A new clinical trial may offer hope to people with Parkinson’s disease (PD) who suffer from depression.
Originally launched at the University of California, San Francisco (UCSF) by Ellen Bradley, MD, and Josh Woolley, MD, PhD, the study is now expanding to include a second site at Yale School of Medicine. Yale researchers Sophie Holmes, PhD, assistant professor of psychiatry and neurology, and Gerard Sanacora, MD, PhD, George D. and Esther S. Gross Professor of Psychiatry, have partnered with the UCSF team to conduct a groundbreaking two-site clinical trial investigating psilocybin—a psychedelic compound—as a potential treatment for depression in PD.
Psilocybin promotes synaptic plasticity—the brain’s ability to form new connections and repair existing ones—which may be particularly beneficial in PD, where synaptic loss contributes to both motor and mood symptoms.
The UCSF trial, funded by an anonymous donor, is now being expanded thanks to funding from the Michael J. Fox Foundation. The trial will aim to enroll 100 participants across UCSF and Yale and will use advanced techniques—including positron emission tomography (PET), magnetic resonance imaging (MRI), and transcranial magnetic stimulation (TMS)—to measure psilocybin’s effects on the brain.
Depression is among the most common and debilitating symptoms experienced by people living with PD. It profoundly impacts quality of life, accelerates disease progression, and remains notoriously difficult to treat effectively.
“Understanding mechanisms is a critical part of this trial,” Holmes says. “We aim not only to determine whether psilocybin can effectively treat depression in PD but, crucially, to understand how it works.
“We will use PET imaging to measure whether psilocybin induces an increase in synaptic connections—previously observed in animal studies but not yet in humans—MRI to identify psilocybin's impact on the functional organization of the brain, and TMS to assess changes in cortical excitability and synaptic strength,” Holmes says. “There's a lot of hype around psychedelics; we are taking a measured, mechanism-focused approach and have carefully designed our trial to tease apart 'specific' drug effects—directly tied to psilocybin's influence on synaptic plasticity—and 'non-specific' effects—those driven by expectation or placebo effects. Understanding these effects will be crucial if psychedelic treatments are to be adopted into clinical practice.”
This innovative trial represents a major initiative of a new program spearheaded by Holmes and Sanacora aimed at bridging psychiatry and neurology at Yale.
“The distinct pathologies underlying neurological disorders invariably affect brain circuits regulating mood and emotion,” says Sanacora. “Understanding the disease-specific mechanisms underlying psychiatric symptoms is essential for developing targeted treatments. Our program is dedicated to breaking down disciplinary silos, fostering collaboration, and accelerating clinical innovation at the intersection of psychiatry and neurology.”
John Krystal, MD, Robert L. McNeil, Jr. Professor of Translational Research and professor of psychiatry, of neuroscience, and of psychology, and chair of the Yale Department of Psychiatry, underscored the significance of the work.
“This trial exemplifies the transformative potential of interdisciplinary research,” he says. “Drs. Holmes and Sanacora are working at the nexus of neurologic and psychiatric neuroscience and positioning Yale to lead the field in developing novel treatments for patients whose complex needs have historically been underserved.”
The study team is currently being assembled and members of the Yale community interested in being involved are encouraged to contact Holmes directly at sophie.holmes@yale.edu.