The antidepressant potential of (2R,6R)-hydroxynorketamine: A detailed review of pre-clinical findings.
European journal of pharmacology – July 15, 2025
Source: PubMed
Summary
A promising breakthrough in depression treatment emerges from pre-clinical research: hydroxynorketamine, a metabolite of ketamine, shows powerful antidepressant effects without the risks of its parent compound. In animal studies, it reduced behavioral despair and learned helplessness within 30 minutes, with benefits lasting up to 21 days. Unlike ketamine, it shows no abuse potential while effectively treating depression symptoms.
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.