Comparing Antidepressant Effects of Psilocybin-Assisted Psychotherapy in Individuals That Were Unmedicated at Initial Screening Versus Individuals Discontinuing Medications for Study Participation

Treatment-resistant depression (TRD) is defined as a depressive episode that has failed to respond adequately to at least two antidepressant trials and affects an estimated 30% of people diagnosed with depression, producing substantial functional impairment and increased healthcare burden. Psilocybin, a serotonergic psychedelic whose active metabolite psilocin is a high-affinity 5-HT2A receptor agonist, has shown preliminary antidepressant effects when delivered alongside psychological support (psilocybin-assisted psychotherapy, PAP). A practical and scientific debate exists about whether concomitant antidepressant medications—particularly serotonergic agents such as SSRIs and SNRIs—should be tapered before PAP, because continuing these medicines might blunt psychedelic effects or alter therapeutic response, whereas tapering carries risks of discontinuation symptoms and relapse. Chisamore and colleagues report a post-hoc analysis addressing this gap: they compare changes in clinician-rated and self-reported depression, anxiety, suicidal ideation, and intensity of the psychedelic experience between participants who were unmedicated at initial screening (UAS) and participants who tapered off antidepressant medications to join an open-label, randomized, waitlist-controlled trial of PAP. The aim was to evaluate whether antidepressant discontinuation affected clinical outcomes following a single 25 mg oral dose of psilocybin delivered with preparatory and integration psychotherapy.

The source data derive from a randomised, waitlist-controlled, open-label clinical trial conducted at a community clinic in Mississauga, Ontario. The trial was approved by an institutional review board and registered on ClinicalTrials.gov. Adults aged 18–75 with a primary diagnosis of major depressive disorder (MDD) or bipolar disorder II (BD-II) experiencing a major depressive episode of at least 3 months were eligible; BD-I patients were excluded and BD-II participants were excluded from this exploratory analysis because they remained on mood stabilisers. TRD was defined using the Massachusetts General Hospital Antidepressant Treatment History Questionnaire as failure to respond to at least two adequate antidepressant trials. Safety screening included physical examination, ECG, bloodwork, urine toxicology, pregnancy testing where applicable, and vital signs. Participants were randomised in blocks to immediate treatment or a 2-week waitlist and could receive up to three 25 mg oral doses of powdered synthetic psilocybin. Each dosing episode was accompanied by one preparatory psychotherapy session (1–2 hours), a supervised dosing session (6–8 hours) and two integration sessions (1–2 hours each). Psychotherapy was delivered by trained multidisciplinary therapist dyads (one member was a licensed medical doctor), using a transtheoretical model adapted from prior psilocybin trials. For participants on contraindicated medications, tapering was performed under clinical supervision, typically over approximately one month with a nominal protocol of 25% dose reduction per week, though flexibility was allowed and tapering could be disallowed if judged unsafe. The primary outcome for this analysis was change in clinician-rated depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included the Generalized Anxiety Disorder 7-Item scale (GAD-7), suicidal ideation assessed using MADRS Item 10, self-reported depression via the Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR), and intensity of the psychedelic experience via the Mystical Experience Questionnaire (MEQ30). Statistical analysis used SPSS v29 and a mixed analysis of variance (ANOVA) to compare MDC (medication discontinued) and UAS groups from baseline to 2 months post-dose; the model controlled for sex, age at baseline, age at first diagnosis, years with depression and number of past medication trials. Assumptions for parametric testing were checked (Shapiro–Wilk, Mauchly's test, Levene's and Box's tests) and Greenhouse–Geisser corrections applied when required. Missing data were handled by last observation carried forward for some participants. The extracted text contains minor inconsistencies in participant counts across sections; the authors report that up to 30 participants received at least one dose and that 26 were included in this analysis after excluding BD-II patients, while group counts are reported variably in different parts of the manuscript.

Participant flow and baseline characteristics: the extracted text states that 30 patients received at least one 25 mg psilocybin dose and that 26 participants were included in this analysis after removal of BD-II cases; elsewhere the sample is described as comprising participants who tapered medications and those unmedicated at screening, with some inconsistencies in exact counts across sections (the text at points reports 21 tapering and nine unmedicated, and other passages refer to 18 discontinued and nine unmedicated). Baseline MADRS scores averaged around 30 in both groups, consistent with moderate depression severity. Adverse events were common (28/30 participants experienced at least one), but were mostly mild to moderate and transient; no serious adverse events were reported in the extracted text. Depression outcomes: a single 25 mg psilocybin dose with psychotherapy produced a significant reduction in MADRS scores over time (mixed ANOVA: F(5,112) = 11.096, p < 0.001, partial η2 = 0.316). However, there was no statistically significant difference in MADRS change over time between MDC and UAS groups (F(1,24) = 0.127, p = 0.724, partial η2 = 0.005). The reported mean difference in MADRS change between groups was 1.191 (95% CI −5.693 to 8.075). Self-reported depressive symptoms (QIDS-SR) also improved over time (F(4,108) = 4.424, p < 0.001, partial η2 = 0.241) with no significant group-by-time difference (F(1,23) = 1.269, p = 0.272). Assigned sex at birth and baseline MADRS score were identified as significant predictors of change in MADRS and QIDS-SR scores. Anxiety and suicidality: GAD-7 scores improved significantly over time (F(2,51) = 3.950, p = 0.023, partial η2 = 0.141), with both MDC and UAS groups showing similar trajectories (no significant between-group difference, F(1,24) = 1.166, p = 0.291). Mean GAD-7 was lowest at 2-week post-dose and trended toward some worsening by 2 months. Suicidal ideation (MADRS Item 10) showed no significant change over time (F(5,116) = 1.259, p = 0.287) and no difference between medication-status groups (F(1,24) = 0.026, p = 0.873); baseline SI was mild in this sample. Intensity of psychedelic experience: MEQ30 scores after the first dose were higher on average in the UAS group (mean 88.56 ± 16.39) compared with the MDC group (mean 59.75 ± 6.71), but this difference did not reach statistical significance (t(23) = −1.909, p = 0.069; 95% CI −60.02 to 2.41). MEQ comparisons at subsequent doses were not conducted due to limited statistical power. Overall, both groups achieved clinically meaningful improvements on the assessed outcomes with no statistically detectable disadvantage associated with prior antidepressant discontinuation in this dataset.

Chisamore and colleagues interpret these exploratory findings as evidence that participants who tapered off antidepressants (MDC) and those unmedicated at screening (UAS) experienced comparable clinical benefit from a single 25 mg dose of psilocybin delivered with structured psychotherapy. Improvements were observed in clinician-rated and self-reported depressive symptoms and in anxiety; suicidal ideation did not increase in either group. The authors note that UAS participants showed a clinically greater, though not statistically significant, intensity of mystical experience. The paper contrasts these results with a recently published randomised trial analysis (Erritzoe et al.) that reported reduced treatment effect among antidepressant discontinuers receiving psilocybin; Chisamore and colleagues highlight differences that may explain the discrepancy, including study design (open-label waitlist-controlled versus double-blind RCT with escitalopram control), participant population (TRD versus MDD), sample size and group balance, and the heterogeneity of medications tapered in their sample versus exclusively serotonergic agents in the comparator study. They suggest that downregulation of the serotonergic system or 5-HT2A receptor occupancy may not be the sole determinant of psychedelic effects and that meaningful altered states and therapeutic responses can occur despite prior antidepressant exposure or tapering. Key limitations acknowledged by the authors include the post-hoc and exploratory nature of the analysis, the open-label design without placebo control, small overall sample size and especially the small UAS subgroup which reduces statistical power, imputation of missing data for the mixed ANOVA, limited follow-up duration by restricting analysis to two months to avoid confounding by additional doses, and a sex imbalance in the sample which limits generalisability. The authors also note that because baseline suicidal ideation was mild, the study has limited ability to compare antisuicidal effects between groups. They conclude that larger, prospective trials designed to directly compare medication-status groups and to examine washout duration are warranted, and they highlight the need for more research on antidepressant discontinuation procedures in PAP for bipolar depression (BD-II).

The authors conclude that in this exploratory analysis of an open-label trial, antidepressant discontinuation did not produce inferior antidepressant or anxiolytic outcomes following a single 25 mg psilocybin dose with psychotherapy compared with participants who were unmedicated at screening. These findings differ from some prior reports and underscore the complexity of how medication tapering may influence PAP efficacy. The paper calls for dedicated clinical trials that directly compare medication-status groups and investigate optimal tapering and washout practices to inform clinical safety and efficacy.