Mavoglurant reduces cocaine use in patients with cocaine use disorder in a phase 2 clinical trial

Cocaine use disorder is a significant public health issue with currently no approved pharmacological treatments. Preclinical models suggest that excessive glutamate signaling in the brain's reward centers, particularly within the nucleus accumbens, contributes to addictive behaviors. This study investigated whether mavoglurant—a selective, noncompetitive antagonist of the metabotropic glutamate receptor 5 (mGluR5)—could safely and effectively reduce cocaine use in humans.

The researchers conducted a phase 2, randomized, double-blind, placebo-controlled trial involving 68 adults with chronic cocaine use disorder. Over a 98-day treatment period, participants received either oral mavoglurant (titrated up to 200 mg twice daily) or a placebo. The efficacy was primarily evaluated through the proportion of cocaine-use days, measured by self-reported Timeline Followback (TLFB) assessments, and supported by secondary measures including urine benzoylecgonine levels and hair sample analysis for drug metabolites.

Mavoglurant showed a statistically significant reduction in cocaine use compared to the placebo group. Analysis via both Bayesian and frequentist methods indicated that treated patients had a lower proportion of cocaine-positive days, with effects becoming more pronounced toward the end of the 98-day trial. Furthermore, the treatment group showed a parallel reduction in alcohol consumption, and participants reported greater functional improvement on the Clinical Global Impression scale. While the drug was generally well-tolerated, psychiatric symptoms occurred more frequently in the treatment group than in the placebo group, although none led to treatment discontinuation.

This trial provides the first clinical evidence that targeting mGluR5 with mavoglurant can decrease cocaine-seeking and consumption. The simultaneous reduction in alcohol use suggests that this pathway may address shared neurobiological mechanisms underlying polysubstance use. Given the high rates of treatment dropout in addiction research, the 76-79% completion rate observed here highlights the potential feasibility of mavoglurant as a therapeutic strategy.