Psilocybin Appears Effective for Depression, but Concerns Linger

Editor's note: After this publication, The BMJ placed an expression of concern on the study about a methodological error that likely overestimated the benefits of psilocybin. The researchers are currently reviewing and responding to the concern.

A meta-analysis of psilocybin trials confirmed its possible benefit as a depression treatment, but raised questions about its safety and use in clinical practice.

Seven of nine studies included in the analysis showed a significant benefit with psilocybin for adults with depression, favoring it over a comparator treatment (Hedges' g 1.64, 95% CI 0.55-2.73, P<0.001), reported Athina-Marina Metaxa, MSc, of the University of Oxford in England, and Mike Clarke, DPhil, of ICS-A Royal Hospitals in Belfast, Ireland.

However, prediction intervals were wide and "crossed the line of no difference (95% CI -1.72 to 5.03), indicating that there could be settings or populations in which psilocybin intervention would be less efficacious," the researchers wrote in The BMJ.

Overall, psilocybin treatment was linked with a higher chance for treatment response compared with placebo (risk ratio [RR] 2.02, 95% CI 1.33-3.07), though there was low heterogeneity between the studies for this outcome, they noted. Psilocybin was also linked with a greater chance of depression remission compared with placebo (RR 2.71, 95% CI 1.75-4.20).

Subgroup analyses showed greater efficacy of psilocybin among people with secondary depression, people with previous use of psychedelics, people who were older, and in studies that used self-reported measures of depression symptoms.

"Efficacy did not appear to be homogeneous across patient types -- for example, those with depression and a life-threatening illness appeared to benefit more from treatment," Metaxa and Clarke observed.

"Although this review's findings are encouraging for psilocybin's potential as an effective antidepressant, a few areas about its applicability in clinical practice remain unexplored," they wrote. It's "unclear whether the protocols for psilocybin interventions in clinical trials can be reliably and safely implemented in clinical practice," they noted.

In clinical trials, psilocybin therapy is delivered in a non-traditional medical setting, like the one described in this 2022 study. Typically, patients receive treatment in a pseudo-living room where they listen to calming music and wear eye shades and noise-canceling headphones while monitored by a trained therapist.

"Standardizing an intervention setting with so many variables is unlikely to be achievable in routine practice, and consensus is considerably lacking on the psychotherapeutic training and accreditations needed for a therapist to deliver such treatment," they pointed out. Before psilocybin can move into clinical practice, a highly standardized treatment setting, treatment cost, and the lack of regulatory guidelines and legal safeguards need to be dealt with, they added.

Bringing this therapy into routine practice may prove tricky, observed Riccardo De Giorgi, MD, DPhil, of the University of Oxford, and Roger Ede, BSc, of Oxford Health NHS Foundation Trust, in an accompanying editorial.

"Adverse experiences, such as the proliferation of unregulated ketamine clinics, and, more recently, the use of psilocybin by unlicensed practitioners in the well-being industry, are a stark reminder of the potential misuse of these interventions," they wrote.

The meta-analysis included data on 436 participants with a mean age of 36 to 60 across the nine studies. Only studies testing psilocybin as a standalone depression treatment were included, and those that involved psilocybin microdosing (under 100 μg/kg) were excluded.

Importantly, the analysis failed to differentiate between patients who would most likely benefit from psilocybin and those more likely to experience adverse events, the editorialists noted.

"Owing to inconsistent reporting across clinical trials, this review did not quantitatively assess the safety of psilocybin use in people with depression," they wrote. Across the trials, all adverse events were labeled as minor and short-lasting, and none were deemed serious.

"The lack of reliable adverse event reporting in trials of psychedelics does not mean that these drugs are safe -- and, because of the high visibility of these agents in the media, particular caution is required to avoid unhelpful setbacks in the development of interventions for clinical use," De Giorgi and Ede added.

While the findings appear promising, they "support a prudent approach in both scholarly and public settings, because more and better evidence is needed before any clinical recommendation can be made about therapeutic use of psilocybin," they wrote.

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