Psilocybin Reversed Depression-Like Behaviors in Stressed Rats and Boosted Brain Growth Signals

For weeks, a group of laboratory rats was exposed to a relentless cycle of stress: tilted cages, flashing lights, and unpredictable disruptions to food and water. Eventually, the animals stopped doing something researchers use as a key sign of lost pleasure. They stopped drinking sweetened water.

Then they received two low doses of psilocybin, spaced a week apart. The change that followed has raised fresh questions about whether psychedelic compounds could one day do more than temporarily ease depression symptoms. The new research suggests psilocybin may reverse some stress-related behaviors in rats while restoring signals linked to brain cell growth, although the findings remain far from proof that the same thing happens in humans.

The Rats Started Drinking Sweet Water Again

Loss of interest in sweetened water is used by researchers as a measure of anhedonia in rodents. Anhedonia refers to a reduced ability to experience pleasure and is also a major feature of depression in humans. After receiving psilocybin, the stressed rats returned to drinking normally, according to findings published in Progress in Neuro-Psychopharmacology and Biological Psychiatry.

The changes did not stop there. The animals were also tested in several behavioral experiments, including a light and dark box, an elevated maze, an open arena, and a water cylinder. Across those tests, the treated rats showed fewer behaviors associated with chronic stress and depression-like states. The study raises a major question that has followed psychedelic research for years: could a treatment trigger longer-lasting changes after the drug itself has left the body?

The Study Put Chronic Stress to the Test

The researchers deliberately exposed the animals to multiple unpredictable stressors before treatment. That matters because chronic stress can alter hormone activity, behavior, and processes associated with brain plasticity.

The team then gave the animals two low doses of psilocybin. The doses were separated by one week, allowing researchers to observe whether the effects continued beyond the compound’s immediate action. Their results suggested that some changes remained visible well after psilocybin had cleared from the animals’ systems.

Stress Hormone Levels Dropped Fast

Chronic stress can keep corticosterone levels elevated in rats. Corticosterone serves a similar role to cortisol in humans and is a major part of the body’s stress response. In the study, corticosterone levels fell within two hours of the first psilocybin dose.

The more striking finding came later. Two weeks after the second dose, the animals still showed normalized hormone levels and increased signals associated with brain growth. That persistence has attracted attention because conventional antidepressants often require weeks before patients experience their full effects. The results do not prove that psilocybin permanently resets the brain’s stress system, but they suggest that the compound may trigger biological changes that outlast its immediate presence.

Researchers Found Signs Linked to New Brain Growth

The hippocampus plays a major role in memory and emotion, and prolonged stress has been associated with changes in this region. In the treated rats, researchers found increased levels of brain-derived neurotrophic factor, or BDNF, in both the hippocampus and the frontal cortex.

BDNF is involved in the survival, growth, and maintenance of neurons. The animals also showed signs associated with neurogenesis, the process through which new neurons are formed. Psilocybin is converted in the body into psilocin, which interacts with serotonin receptors, particularly the 5-HT2A receptor.

Researchers are also investigating whether psilocin interacts with the TrkB receptor, which is closely linked to BDNF signaling. Previous mouse research has found increases in markers such as BrdU and doublecortin in the dentate gyrus, a part of the hippocampus associated with the formation of new neurons. Together, these findings have fueled growing interest in whether psychedelic compounds could influence neuroplasticity in ways that conventional treatments do not.

The Biology Still Has Important Limits

The Polish researchers were careful about what they actually measured. The study examined messenger RNA connected to the growth protein, meaning researchers identified the genetic instructions involved in producing the protein rather than directly confirming the finished protein inside those cells.

That distinction is crucial. Animal models also cannot perfectly reproduce human depression, which involves psychological and social experiences that cannot be recreated inside a laboratory cage. A review of 266 rodent psychedelic studies published between 2014 and 2026 raised further concerns about how animal experiments are conducted. The review found that only 14% tested animals during their active phase, 7% used enriched cages, and 21% described procedures intended to reduce handling-related stress.

• Animal behavior has limits: A rat model can reveal biological mechanisms, but it cannot reproduce the full experience of human depression.
• mRNA is not the finished protein: Measuring genetic instructions does not automatically confirm how much functional protein was produced.
• Human neurogenesis remains unproven: There is currently no direct evidence showing psilocybin causes new neurons to grow in a living person’s hippocampus.
• The research environment matters: Stress caused by handling and housing conditions can influence how laboratory animals behave.

Two Psilocybin Doses Were Compared With Six Weeks of Escitalopram

The human research is more complicated, but it has produced results that continue to drive interest in psilocybin-assisted therapy. In a phase 2 trial at Imperial College London, 59 adults with moderate to severe depression were divided into two groups. Thirty participants received two 25 mg doses of psilocybin, while 29 received daily escitalopram for six weeks at doses of up to 20 mg.

Both groups also received roughly 20 hours of psychological support. After six weeks, remission was reported in 57% of the psilocybin group and 28% of the escitalopram group. However, the trial’s primary measure, average reductions in depression scores, did not show a statistically significant difference between the treatments.

David Nutt, who worked on the trial, described the distinction clearly: “We did show that remission rates were much higher for psilocybin than for escitalopram even though the mean scores for depression reductions were not different.” The finding illustrates why the excitement surrounding psychedelic treatment still requires caution. Different measurements can produce different pictures of how well a treatment performs.

Some Benefits Were Still Present Six Months Later

Researchers continued following 25 people from the psilocybin group and 21 from the escitalopram group for six months. Both groups maintained improvements in their depression symptoms, while participants who received psilocybin reported larger gains in areas including social functioning, connectedness, and a sense that life had meaning.

Nutt stressed that the follow-up had limitations. Once the formal treatment period ended, researchers could no longer fully control other treatments or experiences that may have affected participants. The study was also not designed to detect every small difference between the groups.

Still, Nutt said: “Just 2 psilocybin doses are at least as effective at treating depression as 6 weeks treatment with escitalopram with better remission rates and improved well-being outcomes up to 6 months.” Those results have helped push psilocybin research further into mainstream psychiatric science, even though major regulatory and clinical questions remain unresolved.

Psilocybin Is Still Not a Standard Depression Treatment

The rat research points toward the possibility of longer-lasting biological changes after psilocybin treatment. The animals continued showing improvements after the compound itself was gone from their systems, including a return of interest in sweetened water and changes in stress-related biology.

Human medicine has not reached the same conclusion. Psilocybin is still an experimental treatment for depression, and the controlled settings used in clinical trials are very different from recreational drug use. In April 2026, the FDA granted Compass Pathways a rolling review request for its synthetic psilocybin program for treatment-resistant depression, based on phase 3 data, along with a priority voucher that could accelerate review once an application is submitted.

David Erritzoe, who led the six-month follow-up research, has emphasized the importance of the controlled treatment environment. Psilocybin in clinical research is administered with screening, preparation, psychological support, and professional monitoring. Those safeguards are part of the treatment model being studied.

Erritzoe explained the potential value of the findings by saying: “This is important because improving connectedness and having greater meaning in life can significantly enhance a person’s quality of life and long-term mental health.”

The most intriguing part of the new rat study may be how long the effects appeared to last. The drug was gone, yet some of the animals’ behavior and biological markers remained changed. Whether that same pattern can be safely reproduced in people is one of the biggest questions psychedelic researchers are now trying to answer.

Sources:

• Petrova, K. (2026, August 29). Psilocybin reverses depressive behaviors and restores brain cell growth in stressed rats. PsyPost – Psychology News. https://www.psypost.org/psilocybin-reverses-depressive-behaviors-and-restores-brain-cell-growth-in-stres/
• Pubmed.ncbi.nlm.nih.gov. (n.d.-c). https://pubmed.ncbi.nlm.nih.gov/42009274/