A study led by researchers at Imperial College London’s Centre for Psychedelic Research has found that a single high dose of psilocybin in psychedelic-naive adults produced improvements in well-being, psychological insight and cognitive flexibility a month after the experience, with larger gains linked to more irregular brain activity during the trip. The work, published in Nature Communications, involved 28 healthy participants with an average age of about 41.
The researchers also report possible changes in the brain’s white matter a month after the high dose, though lasting alterations to brain function were largely absent. The findings build on theories that psychedelics disrupt normal brain activity to create a more flexible, less constrained mental state, a concept known as the entropic brain hypothesis.
Participants had never taken a psychedelic before and were given two oral doses one month apart in a fixed order: first a 1-milligram dose acting as a placebo, then a 25-milligram high dose known to induce a profound altered state of consciousness. The design was chosen because the researchers anticipated the high dose would have lasting effects that could carry over into the second session.
Sessions occurred in a controlled, supportive environment with low lighting, music, an eye mask and non-directive supervision. Throughout the dosing days, researchers recorded brain activity with an electroencephalogram (EEG) while participants rested with their eyes closed at one, two and four and a half hours after ingestion. Magnetic resonance imaging brain scans were completed before the study and one month after each dose.
During the high-dose session, EEG recordings showed large increases in brain entropy—rapidly becoming more irregular and unpredictable—peaking one to two hours after the 25-milligram dose, aligning with the height of the psychedelic experience. The same measurements showed a drop in alpha waves; the placebo dose produced no such changes. When asked months later, 94 per cent of respondents who answered said the high dose was the most unusual state of consciousness of their lives.
One month after the high dose, diffusion tensor imaging indicated changes in the brain’s white matter: a decrease in water diffusion along pathways connecting the prefrontal cortex with deeper subcortical regions. The prefrontal cortex is involved in complex thinking and decision-making, and these white matter changes were not observed after the placebo dose.
Other imaging measures showed little lasting change. Functional MRI scans, which track blood flow as a proxy for brain activity and were designated as the primary outcome, revealed changes a month after the high dose that were largely weak and not statistically significant. One metric, known as network modularity, fell compared with the start of the study but not when compared with the month-after placebo session, and larger decreases in modularity tended to coincide with bigger gains in well-being.
An earlier analysis of the same participants’ scans, covered by PsyPost in 2026, found that activity in circuits linking the prefrontal cortex with the striatum and thalamus became more variable a month after the high dose, though the link to improved well-being did not reach statistical significance using that method.
Psychologically, participants showed clear improvements after the 25-milligram dose that were not seen after the placebo. Their psychological insight scores were about 51 points higher (on a 0-to-100 scale) the day after the high dose than after placebo and remained elevated a month later. Well-being scores rose about 4.7 points more after the high dose than after placebo, on a scale from 14 to 70, where the general population averages roughly 51. Participants also made fewer errors on a computer task measuring cognitive flexibility a month after the high dose, particularly when adapting to hidden rule changes.
Looking at relationships between the measures, those with greater brain entropy two hours into the high-dose session tended to report more psychological insight the next day and greater well-being gains a month later. A statistical analysis suggested that the next-day insight partly explained the link between entropy and later well-being. Brain entropy did not predict the observed 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 the modest long-term results align with 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.”
Other scientists welcomed the cautious interpretation. Martin Korsbak Madsen, a physician and postdoctoral researcher at Copenhagen University Hospital who was not involved in the study, said the work addresses an important gap by combining EEG and MRI. “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,” he noted to PsyPost. He also described the imaging findings as plausible indications of how psychedelics could influence brain function, while acknowledging that replication is needed.
He cautioned, however, that the fixed order of doses limits the strength of the conclusions. “A not trivial drawback of the design is the use of a fixed order, meaning everybody got low dose 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.”
Preller also stressed the exploratory nature of the work. “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,” she 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 added that diffusion imaging interpretation is complex. Changes in white matter can reflect learning or aging as well as injury, so the authors caution against over-interpretation until replicated with more advanced imaging.
Looking ahead, Preller said further work in patient populations is needed to understand whether there is a neurobiological basis for observed treatment effects. “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 also urged caution that even significant findings in this study are exploratory and require replication.
Madsen suggested placing psychedelics alongside other well‑being interventions to gauge what is specific to these experiences. “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, titled Human brain changes after first psilocybin use, was led by Taylor Lyons and colleagues and published in Nature Communications. The work adds to the ongoing discussion about how short-lived neural disruption during a psychedelic experience might relate to longer-term personal growth, while emphasising the need for replication and more rigorous trial designs.
