The antidepressant potential of (2R,6R)-hydroxynorketamine: A detailed review of pre-clinical findings.
Isis Koutrouli, Kristýna Mazochová, Rachel R. Horsley
European Journal of Pharmacology July 15, 2025 DOI: 10.1016/j.ejphar.2025.177604 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Selective review Peer reviewed |
|---|---|
| Population | Rodents |
| Interventions | (2R 6R)-hydroxynorketamine |
| Dose | 5 and 125 mg/kg |
| Duration | Up to 21 days |
| Topics | Depression Ketamine |
| Keywords | Behavioral despair Hydroxynorketamine Learned helplessness Pre-clinical Depression treatment Antidepressant research Ketamine derivatives Mental health breakthroughs Preclinical studies |
| Citations | 4 |
| Key findings | (2R,6R)-HNK reduces behavioral despair, anhedonia, anxiety, and social avoidance in rodent models, with rapid and lasting effects, though some studies show no benefit at lower doses in depressed animals. |
Abstract
Depression affects hundreds of millions globally, and in 2019, esketamine, an S-enantiomer of ketamine, was approved for treatment-resistant depression (TRD). While effective, esketamine carries risks, including abuse potential and adverse effects even at low doses. As a result, ketamine's metabolite, (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), has garnered attention for its potential antidepressant effects without these drawbacks. This selective review evaluates preclinical behavioral evidence for (2R,6R)-HNK's antidepressant properties, focusing on rodent studies that used established depression models. Results showed that (2R,6R)-HNK reduced behavioral despair, anhedonia, anxiety, and social avoidance in both stressed and non-stressed rodents. Antidepressant effects were observed at doses between 5 and 125 mg/kg, with rapid onset (30 min) and long-lasting effects (up to 21 days). However, some studies failed to demonstrate significant antidepressant effects at doses below 40 mg/kg, often in models with pre-induced depression. No significant adverse effects were reported, but data on side effects were limited. In conclusion, (2R,6R)-HNK shows promise as a next-generation antidepressant. However, further research is needed to fully understand its long-term safety and mechanisms, and to determine its advantages over existing treatments like esketamine, particularly for TRD patients.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 3
- Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine National Science Review September 5, 2025
- Generation of enantiospecific monoclonal antibodies against (2R,6R)-hydroxynorketamine. Bioorganic & Medicinal Chemistry January 17, 2026
- Dose-dependent adverse events of esketamine in treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Pharmacology 2026
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and 24 more in the library