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SAN FRANCISCO — Luvesilocin, a novel psychedelic 5-hydroxytryptamine receptor 2A (5HT2A) agonist compound formerly known as RE104, was associated with fast and durable improvement in women with moderate-to-severe postpartum depression (PPD).

This was the “first sizable randomized controlled trial of a psychedelic agent” for the treatment of PDD, researchers noted.

In the phase 2 RECONNECT trial, participants who received a single 30-mg subcutaneous dose of the novel treatment showed a significantly greater reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at day 7 than those who received the drug 1.5-mg dose, meeting its primary endpoint. Although there was no true placebo in the study, the 1.5-mg dose was used as an active control.

In addition, the 30-mg dose was linked to a greater MADRS score reduction on day 1 through day 28 and with higher responder and remission rates.

Further, the findings suggest that the drug was well tolerated, as most adverse events (AEs) were mild to moderate and resolved spontaneously.

“The number one message is that for a population of patients who are quite distressed with a common condition that often goes unrecognized, there’s an emerging potential treatment that is rapidly effective,” study investigator Mark H. Pollack, MD, chief medical officer at Reunion Neuroscience Inc, told Medscape Medical News.

The findings were presented on May 18 at the American Psychiatric Association (APA) 2026 Annual Meeting.

Breakthrough Designation

PPD affects approximately 15% of women. Luvesilocin is a novel psychedelic being developed for the treatment of PPD, in addition to other mental health conditions.

The 4-hydroxy-N,N-diisopropyltryptamine prodrug was designed to “deliver rapid efficacy with a short psychoactive experience, making it more convenient than the longer experience and monitoring required with traditional psychedelics like psilocybin or LSD [lysergic acid diethylamide],” according to the drug’s manufacturer. The psychedelic active form of psilocybin is 4-hydroxy-N,N-dimethyltryptamine.

Results from a phase 1 study published in October showed a favorable safety profile for RE104 up to 40 mg, as well as a shorter duration of psychoactive effect (3-4 hours), compared to psilocybin.

In February, the FDA granted Breakthrough Therapy Designation to luvesilocin for the treatment of PPD on the basis of findings from the phase 2 RECONNECT trial.

The double-blind, active-controlled study included 84 participants from 37 sites across the US who had PPD, were aged 18-45 years, and were at least 15 months postpartum (mean duration, around 7 months). All of the women were randomly assigned to receive a single dose of luvesilocin at a dose of either 30 mg (mean age, 33.3 years) or 1.5 mg (mean age, 31.2 years).

The 1.5-mg dose was chosen as the comparator in an attempt to reduce functional unblinding, said Pollack.

Posttreatment monitoring for either dose lasted up to 8 hours, and follow-up continued for 4 weeks. Participants could remain on a preexisting regimen of selective serotonin reuptake inhibitors (SSRIs) or therapy if stable. None was breastfeeding.

The primary outcome was the change in MADRS score between baseline and day 7. Secondary outcomes included MADRS score changes throughout the study and changes on the Barkin Index of Maternal Functioning, which measured items such as infant care and relationship.

Also assessed were response rates, defined as a ≥ 50% improvement from baseline on the MADRS, and remission rates, defined as a MADRS score of ≤ 10.

Rapid Onset, Durable Benefit

Results showed the 30-mg dose of luvesilocin was associated with a 23-point reduction in MADRS score at day 7 vs a 17.2-point reduction for the active control (P = .009). Reductions were also greater for the 30 mg group at day 1 and up to day 28.

Responder and remission rates were higher for those receiving the 30-mg dose at day 7 than those receiving the 1.5-mg dose (77% vs 62% and 71% vs 41%), with high rates maintained through day 28.

“We were anticipating that we’d have positive findings, but the magnitude of the response was a pleasant surprise,” Pollack noted.

“A 70% remission rate is extraordinary because most depression trials have rates that are about half to one third that. So this speaks to the potency of the agent,” he added.

A post hoc analysis of participants with a baseline score of ≥ 22 on the Hamilton Anxiety Rating Scale (HAM-A), signifying moderate-to-severe anxiety, showed significantly greater HAM-A changes for those receiving the 30-mg dose than those receiving the comparator at day 7 (P < .01), day 14 (P < .05), and day 28 (P < .01).

Among the same subgroup, the 30 mg participants also had greater reductions in MADRS scores at day 7 (P < .01) and day 28 (P < .05).

Maternal well-being and function also showed a significant improvement for the higher dose at day 7 (30.7 vs 18.6; P < .01) and day 28 (31.8 vs 23.9; P < .05).

Only one member of the full 30 mg group and five members of the 1.5 mg group withdrew before the study’s end, but none of the withdrawals were caused by AEs. Neither group had any serious treatment-emergent AEs, deaths, or suicidal ideation or behaviors.

The most commonly reported AEs in the 30 mg group were nausea (44%), headache (34%), dizziness (27%), vomiting (24%), and visual hallucinations (22%).

More than 90% of the participants were deemed medically fit for discharge at 4 hours after their single treatment.

In addition to plans for a pivotal phase 3 clinical trial of luvesilocin in PPD to begin later this year, the company has started recruitment for the phase 2 REKINDLE trial in patients with adjustment disorder related to cancer and other medical illnesses and the phase 2 RECLAIM trial in patients with generalized anxiety disorder.

Compelling, With Caveats

Commenting on the findings, Nancy Byatt, DO, a perinatal psychiatrist and professor of psychiatry and behavioral sciences and ob/gyn at UMass Chan Medical School in Worcester, Massachusetts, noted that this type of research is needed because of the negative impact that PPD can have on a mother, her baby, and the entire family.

“We need treatments that work quickly and it is exciting to see the development of new treatment such as RE104,” Byatt, who was not involved with the research, told Medscape Medical News.

She underscored the importance of pairing treatment innovation with greater access to perinatal mental health care to maximize the real-world impact of these therapies.

Also commenting for Medscape Medical News, Yokarla Veras, MD, a New York City-based reproductive psychiatrist, said the most striking part of the study was that it showed an entirely different way of treating PPD.

“This new psychedelic compound is very serotonergic, and targeting the 5HT2A agonism is really interesting because right now we don’t have anything like that,” Veras said, adding that current PPD treatments often include SSRIs and serotonin and norepinephrine reuptake inhibitors.

“The study was compelling and did show significant improvement over a really short period of time, which was promising,” she said.

However, Veras warned that the drug is new as this is deemed the first psychedelic study for PPD, more research with larger patient populations are needed to assess whether the positive outcomes can be reproduced.

She noted that she’d also like to see future studies include a true placebo control, evaluate whether co-treatments affect the drug’s effect, and compare the novel agent to current gold-standard therapies. “We also need to learn more about the potential risks of the medication,” Veras said.

For now, “the takeaway message is that we should be paying attention to how psychedelics can be used to treat postpartum depression, but we need to be very cautious as the findings are still in the early stages,” she said.

Although topline results from the study were released online last year and at the American College of Neuropsychopharmacology Annual Meeting in January, more detailed results were released at the APA Annual Meeting. 

The study was funded by the drug’s developer and manufacturer Reunion Neuroscience; and Pollack reported being an employee of the company. Byatt and Veras reported having no relevant financial relationships.