High-dose psilocybin shows promise for depression treatment

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.Aug 27 2024

Study: Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis. Image Credit: YAR Photographer / Shutterstock.com

Meta-analysis found that high-dose psilocybin was more effective than placebo in treating depressive symptoms in antidepressant trials, though its effect size was small compared to escitalopram.

In a recent study published in The BMJ, researchers compare the effectiveness and acceptability of oral monotherapy with psychedelics for the treatment of depressive symptoms.

Psychedelics in the clinic

Psychedelics like psilocybin, ayahuasca, lysergic acid diethylamide (LSD), and methylenedioxymethamphetamine (MDMA) have shown potential in their potential indication for the treatment of depression by promoting neuroplasticity.

Although meta-analyses report large effect sizes, concerns remain about overestimated efficacy due to compromised blinding and response expectancy. To date, only one double-blind trial has compared psilocybin with escitalopram, in which psilocybin was reported to be more effective.

Further research is needed to accurately determine the true efficacy of psychedelics, as current trials may be biased by compromised blinding and the influence of psychological support.

About the study

The current study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for network meta-analyses.

A comprehensive search of databases, including Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, ClinicalTrial.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform, was conducted until October 12, 2023.

Randomized controlled trials (RCTs) involving adults clinically diagnosed with depression or depressive symptoms related to life-threatening conditions were included in the analysis. Eligible studies involved oral monotherapy with psychedelics, including psilocybin, MDMA, LSD, ayahuasca, or escitalopram, and excluded studies with concurrent antidepressant use.

The primary outcome was the change in depressive symptoms, which was measured by validated scales, such as the 17-item Hamilton Depression Rating Scale (HAMD-17). Secondary outcomes included all-cause discontinuation and severe adverse events.

The authors independently conducted data extraction and risk of bias assessment, resolving any discrepancies through discussion. Bayesian network meta-analysis was used to estimate relative effects between interventions, with sensitivity analyses addressing potential effect-modifying factors.

Publication bias was assessed using funnel plots and statistical tests. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Statistical analyses were performed using R software.

Study findings 

After a thorough database search and removal of duplicates, a total of 3,104 unique studies were identified. Upon screening titles and abstracts, 3,062 studies were excluded.

Following this assessment, 26 studies were excluded for various reasons. Three additional studies were found through a manual search for a final total of 19 studies.

Taken together, these studies comprised 15 trials involving 811 participants in psychedelic trials with an average age of 42.5 years, 54.2% of whom were women. Additionally, 1,968 participants were involved in escitalopram trials, whose average age was 39.4 years, 62.5% of whom were women.

None of the 15 psychedelic trials had a high overall risk of bias. However, concerns were noted in randomization and deviations from intended interventions for 33% of studies. Although 80% of escitalopram trial studies were associated with randomization and other bias domains issues, none were considered to be at a high risk of bias.

Network meta-analysis revealed that most psychedelic interventions, except for extremely low and low doses of MDMA, showed a mean difference that exceeded the minimal important difference of three points on the HAMD-17 scale as compared to placebo. High-dose psilocybin was associated with a more significant effect size when compared to both escitalopram and placebo in antidepressant trials. However, the effect size of high-dose psilocybin decreased from large to small when the placebo in antidepressant trials was used as the reference.

When only considering patients with major depressive disorder, the sensitivity analysis confirmed the superiority of high-dose psilocybin and ayahuasca over placebo in antidepressant trials. The relative effects of these interventions exceeded a mean difference of three, and their credible intervals did not cross zero. Other sensitivity analyses, including adjustments for baseline depression severity and exclusion of high-risk bias studies, supported these findings.

No interventions were associated with higher risks of all-cause discontinuation or severe adverse events as compared to placebo in psychedelic trials. Network meta-regression indicated no significant impact of baseline depression severity, age, or gender on outcomes. Funnel plot analyses and statistical tests suggested no publication bias.

The GRADE assessment indicated moderate to low certainty of evidence across treatment comparisons. Consistency assumptions were upheld through back-calculation and node-splitting methods, thereby confirming the reliability of the network meta-analysis findings.

Conclusions

When compared with a placebo in antidepressant trials, high-dose psilocybin was more effective than escitalopram, with a minimally important difference of three points on the HAMD-17 scale. Among the psychedelics, only high-dose psilocybin consistently outperformed escitalopram.

Taken together, these findings suggest that high-dose psilocybin may offer similar effectiveness to traditional antidepressants, particularly when combined with psychotherapeutic support.