Comparison between Single-Dose and Two-Dose Psilocybin Administration in the Treatment of Major Depression: A Systematic Review and Meta-Analysis of Current Clinical Trials

Major depressive disorder (MDD) is a highly prevalent, disabling condition associated with substantial personal and economic burden and incomplete response to existing treatments. Luciano and colleagues note that about 30% of patients do not respond to two or more standard psychotherapeutic or pharmacological approaches and are commonly labelled as having treatment-resistant depression (TRD). Conventional antidepressants have delayed onset, side effects (for example sexual dysfunction, weight gain, sleep disruption) and withdrawal phenomena, which together motivate the search for novel treatments. Psilocybin, a serotonergic psychedelic found in Psilocybe fungi, has re-emerged as a candidate because it can induce rapid antidepressant effects and may engage processes such as synaptic plasticity via TrkB–BDNF signalling in addition to activity at serotonin receptors. This systematic review and meta-analysis was undertaken to synthesise the recent clinical-trial evidence comparing single-dose and two-dose psilocybin administration for patients with a primary diagnosis of MDD or TRD. The study set out to (1) summarise therapeutic effects of single- and two-dose regimens on depressive symptom severity, and (2) compare the efficacy of those two dosing strategies, noting that trials vary in dose, psychological support, and design and that no recent meta-analysis had directly compared one- versus two-dose approaches in an MDD/TRD sample.

Luciano and colleagues performed a systematic review and meta-analysis following PRISMA guidelines and registered the protocol on PROSPERO (ID: CRD42024543828). Two electronic databases (PubMed and EBSCOhost, which covers PsycINFO, MEDLINE and related sources) were searched to 27 February 2024 using a string combining "psilocybin" terms with diagnostic and trial-type terms. Only English-language clinical trials in humans were eligible. Inclusion required a primary diagnosis of MDD (including TRD) and administration of either a single dose or exactly two doses of psilocybin, with outcomes reported on standardised depression rating scales. Studies were excluded if the primary diagnosis was not MDD, if the intervention used other psychedelics or different numbers of psilocybin doses, or if outcomes/timepoints for depressive symptoms were not reported. Screening and selection were conducted by multiple authors after duplicate removal in Zotero. Data extracted from full texts included study design, sample size and demographics, diagnostic characteristics, dosing regimen (number and mg), details of psychological support, depression measures and outcomes. Risk of bias was assessed with RoB 2 for randomised trials and ROBINS-I for non-randomised or uncontrolled studies; RoB 2 covered five standard domains, while ROBINS-I assessed seven domains including confounding and selection biases. Two meta-analytic approaches were used. First, the standardised mean difference (SMD; Cohen's d) between post-treatment and baseline within active treatment groups was computed to assess change from baseline. Second, where applicable, the SMD between active and control groups at post-treatment was calculated. Random-effects models were chosen because of anticipated heterogeneity. Heterogeneity was quantified by Cochran's Q and the I2 statistic (with 25%/50%/75% as low/moderate/high benchmarks) and τ2 reported; funnel plots and Egger's test were used to assess small-study effects or publication bias. Conversions from SEM to SD used SD = SEM × √n. Analyses were performed in R (version reported as 4.4.1).

The search retrieved 425 records (170 PubMed, 255 EBSCOhost); after removing 138 duplicates, 287 titles/abstracts were screened. Following full-text assessment of 20 articles, 12 clinical trials met inclusion criteria and were included in the review. Across studies the pooled sample was 600 participants; mean age was 41.61 (SD 2.13) years and the sample comprised 51.1% male and 48.9% female participants. Diagnostically, 515 participants (85.8%) had MDD and 85 (14.2%) had TRD; most cases were moderate-to-severe. Risk-of-bias assessment found that the six randomised controlled trials were judged to have low risk of bias across RoB 2 domains. The six non-randomised or open-label trials were assessed with ROBINS-I and carried an overall moderate risk of bias, most commonly due to confounding and outcome measurement, with some studies also showing moderate bias in selective reporting or missing data. Single-dose trials (k described as 6) included several designs and sample sizes. Goodwin et al. ran a dose-finding, double-blind parallel RCT (n groups: 79 at 25 mg, 75 at 10 mg, 79 at 1 mg as low-dose comparator) and reported MADRS decreases at 3 weeks of 12.0 points (25 mg), 7.9 points (10 mg) and 5.4 points (1 mg), with a statistically significant difference between 25 mg and 1 mg (mean difference -6.6, 95% CI [-10.2; -2.9], p < 0.001). An open-label 25 mg single-dose trial in SSRI-augmented TRD (n = 19) reported a MADRS reduction of 14.9 points at 3 weeks (95% CI [-20.7; -9.2]) with early effects by day 2. Raison and colleagues’ RCT (n = 104) found a mean difference favouring a single 25 mg psilocybin plus niacin over two niacin doses at day 43 (mean difference 12.3, p < 0.001). Sloshower et al. used a within-subject fixed-order design (n = 19) and observed significant decreases after both placebo and psilocybin, with larger effect sizes after psilocybin (d = 1.02–2.27) than placebo (d = 0.65–0.99), but no statistically significant between-condition difference. Von Rotz et al. (n = 52) reported MADRS reductions of 13 points at 14 days post 0.215 mg/kg psilocybin relative to placebo (95% CI [-15.0; -1.3], p < 0.01, d = 0.97). Two-dose trials (k described as 7) included several open-label feasibility and randomised designs. Small open-label TRD studies by Carhart-Harris and colleagues and by Lyons and Carhart-Harris (samples 12–20 and 15 respectively) reported large reductions in depressive scores at 1 week and sustained benefits to 3 months; effect sizes reported were large (for example g ≈ 3.1 at 1 week in one small sample, and d = 2.3 at 5 weeks in another). A double-blind randomised trial by Carhart-Harris et al. (n = 59) compared two 25 mg doses 3 weeks apart plus daily placebo against two placebo doses plus daily escitalopram; at 6 weeks the between-group difference in QIDS change was 2 points (95% CI [-5.0; 0.9]) and was not statistically significant. Davis et al.’s randomised study (n = 24) comparing immediate two-dose psilocybin (20 mg then 30 mg) with a waitlist reported large effect sizes at 5 and 8 weeks (d = 2.5–2.6, p < 0.001), and follow-up work by Gukasyan et al. showed sustained reductions up to 12 months with large effect sizes (d ≈ 2.4–2.6). Meta-analytic results showed a large pooled within-active-group effect of psilocybin on depressive symptoms versus baseline (random-effects SMD d = -2.14, z = -12.11, p < 0.001, 95% CI [-2.48; -1.78]). Subgroup estimates were d = -1.87 (95% CI [-2.43; -1.30]) for single-dose studies (k = 6) and d = -2.42 (95% CI [-2.74; -2.11]) for two-dose studies (k = 7); however the test for a subgroup difference was not statistically significant (χ2(1) = 2.86, p = 0.09). Heterogeneity for this analysis was high (I2 = 73.1%, 95% CI [53.2%; 84.5%]; Q(12) = 44.62, p < 0.001; τ2 = 0.27). Visual inspection of funnel plots suggested minor asymmetry and some outliers, but Egger's test did not find significant small-study bias (t(10) = -0.85, p = 0.39). When psilocybin-treated groups were compared with inactive controls (placebo or niacin) across the subset of controlled trials, the pooled effect remained large and significant (random-effects d = -2.37, z = -3.60, p < 0.001, 95% CI [-3.66; -1.08]). Heterogeneity in that comparison was extremely high (I2 = 96.3%, 95% CI [94.3%; 97.6%]; Q(6) = 164.37, p < 0.001). The authors did not conduct subgroup analyses for the active-versus-control comparison because of the small number of controlled studies.

Luciano and colleagues interpret the assembled evidence as indicating that psilocybin—whether given as a single dose or as two doses—produces pronounced reductions in depressive symptom severity in patients with MDD or TRD. Both within-group and controlled analyses showed large effect sizes, and several studies reported sustained benefits extending to months after treatment, in some cases up to 12 months. While the two-dose regimens sometimes yielded numerically larger effects, the meta-analytic subgroup comparison did not reach statistical significance, leaving uncertainty about whether multiple sessions add reliable benefit beyond methodological or contextual differences between trials (for example differences in psychological preparation/integration and per-session dose). In safety terms, the researchers report that psilocybin was generally well tolerated across trials, with common, usually transient adverse events including headache, nausea, dizziness, fatigue and temporary increases in blood pressure. Serious adverse events were rare but included instances of suicidal ideation or self-injurious behaviour in a small number of participants; the authors note these outcomes may be related to the underlying illness as well as to treatment. They highlight practical considerations—doubling sessions increases demands for preparatory/integration therapy and medication exposure, which may affect affordability and accessibility. The authors acknowledge important limitations in the evidence base. Many trials had small sample sizes (several with fewer than 25 participants), gender balance in included samples was uneven with fewer women than expected for MDD prevalence, and about half the studies were open-label with moderate risk of bias. Protocol heterogeneity (dose, timing, psychological support) and unmeasured factors (for example illness duration, comorbidities, prior treatment history) complicate pooled inference. Given these constraints, Luciano and colleagues call for larger, standardised randomised trials that directly compare dosing strategies and systematically evaluate safety and longer-term outcomes, and they suggest exploration of effects on cognitive and metacognitive domains as additional endpoints for future research.

The authors conclude that current clinical-trial evidence supports the efficacy of psilocybin in reducing depressive symptoms in patients with MDD and TRD, with both single-dose and two-dose regimens associated with significant improvements versus baseline and with evidence of benefit versus inactive comparators in controlled trials. Nonetheless, they emphasise the need for further rigorous, larger-scale trials and meta-analyses to clarify optimal dosing strategies, safety profiles, and implementation considerations so that evidence-based guidelines for clinical use can be developed.