Psilocybin's Lasting Antidepressant Effects Linked to Brain Cell Activity, Not Structure

A new study has uncovered why psilocybin, the active compound in magic mushrooms, may produce long-lasting antidepressant effects. Researchers found that a single dose altered the electrical activity of brain cells in rats for months, even after physical changes had disappeared. The findings challenge earlier assumptions about how the drug works in the brain.

The study, published in Neuropsychopharmacology, compared psilocybin with another compound, 25CN-NBOH, which targets the same 5-HT2A receptor. Both substances reduced immobility in rats—a sign of antidepressant-like effects—when compared to a control group. This suggests that activating the 5-HT2A receptor alone may be enough to trigger lasting changes.

Unlike previous theories, the research found no lasting increase in dendritic spines, the tiny structures that help neurons communicate. This means the drug's long-term benefits may not come from permanent structural changes in the brain. Instead, psilocybin appeared to modify the intrinsic electrical properties of neurons, offering a new explanation for its sustained impact on behaviour.

Over the past five years, international research on psilocybin's antidepressant effects has made major progress. Key trials, including those by COMPASS Pathways and the Usona Institute, have shown symptom remission lasting 12–24 months after treatment. Leading institutions such as Johns Hopkins University, Imperial College London, and the University of California San Francisco have played central roles, alongside companies like COMPASS Pathways and MindMed.

The findings suggest that psilocybin's lasting effects depend more on changes in neuronal activity than on structural rewiring. Researchers also noted the need for future studies to include both male and female subjects to confirm broader applicability. The work adds to growing evidence supporting psilocybin as a potential long-term treatment for depression.