Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial

Enrollment and sample. Of 949 people screened by phone, 42 were screened in person and 22 enrolled; 19 completed at least one dosing session and 15 completed both. The analysed sample (n = 19) had a mean age of 42.8 (SD 13.8) years, included 13 women and 6 men, and averaged 20 ± 12 years since depression diagnosis. Mean GRID-HAM-D-17 at screening was 23.9 ± 5.0. Prior lifetime psychedelic exposure was reported by 8/19 (42.1%), but none within the preceding 3 years. Mood and depression outcomes. On the clinician-rated GRID-HAM-D-17 there were significant main effects of time (F(3,99)=17.8, p<0.0001) and drug (placebo versus psilocybin; F(1,99)=49.9, p<0.0001), but no significant drug-by-time interaction (F(3,99)=1.2, p=0.31). Mean reductions in GRID-HAM-D-17 over the 2-week period after dosing were larger following psilocybin (Δ = 6.3–8.7) than after placebo (Δ = 4.4–5.8), yet this difference did not reach statistical significance. Reported effect sizes (d′) were greater post-psilocybin (1.02–2.27) than post-placebo (0.65–0.99). Among the 15 participants who completed both sessions, all achieved a clinically significant response (≥50% reduction in GRID-HAM-D) by the end of week 6: 5 participants (33.3%) responded after placebo prior to psilocybin, and 10 (66.7%) responded only after psilocybin. Remission (GRID-HAM-D-17 ≤7) occurred in 3 (20%) after placebo and in 7 (46.7%) only after psilocybin; by week 6, 10 (66.7%) retained response and 5 (33.3%) remained in remission. Self-reported depression (QIDS-SR-16) decreased over time (F(3,101)=16.5, p<0.0001) and was significantly lower following psilocybin than post-placebo through week 6 (F(1,101)=43.3, p<0.0001), though there was no drug-by-time interaction (F(3,101)=1.3, p=0.29). Extending QIDS-SR-16 to week 16 showed a rapid decrease one day after psilocybin that remained statistically significant through week 12 (time effect F(6,75)=7.47, p<0.0001). Anxiety and quality of life. HAM-A scores declined over time (F(2,75)=14.3, p<0.0001) and were lower following psilocybin versus placebo (F(1,75)=52.9, p<0.0001), but no significant drug-by-time interaction was found (F(2,75)=0.04, p=0.97), and mean anxiety reductions in the week after dosing were similar for placebo and psilocybin. RAND-36 analyses showed significant improvements over time on seven of eight subscales maintained through week 16 (except general health); four subscales (role limitations due to emotional problems, social functioning, general health, emotional well-being) were significantly improved after psilocybin compared with after placebo. Acute subjective effects and blinding. MEQ-30 scores were substantially higher on the psilocybin day (mean 70.0 ± SE 4.9) than placebo (8.4 ± 4.5) (F(1,13)=97.3, p<0.0001). CEQ scores were also higher after psilocybin (28.9 ± 4.8) versus placebo (9.6 ± 2.0) (F(1,18)=17.7, p=0.0005). Maximum MEQ correlated negatively with change in HAM-D after placebo at 1 day (r = -0.55, p = 0.017) and 2 weeks (r = -0.75, p = 0.005), but there were no significant correlations between MEQ or CEQ and symptom changes after psilocybin. Blinding was limited: after placebo sessions 15/19 (78.9%) participants correctly guessed they had received placebo, and after psilocybin sessions 12/15 (80%) correctly guessed they had received the higher dose. Masking among therapists and other staff was not formally assessed. Safety and adverse events. No severe adverse events occurred during dosing sessions and no rescue medications were administered acutely. One participant required psychiatric hospitalisation about 2 weeks after psilocybin for lack of improvement. Adverse events were more frequent on psilocybin days (25 events) than placebo days (3 events) (z = 3.01, p = 0.003); the most common were transient mild-to-moderate headaches, transient anxiety, and dysphoria. Transient elevations in systolic blood pressure (>160 mmHg at one or more time points) occurred in 2/19 (10.5%) placebo sessions and 5/15 (33.3%) psilocybin sessions; elevated diastolic pressure (>100 mmHg) occurred in 2/19 (10.5%) placebo sessions and none during psilocybin sessions. None of the cardiovascular events required medical intervention. No prolonged perceptual changes, persistent psychotic symptoms, or dependency-related behaviours were observed, though several participants expressed a desire for further supervised psilocybin sessions.

Sloshower and colleagues interpret the findings as evidence that a single moderate psilocybin dose given within a manualised ACT-informed psychotherapy protocol produced sizable clinical effects on depressive symptoms, anxiety, and multiple quality-of-life domains, but that these improvements were also observed following placebo and thus could not be attributed solely to the drug in this design. Effect sizes for depression reductions were larger after psilocybin than after placebo, and antidepressant effects following psilocybin persisted on average for about 8 weeks, with several participants achieving response or remission only after the active dose. The investigators emphasise several methodological factors that complicate causal attribution. A notable carryover effect from the placebo phase reduced symptomatic severity prior to the psilocybin session, potentially limiting the detectable additional benefit of psilocybin. The fixed-order design, while intended to limit carryover from an active first dose, therefore may have constrained ability to detect drug-placebo differences. Blinding and expectancy also influenced outcomes: despite enhanced blinding procedures and withholding the low dose, most participants correctly identified dosing condition, and the sample was largely self-referred with generally high expectations for psilocybin's benefit. The authors suggest that expectancy, engagement in psychotherapy during the placebo phase, and anticipation of receiving an active dose likely contributed substantially to the clinical gains observed after placebo. Sample size and generalisability are further limitations cited by the researchers. The trial was primarily powered for electrophysiological endpoints and was small for clinical efficacy comparisons, which increases the risk of type II error. In addition, the sample lacked diversity in race and education, limiting the ability to generalise findings. The investigators note that because the ACT-based psychotherapy was not compared with a minimal or different psychotherapeutic approach, it is not possible in this trial to disentangle the relative contributions of therapy versus dosing sessions to the observed improvements. Looking forward, the authors recommend future trials with parallel-group or factorial designs (for example, with and without psychedelic dosing crossed with with and without psychotherapy) to separate drug, therapy, and expectancy effects. They also highlight the need to test repeated or escalating dosing regimens, given variable durability of response and participants’ expressed desire for additional sessions, and to improve masking strategies—potentially by increasing the number of possible dosing conditions or using active controls—while acknowledging the feasibility challenges these approaches present. Finally, the researchers call for more diverse samples and further investigation into neurobiological and psychosocial mechanisms of action, noting that mystical-type experiences did not correlate with clinical improvement after psilocybin in this sample but were associated with placebo-phase improvement, underscoring the complex role of expectancy.

In this exploratory, placebo-controlled, within-subject fixed-order trial, administration of a single moderate dose of psilocybin within a manualised ACT-informed psychotherapy protocol was associated with clinically meaningful and sometimes durable improvements in depression, anxiety, and several quality-of-life domains. However, comparable improvements were observed after placebo, and differences in primary outcomes between psilocybin and placebo were not statistically significant. The authors conclude that the interplay of expectancy, psychotherapeutic support, and drug effects complicates interpretation, and they recommend that future studies prioritise improved masking, measurement and mitigation of expectancy, evaluation of repeated dosing strategies, and designs that can disentangle the contributions of psychotherapy and pharmacology.