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Psilocybin administered to patients with treatment-resistant depression (TRD) in routine clinical practice was associated with clinically meaningful improvements in depressive symptoms.

Results of a small real-world study provide some of the first systematically collected evidence of psilocybin’s use in routine clinical practice, including in patients with complex, difficult-to-treat depression who are often excluded from clinical trials.

Although some participants received up to four psilocybin sessions, investigators found no clear signal that additional treatments conferred added benefit, though they cautioned that the study was not designed to answer that question.

The findings provide some of the first evidence on the use of psilocybin outside controlled clinical trials, the investigators, led by Johannes Jungwirth, MD, of the Department of Adult Psychiatry and Psychotherapy at the University of Zurich in Zurich, Switzerland, wrote.

“This study marks an important first step in investigating the outcomes and safety of multiple, flexibly scheduled psilocybin sessions in clinical practice,” they added.

The study was published online on June 1 in The Lancet Regional Health. 

A Highly Resistant Population

About half of patients with major depressive disorder (MDD) fail to achieve remission despite multiple antidepressant trials.

Psilocybin, which primarily acts as a 5-HT2A receptor agonist, inducing alterations in cognition, perception, and affect, is emerging as a promising treatment for TRD.

While the specific mechanisms underlying the antidepressant effect of psilocybin aren’t fully understood, they likely involve an interaction between neural plasticity, connectivity changes, and increased psychological flexibility.

Current data suggest that psilocybin is generally safe and well tolerated when administered with psychological support in a clinical setting.

Randomized clinical trials (RCTs) of psilocybin have generally used strict eligibility criteria, often excluding patients with severe treatment resistance, psychiatric comorbidities, or suicidality. In addition, psilocybin’s pronounced psychoactive effects make effective blinding challenging.

As a result, although RCTs provide critical evidence of efficacy and safety, they may not fully capture how psilocybin performs in routine clinical practice.

Another unresolved question is the durability of the drug’s antidepressant effects and whether additional sessions may be clinically useful.

Real-World Findings

Conducted at the University Hospital of Psychiatry in Zurich, the study included 19 patients with TRD who were in stable physical health.

Before receiving psilocybin, participants underwent multiple preparatory and integration sessions with specially trained clinicians. Each session lasted approximately 60 minutes.

All 19 patients underwent at least one psilocybin dosing session. Thirteen received two sessions, five received three sessions, and three received four sessions, for a total of 40 sessions.

Patients received an individualized dose of orally administered synthetic psilocybin, ranging from 20 to 35 mg, in a calm environment. At the end of the dosing day, patients completed a questionnaire to assess adverse events (AEs).

Decisions regarding concomitant medications were guided by clinical judgment and patient preference, with pharmacology consultations provided as needed. Most patients continued antidepressant therapy to maintain clinical stability, pausing treatment only on dosing days.

After each dosing session, patients attended at least two integration meetings focused on processing the psychedelic experience and integrating insights into daily life.

The primary outcomes were changes in scores on the Beck Depression Inventory-II (BDI-II) and Montgomery-Åsberg Depression Rating Scale (MADRS) after the final dosing session. Post-treatment was defined as the first available assessment within 42 days of the final session. Because of missing data, primary outcome analyses included 18 participants.

Mean MADRS scores dropped from 30.78 at baseline to 19.89 after treatment, a reduction of 10.89 points (95% CI, 7.10-14.68) and a large-to-very-large effect size. Mean BDI-II scores fell from 32.33 at baseline to 23.28 after treatment, a reduction of 9.06 points (95% CI, 3.48-14.63) and a medium-to-very-large effect size.

Reductions in both measures were somewhat smaller than those reported in previous clinical trials of patients with TRD or MDD, the authors noted.

Response, defined as a ≥ 50% reduction from baseline, was achieved by 33.3% of patients on the MADRS and 27.8% on the BDI. Mean percentage reductions were 35.6% and 26.8%, respectively.

Remission, defined as a MADRS score ≤ 12 or a BDI score ≤ 13, was achieved by 22.2% of patients on the MADRS and 27.8% on the BDI.

Optimal Dosing Unclear

The researchers noted that response and remission rates were lower than those reported in some previous RCTs of psilocybin in major depressive disorder. They suggested this likely reflects the high degree of treatment resistance and clinical complexity seen in patients referred for psilocybin therapy in routine practice.

They also noted that earlier studies typically included only one or two dosing sessions, excluded concomitant medications, and focused primarily on MDD rather than TRD.

The greatest improvement on both depression scales was observed after the first psilocybin session. However, the authors cautioned that the data were insufficient to determine the optimal number or timing of sessions.

“Even though we observed no further improvement at the group level, there might still be a value in multiple psilocybin sessions, as some patients responded only after the second or third session,” the investigators wrote.

AEs were reported in 30 of 40 dosing sessions, most commonly fatigue, headache, and tearfulness. No serious or persistent AEs occurred.

The findings support the feasibility of psilocybin therapy in routine clinical practice, the authors said.

Key limitations included the small sample size, lack of a control group, underrepresentation of women and non-Europeans, and heterogeneity in treatment protocols and follow-up.

The study received no outside funding. See paper for authors’ declarations of interest.