A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on alcohol relapse.
Marcus W. Meinhardt, Ivan Skorodumov, Jérôme Jeanblanc, Federica Benvenuti, Fahd François Hilal, Esi Domi, Camille André, Sandra Bodeau, Virginie Jeanblanc, Kevin Domanegg, Roberto Ciccocioppo, Mickaël Naassïla, Rainer Spanagel
Neuropsychopharmacology May 1, 2025 DOI: 10.1038/s41386-025-02071-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical randomized controlled trial Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine R-ketamine |
| Dose | 20 mg/kg, 40 mg/kg |
| Topics | Esketamine Ketamine |
| Keywords | Addiction treatment Ketamine therapy Alcohol dependence Gender medicine Substance abuse recovery |
| Citations | 8 |
| Key findings | R-ketamine reduces alcohol relapse in rats with sex-dependent effects linked to higher plasma levels in females. |
Abstract
The drug development process in psychiatry faces significant challenges due to low reproducibility rates in animal testing, which often leads to translation failures. To address this issue, we introduce a new approach in psychiatric drug development: a preclinical randomized controlled trial (preRCT). To demonstrate its potential utility, we conducted a multi-center preRCT using the alcohol deprivation effect (ADE) model to assess the impact of ketamine and R-ketamine on alcohol relapse across three European research centers. Ketamine (20 mg/kg) significantly reduced relapse, while R-ketamine showed efficacy only in females. A higher dose of R-ketamine (40 mg/kg) was also effective in males. These sex-dependent effects were linked to plasma R-ketamine levels, which were two-fold higher in female compared to male rats. Notably, R-ketamine demonstrated a lasting reduction in alcohol consumption without adverse effects. In conclusion, our preRCT demonstrates R-ketamine's effectiveness in reducing alcohol relapse and supports translation to a clinical RCT that accounts for sex-dependent effects.
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 12
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial. American Journal of Psychiatry December 2, 2019
- Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder American Journal of Psychiatry January 11, 2022
and 7 more in the library