We recently described that several 2-(2,5-dimethoxy-4-substituted phenyl)ethylamines (PEAs), including 4-I=2C-I, 4-Br=2C-B, and 4-CH3=2C-D analogs, are partial agonists at 5-HT2C receptors, and show low or even negligible intrinsic efficacy at ...
pmc.ncbi.nlm.nih.gov
There's the study in question. Maybe one of the pharmacology nerds can poke some holes in it for us
I'm far from being a pharmacology expert, but I do take a lot of interest in these things. These kinds of studies tend to be very problematic for a number of reasons. Right off the bat, I see that they are testing rat receptors, and my understanding is that rat serotonin receptors are a poor model of the human receptors. I believe mouse receptors are much closer but still quite a bit different such that this kind of work should be done with human receptors as much as possible. Even then, there are many many problems: differences in chemical environments (which is always a problem because the receptors themselves exist in different chemical environments in different parts of the body and brain and may respond differently to the same drug); the multi-functionality of the receptors which is a critical concept for understanding psychedelic action; and even problems with the data analysis itself including the use of non-linear regressions and improper propagation of uncertainties from the data to the key results (uncertainties which can be extremely high).
Generally speaking, I think it's a bad idea to assume any quantitative results from these assays are more accurate than say in order of magnitude. Because each receptor type requires a different assay, it's fundamentally difficult to compare affinities between receptor types for any given drug unless they are dramatically different from one another. Comparing affinities and efficacies for a particular receptor between multiple drugs is perhaps more tractable, but should only be done if they were subject to the exact same assay, like if they were tested as part of the same study. Even then though, a lot of results of this kind in the literature are inconsistent between studies, likely for reasons I just discussed.
If I had to guess from the studies I've seen, I would say that both LSD and 2C-B are relatively weak in terms of serotonin-like effect. For this reason, some people might describe these drugs as "almost antagonists", but IMO this is very wrong because in all likelihood, the baseline activity at the 5-HT2A receptor is quite low relative to the action of the drug at an effective dose. So, even though LSD or 2C-B may induce serotonin-like effects only weakly upon binding to the receptor, there's still enough drug present at an effective dose to induce far more serotonin-like action than occurs at baseline. Comparing the two, I believe that LSD actually has less serotonin-like than 2C-B even.
Of course, serotonin-like action represents only one possible dimension of action at 5-HT2A. Receptor multi-functionality was actually discovered in part because scientists were trying to understand why LSD makes people trip but many other 5-HT2A (partial-)agonists with serotonin-like action do not. It turns out that LSD and other psychedelics act on the receptors in a way that many other ligands including (probably) serotonin do not. This means that even if LSD or 2C-B had literally zero serotonin-like action at 5-HT2A, it would still be incorrect to conclude that they are antagonists because they are actually acting very effectively on the receptor in a more "LSD-like" way.
As to why taking 2C-B first may "smooth out" an LSD trip, the reason may be mostly to do with pharmacokinetic consequences. It's often assumed that pharmacokinetics only impact intensity versus time, but this assumes that the result of activating the receptor is exactly the same regardless of the recent history of activations. In reality, I think that the results of activating 5-HT2A and other receptors vary a lot depending on the recent history of activity at those and other receptors. If I may explain. Two different doses and administration methods might bind and activate 5-HT2A the same number of times, but the effects may be very different if all those activations occur within a short period of time versus being spread out over a long period of time. On the basis of this reasoning, we should expect different effects from administering the same drug using different ROAs, regardless of whether an attempt is made to find "equivalent" doses. Similar modifications of qualitative effect can be achieved by simply splitting up an oral dose over time, like taking half and then waiting 30 minutes to take the other half. This last point of mine is the one that many pharmacologists would probably push back on because a lack of evidence, but in my view, the only reason evidence is lacking is that the necessary experiments haven't been done yet. I have strong philosophical priors that lead me to believe this is likely true.
Oh---one other possibility re 2C-B softening and weakening an LSD trip is that in the brain at least, action at the 5-HT2B receptor enhances serotonin release in a major way, and any enhancement of serotonin release induced by 2C-B could lead to more competition versus LSD at the 5-HT2A receptor.
All these points should illustrate that the pharmacology of these things is very complicated leading to results that can be surprising and unintuitive when interpreted using overly simple models. Personally, I think it's time for pharmacology as a field to move on from the whole agonist/antagonist/partial-agonist paradigm which just causes unnecessary confusion.
My nose would never be the same again.