Esmethadone
nmda modulator · rapid antidepressant signal in phase ii trial class / nmda modulatorspec sheet7 rows
Esmethadone is the dextro-isomer of methadone, the mirror-image molecule of the opioid used in addiction maintenance therapy, except it barely touches opioid receptors at all. Instead it works as a gentle, uncompetitive NMDA receptor channel blocker, positioning it as an oral, non-dissociative alternative to ketamine that Relmada Therapeutics built its entire public identity around. A Phase IIa adjunctive trial (published 2022 in the American Journal of Psychiatry) showed a real antidepressant signal in major depressive disorder, and the company pushed hard into a Phase III program under the REL-1017 name. But the pivotal Phase III trials in the 2020s failed to separate esmethadone from placebo on the primary endpoint, a high-profile stumble for a compound that had been widely framed as the next ketamine-alternative blockbuster.
- oral dosing
- minimal opioid activity despite methadone lineage
- positive Phase IIa signal
- reported low abuse liability in trials
- mild sedation reported
- dizziness
- Esmethadone and methadone are mirror-image molecules (enantiomers) of each other, but only one of them binds meaningfully to opioid receptors.
- Relmada's stock and public narrative were heavily built around esmethadone as a ketamine-alternative blockbuster before the Phase III miss.
Mechanism
Dextro-isomer of methadone with negligible mu-opioid activity; acts as a low-to-moderate affinity uncompetitive channel blocker, in the same pharmacological family as ketamine and memantine.
Safetyrisks and cautions, not medical advice
Splitting methadone and keeping only the dextro isomer was meant to leave the opioid behind, and the abuse-liability work says it did. In randomised crossover studies in recreational drug users, esmethadone produced no meaningful opioid-agonist or ketamine-like effects and no meaningful abuse potential, and stopping abruptly produced neither morphine nor ketamine withdrawal. In the depression trials the common events were headache, dizziness, constipation, nausea and diarrhoea, mild to moderate, with fewer dropouts than placebo; nausea set the ceiling at 150 mg. The real limit is duration: exposure ran two to four weeks.
History
Developed by Relmada Therapeutics; positive Phase IIa adjunctive MDD trial published 2022; pivotal Phase III trials (the RELIANCE program) reported in the early-to-mid 2020s failed to beat placebo on the primary endpoint.
Subjective profileweighing the evidence above
A clever isomer-engineering play that separated opioid activity from NMDA activity, but still hit the same efficacy wall that has caught nearly every other single-mechanism NMDA antidepressant.
Resources
This entry is here for reference.
Research
- 1.REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial
- 2.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
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is esmethadone the same as methadone?
It's the dextro-isomer of the methadone molecule. The opioid-active isomer (levomethadone) is what's used for opioid maintenance therapy; esmethadone was specifically chosen because it has little to no opioid activity.
Did esmethadone ever get FDA approved?
No. Its pivotal Phase III depression trials did not meet the primary efficacy endpoint versus placebo, despite an earlier positive Phase IIa result.
Limitations of the evidence
- Phase III failed to separate from placebo
Adverse effects
- mild sedation reported
- dizziness