Esmethadone for MDD
Esmethadone (REL-1017) is a novel oral uncompetitive NMDAR antagonist under development as a rapid acting adjunctive treatment of major depressive disorder
Esmethadone (REL-1017) is an investigational compound. Safety and efficacy have not been established, and no regulatory authority has approved this product for any indication. Statements herein reflect interpretations of published or presented data.
Overview
MDD is a serious condition and one of the leading causes of disability with a lifetime prevalence around 20% in the United States (Vos 2015; Hasin 2018). The National Center for Health Statistics found that from August 2021 to August 202З, approximately 1З% of people aged 12 years and older reported depression in the past 2 weeks, compared with 8% from 201З to 2014, a 60% increase in a decade (Brody 2025). About 1 in 10 US adults took prescription medication for depression in 202З (Elgaddal 2025).
Over 50% of patients with MDD have inadequate response to first line antidepressants (Fava 1996). In addition, the STAR*D study reported that after each failed pharmacotherapy trial, remission rates decline; after two or three failed treatment trials, subsequent remission rates averaged less than 15% (Rush 2006; Fava 1996). MDD is currently the leading cause of disability in the United States for ages 15 to 44 years (ADAA 2022). Depression combined with chronic physical disease substantially increases patient risk of death compared to physical disease alone.
Currently, six oral drugs are approved by the Food and Drug Administration (FDA) as adjunctive treatment for MDD in patients who fail to adequately respond to first line antidepressants: lumateperone, cariprazine, aripiprazole, brexpiprazole, olanzapine, and quetiapine. These six drugs are all second-generation antipsychotics (atypical antipsychotics) with class-specific metabolic, cardiovascular, and neurological side effects and delayed efficacy (Tu 2019; Misdrahi 2019; Godin 202З; Smith 2025).
There is an urgent unmet need for novel, rapid acting, safe and well tolerated adjunctive treatments for MDD. This urgency is particularly relevant to the current US landscape, characterized by rising MDD prevalence within an unprecedented metabolic and obesity crisis.
Esmethadone and depression
Esmethadone is a patient friendly antidepressant candidate. It is administered once-daily as a 25 mg oral immediate release tablet. Over 1000 patients have been exposed to doses of esmethadone from 5 mg to 200 mg (Bernstein 2019; Shram 202З; Ferri 2024a; Ferri 2024b; Fava 2022; Fava 2024; Fava 2025; NCT NCT05081167; Guidetti 2025). Esmethadone was very well tolerated and showed a benign side effect profile. The therapeutic dose of 25 mg has been tested for up to 12 months (Fava 2025). There has been no signal of clinically meaningful abuse potential. There are no opioid-like or ketamine-like effects. There has been no signal of metabolic or neurological side effects associated with available oral adjunctive antidepressants. The long-term safety of esmethadone is underscored by decades of esmethadone exposure in millions of patients treated with racemic methadone over the past 70 years with no signal for meaningful organ toxicity.
Extensive evaluation with dedicated preclinical (Henningfield 2022) and clinical (Shram 2023) state of the art abuse potential studies confirm lack of meaningful abuse potential and addiction liability, as anticipated by the Drug Enforcement Agency (DEA 2025).
Esmethadone is associated with modest QT interval prolongation on the electrocardiogram (EKG). While no arrhythmias have been observed with esmethadone, QT prolongation is associated with arrhythmias.
Rapid acting antidepressant efficacy, seen in two randomized controlled trials (Fava 2022; Guidetti 2025), and excellent tolerability, confirmed across all trials, may position esmethadone as the preferred option for patients unresponsive to first line antidepressants.
If approved, esmethadone may become the only oral adjunctive antidepressant option for patients at risk for metabolic, neurological and sexual side effects from atypical antipsychotics.
Esmethadone is the prototypical Neuroplastogen™ drug because it restores impaired neural plasticity (Fogaca 2019) without psychoactive effects (Cooper 2023). The term neuroplastogen™ in the context of neural plasticity modulators was coined and trademarked in 2020 by Levomecor team members.
Mechanism of action
Additional studies are needed to definitively elucidate the mechanisms underlying the rapid antidepressant effects of esmethadone and other uncompetitive NMDAR antagonists. The "homeostatic synaptic plasticity hypothesis" may explain the mechanism of action of esmethadone as a rapid acting antidepressant (Stahl 2022; Comai 2024; De Martin 2025).
Esmethadone preferentially blocks tonically hyperactive GluN2D receptor subtypes (Bettini 2022), increasing BDNF (De Martin 2021).
Synaptic spines increase in size within 24 hours of administration (Fogaça 2019), restoring physiological neuroplasticity (Stahl 2022).
Development progress
All non-clinical studies recommended for NDA readiness were completed (Bifari 2022; Henningfield 2022).
All Phase 1 studies recommended for NDA readiness were completed (Bernstein 2019; Shram 202З; Ferri 2024a; Ferri 2024b).
All clinical studies in patients with MDD indicate favorable safety and tolerability without metabolic, neurological or sexual side effects (Fava 2022; Fava 2024; Fava 2025; NCT NCT05081167; Guidetti 2025).
Rapid antidepressant efficacy at Day 7 has been shown in randomized trials (Fava 2022; Guidetti 2025). Meta-analyses confirm safety and efficacy. Subgroup analysis suggest efficacy in patients with difficult to treat MDD (Fava 2024; Guidetti 2025).
Chemistry, Manufacturing, and Controls: all work completed, registration batch ready for production.
Esmethadone is listed by experts among the most promising novel antidepressants in development (Cooper 2023; Fava 202З; Scala 202З; Correll 2023; Freudenberg 2024; Hoyer 2025).