Psychedelics aren’t just serotonin (or dopamine) agonists
Maybe you already know that some psychedelics aren’t just serotonin agonists. Pharmacology nerds have been mentioning for decades that LSD is a dopamine agonist. But that’s only the beginning. It turns out other classes of receptor, such as the α₂-adrenergic receptors, are also very likely relevant. But nobody has paid much attention to this until recently.
Psychedelic research has been dominated by the 5-HT2A receptor hypothesis since the connection was tentatively made by Glennon (1984). Afterwards there emerged a stronger logic: if study participants are first given a drug (ketanserin) that blocks the 5-HT2A receptor, they won’t experience hallucinogenic effects if they then take psilocybin and LSD. So 5-HT2A agonism must be “how psychedelics work”, right?
Okay, first, what’s “5-HT2A”? The 5-HT is just short for serotonin (a.k.a. 5-hydroxytryptamine), and 2A just identifies one type of receptor that serotonin binds to. There are at least 14 types of serotonin receptor, and they’ve been associated with all sorts of different physiological and psychiatric effects.
Each receptor subtype may be expressed more in one part of the body than another, to serve different local roles. They are not limited to the brain. There’s a meme that 95% of the body’s serotonin is in the enteric (gut) nervous system, but it’s also important that most of the serotonin receptors in the gut are of certain types (mainly 2B, 3, and 4) with gut-specific roles.
Serotonin itself has affinity for all of its receptors, and activates them with high efficacy when it’s around to do so. But other substances that bind to serotonin receptors may have affinity for some types but not others. When binding to a given type of receptor, a drug may have full efficacy at activating it, but might also have 1) only partial efficacy, 2) no efficacy, but still block the efficacy of serotonin or other drugs that would otherwise bind,1 or 3) inverse efficacy, causing an effectively opposite effect to what an agonist like serotonin would produce, downstream. Here are a couple of examples:
The anti-migraine drug sumatriptan binds to the 1B and 1D types more than any of the others (it’s selective for them) and so it specifically causes blood vessels in the brain’s meninges to contract. It typically does not cause hallucinations.
The antidepressant trazodone is both a partial agonist of the 1A type, but also an antagonist of 2A, 2B, and 1D.
A 2025 study by Jain et al. did a deep dive to quantify the efficacy of 41 different psychedelics at whichever of 318 different receptors they were found to have affinity for. They found that 5-HT2A was by no means the sole target. In particular, some psychedelics have efficacy at a broad range of receptors. One class in particular where efficacy was broadly found, but which has traditionally been neglected, is the α₂-adrenergic receptors. Adrenergic receptor activation is known to alter the response to activation of serotonin receptors in animal models, so we might expect that two psychedelics that share the same 5-HT2A efficacy, but differ in efficacy at one or more α₂-adrenergic receptors, might differ in their subjective effects.
A couple of science journalism posts were written in response to Jain et al. 2025, in the usual tone of look at this new discovery! but without adequately qualifying the claim against the history of the field.
“Psychedelics aren’t just serotonin/5-HT2A agonists” is not a 2025 discovery, just one that had largely been neglected before. The original 5-HT2A mechanism paper (Glennon, 1984) didn’t claim that 5-HT2A or even serotonin receptors in general were solely responsible for psychedelic effects, just that there were high correlations with drug discrimination measures in rats, and rough human dose estimates2. They concluded that the mechanism “involves [5-HT2A]-related events”. The activity of LSD at dopamine receptors has been known since at least 1975. And most significantly, Ray 2010 explicitly quantified how strongly different psychedelics bind to a bunch of different not-serotonin receptors.3
The fixation on the 5-HT2A receptor came later. It’s worth mentioning that David E. Nichols, one of the senior authors on the 5-HT2A hypothesis papers and a leading figure in psychedelics research, is also one of the senior authors on Jain et al. 2025. So this isn’t exactly a rift in academia, or something.
Of course there is still variation between different psychedelics in terms of the specific receptors they bind to, and the overall breadth of their receptor binding (or promiscuity). For example, lysergamides like LSD tend to be more promiscuous than tryptamines like psilocin. And this fits with subjective reports that different drugs in the same class can have substantially different subjective qualities, even when they appear to have similar 5-HT2A efficacy.
The ketanserin studies still have weight, and 5HT2A efficacy seems to be necessary for the most subjectively blatant effects of psychedelics, in any case.
But suppose that by giving ketanserin first, you can eliminate self-reports of hallucinations and “yes I’m on a drug right now”. Where is the line between a blatant hallucination, and other effects which might occur and even be psychiatrically relevant, but not rise to conscious/linguistic salience during the experience?
When measures collapse, does this mean there are no effects? Or are studies statistically hobbled by the limited perceptual/introspective clarity of study participants? Clearly, we have more work to do.
Anyway, I hope you’ll leave here with just a little itch in the back of your mind any time you hear (or get ready to say) something like “psychedelics work by pressing the serotonin button in your brain”.
Technically, an antagonist as classically defined is a partial agonist with (near) zero efficacy. A partial agonist is always less efficacious than serotonin itself, a full agonist. All partial agonists will reduce receptor activation to some degree, if there is enough of a full agonist around that they displace a significant amount of it from the receptor.
Such as from Alexander Shulgin’s experiments where he administered drugs to himself and titrated up to different levels of subjective effects.
Ray 2010 did not quantify the efficacy of the substances at (de)activating the receptors upon binding, though, just the affinity for binding. Jain et al. 2025 closes this gap.