Single dose of psilocybin provides rapid relief from depression in double-blind study

A single dose of psilocybin shows rapid and clinically meaningful improvement in depressive symptoms within days, according to a Swedish study.

A single dose of the psychedelic substance psilocybin can provide rapid relief from depressive symptoms, as shown by the first randomized, double-blind study conducted at Karolinska Institutet. The effect persisted for over three months, researchers found. Depression is a public health problem that causes great suffering. SSRI drugs are commonly used but many patients do not benefit from them. Their effects can take several weeks to kick in and side effects are common. Psilocybin, found in so-called magic mushrooms, has shown antidepressant effects in previous studies. However, most of these studies have focused on cancer-related or treatment-resistant depression.

In the current Phase II study published in JAMA Network Open, researchers investigated whether psilocybin could also alleviate common depression. A total of 35 people aged 20 to 65 with moderate to severe recurrent depression participated. They were randomly assigned to receive either a single dose of 25 mg of psilocybin or an active placebo in the form of niacin, which causes a noticeable physical reaction. Both groups received psychotherapeutic support on five occasions: before, during and after treatment.

On the day of dosing, participants were asked to lie down and focus inwardly while wearing an eye mask and listening to music via headphones. The effect of the treatment was measured using the MADRS (Montgomery–Asberg Depression Rating Scale). Measurements were taken by doctors who were blinded to the treatment on days 8, 15, 42 and 365 following dosing.

To be included in the study, participants were required to have a total score of at least 22 points. The primary outcome was the change in depressive symptoms eight days after treatment. At this point, the MADRS score had decreased by an average of 9.7 points in the psilocybin group, compared with 2.4 points in the placebo group. This represents a group difference of 7.3 points in favor of psilocybin and is considered clinically meaningful.

The effect persisted even after 15 and 42 days. Participants also completed a self-report version of the MADRS. Their own assessments showed an antidepressant effect as early as day two, which persisted for just over three months compared to the placebo group. After six weeks, 53% of participants in the psilocybin group were in remission, compared with 6% in the placebo group.

Researchers interpret their results as suggesting that psilocybin can provide rapid, clinically meaningful improvement in depression and may serve as an alternative to standard treatment when fast symptom reduction is important. However, they note that long-term effects are uncertain, and repeated treatments may be needed to prevent relapse. This needs to be investigated in larger studies.

The treatment was generally well tolerated. Most side effects were mild or moderate and transient. However, two participants who received psilocybin reported severe and persistent anxiety that required medical attention. Researchers emphasize that the treatment is not risk-free and that some patients may need extra support.

Blinding challenges and future directions are significant in research into psychedelic treatments because the substances produce strong and easily recognizable experiences. If participants and researchers can tell whether psilocybin or placebo was given, it becomes harder to separate the effect of the treatment from that of expectations. In the current study, almost all participants were able to guess which treatment they had received, which may have influenced the outcomes.

Researchers want to understand how factors such as treatment expectations and lack of blinding affect the results. They plan to analyze data from PET scans, as well as blood and cerebrospinal fluid samples collected before and after dosing. Research suggests that the interaction between parts of the brain is impaired in depression and may be linked to changes in the connections between nerve cells, known as synapses. In preclinical studies, psychedelics have been shown to stimulate synaptic growth.

Researchers conclude by stating that psilocybin therapy linked to reduced depression symptoms in clinical trial suggests its potential as an alternative treatment for depression. Further research is needed to explore long-term effects and the possibility of repeated treatments.