Trial of Psilocybin versus Escitalopram for Depression

Major depressive disorder is common, impairing and costly, and selective serotonin-reuptake inhibitors are first-line treatments but have a delayed onset of action and incomplete efficacy in some patients. Psilocybin, the prodrug of psilocin, acts primarily as a serotonin 5-HT2A receptor agonist and has shown promise in open-label and small randomized studies for mood disorders and anxiety; prior trials have reported reductions in depressive symptoms after one or two doses in a range of populations, including treatment-resistant depression. Carhart-Harris and colleagues set out to compare psilocybin with an established antidepressant, escitalopram, in a Phase II, double-blind, randomized controlled trial among patients with long-standing, moderate-to-severe major depressive disorder. The trial aimed to test whether two dosing sessions of psilocybin plus daily placebo over 6 weeks produced greater reductions in depressive symptoms than two very low psilocybin doses plus daily escitalopram, with the primary outcome specified as change in QIDS-SR-16 score at week 6. The study also collected multiple secondary clinical and experiential outcomes and safety data to inform larger, longer trials.

This was a Phase II, double-blind, randomized, active-comparator trial conducted at an NIHR Clinical Research Facility from January 2019 through March 2020. Adults aged 18 to 80 with a diagnosis of major depressive disorder and a HAM-D-17 score of at least 17 were recruited primarily by self-referral. Major exclusion criteria included a personal or immediate-family history of psychosis, serious suicide attempts, significant medical comorbidity, contraindications to SSRIs or MRI, prior use of escitalopram (prior psilocybin use was allowed), pregnancy, and preexisting psychiatric conditions thought likely to interfere with the limited psychological support available in the trial. Participants were randomised 1:1 by staff independent of the research team to one of two groups. The psilocybin group received two oral doses of 25 mg psilocybin given 3 weeks apart plus 6 weeks of daily placebo capsules. The escitalopram group received two oral doses of 1 mg psilocybin (intended to be pharmacologically negligible) given 3 weeks apart plus daily escitalopram capsules (10 mg for the first 3 weeks after the first dosing day, then increased to 20 mg for the next 3 weeks). Dosing days were supervised by two assigned mental‑health professionals who provided psychological support before, during and after each dosing session; preparatory and integration sessions were also provided. To standardise expectations, all participants were told they would receive psilocybin, but dose assignments were concealed and medication packaging was nondisclosing; investigators and medication‑administration staff were blinded to group assignment. The primary outcome was change from baseline to week 6 on the 16‑item Quick Inventory of Depressive Symptomatology‑Self‑Report (QIDS‑SR‑16). There were 16 prespecified secondary outcomes, including response (≥50% reduction on QIDS‑SR‑16) and remission (QIDS‑SR‑16 score ≤5) at week 6, changes on BDI‑1A, HAM‑D‑17, MADRS, and measures of wellbeing, anhedonia, anxiety, experiential avoidance and social functioning, as well as several acute experiential inventories and a trial‑specific post‑treatment side‑effects scale (PTCS). Adverse events were recorded at every visit and call from dosing day 1 through week 6 and coded using MedDRA v23.0. The trial was powered using prior data and a prespecified 80% power calculation, with a minimum planned recruitment of 30 patients per group (60 total). Analyses were by intention‑to‑treat; the primary outcome was analysed with repeated‑measures ANCOVA adjusted for baseline scores. Logistic regression adjusted for baseline was used for binary secondary outcomes (response, remission). Other continuous outcomes were analysed with ANCOVA or permutation tests as appropriate. There was no prespecified plan to adjust confidence intervals for multiple comparisons of secondary outcomes, and the authors therefore did not report P values or draw clinical conclusions from those analyses.

Fifty‑nine patients underwent randomisation: 30 to the psilocybin group and 29 to the escitalopram group. The mean age was 41 years, 34% were women and most participants were White. Baseline QIDS‑SR‑16 scores were 14.5 in the psilocybin group and 16.4 in the escitalopram group. Median duration of depressive illness differed between groups (mean 22 years in the psilocybin group and 15 years in the escitalopram group), and alcohol use was higher in the escitalopram group; other baseline characteristics were reported as similar. For the primary outcome, the mean (±SE) change from baseline to week 6 on the QIDS‑SR‑16 was −8.0±1.0 points in the psilocybin group and −6.0±1.0 points in the escitalopram group. The between‑group difference was −2.0 points (95% CI −5.0 to 0.9; P = 0.17), indicating no statistically significant difference on the primary endpoint. A per‑protocol analysis yielded similar results. On secondary binary outcomes, 21 patients (70%) in the psilocybin group and 14 (48%) in the escitalopram group met QIDS‑SR‑16 response criteria at 6 weeks (difference 22 percentage points; 95% CI −3 to 48), a difference that the authors report as not statistically significant. QIDS‑SR‑16 remission occurred in 17 patients (57%) receiving psilocybin and 8 patients (28%) receiving escitalopram (difference 28 percentage points; 95% CI 2 to 54). Other secondary continuous measures of depressive symptoms (BDI‑1A, HAM‑D‑17, MADRS) and measures of wellbeing, anhedonia, anxiety and related scales predominantly favoured psilocybin, but the confidence intervals for these between‑group differences were not adjusted for multiple comparisons and thus are not presented as definitive. Treatment adherence and protocol completion varied: in the escitalopram group 5 of 29 patients did not complete protocol requirements (4 ceased escitalopram because of adverse events; 1 missed visits owing to Covid‑19 restrictions), and one reduced dose; in the psilocybin group 3 of 30 patients did not complete all dosing procedures (2 missed dosing‑day 2 owing to Covid‑19 restrictions; 1 stopped daily placebo capsules after guessing their content). No serious adverse events were reported in either group. The proportion of participants reporting any adverse event was similar (87% in the psilocybin group and 83% in the escitalopram group). Escitalopram was associated with higher percentages of reported anxiety, dry mouth, sexual dysfunction and reduced emotional responsiveness, whereas adverse events in the psilocybin group were typically transient, occurring within 24 hours of dosing and most commonly headaches. No visual perceptual changes, psychotic symptoms or dependency‑related behaviours were observed or reported at 6 weeks. Post hoc analyses addressing the baseline imbalance in alcohol use produced results consistent with the main analyses.

Carhart‑Harris and colleagues emphasise that the trial did not demonstrate a significant difference between psilocybin and escitalopram on the prespecified primary outcome of change in QIDS‑SR‑16 at 6 weeks. They note that many secondary outcomes numerically favoured psilocybin, including a higher remission rate, but caution that the analyses of secondary endpoints were not adjusted for multiple comparisons and therefore do not permit definitive clinical conclusions. The authors acknowledge several limitations that constrain interpretation. The lack of a placebo group prevents attribution of observed within‑group improvements to the active agents alone. The escitalopram treatment period was brief relative to usual clinical practice, so a longer course might have produced greater benefit in that group. The trial sample was selected — many participants self‑referred and several expressed a preference for psilocybin — and exclusion criteria omitted patients with certain preexisting psychiatric conditions; these factors, together with the predominantly White and non‑diverse sample, limit generalisability. Blinding effectiveness was not assessed, and expectancy or unblinding may have influenced outcomes despite the active‑comparator design. The discussion also addresses practical and mechanistic considerations. Psilocybin produces an altered quality of conscious experience that necessitates psychological support during and after dosing, which increases treatment complexity. Acute subjective psychedelic effects were not treated as adverse events in this trial because prior work suggests they may mediate therapeutic responses. The authors briefly note preclinical evidence that serotonergic psychedelics can promote neuronal plasticity, a mechanism that could interact with contextual factors to shape therapeutic outcomes. Finally, they conclude that larger and longer trials are required to compare psilocybin with established antidepressant treatments and to resolve the uncertainties identified in this Phase II study.