Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study
Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V. H., & Nutt, D. J. (2016). The lancet. Psychiatry
Study Type: Open-label feasibility trial (no control).
Methodology: Two dosing sessions were held one week apart, and psychological support was provided before, during, and after each session. Depression severity was measured using the Quick Inventory of Depressive Symptoms (QIDS) from 1 week up to 3 months post-treatment.
Sample: 12 adult patients (6 men, 6 women) with moderate-to-severe unipolar TRD.
Dosage: Two oral doses: 10 mg in the first session, followed one week later by 25 mg, with continuous therapist support. Patients discontinued antidepressant medications before dosing.
Key Findings:
– Psilocybin was well tolerated with no serious adverse events
– Depressive symptoms reduced dramatically: at 1 week post-treatment, mean QIDS scores had dropped by ~12 points from baseline (Hedges’ g ≈ 3.1, p=0.002), and at 3 months a sustained reduction of ~9 points was observed (g ≈ 2.0, p=0.003)
– Several participants moved from severe depression to remission.
– Marked improvements in anxiety and anhedonia were also reported
Citation: Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V. H., & Nutt, D. J. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The lancet. Psychiatry, 3(7), 619–627. https://doi.org/10.1016/S2215-0366(16)30065-7
Psilocybin with psychological support for treatment-resistant depression: six-month follow-up
Study Type: Open-label clinical trial with extended follow-up (this included the original 2016 cohort plus additional patients, followed for 6 months.)
Methodology: The same psilocybin treatment protocol (two sessions with psychological support). Depression was assessed from 1 week up to 6 months post-treatment using the self-rated QIDS (16-item) as the primary outcome. No control group was used (all participants received psilocybin). Participants had preparatory and integration therapy sessions.
Sample: 20 adults (6 female; mostly severe unipolar TRD)
Dosage: Two oral doses: 10 mg in the first session, followed one week later by 25 mg, with continuous therapist support. Patients discontinued antidepressant medications before dosing.
Key Findings:
– Psilocybin treatment was generally well tolerated; no long-term or unexpected adverse events emerged.
– Depression severity showed a large decrease after treatment: at 1 week, QIDS scores dropped with a very large effect (Cohen’s d ≈ 2.2, p<0.001), and this improvement was maintained at 5 weeks (d ≈ 2.3).
– At the 5-week mark, 9 of 20 patients (45%) met criteria for treatment response and 4 (20%) for – Positive effects persisted at 3 and 6 months – depressive symptoms were still significantly lower than baseline at 3m (d ≈ 1.5) and 6m (d ≈ 1.4, p<0.001).
– However, some waning of effect was noted over time: by 6 months a portion of patients had experienced some return of symptoms (though group means remained much improved from baseline).
– Notably, no patients sought conventional antidepressant treatment within the first 5 weeks post-psilocybin, reflecting sustained early benefits
– Moreover, greater quality of the acute psychedelic experience (e.g. mystical-type effects) statistically predicted larger depression improvements at 5 weeks.
Citation: R. L. Carhart-Harris, M. Bolstridge, C.M.J. Day, J. Rucker, R. Watts, David Erritzoe, M. Kaelen, B. Giribaldi, M. A P Bloomfield, S. Pilling, J.A. Rickard, B. Forbes, A. Feilding, D. Taylor, H. V. Curran and D.J. Nutt. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 235(2), pp. 399-408. https://doi.org/10.1007/s00213-017-4771-x
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder
Study Type: Randomized clinical trial (waitlist-controlled crossover design).
Methodology: Participants were randomly assigned to either an immediate treatment group (psilocybin therapy right away) or a delayed start group (an 8-week waitlist control, then psilocybin). All participants received two preparatory therapy sessions, two psilocybin treatment sessions, and follow-up integration therapy. Depression severity was primarily measured with the GRID-Hamilton Depression Rating Scale (HAM-D). Blinded raters assessed outcomes at 1 week and 4 weeks after the treatment phase (the delayed group served as a control to compare against the immediate treatment group during the 8-week delay period.)
Sample: 24 adults (average age 39; 16 women; racially diverse with majority white) with major depressive disorder (most had long-term depression averaging ~2 years, and many had prior treatment failures, though not all strictly TRD). Participants had to taper off any antidepressant medications before psilocybin administration (to avoid drug interactions)
Dosage: Two psilocybin-assisted therapy sessions were conducted two weeks apart. The dose in session 1 was ~20 mg/70 kg (moderately high), and in session 2 it was ~30 mg/70 kg (high dose). Each session lasted ~5 hours with participants lying on a couch wearing eyeshades and listening to music, guided by two session monitors. The setting was designed to be supportive and non-directive.
Key Findings:
– Psilocybin produced rapid, substantial, and sustained antidepressant effects in this trial.
– One week after the psilocybin sessions, 67% of the immediate-treatment group had achieved a >50% reduction in depression scores; by four weeks post-treatment, 71% of participants met that response criterion.
– Overall, at the 4-week follow-up 54% of participants were in remission (no longer meeting depression criteria).
– Mean depression ratings plummeted from a baseline of 23 (moderate-severe) to 8 (mild) at the 1- and 4-week marks.
– In contrast, those in the delayed control group showed no improvement during the 8-week waiting period, but then improved similarly after they eventually received psilocybin, confirming the treatment effect.
– Importantly, the magnitude of psilocybin’s effect was about four times larger than typical effects reported for traditional antidepressants in clinical trials.
– This suggests a large effect size for psilocybin (Cohen’s d ~2.8 in this study).
– In terms of safety, psilocybin was well-tolerated: some participants transiently experienced mild-to-moderate increases in blood pressure, headache, or anxiety during sessions, but no serious adverse events were recorded.
Citation: Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M.P., Sepeda, N. D., Johnson, M. W., Finan, P. H., Griffiths, R. R. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481–489. https://doi.org/10.1001/jamapsychiatry.2020.3285
Trial of Psilocybin versus Escitalopram for Depression
Study Type: Phase 2 randomized, double-blind, active-controlled trial. This study directly compared psilocybin therapy to a standard SSRI antidepressant (escitalopram) in patients with depression.
Methodology: Participants were randomized to one of two groups: (1) Psilocybin Therapy (PT) – two high-dose psilocybin sessions (given 3 weeks apart) plus 6 weeks of placebo capsules; or (2) Escitalopram Treatment (ET) – two very-low-dose psilocybin sessions (1 mg, as an active placebo) plus 6 weeks of daily escitalopram (SSRI medication). All participants and investigators were blinded to group assignment. Both groups received identical psychological support: therapy sessions before dosing, during the 6-hour dosing days, and integration therapy after. The primary outcome was change in depression severity on the QIDS-SR16 scale at 6 weeks. Key secondary outcomes included response/remission rates and depression scores at longer follow-up (some outcomes were tracked up to 6 months in a separate analysis).
Sample: 59 patients (average age ~41; 49% on antidepressants at screening which were tapered for trial) with moderate-to-severe major depression (many with treatment-resistant courses, though inclusion required only ≥2 failed antidepressants). Patients with serious medical conditions were excluded, but unlike earlier studies, mild-to-moderate suicidal ideation was not an exclusion as long as there was no imminent risk. Notably, about 30% of participants had treatment-resistant depression as defined by failure of ≥2 prior treatments (a subset analysis was later done for this group).
Dosage:The psilocybin group received two sessions of 25 mg psilocybin (a high, fully psychedelic dose) given at Week 0 and Week 3, under therapist guidance (same protocol as prior studies). They also took daily placebo pills (instead of antidepressant) for 6 weeks to maintain blinding. The escitalopram group, conversely, received two 1 mg psilocybin sessions (a negligible dose expected to have minimal psychedelic effect) at Week 0 and 3, and took daily escitalopram (10 mg for 3 weeks, increased to 20 mg for the remaining 3 weeks). This design ensured both groups had similar expectations (everyone had “psilocybin sessions,” though one group’s doses were essentially placebo) and therapy contact, differing only in the drug administered.
Key Findings:
– Both treatments led to significant depression improvements, and the trial’s primary outcome (QIDS depression score change at 6 weeks) did not significantly differ between psilocybin and escitalopram.
– By week 6, QIDS scores had decreased by an average of ~8.0 points in the psilocybin group vs ~6.0 points in the escitalopram group
– The between-group difference (2 points favoring psilocybin) was not statistically significant on this scale
– However, several secondary endpoints suggested psilocybin’s effects were at least as good as, and on some measures greater than, the SSRI’s effects.
-Notably, the remission rate at 6 weeks was higher with psilocybin: 57% (17/30) of psilocybin-treated patients were in remission (QIDS ≤5) vs 28% (8/29) with escitalopram.
– Likewise, response rates (≥50% symptom reduction) numerically favored psilocybin (≈70% vs 48%). These differences in responder/remitter rates did not reach p<0.05 in this relatively small sample, but they align with a clinically meaningful advantage for psilocybin.
– Participants in the psilocybin arm also showed faster improvement in some aspects (many reported feeling better within 1 day of the first session, whereas SSRI effects accumulated gradually over weeks).
– Additionally, quality-of-life and secondary well-being measures (like feelings of optimism and work/social functioning) tended to improve more with psilocybin.
– In terms of safety, both groups had similar adverse event profiles, aside from transient, expected psychedelic effects in the psilocybin group.
– Importantly, no increase in suicidal ideation or behavior was observed in the psilocybin arm relative to SSRI (an important consideration in TRD).
Citation: Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., & Nutt, D. J. (2021). Trial of Psilocybin versus Escitalopram for Depression. The New England Journal of Medicine, 384(5). https://doi.org/10.1056/NEJMoa2032994
Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression
Study Type: Multi-country, randomized, double-blind phase 2b trial.
Methodology: Participants were enrolled across 22 sites in 10 countries (North America and Europe). Participants were randomly assigned to one of three groups in a 1:1:1 ratio: a single session with 25 mg of psilocybin, 10 mg of psilocybin, or 1 mg of psilocybin. The 1 mg dose served as a placebo-like control, as it is too low to have therapeutic psychedelic effects. All participants received a structured course of psychological support: preparatory counseling, support from trained therapists during the psilocybin session, and follow-up integration therapy. Neither participants nor raters knew which dose was given (double-blind). The primary outcome was change in depression severity on the MADRS (Montgomery–Åsberg Depression Rating Scale) at 3 weeks post-dose. They also tracked outcomes up to 12 weeks, as well as safety measures. (Note: All participants had to discontinue antidepressant medications before the trial to eliminate drug interactions.)
Sample: 33 patients with treatment-resistant MDD (approximately two-thirds female; mean age in 40s, range up to about 65). This large, diverse sample increases confidence that results may generalize to broader TRD populations, including middle-aged and some older adults.
Dosage: A single dosing session was conducted for each patient at the start of the trial (day 0). Depending on randomization, the dose was either 25 mg, 10 mg, or 1 mg of COMP360 psilocybin (a synthetic psilocybin formulation) taken orally. The session lasted about 6–8 hours with two therapists present to provide support. The environment was carefully controlled (eye shades, music, comfortable room) to facilitate an introspective experience. After the session, participants stayed off-site medications and engaged in integration therapy. They were monitored closely for adverse events throughout.
Key Findings:
– The 25 mg dose produced a clear, rapid antidepressant effect in TRD patients, significantly greater than the control (1 mg) dose.
– By the primary endpoint at 3 weeks, patients in the 25 mg group had MADRS scores drop by an additional ~6.6 points more than the 1 mg group on average (a statistically and clinically significant difference, p<0.001 on the MADRS)
– In contrast, the 10 mg dose showed a more modest effect, not significantly different from 1 mg on the primary outcome
– Key responder analyses illustrated the 25 mg advantage: at 3 weeks, ~37% of patients in the 25 mg group achieved a treatment response (≥50% reduction in depression symptoms), compared to only 17.7% in the 1 mg group
– Likewise, approximately 30% of the 25 mg group were in remission (MADRS ≤10) at 3 weeks, double the remission rate of the control group (≈15%)
– Importantly, the antidepressant effect of 25 mg was evident within 1 week (MADRS dropped notably by week 1) and peaked around week 3
– After the single dose, the effects then gradually wore off for many patients by 12 weeks: by the 12-week mark, only about 20% of the 25 mg group maintained a sustained response (continuous response from week 3 through week 12)
– However, even at 12 weeks, the 25 mg group still had more responders than the 1 mg group (which had virtually no sustained responders)
– The 10 mg dose showed intermediate outcomes (some efficacy but not as strong as 25 mg).
– In terms of safety, COMP360 psilocybin was generally well-tolerated at all doses. There were no drug-related serious adverse events. The most common side effects were transient and observed during the dosing day: headache, nausea, transient blood pressure increases, and temporary anxiety or confusion in some patients – these effects resolved without medical intervention. A small number of participants across groups experienced transient suicidal ideation in the follow-up period (not uncommon in TRD trials), but importantly no suicides or suicide attempts occurred, and the incidence of worsening suicidality did not significantly differ between psilocybin and control groups.
Citation: Goodwin, G. M., Aaronson, S. T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J. C., Bird, C., & Malievskaia, E. (2022). Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. The New England Journal of Medicine, 387(18). https://doi.org/10.1056/NEJMoa2206443
Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder
Study Type: Prospective observational follow-up study (not randomized) of patients who had received psilocybin in prior trials.
Methodology: Participants were drawn from two parent studies: the COMP 001 trial (the 233-patient RCT above) and COMP 003 (an 8-person open-label study testing psilocybin while patients remained on certain antidepressants). Importantly, after the initial 3-week blinded phase of the trial, all participants knew their dose group and could seek additional treatments as needed; however, most did not receive another psilocybin session during follow-up (unless they enrolled in another study). The follow-up tracked time to relapse of depression over 52 weeks after the original dose, using the occurrence of a “Depressive Event” (sustained worsening of depression meeting certain criteria) as the primary outcome. Data (including any use of conventional antidepressants, adverse events, and depression scores) were collected periodically via clinical visits or phone contacts from ~1 to 12 months post-dose (Jul 2020–Jul 2022). There was no intervention in this phase; it was purely observational. The main measure was time to relapse (time until a significant depression return, termed a depressive event), analyzed by Kaplan–Meier curves for each original dose group. They also reported the proportion of patients sustaining response at various time points and collected safety data (including any suicidal ideation or adverse events over the year).
Sample: 66 patients consented to be followed (58 from the randomized trial: 22 from the 25 mg arm, 19 from 10 mg, 17 from 1 mg; plus 8 from the open-label study). Baseline characteristics of this subset were similar to the full trial population. Notably, by the nature of enrollment, patients who had improved (and thus were willing to continue without new treatment) might be overrepresented – a point the authors acknowledge.
Dosage: N/A
Key Findings:
– Over the 12-month follow-up, patients who received the 25 mg psilocybin dose tended to maintain their antidepressant gains longer than those who received lower doses
– In the entire COMP 001 sample (all 233 original patients, assuming those who dropped out relapsed at some point), the median time to relapse was 92 days (~3 months) in the 25 mg group, versus 83 days in the 10 mg group and 62 days (~2 months) in the 1 mg group
– In other words, it took about 3 months for half the 25 mg patients to experience a significant return of depression, compared to only 2 months for half of the placebo group. When the analysis was limited to just those who enrolled in the follow-up (which may exclude some early relapsers), the difference was even more striking: among follow-up participants, median time to relapse in the 25 mg group was ~189 days (over 6 months), compared to 43 days for 10 mg and 21 days for 1 mg
– This longer duration in the post hoc subset suggests that many of the 25 mg patients who felt improved at 3 weeks remained depression-free for about 6 months before a relapse.) By Week 12 (3 months), the majority of patients in all groups had experienced at least some depressive return: specifically, by 12 weeks about 49% of the 25 mg group had not yet relapsed (i.e. ~51% had), versus only ~20% of the 1 mg group not yet relapsed
– Looking further out, at 6 months and 12 months, a portion of high-dose patients remained depression-free: e.g., at 6 months, an estimated ~20–30% of the 25 mg group had not had a depressive event
– Notably, some patients remained well for a year after a single psilocybin session (especially in the 25 mg group, a few did not relapse at all in 12 months)
– No new safety concerns emerged over long-term follow-up. Adverse events in the follow-up period were few. There was one report of mild suicidal ideation in a patient from the 1 mg group, deemed possibly related to their depressive state (this patient did not attempt suicide and improved later)
– Importantly, no persistent worsening of suicidality or other adverse outcomes were seen in the 25 mg group in the long run; many patients opted to go on other treatments as needed. Some patients (especially in the 1 mg group) restarted antidepressant medications earlier, which likely shortened their time to “relapse” as defined (since starting an antidepressant was counted as having had a depressive relapse event)
Citation: Goodwin, G. M., Nowakowska, A., Atli, M., Dunlop, B. W., Feifel, D., Hellerstein, D. J., Marwood, L., Shabir, Z., Mistry, S., Stansfield, S. C., Teoh, E., Tsai, J., Young, M. B., & Malievskaia, E. (2025). Results from a long-term observational follow-up study of a single dose of psilocybin for a treatment-resistant episode of major depressive disorder. The Journal of Clinical Psychiatry, 86(1). https://doi.org/10.4088/jcp.24m15449
Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial
Study Type: Single-site open-label trial (12-week follow-up).
Methodology: Participants underwent a carefully structured psilocybin-assisted therapy program at Sheppard Pratt Hospital: they had three preparatory therapy sessions, a single psilocybin dosing day (with two therapists present), and three integration therapy sessions in the weeks post-dose. All psychiatric medications were tapered and stopped at least 2 weeks prior to psilocybin dosing (and patients remained off antidepressants for at least 3 weeks after dosing) to avoid confounds. Depression severity was primarily measured with the MADRS at baseline, week 3, and week 12 post-treatment. Other secondary measures included self-reported depression scales and functional assessments. As an open-label study with no control group, the focus was on within-subject changes from baseline and safety observations.
Sample: 12 adults (18–65 years old) with very difficult-to-treat depression. Notably, 5 of 12 participants also had comorbid PTSD, and many had other comorbidities common in chronic depression (anxiety, etc.). These comorbid conditions were recorded to see if they affected outcomes.
Dosage: A single dose of 25 mg of synthetic psilocybin (Compass Pathways’ formulation) was administered in a controlled setting. The dosing session lasted ~8 hours with therapists present throughout. Patients were instructed to set intentions and were supported during the psychedelic experience. On the dosing day, vital signs and psychological state were monitored closely. After the session, patients stayed in a safe environment overnight. They then participated in integration sessions over the next 3 weeks to discuss and make meaning of their experience.
Key Findings:
– The pilot results were very promising: psilocybin led to rapid and substantial antidepressant effects in this veteran TRD group. At the primary 3-week endpoint, 9 out of 15 veterans (60%) met response criteria (MADRS ≥50% improvement), and 8 out of 15 (53%) achieved remission (virtually no depressive symptoms). This degree of remission in such severe cases is striking. By 12 weeks (3 months post-dose), although some had relapsed, a considerable portion maintained their gains: 47% were still classified as responders and 40% remained in remission
– In other words, nearly half the group had a sustained antidepressant effect lasting at least 3 months from a single treatment – a positive outcome given their prior chronic depression. Veterans also showed improvements in secondary measures like anxiety and hopelessness. For those with co-morbid PTSD, it’s notable that the presence of PTSD did not significantly diminish the antidepressant response in this study
– Veterans with PTSD improved on depression just as much as those without (and some even reported that psilocybin helped them process traumatic memories, though formal PTSD symptom measures were not the primary focus). Additionally, the intensity of the psychedelic experience (as measured by the 5D-ASC questionnaire) did not straightforwardly correlate with outcome in this sample, even those with less intense subjective experiences sometimes had strong clinical improvement, suggesting that benefit can occur across a range of session experiences.
– No unexpected or serious adverse events occurred. Some veterans had transient blood pressure elevations and anxiety during the session onset, all managed supportively without need for pharmacologic intervention. A few experienced brief increases in trauma-related thoughts during the trip, but with therapeutic support they reframed these experiences positively. Importantly, no cases of psychosis or prolonged dissociation were seen. Four participants went back on an antidepressant sometime after the 3-week point due to returning symptoms; those cases were counted as “non-responders from that timepoint” in the analysis
– There were no reports of persistent worsening of PTSD symptoms; on the contrary, many described improvements in mood regulation and perspective.
Citation: Aaronson, S. T., van der Vaart, A., Miller, T., LaPratt, J., Swartz, K., Shoultz, A., Lauterbach, M., Suppes, T., & Sackeim, H. A. (2025). Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial. The American journal of psychiatry, 182(1), 104–113. https://doi.org/10.1176/appi.ajp.20231063
Single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression - A first-in-kind open-label pilot study
Study Type: Open-label pilot trial.
Methodology: Participants underwent one psilocybin dosing session (open-label, everyone received the active treatment) with psychological support. Antidepressant medications were tapered off beforehand to avoid drug interactions (similar to other trials). Depression severity was measured using the MADRS at baseline, at 3 weeks, and 12 weeks post-treatment; standard criteria for response (≥50% drop in MADRS) and remission (MADRS ≤10) were applied. The study also monitored PTSD symptoms and other mental health outcomes qualitatively. Without a control group, efficacy was inferred by pre-post changes and comparison to historical expectations.
Sample: 15 U.S. military veterans (mixed ages, many middle-aged; gender not specified) with severe treatment-resistant depression were enrolled. Inclusion required a major depressive episode that either failed ≥5 prior treatments or lasted >2 years continuously without remission. Notably, a majority of these veterans also had co-occurring PTSD from their service (though this was not exclusionary). All had multiple failed antidepressant trials; some had also tried ECT or ketamine.
Dosage: A single 25 mg oral dose of psilocybin (synthetic) was administered in a comfortable clinical setting. Two trained facilitators were present during the session, employing a vet-specific supportive approach. Veterans were encouraged to focus inward (using eyeshades and music) during the peak psychedelic effects. The acute session lasted ~6–8 hours, followed by debriefing. Therapy sessions were provided before the dose (to build trust and set intentions) and after (for integration of insights). Given the veteran population, special attention was paid to creating a feeling of safety and addressing any combat-related trauma that arose.
Key Findings:
– The pilot results were very promising: psilocybin led to rapid and substantial antidepressant effects in this veteran TRD group. At the primary 3-week endpoint, 9 out of 15 veterans (60%) met response criteria (MADRS ≥50% improvement), and 8 out of 15 (53%) achieved remission (virtually no depressive symptoms). This degree of remission in such severe cases is striking. By 12 weeks (3 months post-dose), although some had relapsed, a considerable portion maintained their gains: 47% were still classified as responders and 40% remained in remission
– In other words, nearly half the group had a sustained antidepressant effect lasting at least 3 months from a single treatment – a positive outcome given their prior chronic depression. Veterans also showed improvements in secondary measures like anxiety and hopelessness. For those with co-morbid PTSD, it’s notable that the presence of PTSD did not significantly diminish the antidepressant response in this study
– Veterans with PTSD improved on depression just as much as those without (and some even reported that psilocybin helped them process traumatic memories, though formal PTSD symptom measures were not the primary focus). Additionally, the intensity of the psychedelic experience (as measured by the 5D-ASC questionnaire) did not straightforwardly correlate with outcome in this sample, even those with less intense subjective experiences sometimes had strong clinical improvement, suggesting that benefit can occur across a range of session experiences.
– No unexpected or serious adverse events occurred. Some veterans had transient blood pressure elevations and anxiety during the session onset, all managed supportively without need for pharmacologic intervention. A few experienced brief increases in trauma-related thoughts during the trip, but with therapeutic support they reframed these experiences positively. Importantly, no cases of psychosis or prolonged dissociation were seen. Four participants went back on an antidepressant sometime after the 3-week point due to returning symptoms; those cases were counted as “non-responders from that timepoint” in the analysis
– There were no reports of persistent worsening of PTSD symptoms; on the contrary, many described improvements in mood regulation and perspective.
Citation: Ellis, S., Bostian, C., Feng, W., Fischer, E., Schwartz, G., Eisen, K., Lean, M., Conlan, E., Ostacher, M., Aaronson, S., & Suppes, T. (2025). Single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression – A first-in-kind open-label pilot study. Journal of affective disorders, 369, 381–389. https://doi.org/10.1016/j.jad.2024.09.133
Long-term outcomes of single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression - 12-month data from an open-label pilot study
Study Type: A long-term observational follow-up of the above 15 veteran TRD patients
Methodology: Participants had MADRS assessments at approximately 6 months, 9 months, and 12 months post-psilocybin. No additional psilocybin sessions were given in this period, though participants were free to seek other treatments as needed (any such interventions were recorded). The main outcomes were depression severity over time and the proportions meeting response/remission at those extended time points, compared to baseline. Given the observational nature, no control group is present, but the data show trends of how the group fared over time.
Sample: Out of the original 15 veterans, 10 completed the full 12-month follow-up (5 were lost to follow-up or withdrew by 12 months).
Dosage: N/A
Key Findings:
– Significant depression improvements persisted compared to baseline across all long-term follow-ups, but there was a gradual return of symptoms in some veterans as time went on
– At 6 months post-treatment, the results were still very strong: out of the 10 veterans assessed, 80% were classified as responders (≥50% depression reduction) and 50% remained in remission. This indicates that at the half-year mark, half of the followed participants were still essentially depression-free, and most had substantial benefit – an unusually prolonged effect for a one-time treatment in TRD. However, by 9 months, signs of waning efficacy emerged
– The data showed that some who had been in remission at 6 months experienced a return of depressive symptoms by 9 months. By the 12-month point, the maintained response rate dropped to 40%, and remission rate to 30% among those 10 veterans
– In other words, after one year, 3 of 10 were still in remission, 4 of 10 still had a meaningful response (but not full remission), and 6 of 10 had experienced a depressive relapse of some kind. Importantly, even at 12 months the average depression scores were better than baseline – meaning everyone was not back to square one, but the group as a whole had lost some of the early gains
– The increase in MADRS from the earlier time-points to 12 months did not reach statistical significance, likely due to the small sample, but the trend was clear (symptoms creeping back)
– No new safety issues were noted over this extended period.
Citation: Ellis, S., Bostian, C., Donnelly, A., Feng, W., Eisen, K., Lean, M., Conlan, E., Ostacher, M., Aaronson, S., & Suppes, T. (2025). Long-term outcomes of single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression – 12-month data from an open-label pilot study. Journal of affective disorders, 119655. Advance online publication. https://doi.org/10.1016/j.jad.2025.119655
Efficacy and safety of psilocybin in the treatment of Major Depressive Disorder (MDD): A dose-response network meta-analysis of randomized placebo-controlled clinical trials
Study Type: Systematic review and dose-response network meta-analysis of randomized controlled trials (RCTs) examining psilocybin for depression.
Methodology: Researchers searched databases (Embase, PubMed, Cochrane, Scopus, etc.) up to July 2024 for RCTs of psilocybin versus placebo in adults with major depression (including TRD). They identified 3 RCTs meeting criteria (total N = 389 patients). These likely included: the 2022 COMPASS Pathways trial (25 mg vs 1 mg), a smaller placebo-controlled trial in major depression (e.g., the 2021 Johns Hopkins waitlist-controlled RCT which had a placebo/delay component), and possibly another trial with low-dose control. Using a network meta-analysis approach, the study compared outcomes of different psilocybin doses (e.g., 1 mg, 10 mg, ~20 mg/70kg, 25 mg) relative to placebo at various time points. The primary outcome aggregated was change in depression scores (MADRS) at Day 8 and Day 15 post-treatment (to capture the rapid effects), as well as at Day 2 (to see immediate effect). Adverse events were also compiled. A dose-response model was used to rank doses by efficacy.
Sample: See methodology
Dosage: See methodology
Key Findings:
– The meta-analysis confirmed that psilocybin has a significant antidepressant effect compared to placebo in the short term. Specifically, by 1 week (Day 8) after treatment, psilocybin-treated patients had much greater symptom improvement than those given placebo (pooled mean difference ~–7.4 MADRS points in favor of psilocybin, p<0.001)
– By 2 weeks (Day 15), this advantage grew (mean difference ~–9.5 MADRS points vs placebo, p<0.001). This roughly corresponds to a large effect size. At 2 days post-dose, however, there was no significant difference yet, indicating psilocybin’s antidepressant action is not immediate same-day, but emerges over several days (likely as psychological insights develop and neuroadaptive changes occur).
– In terms of dose, the network meta-analysis found that 25 mg was the most effective dose tested, outperforming both a 10 mg dose and a weight-adjusted dose around 0.2 mg/kg (~15 mg for 70kg)
– Using a probabilistic ranking (SUCRA – Surface Under Cumulative Ranking curve), 25 mg had a SUCRA of ~92%, meaning it had the highest likelihood of being the best dose for response
– Lower doses had lower efficacy rankings. This quantitatively validates the dose selection used in ongoing phase 3 trials (25 mg seen as optimal). On the safety side, the meta-analysis noted that psilocybin was associated with a higher frequency of mostly mild-to-moderate adverse events compared to placebo
– The most significantly elevated side effect was nausea, psilocybin patients had about 8.35 times the risk of nausea as placebo patients (p<0.001)
– This isn’t surprising given psilocybin often causes transient nausea. Other side effects like headache, transient anxiety, or blood pressure increase were also more common with psilocybin, but generally short-lived. Crucially, no signal of increased serious adverse events emerged (reinforcing safety in controlled setting
Citation: Swieczkowski, D., Kwaśny, A., Pruc, M., Gaca, Z., Szarpak, L., & Cubała, W. J. (2025). Efficacy and safety of psilocybin in the treatment of Major Depressive Disorder (MDD): A dose-response network meta-analysis of randomized placebo-controlled clinical trials. Psychiatry research, 344, 116337. https://doi.org/10.1016/j.psychres.2024.116337
Comparison between Single-Dose and Two-Dose Psilocybin Administration in the Treatment of Major Depression: A Systematic Review and Meta-Analysis of Current Clinical Trials
Study Type: Systematic review and meta-analysis of recent clinical trials of psilocybin for depression.
Methodology: Authors followed PRISMA guidelines and searched for trials (open-label or randomized) involving psilocybin treatment for MDD or TRD. They ended up including 12 studies (published between ~2016 and 2023) that met criteria. These comprised both uncontrolled studies (like Carhart-Harris 2016, 2018) and controlled trials (like Davis 2020, Carhart-Harris 2021, Goodwin 2022, etc.), encompassing several hundred patients in total. The meta-analysis quantitatively compared depression severity before and after psilocybin therapy across studies. It also conducted subgroup analyses on trials that used a single psilocybin session versus those that used two sessions (e.g., some trials gave one dose, others like Davis 2020 gave two doses separated by weeks). Efficacy was measured via standard depression rating scales. Because of variations in scales, they likely used standardized mean differences to pool results.
Sample: See methodology
Dosage: See methodology
Key Findings:
– Across the 12 studies, psilocybin treatment (with therapy) was found to be highly effective in reducing depressive symptoms on average
– The meta-analysis confirmed a large pre-to-post treatment improvement in depression severity scores among patients receiving psilocybin, whether in open-label or controlled contexts
– When comparing one vs two dose regimens: both approaches significantly reduced depression, but in some cases, two-dose administrations yielded more pronounced and/or longer-lasting effects
– For example, trials that gave a second psilocybin session (usually a few weeks after the first) often reported sustained or even enhanced benefits at follow-ups, whereas single-dose trials saw some patients relapse sooner. However, the review noted that it’s not entirely clear if the superiority of two doses is strictly due to the extra psilocybin or could be influenced by other factors (like those particular studies having slightly different patient populations or additional therapy)
– In some of the pooled analyses, the difference between one vs two doses wasn’t statistically huge, indicating that even a single session has a potent effect, but there was a tendency for two-dose protocols to show numerically better outcomes. No serious safety concerns emerged in either single or two-dose studies, reinforcing that even multiple sessions are well-tolerated in clinical settings (with appropriate screening).
Citation: Salvetti, G., Saccenti, D., Moro, A. S., Lamanna, J., & Ferro, M. (2024). Comparison between Single-Dose and Two-Dose Psilocybin Administration in the Treatment of Major Depression: A Systematic Review and Meta-Analysis of Current Clinical Trials. Brain sciences, 14(8), 829. https://doi.org/10.3390/brainsci14080829