Luvesilocin (RE104)

Mechanism of action

RE104 is an inactive-by-design ester prodrug: it is cleaved to 4-OH-DiPT in under 30 minutes in mouse, rat and human plasma at 37 degrees C, and is undetectable in plasma within 5 minutes of subcutaneous administration in vivo. The prodrug itself binds 5-HT2A only weakly (Ki 4,300 nM) and is functionally inactive (inositol-phosphate EC50 >30,000 nM); the pharmacology belongs entirely to the liberated 4-OH-DiPT, which binds 5-HT2A with Ki 120 nM and behaves as a near-full agonist at 5-HT2A in G-protein dissociation assays, with agonist activity also at 5-HT2B and 5-HT2C. 4-OH-DiPT is a positional/alkyl analogue of psilocin and is reported to be more selective across the 5-HT receptor family than psilocin. It produces the head-twitch response in mice, and HTR intensity tracks plasma 4-OH-DiPT concentration (r-squared 0.7019), consistent with classical 5-HT2A psychedelic pharmacology. The anxiolytic rationale specific to this indication is preclinical: in mice, 4-OH-DiPT enhanced fear extinction by activating basolateral-amygdala interneurons via 5-HT2A to increase GABAergic inhibition of principal neurons — a plausible mechanism for suppressing learned fear, and the closest published mechanistic support for a generalized-anxiety indication. The defining property remains kinetic rather than receptor-level: subcutaneous delivery of a rapidly cleaved ester gives a Tmax of ~1 h and a terminal half-life of 2.72-4.12 h for 4-OH-DiPT, roughly halving the acute psychedelic window relative to psilocybin.

Formulations

Luvesilocin (RE104) for Postpartum depression

Phase 2ActivePostpartum depression indication →

Luvesilocin (RE104), a subcutaneous prodrug of the short-acting psychedelic 4-OH-DiPT, for moderate-to-severe postpartum depression — the company's lead indication and the first sizable randomized controlled trial of a psychedelic agent in PPD. RECONNECT (NCT06342310, RE104-201-PPD) randomized 84 women across 38 US sites to a single subcutaneous dose of 30 mg RE104 or 1.5 mg as an active control, with session monitors but no formal psychotherapy, and 28 days of follow-up. It met its primary endpoint: a 23.0-point reduction in MADRS total score at Day 7 versus 17.2 points on active control (difference 5.80; one-sided p=0.0094), from a baseline MADRS of 33.4. Day 7 response was 77.1% vs 61.6% and remission 71.4% vs 41.0%, both maintained through Day 28, with supporting gains on the Barkin Index of Maternal Function, HAM-A and CGI-I. There were no serious adverse events; nausea (43.9%) and headache (34.1%) were the most common TEAEs, and 92.7% of patients were discharge-ready at 4 hours. A companion Phase 1 lactation study (NCT06659263) found breast-milk transfer below 0.1% of the maternal dose, supporting resumption of breastfeeding with minimal interruption. Reunion completed its End-of-Phase-2 meeting in December 2025 and reported FDA feedback that a single successful Phase 3 trial would complete the pivotal package for registration; FDA granted Breakthrough Therapy designation on 2026-02-23. The company has guided to initiating that pivotal Phase 3 — with FDA-supported enrollment of breastfeeding women — during 2026, but as of 2026-07-24 no Phase 3 study is registered on ClinicalTrials.gov under this sponsor and no initiation has been announced, so the program is recorded at Phase 2.

Luvesilocin (RE104) for Generalized anxiety disorder

Phase 2RecruitingGeneralized anxiety disorder indication →

Luvesilocin (RE104), a subcutaneous prodrug of the short-acting psychedelic 4-OH-DiPT, for generalized anxiety disorder — the third and newest RE104 indication, behind postpartum depression (lead) and adjustment disorder. RECLAIM (NCT07489651, RE104-203-GAD) is a multicenter, randomized, double-blind, PLACEBO-controlled Phase 2 in 64 adults with GAD, testing a single subcutaneous 30 mg dose against placebo with a primary endpoint of change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at Week 4. It is the only RE104 trial to use a true placebo rather than a 1.5 mg active control, which should give a cleaner read on effect size than the dose-controlled PPD design did. The program was created and funded on 2025-09-16, when the Series A final tranche was upsized on the strength of the RECONNECT PPD efficacy result, and Reunion earmarked the proceeds for GAD expansion. Guidance was for a Q1 2026 start; the registry records an actual start of 2026-04-20 (recruiting). Estimated primary completion is February 2027 and the company expects data in Q2 2027. No results, publications or regulatory designations exist for this indication. The dose is carried over from PPD with no GAD-specific dose-ranging.

Clinical trials