Well, given the lack of between-study reliability in assessing EC50 values for many psychedelics, I'd be skeptical of trying to carve distinctions beyond partial agonist/full agonist. Also, this appears to be a case where selectivity for signaling cascade matters a lot. IIRC, 2ci is somewhat selective for the PLC-mediated pathway, which results in calcium ion release, over the PLA2 mediated pathway, which results in AA release, the latter proving key for psychedelia (
I find myself referring to this handy summary often).
Yeah, I suppose you're right about the different studies. I've been reading a lot about that lately too, the functional selectivity.... I also don't think it's that simple though. I'm curious: what's the deal with the PLD? Why does no one ever seem interested in it?
Whew...maybe, but I'm not sure if focusing on comically large doses is a good way to try to catalogue differences between compounds.
Well, I may be alone in this thinking, but I actually think that it's one of the best ways. In my experience and extrapolating from those of others', it seems to me that the lower the dose is the more similar all psychedelics are, which makes it harder to figure this kind of stuff out in my opinion.
Ummm...LSD didn't appear in the study that I linked. Referring again to the chart I was thinking of, I was misremembering completely, and LSD in fact lacks strong effects at 5ht2b. My apologies.
Here's the chart I was thinking of:
The only study I saw you link was Psychedelics and the Human Receptorome, was it not? That's the one I looked at that mentioned LSD's activity at 5-HT2A to be stronger than 5-HT2B.
That chart you posted here is what I normally use for thinking about LSD.
Just seems like a congenial conversation to me. I'm enjoying your posts a lot.
Sorry if I've appeared argumentative.
No, you're fine!
I've just had people tell me thought I was being argumentative before when I really wasn't.... I worry that I come off that way a lot.
This is often due to differences in methodology, very often choice of 'hot ligand', which indicates binding via its displacement by the experimental compound.
That makes sense.... Honestly, all this talk is starting to make me lose a lot of faith in any sort of binding studies lol.
I'm not sure that I understand you here though. If our hypothesis is that 5ht2b agonism tends to cause delirium (or any other spectrum of effects), then we'd need at least two points of comparison, a psychedelic with potent binding and reasonable efficacy at 5ht2b and another without, to determine what's causing which effects. If we only have one side of the comparison, we will face difficulty adjudicating what types of activity induce which effects. Additionally, entactogens are pretty 'dirty' comparison cases, as 5ht release of course activates 5ht2b in addition to causing a flurry of other effects. IIRC, though, cathinone series entactogens lack much affinity for 5ht2b (and vmat2, oddly) (note: I could easily be recalling such quite incorrectly, but it follows from known SAR). And then 5-meo-dmt is problematically distinct from other psychedelics, affecting 5ht2a rather weakly.
I also think that the derived dependent measure in the PlosOne paper doesn't work too well for compounds lacking potency by weight of dosage, as indicated by a couple of results lacking face validity, eg, the claim that MDMA lacks significant activity at SERT.
I get what you're saying, but I still think that those actually provide us with great examples.... Even if serotonin releasers activate widespread serotonin receptors, it doesn't mean they won't activate 5-HT2B significantly stronger still than the rest if they're selective for it. And by comparison to 5-MeO-DMT, it actually works great because both represent drugs that are weak at 5-HT2A but having opposing potencies at 5-HT2B. 5-MeO-DMT also acts as a serotonin reuptake inhibitor, so there is at least some level of widespread serotonin release going on there, too.
Good point, though tracing out downstream effects of 5ht2b agonism and ACh antagonism, it should become clearer which question becomes most pertinent; the unifying question is, "At what point do the downstream effects of 5ht2b agonism and ACh antagonism converge, if at all?" The difficulty underlying all this discussion is that the brain involves radically intensive and extensive cross-connectivity, so one needs to take care tracing downstream mechanisms to avoid running into apparent conclusions that everything causes everything else.
I've faced that problem quite a lot; I usually try not to go one or two lines deeper than the original receptor activation for that reason. I feel that I've already provided one reasonable possible mechanism by which they converge, but there are certainly other options as well. But what do you think about the 5-HT3/nicotinic acetylcholine thing? That's a pretty quick and easy relation that I feel they have.
I also think that we need greater conceptual clarity when describing the subjective effect of interest. Do we mean purely visual delirium, as in hallucination of realistic objects/people/scenes, etc., seemingly disparate from the proliferation of patterns typical with psychedelic visuals? Or is this linked to a signature metal effect of interest? Now, if your point of departure is serotonin syndrome as you indicated, this seems pretty important, as severe confusion is one of the most common symptoms of SS.
Errr, somewhere closer to the first one, but not quite, but also a little of both.... I was referring more to the well-structured hallucinations when I say delirium, but I don't think that calling them disparate from the patterns of psychedelics would be right either. Just like both psychedelic patterns and deliriant hallucinations do on their own when mixed with the real world, they blend seamlessly with each other, and some lines can certainly be blurred in their beautifully complex interweaving. It would really be more of a measure of which psychedelic hallucinations in total tend more toward the dream-like structure as opposed to just the chaotic abstractions that don't really form entire realistic scenes. (Note that when I say "realistic" I am including things like DMT breakthroughs.) So it's still pretty close to what you said, but I just wanted to throw that note in.... As for the mental effect, it's not the focus of what I was saying but I don't think it can be discounted either. I think the line sort of blurs between the hallucinations and the mental effects when that point of delirium is reached.
However, continuing on my one theory before of 5-HT3/nicotinic interaction, I think it would be important to consider the potential different effects on acetylcholine that different drugs can have.... As (I believe) I mentioned before, one way I could think about it would be to suggest that lower muscarinic activity could cause the mental delirium while higher nicotinic activity could cause the well-structured hallucinations, something which I think could be at least somewhat supported by the tropane-enhancing effects of scopoletin. If that was the case, and if I was actually on to something through the 5-HT3/nicotinic thing, then it would be significant to mention that serotonergics might be directly activating the hallucinations while bypassing the delirium, depending on, like I said, their different effects on acetylcholine. We already know that serotonin itself lowers acetylcholine in the nucleus accumbens, so that would account for the muscarinic deactivation and delirium. But do we know that about psychedelics?
Do you get what I'm saying?
Just to add my bit in to the conversation: 25C visuals are nothing like deliriant (diphenhydramine) visuals. With 25C things were flashing red and blue and all the lines around me were bending (the shape of everything was morphing) and music sounded pristine. On diphenhydramine I saw the floor and things around me turn into snakes and spiders and come towards me. I also heard plenty of sound-based hallucinations, always voices. Completely different.
Your description of 25C visuals sounds very similar to one of my better diphenhydramine experiences, aside from the red and blue flashing. Like I've said before though, I'm not trying to make an
exact comparison, and I think it would be counterproductive to do so.... Expecting completely the same hallucinations to appear would be taking it too far. Even deliriants differ from one another. Spiders are a common report on diphenhydramine, but I hardly ever hear about them on tropanes. I would go so far as to say that I hear about them on mescaline and MDMA more than datura.
I do appreciate the feedback, though. I'll take all the anecdotes I can get with these.
