Sex and individual differences in ketamine's effects on alcohol drinking in rats.
Sarah D Jennings, Ian Yates, Samantha K Saland, Mohamed Kabbaj
Alcohol Clin Exp Res March 1, 2026 DOI: 10.1111/acer.70275 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study (four experiments) Peer reviewed |
|---|---|
| Population | Male and female Long Evans rats |
| Intervention | Ketamine |
| Dose | 0.0, 1.47, or 2.35 mg/kg intravenous; 0.0, 10, or 20 mg/kg intraperitoneal |
| Topics | Addiction Ketamine Esketamine |
| Keywords | Animals Rats, long-evans Infusions, intravenous Alcohol drinking Individuality Sex factors Sex characteristics Dose-response relationship, drug Female Sex differences Relapse Individual differences Repeated ketamine |
| Key findings | Across four experiments, ketamine generally did not reduce alcohol intake in male or female rats when given during acute withdrawal or after a single abstinence period. In one experiment with repeated dosing, high-drinking females reduced intake after initial and repeated doses, and low-drinking females and high-drinking males responded only to the first dose, but effects did not persist after treatment ended. The authors conclude ketamine's effect appears sex-dependent, acute rather than sustained, and limited to high-drinking females. |
Abstract
Background: Effective pharmacotherapies for Alcohol Use Disorder (AUD) are lacking, and factors such as sex, drinking patterns, and timing of treatment during the addiction cycle may influence treatment efficacy. Clinical studies suggest that ketamine may be effective in AUD; however, preclinical findings have been inconclusive, likely due to varying rodent strains, intake protocols, and ketamine doses/routes. This study investigated ketamine's effects on alcohol drinking in male and female Long Evans rats using multiple validated paradigms.
Methods: In Experiments 1 and 2, rats underwent 4 weeks of intermittent access two-bottle choice (IA2BC) drinking. In Week 5, they received ketamine via intravenous infusion (0.0, 1.47, or 2.35 mg/kg) or intraperitoneal injection (0.0, 10, or 20 mg/kg) during acute withdrawal. Alcohol intake was monitored 24 h posttreatment and for 3 weeks to assess sustained effects. In Experiment 3, rats completed a modified drinking-in-the-dark (DID) protocol for 2 weeks, followed by 2 weeks of forced abstinence. A single ketamine injection preceded re-exposure to alcohol. In Experiment 4, rats were categorized as high or low drinkers after five DID/abstinence cycles. During Cycle 6, six ketamine injections were administered. A final cycle assessed sustained effects.
Results: In Experiments 1-3, ketamine had no significant acute or lasting effects on alcohol intake in either sex when given during acute withdrawal or following a single period of forced abstinence. In Experiment 4, moderate drinkers (low drinking females, high drinking males) showed reduced intake after the first postabstinence ketamine dose, but not to subsequent dosing. High drinking females responded to both initial and repeated treatments; however, effects did not persist after treatment cessation.
Conclusions: Ketamine's ability to reduce alcohol intake appears sex-dependent, acute rather than sustained, and limited to high-drinking females. These findings highlight the need to assess the safety of repeated or chronic ketamine use in AUD treatment.
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 | |
| The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement. Male and female oxycodone-dependent mice | 2023 | 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 |