Psilocybin reshapes brain connections via distinct cellular pathways

A new study led by researchers at the University of California, Santa Cruz reveals how psilocybin, the psychoactive compound found in “magic mushrooms,” reshapes neuronal connections in the brain.

The study, published October 15 in the journal Natural neurosciencedemonstrates in mice that psilocybin rapidly accelerates the formation and maturation of new neuronal connections while promoting the elimination of certain pre-existing connections. Additionally, researchers observed a behavioral response in laboratory mice, indicating that the cellular mechanisms behind this structural plasticity can occur without the psychedelic effects of psilocybin.

Importantly, this provides a cellular framework for developing treatments that promote plasticity with fewer hallucinogenic effects. These findings could inform future research into treatments for depression, post-traumatic stress disorder (PTSD), and other psychiatric disorders.

In the study, the team identified a specific population of cortical neurons essential for psilocybin-induced synapse remodeling. Additionally, they found that psilocybin selectively rewired circuits based on the underlying health of the brain.

I consider this work a major advance, particularly in our understanding of how psilocybin reshapes neural circuits and its potential implications for the treatment of mental disorders. »

Yi Zuo, lead author, professor of molecular, cellular and developmental biology, UC Santa Cruz

History of psychedelic science and regulatory dynamics

Over the past century, the neurobiological study of psychedelics has undergone many major changes. Natural psychedelics were introduced to Western science in the mid-20th century, with researchers identifying active compounds like psilocybin and LSD that produced profound alterations in consciousness and mood. Early clinical investigations showed therapeutic potential for psychiatric care, but research was largely halted after the passage of the federal Controlled Substances Act in 1970.

In recent years, a surge of scientific interest has focused attention on psychedelics as “psychoplastogens,” compounds capable of rapidly stimulating structural and functional neuronal plasticity after a single dose. Recognizing this therapeutic promise, the U.S. Food and Drug Administration (FDA) has previously granted breakthrough therapy designation to substances such as psilocybin and MDMA.

This momentum reached a major milestone last month, when the FDA held a public hearing titled “Considerations for the Potential Future Therapeutic Use of Psychedelic Drugs.” The hearing brought together experts to establish standardized frameworks for provider accreditation, protocols for Risk Evaluation and Mitigation Strategy (REMS), and clinical trial designs. As federal regulatory agencies move toward integrating psychedelic-assisted therapies into health care, understanding the precise cellular mechanics of how these drugs heal brain circuits has become a major goal of biological research.

Watching neural connections rewire in real time

To observe how psilocybin changes neuronal architecture at the microscopic level, the UC Santa Cruz research team used two-photon microscopy to image neurons in the living brain. This high-resolution imaging technique allowed researchers to track individual dendritic spines in living mouse brain cells over several weeks.

Dendritic spines are tiny bulbous protrusions branching off brain cells that act as signal receiving docks, forming communication bridges called synapses with neighboring neurons. When psilocybin was administered, researchers observed a rapid increase in the formation of new dendritic spines within 24 hours.

Additionally, the team found that psilocybin accelerated the physical maturation of these new connections. In untreated mice, new spines usually start as immature “truncated” forms that remain unstable and short-lived. Under psilocybin treatment, a significantly higher proportion of new spines rapidly transformed into large “mushroom” shapes, mature, stable structures equipped with abundant neurotransmitter receptors capable of retaining strong, long-lasting memory and mood signals.

One of the central questions in psychedelic research is whether the psychedelic experience itself is necessary for these lasting changes in brain connectivity, according to Jacob Baker, the study’s lead author. “Psychedelics are fascinating compounds because they have the potential to profoundly transform who we are by reshaping the neural circuits in our brains,” said Baker, a Ph.D. student in Zuo’s lab. “These newly formed connections can integrate into existing neural circuits and persist over time, leaving a lasting structural trace of psilocybin’s effects on the brain.”

Restoring circuits in healthy or stressed brains

A key finding of the study is that the impact of psilocybin depends on the brain’s prior exposure to chronic stress. In healthy control mice, psilocybin induced a temporary increase in the formation of new connections, followed by a gradual return to baseline over three weeks, as older connections existing before psilocybin treatment were eliminated. This balance ensured that the healthy brain maintained its structural stability while updating its circuit wiring.

However, when the team examined mice subjected to chronic stress, using a model of mild, unpredictable stress that mimics human depressive states, psilocybin behaved markedly differently. Chronic stress normally causes severe synapse loss and circuit degradation. In brains affected by stress, psilocybin triggered a significantly higher increase in the formation of new spines while simultaneously stopping the excessive loss of existing connections.

This nuance reframes how neuroscientists evaluate psychedelic therapies. “These results challenge the prevailing view that psilocybin simply increases neuronal connectivity and suggest that its effects depend on the underlying brain state,” Zuo added. “This offers a new perspective on how psychedelics might help restore neural circuits disrupted by stress, with potentially important implications for understanding their therapeutic effects in depression and other psychiatric disorders.”

Uncoupling of synaptic plasticity from hallucinogen-like responses

Historically, scientists have questioned whether the intense perceptual alterations and hallucinations caused by psychedelics are necessary for their long-term therapeutic benefits. To address this question at the cellular level, the team performed genetic experiments focused on serotonin 2A receptors (5-HT2ARs), the chemical docking stations on cell membranes that interact with psilocybin.

The researchers targeted layer 5 pyramidal neurons, the main output cells of the cerebral cortex known to strongly express serotonin 2A receptors. Using specialized mouse lines, the team manipulated the receptors specifically within these layer 5 cells.

When serotonin 2A receptors were restored exclusively in layer 5 pyramidal neurons, psilocybin successfully triggered new synapse formation and structural stabilization. However, these same mice failed to exhibit the head twitch response, a movement in rodents widely recognized as the standard biological indicator of hallucinogenic activity.

Conversely, when serotonin 2A receptors were selectively deleted from layer 5 pyramidal neurons, psilocybin could no longer induce structural synapse growth, but head twitch behavior remained completely intact.

This double dissociation proves that serotonin 2A signaling in layer 5 pyramidal neurons is both necessary and sufficient for psilocybin’s structural neuroplasticity, but completely dispensable for its hallucinogenic behavioral output.

“By showing that therapeutic circuit remodeling and hallucinogenic effects operate via distinct cellular pathways, our study provides a promising model for the design of non-hallucinogenic drug analogs,” Zuo said. “Such therapies could provide the rapid and long-lasting antidepressant benefits of psychedelics while eliminating hallucinogenic side effects, thereby making neuroplasticity treatments safer, more scalable, and accessible to a broader patient population.”

Besides Zuo, other UC Santa Cruz molecular and cellular biologists who co-authored the study include Jacob Baker, Emily Kogan, Shaorong Ma and Ju Lu. This research was funded by grants from the National Institute of Mental Health and the National Institute on Aging. Psilocybin was provided by the National Institute on Drug Abuse (NIDA) Drug Supply Program.