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Psilocybin Therapy for Treatment-Resistant Depression

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Topline Results from COMPASS Pathways Phase IIb Trial

By Olivia Gorzynska

In November 2021, COMPASS Pathways, a mental health care company, published a press release announcing results from its phase IIb trial on psilocybin therapy for treatment-resistant depression (TRD).

Psilocybin is a naturally occurring psychedelic compound found in mushrooms of the Psilocybe genus. “Magic mushrooms” have been used for thousands of years for spiritual and healing purposes but were not studied by modern science until the late 1950s. Psychedelic drugs, including psilocybin, LSD and mescaline were used in psychiatry until being listed as Class A drugs in the Misuse of Drugs Act 1971 (UK), which defined them as highly harmful, addictive and with no known clinical utility. This led to a halt in their medical use and a significant decrease in research in this area. However, the past three decades witnessed a steady revival of clinical and research interest in psychedelics, resulting in promising evidence on their therapeutic potential for treatment of various conditions.

Modern studies have found psychedelics to be effective in reducing symptoms of anxiety, depression, and obsessive-compulsive disorder. Other research has also shown efficacy in alcoholism and tobacco dependence, with similar studies in anorexia, chronic pain, and opioid use disorder being developed.

Study design

To date, the COMPASS study is the largest double-blind randomised controlled trial (RCT) investigating the effects of psilocybin therapy on treatment-resistant depression. Treatment-resistant depression can be defined as depression that has not improved after two or more adequate treatments with antidepressant medication.

The sample consisted of 233 patients, all of whom discontinued antidepressants prior to participation. The participants were divided into three groups and each group received a different single dose of psilocybin (1mg, 10mg, or 25mg) in conjunction with psychological support from therapists. The psilocybin session was preceded by preparation and followed up with integration.

The primary endpoint, or the main outcome that was measured at the end of the trial to see if the treatment was effective, was a reduction of depression symptoms as measured by the change in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 3. MADRS is a ten-item questionnaire which measures the severity of depressive symptoms.


The researchers were interested in comparing the effects of active doses of psilocybin (10mg and 25mg) against the comparator dose of 1mg. The results demonstrated that the 25mg group had a greater reduction in MADRS scores after 3 weeks when compared to the 1mg group, which was statistically significant. The difference in scores between the 1mg and 10mg groups was not statistically significant.

In addition, in the 25mg group, 36.7% (29 patients) showed response to treatment (defined as ≥50% decrease in depression score) and 29.1% (23 patients) were in remission at week 3. Moreover, 24.1% (19 patients) sustained the response to treatment at the end of the trial at week 12.

Safety profile

In order to evaluate the safety of the treatment, the researchers looked at the incidence of treatment-emergent adverse events (TEAEs), which can be defined as undesirable events that occur after treatment has started. Psilocybin was generally well-tolerated. Whilst 179 participants reported at least one TEAE, the vast majority (over 90%) of the events were mild or moderate in severity. The incidence of TEAEs was slightly higher in the 25mg group compared to other groups. The most common adverse events reported by the patients across treatment groups were headache, nausea, fatigue, and insomnia.

It is important to note that TEAE incidence encompasses all events, including those which might be related to the psychedelic experience in the therapeutic setting. Given the unique nature of psychedelics, challenging experiences (or ‘bad trips’) are not uncommon. These reactions can involve feelings of fear, anxiety, dysphoria and/or paranoia. Whilst unpleasant, they are typically short-lived and do not lessen the therapeutic effects of psychedelics in improving symptoms of depression. In fact, challenging experiences can often have cathartic effects.

The study also measured the frequency of treatment-emergent serious adverse events (TESAEs), which were reported by 12 patients and included suicidal behaviour, intentional self-injury, and suicidal ideation. These events occurred more frequently in the 25mg and 10mg groups than in the 1mg group. However, this does not necessarily imply that there is a casual link between psilocybin and the reported TESAEs. Some of the TESAEs might be related to the patients having TRD, given that events such as suicidal ideation and self-harm occur frequently in this population. The study also reports that all instances of suicidal ideation were experienced at least one month after psilocybin administration. It is thus unclear whether there is a causal relationship between the two and further analysis on the onset and duration of TEAEs is currently underway. These are all common symptoms amongst this cohort that did not differ between the three groups which suggests the trip itself did not induce these effects


The preliminary results from this phase IIb trial add to the existing research evidence demonstrating the therapeutic effects of psilocybin on people suffering from treatment-resistant depression. Previous studies, albeit with smaller sample sizes, showed substantial rates of response to treatment and remission. For example, a phase II double-blind RCT comparing psilocybin with the antidepressant escitalopram in 59 individuals with major depressive disorder (MDD) carried out by Imperial College London found that 70% of participants showed a response to treatment in the psilocybin group at 6 weeks (compared to 48% in the escitalopram group). Similarly, a randomized, waiting list–controlled trial conducted by researchers from Johns Hopkins University in 24 patients with MDD had a treatment response rate of 71% at week 4. In addition, over 50% of participants were in remission at the end of both trials.

Being the largest psilocybin trial to date, the COMPASS study presents an exciting development in psychedelic research and is a step in the right direction toward finding an effective treatment for those suffering from severe depression.

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