A single dose of psilocybin might help reduce symptoms in treatment-resistant depression

An open-label study of 12 individuals with severe treatment-resistant depression found that their symptoms significantly decreased three weeks after taking a single dose of psilocybin. These improvements persisted through the 12-week follow-up period. However, participants who also had posttraumatic stress disorder tended to experience less benefit. The research was published in the American Journal of Psychiatry.

Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms, commonly referred to as “magic mushrooms.” In the body, psilocybin is converted into psilocin, which binds to serotonin receptors in the brain. This interaction produces altered perceptions, shifts in mood, and changes in consciousness.

Historically, psilocybin has been used in spiritual and ceremonial practices for centuries. In recent years, it has attracted growing scientific interest due to its potential to treat mental health conditions such as depression, anxiety, posttraumatic stress disorder, and addiction. Clinical studies suggest that psilocybin can promote lasting emotional insight and symptom relief after just one or two guided sessions. Although considered physiologically safe in controlled settings, it can sometimes cause acute psychological distress. Legal status varies worldwide, but interest in therapeutic use and decriminalization is expanding rapidly.

Study author Scott T. Aaronson and his colleagues sought to examine the effects of a single dose of synthetic psilocybin, administered with psychological support, in individuals with severe treatment-resistant depression. This form of major depressive disorder is defined by failure to respond to multiple adequate antidepressant trials. In this study, all participants had failed to improve with at least five different treatments in their current depressive episode.

Up to 55% of people treated for depression may meet criteria for treatment resistance, making it a major public health concern and a high priority for research into new therapies.

The final sample included 12 patients selected from 205 individuals who were screened. There were equal numbers of men and women, and the average age was approximately 41 years. Five participants had a comorbid diagnosis of posttraumatic stress disorder.

Each participant received a single oral dose of 25 milligrams of synthetic psilocybin (COMP360) and was monitored for 12 weeks. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale, a clinician-administered measure. Assessments were conducted at baseline, and then again at 1, 3, and 12 weeks post-treatment. Participants also completed self-report measures of quality of life (the Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form) and anxiety symptoms (the Generalized Anxiety Disorder 7-item scale).

Results showed a sharp reduction in depression symptoms one week after dosing. While symptoms slightly increased again by week 3, they remained significantly lower than at baseline. By week 12, scores had decreased again slightly compared to week 3, particularly according to clinician ratings.

Most participants showed a marked decrease in symptoms. However, a few individuals had smaller improvements, and in some cases, symptoms returned to near-baseline levels. Those with comorbid posttraumatic stress disorder tended to show less reduction in depression symptoms across time.

“As an initial foray into psilocybin treatment for patients with MDD (major depressive disorder) that is difficult-to-treat, this study provided an early indication of safety, tolerability, and promising potential efficacy. An unexplored question concerns the durability of the antidepressant effect beyond 12 weeks and whether durability can be extended with additional dosing,” the study authors concluded.

The findings add to a growing body of research suggesting that psilocybin could be a valuable tool for addressing hard-to-treat depression. However, the study had several important limitations. It was open-label, meaning there was no control or placebo group, and both researchers and participants knew that psilocybin was being administered. This increases the potential for expectancy effects and placebo responses.

Moreover, although clinician-rated scales were used, all results ultimately relied on subjective reporting, either by participants or the clinicians evaluating them. This leaves the data vulnerable to biases such as the Hawthorne effect, where individuals alter their behavior because they know they are being studied.

Without a control group, it’s also impossible to determine how much of the observed improvement was due to the psilocybin itself, rather than natural fluctuations in mood, psychological support, or other external factors.

The paper, “Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial,” was authored by Scott T. Aaronson, Andrew van der Vaart, Tammy Miller, Jeffrey LaPratt, Kimberly Swartz, Audrey Shoultz, Margo Lauterbach, Trisha Suppes, and Harold A. Sackeim.