dextromethadone (REL-1017) / Relmada Therapeutics - LARVOL DELTA

New advances in small molecule drugs targeting NMDA receptors. (PubMed, Acta Pharmacol Sin) - "Among various therapeutic indications, depression has emerged as an especially active area of investigation, with mechanistically diverse compounds ranging from broad-spectrum channel blockers (ketamine, dextromethorphan, esmethadone) to glycine site modulators (rapastinel, 4-chlorokynurenine, D-cycloserine) and allosteric modulators (apimostinel, zelquistinel), progressing through clinical pipelines. Beyond depression, NMDA receptor-targeted drug discovery is also advancing in other challenging CNS disorders, including neurodegenerative diseases (salzanemdor, NYX-458), pain (NYX-2925), epilepsy (radiprodil), and stroke (nelonemdaz, NP10679). Collectively, these developments reflect the maturation of NMDA receptor pharmacology and reaffirm the broad therapeutic potential of NMDA receptor modulation, while highlighting promising directions for future drug discovery."

Journal • Review • Cardiovascular • CNS Disorders • Depression • Epilepsy • Mental Retardation • Pain • Psychiatry

Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Antidepressant Tachyphylaxis: An Exploratory Post Hoc Analysis From a Phase 3 Randomized Controlled Trial. (PubMed, J Clin Psychiatry) - " These post hoc analyses, based on data collected independently pre-randomization, suggest that esmethadone may be an effective adjunctive treatment for patients with AT. These results need to be confirmed in larger prospective clinical trials."

Clinical • Journal • P3 data • Retrospective data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

EFFICACY AND SAFETY OF ESMETHADONE (REL-1017) IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER AND INADEQUATE RESPONSE TO STANDARD ANTIDEPRESSANTS: FINDINGS FROM TWO EARLY-TERMINATED PHASE 3 TRIALS (WPA-WCP 2025) - P3 | "Esmethadone did not produce meaningful opioid effects or dissociative effects and was not associated with meaningful metabolic, neurological, cardiovascular, or sexual side effects, consistent with prior trials. Conclusions Despite the limitations of early study termination, these findings support the development of esmethadone as a once-daily, oral, rapid-acting adjunctive antidepressant with a potentially favorable benefit-risk profile compared to existing treatments."

Clinical • P3 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Reasons for Maintaining the Classification of Esmethadone as an Investigational Uncompetitive NMDAR Antagonist Rapid Antidepressant: Reply to Ferré and Michaelides. (PubMed, J Clin Psychiatry) - No abstract available

Journal

New and emerging pharmacologic treatments for MDD. (PubMed, Front Psychiatry) - "Furthermore, the combination of dextromethorphan and bupropion has shown promise. Brexanolone, administered via infusion, and zuranolone, available as an oral formulation, both have demonstrated efficacy in clinical settings. Novel treatments targeting opioid pathways, such as esmethadone, and selective kappa receptor antagonists offer new hope for addressing the symptoms of MDD through mechanisms not traditionally associated with antidepressant action."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry

All Roads Lead to Glutamate: NMDA and AMPA Receptors as Targets for Rapid-Acting Antidepressants. (PubMed, Pharmacol Res) - "Beyond established rapid-acting antidepressants (RAADs), such as (es)ketamine and dextromethorphan/bupropion (AXS-05), we highlight novel therapeutic directions involving esmethadone (REL-1017), nitrous oxide, and positive allosteric modulators (PAMs) of NMDA receptors (e.g. rapastinel, zelquistinel, and apimostinel). Moreover, we discuss forward-looking strategies using AMPA receptor PAMs (e.g. osavampator and tulrampator) and targeting of AMPA receptor-interacting proteins...Together, targeting glutamatergic signalling represents a transformative path for TRD treatment with high efficacy by more directly modulating pathologically affected signalling modules. These developments place glutamatergic agents at the forefront of next-generation AD strategies."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Psychedelics, entactogens and psychoplastogens for depression and related disorders. (PubMed, Br J Pharmacol) - "Currently, the most actively investigated rapidly acting antidepressants, anxiolytics and/or anti PTSD agents, include psychedelics e.g. psilocybin, LSD, N,N-dimethyltryptamine, ayahuasca; non-hallucinogenic entactogens, e.g. MDMA; psychoplastogens which rapidly promote neuroplasticity, e.g. ibogaine, ketamine and esketamine; and other atypicals e.g. dextromorphan/bupropion, esmethadone...Psychedelics and entactogens target common end pathways, namely neuroplasticity/synaptogenesis, either directly via monoamine or glutamate receptors and/or indirectly, via BDNF and mTORC1 pathways. Together, these findings strongly support a biological basis for MDD, GAD, PTSD and related conditions, which can be considered as mixed biochemical, neurological and neuroimmune disorders, and are profoundly modified by psychedelics, entactogens and the newly developed psychoplastogens."

Journal • Review • CNS Disorders • Depression • General Anxiety Disorder • Major Depressive Disorder • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry • BDNF

New Vistas in the Treatment of Mood and Anxiety Disorders: Psychedelics, Neuromodulation and More (APA 2025) - "The combination of dextromethorphan and bupropion was recently FDA approved for major depression, as was intranasal esketamine. Promising novel agents under scrutiny in clinical trials for depression include lumateperone, already approved for the treatment of schizophrenia and bipolar disorder, esmethadone, a non-mµ opiate receptor antagonist and more than one kappa opiate antagonist for the treatment of depression with prominent anhedonia, positive allosteric modulators of the GABA-A receptor for GAD and MDD (as a follow up to the approval of brexanolone and zuranolone for the treatment of post-partum depression), a novel agent that acts as a thyroid hormone receptor agonist for MDD, fasedienol for the treatment of social anxiety disorder, a novel intracellular modulator of MTORC1 in the treatment of depression, triple (DA, NE, 5HT) reuptake inhibitors for depression and an orexin antagonist for the treatment of depression. Instructional Level Intermediate;..."

Bipolar Disorder • CNS Disorders • Depression • General Anxiety Disorder • Major Depressive Disorder • Postpartum Depression • Post-traumatic Stress Disorder • Psychiatry • Schizophrenia • Social Anxiety Disorder • Vascular Neurology

Correction. Long-Term Safety and Efficacy of Esmethadone in Patients With Major Depressive Disorder: Findings From a 12-Month Open-Label Study. (PubMed, J Clin Psychiatry) - No abstract available

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Efficacy and tolerability of esmethadone in patients with major depressive disorder: A meta-analysis of 3 randomized controlled trials. (PubMed, Psychiatry Res) - "Esmethadone is a rapid-onset antidepressant, showed sustained efficacy of the reduction in depression syndrome during the 14-day treatment period, with mild to moderate side effects. However, no significant difference was observed at day 28. The long-term efficacy and safety of esmethadone are still needed to evaluate in future trials."

Journal • Retrospective data • Review • CNS Disorders • Constipation • Depression • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry • Respiratory Diseases

Long-Term Safety and Efficacy of Esmethadone in Patients With Major Depressive Disorder: Findings From a 12-Month Open-Label Study. (PubMed, J Clin Psychiatry) - P3 | "The antidepressant efficacy of esmethadone was sustained over 12 months. Trial Registration: ClinicalTrials.gov identifier: NCT04855760."

Clinical • Journal • Cardiovascular • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

New Synthesis and Pharmacological Evaluation of Enantiomerically Pure (R)- and (S)-Methadone Metabolites as N-Methyl-d-aspartate Receptor Antagonists. (PubMed, J Med Chem) - "(S)-Methadone (esmethadone), has recently shown promising efficacy for the treatment of major depressive disorder. Strikingly, N-demethylated (6R)-methadol metabolites retain the higher NMDAR uncompetitive antagonism of (R)-methadone, while presenting lower opioid receptor affinity compared to (S)-methadone. These compounds could represent novel candidates for drug development in CNS disorders."

Journal • CNS Disorders • Depression • Developmental Disorders • Major Depressive Disorder • Mood Disorders • Psychiatry

REL-1017-305: A Study to Evaluate the Efficacy and Safety of REL-1017 As Adjunctive Treatment of Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: MGGM LLC | N=146 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RELIGHT: Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as Adjunctive Treatment for MDD (clinicaltrials.gov) - P3 | N=27 | Terminated | Sponsor: Relmada Therapeutics, Inc. | N=340 ➔ 27 | Recruiting ➔ Terminated; Program Discontinued

Enrollment change • Trial termination • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RELIANCE-II: A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=236 | Terminated | Sponsor: Relmada Therapeutics, Inc. | N=340 ➔ 236 | Recruiting ➔ Terminated; Program Discontinued

Enrollment change • Trial termination • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

REL-1017-305: A Study to Evaluate the Efficacy and Safety of REL-1017 As Adjunctive Treatment of Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=146 | Recruiting | Sponsor: MGGM LLC

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Glu-REST: A Proof of Concept, Phase 2, Double-blind, Randomized Trial With d-Methadone Product Versus Placebo (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Mauro Manconi | Trial completion date: Jul 2025 ➔ Dec 2025 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression. (PubMed, Eur Arch Psychiatry Clin Neurosci) - "Specifically, here we focus on substances beyond (es)ketamine, for which meaningful data from clinical trials are available, including arketamine, esmethadone, nitrous oxide and other glutamate receptor modulators. Molecules only successful in preclinical settings and case reports/series are only marginally discussed. With this review, we aim underscore the critical role of glutamatergic modulation in advancing antidepressant therapy, thereby possibly enhancing clinical outcomes but also to reducing the burden of depression through faster therapeutic effects."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment. (PubMed, Drugs R D) - "Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis."

Journal • PK/PD data • Chronic Kidney Disease • CNS Disorders • Depression • Hepatology • Major Depressive Disorder • Mood Disorders • Nephrology • Psychiatry • Renal Disease

RELIGHT: Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as Adjunctive Treatment for MDD (clinicaltrials.gov) - P3 | N=417 | Recruiting | Sponsor: Relmada Therapeutics, Inc. | N=300 ➔ 417

Enrollment change • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RELIANCE-II: A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=300 | Recruiting | Sponsor: Relmada Therapeutics, Inc. | Trial completion date: Jun 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

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. (PubMed, J Clin Psychiatry) - P3 | "Esmethadone was well tolerated, consistent with prior studies. Trial Registration: ClinicalTrials.gov identifier: NCT04688164."

Clinical • Journal • P3 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017). (PubMed, J Clin Psychiatry) - P2a | " Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset. Trial Registration: ClinicalTrials.gov identifier: NCT03051256."

Clinical • Journal • P2 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice. (PubMed, Front Neurol) - "REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles. In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Depression • Major Depressive Disorder • Psychiatry • CLSPN, • DLG4

Long-Term Safety and Efficacy of Esmethadone in Patients with Major Depressive Disorder: Findings from a 12-Month Open-Label Study (ASCP 2024) - "Long-term treatment with esmethadone was well tolerated with no signal for meaningful neurological, cardiovascular, metabolic or sexual side effects. No new safety concerns were identified. Patients showed a mean CFB in MADRS scores of approximately -20 points, with consistent improvements in CGI-S, CGI-I, and HAM-A scores."

Clinical • Late-breaking abstract • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry