Psilocybin Induces Lasting Brain Changes Up to a Month After Administration

A single dose of psilocybin, the psychedelic compound found in magic mushrooms, can trigger measurable physical alterations in the brain that remain detectable for at least a month, according to researchers at the University of California, San Francisco, and Imperial College London.

The study, published in Nature Communications, examined healthy adults who had never used psychedelics before. None of the participants had diagnosed mental health conditions, yet the findings may shed light on why psilocybin shows therapeutic promise for depression, anxiety, and addiction.

The investigation centered on temporary spikes in brain “entropy,” a metric that captures the variety and unpredictability of neural activity. The results suggest that increased entropy can foster psychological insight, with the psychedelic experience itself playing a crucial role in the lasting benefits observed.

Participants who experienced larger entropy increases in the minutes and hours following a high dose reported greater emotional insight the next day. These individuals also reported higher well‑being one month later.

“Psychedelic means ‘psyche‑revealing,’ or making the psyche visible,” said senior author Robin Carhart‑Harris, PhD, the Ralph Metzner Distinguished Professor of Neurology at UCSF. “Our data shows that such experiences of psychological insight relate to an entropic quality of brain activity and how both are involved in causing subsequent improvements in mental health. It suggests that the trip – and its correlates in the brain – is a key component of how psychedelic therapy works.”

Measuring Psilocybin’s Effects on the Brain

The researchers employed several techniques to assess brain activity, connectivity, and structure. Measurements were taken before drug administration, at the peak of the experience, and again one month later.

Because none of the 28 volunteers had a diagnosed mental health condition, the team was able to conduct a broader array of tests than would typically be possible in a clinical patient group.

During the initial phase, participants received a 1 mg dose of psilocybin, which the researchers treated as a placebo. Their brain activity was monitored with electroencephalography (EEG) during this period.

Over subsequent weeks, the researchers evaluated psychological insight, well‑being, and cognitive performance. They also used functional MRI (fMRI) to study brain activity and diffusion tensor imaging (DTI) to examine the integrity of neural pathways.

One month after the placebo session, participants were given a 25 mg dose of psilocybin, sufficient to produce a robust psychedelic experience. EEG recordings were again taken during the trip, and the same psychological and imaging assessments were repeated in the following weeks.

This design enabled the team to compare the effects of a full psychedelic dose with those observed after the 1 mg placebo.

Psilocybin Increases Brain Entropy

Within 60 minutes of taking the 25 mg dose, EEG recordings revealed a marked rise in brain entropy. This indicates that psilocybin prompts the brain to generate and process a broader range of information.

When the researchers performed DTI scans one month later, they observed signs of denser and more intact neural tracts. DTI measures how water moves along brain pathways, providing insight into structural connectivity.

These changes are the opposite of those typically associated with aging, where neural tracts tend to become more diffuse.

The researchers noted that additional studies are needed to fully understand what these structural findings mean. Nonetheless, they described the result as a previously unseen indication that psychedelics can produce lasting brain modifications.

Lasting Gains in Insight and Well‑Being

The day after receiving the 25 mg dose, 27 of the 28 participants described the experience as the “single most” unusual state of consciousness they had ever encountered. The remaining participant ranked it among the five most unusual experiences of their life.

Participants also reported substantially higher psychological insight after the high dose compared with the 1 mg placebo.

Assessments of well‑being improved at both two weeks and four weeks post‑dose. These measures included responses to statements such as, “I’ve been feeling optimistic about the future” and “I’ve been dealing with problems well.”

One month after the experiment, participants also performed better on a test of cognitive flexibility, which gauges the ability to adapt thinking in response to changing information.

“Psilocybin seems to loosen up stereotyped patterns of brain activity and give people the ability to revise entrenched patterns of thought,” said Taylor Lyons, PhD, a research associate at Imperial College London and the first author of the paper. “The fact that these changes track with insight and improved well‑being is especially exciting.”

How the Psychedelic Experience May Drive Benefits

Participants who exhibited the largest increases in brain entropy shortly after taking psilocybin were also the most likely to report greater insight the following day. Those insight gains were then linked to stronger improvements in well‑being one month later.

The researchers concluded that the experience of psychological insight appears to drive the later enhancements in well‑being. The findings could eventually help clinicians refine psilocybin treatments by identifying a dose that balances therapeutic insight with manageable intensity.

“We already knew psilocybin could be helpful for treating mental illness,” Carhart‑Harris said. “But now we have a much better understanding of how.”

Authors: Additional UCSF contributors are Manesh Girn, PhD, Hannes Kettner, and Adam Gazzaley, MD, PhD. Full author list is provided in the paper.

Funding: This work was supported by philanthropic donations to the Centre for Psychedelic Research at Imperial College London, the Alex Mosley Charitable Trust, and the Beckley Foundation. Carhart‑Harris is supported by the Ralph Metzner Distinguished Professorship and philanthropic donations to the Psychedelics Division, Neuroscape, UCSF, and to the Carhart‑Harris Lab.

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