High-dose psilocybin may help treat depressive symptoms, with small effect size

Key takeaways:

• Patients treated with high-dose psilocybin had better responses compared with placebo in antidepressant trials.
• Placebo response was greater in antidepressant vs. psychedelic trials.

High-dose psilocybin showed the potential to treat depressive symptoms, although the effect size appeared small and comparable to that of escitalopram, according to results of a network meta-analysis published in The BMJ.

“Among the included psychedelics, only high-dose psilocybin was more likely to be better than escitalopram 10 mg or 20 mg,” Tien-Wei Hsu, MD, a doctoral researcher in the department of psychiatry at I-Shou University and the Graduate Institute of Clinical Medicine at Kaohsiung Medical University in Taiwan, and colleagues wrote.

“Taken together, our study findings suggest that among psychedelic treatments, high-dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design, while the effect size of psilocybin was similar to that of current antidepressant drugs,” they added.

Because prior studies may have been limited by unsuccessful blinding, the researchers sought to compare the effectiveness and acceptability of oral monotherapy using psychedelics or escitalopram to treat patients with depressive symptoms. They conducted a systemic review and Bayesian network meta-analysis, separating placebo responses from psychedelic and antidepressant trials to avoid overestimating the treatment effects of psychedelics.

The researchers searched Medline, WHO’s International Clinical Trials Registry Platform and other databases to identify 19 randomized controlled trials involving patients with depressive symptoms treated with escitalopram or psilocybin, LSD, MDMA or ayahuasca without concomitant use of antidepressants.

They included 15 psychedelics trials involving 811 participants (mean age, 42.49 years; 54.2% women) and five trials of escitalopram involving 1,968 participants (mean age, 39.35 years; 62.5% women).

The primary outcome was change in depressive symptoms measured using a validated rating scale, such as the Hamilton Depression Rating Scale (HAMD-17), for which a mean difference (MD) that exceeded three points indicated a clinically significant relative effect. Secondary outcomes included all-cause discontinuation and severe adverse events, such as admission to hospital, suicide attempt and death.

Overall, results showed that placebo response in psychedelic trials was lower than that in trials of escitalopram (MD = 3.9; 95% credible interval, 7.1 to 0.96).

Furthermore, although most psychedelics were more effective than placebo in psychedelic studies, only high-dose psilocybin was better than placebo in escitalopram antidepressant trials (MD = 6.45; 95% credible interval, 3.19-9.41).

However, the standardized MD of high-dose psilocybin decreased from 0.88 when the reference arm was placebo response in psychedelic trials, to a small effect, at 0.31, when using escitalopram trials.

Finally, the researchers found that the relative effect of high-dose psilocybin (6.52; 95% credible interval, 3.19-9.57) was larger than that of escitalopram 10 mg (1.86; 95% credible interval, 0.21-3.5; MD = 4.66; 95% credible interval, 1.36-7.74) and 20 mg (1.82; 95% credible interval, 0.16-3.43; MD = 4.69; 95% credible interval, 1.64-7.54) in antidepressant trials.

The researchers also performed a sensitivity analysis that included only patients with major depressive disorder and found that the relative effects of escitalopram, ayahuasca and high-dose psilocybin had better responses than placebo in antidepressant trials.

None of the interventions were associated with more significant all-cause discontinuation or more severe adverse effects compared with placebo.

The researchers acknowledged several study limitations, including a small sample size of psychedelic trials, examining only the acute effects of interventions and insufficient statistical power to detect publication bias.

“Of the available psychedelic treatments for depressive symptoms, patients treated with high-dose psilocybin showed better responses than those treated with placebo in the antidepressant trials, but the effect size was small,” Hsu and colleagues wrote.

Future studies with improved blinding methods will help to better estimate the efficacy of psychedelics as a treatment for depression and other psychiatric conditions, they added.