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 : official publication of the American College of Neuropsychopharmacology May 1, 2025 DOI: 10.1038/s41386-025-02071-w via PubMed
Summary
AI-generated from the abstractA new approach in psychiatric drug development, the preclinical randomized controlled trial (preRCT), was tested across three European centers using a rat model of alcohol relapse. Ketamine (20 mg/kg) reduced relapse, while R-ketamine worked only in females at the same dose; a higher dose (40 mg/kg) was effective in males. The sex-dependent effects were linked to plasma R-ketamine levels, which were twice as high in females. R-ketamine produced a lasting reduction in alcohol consumption without adverse effects. The findings support moving to a clinical trial that accounts for sex differences.
Study at a glance
| Characteristics | Preclinical randomized controlled trial Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine R-ketamine |
| Dose | 20 mg/kg, 40 mg/kg |
| Keywords | Addiction treatment Ketamine therapy Alcohol dependence Gender medicine Substance abuse recovery |
| Citations | 8 |
| Key finding | 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.