(R)-Ketamine reduces alcohol intake and alcohol seeking induced by reconsolidation of alcohol-related memories in female Marchigian Sardinian alcohol-preferring rats.
Elisabetta Ciccocioppo, Sara Massetti, Marcus W. Meinhardt, Fabio Fumagalli, Patrizia Romualdi, Marisa Roberto, Rainer Spanagel, Roberto Ciccocioppo, Esi Domi
Psychopharmacology November 15, 2025 DOI: 10.1007/s00213-025-06964-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male and female genetically selected Marchigian Sardinian alcohol-preferring (msP) rats |
| Intervention | (R)-ketamine |
| Dose | 10, 20 and 40 mg/kg |
| Topics | Ketamine Esketamine |
| Keywords | Psychedelics Dissociative psychedelic Reducing alcohol intake Alcohol consumption reduction Combating aud New aud treatments Impaired memory retrieval Alcohol-related memory retrieval Sex-specific effects Sex-specific benefit Gender differences |
| Key points | (R)-ketamine reduced alcohol consumption and attenuated retrieval of alcohol-related memories in female but not in male msP rats. |
Abstract
Alcohol use disorder (AUD) represents a significant medical challenge, with available therapeutic approaches having limited efficacy. Emerging data suggest that psychedelic compounds could represent an alternative treatment for AUD. Among this class of molecules, ketamine, a dissociative psychedelic, shows promising properties. It reduces alcohol drinking in rodents and in humans it is used to treat depression, a condition often comorbid with AUD. Unfortunately, the marked dissociative and anesthetic effects of this molecule severely limit its therapeutic application. Ketamine is a racemic mixture of (S, R)-enantiomers, and the R-enantiomer possesses lower dissociative and anesthetic properties compared to the racemic mixture. METHODS: Here, using male and female genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, we evaluated the potential efficacy of (R)-ketamine, in alcohol-related behaviours including home cage voluntary drinking and alcohol self-administration. We also evaluated whether R ketamine may affect the reconsolidation process of alcohol-related memories. In the two-bottle free choice (free choice between 10% alcohol and water) 24-h drinking paradigm R-ketamine given orally (10, 20 and 40 mg/kg) significantly reduced alcohol consumption in female but not in male rats. No effect was observed on alcohol self-administration. We subsequently tested (R)-ketamine on alcohol memory consolidation/ retrieval task and found a significant attenuation in the retrieval of alcohol-related memories in female but not in male msP rats. Taken together, our findings indicate that (R)-ketamine attenuates alcohol-related behaviors in a sex-dependent manner with females showing a higher sensitivity to its effects. Given its more favorable safety profile compared to the racemic mixture, these results support the clinical investigation of (R)-ketamine as a therapeutic intervention in patients with AUD. Particular attention should be paid to sex-specific effects observed with (R)-ketamine, as they may have important clinical implications.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 21
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder JAMA Psychiatry August 24, 2022
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine Journal of Neuroscience November 30, 2020
and 16 more in the library