Single dose of psilocybin linked to lasting symptom relief in treatment-resistant depression

A new study of U.S. military veterans suffering from severe treatment-resistant depression found that a single dose of psilocybin was associated with significant reductions in depressive symptoms that lasted up to 12 months. Six months after the intervention, 50% of participants were in remission and 80% showed a clinically meaningful response. The antidepressant effects began to wane after 9 months. The study was published in the Journal of Affective Disorders.

Depression is a mental health disorder characterized by persistent sadness, loss of interest, low energy, and difficulty functioning in daily life. It can impact mood, cognition, and physical well-being, often interfering with work, relationships, and quality of life. Standard treatments include antidepressant medications, psychotherapy, or a combination of both.

However, many individuals fail to improve with these interventions. When someone does not respond to at least two adequate trials of different antidepressants, their condition is referred to as treatment-resistant depression (TRD). People with TRD tend to experience more severe, longer-lasting depressive episodes and are at greater risk for chronic impairment.

Mental health professionals often try various strategies for TRD, such as switching medications, combining drugs, or augmenting antidepressants with other agents like antipsychotics or mood stabilizers. However, these alternatives often provide limited relief. As a result, researchers continue to explore more effective options—including psychedelic compounds such as psilocybin.

Study author Sara Ellis and her colleagues note that previous studies have shown short-term benefits of psilocybin for depression, but few have examined how long those effects last. Their study sought to track changes in depression symptoms over a 12-month period following a single dose of psilocybin in a group of military veterans.

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Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms, often referred to as “magic mushrooms.” In medical research, psilocybin is being studied for its potential to treat conditions such as depression, anxiety, post-traumatic stress disorder, and addiction. When administered in a controlled setting with psychological support, clinical trials suggest psilocybin may produce rapid and lasting improvements. However, it can also cause adverse effects such as distressing hallucinations, anxiety, confusion, and nausea, and it remains a controlled substance in many jurisdictions.

In this pilot study, the researchers followed 10 U.S. military veterans diagnosed with severe treatment-resistant depression. Although the sample size was small, military veterans represent a high-risk group for depression, particularly forms that are resistant to treatment, making the study especially relevant.

Before dosing, participants took part in two 60-minute and one 90-minute preparatory therapy sessions. On the dosing day, they each received a single 25 mg capsule of psilocybin. Sessions were conducted at Stanford University School of Medicine with two licensed therapists present, lasting 6 to 8 hours. Participants’ vital signs were monitored before and after dosing. The next day, they participated in a 90-minute integration session, followed by at least two additional integration sessions—one during the first week and one at 12 weeks post-treatment.

Participants were assessed for depressive symptoms, anxiety, and functional impairment at multiple timepoints up to 12 months after dosing. Measures included the Montgomery–Åsberg Depression Rating Scale (MADRS), the Quick Inventory of Depressive Symptoms (QIDS), and the Sheehan Disability Scale (SDS). They also completed the Five-Dimensional Altered States of Consciousness scale to assess their psychedelic experience, and safety and tolerability were monitored throughout.

The results showed a significant reduction in depression scores across all timepoints. At 6 months, 50% of participants met criteria for remission—meaning their symptoms were minimal or absent—and 80% experienced a clinically meaningful reduction in symptoms.

However, the antidepressant effects began to fade after 6 months. By 12 months, 40% of participants still met response criteria and 30% remained in remission. While scores were higher than at 3 or 12 weeks post-treatment, they were still significantly lower than at baseline.

“In this first-of-kind study on long-term effects of psilocybin for Veterans with severe TRD [treatment-resistant depression], depression scores showed significant sustained reductions up to 12-months. However, the antidepressant effects began to wane at 6 months, and then more substantially after 9 months, although these increases in MADRS did not reach statistical significance. Further research is needed,” the study authors concluded.

The study adds to growing evidence that psilocybin may offer long-term benefits for depression, especially in populations that have not responded to conventional treatments. However, the study had several important limitations. It did not include a control group, and participants were aware they were receiving psilocybin, which raises the possibility of expectancy effects or placebo responses. This introduces the potential for the Hawthorne effect, in which individuals change their behavior because they know they are being observed.

Without a control condition, it is difficult to determine how much of the observed improvement is due to psilocybin itself, and how much might be attributed to psychological support, natural symptom fluctuations, or other factors. The small sample size further limits the generalizability of the results.

The paper, “Long-term outcomes of single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression – 12-month data from an open-label pilot study,” was authored by Sara Ellis, Catherine Bostian, Anna Donnelly, Wendy Feng, Katherine Eisen, Melanie Lean, Elizabeth Conlan, Michael Ostacher, Scott Aaronson, and Trisha Suppes.