A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on alcohol relapse.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology – May 01, 2025
Source: PubMed
Summary
A promising breakthrough in addiction treatment reveals that R-ketamine may help prevent alcohol relapse, with particularly strong effects in women. Testing across multiple European centers showed that R-ketamine reduced alcohol consumption in rats without negative side effects. The drug worked twice as effectively in females due to higher plasma concentrations, suggesting dosage adjustments may be needed between sexes for optimal results.
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.