Scientific literature
Publications supporting safety and efficacy of esmethadone as adjunctive treatment of MDD in patients unresponsive to first line antidepressants
Phase 1 studies
Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, Inturrisi C, Manfredi PL, Vitolo OV. 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. DOI: 10.1097/JCP.0000000000001035
Shram MJ, Henningfield JE, Apseloff G, Gorodetzky CW, De Martin S, Vocci FL, Sapienza FL, Kosten TR, Huston J, Buchhalter A, Ashworth J, Lanier R, Folli F, Mattarei A, Guidetti C, Comai S, O'Gorman C, Traversa S, Inturrisi CE, Manfredi PL, Pappagallo M. 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. DOI: 10.1038/s41398-023-02473-8
Ferri N, De Martin S, Stuart J, Traversa S, Folli F, Pappagallo M, O'Gorman C, Guidetti C, Mattarei A, Inturrisi CE, Manfredi PL. Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism. Drugs R D. 2024 Mar;24(1):51–68. DOI: 10.1007/s40268-023-00450-6
Ferri N, De Martin S, Stuart J, Traversa S, Mattarei A, Comai S, Folli F, Pappagallo M, Guidetti C, Inturrisi CE, Manfredi PL. Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment. Drugs R D. 2024 Jun;24(2):341–352. DOI: 10.1007/s40268-024-00477-3
Phase 2 and Phase 3 studies
Fava M, Stahl S, Pani L, De Martin S, Pappagallo M, Guidetti C, Alimonti A, Bettini E, Mangano RM, Wessel T, de Somer M, Caron J, Vitolo OV, DiGuglielmo GR, Gilbert A, Mehta H, Kearney M, Mattarei A, Gentilucci M, Folli F, Traversa S, Inturrisi CE, Manfredi PL. 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. DOI: 10.1176/appi.ajp.2021.21020197
Fava M, Stahl SM, Pani L, De Martin S, Cutler AJ, Maletic V, Gorodetzky CW, Vocci FJ, Sapienza FL, Kosten TR, Kröger C, Champasa P, O'Gorman C, Guidetti C, Alimonti A, Comai S, Mattarei A, Folli F, Bushnell D, Traversa S, Inturrisi CE, Manfredi PL, Pappagallo M. 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. DOI: 10.4088/JCP.24m15265
Fava M, Pani L, De Martin S, Cutler AJ, Gorodetzky CW, Vocci FJ, Sapienza FL, Kosten TR, Kröger C, Champasa P, Guidetti C, Comai S, Mattarei A, Folli F, Bushnell D, Traversa S, Inturrisi CE, Manfredi PL, Pappagallo M. 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. DOI: 10.4088/JCP.24m15438
Guidetti C, Frigo AC, De Martin S, Mattarei A, Comai S, Pani L, Gorodetzky CW, Vocci FJ, Kosten TR, Folli F, Inturrisi CE, Gentilucci M, Rizzo G, Pappagallo M, Manfredi PL, Stahl SM, Fava M. 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/Poster/Presentation:World Congress of Psychiatry October 6, 2025, Prague (CZ)
Additional studies supporting efficacy
De Martin S, Gabbia D, Folli F, Bifari F, Fiorina P, Ferri N, Stahl S, Inturrisi CE, Pappagallo M, Traversa S, Manfredi PL. REL-1017 (Esmethadone) Increases Circulating BDNF Levels in Healthy Subjects of a Phase 1 Clinical Study. Front Pharmacol. 2021;12:671859. PMID: 33995104. DOI: 10.3389/fphar.2021.671859
Zhang L, Bao D, Wang C. 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. DOI: 10.1016/j.psychres.2025.116490
Guidetti C, Serra G, Pani L, Pappagallo M, Maglio G, Martin S, Mattarei A, Folli F, Manfredi PL, Fava M. 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. DOI: 10.4088/PCC.22m03267
Guidetti C, Fava M, Manfredi PL, Pappagallo M, Gomeni R. A novel artificial intelligence-based methodology to predict non-specific response to treatment. Psychiatry Res. 2025 Apr 19;348:116506. PMID: 40262198. DOI: 10.1016/j.psychres.2025.116506
Guidetti C, Papakostas GI, Pani L, De Martin S, Serra G, Apicella M, Kröger C, Champasa P, Comai S; Mattarei A, Folli, Pappagallo M, Manfredi PL,Fava M. 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. October 6, 2025
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.DOI: 10.3390/ph15080997
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. DOI: 10.1037/pha0000310
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. DOI: 10.3390/ph15070882
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. DOI: 10.1038/s41386-019-0501-x
Mechanism of action: other publications
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. Epub 2024 May 28. PMID: 38806691; PMCID: PMC11609086. DOI: 10.1038/s41380-024-02621-6
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. PMID: 36293063; PMCID: PMC9602945. DOI: 10.3390/ijms232012196
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. PMID: 39770460; PMCID: PMC11728621. DOI: 10.3390/ph17121618
De Martin S, Comai S, Mattarei A, Kosten TR, Vocci FJ, Gorodetzky CW, Pappagallo M, Manfredi PL. Reasons for Maintaining the Classification of Esmethadone as an Investigational Uncompetitive NMDAR Antagonist Rapid Antidepressant: Reply to Ferré and Michaelides. J Clin Psychiatry. 2025 Sep 8;86(4):25lr15973a. DOI: 10.4088/JCP.25lr15973a. PMID: 40965842
Review articles
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. Epub 2023 Mar 29. PMID: 36988262; PMCID: PMC10076337. DOI: 10.1177/02698811231158891
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. Epub 2023 Jun 30. PMID: 37381161; PMCID: PMC10373854. DOI: 10.1097/YIC.0000000000000488
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.. Epub ahead of print. PMID: 39207462. DOI:10.1007/s00406-024-01875-z
Hoyer D. Psychedelics, entactogens and psychoplastogens for depression and related disorders. Br J Pharmacol. 2025 Jun 15. Epub ahead of print. PMID: 40518133. DOI: 10.1111/bph.70088
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. Epub 2023 Mar 8. ph15080997 PMID: 36890259; PMCID: PMC10465385. DOI: 10.1007/s00406-023-01571-4
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. DOI: 10.3389/fphar.2022.863959
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 PMID: 35794162; PMCID: PMC9259683. DOI: 10.1038/s41598-022-15055-3
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. Epub 2023 Dec 25. PMID: 38145984; PMCID: PMC11221360 DOI: 10.1038/s41380-023-02353-z
Neuroplastogen™ pipeline
Banzato M, Furlan A, Locatelli P, Sgrignani J, Ongaro A, Dolmella A, De Martin S, Comai S, Cavalli A, Inturrisi C, Bettini E, Manfredi PL, Mattarei A. New Synthesis and Pharmacological Evaluation of Enantiomerically Pure (R)- and (S)-Methadone Metabolites as N-Methyl-d-aspartate Receptor Antagonists. J Med Chem. 2025 Mar 13;68(5):5455-5470. DOI: 10.1021/acs.jmedchem.4c02605. Epub 2025 Feb 25. PMID: 39999356; PMCID: PMC11912475.