Serotonin Receptor Overview

Following FDA’s commitment to psychedelics (5-HT2A agonists), it might be interesting to give an overview of serotonin receptors and what they do, because really they’re fascinating and one of the most complex receptor families. As evidenced by their name (which isn’t strictrly obvious), they’re activated by serotonin, also known as 5-hydroxytryptamine, hence 5-HT.

SSRIs, MDMA, LSD, and many other drugs target the serotonin receptors in the brain. The two former mostly just increase your natural serotonin levels, but psychedelics specifically activate the receptors differently.

In general, a drug attaches to a receptor located near the synapse and makes the cell do things, or stop doing things. How well something will work can be estimated, but it’s hard to really know what’s going on because brains are big and neurons are deep, and something that works in a lab might not work in a living brain.

Unlike some much more simple systems, like the dopamine receptors for example, serotonin ones are very complicated and even a very subtle change can significantly alter the resulting effects, notably which cellular pathways will be used.

There’s at least a dozen of different subtypes of serotonin receptors, with 1A and 2A being the two associated with psychedelics, and 5-HT3 with nausea. 5-MeO-DMT primarily activates the 1A subtype, and most other psychedelics activate mostly the 2A subtype. Despite both being serotonin receptors, they are very different in their effects, including the psychedelic trip that they produce.

5-MeO-DMT produces a state of profound abcense of self, with little visual distortion, but an extreme shift in perception. LSD and others, on the other hand, give the typical visual distortions, breathing walls, and other effects like that.

Except that’s not the whole story and it’s much more complex. Firstly, not all 2A agonists produce a psychedelic experience. Some have been shown to have little to no perceptible psychedelic activity, like lisuride, JRT, etc.

What drives the effects is not just the serotonin receptor itself, but a heterodimer complex that it can form with a subtype of a glutamate receptor, 5-HT2A/mGluR2. Those are primarily located in the zone in between your top-down priors (aka beliefs, assumptions) and bottom-up sensory information. Activating the receptors there then produces the psychedelic state, with the specific nuances of each drug molecule producing distinct effects: visual and sensory perturbations, their exact form and shape.

It’s not entirely clear if the trip is in itself needed for the therapeutic effects. Some pharma companies bet on it not being needed, as that would of course simplify things a lot. Recent research (Xu et al. 2026) suggests that Gi-specific signalling is what produces the psychedelic effects, and you can avoid them and still get the therapeutic effects (in mice).

Dendritic spine remodeling (there are videos of them literally growing out of the neuron, it’s quite cute) and receptor reorganization are the most likely mechanisms for the therapeutic effects. The plasticity window is around 24 hours, with broader integration period likely needed for the effects to persist.

Having too much of a trip often doesn’t help, and may even worsen the condition or result in typical failure modes: 5-Meo-DMT may give a persistent dissociative state, with people saying things like “we are all one,” and classical psychedelics may give bizarre beliefs, often perceived as revelations.

Some people really underestimate the sheer shock of the experience for the average person, someone who probably isn’t very spiritual or interested in the mindbreaking effects, and the possible failure modes. Your average Joe is sad and paid $1000 for the session to make him not sad, and instead has the universe being shot into his head. For that reason, I believe MDMA-assisted therapy might be a better choice in general, to not scramble Joe’s priors too much lest he starts believing the news.