A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 As Adjunctive Treatment for Major Depressive Disorder (MDD)

Study Overview This clinical trial is a Phase 3 research study designed to test the safety and effectiveness of an investigational drug called REL-1017 (esmethadone HCl). The goal is to determine if REL-1017 can help people with major depressive disorder (MDD) who are already taking other antidepressant medications but have not experienced enough improvement.
Why This Study Is Important MDD is a serious condition that affects mood, cognition, motivation, energy, and daily life. Some people do not respond fully to standard antidepressants. REL-1017 is being tested as an additional treatment to see if it can improve symptoms more effectively.
Who Can Participate The study is enrolling adults diagnosed with major depressive disorder who do not have enough relief from their current antidepressant medications. Specific criteria must be met to join the study.
What Happens in the Study Participants will be randomly assigned to receive either REL-1017 or a placebo (an inactive substance) along with their current antidepressant. This process helps researchers understand the effects of the drug. Neither the participants nor the researchers will know who receives REL-1017 or the placebo during the study.
Study Details Duration: The study involves several weeks of treatment and follow-up visits. Assessments: Participants will complete health evaluations, including physical exams and questionnaires, to monitor progress and side effects.
Costs: Study-related treatments and assessments are provided at no cost to participants.
Potential Benefits and Risks Benefits: Participants may experience improvements in depressive symptoms. Risks: As with any investigational medication, there may be side effects. All participants will be closely monitored by the study team.

Start Date27 Dec 2024

Sponsor / Collaborator-

NCT06011577

/ TerminatedPhase 3

A Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as an Adjunctive Treatment for Major Depressive Disorder (RELIGHT)

A Phase 3, randomized, double-blind, placebo-controlled, multicenter trial of REL-1017 in patients with major depressive disorder (MDD).

Start Date17 Aug 2023

Sponsor / Collaborator

Relmada Therapeutics, Inc.

NCT04145674

/ RecruitingPhase 2IIT

A Proof of Concept, Multicentre, Phase 2, Double-Blind, Randomized, Placebo-Controlled Study on the Efficacy, Safety and Tolerability of d-Methadone in Moderate to Very Severe Restless Legs Syndrome With Periodic Limb Movements: the Glu-REST Study

Proof of concept, double-blind, randomized, placebo-controlled trial with d-methadone proposed for the first time for use in the treatment of patients diagnosed with primary, moderate to very severe Restless Legs Syndrome (RLS). Its glutamatergic mechanism of action might be effective on RLS arousal pattern and sleep disturbance which highly impair the quality of life of RLS's patients.
Patients will take the study drug/placebo once a day for 30 consecutive days.

Start Date22 Oct 2022

Sponsor / Collaborator

Ente Ospedaliero Cantonale

100 Clinical Results associated with (S)-Methadone

100 Translational Medicine associated with (S)-Methadone

100 Patents (Medical) associated with (S)-Methadone

410

Literatures (Medical) associated with (S)-Methadone

01 Oct 2025·PHARMACOLOGICAL RESEARCH

All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants

Review

Author: Freudenberg, Florian ; Reif, Andreas ; McKernan, Ruth M ; Reif-Leonhard, Christine ; Dawson, Gerard R

Treatment-resistant depression (TRD) represents a major clinical challenge. Affecting about 30 % of major depressive disorder (MDD) patients, effective treatments for TRD are urgently needed. While depression research and antidepressant (AD) development have long centred on monoaminergic targets, research over the past 35 years has increasingly explored glutamatergic mechanisms. Here we present an extended discussion on developments in glutamatergic drug discovery, focusing on mechanistic convergence between NMDA and AMPA receptor signalling. 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. By integrating recent clinical evidence with molecular and physiological findings, we highlight a convergent mechanism across these compounds. This involves increased AMPA receptor activation, triggering BDNF release and mTOR signalling, promoting synaptic strengthening through enhanced AMPA receptor trafficking and dendritic spine formation. 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.

01 Sep 2025·PHARMACOLOGICAL RESEARCH

Distinctive biochemical properties of the μ-opioid receptor-corticotropin- releasing factor CRF1 receptor heterotetramer

Article

Author: Casadó, Vicent ; Casajuana-Martín, Nil ; Cai, Ning-Sheng ; Sanchez, William N ; Ferré, Sergi ; Ciruela-Jardí, Marc ; Pardo, Leonardo ; Yauch, Anne ; Plant, Leigh D ; Quiroz, Cesar ; Chang, Ya Gin ; Moreno, Estefanía

Heteromerization of Gs with Gi protein-coupled receptors has been suggested to be necessary to sustain the canonical Gi-Gs antagonistic interaction at adenylyl cyclase (AC). These heteromers have a tetrameric quaternary structure, composed by two homodimers each one coupled to its corresponding G protein. We describe the heterotetramer formed by the Gi-coupled μ-opioid receptor (MOR) and the Gs-coupled corticotropin releasing factor CRF₁ receptor (CRF₁R), which also sustains a canonical interaction at AC and reciprocal allosteric interactions between MOR and CRF₁R ligands. In addition, we found that CRF₁R can also couple to Gq proteins in the MOR-CRF₁R heteromer, providing the frame for also canonical Gi-Gq antagonistic interactions that include other effectors, such as phospholipase C and its Ca^2 + -dependent signaling, and which control glutamate release in the central amygdala (CeA). The specific pharmacodynamic properties of the MOR-CRF₁R heteromer, including its sensitivity to S-methadone, as well as its localization in the CeA suggest it might represent a significant pharmacological target for the analgesic, antistressor and antidepressant effects of opioids and the hyperalgesia of opioid withdrawal.

15 Jun 2025·British Journal of Pharmacology

Psychedelics, entactogens and psychoplastogens for depression and related disorders.

Review

Author: Hoyer, Daniel

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. Late-stage clinical trials support psychedelics and/or MDMA-assisted psychotherapy as rapidly acting treatments for major depressive disorder (MDD), treatment-resistant depression (TRD), PTSD or generalised anxiety disorders (GAD). Psilocybin, MDMA and LSD were granted FDA breakthrough status for TRD/MDD, PTSD and GAD, respectively, although FDA recently rejected the new drug application of MDMA in PTSD. Most of these drugs target the 5-HT and monoamine systems. Classical psychedelics act as 5-HT_2A receptor agonists, although LSD, DMT and psilocybin target other 5-HT and/or dopamine receptors. Psychedelic-dependent 5-HT_2A receptor agonism also has profound anti-(neuro)inflammatory effects. Advanced imaging studies suggest that brain 5-HT levels are reduced in depression. Functional magnetic resonance studies show that neural networks (cortico thalamic, salience, default mode) are profoundly impaired in depression. Such network defects are corrected upon psychedelic/entactogen treatment, offering a unique opportunity to serve as biomarkers for depression, anxiety and PTSD precision medicine trials. 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.

News (Medical) associated with (S)-Methadone

14 Jul 2025

·www.biospace.com

After Three Strikes, Relmada Abandons Depression Drug Esmethadone

iStock, Wel_nofri The development saga for the depression molecule has been rocky for years, unable to ease symptoms in multiple late-stage trials. Relmada Therapeutics has halted development of its investigational NMDA receptor blocker esmethadone, ending what has been a rough journey for the asset. The company made the announcement in an SEC filing on Friday. The company said that it will terminate a January 2018 licensing agreement , under which it obtained global rights to esmethadone. The molecule was originally deveoped by Charles Inturrisi, a professor at Weill Cornell Medical. Inturrisi then himself licensed it to Medeor, co-founded Paolo Manfredi. Medeor merged with Relmada in 2013. As per the terms of the original contract, Relmada paid a nonrefundable sum of $180,000 upfront to Inturrisi and Manfredi, plus $45,000 every three months ever since. Those quarterly payments were intended to continue until certain conditions were met, including the first market sale of esmethadone or the expiration of its patent. None of such events occurred over the course of the partnership. Esmethadone’s development history has been fraught for some time now. In October 2022, the drug asset failed the Phase III RELIANCE III trial in major depressive disorder (MDD), unable to significantly ease the severity of depressive symptoms as a monotherapy versus placebo. Esmethadone delivered another late-stage disappointment in December of the same year, when the drug again showed no significant benefit in the RELIANCE I study, this time as an adjunctive MDD treatment. For both RELIANCE I and RELIANCE III trials, Relmada blamed an “unplausible placebo response” for the lack of significant efficacy signals for esmethadone. Then, in December 2024, the Phase III RELIANCE II also ended in failure , with an interim analysis finding a high likelihood of futility. A couple of weeks later, Relmada discontinued RELIANCE II and the Phase III RELIGHT study, also in MDD. With esmethadone now gone from its pipeline, Relmada has “made the exploration of strategic product acquisitions our primary focus,” according to a note to investors on its website . The company is focusing its efforts on NDV-01, a Phase II proprietary sustained-release formulation of gemcitabine and docetaxel being trialed for non-muscle invasive bladder cancer. Relmada licensed NDV-01 from Trigone Pharma in March. Phase II data presented in April showed an 85% three-month overall response rate . Relmada is the latest biotech to stumble in the difficult depression space. Last month, for example, Alto Neuroscience’s ALTO-203 was unable to significantly boost mood in patients with MDD in a Phase II study, forcing the California company to dig into exploratory endpoints and look at EEG biomarkers for signals of efficacy. In February, Supernus Pharmaceuticals likewise had a mid-stage stumble when its asset SPN-820 failed to improve symptom burden in patients with treatment-resistant depression. Even Big Pharma seems to have been having trouble making headway into depression, with Johnson & Johnson in March discontinuing the late-stage VENTURA program after its kappa opioid receptor blocker aticaprant failed to demonstrate sufficient efficacy signals to support continued development.

Phase 2Phase 3License out/inClinical ResultClinical Trial Failure

11 Jul 2025

·www.fiercebiotech.com

Relmada terminates license agreement for troubled phase 3 depression asset

Relmada originally licensed esmethadone in 2018 for $180,000 upfront and subsequent payments of $45,000 every three months.\n After prematurely ending two phase 3 depression trials last year, Relmada Therapeutics has formally given up on the asset they were testing. The Florida-based biotech terminated its license agreement for esmethadone on July 7, with all of their obligations under the deal set to expire on Oct. 5.Relmada has tested esmethadone, which it called REL-1017, in several phase 3 trials for various major depressive disorder (MDD) indications. The prospect flopped in just about every one of them.In October 2022, REL-1017 failed to top placebo as an MDD monotherapy in the phase 3 RELIANCE III trial. Another stumble followed just months later, this time as an adjunctive MDD treatment in late-stage RELIANCE I, which the company attributed to “a limited number of high-enrolling sites with unplausible placebo response.”Esmethadone did better in a 2023 open-label trial, successfully improving depression symptoms, but the study had no placebo arm.The third phase 3 strike for REL-1017 came in December 2024, when Relmada revealed that its RELIANCE II trial, which was testing esmethadone as an adjunctive treatment for MDD, was unlikely to hit its primary endpoint. As a result, Relmada scrapped the trial and another related study, RELIGHT, which used a similar design, and announced plans to pursue strategic alternatives like a merger or sale of the company.Esmethadone is a component of methadone, the pain and substance use medication. Relmada originally licensed the candidate in January 2018 from Charles Inturrisi, Ph.D., and Paolo Manfredi, M.D., for an upfront fee of $180,000. Inturrisi, a pharmacologist at Cornell University, originally developed esmethadone and licensed it to Medeor, which Manfredi co-founded. Relmada merged with Medeor in 2013.Manfredi’s Medeor is not to be confused with kidney transplant company Medeor Therapeutics. As part of the licensing deal, Relmada was paying Inturrisi and Manfredi $45,000 every three months, a stipulation that was set to continue until esmethadone was sold as a commercial product or the patent on it expired.Relmada is now focused on making strategic asset acquisitions, according to its website, as well as advancing remaining assets NDV-01 and sepranolone. NDV-01 is currently being tested in an open-label phase 2 trial in non-muscle invasive bladder cancer, while sepranolone is a phase 2 Tourette syndrome asset that Relmada purchased in February from Asarina Pharma.

Phase 3Phase 2License out/inAcquisitionClinical Trial Termination

07 Feb 2025

·www.pharmaceutical-technology.com

Relmada acquires Tourette’s therapy rights from Asarina

The therapy has shown potential in improving the symptoms of Tourette’s syndrome in a Phase IIa study. Credit: Jack_the_sparow/Shutterstock. Relmada Therapeutics has acquired complete worldwide ownership rights to Sepranolone from Sweden-based Asarina Pharma. Sepranolone is a neurosteroid being developed as a potential treatment for Tourette’s syndrome (TS) and other compulsive disorders. TS is a complex neurological condition characterised by involuntary tics. The asset purchase agreement between the two companies is valued at €3m ($3.12m). The therapy has demonstrated a favourable safety profile in clinical neuro/hormonal trials with more than 335 subjects. Relmada Therapeutics CEO Sergio Traversa stated: “We are very pleased to announce this agreement with Asarina. Sepranolone aligns with our company’s mission to find solutions for difficult-to-treat central nervous system (CNS) disorders. There is a serious unmet need for improved TS therapies – not only [in] reducing tics but also improving quality of life without serious side effects. “We have been impressed by the encouraging Phase IIa efficacy signal with clinically meaningful tic reductions and quality-of-life improvements, combined with a robust safety data package showing no CNS off-target effects, that we believe reflect the compound’s selective binding properties.” As a first-in-class GABAA-modulating steroid antagonist (GAMSA), Sepranolone works by normalising the activity of the GABAA receptor by targeting alpha-2 and alpha-4, the receptor subtypes. This mechanism avoids direct interference with GABAA signalling, offering a selective treatment approach for TS and associated disorders. The therapy is under the protection of several issued patents extended until 2038. The therapy has shown potential in improving TS symptoms in an open-label Phase IIa study compared to standard of care alone. The changes were measured by the Yale Global Tic Severity Scale (YGTSS) scoring system, compared to the baseline. In August 2022, the US Food and Drug Administration granted fast-track status to Relmada’s REL-1017 as a single agent for treating major depressive disorder.

Phase 2Clinical ResultFast TrackLicense out/in

100 Deals associated with (S)-Methadone

External Link

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-	(S)-Methadone	-	DB15198

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 3	United States	Relmada Therapeutics, Inc.	08 Jan 2021
Depressive Disorder, Treatment-Resistant	Phase 2	United States	Relmada Therapeutics, Inc.	11 May 2018
Neuralgia	Phase 1	-	Relmada Therapeutics, Inc.	04 Dec 2014
Rett Syndrome	Preclinical	United States	Relmada Therapeutics, Inc.	20 Feb 2019
Amyotrophic Lateral Sclerosis	Preclinical	United States	Relmada Therapeutics, Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04855760 (Pubmed \| J Clin Psychiatry)	Phase 3	Depressive Disorder, Major	624	Esmethadone	psippdhagh(rycyxtuqgy) = 2.6% gatrmnjtza (waszxaatpc ) View more	Positive	17 Feb 2025
NCT04855747 (Reliance II, GlobeNewswire) Manual	Phase 3	Depressive Disorder, Major	-	REL-1017	eygjcgmnnc(jmszrbpyhz) = futile and is unlikely to meet the primary efficacy endpoint. rgzhiyduoh (bbwwngixzg ) Not Met View more	Negative	04 Dec 2024
NCT04855760 (RELIANCE-OLS, CTgov)	Phase 3	Depressive Disorder, Major	627	REL-1017	trizdgzvux = absbbihjmj eqhqazckqm (uffraliije, fodihuyxkw - rgfhdmwudp) View more	-	09 Aug 2024
NCT04688164 (Psychiatry) Manual	Phase 3	Depressive Disorder, Major	227	REL-1017	laoyfhzkws(lyemgdjtqm) = wdqcdfuysa clbfvnrewq (lvrahqrcsk, 11.3) View more	Negative	17 Jun 2024
				Placebo	laoyfhzkws(lyemgdjtqm) = yrauixkcxv clbfvnrewq (lvrahqrcsk, 10.4) View more
NCT03051256 (REL-1017, Pubmed)	Phase 2	Depressive Disorder, Major	62	Esmethadone 25 mg	rsumjztkfp(jdljczhagf) = nrrczmalfz xejotcaezv (globyqksqt ) View more	Positive	13 May 2024
				Esmethadone 50 mg	rsumjztkfp(jdljczhagf) = cleirwvvbw xejotcaezv (globyqksqt ) View more
NCT05081167 (RELIANCE III, CTgov)	Phase 3	Depressive Disorder, Major	232	Placebo	robphspzpz(croykhjtng) = umdjycqybf yrowsmvfjh (mkzsttuewp, 10.8) View more	-	26 Mar 2024
NCT04855760 (RELIANCE-OLS, Biospace) Manual	Phase 3	Depressive Disorder, Major	627	REL-1017	kifgmrvqrz(fjcfizinpv) = COVID-19 (9.7%), headache (9.7%), upper respiratory tract infection (8.6%), and nausea (5.0%). tbzuyiwiwx (lkqdxjzbue ) View more	Positive	20 Sep 2023
NCT05081167 (RELIANCE III, Corporate Publications) Manual	Phase 3	Depressive Disorder, Major	232	REL-1017	abcjzbdveo(olmgdhkewj) = wngqwhzauo bwzxxxzqsj (jcghfgoanr ) Not Met	Negative	13 Oct 2022
				Placebo	abcjzbdveo(olmgdhkewj) = ekjgjcilmj bwzxxxzqsj (jcghfgoanr ) Not Met
NCT03051256 (REL-1017, CTgov)	Phase 2	Depressive Disorder, Major \| Depressive Disorder, Treatment-Resistant	62	REL-1017 (REL-1017 25 mg)	kpkvpfbfbn = ligrzuzvvw bdmdfgbijw (adilcstexs, qfpbokidjs - voeqhgkdyk) View more	-	17 Mar 2021
				REL-1017 (REL-1017 50 mg)	kpkvpfbfbn = yoajczcqsu bdmdfgbijw (adilcstexs, hrcjxswkwp - hwjrbesfyi) View more
NCT00588640 (CTgov)	Phase 1/2	Colonic Cancer \| Esophageal Carcinoma \| Central Nervous System Neoplasms ... View more	10	d-methadone (Phase I, Cohort l)	mulqzrtyhz = lypqfgwmyq kuuveoopvu (xydoienqeq, ddwejecbie - znsbejhfke)	-	10 Aug 2016
				D-methadone (Patients Receiving D-methadone 40 mg)	rpudkkphvn(qwbfqxpger) = huprcdorgg bstjqkuuds (kwzpaehsnn, oaawukbayq - bodelmrjtn) View more

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