Researchers at the University of Southern California will investigate whether mindfulness meditation can improve the effects of psilocybin-assisted therapy for people living with depression, in a clinical trial supported by up to US$4 million in federal funding.
The study, led by researchers at the Keck School of Medicine of USC and the university’s Brain and Creativity Institute, will enrol 80 adults with depression in Los Angeles. Participants will receive psilocybin-assisted therapy either on its own or alongside an eight-week mindfulness training programme, allowing researchers to compare the outcomes of the two approaches.
The research is supported by the Advanced Research Projects Agency for Health (ARPA-H), an agency within the US Department of Health and Human Services that funds projects aimed at advancing healthcare.
While psilocybin has attracted considerable interest as a potential treatment for depression, the USC team is investigating a question that could have implications for how psychedelic therapy is delivered: whether structured meditation practice can help people maintain improvements after treatment.
Investigating the role of mindfulness in psychedelic therapy
The trial, known as Evaluation of Integrated Digital, Biomarker and Neurophysiological Tracking in Mindfulness-Assisted Psilocybin Therapy (EVIDENT-MAP), builds on earlier research by the USC team involving healthy participants.
That earlier study explored the combination of psilocybin and mindfulness training in 24 people without mental health conditions. Researchers reported encouraging early findings, prompting further investigation into whether the approach could also benefit people experiencing depression.
Rael Cahn, a clinical associate professor of psychiatry and the behavioural sciences at the Keck School of Medicine, leads the new trial and directs the USC Center for Mindfulness Science. He and his colleagues believe mindfulness may help participants process their psychedelic experiences and incorporate any resulting insights into their everyday lives.
Assal Habibi, an associate professor of psychology at USC’s Brain and Creativity Institute and one of the project’s principal investigators, said psychedelic experiences may help people adopt new perspectives, but maintaining those changes can require ongoing support.
The research will examine whether mindfulness training can help sustain the effects of psilocybin-assisted therapy beyond the treatment sessions themselves.
The distinction is important because the potential for lasting improvements remains a key question in psychedelic research. A positive response during or shortly after treatment does not necessarily mean those benefits will persist, and researchers are continuing to investigate the factors that influence longer-term outcomes.
How the clinical trial will work
The 80 participants will be divided into two groups. One will receive psilocybin-assisted therapy, while the other will receive the same treatment alongside an eight-week mindfulness programme.
Participants will complete two psilocybin sessions approximately one month apart. Before their first session, they will undertake six hours of preparatory psychotherapy to help them understand and prepare for the experience.
The treatment protocol also includes integration sessions designed to help participants reflect on and process their experiences. Three sessions will take place between the two psilocybin treatments, followed by another three after treatment has finished.
During the psychedelic sessions, therapists will take a supportive approach rather than directing the experience through highly structured psychotherapy. The aim is to provide a safe therapeutic environment in which participants can work through their experiences with professional support.
Those assigned to the mindfulness group will complete an eight-week programme covering mindful awareness, loving-kindness and compassion, alongside daily meditation practice at home. Their first psilocybin session will take place during the second or third week of the programme.
By comparing the two groups, researchers hope to determine whether the addition of mindfulness training produces measurable differences in treatment outcomes.
Brain imaging and biological data will help track outcomes
EVIDENT-MAP will collect a broad range of clinical and biological information to investigate how participants respond to treatment.
Assessments will include electroencephalography (EEG) recordings, MRI brain scans, psychological and cognitive testing, and saliva, blood and stool samples. Participants will also use wearable tracking devices to provide additional information throughout the study.
The researchers intend to use these measurements to examine changes in brain activity, psychological symptoms and other biological indicators associated with treatment.
The project forms part of ARPA-H’s Evidence-Based Validation & Innovation for Rapid Therapeutics in Behavioral Health (EVIDENT) initiative. The programme aims to accelerate behavioural health research by collecting detailed data that could help researchers identify patterns associated with rapid changes in mental health.
Participating projects contribute de-identified information to a secure national repository, supporting broader efforts to understand why certain treatments work for some people and how their effects might be improved.
For psychedelic medicine, this approach could help researchers move beyond relying primarily on participants’ reported experiences to develop a more detailed picture of treatment response.
Music and the therapeutic environment
The study will also investigate the role of music in shaping the psilocybin experience.
Previous psychedelic research has suggested that environmental factors, including music, can influence the nature of a person’s experience during treatment. Drawing on this work, Habibi collaborated with clinicians and music therapists to develop a playlist intended to complement the progression of psilocybin’s effects.
The playlist features instrumental music drawn from different musical traditions, with individual pieces selected and timed to correspond with different stages of the treatment session.
After treatment, participants will undergo additional MRI scans while listening to the same music. Researchers will look for brain signals associated with the therapeutic experience and investigate whether music might eventually have a role in supporting therapeutic outcomes without the need for psychedelics.
This part of the research could help clarify how different elements of the treatment environment contribute to the overall experience, although its potential clinical applications remain to be established.
A broader effort to understand psychedelic treatment
The USC trial adds to ongoing efforts to establish how psilocybin-assisted therapy might be used in mental healthcare and which approaches could help people achieve more sustained improvements.
Psilocybin has shown promise in clinical research involving depression and other mental health conditions, but questions remain about its effectiveness across different patient populations, the durability of its effects and the therapeutic support needed to achieve the best outcomes.
By examining mindfulness alongside psilocybin, the USC team is testing whether a structured psychological practice can contribute to the treatment’s effectiveness rather than treating the psychedelic session as an isolated intervention.
The study’s combination of clinical assessments, neuroimaging and biological data may also provide insights into the mechanisms underlying treatment response.
The results will be needed to determine whether mindfulness offers a meaningful advantage over psilocybin-assisted therapy alone. Until those findings are available, the approach remains investigational rather than an established treatment for depression.
For researchers working to develop psychedelic therapies, the trial represents another step towards understanding not only whether these treatments can help, but also how their potential benefits might be maintained over time.
