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Esmethadone Safe and Tolerable in Phase 2a Trial in Major Depressive Disorder

Key findings

  • Uptake of N-methyl-D-aspartate receptor (NMDAR) channel blockers, which have rapid antidepressant activity, has been limited by dissociative and psychotomimetic effects that require patient supervision during and after administration
  • Esmethadone (also called REL-1017 and dextromethasone) is a low-potency NMDAR channel blocker that had favorable tolerability, safety and pharmacokinetic profiles in a phase 1 trial
  • This seven-day double-blind, randomized phase 2a trial evaluated two dosages of esmethadone and placebo as an adjunctive treatment for 62 patients with major depressive disorder and inadequate response to current antidepressant treatment
  • The results confirmed favorable safety and tolerability of esmethadone while patients were hospitalized for the trial, including no withdrawal effects upon abrupt discontinuation and no dissociative or psychotic symptoms
  • Esmethadone induced robust, rapid antidepressant effects that were sustained through day 14, the last day of follow-up

N-methyl-D-aspartate receptor (NMDAR) channel blockers, such as intravenous ketamine and intranasal esketamine, have rapid antidepressant activity and can benefit individuals who have an inadequate response to conventional antidepressants. However, their adoption has been limited by dissociative and psychotomimetic effects that require patient supervision during and after administration.

Esmethadone (also called REL-1017 and dextromethasone) is the S-isomer of racemic methadone and a low-potency NMDAR channel blocker. Compared with levomethadone, the R-isomer of methadone, esmethadone has a 20-fold lower affinity for mu-opioid receptors, and in rodent studies, it had no opioid effects.

In a phase 1 trial reported in the Journal of Clinical Psychopharmacology, esmethadone had favorable tolerability, safety and pharmacokinetic profiles in patients with major depressive disorder (MDD). Maurizio Fava, MD, psychiatrist-in-chief at Massachusetts General Hospital, and colleagues recently completed a phase 2a trial that confirmed those findings and showed esmethadone provides rapid, sustained relief of depressive symptoms. They published their results in The American Journal of Psychiatry.


The trial participants were 62 adults with MDD, ages 18–65 years (mean age 49; 45% female), who had an inadequate response to one to three courses of antidepressant treatment in a current major depressive episode that had lasted eight weeks to 36 months. They were treated as inpatients at 10 U.S. centers between May 2018 and August 2019.

The procedure for the randomized, double-blind trial was:

  • 7 consecutive days of esmethadone 25 mg, esmethadone 50 mg or placebo (loading doses on day 1), given as adjunctive treatment
  • Clinical supervision for at least 48 hours after the last dose; discharge on day 9
  • Follow-up visit seven days after the last dose
  • Telephone follow-up 14 days after the last dose


Key safety and tolerability measures were:

  • Treatment-emergent adverse events (TEAEs)—Placebo group, 55% of patients; esmethadone 25 mg, 47%; esmethadone 50 mg, 71%
  • Most common TEAEs in ≥5% of all participants—Headache, constipation, nausea and somnolence; no AE of special interest in the esmethadone groups compared with placebo
  • TEAEs that resulted in treatment discontinuation or discontinuation from the trial—None
  • Clinically meaningful QTc prolongation—No episodes
  • Serious adverse events—None
  • Suicidal behavior—None
  • Clinical Opiate Withdrawal Scale—Scores were ≤1 at days 8, 9 and 14
  • Clinician-Administered Dissociative States Scale—No dose-related trends were observed
  • Psychotic symptoms on the Positive Symptom Rating Scale—None


The study was not powered for efficacy detection, but several endpoints were explored. On the Montgomery-Åsberg Depression Rating Scale (MADRS), the least square mean differences for esmethadone compared with placebo were:

  • Day 7, 25 mg: −8.7 (P=0.0122; effect size 0.8)
  • Day 7, 50 mg: −7.2 (P=0.0308; effect size 0.7)
  • Day 14, 25 mg: −9.4 (P=0.0103; effect size 0.9)
  • Day 14, 50 mg −10.4 (P=0.0039; effect size 1.0)

Effect sizes were similar for the Symptoms of Depression Questionnaire, Clinical Global Impressions severity scale and Clinical Global Impressions improvement scale.

Remission rates (MADRS ≤10) on day 14 were 5% for the placebo group, 31% for esmethadone 25 mg (P=0.035), and 39% for esmethadone 50 mg (P=0.01).

Next Steps

To better establish the efficacy and safety of esmethadone, four phase 3 trials are now recruiting in the U.S.

The drug will also be tested for its abuse potential before undergoing consideration by the FDA for approval to treat MDD.

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