The study, published in Nature Communications, involved healthy adults who had never previously used a psychedelic. Although none of the participants had a diagnosed mental health condition, the findings may offer clues about why psilocybin has shown therapeutic potential for depression, anxiety, and addiction.

Researchers focused on temporary increases in brain "entropy," a term describing the variety and unpredictability of neural activity. Their results suggest that this more diverse pattern of brain activity may promote psychological insight and that the psychedelic experience itself could play an important role in psilocybin's longer-term effects.

A larger rise in entropy during the minutes and hours after a high dose was associated with greater emotional insight the following day. Participants who reported more insight were also more likely to describe improved 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 used several methods to examine brain activity, connectivity, and structure. Measurements were taken before the psychedelic dose, during 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 perform a broader range of tests than might have been possible in a clinical patient group.

During the first stage of the experiment, participants received 1 mg of psilocybin, which the researchers treated as a placebo dose. Their brain activity was then monitored with electroencephalography (EEG), which records electrical signals through electrodes placed on the scalp.

Over the following 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 connections between different parts of the brain.

One month after receiving the placebo dose, the participants were given 25 mg of psilocybin, an amount capable of producing a powerful psychedelic experience. Researchers again recorded brain activity with EEG during the trip and repeated the same psychological and imaging assessments over the weeks that followed.

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

Psilocybin Increased Brain Entropy

Within 60 minutes of taking the 25 mg dose, EEG recordings showed a rise in brain entropy. The finding suggests that the brain was generating and processing a broader range of information while under the influence of psilocybin.

When the researchers examined participants one month later with DTI, they found signs that neural tracts were denser and showed greater integrity. DTI works by measuring how water moves along pathways in the brain.

This pattern was the reverse of changes commonly associated with aging, when neural tracts tend to become more diffuse.

The researchers emphasized that additional studies are needed to determine exactly what these structural findings mean. Even so, they described the result as a previously unseen indication that psychedelics may produce lasting changes in the brain.

Lasting Gains in Insight and Well-Being

The day after taking 25 mg of psilocybin, 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 more psychological insight after the 25 mg dose than after the 1 mg placebo.

Measures of well-being improved two weeks and four weeks after the high dose. These assessments 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 measures the ability to adapt thinking and respond 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

The participants with the largest increases in brain entropy during the first minutes and hours after taking psilocybin were also the most likely to report greater insight the next day.

Those increases in insight were then associated with stronger improvements in well-being one month later. The researchers concluded that the experience of psychological insight appeared to drive the later gains in well-being.

The findings could eventually help clinicians refine psilocybin treatments for people with mental health conditions. One possibility would be to identify a dose that produces enough brain entropy to encourage meaningful insight without creating an unnecessarily intense experience.

"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: Other UCSF authors are Manesh Girn, PhD, Hannes Kettner, and Adam Gazzaley, MD, PhD. For all authors, see the paper.

Funding: This work was funded by philanthropic donations to the Centre for Psychedelic Research, 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, plus philanthropic donations to the Carhart-Harris Lab.