Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial

• Major depressive disorder (MDD): A serious, long-lasting mood disorder with persistent low mood and loss of interest, which impairs daily life.

• Psilocybin: The active compound in “magic mushrooms,” a classic psychedelic being studied as a treatment for depression.

• Randomized clinical trial (RCT): A study in which participants are assigned to treatments by chance, which allows fair comparison.

• Double-blind, placebo-controlled: Neither participants nor assessors are supposed to know who received the real drug or the placebo.

• Active placebo (niacin): A substance that produces noticeable bodily sensations, such as flushing, without treating depression. It makes the placebo harder to tell apart from the real drug.

• Functional unblinding: When participants or raters work out which treatment was given, for example from the strong psychedelic experience, so the “blind” fails.

• Expectancy: The belief that a treatment will work, which can itself improve outcomes.

• MADRS / MADRS-S: The Montgomery-Åsberg Depression Rating Scale, scored by a clinician (MADRS) or self-reported (MADRS-S). Higher scores mean more severe depression.

• Response / remission: Response is a large drop in symptoms (here ≥50%). Remission is symptoms falling to a very low level (here a MADRS score below 10).

• Treatment-emergent adverse event (TEAE): Any unwanted health event that appears after treatment starts.

• Intention-to-treat (ITT): Analyzing all participants in the group they were randomized to, regardless of what happened later.

• Confidence interval (CI) / P value: Statistical tools indicating the precision of an estimate and whether a result is unlikely to be due to chance (conventionally P < .05).

• SSRIs: Selective serotonin reuptake inhibitors, the most common first-line antidepressants.

1. Does a single oral 25-mg dose of psilocybin, given with psychological support, reduce depressive symptoms in adults with recurrent MDD within 8 days (primary question)?

2. How long do any effects last (at 15 days, 42 days and 12 months) compared with an active placebo?

3. Is psilocybin tolerable and safe in this broader MDD population, not only in treatment-resistant or cancer-related depression?

4. Does antidepressant use during the year differ between groups?

5. How well was the blinding maintained, and how might expectancy and the subjective drug experience have shaped the results?

Design. This phase 2, double-blind, placebo-controlled RCT ran at the Northern Stockholm Psychiatric Clinic in Sweden from 2021 to 2024. It included 35 adults (60% female, mean age 41) with moderate-to-severe recurrent MDD. All were psychedelic-naive and not taking antidepressants. Seventeen received psilocybin (25 mg) and 18 received niacin (100 mg). Both groups had five psychotherapeutic support sessions over 17 days and were followed for 365 days.

Primary outcome. On day 8, clinician-rated MADRS scores fell 7.27 points more with psilocybin than with niacin (95% CI −12.89 to −1.65; P = .01).

Clinician-rated (MADRS) results over time

• Day 15: difference of −11.03 (P < .001).

• Day 42: difference of −8.33 (P = .004).

• Day 365: difference of −3.68 (P = .20), which was no longer significant.

Self-reported (MADRS-S) results. Psilocybin showed greater symptom reduction from day 2 (−9.58; P = .004). The advantage persisted through day 102 (−6.60; P = .04), with isolated significant differences on days 283 and 343. When participants who started antidepressants were excluded, the advantage lasted until about day 72.

Remission

• At day 42, remission was 52.9% with psilocybin versus 5.9% with niacin.

• At 12 months, it was 52.9% versus 41.2%, not a significant difference. Psilocybin remission stayed high from day 8 onward, while niacin remission rose from 11.8% to 41.2%.

Other outcomes. Disability, quality of life and anxiety measures broadly followed the same pattern, favoring psilocybin. Antidepressant initiation did not differ (6 of 17 vs 7 of 18), with similar timing (about 130 vs 128 days).

Safety

• Most adverse events were transient and mild to moderate. The most common in the psilocybin group were headache, anxiety, hallucination, agitation, hypertension and paresthesia.

• Ten serious adverse events were reported, none judged drug-related.

• Two psilocybin participants had severe anxiety lasting weeks that needed medical attention.

Blinding and expectancy

• Blinding largely failed. By day 365, 94% of psilocybin and 100% of niacin participants correctly guessed their allocation. Blinded raters were correct in 70–88% of guesses.

• Psychedelic intensity ratings were much higher with psilocybin (mean 7.06/10) than niacin (1.22/10).

• Expectancy before treatment was moderate and equal across groups (about 57/100).

Interpretation. The authors report that psilocybin produced a clinically meaningful improvement by day 8. They say this is the first time, to their knowledge, that this has been shown as a primary endpoint. Self-reports pointed to an effect by day 2. They describe this speed as comparable only to ketamine and possibly electroconvulsive therapy, and faster than SSRIs, cognitive behavioral therapy or repeated transcranial magnetic stimulation. The 6-week remission rate (52.9%) exceeded the rates seen in earlier antidepressant trials (about 40–45%). The placebo response was unusually low, which may reflect the active placebo and the study’s design.

Durability. Effects were “relatively long-lasting” but shorter than earlier uncontrolled studies suggested. The clinician-rated advantage disappeared by 12 months as the niacin group also improved, consistent with the episodic nature of depression and possible spontaneous remission. The authors argue that uncontrolled follow-ups probably overestimate lasting benefit. Time to relapse after psilocybin appears similar to that after stopping other treatments. They therefore suggest repeated dosing, booster doses or maintenance therapy may be needed.

Clinical relevance. Psilocybin could be a valuable addition to current treatments, especially when rapid relief matters. Because a few people experienced severe, persistent anxiety, some patients may need extra support after dosing.

Limitations

• The sample was small, and chance imbalances at baseline were evident, such as more prior SSRI use in the niacin group.

• The study was powered for the primary outcome, not for long-term findings.

• Recruitment through social media may have introduced self-selection and expectancy effects.

• The weak blinding, among participants and among raters who were also study physicians, may have inflated effect sizes. This is especially a concern for subjective outcomes, since self-reports may be more sensitive than clinician ratings.

• Secondary outcomes were not adjusted for multiple comparisons.

Recommendations for future research

• Run larger RCTs to establish long-term effects.

• Test repeated-dose or adjunctive strategies.

• Improve trial designs to address functional unblinding.

• Disentangle the drug’s direct pharmacological effects from expectancy and the subjective experience.

Keep reading on Amurdat

Explainer: rTMS for psychological disorders

Review: cold exposure and mental health

Study summary: a person-centred lifestyle programme in mental health care