Esmethadone

Esmethadone (REL-1017, d-methadone, dextromethadone) is the (S)-enantiomer of the synthetic opioid methadone and a low-potency, voltage-dependent, uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor that was advanced through Phase 3 clinical development by Relmada Therapeutics for the adjunctive and monotherapy treatment of major depressive disorder (MDD). Unlike the (R)-enantiomer levomethadone, which carries the analgesic opioid activity of the racemate, esmethadone exhibits approximately 10-fold lower affinity at mu-opioid receptors and lacks clinically meaningful opioid agonist effects, respiratory depression, reinforcing properties, or physical dependence liability at the doses studied for antidepressant activity. The compound blocks NMDA receptor ion channels with IC50 values in the low micromolar range (approximately 13 to 68 micromolar across GluN2A through GluN2D subunit combinations), with functional selectivity for tonically active GluN2D-containing receptors under physiological magnesium concentrations. This tonic blockade is proposed to disinhibit downstream alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated glutamatergic transmission, activate mammalian target of rapamycin complex 1 (mTORC1) signaling, and increase brain-derived neurotrophic factor (BDNF) expression, producing rapid-onset antidepressant effects comparable in mechanism (though not in potency or dissociative liability) to ketamine and esketamine. Preclinical studies in rodent models of depressive-like behavior (forced swimming test, novelty-suppressed feeding test, female urine sniffing test, chronic unpredictable stress) demonstrated that oral esmethadone produced antidepressant effects comparable to injectable ketamine in magnitude and duration, mediated by mTORC1 signaling in the medial prefrontal cortex and blocked by the selective mTORC1 inhibitor rapamycin. A Phase 1 study in healthy volunteers demonstrated that esmethadone increased circulating BDNF levels, providing translational biomarker support for the preclinical mechanism. Pharmacokinetics are characterized by approximately 70 to 80 percent oral bioavailability, a long elimination half-life exceeding 30 hours that supports dosing, and hepatic metabolism principally through CYP3A4/5 and CYP2B6 to the inactive metabolite EDDP, with approximately half the dose recovered in urine and 40 percent in feces. The compound is a CYP2D6 inhibitor in vitro, producing clinically relevant increases in exposure of CYP2D6 substrates such as dextromethorphan. The Phase 2a randomized, double-blind, placebo-controlled adjunctive trial in MDD patients with inadequate response to standard antidepressants (Fava et al., American Journal of Psychiatry, 2022) demonstrated rapid and sustained improvement on the Montgomery-Asberg Depression Rating Scale (MADRS) at 25 mg and 50 mg doses, with effect sizes of 0.7 to 1.0 and day-14 remission rates of 31 percent and 39 percent versus 5 percent on placebo. No dissociative or psychotomimetic effects were observed. The Phase 3 Reliance I trial (published 2024) did not meet its primary efficacy endpoint, attributed in part to an elevated placebo response during the COVID-19 pandemic enrollment period. A second Phase 3 trial (Reliance II) was initiated, but interim analysis in late 2024 indicated that the study was unlikely to meet its primary efficacy endpoint, and Relmada Therapeutics paused further development of REL-1017. A 12-month open-label extension study in 624 MDD patients confirmed long-term safety and tolerability, with the most common treatment-related adverse events being headache (4.6 percent), nausea (4.2 percent), and dizziness (2.6 percent), no signal for cardiovascular, metabolic, neurological, or sexual adverse events, no suicides or suicide attempts, and no withdrawal syndrome on discontinuation. A dedicated abuse-potential study in recreational drug users demonstrated no meaningful abuse potential. The compound is not approved by any regulatory authority. This monograph reviews the chemistry, stereochemistry, and synthesis of esmethadone; the NMDA receptor pharmacology including subunit selectivity and downstream signaling; the opioid receptor binding profile; comprehensive pharmacokinetics including drug-drug interactions; the preclinical and clinical evidence base across Phase 1, Phase 2, and Phase 3 programs; sourcing and quality considerations; reconstitution and handling; stack interactions; the adverse-event and safety profile; and a comparative assessment of five alternative NMDA receptor-targeting antidepressant candidates against esmethadone on five competency standards.