Magic mushrooms rewire the brain in a way scientists didn’t expect

The research, published October 15 in Nature Neuroscience, found that psilocybin rapidly encourages brain cells to form new connections and helps those connections mature. At the same time, it promotes the removal of certain older connections, suggesting that its effects involve more than simply increasing communication between neurons.

Experiments in mice also revealed something especially intriguing. The researchers were able to separate the cellular changes responsible for this rewiring from a behavioral response commonly associated with psychedelic effects. This suggests that some of psilocybin’s effects on brain structure may be achievable without the hallucinations typically associated with the drug.

The discovery could provide a foundation for developing medications that enhance the brain’s ability to adapt and reorganize itself, a property known as neuroplasticity. Such treatments might eventually offer new approaches for depression, post-traumatic stress disorder (PTSD), and other psychiatric conditions.

The team also identified a particular group of neurons in the cerebral cortex that plays an essential role in psilocybin’s effects on brain connections. Importantly, the researchers discovered that the drug does not affect every brain in the same way. Its influence depends partly on whether the brain has previously experienced chronic stress.

“I consider this work a major advance, particularly in our understanding of how psilocybin reshapes neural circuits and its potential implications for treating mental disorders,” said senior author Yi Zuo, professor of molecular, cell, and developmental biology at UC Santa Cruz.

Why Scientists Are Taking a New Look at Psychedelics

Scientific interest in psychedelic drugs has changed dramatically over the past century. During the middle of the 20th century, substances such as psilocybin and LSD attracted attention from Western researchers because of their powerful effects on perception, consciousness, and mood.

Early studies suggested these compounds might have applications in psychiatric treatment. However, scientific investigations slowed substantially after the United States passed the Controlled Substances Act in 1970, which imposed strict restrictions on these substances.

In recent years, researchers have renewed their interest in psychedelics, particularly their ability to produce rapid and potentially lasting changes in brain function.

Scientists sometimes describe these compounds as “psychoplastogens” because they can stimulate neuroplasticity after a single dose. Neuroplasticity refers to the brain’s capacity to change its structure and activity by forming, strengthening, reorganizing, or removing connections between neurons.

This property is particularly interesting for mental health treatment because conditions such as depression can involve disruptions in the circuits responsible for regulating mood, emotions, and behavior.

The U.S. Food and Drug Administration (FDA) has previously recognized the therapeutic potential of psychedelic research by granting Breakthrough Therapy designations to substances including psilocybin and MDMA. These designations are intended to accelerate the development and review of promising treatments for serious medical conditions.

In September 2026, the FDA took another step toward evaluating psychedelic treatments by organizing a public hearing titled “Considerations for Potential Future Therapeutic Use of Psychedelic Drugs.”

Experts discussed how healthcare professionals administering psychedelic treatments should be qualified, how potential risks could be managed through Risk Evaluation and Mitigation Strategy (REMS) programs, and how future clinical trials should be designed.

As regulators examine ways psychedelic treatments might eventually become part of mainstream healthcare, researchers are increasingly focused on understanding exactly what these substances do to the brain. Identifying the cellular mechanisms behind their effects could help scientists develop treatments that are both effective and safer to administer.

Watching Psilocybin Rewire the Brain

To investigate how psilocybin changes brain structure, the UC Santa Cruz team used an advanced imaging method called two-photon microscopy.

This technology allows scientists to observe extremely small structures inside living tissue with remarkable detail. Using it, the researchers followed individual connections on neurons in living mice over several weeks, allowing them to see how those structures changed after psilocybin treatment.

Their attention centered on tiny projections called dendritic spines. These structures extend from neurons and receive messages from neighboring nerve cells. They help form synapses, the specialized junctions through which neurons communicate.

Synapses are essential for processing information and supporting functions such as learning, memory, and emotional regulation. Changes in their number, strength, and organization can alter the way information travels through the brain.

Within just 24 hours of psilocybin administration, the researchers observed a substantial increase in newly forming dendritic spines.

But the drug did more than encourage new connections to appear. It also helped them develop into more mature structures at an unusually rapid pace.

Normally, newly formed spines often begin as small, immature structures described as “stubby.” Many remain unstable and disappear before becoming fully developed connections.

After psilocybin treatment, however, a much larger proportion developed into structures with a distinctive “mushroom” appearance. These mature spines are generally more stable and contain higher concentrations of receptors that receive chemical signals from neighboring neurons.

Because of these features, mature spines can support stronger and more persistent communication between brain cells, potentially contributing to lasting changes in circuits involved in memory and mood.

For lead author Jacob Baker, one of the biggest questions is whether these structural changes require the intense psychedelic experience typically produced by psilocybin.

“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 circuitry and persist over time, leaving a lasting structural trace of psilocybin’s effects on the brain.”

Psilocybin Affects Healthy and Stressed Brains Differently

One of the study’s most revealing findings was that psilocybin’s influence on brain connections changed depending on whether the mice had experienced prolonged stress.

In healthy mice, psilocybin initially stimulated the formation of new dendritic spines. Over the following three weeks, however, the number of connections gradually moved back toward its previous level.

This happened partly because the brain eliminated some connections that had existed before treatment. Rather than simply accumulating additional synapses, the healthy brain appeared to reorganize its existing circuitry while maintaining an overall balance.

The researchers observed a different response in mice exposed to chronic stress.

To investigate this, they used an unpredictable mild stress model, which exposes animals to varying low-intensity stressors and produces changes that resemble certain features of human depression.

Prolonged stress is known to interfere with neural communication and can cause substantial losses of synaptic connections. Over time, these changes can weaken the circuits involved in important brain functions.

When the stressed mice received psilocybin, the researchers observed an especially strong increase in the formation of new dendritic spines.

At the same time, psilocybin prevented the unusually high rate of connection loss associated with chronic stress.

Together, these effects suggest that psilocybin may do more than temporarily increase the number of connections in the brain. Under stressful conditions, it may also help preserve existing connections and restore circuitry that has been disrupted.

“These findings challenge the prevailing view that psilocybin simply increases neural connectivity and suggest that its effects depend on the brain’s underlying condition,” Zuo added.

“This provides 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.”

Could Psilocybin Rewire the Brain Without Hallucinations?

Perhaps the most significant implication of the research concerns a longstanding question in psychedelic medicine: Are hallucinations and altered states of consciousness necessary for the brain changes that might contribute to therapeutic benefits?

To explore this possibility, the scientists examined the role of serotonin 2A receptors (5-HT2ARs), which are proteins on the surfaces of cells that respond to chemical signals. These receptors are central to the effects of psilocybin and other classic psychedelics.

The researchers focused on a group of nerve cells called Layer 5 pyramidal neurons. These cells are located in the cerebral cortex, the outer region of the brain involved in complex functions such as perception, reasoning, and decision-making.

Layer 5 pyramidal neurons serve as important communication pathways that send information from the cortex to other brain regions. They also contain high levels of serotonin 2A receptors, making them especially relevant to understanding psilocybin’s effects.

Using genetically modified mice, the team selectively changed whether these neurons possessed the receptors.

The results revealed a striking separation between changes in brain connections and a behavior associated with psychedelic activity.

When the researchers restored serotonin 2A receptors only in Layer 5 pyramidal neurons, psilocybin was still able to stimulate the development of new synapses and help stabilize them.

Surprisingly, these mice did not display the characteristic head twitch response that researchers commonly use as an indicator of psychedelic activity in rodents.

The scientists then performed the opposite experiment.

When they removed serotonin 2A receptors specifically from Layer 5 pyramidal neurons, psilocybin lost its ability to stimulate the same structural growth of synapses.

However, the mice still exhibited the head twitch response.

These contrasting results demonstrate that serotonin 2A receptor signaling in Layer 5 pyramidal neurons is necessary and sufficient for the structural brain changes observed in the experiments, while those same receptors are not required for the psychedelic-associated behavioral response.

In other words, the cellular pathway responsible for psilocybin’s brain rewiring can be separated from the pathway responsible for this particular behavioral marker of psychedelic activity.

Because mice cannot describe subjective experiences, the head twitch response does not directly establish whether an animal is experiencing hallucinations. Nevertheless, the findings provide important evidence that these two effects involve distinct cellular mechanisms.

A Potential Path Toward Psychedelic Treatments Without the Trip

The discovery could have major implications for the development of future psychiatric medications.

If researchers can identify compounds that activate the brain’s ability to rebuild and reorganize neural connections without triggering psychedelic effects, it may become possible to create treatments that preserve some of psilocybin’s therapeutic potential while avoiding the need for patients to undergo intense altered states of consciousness.

Such medications could be easier to administer and might require less intensive clinical supervision than conventional psychedelic-assisted therapies.

“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.

“Such therapeutics could deliver the fast and lasting antidepressant benefits of psychedelics while eliminating hallucinogenic side effects — making neuroplasticity treatments safer, more scalable, and accessible to a broader patient population.”

Although the results are promising, the experiments were conducted in mice. Additional research will be necessary to determine whether the same cellular mechanisms operate in humans and whether separating brain rewiring from psychedelic effects can produce effective treatments for depression, PTSD, or other psychiatric disorders.

For now, the findings provide a more detailed picture of how psilocybin changes the brain and reveal a potential strategy for harnessing its effects on neural connections without relying on the psychedelic experience itself.

The study’s other UC Santa Cruz coauthors include molecular and cell biologists Jacob Baker, Emily Kogan, Shaorong Ma, and Ju Lu, alongside Zuo.

Funding came from the National Institute of Mental Health and the National Institute on Aging. The psilocybin used in the experiments was supplied through the National Institute on Drug Abuse (NIDA) Drug Supply Program.