Only a specific dose of psilocybin induces lasting antidepressant-like effects, study suggests

A new study published in Progress in Neuropsychopharmacology & Biological Psychiatry has found that a single moderate dose of psilocybin produces rapid and lasting antidepressant-like effects in rats, without the unwanted side effects seen at higher doses. The researchers showed that only an intermediate dose improved mood-related behaviors and social interaction while avoiding changes in body temperature, locomotion, and weight gain.

Psilocybin is the active ingredient in so-called magic mushrooms. It is a psychedelic compound that alters perception and consciousness and has attracted increasing interest as a potential treatment for depression, especially among individuals who have not responded to traditional antidepressants. Clinical trials have shown that even a single administration of psilocybin can lead to significant improvements in symptoms, sometimes lasting for weeks or months. However, because it can also produce strong hallucinogenic effects and other physiological changes, scientists are still working to determine the safest and most effective dosage.

In this new study, a team of researchers led by Lenka Seillier at Charles University in Prague aimed to better understand the relationship between psilocybin dose and its behavioral and physiological effects in an animal model. By testing a range of doses, they hoped to pinpoint the amount of psilocybin that produces therapeutic benefits while minimizing adverse outcomes.

The researchers used 40 male Wistar rats and divided them into five groups. Each group received either a saline control injection or one of four psilocybin doses: 0.1, 0.32, 1.0, or 3.2 milligrams per kilogram of body weight. The study design included multiple behavioral tests to assess antidepressant-like effects, social interaction, and pleasure responses. They also monitored side effects such as changes in body temperature, movement, and weight gain. In addition, they examined whether psilocybin altered levels of brain-derived neurotrophic factor (BDNF), a protein involved in brain plasticity that is often linked to depression.

To assess antidepressant-like effects, the researchers used the forced swim test, a standard behavioral test in animal models of depression. In this task, less immobility and more active behaviors such as climbing are considered signs of a more hopeful or motivated behavioral state. They also used a sucrose preference test to evaluate sensitivity to reward and a social interaction test to measure sociability. Each test was repeated across several weeks to assess both immediate and long-term effects.

The researchers found that the 0.32 mg/kg dose of psilocybin had the strongest antidepressant-like effect. Rats that received this dose were more active in the forced swim test, spent more time engaging in social behavior, and showed a stronger preference for sweetened water—an indicator of heightened sensitivity to pleasure. Importantly, these effects were evident both shortly after treatment and weeks later, suggesting that the benefits were long-lasting.

Higher doses of psilocybin, by contrast, did not produce these same benefits. In fact, the rats that received 1.0 or 3.2 mg/kg showed no improvement in mood-related behaviors. These higher doses also led to adverse effects, including reduced locomotion, decreased body temperature, and lower body weight gain over time. The results suggest that these side effects may mask or interfere with potential antidepressant effects at higher doses.

The team also measured head-twitch responses, a behavior commonly used in rodents as a proxy for psychedelic effects in humans. The number of these responses followed an inverted U-shaped curve, peaking at the 0.32 mg/kg dose and declining at the higher doses, likely due to the overall suppression of movement caused by those doses.

In terms of biological effects, the researchers found that psilocybin increased levels of BDNF in the hippocampus and prefrontal cortex—two brain regions implicated in mood and depression. These increases occurred in a dose-dependent, linear fashion, meaning the more psilocybin the rats received, the higher the BDNF levels. However, this pattern did not align with the behavioral improvements, which only occurred at the moderate dose. This suggests that while BDNF may play a role in psilocybin’s effects, it is not the only factor at work and may not directly predict therapeutic outcomes.

The study highlights a narrow window of optimal dosing for psilocybin. At low doses, there was little effect. At moderate doses, the drug enhanced mood-related behavior without causing harmful physiological changes. But at high doses, the risk of side effects increased, and the benefits disappeared. This finding underscores the importance of dose selection in ongoing research and clinical applications.

As with any study, there are limitations. The study was conducted in healthy rats rather than animal models of depression, which may limit its generalizability. The researchers also note that they did not examine potential sex differences, which could be relevant for translating findings to human populations. Additionally, while they identified a mismatch between BDNF levels and behavioral outcomes, they did not investigate other molecular pathways that might help explain the observed effects.

Future studies could expand on this work by exploring how psilocybin affects rats with depression-like symptoms, whether similar effects are seen in female animals, and what other brain systems may contribute to the therapeutic effects. Investigating the role of specific serotonin receptors could also help clarify how different doses influence mood, perception, and physical responses.

The study, “Psilocybin has a narrow therapeutic window as an antidepressant treatment,” was authored by Lenka Seillier, Barbora Čechová, Alexandre Seillier, and Romana Šlamberová.