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. Across all studies, patients receiving REL-1017 continued to improve up to the end of treatment.

Are there data indicating that esmethadone retains efficacy over time?

Antidepressants in randomized trials show only a small improvement over placebo, however the effect of the active drug increases the probability that any patient will benefit substantially (Thase 2011; Stone 2022).

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; Guidetti ASCP 2026 presentation).

Meaningful improvements in response and remission rates seen across esmethadone trials are likely to underpin substantial benefits for real-world patients with inadequate response to first line antidepressants.  

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).

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 need 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 other serious diseases, such as diabetes, obesity or neurological consitions.

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 (Auvelity is not FDA approved 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), for pseudobulbar affect (dextromethorphan-quinidine) and for agitation in patients with dementia (dextromethorphan-bupropion). Due to its overall PK and PD profile, esmethadone may be potentially developed for these and other neuropsychiatric conditions.

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 first trademarked in the EU (2020) and then in the US (2022).

In summary, neuroplastogen™ refers to a proprietary class of molecules designed to restore physiological neural plasticity without psychoactive effects (Cooper 2023).

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.