Psilocybin's effect on brain connections separated from a psychedelic marker in mice

Psilocybin triggers rapid growth and maturation of synaptic connections in the mouse cortex, while also pruning some older ones, according to researchers at the University of California, Santa Cruz. The structural changes depended on serotonin 2A receptors in one class of cortical neurons, and could be separated from the head twitch response, a behaviour widely used as a marker of psychedelic activity in rodents. The work was published in Nature Neuroscience.

Tracking single connections over weeks

The team, led by senior author Yi Zuo, professor of molecular, cell and developmental biology, and PhD student Jacob Baker as lead author, used two-photon microscopy to image living mice. This allowed them to follow individual dendritic spines, the small protrusions on neurons that receive input and help form synapses, across several weeks after a dose of psilocybin.

Within 24 hours, the number of newly formed spines had risen markedly. Many of these new spines also matured quickly. Newly formed spines are usually small and stubby, and many vanish before stabilising. After psilocybin, a larger share took on the mushroom-shaped form associated with greater stability and a higher density of receptors for incoming signals.

Healthy and stressed brains respond differently

The effect was not a simple, lasting increase in connectivity. In healthy mice, spine numbers drifted back towards their starting level over the following three weeks. This was partly because some connections that existed before treatment were removed, which suggests a reorganisation of circuitry rather than an accumulation of extra synapses.

Mice subjected to chronic stress behaved differently. The researchers used an unpredictable mild stress model, which produces features resembling aspects of human depression and is known to cause synaptic loss. In these animals, psilocybin produced an especially strong rise in new spines and also prevented the elevated rate of connection loss that accompanied the stress. The authors argue that this challenges the prevailing view that psilocybin simply boosts connectivity, and indicates that its effects depend on the prior state of the brain.

One neuron type, two separable outcomes

To identify the cells responsible, the researchers focused on Layer 5 pyramidal neurons in the cerebral cortex. These cells project to other brain regions and carry high levels of serotonin 2A receptors, which are central to the action of classic psychedelics. Using genetically modified mice, the team either restored the receptors only in these neurons or removed them only from these neurons.

• With receptors restored only in Layer 5 pyramidal neurons, psilocybin still promoted new synapses and their stabilisation, but the head twitch response did not appear.
• With receptors removed from these neurons, psilocybin no longer drove the structural growth, yet the head twitch response persisted.

The results indicate that receptor signalling in these neurons is both necessary and sufficient for the structural changes, but not required for the head twitch.

Limitations and what comes next

The findings come from mice, and the head twitch response is only a proxy. Mice cannot report subjective experience, so the data do not show whether hallucination-like effects were absent. The study also does not test whether the observed synaptic changes produce therapeutic benefit, and the stress model captures only some features of depression. Any translation to people would need to be examined in separate studies.

Even so, the work offers a cellular framework for a long-standing question in psychedelic research: whether the altered state itself is needed for the plasticity that may underlie treatment effects. If the two can be pulled apart, compounds designed to engage the plasticity pathway in specific cortical neurons might be developed for depression, post-traumatic stress disorder and related conditions without an intense psychedelic experience. The interest is timely. Psilocybin and MDMA have both received Breakthrough Therapy designations from the US Food and Drug Administration, and the agency held a public hearing in September 2026 on possible future therapeutic use, covering practitioner qualifications, risk management and trial design.

Natural next steps include testing whether the structural changes track with behavioural improvements in stressed animals, determining which circuits the new Layer 5 connections join, and checking whether non-hallucinogenic receptor agonists reproduce the effect.

Source: Magic mushrooms rewire the brain in a way scientists didn't expect (ScienceDaily: health and medicine, 7 November 2026).

Image: AI-generated illustration.