Summary: A randomized, double-blind phase 2 study compared the psychedelic compound psilocybin with the selective serotonin reuptake inhibitor (SSRI) escitalopram for people with moderate-to-severe major depressive disorder. Over a six-month follow-up both treatments produced sustained reductions in depressive symptoms, but participants who received psilocybin reported larger and lasting gains in psychosocial measures such as meaning in life, psychological connectedness, and social functioning.
The findings suggest that psilocybin-assisted therapy may offer a broader, more holistic benefit for some patients with depression by addressing both symptom severity and elements of well-being that contribute to everyday functioning. Psilocybin remains an experimental therapy and was administered in carefully controlled clinical settings in this trial.
Key facts:
- Both psilocybin therapy and escitalopram reduced depressive symptom severity up to six months after treatment.
- Psilocybin therapy produced greater improvements in meaning in life, psychological connectedness, and social functioning compared with escitalopram.
- Psilocybin is still experimental and was delivered under strict clinical supervision in this study.
Source: European College of Neuropsychopharmacology
Headline: Direct comparison finds similar antidepressant effects but additional psychosocial benefits with psilocybin
Researchers comparing two different treatment approaches for depression—psilocybin-assisted therapy and a standard SSRI, escitalopram—found comparable reductions in depressive symptoms over six months, while psilocybin was associated with larger improvements in psychosocial outcomes. The work was presented at the ECNP Congress in Milan and is accompanied by a related open-access paper in EClinicalMedicine.
Lead researcher Tommaso Barba (PhD candidate, Imperial College London) explained that this study is among the first to evaluate long-term outcomes beyond symptom reduction, examining overall well-being and daily functioning. Earlier reports from the same trial showed similar improvements in core depressive symptoms at six weeks. The current six-month observational follow-up highlights additional domains where psilocybin therapy appears to outperform escitalopram, notably in meaning, connectedness, and social and occupational functioning.
Barba noted that prior research and patient reports suggest psilocybin can sometimes improve sexual drive, whereas SSRIs commonly reduce libido—though this trial did not focus on sexual functioning as a primary outcome. He emphasized that while SSRIs are effective for many patients, psilocybin-assisted therapy could represent an alternative for some people concerned about SSRI side effects or seeking broader improvements in quality of life.
The trial, conducted by researchers at Imperial College London, enrolled 59 participants with moderate-to-severe major depressive disorder. Thirty participants received two oral 25 mg doses of psilocybin combined with psychological support (psilocybin therapy), while 29 participants received a six-week course of escitalopram (10 mg daily for three weeks, then 20 mg daily for three weeks) with matched psychological support. Each group received a comparable amount of therapeutic contact—about 20 hours in total. Follow-up assessments continued for six months after treatment.
Both treatment arms showed sustained improvement in depressive symptoms through the six-month follow-up period. The between-group difference in the primary clinical measure (QIDS-SR-16) at six months was small and not statistically significant. However, secondary outcomes revealed substantial differences favoring psilocybin therapy: measures of work and social adjustment, psychological connectedness, and meaning in life all showed larger mean improvements in the psilocybin arm, with effect sizes judged to be clinically meaningful.
Dr. David Erritzoe, Clinical Director and Deputy Head of the Centre for Psychedelic Research at Imperial College, commented that improvements in connectedness and life meaning can have a profound impact on daily functioning and long-term mental health. He added that psilocybin therapy may be a more holistic option for some patients by addressing both symptoms and broader aspects of well-being.
The authors caution that psilocybin remains an experimental treatment. In the trial it was administered in secure, clinically supervised settings with psychological support before, during, and after dosing—conditions that differ substantially from recreational use. Recreational psychedelic use carries unpredictable risks and can be harmful, particularly for people with pre-existing mental health vulnerabilities.
External commentators note important caveats: the trial was relatively small and not powered to detect subtle differences between treatments, missing data and the potential for additional interventions during follow-up complicate interpretation, and safety in the extended follow-up period was not comprehensively assessed. Such limitations underline the need for larger, well-controlled studies before drawing firm conclusions about comparative effectiveness and safety.
About this psychopharmacology research news
Author: Tommaso Barba
Source: European College of Neuropsychopharmacology
Contact: Tommaso Barba – European College of Neuropsychopharmacology
Image: The image is credited to Neuroscience News
Original research: Open access. “Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial” by Tommaso Barba et al., published in EClinicalMedicine.
Abstract
Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial
Background
Psilocybin-assisted therapy has been shown to produce rapid antidepressant effects in major depressive disorder (MDD). However, before this trial there had not been a long-term comparison between psilocybin therapy and established pharmacotherapies such as SSRIs in terms of both symptom reduction and broader measures of well-being.
Methods
This six-month follow-up reports outcomes from a phase 2, double-blind, randomized controlled trial conducted in the UK. Eligible adults (18–80) had a confirmed diagnosis of MDD, moderate-to-severe depression (HAM-D ≥17), and no contraindications to MRI or SSRIs. Participants were randomly assigned to either psilocybin therapy—two oral doses of 25 mg psilocybin with psychological support—or to a six-week escitalopram regimen (10 mg daily for three weeks, 20 mg daily for three weeks) with matched psychological support. The trial’s primary outcome at six weeks (QIDS-SR-16 change) has been reported previously; this report focuses on the six-month observational follow-up. Secondary outcomes included measures of social functioning, connectedness, and meaning in life. Study registration: NCT03429075.
Findings
Between January 2019 and March 2020, 59 participants were randomized (30 to psilocybin, 29 to escitalopram). At six months, 25 participants in the psilocybin arm and 21 in the escitalopram arm completed follow-up assessments. Both groups showed sustained reductions in depressive symptom severity at six months. The between-group difference on the self-reported depression scale (QIDS-SR-16) was small and not statistically significant. Secondary outcomes revealed larger improvements for the psilocybin group in work and social adjustment, psychological connectedness, and meaning in life, with statistically significant between-group differences on these measures.
Interpretation
Six-week intensive interventions of either psilocybin therapy or escitalopram, each combined with psychological support, were associated with lasting improvements in depressive symptoms up to six months. The psilocybin arm demonstrated greater improvements in psychosocial functioning, connectedness, and meaning in life, suggesting potential added benefits worth further investigation. These findings are descriptive and should be interpreted cautiously given limited power, missing data, potential additional treatments during follow-up, and reliance on self-reported measures.
Funding
This research was supported by the Alexander Mosley Charitable Trust and founding partners of Imperial College London’s Centre for Psychedelic Research.