Esmethadone (REL-1017) publications
Phase 2 and Phase 3 studies
Fava M, Stahl S, Pani L et al. REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial. Am J Psychiatry. 2022 Feb;179(2):122–131.
Fava M, Stahl SM, Pani L et al. Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial. J Clin Psychiatry. 2024 Jun 17;85(3):24m15265.
Fava M, Pani L, De Martin S et al. Long-Term Safety and Efficacy of Esmethadone in Patients With Major Depressive Disorder: Findings From a 12-Month Open-Label Study. J Clin Psychiatry. 2025 Feb 17;86(1):24m15438.
Phase 1 studies
Bernstein G, Davis K, Mills C et al. Characterization of the Safety and Pharmacokinetic Profile of D-Methadone, a Novel N-Methyl-D-Aspartate Receptor Antagonist in Healthy, Opioid-Naive Subjects: Results of Two Phase 1 Studies. J Clin Psychopharmacol. 2019 May/Jun;39(3):226–237.
Ferri N, De Martin S, Stuart J et al. Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism. Drugs R D. 2024 Mar;24(1):51–68.
Ferri N, De Martin S, Stuart J et al. Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment. Drugs R D. 2024 Jun;24(2):341–352.
Shram MJ, Henningfield JE, ApseIoff G, et al. The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users. Transl Psychiatry. 2023 Jun 7;13(1):192.
Additional studies supporting efficacy
De Martin S, et al. REL-1017 (Esmethadone) Increases Circulating BDNF Levels in Healthy Subjects of a Phase 1 Clinical Study. Front Pharmacol. 2021;12:671859. PMID: 33995104.
Guidetti C, et al. Subanalysis of Subjective Cognitive Measures From a Phase 2, Double-Blind, Randomized Trial of REL-1017 in Patients With Major Depressive Disorder. Prim Care Companion CNS Disord. 2023;25(1):22m03267. PMID: 36821775.
Guidetti C, et al. A novel artificial intelligence-based methodology to predict non-specific response to treatment. Psychiatry Res. 2025 Apr 19;348:116506. PMID: 40262198.
Zhang L, et al. Efficacy and tolerability of esmethadone in patients with major depressive disorder: A meta-analysis of 3 randomized controlled trials. Psychiatry Res. 2025 Apr 11;348:116490.. PMID: 40233565.
Mechanism of action: in vitro and in vivo studies
Bettini E, Stahl SM, De Martin S, Mattarei A, Sgrignani J, Carignani C, Nola S, Locatelli P, Pappagallo M, Inturrisi CE, Bifari F, Cavalli A, Alimonti A, Pani L, Fava M, Traversa S, Folli F, Manfredi PL. Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors. Pharmaceuticals (Basel). 2022 Aug 13;15(8):997.
Bettini E, De Martin S, Mattarei A, Pappagallo M, Stahl SM, Bifari F, Inturrisi CE, Folli F, Traversa S, Manfredi PL. The N-Methyl-D-Aspartate Receptor Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by Glutamate, Quinolinic Acid, and Gentamicin. Pharmaceuticals (Basel). 2022 Jul 17;15(7):882.
Fogaça MV, Fukumoto K, Franklin T, Liu RJ, Duman CH, Vitolo OV, Duman RS. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019 Dec;44(13):2230-2238.
Hanania T, Manfredi P, Inturrisi C, Vitolo OV. The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats. Exp Clin Psychopharmacol. 2020 Apr;28(2):196-201.
Mechanism of action other publications
Fava M, Stahl SM, De Martin S, Mattarei A, Bettini E, Comai S, Alimonti A, Bifari F, Pani L, Folli F, Guidetti C, Furlan A, Sgrignani J, Locatelli P, Cavalli A, O'Gorman C, Traversa S, Inturrisi CE, Pappagallo M, Manfredi PL. Esmethadone-HCl (REL-1017): a promising rapid antidepressant. Eur Arch Psychiatry Clin Neurosci. 2023 Oct;273(7):1463-1476. doi: 10.1007/s00406-023-01571-4. Epub 2023 Mar 8. PMID: 36890259; PMCID: PMC10465385.
Stahl SM, De Martin S, Mattarei A, Bettini E, Pani L, Guidetti C, Folli F, de Somer M, Traversa S, Inturrisi CE, Pappagallo M, Gentilucci M, Alimonti A, Fava M, Manfredi PL. Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling. Int J Mol Sci. 2022 Oct 13;23(20):12196. doi: 10.3390/ijms232012196. PMID: 36293063; PMCID: PMC9602945.
Comai S, De Martin S, Mattarei A, Guidetti C, Pappagallo M, Folli F, Alimonti A, Manfredi PL. N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity. Pharmaceuticals (Basel). 2024 Nov 30;17(12):1618. doi: 10.3390/ph17121618. PMID: 39770460; PMCID: PMC11728621.
Pappagallo M, Kosten TR, Gorodetzky CW, Vocci FJ, Sapienza FL, De Martin S, Comai S, Mattarei A, Inturrisi CE, Manfredi PL. Letter to the Editor regarding 'Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone'. Mol Psychiatry. 2024 Dec;29(12):3935-3937. doi: 10.1038/s41380-024-02621-6. Epub 2024 May 28. PMID: 38806691; PMCID: PMC11609086.
Recent review articles discussing esmethadone
Cooper T, Seigler MD, Stahl S. Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions. J Psychopharmacol. 2023 Mar;37(3):242-247. doi: 10.1177/02698811231158891. Epub 2023 Mar 29. PMID: 36988262; PMCID: PMC10076337.
"However, oral NMDA antagonists such as dextromethorphan and esmethadone as well as the GABA A PAMs do not induce such mental status changes yet are rapid onset plasticity inducers with rapid acting antidepressant actions and can be considered “neuroplastogens.”
Freudenberg F, Reif-Leonhard C, Reif A. Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression. Eur Arch Psychiatry Clin Neurosci. 2024 Aug 29. doi: 10.1007/s00406-024-01875-z. Epub ahead of print. PMID: 39207462.
“Esmethadone is the next substance with potential for market introduction.”
Hoyer D. Psychedelics, entactogens and psychoplastogens for depression and related disorders. Br J Pharmacol. 2025 Jun 15. doi: 10.1111/bph.70088. Epub ahead of print. PMID: 40518133.
“However, the glutamate system is also targeted by some more recently developed and marketed rapid antidepressants such esketamine, dextromethorphan/bupropion or esmethadone, but the final common pathway of these intervention may well be neuroplasticity and neuroimmunomodulation.”
Scala M, Fanelli G, De Ronchi D, Serretti A, Fabbri C. Clinical specificity profile for novel rapid acting antidepressant drugs. Int Clin Psychopharmacol. 2023 Sep 1;38(5):297-328. doi: 10.1097/YIC.0000000000000488. Epub 2023 Jun 30. PMID: 37381161; PMCID: PMC10373854.
"For psilocybin,zuranolone, and esmethadone, data are available on the onset of therapeutic effect before the first week of treatment.”
In vivo safety studies
Bifari F, Pappagallo M, Bleavins M, Traversa S, Folli F, Manfredi PL. REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats. Front Pharmacol. 2022 Apr 25;13:863959.
Henningfield J, Gauvin D, Bifari F, Fant R, Shram M, Buchhalter A, Ashworth J, Lanier R, Pappagallo M, Inturrisi C, Folli F, Traversa S, Manfredi PL. REL-1017 (esmethadone; D-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats. Sci Rep. 2022 Jul 6;12(1):11389. doi: 10.1038/s41598-022-15055-3. PMID: 35794162; PMCID: PMC9259683.
Levinstein MR, De Oliveira PA, Casajuana-Martin N, Quiroz C, Budinich RC, Rais R, Rea W, Ventriglia EN, Llopart N, Casadó-Anguera V, Moreno E, Walther D, Glatfelter GC, Weinshenker D, Zarate CA Jr, Casadó V, Baumann MH, Pardo L, Ferré S, Michaelides M. Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone. Mol Psychiatry. 2024 Mar;29(3):624-632. doi: 10.1038/s41380-023-02353-z. Epub 2023 Dec 25. PMID: 38145984; PMCID: PMC11221360.
Publications under embargo
Guidetti C, Frigo AC, De Martin et al. Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: Results from Two Early-Terminated Phase 3 Randomized Controlled Trials. Abstract submitted to World Congress of Psychiatry 4-8 October 2025, Prague (CZ).
MANUSCRIPT IN PREPARATION
Guidetti C et al. Esmethadone (REL-1017) in Patients with Major Depressive Disorder (MMD) and Antidepressant Tachyphylaxis: A Post Hoc Analysis from a Phase 3 Randomized Controlled Trial. Journal of Clinical Psychiatry.
IN PRESS
Guidetti C et al. Depression Severity and Efficacy Outcomes: Post Hoc Analyses from a Phase 3 Trial of the Novel NMDAR Antagonist Antidepressant Candidate Esmethadone for the Adjunctive Treatment for MDD with Inadequate Response to Standard Antidepressants.
MANUSCRIPT SUBMITTED