Cleveland Clinic researchers have launched a Phase 2 clinical trial investigating a novel synthetic psychedelic compound as a potential treatment for postpartum depression, a condition affecting approximately one in seven women after childbirth.
The study focuses on RE104, a synthetic compound similar to psilocybin (the active ingredient in "magic mushrooms") but with shorter-acting psychedelic effects, potentially making it more practical for clinical use if eventually approved by the FDA.
"Potentially, if this was approved by the FDA, that short-acting characteristic would make it easier to give to patients," explained Dr. Brian Barnett, a physician with the Center for Adult Behavioral Health at Cleveland Clinic – Lutheran Hospital, who is leading the Clinic's participation in the study.
Rising Rates of Postpartum Depression
The clinical trial comes at a critical time, as postpartum depression rates have risen dramatically in recent years. A recent study published in JAMA documented that diagnosis rates doubled from 9.4% in 2010 to 19% in 2021 across all racial and ethnic groups in the United States.
While selective serotonin reuptake inhibitors like Zoloft are commonly prescribed for postpartum depression, Dr. Barnett notes that "many women don't want to take a daily medication." The appeal of RE104 lies in its potential as a single-dose treatment that could provide lasting relief.
Study Design and Participant Experience
The Cleveland Clinic is one of 25 U.S. sites participating in this multicenter trial. Researchers are currently recruiting women who:
- Are up to 15 months post-delivery
- Are not currently breastfeeding
- Have been diagnosed with postpartum depression
Participants will receive a single dose of RE104 administered subcutaneously at Lutheran Hospital. Following administration, they will be monitored for several hours in a specially designed comfortable environment with soothing décor.
"After taking RE104, study participants may feel euphoric, or experience altered perceptions such as brighter colors or hallucinations," Dr. Barnett explained. Due to the tendency of psychedelics to increase blood pressure and heart rate, vital signs will be closely monitored throughout the experience.
The study protocol includes approximately 11 visits over a six-week period, with assessments both before and after drug administration. The primary endpoint will evaluate whether participants experience reduced depression symptoms up to four weeks after treatment.
How Psychedelics May Affect Depression
RE104 works by affecting serotonin receptors in the brain. Researchers believe psychedelics like RE104 and natural psilocybin may help depression through multiple mechanisms:
- Increasing brain neuroplasticity, making it more receptive to learning new behaviors and thought patterns
- Temporarily deactivating the brain's default mode network, which is often overactive in depression
"The default mode network is overactive because they're ruminating on their own problems over and over, and can't get out of that thought pattern," Dr. Barnett said. Psychedelics appear to reset this network by temporarily turning it off. "When it reactivates, it's in a less rigid state," he explained.
Changing Attitudes Toward Psychedelic Medicine
The Cleveland Clinic's investigation of RE104 reflects a broader shift in attitudes toward psychedelic compounds for medical use. While substances like psilocybin and LSD remain federally illegal in the United States, research into their therapeutic potential has accelerated in recent years.
Dr. Barnett previously led the Clinic's participation in a national study examining LSD for severe anxiety. Though results have not yet been published, he described them as promising: "Three months after patients received a single dose of 100 micrograms of LSD, about half no longer had anxiety disorder. We have never seen anything that effective."
This growing body of research suggests psychedelics may offer new options for patients who haven't responded to conventional treatments. "The patients I see are suffering tremendously," Barnett noted. "They're often willing to try anything to help with these conditions that they've had for years or decades."
Safety Considerations and Next Steps
A separate study is currently investigating whether RE104 passes into breast milk. Until those results are available, the FDA requires that study participants not be breastfeeding.
The Cleveland Clinic is actively recruiting for this study, which is based at Lutheran Hospital. Interested individuals who meet the criteria can call 216-425-7426 or email psychresearch@ccf.org for more information.
If successful, this research could potentially lead to a new treatment option for the growing number of women experiencing postpartum depression, offering relief through a single-dose intervention rather than ongoing medication.
