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.