Study separates psilocybin brain rewiring from a psychedelic-linked behavior

The study, published in Nature Neuroscience, used an advanced imaging method called two-photon microscopy to observe connections on neurons in living mice over several weeks. The team centred its attention on tiny projections called dendritic spines, which receive messages from neighbouring nerve cells.

Scientific interest in psychedelics has shifted dramatically over the past century, and in recent years researchers have renewed their interest in the compounds' ability to produce rapid and potentially lasting changes in brain function. The FDA has granted Breakthrough Therapy designations to psilocybin and MDMA, and in September 2026 held a public hearing to discuss the future of psychedelic therapies. Scientists sometimes describe these compounds as 'psychoplastogens' due to their ability to stimulate neuroplasticity, the brain's capacity to reorganise itself.

Within just 24 hours of psilocybin administration, the researchers observed a substantial increase in newly forming dendritic spines. The drug helped a larger proportion of these structures develop into mature spines with a distinctive 'mushroom' appearance; these are generally more stable and can support stronger and more persistent communication between brain cells. In healthy mice, over the following three weeks, the brain also eliminated some connections that existed before treatment, suggesting a process of active reorganisation rather than simply adding new synapses.

The researchers observed a different response in mice exposed to chronic stress. In those mice, psilocybin strongly stimulated new spine formation while preventing the unusually high rate of connection loss associated with stress. 'These findings challenge the prevailing view that psilocybin simply increases neural connectivity and suggest that its effects depend on the brain's underlying condition,' said senior author Yi Zuo, professor of molecular, cell, and developmental biology at UC Santa Cruz.

Experiments with genetically modified mice focused on serotonin 2A receptors on Layer 5 pyramidal neurons in the cortex. The team showed that serotonin 2A receptor signaling in these neurons was necessary and sufficient for the structural brain changes. Removing the receptors from these neurons did not stop the mice from displaying a head twitch response commonly used as a behavioural marker of psychedelic activity. The cellular pathway responsible for the brain rewiring could be separated from the pathway responsible for this behavioural marker, which does not directly establish whether mice experience hallucinations. 'By showing that therapeutic circuit remodeling and hallucinogenic effects operate through distinct cellular pathways, our study provides a promising blueprint for designing non-hallucinogenic drug analogs,' Zuo said.

The results open the possibility of developing medications that capture psilocybin's neuroplastic benefits without requiring patients to undergo intense altered states of consciousness, potentially making treatments safer and easier to administer. 'Psychedelics are fascinating compounds because they have the potential to profoundly transform who we are by reshaping the neural circuits in our brains,' said lead author Jacob Baker, a PhD student in Zuo's lab. The researchers caution the experiments were conducted in mice, and further research is needed to confirm whether the same mechanisms operate in humans.