Psilocybin in Depression: Results of Johns Hopkins Studies and Phase 3 COMPASS
The Johns Hopkins studies and the COMPASS trial measured the effect of psilocybin in depression. We check which results come from phase 2 and what is known about phase 3.
Depression that does not respond to various antidepressants remains one of the most challenging problems in psychiatry. Over the past five years, two centers have filled this topic with data: the team from Johns Hopkins University and COMPASS Pathways. Their results are often summarized in one sentence about seventy percent effectiveness, which obscures the most important thing, namely how small and how early these trials were. Below, we break them down in order: who participated, how many people, how long the measurement lasted, and what came of it. Separately, we show why the trial most often described as phase 3 was actually a phase 2 study, what is known today about the proper phase 3, and which safety signals are omitted from the summaries. Finally, we provide the legal status in Poland.
KEY INFORMATION
• The Johns Hopkins study (Davis et al., JAMA Psychiatry, 2021) included 27 individuals with depression, of which 24 completed the protocol. After four weeks, 71 percent had a response, and 54 percent were in remission.
• The COMPASS trial on 233 individuals, commonly described as phase 3, was a phase 2 study published in NEJM in 2022, with measurement in the third week.
• The proper phase 3 study (NCT05624268) involved 258 individuals and completed data collection on May 28, 2025. Results have not been published or registered (as of August 16, 2026).
• Psilocybin is a psychotropic substance of group I-P in Poland. Possession and trade are prohibited, and there are no legal therapeutic programs.
What is psilocybin and how does it differ from classic antidepressants?
Psilocybin is a compound found naturally in mushrooms of the genus Psilocybe. In the body, it is dephosphorylated to psilocin, which acts as an agonist of serotonin receptors 5-HT2A. This transformation is responsible for the change in consciousness and its effect on the central nervous system (Nichols, Pharmacological Reviews, 2016).
The difference from selective serotonin reuptake inhibitors (SSRIs) is primarily in the method of administration. SSRIs are taken daily for months, and the clinical effect builds up over weeks. In psilocybin studies, the substance was administered once or twice, and the improvement was measured over the following weeks, when neither psilocybin nor psilocin was present in the body.
This leads to the hypothesis that the effect does not depend on the presence of the substance but on the changes it triggers. In this context, there is talk of increased synaptic plasticity and transient destabilization of the resting state network, which is associated with rumination. However, it is important to separate two things. The clinical effect has been measured in several human trials. The mechanism that would explain it remains a hypothesis mainly supported by imaging and animal studies, not a conclusion derived from these trials.
What did the Johns Hopkins study on psilocybin in depression measure?
The team from Johns Hopkins University published the results of a randomized controlled trial with a waiting list control group in 2021 in JAMA Psychiatry. The study included 27 adults diagnosed with depression, of which 24 completed both sessions and measurements. Participants did not take antidepressants during this time. They received two doses of psilocybin calculated by body weight, 20 and 30 milligrams per 70 kilograms, in the context of supportive psychotherapy lasting about eleven hours (Davis et al., JAMA Psychiatry, 2021).
After four weeks from the intervention, 17 out of 24 participants, or 71 percent, met the response criterion defined as a decrease in the GRID-HAMD score by at least half, and 13 individuals, or 54 percent, were in remission. The effect sizes were very large. A separate work by the same team tracked the outcomes of all 24 participants over twelve months: the response was maintained in 75 percent, and remission in 58 percent, with no serious adverse events attributed to psilocybin (Gukasyan et al., Journal of Psychopharmacology, 2022).
Two caveats must be made immediately. The group consisted of a dozen individuals per arm, so each individual participant shifts the percentage by a few percentage points. Participants also did not have treatment-resistant depression: the criterion excluded current antidepressant use, and the work distinguishes its population from those with treatment-resistant depression. Therefore, transferring this result to individuals after several unsuccessful treatments is an overreach.
| Study | Phase and Population | Primary Outcome |
|---|---|---|
| Davis et al., JAMA Psychiatry, 2021 | Depression, no antidepressants, n=27 (24 assessed) | Response 71 percent, remission 54 percent at 4 weeks |
| Carhart-Harris et al., NEJM, 2021 | Phase 2, moderate or severe long-term depression, n=59 | No significant difference compared to escitalopram, p=0.17 |
| Goodwin et al., NEJM, 2022 | Phase 2, treatment-resistant depression, n=233 | Decrease in MADRS by 12.0 points at 25 mg vs 5.4 points at 1 mg |
| COMP005, NCT05624268 | Phase 3, treatment-resistant depression, n=258 | Data collected in May 2025, results unpublished |
Was the COMPASS study on 233 individuals a phase 3 study?
No, it was not. This is one of the most frequently repeated misconceptions on this topic, and it is worth breaking it down into parts, as it concerns the phase of the study, the year of publication, and the measurement point. The trial on 233 participants with treatment-resistant depression is a phase 2 study, published in New England Journal of Medicine in 2022. Participants were randomly assigned to one dose of COMP360: 79 individuals received 25 milligrams, 75 individuals 10 milligrams, and 79 individuals 1 milligram as a control (Goodwin et al., NEJM, 2022).
The primary endpoint was measured in the third week, not the sixth, and it was the change in the MADRS scale. The average change was 12.0 points at the 25 mg dose, 7.9 points at 10 mg, and 5.4 points at 1 mg. The advantage of the 25 mg dose over the control was 6.6 points (95 percent confidence interval from 2.9 to 10.2 points; p below 0.001). The 10 mg dose did not differ significantly from the control (p=0.18). The authors conclude that larger and longer trials are needed, including comparisons with existing treatment methods.
The second thing lost in summaries is safety. Adverse events occurred in 179 out of 233 participants, or 77 percent, most commonly as headaches, nausea, and dizziness. The authors also noted that suicidal thoughts or behaviors or self-harm appeared in all dosing groups. The study was funded by COMPASS Pathfinder, the entity developing the tested preparation.
What is known today about the proper phase 3?
The phase 3 study exists and is separate from the one described above. It is registered as NCT05624268, conducted by COMPASS Pathways, multicenter, double-blind, and placebo-controlled, involving 258 individuals with treatment-resistant depression. Its primary endpoint is the change in MADRS score in the sixth week at a dose of 25 milligrams compared to placebo. Primary data collection was completed on May 28, 2025, and the study status is completed.
As of August 16, 2026, the results of this study have not been posted in the registry, and searching in Europe PMC does not return any publication presenting its results. A second phase 3 study, NCT05711940, involving 572 individuals and testing two doses, is still ongoing and is not recruiting new participants. This means that the statement about confirming the effectiveness of psilocybin in phase 3 is premature today, regardless of how often it is repeated.
This state of affairs has a simple consequence for the reader. All numbers that can be honestly provided today come from phase 2 trials and one small academic trial. They are encouraging and have been published in high-ranking peer-reviewed journals, but they are not the same as registration evidence. We describe this method more broadly in the text about psilocybin as an element of psychotherapy.
Can psilocybin be combined with antidepressants?
This question often arises, and the answer is: this was not done in clinical trials. The work comparing psilocybin with escitalopram assigned 59 patients with moderate or severe long-term depression to two arms, but no one received both substances simultaneously. In the primary endpoint, which was the change in QIDS-SR-16 score after six weeks, the difference between groups was 2.0 points and was not statistically significant (p=0.17) (Carhart-Harris et al., NEJM, 2021).
It is worth being cautious with this work. Secondary endpoints generally favored psilocybin, including response rates of 70 versus 48 percent and remission rates of 57 versus 28 percent. However, the authors explicitly state that these analyses were not adjusted for multiple comparisons, so they should not be presented as demonstrated superiority. The study did not show a significant difference in its main measurement, and that is how it should be summarized.
In research protocols, participants discontinued antidepressants before sessions, under the supervision of a psychiatrist. Discontinuing medication on one’s own is a dangerous move for someone with severe depression and has nothing to do with what was done in the studies. Interactions of psychedelics with SSRIs and MAOIs are discussed separately in the text about contraindications and serotonin syndrome.
What risks does psilocybin carry and what is its legal status in Poland?
A safety review covering eight clinical trials, including three open-label and five placebo-controlled, did not report serious adverse events associated with psilocybin and LSD. However, the authors note that concerns remain regarding dissociation, paranoid states, and confusion, and that larger group trials are needed (Rossi et al., Expert Opinion on Drug Safety, 2022). This is not a systematic review with a meta-analysis, but rather an expert report, and its evidential strength should be weighed accordingly.
Separately, there is the risk of psychosis in predisposed individuals. The Johns Hopkins study excluded individuals with a history of psychotic disorders, and excluding such participants is standard practice in this field. The consequence is simple: the discussed trials say nothing about how psilocybin works in individuals with such burdens, as such individuals were not admitted to them. The signal of suicidal thoughts and behaviors in all dosing groups of the phase 2 study shows that participation in a carefully conducted trial does not eliminate the risks associated with severe depression.
In Poland, psilocybin is listed under position 86, and psilocin under position 76, in the list of psychotropic substances of group I-P, which is Annex 1 to the regulation of the Minister of Health (consolidated text Dz.U. 2024 poz. 1139), issued under Article 32 of the Act on Counteracting Drug Addiction (consolidated text Dz.U. 2023 poz. 1939). There is no separate entry for hallucinogenic mushrooms: they are covered by the ban due to what they contain. Possession and trade are prohibited, and there are no legal therapeutic programs with psilocybin in Poland. The state of research on other substances in this group is described in the text about therapies using psychedelics, and the separate case of MDMA in the text about phase 3 studies on MDMA in PTSD.
Frequently Asked Questions
How does psilocybin affect the brain?
Psilocybin is converted in the body to psilocin, which stimulates serotonin receptors 5-HT2A. Hypotheses explaining the antidepressant effect refer to increased synaptic plasticity and transient destabilization of the resting state network, but these are mechanistic hypotheses, not results from clinical trials.
What did the Johns Hopkins study measure?
The trial included 27 individuals with depression, of which 24 completed the protocol of two sessions with psilocybin. After four weeks, 71 percent had a response, and 54 percent were in remission. After twelve months, the response was maintained in 75 percent, and remission in 58 percent of participants.
Was the COMPASS study on 233 individuals a phase 3 study?
No. This trial is a phase 2 study, published in NEJM in 2022, with a primary measurement in the third week. The phase 3 study is a separate trial involving 258 individuals, which completed data collection in May 2025, and whose results have not yet been published.
Is psilocybin safe?
In clinical settings and with careful participant selection, no serious adverse events were reported, but concerns remain regarding dissociation, paranoid states, and confusion. In the phase 2 study, suicidal thoughts and behaviors appeared in all dosing groups.
Is psilocybin more effective than antidepressants?
This has not been demonstrated. The only direct comparison, with escitalopram in 59 patients, showed no significant difference in the primary endpoint (p=0.17). Secondary outcomes were more favorable for psilocybin, but the authors did not adjust for multiple comparisons.
What is the legal status of psilocybin in Poland?
Psilocybin is listed under position 86, and psilocin under position 76 in the list of psychotropic substances of group I-P. Possession, production, and trade are prohibited. There is no legal therapeutic program with psilocybin in Poland, and access is only possible in scientific research conducted with permission.
This article is for informational and educational purposes. It describes clinical trials in which the substance is administered under medical supervision after participant qualification; self-use of these conditions does not replicate. These substances are controlled in Poland by the Act on Counteracting Drug Addiction. If you have suicidal thoughts, call the free, 24-hour numbers 116 123 or 800 70 2222. In life-threatening situations: 112.
Author: Michał Waluk · Published: 2026-08-09 · Updated: 2026-08-16
