In an open‑label trial of 27 treatment‑resistant depression patients given a single 25 mg psilocybin dose with psychotherapy, those who had discontinued antidepressants before treatment showed comparable reductions in clinician‑rated and self‑reported depression, anxiety and suicidality to patients unmedicated at screening. Both groups experienced clinically significant improvements and similar intensity of psychedelic experience, suggesting medication tapering did not alter short‑term antidepressant effects in this sample.
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Haikazian, S., Chen-Li, D., Johnson, D. et al. · Psychiatry Research (2023)
Objective
To compare changes in depression, anxiety, and suicidality symptoms after a single 25 mg oral dose of psilocybin between treatment-resistant depression participants not on antidepressants at screening to participants that discontinued antidepressant medications leading up to receiving psilocybin-assisted psychotherapy (PAP).
Methods
Participants (n = 27) received at least one 25 mg dose of psilocybin accompanied by psychotherapy as part of an exploratory analysis from an open-label, randomized, waitlist-controlled clinical trial. The primary outcome of changes in depression symptoms was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included changes in anxiety symptom severity (Generalized Anxiety Disorder 7-Item [GAD-7]), suicidal ideation (MADRS Item-10), self-reported depression symptoms (Quick Inventory for Depression Symptomology [QIDS-SR]), and intensity of psychedelic experience (Mystical Experience Questionnaire 30-item [MEQ30]). Patients were separated into two groups for analysis; those who were unmedicated at initial screening versus participants that had to taper off antidepressant medications to be eligible for the trial. A mixed analysis of variance was used to evaluate clinical outcomes over time from baseline to 2 months post-dose.
Results
No significant differences were found between medication discontinued (n = 18) and unmedicated at screening (UAS) (n = 9) groups in clinician rated depression (p = 0.759), self-reported depression (p = 0.215), anxiety (p = 0.178), and suicidality (p = 0.882) symptoms over time, with both groups having clinically significant benefits on all outcomes assessed. Both groups also had a similar intensity of psychedelic experience (p = 0.191).
Conclusion
Comparable improvements were observed in depression and anxiety and symptoms between antidepressant discontinued and UAS patients. These findings contrast with and contribute to the growing literature on the effects of medication tapering leading up to PAP. Further clinical research is needed to directly compare efficacy across medication statuses, in addition to evaluating psychedelic effects in individuals continuing antidepressants during PAP.
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.
The primary outcome of this analysis was the absolute change in depression symptom severity over time as assessed by the clinician-administered Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included change in anxiety symptom severity (Generalized Anxiety Disorder 7-Item (GAD-7)), suicidal ideation (Question 10 on the MADRS), and self-report of depression symptoms (Quick Inventory for Depression Symptomology (QIDS-SR)). The Mystical Experiences Questionnaire (MEQ) 30-item was used to evaluate the intensity of psychedelic experiences following psilocybin dosing sessions.
This exploratory analysis from an open-label clinical trial demonstrated that antidepressant MDC and UAS participants had comparable improvements in depression symptoms following a single dose of psilocybin with supportive psychotherapy. Comparable improvements were also found in self-reported depression symptoms and anxiety symptoms between groups. Neither group experienced significant increases or reductions in suicidal ideation over time. The UAS group had a clinically but not statistically significant greater intensity of psychedelic experience. Our findings contribute to the growing literature on how the efficacy of psilocybin may be impacted by antidepressant medications. Our results contrast with a recently published article examining the effects of discontinuing serotonergic antidepressants before psilocybin therapy. A post-hoc analysis of an RCTcomparing PAP to escitalopram found that antidepressant discontinuers in the psilocybin group had a reduced treatment effect compared to unmedicated participants.While these results cannot determine the causation of medication status on PAP efficacy, they suggest the potential for a substantial impact exists.A greater treatment effect was observed in MDC participants receiving escitalopram, likely as a result of reintroducing an SSRI to those potentially with serotonin withdrawal symptoms.It should be acknowledged that there were significant differences between the original trial design and the analyses of Erritzoe et al. Firstly, the data in this analysis stemmed from an open-label, waitlist-controlled trial as opposed to an RCT where escitalopram was used as a control. Erritzoe et al. also analyzed results from MDD patients rather than TRD. Our analysis also has a comparatively smaller sample size and an uneven distribution of MDC and UAS participants (2:1 ratio, respectively, at baseline). The tapered antidepressant medications themselves also differed significantly. In contrast, only SSRIs or SNRIs medications were analyzed in the Erritzoe et al. analysis. The sample for this analysis was required to taper off a more mechanistically diverse range of medications for depression compared to solely serotonergic antidepressants. The reduced prevalence of serotonergic medications among tapering patients could explain why they had a similar response to UAS patients. Overall, the discrepancy in findings between this and the Erritzoe et al. analysis could be attributable to these differences in study design and sample characteristics. The degree and intensity of psychedelic effects at the first dose were comparable between UAS and MDC participants, though UAS participants had clinically higher MEQ scores. These results support that statistically similar, although not identical from a clinical perspective, strength psychoactive experiences can be produced by a psilocybin dose, even in those requiring a washout period. The analysis from Erritzoe et al. also found comparable psychedelic effects between medication status groups. Furthermore, a study of concomitant SSRIs TRD patients receiving PAP also experienced significant psychedelic effects and improvements in depression symptoms.Taken together, it appears that continued downregulation of the serotonergic system and 5-HT2A receptor occupancy is not the sole mediator of the psychedelic effects of psilocybin.There may be slight variation in intensity of psychedelic effects, but PAP dosing sessions can still meet the threshold of an altered state of consciousness irrespective of these variations. Previous animal research does implicate the serotonergic system in producing psychedelic effects, although other pharmacological factors likely have a role as well.A webbased retrospective survey study of psilocybin users found that serotonergic antidepressant usage was associated with a lower intensity of psychedelic experience compared to nonserotonergic antidepressant usage.While this study suggests that dampened psychedelic effects could result from more recent antidepressant use, our results and recent clinical research suggest that a profound and therapeutic dosing experience can still occur regardless. Further research is required into what pharmacological factors influence the efficacy and psychedelic experience of PAP. It is currently unknown whether or how exactly the psychedelic experience contributes therapeutic outcomes of PAP.There are limitations to this analysis that should be addressed. Firstly, this post-hoc analysis is from an openlabel trial that lacked a placebo control group and primarily focused on feasibility rather than efficacy. The sample size is small, particularly in the UAS group with only nine participants, reducing the statistical power to detect more nuanced differences in clinical efficacy between groups. This lack of statistical power renders our analysis better described as exploratory rather than being able to display a noninferiority. Another limitation was that to conduct a mixed ANOVA, some values had to be extrapolated forwards where there was missing data. By looking at outcomes up to only 2 months, the ability to assess longer term efficacy is limited. As well, the study sample had a greater proportion of male than female participants. Considering that depression is more prevalent among females, having a smaller female patient sample reduces the generalizability and representativeness of our analysis. Lastly, mild baseline suicidal ideation limits our ability to compare differences in antisuicidal effects between medication status groups. Despite these limitations, this analysis is able to contribute to an increasingly important topic on how medication tapering procedures could impact the antidepressant efficacy of PAP. Future studies should further evaluate the relationship between antidepressant medication tapering and the efficacy of PAP in greater detail. A larger sample size in future clinical research that directly compares the impact of medication tapering on antidepressant efficacy is warranted. Furthermore, it is still being determined if and how the duration of the washout period differentially affects clinical outcomes. As this analysis did not include the four bipolar depression patients from the study, it is important to highlight the lack of research on antidepressant medication discontinuation in PAP for BD-II, where there are likely additional clinical factors to consider in medication tapering.
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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.