In a retrospective case series of 19 treatment‑resistant depression patients treated with 20–35 mg psilocybin in routine clinical practice, depressive symptoms decreased significantly with large effect sizes on MADRS and BDI, though response and remission rates were lower than in controlled trials and no additive benefit of multiple doses was found. No serious adverse events occurred, but the observational design and small sample size mean larger prospective studies are needed to confirm effectiveness and identify predictors of response.
Psilocybin has demonstrated promising antidepressant effects in depression and treatment-resistant depression (TRD) in controlled clinical trials. However, its effectiveness and safety in real-world therapeutic settings remain largely unknown. Although psilocybin is not yet approved as an antidepressant treatment, Switzerland’s unique legal framework allows its limited medical use for TRD. We conducted a retrospective analysis of medical records from 19 TRD patients treated with psilocybin (20–35mg) across one to four dosing sessions at the Psychiatric University Hospital Zurich. Depression severity was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Beck Depression Inventory II (BDI). Changes from baseline to interim and post-treatment were analyzed, including response, remission, and the reliable change index. MADRS scores significantly decreased from baseline ( M = 30.78) to post-treatment ( M = 19.89), with a large effect size (Hedges’ g = 1.37, p < .001). BDI scores also decreased significantly ( M = 32.33 to M = 23.28), with a large effect ( r = .80, p = .003). Response and remission rates were 33.3% and 22.2% (MADRS), and 27.8% and 27.8% (BDI). No additive effect of multiple dosing was found. No serious adverse events occurred. We observed a significant and clinically meaningful reduction in depressive symptoms after psilocybin treatment, with response and remission rates below those reported in previous trials. Although observational and limited by its sample size, this study provides some of the first real-world evidence on psilocybin. Larger, prospective trials are needed to confirm our findings and identify predictors to increase treatment effectiveness.
Papers cited by this study that are also in Blossom
Vollenweider, F. X., Preller, K. H. · Nature Reviews Neuroscience (2020)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Raison, C. L., Sanacora, G., Woolley, J. D. et al. · JAMA (2023)
Schindowski, E. M., Jungwirth, J., Schuldt, A. et al. · EClinicalMedicine (2023)
Depressive disorders are highly prevalent and a major contributor to global disease burden; a substantial proportion of people with major depressive disorder (MDD) fail to achieve remission after two or more antidepressant trials and are classified as having treatment-resistant depression (TRD). Psilocybin, a 5-HT2A receptor agonist that produces dose-dependent alterations in cognition, perception and affect, has shown antidepressant effects in several randomized controlled trials (RCTs). However, RCTs often use strict eligibility criteria, have difficulties with blinding because of pronounced subjective effects, and typically test single-dose paradigms, which limits generalisability to more complex clinical populations and leaves unanswered questions about optimal dosing schedules and durability of effect. This retrospective study by J. and colleagues set out to examine the effectiveness and tolerability of psilocybin therapy delivered in a real-world clinical setting in Switzerland, where limited medical use exemptions have allowed flexible administration. The authors aimed to describe changes in depressive symptoms and adverse events in TRD patients receiving between one and four oral psilocybin dosing sessions (20–35 mg), and to test the hypothesis that psilocybin would reduce depressive symptoms and that additional dosing sessions would produce further symptom reduction. The focus is on naturalistic outcomes that may complement findings from tightly controlled trials and inform future clinical practice and research on multidose paradigms.
Design and setting: This was a retrospective observational study of electronic health records from the University Hospital of Psychiatry Zurich, covering treatments between February 2023 and May 2025. Ethical approval was obtained from the Cantonal Ethics Committee Zurich and patients provided written informed consent for the use of anonymised clinical data. Participants: The sample comprised 19 outpatients with ICD-10–diagnosed treatment-resistant depressive episodes who attended a specialised Second Opinion Consultation Service for Depression. Inclusion required failure of at least two prior antidepressant trials. Patients were aged 27–67 and were screened for physical health and contraindications using medical history, physical exam, laboratory tests, cranial MRI, ECG and EEG. Exclusion criteria included a personal or first-degree family history of psychotic or bipolar disorders, uncontrolled hypertension, recent cardiovascular events, certain cerebrovascular conditions, increased intracranial pressure, inadequately treated hyperthyroidism, and pregnancy or breastfeeding. Intervention and clinical procedures: Treatment was delivered in single in-/outpatient or group inpatient formats; patients received between one and four dosing sessions. Inpatient group courses were typically two sessions two weeks apart within a four-week stay, whereas single-setting sessions were individually scheduled. Psilocybin (synthetic, 5 mg capsules) was administered orally at individualized doses of 20–35 mg formulated under Good Manufacturing Practice. Preparation included at least two preparatory sessions to build therapeutic rapport and set expectations. Antidepressant medications were generally continued but paused on dosing days; medications with 5-HT2 receptor–blocking properties were paused for at least three half-lives. Dosing days were supervised by trained therapists (at least one in single sessions, at least two in group sessions). Integration meetings followed dosing to support reflection and transfer of insights. Adverse events were assessed via a 16-item questionnaire given immediately after dosing and via routine clinical documentation of serious adverse events. Outcomes and timing: Primary outcomes were depressive symptom scores on the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) and the self-report Beck Depression Inventory II (BDI). Assessments were taken at baseline (closest measurement prior to the first dosing), between dosing sessions and at the first follow-up within 42 days after the final dosing session (used as the post-treatment measurement). Secondary outcomes included categorical indicators: response (≥ 50% reduction from baseline), remission (BDI ≤ 13; MADRS ≤ 12) and reliable change assessed by the Reliable Change Index (RCI). Adverse events (AEs) and serious AEs were secondary outcomes. Statistical analysis: Paired t-tests and Wilcoxon signed-rank tests were used to compare baseline to post-treatment scores depending on normality; Hedges' g and rank-biserial correlation were reported as effect sizes. A multiple linear regression was used to examine potential bias from variable timing of post-treatment assessments (details reported in the supplement). To examine change across dosing sessions, linear mixed-effects models were fitted with session number as a fixed effect (0–4) and participant random intercepts; estimated marginal means and Tukey-adjusted pairwise comparisons were reported. AEs were summarised by number of participants affected and frequency across dosing sessions. Analyses were conducted in R; two-tailed p < 0.05 was the threshold for statistical significance.
Sample and treatment exposure: Nineteen patients entered treatment and completed the first dosing session. Thirteen completed two dosing sessions, five completed three, and three completed four. For primary endpoint analyses, one participant lacked a valid MADRS endpoint and a different participant lacked a valid BDI endpoint, yielding n = 18 for analyses on both instruments. Primary outcomes — clinician-rated MADRS: MADRS scores decreased from baseline (mean = 30.78, SD = 9.02) to the post-treatment assessment after the last dosing session (mean = 19.89, SD = 9.65). The mean reduction was 10.89 points; the paired t-test was t(17) = 6.067, p < .001. The effect size was very large (Hedges' g = 1.37). On categorical outcomes, 6 of 18 patients (33.3%) met the response criterion (≥ 50% reduction) on the MADRS, and 4 of 18 (22.2%) met the remission threshold (MADRS ≤ 12). The mean percentage reduction on the MADRS was 35.6%. Using the RCI (threshold = 8.21 points), 10 patients (55.6%) showed reliable improvement, eight (44.4%) showed no reliable change, and none showed reliable deterioration. Primary outcomes — self-reported BDI: BDI scores decreased from baseline (mean = 32.33, SD = 12.25) to post-treatment (mean = 23.28, SD = 13.88). A Wilcoxon signed-rank test indicated a significant reduction in BDI scores (V = 153.5, p = .003). The mean reduction was 9.06 points and the effect size was large (r = .80). Five of 18 patients (27.8%) met response criteria on the BDI, and five (27.8%) met remission criteria (BDI ≤ 13). The mean percentage reduction on the BDI was 26.8%. Using the RCI (threshold = 9.5 points), eight patients (44.4%) showed reliable improvement, ten (55.6%) showed no reliable change, and none showed reliable deterioration. Change across dosing sessions: Analyses examining depressive symptoms across multiple dosing sessions indicated that the largest improvement occurred after the first dosing session, and subsequent sessions did not show consistent additive benefits at the group level. MADRS scores remained significantly decreased versus baseline across sessions, but pairwise significance compared with baseline disappeared from the third session onwards. On the BDI, significant improvement over baseline was observed after the first two sessions, with only trend-level improvements thereafter. The authors note that only a small number of patients received more than two sessions, increasing uncertainty around these session-level comparisons. Adverse events and tolerability: Across 30 recorded dosing sessions, at least one adverse event was reported in 24 sessions (80%). Patients reporting any AE tended to report multiple events (mean number of AEs per affected patient = 3.53, SD = 2.11, range 1–8). The most frequent AEs were fatigue (n = 20 occurrences), headache (n = 16) and tearfulness (n = 15). All reported AEs were transient, and no serious adverse events were recorded during the observation period.
J. and colleagues interpret their findings as evidence that psilocybin administered flexibly in a real-world clinical setting was associated with statistically significant and clinically meaningful reductions in depressive symptoms among TRD patients on both clinician-rated and self-report measures. The magnitude of mean symptom reductions (MADRS reduction = 10.89 points; BDI reduction ≈ 9 points) and large effect sizes were noted, although the authors state these improvements were somewhat smaller than pooled effects reported in prior clinical trials of MDD and TRD. Response and remission rates observed here (MADRS: response 33.3%, remission 22.2%; BDI: response 27.8%, remission 27.8%) were lower than those in some earlier RCTs that reported higher short-term response and remission, but fall within the lower range of more recent large trials. Regarding multiple dosing, the authors found no clear additive benefit at the group level: the largest symptom change occurred after the first dosing session, with limited incremental improvement from subsequent sessions. They propose several explanations: the small number of participants receiving more than two sessions (limiting power), continuation of treatment even when early non-response occurred (so later sessions were more often administered to poorer responders), heterogeneity in inter-session intervals (a possible optimal timing window is unknown), and the possibility that additional sessions simply do not confer added benefit for many patients. They also note that some individual patients did respond only after a second or third session, suggesting potential individual-level benefits. The authors situate their study as among the first to examine a multidose psilocybin paradigm in a naturalistic TRD population and argue that the sample reflects the complexity of routine clinical care—patients with multiple comorbidities, numerous prior treatment failures and chronic illness—thereby addressing a limitation of highly selective RCT samples. Nevertheless, they acknowledge important limitations: small sample size and attendant limited statistical power; underrepresentation of female and non-European patients limiting generalisability; retrospective design and reliance on clinical records that preclude causal inference; heterogeneity in treatment procedures, concomitant pharmacotherapy and psychotherapy, dosing schedules and measurement timepoints; absence of a control group; and the possibility that some patients received further dosing after the measurement window. These factors make it difficult to attribute observed changes solely to psilocybin rather than to adjunct treatments or nonspecific clinical effects. The authors recommend that future research employ larger prospective observational designs, ideally with comparator treatments (for example esketamine or electroconvulsive therapy), and control for concomitant medication, psychotherapy type and setting. They also highlight the need to identify biomarkers or predictors of treatment response to improve patient stratification and cost-effectiveness, given the resource intensity of current psilocybin treatment models. In sum, the authors conclude that their study provides initial real-world evidence of clinically meaningful symptom reduction and acceptable tolerability in TRD patients treated with one to four psilocybin sessions, while emphasising that larger, prospective studies are required to draw more definitive conclusions.
Depressive disorders affect an estimated 330 million people globally and rank among the leading contributors to disease burden, with major depressive disorder (MDD) as the most prevalent subtype. Approximately half of the individuals with MDD who complete at least two antidepressant trials do not achieve remission. This group is commonly de ned as suffering from treatment-resistant depression (TRD). Apart from treatment resistance, patients with TRD show a signi cantly lower quality of life and higher all-cause mortality, underscoring the urgent need for novel therapeutic options. In this context, psilocybin is emerging as a promising candidate. It primarily acts as a 5-HT2A receptor agonist, inducing dose-dependent alterations in cognition, perception, and affect. While the speci c mechanisms underlying the antidepressant effect of psilocybin are not fully understood, they are likely involving an interaction between neural plasticity, connectivity changes, and increased psychological exibility (8). Over the past decade, several randomized controlled trials (RCTs) have demonstrated the e cacy of psilocybin in the treatment of MDD, including TRD. Current data suggests that psilocybin is generally safe and well tolerated when administered with psychological support in a supervised clinical setting. Despite these encouraging ndings, RCTs on psilocybin have faced methodological challenges. First, they are conducted under strict eligibility criteria. Patients suffering from severe treatment resistance, comorbidities, suicidality or speci c medication histories are thus often excluded. Consequently, the generalizability of results from these tightly controlled studies to the broader clinical populations remains uncertain. Second, the pronounced subjective effects of psilocybin make effective blinding di cult in both patients and raters, increasing the risk of strong con rmation and expectancy biases in treatment groups, and potential frustration in control groups. This may in ate the estimation of psilocybin`s therapeutic e cacy. Taken together, these limitations suggest that, despite their clear value, RCTs alone are insu cient to capture psilocybin's impact on clinical practice. Another unresolved question is whether current psilocybin treatment paradigms are clinically optimal with respect to both e cacy and durability. Most clinical trials rely on a single medium-to-high dose of psilocybin. However, a recent follow-up study byindicated that relapses may begin to occur as early as three months after participants received one dose of 25 mg psilocybin, challenging the durability of the antidepressant effect (16). A solution to prevent these relapses may lie in multiple dosing sessions. Yet, data on multiple psilocybin sessions are con icting and scarce. A metaanalysis by Yu et al.suggested a stronger antidepressant effect of two psilocybin dosing sessions compared to one, and in a small scaleobserved that up to three exibly planned dosing sessions were associated with further reductions in depressive symptoms in patients with TRD. In contrast, a meta-analysis by Salvetti et al.found no signi cant difference between one and two psilocybin dosing sessions. Collectively, the uncertainty of response durability and the emerging evidence supporting multidose paradigms, along with the methodological limitations of current RCTs, emphasize the necessity to examine psilocybin treatment under exible clinical conditions. Switzerland offers a unique legal framework to explore psilocybin treatment for TRD. From 2021, psilocybin can be prescribed under a so-called "limited medical use exemption" for several treatment-resistant indications issued by the Federal O ce of Public Health. In contrast to typical trial conditions, such treatment can be exibly scheduled. Patients can undergo multiple psilocybin sessions, and antidepressant medication can be continued, providing ideal conditions to explore the feasibility of psilocybin treatment. To our knowledge, there have only been two studies exploring the effects of psilocybin in a comparable setting. The rst used a sample of eight patients to explore the long-term effects of psilocybin on alleviating distress associated with life-threatening diseases in Canada. The second, by Calder et al., primarily examined the relationship between the acute subjective drug effects and the change in depression scores with both lysergic acid diethylamide (LSD) and psilocybin. While they included patients who were given up to ve dosing sessions, they did not explore the course of depression across these dosing sessions. This present investigation therefore aims to examine the clinical course of TRD patients, receiving up to four psilocybin dosing sessions in a real-world clinical setting. We retrospectively assess changes in depressive symptoms as well as tolerability of repeated psilocybin administrations. We hypothesize that psilocybin treatment will signi cantly reduce depressive symptoms and that each additional dosing session will further reduce depressive symptoms. By evaluating the e cacy and safety of multiple psilocybin dosing sessions in a real-world clinical setting, we hope to inform future trials as well as the formation of clinical treatment plans as regulatory approval processes are expected in the upcoming years.
This retrospective observational study was conducted at the University Hospital of Psychiatry Zurich, a multi-site psychiatric institution in Switzerland. Data were extracted from electronic health records in 2025. Ethical approval was granted by the Cantonal Ethics Committee Zurich (BASEC-Nr. 2025 - 00559). Prior to treatment, all patients provided written informed consent for the use of anonymized clinical data in research.
We included 19 patients who underwent psilocybin treatment at the Second Opinion Consultation Service for Depression, a specialized outpatient consultation and treatment service for TRD patients. Patients were referred to the consultation service by external and internal psychiatrists, psychotherapists, or general practitioners. Participants were between 27 and 67 years old and underwent psilocybin treatment between 02.2023 and 05.2025. All had been diagnosed with a treatment-resistant mild to severe depressive episode by trained psychiatrists according to ICD-10 criteria. To be categorized as treatment-resistant, patients had to have undergone at least two unsuccessful antidepressant trials. Patients were required to be in stable physical health and not showing any contraindications as determined by medical history, physical examination, routine laboratory tests, cranial magnetic resonance imaging (cMRI), electrocardiogram (ECG), and electroencephalogram (EEG). Exclusion criteria were a personal or rst-degree family history of psychotic or bipolar disorders. Patients were also excluded if they presented with uncorrected hypertension, a history of stroke, intracerebral hemorrhage, or aneurysm (intracranial, thoracic, abdominal, or peripheral), recent cardiovascular events (within eight weeks), increased intracranial pressure, or inadequately treated hyperthyroidism. Individuals who were pregnant, breastfeeding, or planning pregnancy during the treatment period were not eligible. A summary of patient demographics and clinical characteristics is given in Table.
The treatment procedure assigned to each patient was based on availability as well as clinical judgement. Patients were either treated in a single in-or outpatient setting or in a group inpatient setting and received between one and four dosing sessions. The number of dosing sessions in the single setting was determined by clinical assessment and was individually and dynamically planned and could be a few months apart. In the inpatient group setting, the number of dosing sessions was preplanned to two dosing sessions two weeks apart during a four-week in-patient treatment course. Patients received an individualized dose of orally administered synthetic psilocybin, ranging from 20 to 35 mg. Psilocybin was obtained from Dr. Hysek, Biel, Switzerland and formulated according to Good-Manufacturing-Practice in capsules containing 5 mg.
Prior to preparation, patients underwent psychiatric assessment including biographical history, psychometric testing, and medical examinations. Patients then completed at least two initial sessions focused on establishing therapeutic rapport and managing expectations. Antidepressant medication was generally continued and only paused on the dosing day. Medication with 5-HT2 receptor blocking properties were paused at least three half-lives prior to the dosing session. More information on medication management can be found in the supplement.
Patients received psilocybin in a calm and speci cally arranged room at the University Hospital of Psychiatry Zurich. In the single setting, at least one speci cally trained therapist was present during the whole duration of the therapy session. In the group setting, at least two therapists were present during the whole duration of the session. At the end of dosing day, patients were given a questionnaire to assess adverse events. Patients were also encouraged to write a report about the experience.
Following dosing day, patients participated in a series of integration meetings aimed at re ecting the psychedelic experience, discussing emerging insights, and supporting transfer to daily life. Detailed information on preparation, dosing day, integration, and patient ow can be found in the supplement and in supplementary Table.
The primary outcomes were scores on the Beck Depression Inventory II (BDI)and the Montgomery-Åsberg Depression Rating Scale (MADRS) after the nal dosing session. Assessments were made according to clinical relevance before treatment, between dosing sessions and after the last dosing session. Secondary outcomes included categorical indicators of clinical improvement. Speci cally, response was de ned as a ≥ 50% reduction from baseline; remission was de ned as a total score reduction to ≤ 13 on the BDI and to ≤ 12 on the MADRS; and reliable change de ned by the Reliable Change Index (RCI). Adverse Events (AEs) AEs were a secondary outcome collected through a questionnaire containing 16 commonly occurring AEs during psilocybin treatment (Table). Patients were asked to indicate whether they had experienced any of these AEs or not. Questionnaires were given to patients directly after the dosing session and were worded to capture AEs during and after treatment. Serious AEs were monitored as part of routine clinical procedures and documented in the medical record. AEs were a secondary outcome collected through a questionnaire containing 16 commonly occurring AEs during psilocybin treatment (Table). Patients were asked to indicate whether they had experienced any of these AEs or not. Questionnaires were given to patients directly after the dosing session and were worded to capture AEs during and after treatment. Serious AEs were monitored as part of routine clinical procedures and documented in the medical record.
The primary objective of this study was to quantify the improvement of depression in patients who underwent psilocybin treatment. On all analyses, baseline was determined as the closest measurement prior to the rst dosing session, with both BDI and assessed on the same If assessments were not done on the same day, the next assessment was chosen.
For the paired t-test, Wilcoxon signed-rank test, multiple regression, remission, response, and RCI the rst follow-up measure within 42 days after the nal dosing session was used as post-treatment measurement. To assess the changes in depressive symptoms from baseline to post-treatment, a paired t-test was conducted. To determine the effect size of the reduction, Hedges' g was calculated (26). Assessments of normality (Q-Q plot and Shapiro-Wilk) indicated some deviation in the difference scores on the BDI. A Wilcoxon signed-rank test was thus conducted, and a rank-biserial correlation was calculated to determine the size of the reduction. For transparency purposes, and since the results were nearly identical, the corresponding t-test and effect size are reported in the Supplementary Materials. To account for a possible bias in the assessment timing, since post-treatment scores were collected at different time-points, a multiple linear regression model was tted to predict post-treatment scores using baseline scores and the number of days since treatment as predictors. Results can be found in the supplement To assess whether group-level changes were clinically meaningful, remission (MADRS ≤ 12; BDI ≤ 13), response (≥ 50% reduction), and the RCI were calculated. Thresholds for clinically reliable improvement and clinically reliable deterioration were set to 1.96 and - 1.96 respectively, corresponding to a 95% con dence interval (CI).
To effects across multiple dosing sessions, mixed-effects was using the lm4 package. The outcome variable for the linear mixed model was derived by selecting the rst available score recorded within 42 days after each dosing session. The model included sessions as a factor from 0 (baseline) to 4 (fourth dosing session) as a xed effect and participants as random intercepts to account for baseline differences among individuals. Estimated marginal means (EMMs) were calculated and pairwise compared to inspect differences between sessions. Pairwise comparison was adjusted using the Tukey method.
AEs were summarized by type, rst, based on how many participants exhibited them at least once, and second, on how many times it occurred in all dosing sessions. All analyses were conducted using R (version 4.5.0) and RStudio (version 2025.05.1 + 513). Statistical tests used p < 0.05, two-tailed, to determine statistical signi cance. A full list of the key packages, assumptions tested and further explanations of RCI can be found in the supplement.
The nal sample consisted of 19 patients. All 19 had a baseline assessment and completed the rst dosing session. Thirteen completed two dosing sessions, ve completed three dosing sessions, and three completed four dosing sessions. For the primary endpoint analyses one participant did not have a valid endpoint assessment on the MADRS and another did not have a valid assessment on the BDI, leading to a nal n = 18 on both instruments. A full participant ow is provided in the Supplement. The MADRS scores signi cantly decreased from baseline (M = 30.78; SD = 9.02) to after the last dosing session (M = 19.89; SD = 9.65), t(17) = 6.067, p < .001; Fig.). The mean reduction was 10.89 points, 95% CI.68], with a very large effect size (Hedges' g = 1.37). A Wilcoxon signed-rank test was conducted to compare BDI scores before (M = 32.33, SD = 12.25) and after the last dosing session (M = 23.28, SD = 13.88). A signi cant reduction in depressive symptoms was found (V = 153.5, p = .003; Fig.). The mean reduction in BDI scores was 9.06 points, 95% CI. Again, the effect size was very large (r = .80). These results indicate that patients improved across the treatment period across both clinician-and self-rated measures. Out of 18 patients, 6 (33.3%) and 5 (27.8%) were classi ed as responders on the MADRS and BDI respectively. The mean percentage reduction was 35.6% on the MADRS and 26.8% on the BDI. In total, 4 patients (22.2%) on the MADRS and 5 patients (27.8%) on the BDI met remission criteria at the end of treatment period. On the MADRS, 10 (55.6%) patients showed reliable improvement, 8 patients (44.4%) showed no reliable change, and no patient showed reliable deterioration. The threshold for a reliable change was 8.21 points. On the BDI, 8 patients (44.44%) showed reliable improvement, 10 patients (55.6%) showed no reliable change, and none showed reliable deterioration. The threshold for a reliable change was 9.5 points.
In 24 (80%) of the 30 recorded dosing sessions, at least one AE was reported. Patients experiencing an AE typically reported more than one (M = 3.53, SD = 2.11, Min = 1, Max = 8). The most frequent AEs were fatigue (n = 20), headache (n = 16), and tearfulness (n = 15). All AEs were transient, and no serious AEs were recorded.
In retrospective real-world study of patients with TRD, psilocybin was administered between one and four times, exibly tted to the course of each patient by clinical decisions. A signi cant and clinically relevant improvement in depressive symptoms between baseline and after the nal dosing session was found on both self-reported and clinician-rated instruments. No serious or sustained AEs occurred. The mean reduction of -10.89 points (MADRS) and of 9.08 points (BDI) observed in this study were slightly lower to the mean reduction of 12.11 points across clinical trials on both TRD and MDD. Response and remission numbers of this study were lower than those observed in previous RCTs on MDD, which had up to 70% of patients responding and roughly 50% remitting within weeks of treatment. However, they fell within the lower range of recent large scale RCTs with response rates between 37% and 42%, and remission rates between 29% and 25%. The effect sizes found in this study were also within the range of prior trials, but smaller in size. Taken together, these ndings indicate that results from clinical trials, to some extent, translate into routine clinical practice, although outcomes appear smaller in scale. However, such comparisons warrant caution, as existing studies involved one or two dosing sessions and focused mainly on MDD rather than TRD. Contrary to our expectation, we did not nd an additive effect of multiple psilocybin sessions. On both scales, the strongest improvement in depressive symptoms occurred after the rst dosing session, and subsequent dosing sessions did not differ from the initial improvement after the rst session. These results could suggest a stabilization or ceiling effect. MADRS scores after all sessions were signi cantly decreased compared to baseline, but in pairwise comparisons this signi cance disappeared from session three onwards. On the BDI, only the rst two sessions showed signi cant improvement over baseline, while still showing a trend-level improvement thereafter. Several factors may account for this pattern. First, only a very small number of patients underwent more than two dosing sessions, increasing the uncertainty of the results. Second, we continued treatment even when patients did not respond. In fact, most patients who had more than two dosing sessions did not respond to the treatment. A possible explanation for this lack of response could be that these patients suffered from a more severe form of treatment-resistance. Third, the time between dosing sessions varied greatly between patients, and it may be that there is a speci c time window in which an additional dose is most effective. There is currently no data to support this claim, as data on multiple treatment sessions are scarce. Finally, there is the possibility that there is simply no additive or not even a maintaining effect of two or more than two psilocybin sessions. The two meta-analyses conducted on this topic yield inconsistent results; one found that two psilocybin sessions had a greater and longer-lasting effect than one, while the other failed to nd a statistically robust difference. It should be noted that even though we found no further improvement on a group level, there might still be a merit in multiple psilocybin sessions, as some patients only responded for the rst time after the second or third session. The study at hand is among the rst to explore a multidose paradigm as well as the feasibility of psilocybin in a naturalistic clinical real-world setting. The naturalistic setting is especially important for patients with TRD, as they may not be adequately represented in trials, due to strict exclusion criteria (4). By including individuals with complex treatment resistance, multiple comorbidities, numerous unsuccessful antidepressant trials, several augmentation attempts, and chronic depression of many years' duration, our sample re ects a representative TRD population (4). Finally, the multidose paradigm provides unique insights into how psilocybin could be used in practice and may inform the design of future trials, especially regarding the timing and number of dosing sessions. While this study offers important data on the real-world use of psilocybin, there are limitations that need to be acknowledged. A major limitation was the small sample size, which limits statistical power. This was most apparent in the loss of signi cance for the effects observed after the third and fourth sessions once corrected for multiple testing. Further, female patients and patients of non-European decent were underrepresented, reducing generalizability. Although data were collected in a longitudinal manner, we only retrospectively reviewed health records, which precludes any causal inference. Adding to this, data was drawn from health records in active clinical service, so some patients may have returned for more dosing sessions after our measurement period. Furthermore, treatment procedures and data collection were guided by clinical practice rather than a standardized research protocol. As a result, substantial heterogeneity was present across treatment duration, number of dosing sessions, measurement timepoints, concomitant psychopharmacotherapy, psychotherapy, and follow-up schedules. This variability paired with the fact that we did not have a control group makes it di cult to determine if changes can be attributed to the psilocybin treatment alone or whether they may be better explained in conjunction with factors such as adjunct medication or the difference in treatment exposure. While it is important to note that these issues are somewhat common in real-world settings, future research could mitigate some of these limitations by running prospective observational designs comparing psilocybin treatment to other treatment options for TRD such as esketamine or electroconvulsive therapy. Ideally, larger observational studies should control for variables such as concomitant medication and psychotherapy, type of psychotherapy, setting, and treatment duration. Given the resource intensive nature of current psilocybin treatment paradigms, future studies should aim to identify biomarkers or other predictors for treatment success that enable patient strati cation to increase effectiveness and economic viability. In sum, this study demonstrates that psilocybin treatment led to a signi cant and clinically meaningful improvement in depressive symptoms among patients with TRD, replicating ndings from clinical trials with a slightly lowered e cacy. We further explored the bene t of multiple psilocybin sessions, nding no additive but likely a sustaining or ceiling effect. This study marks an important rst step in investigating the effectiveness of multiple, exibly scheduled psilocybin sessions in clinical practice. For more de nitive conclusions, studies with larger sample sizes are needed.
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