Investigational Psychedelic RE104 for Postpartum Depression Delivers Positive Phase 2 Results: Reunion Neuroscience Update

In women with moderate-to-severe postpartum depression (PPD), RE104, a psychedelic-inspired investigational therapy, met the primary endpoint in Reunion Neuroscience's phase 2 RECONNECT trial. The single 30 mg subcutaneous dose produced a mean reduction from baseline of 23.0 points on the Montgomery-Åsberg Depression Rating Scale (MADRS) at day 7, compared with 17.2 points in the 1.5 mg active control arm. The 5.8-point treatment effect was as statistically significant (P =.001), according to a Reunion Neuroscience statement.1

Anita H Clayton, MD

Lead Investigator, RECONNECT Trial

Courtesy of UVA Health

The company reported clinically meaningful reductions in MADRS scores as early as the day following administration of the 30 mg dose that persisted through the 28-day follow-up. At day 7, more than three-quarters (77.1%) of RECONNECT participants achieved response, defined as at least a 50% improvement in MADRS score, compared with 61.6% in the active control group.

Nearly three-quarters (71.4%) of participants treated with the 30 mg dose reported symptom remission, defined as a MADRS total score of 10 or less, compared with 41.0% of those receiving active control. Both response and remission rates were maintained through day 28.1

Back to Life with a New Baby

Among key secondary endpoints and consistent with the primary outcome, were improvements in maternal functioning as assessed via the Barkin Index of Maternal Functioning (BIMF), a self-report measure that elicits a new mother's well being and "ability to manage life with a new baby," the statement said.

At 4 hours post-dose, nearly all (92.7%) of RECONNECT participants in the 30 mg group met discharge readiness criteria.1

PPD affects approximately 15% of new mothers within the first postpartum year and persists as the "most common complication of pregnancy and childbirth in the US," RECONNECT lead investigator Anita H. Clayton, MD, Wilford W. Spradlin Professor and chair of psychiatry and neurobehavioral sciences at the University of Virginia School of Medicine, said in the statement. That translates to nearly 500,000 women in the US diagnosed annually. “Despite its prevalence and severity, current treatment options for PPD remain limited and are often slow-acting and burdensome, leaving many new mothers without timely, effective care."1

RE104 Mechanism, Tolerability

RE104 is a prodrug that converts to 4-OH-DiPT (4-hydroxy-N,N-diisopropyltryptamine) in the body, which then acts on serotonin 2A receptors, according to Reunion Neuroscience. The investigational treatment is designed to produce psychedelic effects similar to those of psilocybin, but with a significantly shorter duration of action (approximately 3-4 hours vs 6-8 hours for psilocybin) without accompanying sedation. "The RECONNECT findings point to the agent's potential as a single subcutaneous injection therapy that addresses limitations of current treatments by delivering symptom relief quickly and safely," Clayton added.2

Clayton et al reported that RE104 was generally well-tolerated. The most common treatment-emergent adverse events (TEAE) were nausea (43.9%) and headache (34.1%), typically mild to moderate, occurring on the treatment day and resolving spontaneously. There were no serious AEs reported and researchers observed no treatment-emergent suicidal ideation, seizures, serotonin toxicity, or clinically significant electrocardiogram abnormalities.

The RECONNECT trial enrolled 84 women (mean age 32 years [range 21-25]) across 38 research sites in the US. The cohort's mean postpartum period was 7.3 months (range: 1.5–17.7). Each received either 30 mg or 1.5 mg RE104 via single subcutaneous injection. Psychotherapy was not provided as part of the protocol, according to the Reunion statement.2

“With PPD, it can seem as if women are watching life from the sidelines, feeling emotionally detached, lacking joy, and unable to bond with their newborns while struggling with guilt and shame that can come with debilitating depression," Camille Hoffman, MD, MSc, obstetrician-gynecologist and professor of maternal and fetal medicine at the University of Colorado School of Medicine," noted in the statement. "Our current treatment options are limited, and we need therapies that help our patients recover rapidly during such a dynamic time of life."1

Lactation Study and Phase 3 Planning

Reunion also disclosed initial findings from a lactation study. Maternal breast milk contained less than 0.1% of the 30 mg RE104 dose, a level considered well below that which might pose risk to infants. The company stated that final data will be reviewed by the FDA, but preliminary results suggest limited interruption to breastfeeding may be required.

“We are encouraged by the results from our RECONNECT phase 2 trial, which provide strong clinical validation for RE104 as a well-tolerated and effective treatment for PPD offering rapid relief with minimal interruption to daily activities," Reunion CEO Mark Pollack, MD, said. "These data support our proposed plan to advance RE104 into a pivotal phase 3 trial in 2026.” 1

Pollack noted that Reunion will launch a phase 2 trial in adjustment disorder related to cancer and other illnesses (REKINDLE, NCT07002034) in the third quarter of 2025, with an additional Phase 2 study in another psychiatric indication planned for early 2026.1

References

1. Reunion Neuroscience announces positive topline results from RECONNECT phase 2 clinical trial of RE104 for the treatment of postpartum depression. News release. Reunion Neuroscience. August 18, 2025. Accessed August 18, 2025. https://reunionneuro.com/wp-content/uploads/2025/08/FINAL-Reunion-RECONNECT-Topline-Results-Release-081325-2.pdf

2. RE104 safety and efficacy in postpartum depression. ClinicalTrials.gov ID NCT06342310. Updated July 23, 2025. Accessed August 18, 2025. https://clinicaltrials.gov/study/NCT06342310