studies is related to 5-HT1A agonism. But it's hard to tell how much animal studies about subjective effects will ever carry over to humans.

Dopamine receptors definitely contribute to lysergamide effects, though how importantly is still up for debate for sure. Most human studies I've seen so far seem to suggest that most all of the significant effects of LSD can be blocked by a 5-HT2A receptor antagonist. When it comes to psychedelics in general, so far I tend to assume that everything outside of 5-HT2A is more modulatory than crucial, though I'm sure those modulatory effects can be very real and significant in their own ways. However, I wouldn't put much stock in what animals think are "similar" to LSD myself, especially not in the later phases which in my experience definitely are less psychedelic overall. Rats aren't as discerning as humans and don't even really know what they're looking for in the first place, I've definitely seen things like cocaine substituting for ketamine and heroin substituting for THC and so on and so forth.... Those things don't mean too much to me anymore.

 

[chompy]

I can only tolerate mushrooms. A good trip or a bad trip will cure my depression/anxiety for a good few months. Haven't done LSD so I have no experience with that. 2c's just make me depressed and feel strange.

 

[bindingaffinity]

Thanks for the links and info! Lots of good reading for me to cover.

It also claims that 2C-I was found to activate IP release strongly like the other psychedelics, but only did AA release very weakly, so much so that they didn't even measure its binding affinity. In addition, before considering this all this, you also have to note that serotonin is also on the list, with a value of 1.8140. How could this be? Well, it must be noted that there are actually multiple 5-HT2A receptor pathways tied to PLA2 activation, one being by Gα12/13 proteins and the other being by Gαi/o proteins, the latter of which has already been shown to be activated by LSD but not lisuride. For me, there are two important implications to consider here because of this: first of all, if serotonin is truly "non-psychedelic" in the way that lisuride seems to be, it's possible that it also does not work through the Gαi/o pathway and is instead producing its arachidonic acid release primarily via the Gα12/13 pathway, and second, if that's the case, it means that even though all these psychedelic pathways may indeed work through Gαi/o, they may also work through Gα12/13, and therefore their arachidonic acid release must be taken with a grain of salt, because theoretically only part of it may actually relate to the more truly psychedelic effects of 5-HT2A receptor activation. Of course, this is on top of the fact that other variables, such as the efficacy at activating each pathway, also come into effect on top of the affinity ratios and such, so really the whole thing should be taken with a grain of salt anyway, but with that all in mind, I don't think it hurts to theorize a bit.

Do you happen to know if both of the PLA2 pathways are activated by the 5-HT2A/mGluR2 dimer? For mGluR2 itself, I could only find information saying that it activates Gαi/o. If that's the case, then perhaps mGluR2 antagonism has as much to do with the psychedelic effects as 5-HT2A itself does. But I'm just spitballing here, I don't know much about mGluRs.

Dopamine receptors definitely contribute to lysergamide effects, though how importantly is still up for debate for sure. Most human studies I've seen so far seem to suggest that most all of the significant effects of LSD can be blocked by a 5-HT2A receptor antagonist. When it comes to psychedelics in general, so far I tend to assume that everything outside of 5-HT2A is more modulatory than crucial, though I'm sure those modulatory effects can be very real and significant in their own ways. However, I wouldn't put much stock in what animals think are "similar" to LSD myself, especially not in the later phases which in my experience definitely are less psychedelic overall. Rats aren't as discerning as humans and don't even really know what they're looking for in the first place, I've definitely seen things like cocaine substituting for ketamine and heroin substituting for THC and so on and so forth.... Those things don't mean too much to me anymore.

Yeah, I don't take discriminative stimulus studies in animals all that seriously ever since I saw one showing that fluoxetine substituted for cocaine in pigeons. I still think there's something to them, but that "something" may only be about differences in the roles these targets play in animal vs human cognition. As for stuff like heroin substituting for THC, I think it's very easy for these studies if poorly designed or implemented to train animals to respond if there's any drug administered, rather than a drug similar to the training stimulus. I may need to start compiling a list of discriminative stimulus and related studies in humans to see if they're any better on average. The results I've seen from those studies seem a lot more reasonable, especially because you can actually ask humans to rate drug effects on scales of, e.g. stimulation vs. sedation, euphoria vs. dysphoria, et cetera. Then again you could probably get similar results from data mining trip reports, applying sentiment analysis and similar tools... maybe I gotta start doing that.

 

[bindingaffinity]

I keep coming back to the idea of rationally comparing psychedelic effect profiles, in particular to try to find what the most suited psychedelics for a particular application might be. Departing from the dubious framing in the OP of bundling all cognitive effects together, here are some different kinds of effects that I've noticed in my personal experience, and the substances that manifested them the most:

• Empathy, perspective-taking - 5-MeO-EiPT
• Feelings of unity and transcendence - 2C-B-FLY
• Visual geometry - 4-HO-MET, DOC
• Visual enhancements or alterations (tracers, drifting surfaces) - 4-HO-MET, 2C-I
• Formal thought disorder - DOC, 2C-I
• Lucid thinking - 4-HO-MET, DOC (oddly enough this one seems to vary during the trip from disorganized to lucid thoughts)
• Perceived intoxication (euphoria, giggling, perception of impairment) - 5-MeO-MiPT
• Emotional amplification and catharsis - 4-HO-MET
• Thought loops and short-term memory impairment- DOC, 2C-I
• Somatic euphoria (body high, pleasurable physical sensations) - 5-MeO-MiPT, 4-HO-DiPT
• Somatic discomfort - 5-MeO-MiPT (towards the end of a trip), DOC, 2C-I
• Somatic transparency (lack of body load or strong body high) - AL-LAD
• Sense of wonder and curiosity at the outside world - 5-MeO-MiPT, 5-MeO-EiPT, DOC

Note that my experience is limited to a relatively short list of substances, several of which I haven't tried all that much (in particular I have one experience with each of 2C-B-FLY, AL-LAD, and 4-HO-DiPT). As I gain more experience I'll hopefully write these things down somewhere... I have a large chunk of experiences that I never wrote TRs of any kind for, and another sizeable chunk that are stored in an obsolete file format on a dying hard drive.

Also, I'm a bit of a hardhead and don't have much experience with the classic entheogens (such as mescaline, mushrooms, LSD, or DMT), so there are a wide range of effects such as entity contact, experiencing another world, psychotherapeutic breakthroughs, experiences that profoundly alter spiritual or philosophical outlook, etc. that I simply have not experienced on classical psychs yet (although I have had those all on my #1 fave substance, methoxetamine).