The psychedelic substance psilocybin has long been known for its ability to alter perception and cognition, often leaving users feeling disoriented. A new study published in the European Journal of Neuroscience explores how this drug affects brain activity at the level of individual neurons. By studying mice navigating a virtual environment, researchers discovered that psilocybin disrupts the brain’s ability to encode spatial information, shedding light on why people under its influence often experience a distorted sense of space.

Psilocybin is a naturally occurring compound found in certain types of mushrooms, often referred to as “magic mushrooms.” When ingested, it is converted in the body to psilocin, which acts on serotonin receptors in the brain, particularly the serotonin 2A receptor. Psilocybin is known for its psychedelic effects, which include altered perception, mood, and cognition, as well as experiences of profound changes in the sense of self, space, and time. While traditionally used in religious or spiritual rituals, psilocybin has gained significant scientific interest in recent years due to its potential therapeutic effects on mental health conditions such as depression, anxiety, and post-traumatic stress disorder.

Researchers are particularly interested in understanding how psilocybin works at a biological level. Studies using brain imaging in humans have shown that psychedelics like psilocybin disrupt the normal patterns of communication between different brain regions. These disruptions are thought to result in the altered states of consciousness that people experience when using the drug.

However, much of the existing research has been done using indirect measures like functional magnetic resonance imaging, which gives a broad overview of brain activity but doesn’t provide detailed information about how individual neurons are affected. This is where studies using animal models, such as this one, come into play—they allow scientists to explore the effects of psychedelics at the cellular level, offering a more precise understanding of how these substances impact brain function.

A specific focus was placed on the retrosplenial cortex, a brain region important for spatial orientation and navigation. Some neurons in this area respond to specific locations in an environment, similar to “place cells” in the hippocampus, which are critical for forming a mental map of one’s surroundings. The researchers wanted to see how psilocybin would impact this spatial encoding, potentially explaining why people on psychedelics often report changes in their sense of location.

“Psychedelics have profound effects on mental function, but we still don’t know much about how they affect information processing performed by groups of neurons,” said study author Aaron J. Gruber, a neuroscience professor at the University of Lethbridge. “Advances in cellular-level imaging in animals and computational analysis allow us to study how drugs affect the dynamical encoding of information in populations of neurons. We recorded neurons in a brain region important for forming a mental representation of the spatial environment.”

The study used ten adult mice that were genetically modified to allow for the visualization of neural activity through imaging techniques. Each mouse was trained to run on a treadmill in a head-fixed position, where they navigated a belt with specific tactile, visual, and auditory cues. The treadmill was designed to simulate a virtual environment, with rewards given after completing laps. This setup allowed the researchers to record and analyze the activity of neurons in the retrosplenial cortex as the mice performed the task.

After the mice were trained, the researchers conducted imaging sessions to monitor brain activity. They recorded the baseline neural activity in each mouse, then administered either psilocybin or a saline solution. The psilocybin was given at a dose of 15 mg/kg, and the mice were recorded again to compare neural activity before and after the drug administration. In some trials, the mice were pre-treated with a drug called ketanserin, which blocks the serotonin 2A receptor (a key receptor involved in psychedelic effects), to see if this would alter psilocybin’s impact.

The neural activity was measured using two-photon imaging, a sophisticated technique that allows researchers to observe the activity of hundreds of neurons simultaneously. The researchers focused on how neurons encoded the mouse’s position on the treadmill belt and analyzed the stability of this spatial encoding across trials.

The results showed that psilocybin had a profound effect on the neurons in the retrosplenial cortex. Normally, many neurons in this brain region are active when the mouse passes specific locations on the treadmill belt. However, after psilocybin was administered, the specificity of these neurons to particular locations was significantly reduced. This means that the neurons were no longer as reliably activated by certain places, leading to a decrease in the brain’s ability to encode spatial information.

Furthermore, the stability of this place-related neural activity across multiple trials also decreased under the influence of psilocybin. In other words, the neurons were less consistent in how they responded to specific locations from one lap of the treadmill to the next. This instability in spatial encoding likely mirrors the sense of disorientation and altered perception of space that people often experience when using psychedelics.

Another key finding was that psilocybin reduced the coordination, or functional correlation, between neurons. Neurons that usually fire together when encoding spatial information became less synchronized, suggesting that psilocybin disrupted the normal communication patterns within the retrosplenial cortex. This reduction in coordinated neural activity supports the idea that psychedelics increase the randomness, or entropy, of neural signaling.

“Psilocybin administration temporarily impaired the coordinated brain activity that tracks the animal’s position in an environment,” Gruber told PsyPost. “If something similar occurs in humans, it may help account for the altered sense of time and space frequently reported during psychedelic use.”

The role of serotonin in these effects was confirmed by the experiments involving ketanserin. When the mice were pre-treated with ketanserin before receiving psilocybin, the changes in neural activity patterns were largely prevented. This indicates that the serotonin 2A receptor is a key player in mediating psilocybin’s effects on the brain.

“Several recent high-profile reports indicate that psychedelics promote synapse formation,” Gruber noted. “We therefore expected that the high-dose psilocybin administration we used would cause a lasting change in information processing that we could detect days after the last administration. We did not find evidence for lasting changes. This suggests that any changes in synaptic structure had a very subtle effect in the neocortical brain region we investigated.”

“We previously tested the effects of the non-classic psychedelic ibogaine on the same task and setup. The effects of ibogaine and psilocybin were qualitatively similar, but ibogaine had much stronger acute effects. Ibogaine also did not have obvious long-term effects on the brain activity we investigated.”

While this study sheds light on how psilocybin affects neural activity in a specific brain region, there are several limitations to consider. First, the experiment was conducted on mice, so the findings may not fully translate to humans. While the retrosplenial cortex plays a similar role in spatial navigation across species, human experiences with psychedelics are more complex and involve higher-order cognitive functions that go beyond basic spatial encoding.

Moving forward, the researchers plan to explore how psilocybin affects other brain regions, particularly those involved in motivation and decision-making, which are relevant to conditions like depression. Understanding the broader impact of psychedelics on brain networks could offer valuable insights into how these substances might be used in therapeutic settings to help treat mental health disorders.

“This research has several goals,” Gruber explained. “One is to use the profound effects of psychedelics on perception and brain function as a tool to understand how the brain normally processes information. We also want to understand how psychedelics may help treat illnesses like major depressive disorder. The current project investigated effects in a brain region involved in memory, orientation, and navigation. Future research will investigate other brain regions more directly associated with motivational components of depression.”

The study, “Psilocybin reduces functional correlation and the encoding of spatial information by neurons in mouse retrosplenial cortex,” was authored by Victorita E. Ivan, David P. Tomàs-Cuesta, Ingrid M. Esteves, Artur Luczak, Majid Mohajerani, Bruce L. McNaughton, and Aaron J. Gruber.