A single high dose of psilocybin in people who had never taken a psychedelic was followed by improvements in well-being, psychological insight, and cognitive flexibility a month later, and participants whose brain activity became more irregular during the experience tended to show the largest well-being gains. Lasting changes in brain function, however, were largely absent, though the researchers detected possible changes in the brain’s white matter. The findings were published in Nature Communications.
Psilocybin is the active psychedelic compound found in “magic mushrooms.” It works primarily by stimulating a specific type of serotonin receptor in the brain. Some scientists have proposed that this chemical action scrambles normal brain activity into a more flexible, highly disordered state. For instance, a 2014 theoretical paper by Robin Carhart-Harris, the senior author of the new study, introduced the “entropic brain” hypothesis, suggesting that psychedelics expand conscious experience by making brain signals more unpredictable.
Researchers have suspected that this temporary disruption might lead to lasting benefits. Along these lines, a 2021 open-label study of 24 people with depression found that psilocybin improved cognitive flexibility for at least a month. Cognitive flexibility is a person’s ability to successfully adapt their thinking and switch between different rules or concepts.
Scientists then began tracking healthy volunteers for weeks after a single dose to see whether these acute disruptions leave enduring functional or physical marks on the brain. For example, a small 2020 study of 12 healthy volunteers found that some changes in mood and resting brain connectivity were still detectable a month after a single high dose, although others had faded. Similarly, research covered by PsyPost in 2024 found that psilocybin temporarily scrambled brain network connections, with most changes fading within weeks but some, such as reduced connectivity between the hippocampus and a network involved in self-reflection, persisting.
Building on this progression, the current research, led by Taylor Lyons of the Centre for Psychedelic Research at Imperial College London, sought to capture a comprehensive picture of what happens in the brain of someone taking a psychedelic for the very first time. The researchers aimed to connect the immediate, disorganized brain state during a trip to the psychological benefits reported weeks later. They also wanted to test whether a single high dose of psilocybin physically alters the structure of the brain’s white matter.
The study involved 28 healthy adults, averaging 41 years old, who had never taken a psychedelic drug before. Each participant received two oral doses of psilocybin one month apart, always in the same order: first a 1-milligram dose, too low to produce noticeable psychedelic effects, which served as a placebo, and then a 25-milligram high dose known to induce a profound altered state of consciousness. The researchers used this fixed order because they expected the high dose to have lasting effects that could carry over into a later session. To limit expectations, participants were told only that they would receive a variable dose of up to 25 milligrams at each session.
Both dosing sessions took place in a supportive environment featuring low lighting, music, an eye mask, and non-directive guided supervision. During dosing days, the research team recorded electrical brain activity using an electroencephalogram, or EEG, while participants rested with their eyes closed at one, two, and four and a half hours after ingestion. Participants also completed magnetic resonance imaging brain scans before the study began and one month after each dose.
During the high-dose session, the EEG recordings showed large increases in brain entropy, meaning the electrical signals became highly irregular and unpredictable. This peak in disorganized activity occurred one to two hours after taking the 25-milligram pill, aligning with the peak intensity of the psychedelic experience. The recordings also showed a drop in alpha waves, a rhythm of electrical activity common when people are awake and relaxed, while the 1-milligram placebo dose produced no such changes. When asked months later, all but one of the participants who answered (94 percent) rated the high dose as the most unusual state of consciousness of their lives.
When analyzing the brain scans taken a month after the high dose, the researchers found possible changes in the brain’s white matter, the bundles of insulated nerve fibers that carry signals between brain regions. Using a technique called diffusion tensor imaging, which maps how water moves along these fiber pathways, they observed a decrease in water diffusion along tracts connecting the prefrontal cortex to deeper subcortical regions. The prefrontal cortex is involved in complex thinking and decision-making, and this alteration was not observed following the placebo dose.
Other brain imaging measures showed little lasting change. Functional MRI scans, which track blood flow as a proxy for brain activity and which the researchers had designated as their primary outcome, revealed changes one month after the high dose that were largely weak and not statistically significant. One measure, network modularity, reflects how sharply the brain divides into separate, tightly knit networks; it decreased compared with the start of the study but not compared with the month after the placebo dose, and participants with larger decreases tended to show larger gains in well-being.
An earlier analysis of the same participants’ brain scans, covered by PsyPost in 2026, focused on circuits linking the prefrontal cortex with the striatum and thalamus, the same pathways where the white matter changes appeared. Using a different analytic approach, it found that activity in these circuits became more variable a month after the high dose than after the placebo dose, although the difference from the start of the study and the link with improved well-being fell short of statistical significance.
On a psychological level, participants showed improvements after the 25-milligram dose that were not seen after the placebo dose. Their psychological insight scores were about 51 points higher (on a 0-to-100 scale) the day after the high dose than after the placebo dose and remained elevated a month later. Well-being scores rose about 4.7 points more after the high dose than after the placebo dose, on a scale running from 14 to 70 on which the general population averages about 51. Participants also made fewer errors on a computer task measuring cognitive flexibility a month after the high dose, specifically when they had to adapt to hidden rule changes.
When the researchers looked at how these measures related to one another, a pattern emerged. Participants whose brain entropy rose more two hours into the high-dose session tended to report more psychological insight the next day, and greater entropy across the session predicted larger gains in well-being a month later. A statistical analysis suggested that next-day insight partly accounted for the link between entropy and later well-being. Brain entropy did not predict the white matter changes.
“The most surprising – and therefore potentially also important – takeaway is that even in a highly exploratory and multimodal study as described here, psilocybin does not seem to have a pronounced lasting effect on the brain in healthy volunteers,” said Katrin Preller, a junior group leader at the University of Zurich and visiting assistant professor at Yale University who was not involved in the research. “One month after psilocybin administration only very marginal changes were detected. Given the nature of the study, the robustness of these changes needs to be determined in future studies.”
Preller noted that these modest long-term results match an emerging trend in neuroimaging research. “There is accumulating evidence that the neurobiological changes induced by psychedelics may be short lived and alterations are back to baseline levels after a few weeks,” she told PsyPost. “The study therefore confirms these initial reports and extends those by showing that this holds true even for psilocybin-naive participants.”
Martin Korsbak Madsen, a medical doctor and postdoctoral researcher at the Neurobiology Research Unit at Copenhagen University Hospital Rigshospitalet who was not involved in the study, focused on what the findings might reveal about how psychedelics work.
“It is well established that psychedelics can have long-term effects but underlying mechanisms are unknown, and the present study seeks to address this gap by using both EEG and MRI,” Madsen said. “The study confirms previous electrophysiological findings, showing acutely reduced alpha waves and increased complexity. The latter was positively associated with better psychological insight and well-being, so this might be a relevant mechanism for subsequent change.”
Madsen added that the imaging metrics pointed toward potential physiological routes for these mental shifts. “MRI findings suggested that brain function, on average, was less constrained, and that white matter bundles connecting deep and more superficial layers of the brain were also affected,” he told PsyPost. “Taken together the study is a good and thorough first step, and it provides plausible mechanisms, which subsequent studies can test.”
As with all research, there are some caveats to consider. Because all participants received the 1-milligram dose first and the 25-milligram dose second, order effects, such as simply getting used to the testing procedures, could have influenced the results. The authors argue that the changes after the high dose far exceeded any such effects, noting that no changes appeared after the placebo dose. They also acknowledge that their main hypotheses were not registered in advance and that their statistical corrections were applied within, but not across, the many outcomes they examined.
Preller also stressed the study’s exploratory nature. “This is a highly exploratory study which is reflected in a rather limited protection against Type I errors, i.e., the study is optimized for detecting effects but is not rigorously protected against false positive findings,” Preller told PsyPost. “The fixed administration sequence is justifiable in this study but increases the risk that the observed effects are due to habituation or other time-related factors and may not be causally linked to drug administration. All effects observed therefore need replication in better controlled and larger studies before any conclusions can be drawn.”
Madsen also noted that this structure limits how firmly conclusions can be drawn. “A not trivial drawback of the design is the use of a fixed order, meaning everybody got low dose (placebo condition) before the high dose,” Madsen said. “Although this has some benefits, one cannot exclude order effects, and a classic two-arm randomized, double-blind design of sufficient sample size would have been an improvement.”
Interpreting changes in white matter using diffusion imaging can also be complicated. The type of change seen here has been linked to processes such as learning and meditation, but also to nerve fiber injury and aging, so it is unclear what it reflects biologically. The authors speculate it could involve the pruning of weak connections or the growth of new, not-yet-insulated nerve fibers, but they caution against interpreting the finding until it is replicated with more advanced imaging. A second analysis method also failed to detect the white matter changes.
Looking ahead, Preller said studies in patients are needed. “We need more mechanistic long-term studies in patient populations in order to understand whether there is a detectable neurobiological basis for the observed treatment effects,” she told PsyPost. She added that readers should keep in mind that “even the significant findings in this study are highly exploratory and require replication.”
Madsen suggested that future investigations should evaluate psychedelics alongside other established practices that promote personal growth. “Intake of psychedelics is not the only way of improving well-being or gaining psychological insight, and comparing psychedelics to non-drug interventions such as psychotherapy, mindfulness or art therapy, might help elucidate which effects are specific to psychedelics as opposed to general psychological development,” he explained.
The study, “Human brain changes after first psilocybin use,” was authored by T. Lyons, M. Spriggs, L. Kerkelä, F. E. Rosas, L. Roseman, P. A. M. Mediano, C. Timmermann, L. Oestreich, B. A. Pagni, R. J. Zeifman, A. Hampshire, W. Trender, H. M. Douglass, M. Girn, K. Godfrey, H. Kettner, F. Sharif, L. Espasiano, A. Gazzaley, M. B. Wall, D. Erritzoe, D. J. Nutt, and R. L. Carhart-Harris.
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