Few mental health topics have generated as many headlines in recent years as psilocybin for depression. Between the enthusiasm of some and the skepticism of others, it is hard to know what the studies have actually shown.
This article summarizes the main clinical trials, with their figures and their limits, and explains where regulation stands as of October 2026. It is educational information: it is not medical advice or an invitation to treat depression on your own.
Key takeaways
- Several controlled trials have found that one or two high doses of psilocybin, with psychological support, reduce depressive symptoms quickly.
- The effect is real but more moderate than the first studies suggested, and it does not work for everyone.
- The trials have important limitations, above all the difficulty of maintaining blinding.
- As of October 2026 it is not approved as a medicine in Europe or in the United States. In Spain it is only accessible within clinical trials.
- What is being studied is not the substance alone, but a complete treatment with preparation, supervision and integration.
What exactly is being studied
In the trials, psilocybin is administered in synthetic form, at a known dose, in a prepared room and with professionals present during the hours the effects last. There are preparation sessions beforehand and integration sessions afterward. Participants go through a medical and psychological screening that excludes, among others, people with a history of psychosis.
That whole package is what gets evaluated. Taking mushrooms at home does not reproduce those conditions.
The main trials
Johns Hopkins, 2021
A trial published in JAMA Psychiatry studied 24 people with major depression, who received two psilocybin sessions with supportive psychotherapy. At four weeks, 71% had responded to the treatment and 54% were in remission. The comparison group was a waiting list, a weak control that tends to inflate results.
Psilocybin versus escitalopram, 2021
Imperial College London compared, in 59 patients, two psilocybin sessions with six weeks of escitalopram, a commonly used antidepressant. The study, published in The New England Journal of Medicine, found no significant differences on the primary measure of depression. Several secondary measures favored psilocybin, but the study was not designed to draw conclusions from them. It is often cited as a triumph. Strictly speaking, it showed that psilocybin was no worse than the drug over that period.
Treatment-resistant depression, phase 2, 2022
The largest phase 2 trial included 233 people with treatment-resistant depression, divided among three single doses: 25 mg, 10 mg and 1 mg as a control. At three weeks, the depression score had dropped 12 points with 25 mg compared with 5.4 with 1 mg. At twelve weeks, 20% of the 25 mg group maintained the response, compared with 10% of the control group. In other words, a clear effect at the start that in many cases faded.
Major depression, 2023
A trial published in JAMA compared, in 104 adults, a 25 mg dose with an active placebo, niacin. At 43 days, the reduction in symptoms was clearly greater with psilocybin, with a difference of about 12 points on the depression scale.
The phase 3 trials
These are the largest ones and the ones that will decide approval. According to the data reported by the company sponsoring them, in treatment-resistant depression:
- The first, with 258 participants, found at six weeks a difference of 3.6 points on the depression scale between 25 mg and placebo.
- The second, with 581 participants, found a difference of 3.8 points between 25 mg and a 1 mg control dose, with a benefit that was maintained at six months.
Both results are statistically significant. The magnitude, however, is considerably smaller than in the small early studies. It is a common pattern in medicine: effects become more moderate as trials grow.
What can be concluded
- Psilocybin with psychological support has an antidepressant effect that appears in days rather than weeks.
- It works with one or two administrations, not with a daily dose.
- Some patients improve a great deal and others do not respond.
- The duration of the benefit varies. In some studies it fades over the months.
- It has not been shown to be superior to standard antidepressants.
The limitations
The blinding problem
Someone who receives a high dose of psilocybin almost always knows they did not get the placebo. That breaks the blind and allows expectations to influence the result, in both directions: enthusiasm in some, disappointment in others.
Who takes part
The trials exclude people with a history of psychosis, with high suicide risk or on certain medications. And they attract participants with a prior interest in psychedelics. The results do not simply carry over to anyone with depression.
The role of psychological support
It is not clear how much of the effect is due to the substance and how much to the intensive support that surrounds it.
The follow-up
Most studies follow patients for weeks or a few months. Little is known about what happens years down the line.
The risks observed
The most frequent adverse effects are headache, nausea, dizziness and anxiety during the session, almost always temporary. In the phase 2 trial, 77% of participants had some adverse effect, and cases of suicidal ideation and self-harming behavior were recorded in the following weeks, in all groups and somewhat more at the high doses. It is a finding that makes continued clinical supervision necessary.
Outside a trial, with no screening or follow-up, the risks are different and greater. We go over them in who should not take psychedelics.
Where approval stands
As of October 2026:
- In the United States, the regulatory agency granted psilocybin breakthrough therapy designation years ago. The company sponsoring the phase 3 trials is submitting its application for authorization in stages and expects to complete it at the end of 2026. It is not approved.
- In Australia, since 2023, authorized psychiatrists can prescribe it for treatment-resistant depression under strict conditions.
- In the European Union there is no marketing authorization.
- In Spain it is only accessible within authorized clinical trials. We explain this in detail in the legal status of psychedelics in Spain.
This situation may change quickly. It is worth checking the date of any information you read, including this.
What these studies do not mean
- They do not mean that taking mushrooms cures depression.
- They do not mean that it is a good idea to stop taking an antidepressant. Doing so on your own carries serious risks, which we explain in psychedelics and antidepressants.
- They say nothing in favor of microdosing, which is a different practice with different evidence. We cover it in microdosing: what the science says and what is placebo effect.
- They do not turn psychedelics into a solution for everyone.
If you have depression
Depression has effective treatments that are available today. The first step is your GP or a mental health professional. If you are interested in taking part in research, ask your psychiatrist about open clinical trials. And if you have thoughts of harming yourself, call 024, Spain’s suicide prevention helpline, or 112.
The role of RILOFU
At RILOFU we do not treat depression or any other health problem, and we do not sell or supply substances. We offer emotional support and integration, which do not replace treatment. We explain the difference in what emotional support is and how it differs from psychotherapy.
→ Book a free first consultation
Sources
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 2021.
- Trial of Psilocybin versus Escitalopram for Depression. The New England Journal of Medicine, 2021.
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. The New England Journal of Medicine, 2022.
- Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA, 2023.
- Compass Pathways: press releases on the COMP005 and COMP006 phase 3 trials, 2025 and 2026.