A new study published in Translational Psychiatry has provided the most detailed look yet at how psilocybin affects brain activity in rodents. Researchers found that psilocybin produces widespread changes in brain network organization, disrupting normal patterns of communication between brain regions and creating a unique state of high-frequency neural connectivity. These effects varied depending on dose and time, revealing two distinct phases of brain dynamics.
Psilocybin is the active compound found in certain mushrooms and has gained attention for its potential to treat conditions such as depression, anxiety, and addiction. When consumed, psilocybin is converted into psilocin, a substance that binds to serotonin receptors in the brain and produces profound changes in perception, emotion, and sense of self. In humans, psilocybin is known to temporarily alter how different parts of the brain interact, but less is known about how these effects emerge over time or whether animal models can capture the complexity of the psychedelic state.
“We use neurochemical and neurophysiological approaches, including brain network changes, to understand the mechanistic basis of different states of consciousness and our ongoing work with psychedelics is another step in that direction,” explained study author Dinesh Pal, an associate professor at the University of Michigan.
“One of the primary challenges of studying psychedelics in animal models is the lack of a verbal report, but that also makes it fascinating, because any evidence (e.g., EEG based metrics) for a ‘psychedelic’ state in animal models, akin to what occurs in humans, would bring us closer to the idea that consciousness is a universal phenomenon; it just manifests in different ways in different species.”
To address this, the researchers used high-resolution electroencephalography (EEG) to monitor brain activity across 27 sites in the rat cortex. EEG is a noninvasive technique that measures electrical activity in the brain using sensors placed on the scalp. It records the brain’s natural oscillations, or “brain waves,” which reflect patterns of neural communication across different regions. The goal was to map how psilocybin changes the organization of brain networks and to identify specific patterns of activity that might reflect altered states of consciousness.
The study involved 12 adult Sprague Dawley rats—six male and six female—that were surgically implanted with EEG electrodes. Each rat received intravenous infusions of psilocybin at three different doses (0.1, 1, and 10 milligrams per kilogram), as well as a saline control, on separate days. The researchers recorded EEG data before, during, and after each 60-minute infusion and also monitored behavior through video recordings and movement sensors. By using a continuous infusion method rather than a single injection, the researchers were able to observe gradual changes in brain activity as the drug took effect.
The team focused on three specific frequency bands in the EEG data: theta (4–10 Hz), medium gamma (70–110 Hz), and high gamma (110–150 Hz). These frequencies are thought to play a role in coordinating communication between brain regions. Psilocybin altered both the strength and organization of activity in these bands, but not in a simple or linear way.
At moderate doses (1 mg/kg), psilocybin increased activity in the posterior theta network and strengthened communication between frontal and parietal brain areas in the gamma bands. This state was marked by widespread increases in high gamma activity in the frontal cortex and greater connectivity across distant brain regions. The researchers also found that psilocybin disrupted the normal relationship between theta and gamma activity, a phenomenon known as phase-amplitude coupling. This decoupling was most evident in frontal areas and occurred in a dose-dependent fashion.
At higher doses (10 mg/kg), a different pattern emerged. Early in the infusion, the brain showed a similar increase in gamma connectivity, but as the dose accumulated, theta connectivity in posterior regions decreased, and the gamma network in the frontal cortex became more dominant. These changes unfolded over time, revealing a shift from one state of brain organization to another as psilocybin levels rose. Notably, these effects occurred even as the rats became less physically active, suggesting the brain changes were not simply a result of movement or arousal.
The behavioral data supported this nonlinear pattern. Moderate doses of psilocybin increased the number of head-twitch responses—a common indicator of psychedelic activity in rodents—and briefly heightened movement. But at the highest dose, movement decreased significantly after about 30 minutes, even though gamma connectivity continued to increase. This suggests that the changes in brain dynamics were not just reflections of behavior but may correspond to a unique internal state.
“It was a bit surprising to note that the changes in EEG gamma connectivity – shown to be closely linked to states of consciousness – occurred in the absence of any behavioral activity or after the psilocybin-induced locomotion and/or head twitches ceased,” Pal told PsyPost. “This dissociation suggests the need for a careful assessment of head twitch response as a surrogate for psychedelic or non-ordinary states induced by psychedelic drugs in rodents.”
To quantify brain network organization, the researchers used measures such as node degree (the number of connections a brain region has) and the strength of synchronization between regions. These metrics showed that psilocybin reorganized networks in both frequency-specific and region-specific ways. The theta network, typically involved in memory and attention, became stronger in posterior regions at moderate doses but weakened at higher doses. In contrast, the high gamma network, which is thought to reflect localized activity and potentially neuroplasticity, became stronger in frontal areas as the dose increased.
One of the most striking findings was the decoupling of gamma activity from the theta phase. Under normal conditions, gamma bursts tend to occur at specific points in the theta rhythm, a coupling that is thought to help organize information flow in the brain. Psilocybin disrupted this timing relationship, particularly at higher doses, suggesting a breakdown in the usual coordination between local and long-range neural signals. This kind of decoupling has been observed in other psychedelic states and is believed to reflect a loosening of the brain’s typical constraints, allowing for more flexible or unusual patterns of thought and perception.
While the study does not prove that rats experience anything like a human psychedelic trip, the results suggest that the psilocybin state is marked by identifiable changes in brain network architecture that can be studied in animal models. These findings align with reports from human studies showing increased connectivity between distant brain regions and decreased segregation of functional networks during psychedelic experiences.
“Our findings related to brain network changes in this study, along with the data from other laboratories showing cellular and molecular level neural changes, show that rodents could indeed be a good model system to study non-ordinary states of consciousness such as a psychedelic state,” Pal said.
But there are important limitations to consider. Because rodents cannot report their subjective experiences, the researchers could not directly link changes in brain activity to changes in perception or emotion. Also, although the results support a role for serotonin receptor signaling, the study did not manipulate specific receptors to determine their causal role. Additionally, the EEG method used in this study does not measure deep brain structures like the thalamus or claustrum, which are also thought to be involved in the psychedelic state.
Despite these caveats, the findings have important implications for future research. The ability to map dynamic changes in brain networks during a psychedelic experience opens new avenues for understanding how these drugs affect consciousness and cognition. The study also provides a foundation for testing how different psychedelics might produce similar or distinct patterns of brain activity.
“One of our main focus areas is to understand if there is any unique neurophysiological or neurochemical signature that can be associated with a ‘psychedelic’ state in animal models,” Pal explained. “To that end, we have completed studies using diverse psychedelics, including subanesthetic ketamine, nitrous oxide, N’N-dimethyltryptamine, and psilocybin in the recent paper. We intend to mine these datasets for shared EEG signatures across psychedelics. In addition, we are conducting animal studies to determine the therapeutic potential of psychedelics in alleviating chronic pain (PMID: 38113836).”
The study, “Intravenous psilocybin induces dose-dependent changes in functional network organization in rat cortex,” was authored by Brian H. Silverstein, Nicholas Kolbman, Amanda Nelson, Tiecheng Liu, Peter Guzzo, Jim Gilligan, UnCheol Lee, George A. Mashour, Giancarlo Vanini, and Dinesh Pal.
