A team of USC researchers has received an up to $4 million award from the Advanced Research Projects Agency for Health (ARPA-H) to conduct a clinical trial of psychedelic therapy and mindfulness training for depression. Across 80 participants, researchers will compare the effects of psilocybin therapy with and without an eight-week mindfulness training program to test whether the two may have a synergistic effect.
Psilocybin is a psychedelic compound found in certain types of mushrooms that has shown promise for treating mental health conditions such as depression and substance use disorder. In 2019, the U.S. Food and Drug Administration granted "breakthrough therapy" designation to psilocybin-based treatment for major depressive disorder, opening the door to clinical research on its therapeutic effects.
Previous studies of experienced meditators suggest that practicing meditation may enhance a person's response to psychedelics. To investigate this further, Rael Cahn, MD, PhD, a clinical associate professor of psychiatry and the behavioral sciences at the Keck School of Medicine of USC, led the development of a structured mindfulness and meditation intervention designed to amplify and prolong the benefits of psychedelic therapy. He and his team hypothesize that the combination will help people with depression better integrate the insights gained during treatment and sustain improvements in their symptoms.
"Psychedelics appear to ignite something in the brain and behavior that allows people to adopt new perspectives. But after this ignition, they need tools to help maintain that mindset of self-exploration and discovery," said Assal Habibi, PhD, an associate professor of psychology at the Brain and Creativity Institute at the USC Dana and David Dornsife College of Letters, Arts and Sciences and one of the project's principal investigators.
The study, known as Evaluation of Integrated Digital, Biomarker and Neurophysiological Tracking in Mindfulness-Assisted Psilocybin Therapy (EVIDENT-MAP), is supported by ARPA-H, an agency within the U.S. Department of Health & Human Services focused on high-impact innovation to solve today's most pressing health problems. EVIDENT-MAP builds on recent work from the same USC team, an ongoing study that has so far tested psilocybin and mindfulness training in 24 people with no mental health issues and yielded encouraging early results.
"Almost everyone reported that this is one of the most meaningful experiences of their lives, even months later. Now we're asking whether it can also improve the lives of people with depression-and whether mindfulness can deepen those benefits," said Cahn, who leads EVIDENT-MAP and directs the USC Center for Mindfulness Science.
Sustaining the benefits of psilocybin
For the trial, researchers will recruit 80 adults living in Los Angeles who have depression but do not have experience with psychedelics or meditation. Half of the group will receive psilocybin therapy alone; the other half will receive psilocybin therapy and meditation training.
Throughout the trial, the researchers will collect detailed data on each patient to measure the therapy's effects. This includes EEG and MRI brain recordings; saliva, blood, and stool samples; psychological and cognitive assessments; and additional data from wearable trackers.
Each patient will complete two psilocybin sessions, about one month apart. Before the first session, they will attend six hours of preparatory psychotherapy. They will also attend three "integration" sessions between the psilocybin sessions-and three more after treatment is complete-to help process their experiences.
During the psilocybin sessions, we move away from the standard approach to psychotherapy, which tends to be more structured and guided. Instead, the therapist serves more as a supportive observer than an active intervener."
Rael Cahn, MD, PhD, clinical associate professor of psychiatry and behavioral sciences, Keck School of Medicine of USC
Participants in the mindfulness training group will also complete an eight-week program designed to cultivate mindful awareness, loving kindness and compassion, including daily meditation practice at home. The first psilocybin session will take place between weeks two and three of the meditation program.
Shaping the therapeutic setting
Past research on psychedelic therapy has shown that a person's physical surroundings, including music, can significantly impact their experience. Drawing on these findings, Habibi worked with a team of clinicians and music therapists to design a playlist aimed at enhancing the therapy's effects.
The songs included are lyric-free and span a range of musical traditions. They are carefully timed to align with the progression of psilocybin's effects, with a highly emotional piece played during the period of peak intensity. After treatment is complete, researchers will collect MRI scans while patients listen to the same music to determine whether they can detect a brain signal linked to the therapeutic effects of the experience.
"We're interested in whether that same music can have therapeutic utility in the future, without the use of psychedelics," Habibi said.
In addition to Cahn and Habibi, Shrikanth (Shri) Narayanan, PhD, is also a principal investigator of EVIDENT-MAP. Narayanan is a University Professor, the Niki and Max Nikias Chair in Engineering, vice president for presidential initiatives at USC, and professor of electrical and computer engineering, computer science, linguistics, pediatrics, otolaryngology-head and neck surgery, and music.
About this research
The study is supported by ARPA-H's the Evidence-Based Validation & Innovation for Rapid Therapeutics in Behavioral Health (EVIDENT) initiative, which aims to accelerate behavioral health research through detailed, real-time clinical data collection. Using digital tools, brain measures, and biological sampling, EVIDENT-supported projects contribute de-identified data to a secure national repository, helping researchers identify patterns associated with rapid changes in mental health. ARPA-H is an agency within the U.S. Department of Health and Human Services that supports bold, high-impact research designed to transform health outcomes.
This research was funded, in part, by the Advanced Research Projects Agency for Health (ARPA-H). The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the U.S. Government.
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