Psilocybin reverses depressive behaviors and restores brain cell growth in stressed rats

Two doses of the psychedelic compound psilocybin can reverse signs of depression and anxiety in rats exposed to chronic stress. The substance appears to work by encouraging the growth of new brain cells and normalizing stress hormone levels. The research was published in Progress in Neuropsychopharmacology & Biological Psychiatry.

Major depressive disorder affects millions of people worldwide. Its core symptoms include persistent low mood, severe anxiety, and an inability to feel pleasure. The condition is associated with a loss of synaptic connections in areas of the brain responsible for regulating emotions. Current medications, such as selective serotonin reuptake inhibitors, do not work for every patient and often take weeks to show any benefit.

Researchers are increasingly looking toward psychedelic substances as alternative therapies. Psilocybin is the active compound found in “magic mushrooms” and has shown promise in treating depression in human trials. Scientists are trying to figure out exactly how the chemical alters the brain to produce these lasting benefits.

Prolonged psychological stress can physically alter the brain by reducing the formation of new connections between neurons. Chronic stress also hyperactivates the body’s natural response to threats, leading to an overproduction of stress hormones from the adrenal glands. Over time, this hormonal flood impairs a region of the brain called the hippocampus, which handles emotion and memory.

Agnieszka Bysiek and Krystyna Gołembiowska, researchers at the Polish Academy of Sciences, led an investigation into how psilocybin might repair this stress-induced damage. They worked alongside colleagues from the Medical University of Warsaw. The team designed an experiment to track behavioral changes and biological markers of brain healing.

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The researchers conducted a small study using adult male rats. They divided the animals into groups and exposed one group to a routine of unpredictable mild stressors over several weeks. These stressors included temporary food or water deprivation, tilted cages, and strobe lights.

The goal was to induce a state similar to human depression, particularly a loss of pleasure known as anhedonia. To measure this loss of pleasure, the researchers tracked how much sweetened water the rats chose to drink. The stressed animals drank substantially less sugar water than the unstressed control group.

The researchers then administered two low doses of psilocybin to the animals, spaced one week apart. Following the treatment, the stressed rats resumed drinking the sweetened water at normal levels. This behavioral shift indicated that the psychedelic compound had effectively reversed their anhedonia.

Next, the team evaluated anxiety-like behavior using specialized laboratory enclosures. One test used a box divided into a brightly lit area and a dark compartment, while another used an elevated maze with both open and enclosed walkways. Stressed rats naturally avoided the light and open spaces, seeking the safety of the dark or enclosed areas.

Following the psilocybin treatment, these stressed animals spent more time exploring the bright and open sections of the enclosures. This change in movement patterns suggested a marked reduction in anxiety. The researchers also monitored the animals for head shakes, a common physical reaction in rodents that indicates a drug is causing hallucinatory effects. Both the stressed and non-stressed rats exhibited these shakes after receiving psilocybin.

The researchers also observed the rats in a cylinder filled with water to measure behavioral despair. Rats that simply float without trying to escape are considered to be exhibiting a depressive-like lack of motivation. The psilocybin treatment reduced this immobility, causing the stressed rats to actively swim and climb the walls of the cylinder.

To ensure the animals were not simply experiencing general hyperactivity from the drug, the team placed them in a large, circular open arena. The stressed rats given psilocybin walked around and explored the center of the arena more than untreated stressed rats. The psilocybin actually reduced walking and exploration in the non-stressed control rats.

The team then examined the brains of the animals to understand the biological changes driving these behavioral shifts. They used chemical markers to identify newly formed cells in the hippocampus. The chronic stress had suppressed the creation of new neurons in this region.

The psilocybin injections reversed this cellular deficit. The drug promoted the proliferation, maturation, and survival of new brain cells in the stressed rats. This finding supports the idea that psychedelics help the brain rewire itself by physically growing new cellular architecture.

The researchers also analyzed the genetic expression of a molecule called brain-derived neurotrophic factor. This protein helps neurons grow and form new synaptic connections. They found that psilocybin boosted the genetic instructions for producing this growth protein in both the hippocampus and the prefrontal cortex.

This boost in genetic signaling was apparent just two hours after the first dose. The elevated signals persisted for two weeks after the second dose in the stressed animals. Finally, the researchers measured corticosterone, a major stress hormone in rodents.

The chronically stressed rats had elevated levels of this hormone in their blood. A single dose of psilocybin brought these hormone levels back down to normal within two hours. Fourteen days after the second dose, the stressed animals still maintained lower, healthier hormone levels.

The study comes with a few limitations that provide context for the results. Animal models of depression do not perfectly map onto complex human psychological conditions. The testing environment also heavily influenced the behavior of the rodents, as the animals reacted differently depending on whether they were in an open arena or an enclosed box.

The biological measurements also require a measured interpretation. The research team measured the messenger RNA for the brain growth protein rather than the actual protein itself. Messenger RNA acts as a temporary set of genetic instructions translated from DNA. An increase in these instructions does not always guarantee a proportional increase in the final functional protein product within the brain’s cells.

Future research will need to measure the actual protein levels in the brain to confirm that the biological building blocks were fully assembled. Scientists also plan to investigate how long these cellular changes last after the psychedelic compound leaves the body.

The research provides a foundation for understanding how psychedelic therapies might repair the physical toll of chronic stress. The study, “Psilocybin restores behavioral and neuroplastic deficits induced by chronic stress in rats,” was authored by Agnieszka Bysiek, Izabela Szpręgiel, Adam Wojtas, Marzena Maćkowiak, Agnieszka Wawrzczak-Bargieła, Monika Leśkiewicz, Ewa Trojan, Katarzyna Kamińska, Weronika Kumorek, Wiktor Bilecki, and Krystyna Gołembiowska.