What clinical conditions is dextromethadone (neurocept) being developed to treat and what trial results exist as of 2025?
Executive summary
Dextromethadone (esmethadone; REL‑1017) has been developed principally as a rapid‑acting oral antidepressant for major depressive disorder (MDD), with additional exploratory work in neuropathic pain, restless legs syndrome (RLS) and chronic pain reported in registries and company statements [1] [2] [3]. Randomized placebo‑controlled Phase 2 studies showed rapid antidepressant effects and favorable tolerability, but a mid‑2020s Phase 3 program failed to reproduce those signals in larger outpatient populations and the development program was discontinued and the license terminated in 2025 according to retrospective industry summaries [4] [5] [6].
1. Development focus: a post‑ketamine, oral rapid antidepressant
Relmada and academic authors framed dextromethadone as an oral, once‑daily, low‑potency, uncompetitive NMDAR channel blocker intended to give rapid antidepressant benefit without the dissociation and abuse issues of ketamine; the agent received FDA fast‑track attention as an adjunctive treatment for MDD and was positioned as a potential first‑in‑class “post‑ketamine” oral therapy if Phase 3 confirmed Phase 2 results [6] [7] [1].
2. Other indications under investigation: pain and RLS
Beyond MDD, trial registries and company materials document earlier development of d‑methadone for neuropathic pain (multiple ascending dose studies) and listing of clinical trial records for chronic pain and RLS, indicating Relmada and others explored analgesic and sensorimotor indications in addition to depression [2] [8] [3] [9]. Available sources do not mention regulatory approval for any non‑MDD indication [2].
3. Phase 1 and safety profiling: favorable tolerability, low abuse signal
Phase 1 studies in opioid‑naïve subjects characterized pharmacokinetics and safety; recreational‑user studies designed to probe abuse potential reportedly showed “no meaningful abuse potential,” and safety signals in trials were described as favorable with dose‑related nausea and somnolence at higher doses [1] [6] [7].
4. Phase 2 results: rapid onset, clinically meaningful short‑term effects
Randomized Phase 2 data—both adjunctive and monotherapy designs—demonstrated statistically significant antidepressant responses emerging within days and short‑term symptomatic benefit out to two weeks in controlled inpatient settings; investigators and trade press described these outcomes as “compelling” and clinically meaningful, prompting initiation of Phase 3 programs [10] [11] [1] [12].
5. Meta‑analysis and nuance: efficacy signal concentrated early, less consistent at day‑28
A 2025 meta‑analysis pooling three randomized placebo‑controlled trials reported rapid and sustained reduction of depression syndrome in the 14‑day window but found no significant difference at day 28, and it flagged the need for longer‑term data on efficacy and tolerability [5]. This frames dextromethadone’s effect as strongest early in treatment and more uncertain over a month.
6. Phase 3 failures and program termination: what the reporting says
Industry summaries and retrospective analyses say the RELIANCE Phase 3 program failed to meet primary endpoints in larger outpatient trials; a data monitoring committee declared futility for at least one trial, Relmada discontinued RELIANCE II and RELIGHT in late 2024, and the license for esmethadone was terminated in July 2025, effectively ending the clinical development program despite preservation of a favorable safety profile across studies [4] [13] [5].
7. Interpretations and competing perspectives
Supporters pointed to rapid onset, tolerability, and a low abuse signal from early studies as reasons it might have been a valuable oral alternative to ketamine/esketamine [6] [10]. Skeptics and the Phase 3 outcomes argue that robust inpatient or small‑trial signals did not generalize to heterogeneous outpatient populations, undercutting regulatory prospects and commercial viability [4] [5]. Sources differ on whether negative Phase 3 results reflect a failure of the drug or of trial design/setting [4] [5].
8. What’s missing or uncertain in current reporting
Available sources do not provide full, peer‑reviewed Phase 3 datasets, patient‑level results, or regulatory filings detailing exact primary endpoint statistics and effect sizes for the failed trials; those gaps limit definitive conclusions about subgroup effects, dose‑response, or whether alternate trial designs could have shown efficacy [4] [13]. Sources also do not report any regulatory approval for dextromethadone in any indication [4].
9. Bottom line for clinicians, patients and investors
Dextromethadone showed promise as a rapid oral antidepressant in early randomized trials with acceptable tolerability and low abuse signal, but Phase 3 failures and subsequent termination of licensing halted its path to approval; follow‑up analyses and unpublished data would be needed to determine whether the program failed because the drug lacks reliable outpatient efficacy or because of trial design and population issues [10] [5] [4].