The Novel Uncompetitive Nmda Receptor Antagonist Esmethadone (Rel-1017) Has No Meaningful Abuse Potential in Recreational Drug Users

Authors

Megan J Shram
Jack E Henningfield
Glen Apseloff
Charles W Gorodetzky
Sara De Martin
Frank L Vocci
Frank L Sapienza
Thomas R Kosten
Jeff Huston
August Buchhalter
Judy Ashworth
Ryan Lanier
Franco Folli
Andrea Mattarei
Clotilde Guidetti
Stefano Comai
Cedric O'Gorman
Sergio Traversa
Charles E Inturrisi
Paolo L Manfredi
Marco Pappagallo

Publication Date

6-7-2023

Journal

Translational Psychiatry

DOI

10.1038/s41398-023-02473-8

PMID

37286536

PMCID

PMC10247777

PubMedCentral® Posted Date

6-7-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p <  0.001) lower Drug Liking VAS Emax compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p <  0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p <  0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.

Keywords

Humans, Oxycodone, Receptors, N-Methyl-D-Aspartate, Dextromethorphan, Ketamine, Analgesics, Opioid, Cross-Over Studies, Double-Blind Method, Illicit Drugs, Diseases, Depression

Published Open-Access

yes

Recommended Citation

Shram, Megan J; Henningfield, Jack E; Apseloff, Glen; et al., "The Novel Uncompetitive Nmda Receptor Antagonist Esmethadone (Rel-1017) Has No Meaningful Abuse Potential in Recreational Drug Users" (2023). Faculty and Staff Publications. 6042.
https://digitalcommons.library.tmc.edu/baylor_docs/6042