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Exploring the role of mu opioid receptors in the therapeutic potential and abuse liability of (S)-ketamine

Neuropsychopharmacology volume 49, pages 315–316 (2024)Cite this article

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(R,S)-ketamine is a racemic mixture made up of (S)-ketamine and (R)-ketamine enantiomers in equal proportion. (R,S)-ketamine has shown promise as a rapid-acting antidepressant and (S)-ketamine is an FDA-approved medication for major depressive disorder with acute suicidal ideation and treatment-resistant depression. (R,S)-ketamine and its enantiomers are controlled substances. (R,S)-ketamine has known abuse liability and (S)-ketamine is believed to be the primary driver of its abuse liability [1].

Both (R,S)-ketamine and (S)-ketamine are traditionally regarded as N-methyl-D-aspartate receptor (NMDAR) antagonists and this interaction has been credited as the main mechanism behind their therapeutic actions as well as their abuse liability. However, both (R,S)-ketamine and (S)-ketamine also bind to and activate the μ opioid receptor (MOR) in vitro [1, 2]. Several decades ago, it was shown that (R,S)-ketamine displaced [3H]diprenorphine in MOR-expressing cells, furthermore (S)-ketamine did so with higher affinity than (R)-ketamine [2].

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Funding

Funding

This work was funded by NIDA Intramural Research Program (ZIA000069) to MM.

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Authors and Affiliations

  1. Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA

    Marjorie R. Levinstein & Michael Michaelides

  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Michael Michaelides

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  1. Marjorie R. Levinstein
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  2. Michael Michaelides
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MRL and MM wrote the paper.

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Correspondence to Marjorie R. Levinstein or Michael Michaelides.

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Competing interests

MM has received research funding from AstraZeneca, Redpin Therapeutics, and Attune Neurosciences. MRL has nothing to disclose.

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Levinstein, M.R., Michaelides, M. Exploring the role of mu opioid receptors in the therapeutic potential and abuse liability of (S)-ketamine. Neuropsychopharmacol. 49, 315–316 (2024). https://doi.org/10.1038/s41386-023-01652-x

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