Trajectory of Antidepressant Effects after Single- or Two-Dose Administration of Psilocybin: A Systematic Review and Multivariate Meta-Analysis

Psilocybin is a serotonergic hallucinogen that is rapidly converted to psilocin and acts as a 5-HT2a receptor agonist, producing altered perception, cognition and self-boundary experiences. Interest in psychedelics as therapeutics has resurged since the 1990s on the back of increasing knowledge of their neurobiology; prior studies and early meta-analyses have suggested antidepressant effects but frequently combined different psychedelics and mixed healthy volunteers with clinical populations. Acute sympathetic responses—notably transient increases in blood pressure and heart rate—and rare persisting perceptual disorders (HPPD) are recognised safety concerns that require monitoring in clinical research. Yu and colleagues designed the present study to address specific gaps in the existing literature by characterising the time course of antidepressant effects after single- or two-dose psilocybin administration and by assessing cardiovascular safety and acceptability. Because depressive symptom measures were reported at multiple post-treatment time points in the primary studies, the investigators used a multivariate meta-analytic approach to model correlated effect sizes across day 1, week 1, month 1, month 3 and month 6, and they also planned meta-regression and subgroup analyses to explore sources of heterogeneity such as dose and number of sessions.

This work is a systematic review and multivariate meta-analysis of clinical trials examining psilocybin's effects on depressive symptoms. The review followed PRISMA 2020 guidance and a prespecified protocol registered on PROSPERO (CRD42021252492). The investigators searched MEDLINE, Cochrane Central, Embase and PsycINFO from inception to 27 January 2021, and they supplemented electronic searches by screening reference lists of eligible studies and prior meta-analyses. Eligibility criteria included clinical trials in which the primary outcome was antidepressant effects of psilocybin; both participants with primary major depressive disorder (MDD) and participants with depressive symptoms comorbid with physical illness were eligible. Case reports, small case series (n < 10), conference abstracts and protocols were excluded. Two reviewers independently screened records and resolved disagreements with a third reviewer. Primary outcomes were changes in depressive symptoms at prespecified time points (day 1, week 1, month 1, month 3 and month 6) after single- or two-dose psilocybin. Changes were analysed as either between-group pre–post differences (psilocybin versus placebo) or within-group pre–post changes when no placebo arm existed. Secondary outcomes comprised all-cause discontinuation (acceptability) and cardiovascular safety on the day of administration, specifically peak systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). Two authors independently extracted aggregate trial-level data and assessed risk of bias with the Cochrane Risk of Bias Tool. If body weight was not reported, a default 70 kg was used to calculate mg/kg doses. When numerical data appeared only in figures, WebPlotDigitizer was employed. Statistical analyses used R (v4.0.3) and Stata 16.0. The primary analysis fit a multivariate random-effects model (metafor/metaphor package in R) to account for correlation among multiple time-point effect sizes per study; pooled estimates were calculated as standardized mean differences (SMDs) for depressive symptoms, mean differences for BP and HR, and odds ratios for acceptability. Heterogeneity was summarised using τ2 and I2. Preplanned meta-regressions and subgroup analyses examined moderators including dose, number of doses, age, sex proportion, diagnostic group (MDD vs cancer), psychotherapy co-administration, trial design (RCT vs non-RCT) and whether SMDs derived from placebo-controlled trials differed from pre–post SMDs. Sensitivity checks included 1-way study removal, influence diagnostics, Baujat plots, dose-adjusted funnel plots and Egger's tests, plus alternative multivariate model specifications (linear, quadratic, restricted cubic spline) and robust variance estimation to assess dependency among effect sizes.

Searches identified 938 unique records; after screening and eligibility assessment ten trials published between 2011 and 2020 met inclusion criteria. The ten studies comprised five open-label trials, four randomised controlled trials (RCTs) and one post-RCT follow-up. Across studies there were 208 participants (mean age 48.4 years, SD 7.0; 44.3% women). Study populations comprised five MDD trials, four cancer-related depression trials and one trial in people with HIV/AIDS. Five trials used a single psilocybin dose and five tested two doses. Risk-of-bias assessment found that eight of the ten included studies had a high risk of bias in at least one domain, with blinding of outcome assessment the most frequent concern; among the RCTs two were judged to have high risk for blinding. Sample sizes per trial were small, ranging from 12 to 56 participants. Primary outcome—depressive symptoms: pooled multivariate estimates indicated statistically significant, moderate-to-large reductions in depressive symptoms from day 1 through month 6 following single- or two-dose psilocybin. Reported standardized mean differences (negative values indicate improvement) were: day 1 SMD = -0.75 (95% CI -1.15 to -0.35; 5 studies); week 1 SMD = -1.74 (95% CI -2.15 to -1.32; 5 studies); month 1 SMD = -1.35 (95% CI -1.77 to -0.93; 6 studies); month 3 SMD = -0.91 (95% CI -1.31 to -0.51; 6 studies); and month 6 SMD = -1.12 (95% CI -1.56 to -0.68; 5 studies). In sensitivity analyses restricted to RCTs, the day 1 effect was not statistically significant (SMD = -0.50, 95% CI -1.18 to 0.17), whereas substantial effects were observed at week 1 (SMD = -1.90, 95% CI -2.84 to -0.84), month 1 (SMD = -1.40, 95% CI -2.20 to -0.20), month 3 (SMD = -0.95, 95% CI -1.83 to -0.806) and month 6 (SMD = -1.23, 95% CI -2.03 to -0.03). Meta-regressions and subgroup findings: higher psilocybin dose was associated with greater reductions in depressive symptoms (slope = -1.89, p = 0.02), accounting for 64.1% of between-study variance in change scores (R2 = 64.1%; I2 = 59.9%). Two-dose regimens were associated with greater symptom reduction than single-dose regimens (slope = -0.50, p = 0.049). Other planned moderators (including trial design: RCT vs non-RCT, and whether effect sizes were placebo-controlled versus pre–post) were not statistically significant. Publication bias and influence diagnostics: Egger's test suggested small-study effects for primary outcomes (p < 0.01), but a dose-adjusted funnel plot did not indicate significant publication bias (p = 0.12). One-study removal sensitivity analyses supported robustness of pooled effects. Influence diagnostics identified the study by Anderson et al. as contributing relatively more to heterogeneity, but no included study met criteria as a definitive outlier across multiple influence measures. Secondary outcomes—acceptability and cardiovascular measures: compared with placebo, psilocybin was associated with acute increases in SBP and DBP on the day of administration. Reported SBP increases ranged from 13.58 mmHg to 24.41 mmHg, with an average increase of 19.00 mmHg; DBP increases ranged from 5.18 mmHg to 12.15 mmHg, with an average increase of 8.66 mmHg. There was no significant difference versus placebo in all-cause discontinuation (acceptability) or heart rate.

Yu and colleagues interpret their findings as evidence that single- or two-dose psilocybin produces a rapid onset of antidepressant effects—detectable by day 1—and sustained benefit through six months in the pooled trial data. The pooled effect sizes were moderate-to-large, largest at week 1, and remained clinically meaningful at later follow-ups. The authors note that the rapidity of response contrasts with typical oral antidepressants, which generally require at least two weeks for onset, and they draw a parallel to ketamine, which also shows early maximal response within the first two weeks. The study team highlights dose and dosing frequency as important moderators: higher psilocybin doses and two-session regimens were associated with greater reductions in depressive symptoms. They suggest that stronger subjective acute experiences—such as mystical-type or peak experiences—may mediate longer-term clinical benefit, although optimal dose and dosing schedules remain to be established. Cardiovascular effects were measurable but characterised as transient and self-limiting; average increases in SBP and DBP were 19.00 mmHg and 8.66 mmHg, respectively, while heart rate and discontinuation rates did not differ from placebo. The authors acknowledge several limitations. Inclusion of non-randomised and open-label trials may inflate effect estimates due to pre–post changes and expectation effects; two of four RCTs had high risk of bias related to blinding. Many trials used small samples (n = 12–56), and few used validated structured diagnostic interviews for depression. The extracted data did not allow examination of long-term adverse outcomes such as HPPD or psychosis. Publication bias indicators were mixed, with Egger's test suggesting small-study effects but dose-adjusted analyses not confirming bias. Given these uncertainties, the investigators conclude that larger, well‑designed RCTs with longer follow-up and systematic safety monitoring are required to confirm the observed trajectory, to define optimal dosing strategies, and to characterise long-term risks.

The meta-analysis found that psilocybin administration—single or two doses—was associated with rapid and sustained improvements in depressive symptoms up to six months after treatment, with larger benefits observed at higher doses and following two-dose regimens. Psilocybin produced acute, self-limiting increases in systolic and diastolic blood pressure but was otherwise relatively well tolerated in the included trials. The authors emphasise that these findings are tentative and call for additional, rigorously designed RCTs to confirm efficacy, determine optimal dosing, and define long-term safety.