Psilocybin's Brain Rewiring and Its Head Twitches Come Apart in Mice

A study in mice has pulled apart two effects of psilocybin that normally arrive together: the rewiring of connections between brain cells, and the head twitching that researchers use as a rodent stand-in for a hallucination. Jacob J. Baker, Yi Zuo and colleagues at the University of California, Santa Cruz trace the rewiring to one serotonin receptor in a single class of cortical cells, and report that the same receptor there is not needed for the twitching. Their paper was published Oct. 15, 2026, in Nature Neuroscience.

The authors set the work up as an open question: it was unclear how these receptors, known as 5-HT2A, act in the large cells of the cortex's fifth layer to produce psilocybin's hallucinations on one side and its remodeling of the brain's wiring on the other. Their Brief Communication answers it for the remodeling.

The authors report that psilocybin both builds new synapses, the junctions through which brain cells pass signals, and pushes them to mature, while speeding up the loss of synapses already in place. A manipulation aimed at one cell type then showed that this receptor signaling in the fifth-layer cells is both required for that remodeling and enough on its own to produce it. It is not required for the head-twitch response, which is the stand-in the field uses for a hallucination in a rodent rather than a measure of what the animal experiences.

The work is in mice throughout, and the paper is a Brief Communication, the journal's short format. Source data are published with it, and the group has posted its analysis code publicly on GitHub.