A recent study published in the journal Nature Communications suggests that a single high dose of psilocybin can cause lasting changes in human brain connectivity and psychological well-being. Scientists found that these brain changes provide evidence of increased mental flexibility and insight lasting at least a month after the experience. The research offers a rare glimpse into the biological and psychological shifts that occur when a person takes a psychedelic substance for the very first time.
Psilocybin is the primary psychoactive compound found in certain species of mushrooms. When a person consumes this substance, their body converts it into psilocin, a chemical that interacts with serotonin receptors in the brain to produce altered states of consciousness. These altered states often include visual changes, deep emotional shifts, and an altered sense of self or reality.
Scientists have noticed that psilocybin shows promise as a therapy for various mental health conditions, such as depression and anxiety. Previous clinical trials suggest that a single dose can lead to enduring improvements in mood and mindset. However, the physical and functional changes in the brain that accompany these lasting psychological benefits are not fully understood.
To address this gap in knowledge, researchers at UC San Francisco and Imperial College London conducted an exploratory study to observe what happens in the brain of someone experiencing a high dose of psilocybin for the first time. They wanted to track both the immediate effects while the drug was active and the long-term changes occurring weeks later. By looking at people who had never taken a psychedelic before, and who had no diagnosed mental health conditions, the scientists had greater freedom to do extensive testing and capture the pure effects of the drug.
They specifically aimed to measure a concept known as the entropic brain effect. In physics, entropy refers to the level of disorder or randomness in a system. When applied to the human mind, the entropic brain theory proposes that the psychedelic state creates a highly diverse and unconstrained pattern of brain activity.
During normal waking hours, human brain activity tends to follow predictable and rigid patterns. Under the influence of a psychedelic, brain entropy increases, meaning neural activity becomes more unpredictable and varied. The brain processes a richer body of information, which is experienced subjectively as a highly intense, content-rich state of consciousness. The scientists wanted to see if this temporary shift in brain entropy could predict positive psychological outcomes.
To conduct the study, researchers recruited 28 healthy adults with an average age of 41. The group was evenly split between men and women. None of the participants had ever used a psychedelic drug in their lifetime. The study was designed to compare a tiny, inactive dose of psilocybin with a larger, fully active dose within the exact same group of people.
The participants went through two separate dosing sessions spaced exactly one month apart. During the first session, they received a one-milligram dose of psilocybin. This is considered a placebo because it is too small to produce noticeable psychological effects. One month later, the participants returned to the laboratory to receive a 25-milligram dose, which is an amount widely known to induce a strong psychedelic experience.
The researchers used several techniques to measure brain activity and structure throughout the duration of the study. To capture the immediate effects of the drug, they used electroencephalography. This technique involves placing an array of sensitive sensors on a person’s scalp to record the electrical signals produced by active brain cells. The participants wore these sensors for four-minute intervals while resting with their eyes closed before taking the drug, and then again at one, two, and four and a half hours after ingestion.
To examine longer-lasting physical and functional brain changes, the scientists used magnetic resonance imaging. This brain scanning technology uses powerful magnets to take detailed pictures of the brain. The participants underwent these brain scans at the very beginning of the study, one month after the placebo dose, and one month after the high dose.
The scientists utilized a specific type of magnetic resonance imaging that tracks the diffusion of water molecules along the white matter tracts in the brain. White matter acts like a communication highway, connecting different brain regions so they can send electrical signals to one another. By measuring how water moves through these specific pathways, researchers can estimate the physical health and microscopic structure of the brain’s internal connections.
The scientists also asked participants to complete various surveys and computer tasks to measure their cognitive flexibility, psychological insight, and overall well-being. Cognitive flexibility refers to the mental ability to switch between thinking about two different concepts. Psychological insight involves gaining new perspectives or a deeper understanding of one’s own thoughts, emotions, and behaviors. The participants completed these behavioral assessments at various scheduled points before and up to a month after each dosing session.
When the researchers analyzed the data, they found that the one-milligram placebo dose produced no significant brain or psychological changes. However, the 25-milligram dose resulted in measurable alterations in both brain activity and mental health. The day after the high dose, all but one of the 28 subjects rated the trip as the single most unusual state of consciousness they had ever experienced. The remaining person rated the event as being among their top five most unusual experiences.
During the active session, the electroencephalography recordings showed a robust increase in brain signal complexity within 60 minutes of taking the drug. This increase in electrical randomness aligns with the entropic brain theory, showing that the brain enters a highly flexible state and processes a richer body of information under the direct influence of the compound.
This temporary increase in brain entropy tended to predict positive psychological outcomes for the volunteers. Participants who experienced higher levels of electrical randomness during their active session reported experiencing more psychological insight the very next day. In turn, the individuals who reported the most psychological insight tended to show the greatest improvements in overall well-being two and four weeks later, reporting that they felt optimistic about the future and were dealing with problems well.
The authors suggest that this sequence provides evidence that the chaotic brain changes directly enable a shift in perspective that enhances long-term mental health.
“Psychedelic means psyche-revealing, or making the psyche visible,” said senior author Robin Carhart-Harris. “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.”
One month after the high dose, the brain scans revealed physical changes in the white matter pathways connecting the front of the brain to deeper regions. The scientists observed a decrease in water diffusion along these tracts, which indicates that the neural pathways were denser and possessed more integrity. The authors note that this is the opposite of what happens during the normal aging process, which tends to make these neural tracts more diffuse.
These physical alterations correlated with decreases in brain network modularity. Modularity is a measure of how rigidly the human brain is divided into separate, independent functional networks. A decrease in modularity means the brain is communicating more fluidly across its different regions. The participants also demonstrated improved performance on tests of cognitive flexibility one month after the high dose.
“Psilocybin seems to loosen up stereotyped patterns of brain activity and give people the ability to revise entrenched patterns of thought,” said Taylor Lyons, the first author of the paper. “The fact that these changes track with insight and improved well-being is especially exciting.”
These findings could help improve treatments for mental illness by ensuring the correct dosage is used to produce the right amount of brain entropy to promote insight.
“We already knew psilocybin could be helpful for treating mental illness,” Carhart-Harris said. “But now we have a much better understanding of how.”
While the study provides exciting evidence regarding the brain’s response to psilocybin, the authors highlight a few potential misinterpretations and limitations. The researchers caution that more work needs to be done to better understand the exact biological meaning of the white matter changes. Interpreting these structural alterations is complex, as they could reflect the pruning of weak neural connections, the growth of new connections, or changes in the protective coating around nerve fibers.
The study used a fixed-order design, meaning every participant received the placebo first and the high dose second. The scientists chose this structure because a high dose of psilocybin can cause lasting psychological changes that might contaminate a later placebo session. Because of this design, some of the improved performance on cognitive tests could be related to practice effects rather than the drug itself.
Another limitation is the small sample size of just 28 people. Studies with smaller groups can sometimes produce findings that do not perfectly represent the broader population. Future research is needed to verify these findings using different study designs, larger groups of people, and more advanced imaging techniques.
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 & R. L. Carhart-Harris.
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