Investigating the Effect of Psilocybin in Treatment-Resistant Depression

Psilocybin taken within a psychotherapeutic session for treatment-resistant depression (TRD) evidenced some reduction in symptoms within 1 week but was not distinguished from active placebo in the primary measure of clinically significant improvement at week 6, in a controlled trialdesigned to overcome some limitations of previous investigations of psychedelics.¹

Despite the potential benefit indicated by multiple studies, "current evidence is constrained by methodological challenges, including small sample sizes, insufficient pharmacovigilance, functional unblinding and expectancy effects," indicated lead author Lea Mertens, MSc, Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, and colleagues.

"Using a randomized parallel-group design with a second dosing after the primary end point (at 6 weeks), the study aimed to reduce dropouts during the first treatment phase, until the primary end point; reduce disappointment and symptom worsening in comparator groups if unblinding occurred, and meet ethical obligations to offer active treatment to this vulnerable population," the investigators explained.

In an accompanying editorial, James Hudson, MD, ScD, and Harrison Pope, Jr, MD, MPH, of the Biological Psychiatry Laboratory and Psychiatric Epidemiology Research Program, McLean Hospital, Belmont, MA, commended the investigators, but characterize their goal to overcome challenges such as functional unblinding—the potential bias from knowing treatment assignment based on whether psilocybin effects are experienced—as an "aspiration" rather than accomplishment.²

The challenge in assessing psilocybin’s effect on depression, Hudson and Pope asserted, is in distinguishing between direct biologic effect and enlightenment from the guided psychedelic experience, confounded by the methodological limitation of functional unblinding. That limitation, they suggested, is further complicated by an expectation of beneficial response, and even a felt responsibility to attain the response.

"Owing to the current limits of its testing methodology, science still faces daunting challenges in the lofty goal of confirming the efficacy, much less the authority, of psychedelic experiences and other paths to enlightenment and healing," Hudson and Pope remarked.

Discerning Psilocybin’s Effect

The EPISODE phase 2b clinical trial employed triple-blinding (of investigator, participant, and rater); an active placebo; and 144 participants randomized into 4 groups receiving 2 doses 6 weeks apart. The primary endpoint of 50% or greater reduction in Hamilton Rating Scale for Depression, German (HAMD17) score was measured at 6 weeks, prior to the second dose, for clinical relevance and consistency with trials of traditional antidepressants.

The participants had baseline HAMD17 scores of 17 or greater, and history of major depressive disorder without adequate response to at least 2 antidepressant regimens of different classes at appropriate dose and duration. Participants discontinued psychotherapy prior to the trial and had not taken antidepressant medication for at least 2 weeks (5 weeks with fluoxetine).

Participants were randomly assigned to 4 groups on a 2:2:1:1 basis to receive 2 doses, separated by 6 weeks of either: nicotinamide 100 mg then psilocybin 25 mg; psilocybin 5 mg then 25 mg; psilocybin 25 mg then 5 mg; or psilocybin 25 mg in both doses. Both doses of active agent and placebo were administered within a 6 to 8 hour structured psychotherapeutic program and overnight stay. Throughout the duration of the trial, participants completed 8 in-person visits and 8 weekly therapist safety calls.

Nicotinamide was used as an active placebo for exerting some physiologic effect, albeit not psychoactive, and as the available alternative to niacin, which is not approved in the European Union. Psilocybin 5 mg was also used, as subtherapeutic but with mild subjective effects. Each group received at least 1 dose of 25 mg psilocybin during the trial which, the investigators indicate, "served both methodological and ethical purposes."

Assessments included self-report and clinician-rated scales, laboratory assessments, a neuropsychological battery and functional magnetic resonance imaging scans. The HAMD17 was administered at week 1, 6, 7, and 12; with the primary endpoint of 50% reduction from baseline at week 6.Secondary endpoints included clinically relevant changes from baseline on the HAMD17, defined as 3 to 5 points, at week 1 and 12; and on the Beck Depression Inventory II (BDI-II), defined as 3 to 6 points, at day 1 and weeks 1, 6, and 12.

Mertens and colleagues reported no statistically significant difference between groups in meeting the primary endpoint of 50% reduction in HAMD17 from baseline to 6 weeks after the first dose. There was however, an indication of clinically meaningful effect of psilocybin 25 mg on the secondary measures with the HAMD17 and BDI-II. At week 1, for example, response rates with psilocybin 25 mg were higher than with either the 5 mg dose or nicotinamide (odds ratio, 7.60 [95%CI, 2.29-34.75] favoring psilocybin over nicotinamide).

There was some advantage of 25 mg psilocybin over nicotinamide evident at week 6, but with less differences between the groups. After the second dose (week 12), however, there were no group differences in either HAMD17 or BDI-II measures, with all demonstrating "clinically relevant improvements." Psilocybin 25 mg was relatively well tolerated but linked to adverse events including higher reports of suicidal ideation on dosing days (4% vs 1% to 2% with comparators) and 1 case of persistent hallucinations.

The investigators suggested that the mixed results provide evidence of potential efficacy, but that the divergence between primary and key secondary outcomes "warrants cautious interpretation."

Hudson and Pope concurred with that sentiment, noting that the reduction on the secondary depression rating measures, "although likely exceeding the effects of chance, would plausibly fall well within the limits of expectation effects alone."

Mertens and colleagues suggested that the indication of benefit, feasibility, and relative safety warrant follow-up with larger trials. "These findings highlight the potential of psilocybin with adjunct psychotherapy for depression, including TRD, while emphasizing the need for larger, adequate powered confirmatory trials with long-term follow-up to clarify durability and mechanisms of action," they concluded.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Mertens LJ, Koslowski M, Betzler F, et al. Efficacy and safety of psilocybin in treatment-resistant major depression: the EPISODE randomized clinical trial. JAMA Psychiatry. 2026;e260132.

2. Hudson JI, Pope HG Jr. Enlightenment in a pill—testing the efficacy of psilocybin. JAMA Psychiatry. 2026. Online ahead of print.