Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of ( 2R,6R )-hydroxynorketamine
Open accessAbstract
Background: ( R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, ( 2R,6R)-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine’s adverse effects and abuse potential, in rodents. Methods: We evaluated the oral bioavailability of ( 2R,6R)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of ( 2R,6R)-hydroxynorketamine in mice. Oral administration of ( 2R,6R)-hydroxynorketamine was assessed for adverse behavioral effects and for antidepressant efficacy in the mouse forced-swim and learned helplessness tests. Results: ( 2R,6R)-hydroxynorketamine had absolute bioavailability between 46–52% in mice, 42% in rats, and 58% in dogs. Compared to intraperitoneal injection in mice, the relative oral bioavailability of ( 2R,6R)-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, ( 2R,6R)-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67–1.2 in mice and rats. Oral administration of ( 2R,6R)-hydroxynorketamine to mice did not alter locomotor activity or precipitate behaviors associated with discomfort, sickness, or stereotypy up to a dose of 450 mg/kg. Oral ( 2R,6R)-hydroxynorketamine reduced forced-swim test immobility time (15–150 mg/kg) and reversed learned helplessness (50–150 mg/kg) in mice. Conclusions: These results demonstrate that ( 2R,6R)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.
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Unlike ketamine, (2R,6R)-HNK does not appear to drive self-administration or hyperlocomotion.
“there is evidence that (2R,6R)-HNK does not elicit the same desire to self-administer or hyperlocomotion effects as ketamine”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Highland et al., 2019
The Results section, “Lack of adverse effects of (2R,6R)-HNK in mice” (page unavailable), reports no change in locomotor activity after oral HNK. The Discussion says this is consistent with prior findings of no ketamine-associated hyperlocomotion, and also reports a prior finding of lower abuse potential. Our copy does not report a self-administration test or specifically establish a lack of desire to self-administer HNK. (LLM, conf=0.82)
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- Authors
- Highland, J. N., Morris, P. J., Zanos, P., Lovett, J., Ghosh, S., Wang, A. Q., Zarate, C. A., Thomas, C. J., Moaddel, R., & Gould, T. D.
- Affiliations
- University of Maryland, Baltimore (US)
- National Center for Advancing Translational Sciences (US)
- National Institutes of Health (US)
- Corresponding author
- Gould, Todd D
- ORCID
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2018-11-29
- Volume
- 33
- Issue
- 1
- Pages
- 12-24
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- PMC
- PMC6541551
- OpenAlex
- W2903075408
- Cited by
- 62
- References
- 52
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 6 · 2023: 10 · 2022: 11 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 1
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Advancing Translational Sciences
- National Institute on Aging
- Harrington Discovery Institute
- National Institutes of Health (MH107615)
- National Institute of General Medical Sciences (GM008181)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- (2R,6R)-hydroxynorketamine, ketamine metabolites, antidepressant efficacy, oral bioavailability, treatment-resistant depression, forced swim test, learned helplessness, brain penetration, species comparison
- MeSH terms
- Administration, Oral, Animals, Antidepressive Agents, Behavior, Animal, Biological Availability, Depression, Disease Models, Animal, Dogs, Female, Ketamine, Locomotion, Male, Species Specificity, Tissue Distribution, Rats, Sprague-Dawley, Mice, Rats
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