A new study published in Human Brain Mapping suggests that a single high dose of psilocybin, the active compound in “magic mushrooms,” changes how information flows through specific brain circuits up to a month later. By using computer models to analyze brain scans, researchers found evidence that the brain becomes more flexible and shifts its communication patterns from top-down control to bottom-up sensory processing. These long-term changes in brain dynamics might help explain why the substance tends to relieve symptoms across various mental health conditions.
Psilocybin is currently being explored as a potential treatment for debilitating conditions like depression, anxiety, addiction, and eating disorders. Clinical trials provide evidence that one or two moderate to high doses can improve mental well-being for up to six months. The serotonin receptor known as 5-HT2A acts as the primary target for psilocybin in the brain. When this receptor is activated, people experience the immediate psychedelic effects of the drug.
Brain imaging has shown that during this acute phase, higher-level cognitive networks become less cohesive, allowing different parts of the brain to communicate more freely. Much less is known about how the brain reorganizes itself weeks after the drug wears off. Past research points to enduring changes in regions connected by fronto-striatal-thalamic circuits. These pathways connect the frontal lobes, which handle complex decision-making, to deeper structures like the striatum and thalamus, which process rewards, motivation, and sensory information.
“Psilocybin has shown remarkable promise in producing rapid and sustained improvements in symptoms across several psychiatric disorders, yet the brain mechanisms underlying these long-term effects remain poorly understood,” said Lorenzo Pasquini, an assistant professor in the Department of Neurology at the Weill Institute for Neurosciences at the University of California, San Francisco.
“Recent studies in healthy volunteers have suggested that psilocybin can induce lasting structural changes in frontostriatal circuits, a network involved in motivation and goal-directed behavior. We wanted to build on these findings by examining how the functional dynamics of these circuits change over time after a single dose of psilocybin, and whether computational modeling could provide insights into the underlying neurochemical mechanisms.”
The authors recruited 25 healthy adults who had never taken psychedelic drugs. The participants underwent brain scans using functional magnetic resonance imaging, a technique that measures brain activity by tracking blood flow. The participants completed a baseline brain scan and a survey measuring their mental well-being on a scale with a general population average of 51.
The next day, they received a small, one-milligram dose of psilocybin. This served as a control condition because it is too low to produce noticeable psychedelic effects. Four weeks after this control dose, the participants returned for a second brain scan and well-being survey. The next day, they received a fully active, 25-milligram dose of psilocybin. Finally, four weeks after the high dose, the participants underwent their third and final brain scan and completed the well-being survey one last time.
The scientists first examined how uniform the activity in the frontal, striatal, and thalamic brain regions remained over the course of each scanning session. They found that the differences were not statistically significant when comparing the baseline scan and the scan four weeks after the low control dose. However, four weeks after the 25-milligram dose, the brain activity in these regions became much more variable over time compared to the one-milligram control scan.
This increased flexibility in brain activity tended to align with increases in the participants’ self-reported mental well-being scores. The researchers controlled for the participants’ baseline well-being, baseline brain activity, and head movement during the scans to ensure these factors did not distort the findings.
To figure out the mechanics of this increased flexibility, the researchers used a mathematical computer model to simulate the brain’s physical wiring. The physical wiring of the brain normally restricts how different regions fire together, acting like roads that guide traffic. The computer model provides evidence that four weeks after the high dose of psilocybin, this physical wiring had a weaker constraining effect on the brain’s functional activity. This reduced structural constraint allowed the brain regions to adopt more diverse and flexible activity patterns.
Next, the authors looked at the direction of information flow between different brain areas, a concept known as effective connectivity. By analyzing the timing of the brain signals, the model estimates whether one region is sending information to another. The models showed that four weeks after the high dose, top-down information flow from higher-order cortical areas, like the prefrontal cortex, decreased. In contrast, bottom-up information flow from deeper, lower-order subcortical regions, such as the thalamus and putamen, increased.
The researchers then mapped these changes in information flow onto publicly available atlases that show where specific chemical receptors are concentrated in the brain. They found that the decreases in top-down control matched the physical distribution of serotonin 5-HT2A receptors in the cortex. At the same time, the increases in bottom-up information flow from deeper brain regions matched the distribution of dopamine D2 receptors. Dopamine is a chemical messenger heavily involved in processing rewards and learning.
“One of the most exciting aspects of the study was how computational modeling was able to reveal potential neurochemical mechanisms that would not have been apparent from brain imaging data alone,” Pasquini told PsyPost. “This highlights the value of combining neuroimaging with mechanistic modeling to better understand how neuropharmacological interventions affect the brain over time.”
“Our findings suggest that a single psilocybin experience may produce lasting changes in the way brain regions involved in motivation communicate with one another,” Pasquini added. “By combining brain imaging with computational modeling, we found evidence that these long-term changes are consistent with contributions from both serotonin- and dopamine-related systems. While more work is needed, these results provide new clues about how psilocybin may support lasting changes in mood and behavior.”
The small sample size of 25 participants means that the statistical evidence supporting these brain changes is relatively modest. The exact mathematical parameters and simulated brain patterns serve as tentative approximations rather than definitive biological facts. Because all participants received the exact same doses in the exact same order, factors like getting used to the scanning environment or expecting a positive outcome could have influenced the brain activity readings. The study design makes it difficult to completely separate the chemical effects of the drug from the psychological effects of participating in a month-long trial.
Another limitation is the use of generalized, public brain maps to locate serotonin and dopamine receptors. Every individual has a slightly different brain structure and chemical makeup, so relying on group averages obscures personal differences that might dictate how someone responds to psilocybin. The study also focuses narrowly on specific frontal and striatal circuits, leaving out other brain networks, like those involving the hippocampus.
“An important point is that our study does not directly measure serotonin or dopamine activity,” Pasquini noted. “Instead, our conclusions are based on computational models informed by known receptor distributions. These findings should therefore be viewed as generating mechanistic hypotheses that will need to be tested in future experimental studies.”
Future research needs to track these brain changes using larger groups of people, individualized brain scans, and randomized, placebo-controlled designs.
“Our long-term goal is to better understand how psilocybin influences motivation, social behavior, and well-being over time,” Pasquini said. “We are now extending this work into longitudinal clinical trials to investigate how changes in brain function relate to meaningful improvements in psychological health, particularly in older adults.”
“This study was a wonderful international collaboration between researchers at the University of California, San Francisco, Universitat Pompeu Fabra, and Imperial College London,” Pasquini concluded. “We are also grateful for the support of the Alexander von Humboldt Foundation, which helped make this collaboration possible.”
The study, “Modeled Long-Term Effects of Psilocybin on Dynamic Activity and Effective Connectivity of Fronto-Striatal-Thalamic Circuits,” was authored by Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs, Yonatan Sanz Perl, Adrian Ponce-Alvarez, Sebastian Idesis, Manesh Girn, Leor Roseman, Jennifer M. Mitchell, Adam Gazzaley, Robin L. Carhart-Harris, Morten L. Kringelbach, and Gustavo Deco.