Recent research published in journals nature communications Our results suggest 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, with evidence of increased mental flexibility and insight, persisted for at least a month after the experience. This study provides a rare glimpse into the biological and psychological changes that occur when a person takes a psychedelic substance for the first time.
Psilocybin is the main psychoactive compound found in certain types of mushrooms. When a person ingests this substance, the body converts it to psilocin. Psilocin interacts with serotonin receptors in the brain, causing an altered state of consciousness. These altered states often include visual changes, deep emotional changes, and changes in the sense of self and reality.
Scientists have found that psilocybin shows promise as a treatment for a variety of mental health conditions, including depression and anxiety. Previous clinical trials suggest that a single dose can lead to lasting improvements in mood and thinking. However, the physical and functional changes in the brain that accompany these lasting psychological benefits are not fully understood.
To address this knowledge gap, researchers from the University of California, San Francisco and Imperial College London conducted an exploratory study to look at what happens in the brains of people who experience high doses of psilocybin for the first time. They wanted to track both the immediate effects while the drug was active and the long-term changes that occurred after a few weeks. By looking at people who had never taken psychedelics before and had no diagnosed mental health conditions, scientists had more freedom to conduct large-scale testing and understand the drugs’ pure effects.
They specifically aimed to measure a concept known as the entropic brain effect. In physics, entropy refers to the level of disorder or randomness within a system. The entropic brain theory, when applied to the human mind, proposes that psychedelic states produce highly diverse and unconstrained patterns of brain activity.
Human brain activity during normal waking hours tends to follow a strict, predictable pattern. Under the influence of psychedelic drugs, the entropy of the brain increases. This means that neural activity becomes more unpredictable and diverse. The brain processes richer information, which is subjectively experienced as a highly intense and content-rich state of consciousness. Scientists wanted to see if this temporary change in brain entropy could predict positive psychological outcomes.
To conduct the study, researchers recruited 28 healthy adults with an average age of 41 years. The group was divided equally between men and women. None of the participants had ever used hallucinogens. This study was designed to compare a small, inactive dose of psilocybin to a larger, fully active dose within the exact same group of people.
Participants received two separate administration sessions exactly one month apart. During the first session, they were given 1 milligram of psilocybin. It is considered a placebo because it is too small to produce a significant psychological effect. One month later, the participants returned to the lab to receive 25 milligrams, a dose widely known to induce intense psychedelic experiences.
The researchers used several techniques to measure brain activity and structure throughout the study period. To understand the immediate effects of the drug, they used electroencephalography. The technique involves placing a series of sensitive sensors on a person’s scalp to record electrical signals produced by active brain cells. Participants wore these sensors at 4-minute intervals while resting with their eyes closed before ingesting the drug, and again 1, 2, and 4.5 hours after ingestion.
To examine physical and functional changes in the brain over time, scientists used magnetic resonance imaging. This brain scanning technology uses powerful magnets to take detailed pictures of the brain. Participants underwent these brain scans at the start of the study, one month after receiving the placebo, and one month after receiving the high dose.
The scientists used a specific type of magnetic resonance imaging that tracks the diffusion of water molecules along white matter tracts in the brain. White matter acts like a communication highway, connecting different brain regions so they can send electrical signals to each other. 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 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 and gaining a deeper understanding of your own thoughts, feelings, and behaviors. Participants completed these behavioral assessments at various scheduled time points before each dosing session and up to 1 month after dosing.
When the researchers analyzed the data, they found that 1 milligram of the placebo did not cause any significant changes in the brain or psychology. However, a dose of 25 milligrams produced measurable changes 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 most unusual state of consciousness they had ever experienced. The rest rated the event as being in the top five most unusual experiences.
Electroencephalogram recordings during active sessions showed a significant increase in brain signal complexity within 60 minutes of drug ingestion. This increase in electrical randomness is consistent with entropic brain theory, indicating that the brain enters a highly flexible state and processes richer information under the direct influence of compounds.
This temporary increase in brain entropy tended to predict positive psychological outcomes for the volunteers. Participants who experienced higher levels of electrical randomness during active sessions reported experiencing more psychological insight the following day. In turn, those who reported the most psychological insight tended to have the greatest improvements in their overall well-being after two and four weeks, and reported feeling more optimistic about the future and coping better with their problems.
The authors suggest that this sequence provides evidence that chaotic brain changes directly enable changes in perspective that enhance long-term mental health.
“Psychedelic means revealing the mind or making the mind visible,” said senior author Robin Carhart Harris. “Our data show how the experience of such psychological insight is related to the entropic quality of brain activity, and how both are involved in subsequent improvements in mental health. We suggest that this trip and its correlation in the brain is a key component of how psychedelic therapy works.”
Brain scans one month after high doses revealed physical changes in the white matter pathways that connect the front and deep parts of the brain. Scientists observed a decrease in the diffusion of water along these pathways. This indicates that the neural pathways were denser and had more integrity. The authors note that this is the opposite of what occurs during the normal aging process, where the neural tube tends to become more diffuse.
These physical changes were correlated with decreased modularity of brain networks. Modularity is a measure of how tightly the human brain is divided into separate and independent functional networks. Less modularity means the brain communicates more fluidly between different regions. Participants also showed improved performance on tests of cognitive flexibility one month after receiving the high dose.
“Psilocybin appears to loosen fixed patterns of brain activity, giving people the ability to modify rigid thinking patterns,” said Taylor Lyons, lead author of the study. “The fact that these changes can be tracked with insight and improve well-being is particularly exciting.”
These findings could help improve the treatment of mental illnesses by ensuring that the correct doses are used to generate the right amount of brain entropy to promote insight.
“We already knew that psilocybin could help treat mental illness,” Carhart-Harris said. “But now we have a better understanding of how to do it.”
Although this study provides interesting evidence about the brain’s response to psilocybin, the authors highlight several potential misconceptions and limitations. The researchers caution that further research is needed to better understand the exact biological meaning of the white matter changes. Interpretation is complicated because these structural changes may 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, with all participants receiving a placebo first and then a higher dose. The scientists chose this structure because high doses of psilocybin can cause lasting psychological changes and contaminate subsequent placebo sessions. With this design, some of the improved performance on cognitive tests may be related to the effects of the practice rather than the drug itself.
Another limitation is the small sample size of only 28 people. Studies of small groups may yield results that are not completely representative of the broader population. Future studies are needed to validate these findings using different study designs, larger groups of people, and more advanced imaging techniques.
Lyons T, Spriggs M, Kerkela L, Kerkela FE, Rosas L, Roseman L, Mediano PAM, Timmerman C, Oestreich L, Pagni BA, Seifman RJ, Hampshire A, Trender W, Douglas HM, Gahan M, Godfrey K, Kettner H, et al. Sharif, L. Spanish, A. Ghazali, MB Wall, D. Elizzo, DJ Nutt, and RL Carhart-Harris.
