Psilocybin

What psilocybin is

Psilocybin is a molecule from mushrooms of the genus Psilocybe. In the body it is converted into psilocin, which fits serotonin receptors, above all one type in the cerebral cortex. Hence the hours of altered experience.

The idea for depression builds on this: the brain is said to be shaken out of entrenched patterns and to be more flexible afterwards. A nice image — but so far more image than evidence. The chain from the receptor to a lasting change in mood has not been measured in humans.

The study that started the hype

In 2022, the New England Journal of Medicine published a study of 233 people with treatment-resistant depression: a single supervised dose, three groups, a difference of 6.6 points in favor of the high dose. The rest is cited less often. The medium dose was not significant, after 12 weeks the lead was no longer robust, and suicidal thoughts or self-harm occurred in all groups. The study was funded by Compass Pathways, which owns the formulation; the first author is employed there.

The problem that cannot be removed

Anyone who receives 25 milligrams notices it after an hour. Anyone who receives 1 milligram notices nothing. So everyone knows where they stand, and the blinding is gone. Compass itself writes that unblinding is unavoidable with psychedelics, and that dose dependence must therefore count. An argument, not proof.

The most honest attempts to counter this work with an active placebo: niacin, that is vitamin B3, triggers skin flushing so that the control group at least feels something. Better than an empty capsule — but even the most attentive participant can tell a flush from six hours of altered experience. In addition, hours of psychotherapy run alongside in all studies. How much of the effect is the substance and how much the attention, nobody knows.

What remains in the large trials

Of the 6.6 points, 3.6 and 3.8 remained in phase 3. A good half of the effect disappears as soon as the trial gets larger — a pattern familiar from antidepressant research. And 3.6 points on a 60-point scale is a magnitude that would be disputed for any other antidepressant. So far, both results are available only as press releases from the manufacturer. The application for approval in the US is going ahead anyway.

Microdosing

The trend promises the sensible version: small dose, no trip, small effect. It is not the sensible version; it is the unsupported one. Three blinded studies, three null findings — in the largest, well-being, creativity and mood improved just as much in the placebo group. Anyone who takes an empty capsule and feels more creative has experienced something real, just not the effect of a mushroom.

The setting the numbers depend on

Reported use, not a recommendation: in the studies, synthetic psilocybin is given once or twice, in a protected room, with trained supervision over hours. Antidepressants are discontinued, and a history of psychosis is an exclusion criterion. The numbers depend on this framework. A dried mushroom from the internet has none of it, not even the dose, because the content varies.

What the studies show

Compass Pathways, New England Journal of Medicine 2022

233 people with treatment-resistant depression, one supervised dose in three groups: 25, 10 or 1 milligram. Measurement after 3 weeks on a scale of 0 to 60, starting at 32: high dose minus 12 points, sham comparison minus 5, difference 6.6 points. 77 percent had side effects, mostly headache, nausea, dizziness.

Johns Hopkins 2021

24 people analyzed, 2 sessions, 71 percent response after 4 weeks. The control group, however, was a waiting list and knew it had received nothing. The design is not sufficient for a statement on efficacy.

Imperial College London 2021, psilocybin versus escitalopram

Head-to-head comparison in 59 people against a standard antidepressant. The primary endpoint after 6 weeks was not significant — the comparison that would be most useful for practice ended in a draw.

Usona Institute 2023

104 people with ordinary depression, psilocybin versus niacin as active placebo: after 6 weeks, a difference of 12.3 points in favor of psilocybin, considerably more than at Compass, though in depression that was not treatment-resistant. Nonprofit-funded and the cleanest attempt to defuse the blinding problem – but a trip can be unblinded even against niacin.

Phase 3, summer 2025 and February 2026

First 258 people, 25 milligrams versus placebo over 6 weeks, difference 3.6 points. Then 581 people with 2 doses, 3.8 points versus 1 milligram. Both statistically clear, both so far only a press release.

EPIsoDE, JAMA Psychiatry 2026

German study from Mannheim and Berlin, funded by the Federal Ministry of Research. 144 people with treatment-resistant depression, 25 versus 5 milligrams versus nicotinamide, response after 6 weeks: 17 percent versus 12.5 versus 10.6 percent. Not significant; the authors themselves call the result inconclusive.

Three blinded microdosing studies

Imperial College London 2021: 191 people, self-blinding over 4 weeks, equal improvement in both groups. Argentina 2022: 34 people, double-blind, rather small deteriorations in creativity and cognition. Plus a Dutch study with no effect on anxiety or depression.

Where the data stop — and where they speak against it

For microdosing, the data do not just fail to support it, they speak against it: three blinded studies, three null findings, including the largest with 191 participants. The experience is real; the cause is expectation. With the high dose the situation is different, but there too certainty ends earlier than the coverage suggests: the blinding does not hold, the government-funded German study missed its primary endpoint, and nobody knows how much of the effect is due to the supervision.

Status, approval and legal

In Germany, psilocybin is listed in Schedule 1 of the Narcotics Act: not legally marketable and not prescribable. Since July 2025 there has been a hardship program confirmed by the BfArM, through which people with treatment-resistant depression can be treated at two centers in Mannheim and Berlin; according to the BfArM, the current term runs until June 2027. This is an exception in individual cases, not an approval. There is no approved product in either the EU or the US; the American application for approval has been partly submitted, with completion planned for the end of 2026. The exceptions are narrow: since July 2023, Australia has allowed specially authorized psychiatrists to prescribe it for treatment-resistant depression, Oregon has had licensed centers since 2023, Colorado since 2025 — at the federal level it remains prohibited in the US. In the Czech Republic, therapeutic administration has been legally permitted since January 2026; provision of care there is only just starting.

Safety

A 2024 meta-analysis of more than 3,500 study participants found no serious events in healthy people, but around 4 percent in those with a psychiatric history: worsening of depression, suicidal behavior, psychosis, seizures. Selection is decisive — studies usually exclude a history of psychosis or mania; outside studies, nobody does. Added to this is the persistent perceptual disorder HPPD: rare, but real, 1 case in EPIsoDE, and more suicidal thoughts on dosing days. With regular use over months, a separate question arises: psilocin also binds to the serotonin receptor type 2B in the heart, through which fenfluramine and pergolide damaged heart valves. A 2024 review calls this an open question. No evidence that it happens — but no study that rules it out.

Sources

• Goodwin et al. (Compass Pathways), phase 2b trial on treatment-resistant depression, New England Journal of Medicine 2022
• Davis et al. (Johns Hopkins), randomized trial on psilocybin in depression, JAMA Psychiatry 2021
• Carhart-Harris et al. (Imperial College London), psilocybin versus escitalopram, New England Journal of Medicine 2021
• Raison et al. (Usona Institute), psilocybin versus niacin in depression, JAMA 2023
• Compass Pathways, press release of June 23, 2025 on the phase 3 trial COMP005 (258 participants, 3.6 points)
• Compass Pathways, press release of February 17, 2026 on the phase 3 trial COMP006 (581 participants, 3.8 points)
• EPIsoDE study, Mertens et al., JAMA Psychiatry 2026
• Szigeti et al. (Imperial College London), self-blinded microdosing study, eLife 2021
• Hinkle et al., meta-analysis of adverse events with psychedelics, JAMA Psychiatry 2024