Depression treatment is shifting, and this mushroom-derived compound is driving one of psychiatry’s biggest new tests

Depression is a debilitating mental health disorder that is estimated to affect approximately 5% of people worldwide. It is characterized by persistent feelings of sadness and hopelessness, a lack of interest in everyday activities, sleep disturbances, and possible changes in appetite. There are now several treatments for depression, including medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), as well as cognitive behavioral therapy (CBT) and other psychotherapeutic approaches. While many people diagnosed with depression respond well to one or more of these treatments, some experience few or no benefits.

Over the past decades, researchers have thus been trying to identify alternative treatments that could benefit patients who are resistant to available medications. Some recent studies suggest that psychedelic drugs—particularly a compound known as psilocybin, found in some mushrooms—could be effective in easing symptoms of depression.

Researchers from the University of Pennsylvania, Vrije University Amsterdam and other institutes recently reviewed 15 clinical trials assessing the potential of psilocybin as a treatment for depression. Their paper, published in Nature Mental Health, statistically combines the results of these trials, while also summarizing the experimental methods they relied on and their limitations.

“Depression is a growing and widespread debilitating illness, yet novel treatments are lacking,” Parker Singleton, first author of the paper, told Medical Xpress. “We sought to understand the current evidence base of psilocybin therapy for depression, while committing to updating our review periodically so that it remains up to date with the rapidly progressing field.”

Combining the results of 15 past studies

Singleton and his colleagues analyzed a total of 15 past randomized controlled trials, clinical trials in which people diagnosed with depression were randomly assigned to either an experimental or control group. People in the experimental group were treated with psilocybin, while those in the control group were given a different antidepressant, a placebo drug (e.g., a sugar pill), or a very low dose of psilocybin.

The researchers found the papers for their review on an open-access research database. The 15 studies they examined collectively included data collected from 801 participants. In their meta-analysis, the researchers examined the findings of only 12 of the studies, with a total of 585 participants.

“We searched through thousands of search results from scholarly databases to identify 15 randomized controlled trials of psilocybin for depression,” explained Singleton. “We extracted all depression-related outcomes from these trials and include them in our new publicly released database. We used meta-analytic modeling to synthesize the evidence across these trials and to identify aspects of trial design that contribute to heterogeneity in the literature.”

Across the studies examined by the researchers, psilocybin was found to significantly reduce symptoms of depression compared to the other antidepressant or inactive compounds they were compared to. Despite their promising results, the team observed that the studies had small sample sizes and highlighted the need for larger, more rigorous clinical trials.

Towards new promising treatments for psychiatric disorders

The recent work by Singleton and his colleagues could soon inspire further research assessing the potential of psilocybin as an antidepressant. The study limitations identified by the researchers and the recommendations included in their paper could help to plan more reliable large-scale clinical trials.

“Psilocybin for depression research is progressing rapidly,” said Singleton. “Four trials were published in 2025 alone, with several more anticipated this year. While traditional reviews quickly become outdated, our living review will be updated annually, ensuring that new evidence is reflected in the findings.”

The team are actively involved in a project called SYPRES (Synthesis of Psychedelic Research Studies). As part of this project, they published an interactive online dashboard and database that summarizes the latest findings in this field, also including programming code, clinical data, and other information that can be used by researchers who are conducting psychedelics-related mental health research.

“As part of the SYPRES initiative, we will now be covering more areas of the clinical psychedelic literature,” added Singleton. “We’ve already released another pre-printed review paper focusing on MDMA for PTSD treatment.”

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