The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement.
Caryssa R Drinkuth, Michael J Lehane, Gregory C Sartor
Drug and Alcohol Dependence December 1, 2023 DOI: 10.1016/j.drugalcdep.2023.110987 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male and female oxycodone-dependent mice |
| Interventions | (2R 6R)-hydroxynorketamine (HNK) |
| Dose | 10 or 30 mg/kg, s.c. |
| Topics | Addiction Ketamine |
| Keywords | Hnk Hydroxynorketamine Oxycodone Precipitated withdrawal |
| Citations | 9 |
| Key points | Pretreatment with (2R,6R)-HNK reduced withdrawal behaviors and blocked reinstatement of oxycodone conditioned place preference in mice. |
Abstract
Despite the thousands of lives lost during the ongoing opioid crisis, a scarcity of new and effective clinical treatments for opioid use disorder (OUD) remains. To address this unmet need, some researchers have turned to dissociative and psychedelic drugs to treat multiple psychiatric conditions. In particular, low doses of ketamine have been shown to attenuate opioid withdrawal and drug use in clinical and preclinical studies. However, ketamine has misuse liability and dissociative side effects that may limit its widespread application as a treatment for OUD. More recently, (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite that lacks misuse potential, has gained attention for its effectiveness in depression and stress models. To uncover its role in OUD, we tested the time-dependent effects of (2R,6R)-HNK on oxycodone withdrawal and reinstatement of oxycodone conditioned place preference (CPP). In male and female oxycodone-dependent mice, we found that 24h pretreatment with (2R,6R)-HNK (10 or 30mg/kg, s.c.) reduced the frequency of withdrawal-like behaviors and global withdrawal scores during naloxone-precipitated withdrawal, whereas 1h pretreatment with (2R,6R)-HNK only reduced paw tremors and the sum of global withdrawal scores but not GWS Z-scores. In other experiments, both 1h and 24h pretreatment with (2R,6R)-HNK (30mg/kg, s.c.) blocked drug-induced reinstatement of oxycodone CPP. Finally, we found (2R,6R)-HNK (30mg/kg, sc) had no effect on locomotor activity and thigmotaxis. Together, these results indicate that acute (2R,6R)-HNK has efficacy in some preclinical models of OUD without producing locomotor or anxiety-like side effects.
Comparable studies
Other preclinical and animal studies on ketamine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder. Morphine-dependent rats and mice | 2020 | Preclinical study | |
| Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile. Adolescent rats of both sexes, including naïve and early-life stressed (maternal... | 2025 | Preclinical study | |
| Exploring ketamine's reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats. Long Evans rats | 2024 | Preclinical experimental study | |
| Brain acid sphingomyelinase controls addiction-related behaviours in a sex-specific way. Male and female mice with forebrain ASM overexpression | 2025 | Experimental study | |
| Cannabidiol or ketamine for preventing the impact of adolescent early drug initiation on voluntary ethanol consumption in adulthood. Male and female Sprague-Dawley rats | 2024 | Preclinical study |
Citations in the library
Cited by 3
- Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations. Clinical Pharmacology & Therapeutics February 1, 2025
- Ketamine and Hydroxynorketamine as Novel Pharmacotherapies for the Treatment of Opioid Use Disorders. Biological Psychiatry March 15, 2025
- Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice. Journal of Pharmacological Sciences March 1, 2024
Cites 22
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Ketamine – More mechanisms of action than just NMDA blockade Trends in Anaesthesia and Critical Care March 22, 2014
and 17 more in the library