Is esmethadone FDA approved?

 No. Esmethadone is not approved by the FDA or any other regulatory agency.

Are there data for esmethadone showing rapid (Day 7) antidepressant effects?

Yes. Statistical significance was achieved at Day 7 in two well-designed multicenter RCTs: REL-1017-202 and REL-1017-302 (Fava 2022; Guidetti 2025 WCP presentation).

Did esmethadone always reach statistical significance in MDD trials?

No. Esmethadone did not reach statistical significance for the primary endpoint at Day 28 in studies REL-1017-301, REL-1017-302 and REL-1017-303.

Esmethadone reached statistical significance at Day 7 in study REL-1017-202 and in study REL-1017-302. Day 7 was the primary endpoint for REL-1017-202 and was one of the key secondary endpoints for REL-1017-302. Statistical significance was sustained up to the last study timepoint (Day 14) for study REL-1017-202. Statistical significance was lost after Day 7 for study REL-1017-302. However, the loss of statistical significance after Day 7 for study REL-1017-302 was not due to loss of efficacy in the REL-1017 arm, which continued to improve up to the end of treatment, but was due to improvement in the placebo arm.

Are there data indicating that esmethadone retains efficacy over time?  

Yes. All REL-1017 studies show an improving MADRS trajectory up to end of treatment: REL-1017-202, REL-1017-301, REL-1017-302, REL-1017-303, REL-1017-304 and REL-1017-310 (Fava 2022; Fava 2024; Guidetti 2025 WCP presentation; Fava 2025).

In all studies there was a progressive MADRS improvement up to the end of treatment (14-16 points). However, by the end of treatment the mean difference between treatment arms across studies was only ~1-2 points. As underscored by >10% absolute difference in response rate (REL-1017-301) and remission rate (REL-1017-302), these small mean differences may underpin larger and meaningful differences for treatment responders. Similar conclusions were drawn from studies of serotonergic antidepressants: substantial efficacy is seen in treatment responders rather than small improvements across all patients. Therefore, although the mean effect of antidepressants in randomized trials may be only a small improvement over placebo, the effect of the active drug increases the probability that any patient will benefit substantially (Thase 2011; Stone 2022).

 
Are there additional results supportive of sustained efficacy?

Yes. Study REL-1017-301 showed statistically significant response rate at Day 28 (p=0.044), with additional efficacy signals in protocol-compliant patients (p=0.051) and in the severe depression subgroup (p=0.006) (Fava 2024), and in the subgroup of patients with antidepressant tachyphylaxis (Guidetti 2025).  

Are there data indicating that esmethadone is safe and well-tolerated?

Yes. Data totaling over 1000 individual exposures from 5 mg to 200 mg for up to 12 months did not show unexpected side effects (Bernstein 2019; Shram 2023; Ferri 2024; Ferri 2024; Fava 2022; Fava 2024; Guidetti 2025 WCP presentation; Fava 2025). 

Does esmethadone have opioid-like or ketamine-like effects?

No. Esmethadone lacks opioid-like or ketamine-like psychoactive effects and lacks meaningful abuse potential (Henningfield 2022; Shram 2023) and lacks significant addiction liability (DEA 2025).

Is esmethadone a controlled substance?

Yes.  Esmethadone also known as (S)-methadone or dextro-methadone is one of the two enantiomers of racemic methadone, also known as (R,S)-methadone. Racemic methadone and its isomers are Schedule II substances. The opioid agonist effects are due to levomethadone; esmethadone lacks significant respiratory depressant action and addiction liability (DEA 2025). Esmethadone does not interconvert to levomethadone in vivo or in vitro. If approved, the esmethadone drug product schedule would be determined by DEA and, based on available data, is likely to become unscheduled or Schedule V (Shram 2023).
 

Are there potential explanations specific to esmethadone for not achieving statistically significant differences from placebo in some clinical trials?

Yes. However, these explanations are complex and are at the center of scientific research in the field of MDD clinical trials. The response in MDD clinical trial participants is affected by several factors that go under the umbrella definition of determinants of non-specific response to treatment.  One of these factors is a well-known biological phenomenon called placebo effect. The placebo effect is a biological phenomenon which can be determined by neurotransmitter modulation, such as endorphin release, and/or immune system modulation. The placebo effect is elicited by any treatment, including biologically inactive treatments (placebo) and active treatments (study drugs). In the real-world, the placebo effect is an important asset for caregivers, because due to the placebo effect patients will improve regardless of the effectiveness of the interventions. However, in the context of clinical trials, the placebo effect confounds the interpretation of results and the assessment of treatment efficacy. This is particularly true in MDD trials, where patients assigned to the placebo and active treatment arm have been shown to improve over time (Stone 2022). Functional unblinding, caused by patient-perceived and or caregiver-detected effects of the active treatment, is an important confounder of MDD trials. The placebo effect is stronger when patients think they are being treated with active drug and weaker/null or even negative (nocebo effect) when patients think they are receiving inactive drug. Functional unblinding from drugs with side effects may therefore determine enhanced outcomes in the treatment arm and reduced outcomes in the placebo arm. Study subjects, when perceiving side effects, assume they are on active treatment and thereby may artificially enhance the study drug efficacy. Importantly, drugs that do not have perceivable effects, such as esmethadone (Bernstein 2019; Shram 2023), in the context of clinical trials, where patients are repeatedly told they may be receiving an inactive treatment, may experience a null placebo effect or even a nocebo effect, out of the erroneous assumption of receiving inactive treatment. Paradoxically, drugs with perceivable side effects, such as dissociative drugs and psychedelic agents, and, arguably, serotonergic drugs and second-generation antipsychotics (SGA), are subject to artificial inflation of treatment effect in randomized clinical trials. It is likely that the artificially enhanced efficacy of drugs with side effects seen in clinical trials caused by functional unblinding will not translate to the real-world, where side effects are identified as such and may instead be associated with poor adherence to treatment. Therefore, in the context of MDD clinical trials, esmethadone-like molecules may be penalized, because of lack of perceivable side effects, compared to drugs with perceivable psychoactive or other side effects.

For all of the reasons outlined above, the mean differences between treatment arms seen across all esmethadone placebo-controlled trials may be potentially associated with substantial real-world rapid and sustained antidepressant effects in treatment responders.

The potential for benefit must be weighed against the risks associated with antidepressant drugs. The benign side effect profile of esmethadone, together with its potential rapid and sustained antidepressant action may position esmethadone, if approved, as a preferred pharmacological treatment for patients unresponsive to first line antidepressants.

Additionally, in the open-label long-term trial of esmethadone in over 600 patients with MDD, patients receiving esmethadone experienced a sustained decrease of more than 20 MADRS points with high rates of remission and response (Fava 2025). While the efficacy results of open label trial are in general difficult to interpret because of the unbalanced placebo effect, these results are supportive of meaningful and sustained efficacy with favorable tolerability.
 

Why is there an urgent unmet need for novel safe and effective rapid-acting adjunctive antidepressants?

MDD is one of the leading causes of disability with a lifetime prevalence around 20% in the United States (Vos 2015; Hasin 2018). About 1 in 10 US adults took prescription medication for depression in 2023 (Elgaddal 2025). Over 50% of patients do not respond to first line antidepressants (Fava 1996). The only available oral adjunctive antidepressants are all second-generation antipsychotics, which are associated with type 2 diabetes mellitus and weight gain (Smith 2025). There is a clear therapeutic gap for patients with MDD unresponsive to first-line therapy. For lack of alternatives, a serious disorder like MDD unresponsive to first line therapy is often treated with drugs that may cause or worsen serious diseases, such as diabetes and obesity.

How can we summarize the body of available data for esmethadone?

In summary, pending regulatory evaluation, esmethadone shows potential for providing rapid, sustained and meaningful antidepressant activity in treatment responders, without the heavy side effect burden associated with available adjunctive treatments.

The statistically significant Day 7 improvement seen in studies 202 and 302 demonstrates rapid antidepressant effects that are meaningful and clinically relevant. While the safety and efficacy of esmethadone may warrant further evaluation, given the urgent unmet medical need, additional data could be gathered post-marketing, if esmethadone is approved by regulatory agencies.
 

Are there other uncompetitive NMDAR antagonists with rapid antidepressant activity?

Yes. Actually, esmethadone, if approved, would become the third uncompetitive NMDAR antagonist rapid antidepressant.

The first uncompetitive NMDAR antagonist rapid antidepressant was ketamine (Berman 2000). The first approved uncompetitive NMDAR antagonist rapid antidepressant was esketamine (Spravato).

The second FDA approved uncompetitive NMDAR antagonist rapid antidepressant was the combination dextromethorphan-buproprion (Auvelity). 

If approved, potential differentiation of esmethadone from Spravato include the lack of dissociative effects, the lack of effects on blood pressure and once-daily oral outpatient administration, instead of inpatient, intermittent intranasal administration.

If approved, potential differentiation of esmethadone from Auvelity include the indication as adjunctive treatment, the advantages of a single agent compared to a fixed combination product and once-daily administration, instead of twice-daily.

Are drugs acting as uncompetitive NMDAR antagonists approved for other diseases and conditions?

Yes. Uncompetitive NMDAR antagonists have been approved for Alzheimer’s disease (memantine) and for pseudobulbar affect (dextromethorphan-quinidine).

Is esmethadone undergoing clinical trials for other indications?

Yes. Esmethadone is currently in Phase 2 for restless leg syndrome. Also, esmethadone has received orphan status designation by FDA for the treatment of amyotrophic lateral sclerosis (ALS). Presently, esmethadone is not in clinical trials for ALS.

Does Levomecor have a pipeline of novel molecules? 

Yes. Levomecor has a proprietary library of neuroplastogens™ that may represent the next generation of rapid-acting uncompetitive NMDAR antagonists.

What are neuroplastogens™?

Neuroplastogens™ are molecules that may restore physiological neural plasticity, the structural and functional balance between LTP and LTD.

Neuroplastogen molecules, in contrast with psychoplastogen molecules, do not cause psychoactive effects, such as dissociative effects or psychedelic effects (Cooper 2023).

The term “neuroplastogen” was coined by members the Levomecor team as outlined in their 2019 patent applications and was trademarked in the US (2022) and EU (2020).

In summary, neuroplastogen™ refers to a proprietary class of molecules designed to restore physiological neural plasticity without psychoactive effects.

Where does Levomecor perform its research and development?

Levomecor performs its research and development through MGGM Therapeutics, a US corporation. With a focus on the development of Neuroplastogens™ , MGGM has been collaborating for over 6 years with University of Padova (Italy), Universita` della Svizzera Italiana (CH), Evotec and Eurofins, among other institutions and research facilities.  Current research performed by MGGM and sponsored by Levomecor includes in silico, in vitro, in vivo and clinical studies advancing neuroplastogens™ as potential therapeutics.