Researchers from four countries reported success in the second phase of clinical trials of the metabotropic glutamate receptor antagonist mavoglurant for cocaine use disorder. Participants taking the drug consumed significantly less cocaine and alcohol than those taking a placebo. The study was published in the journal Science Translational Medicine.
Glutamate is the primary excitatory neurotransmitter. Its rapid effects are mediated by ionotropic NMDA and AMPA receptors, while its slow effects are mediated by G-protein-coupled metabotropic receptors (mGluRs), of which there are eight known types. Preclinical studies have shown that pharmacological inhibition of mGluR5 suppresses cocaine seeking and self-administration in animals, while knockout of the mGluR5 gene abolishes the rewarding and stimulant effects of the substance. Mavoglurant (AFQ056) binds to the mGluR5 allosteric site in a dose-dependent manner and acts as a selective, non-competitive antagonist of these receptors.
Fabrizio Gasparini of Novartis Pharma and colleagues from Argentina, Spain, the United States, and Switzerland conducted double-blind, randomized, placebo-controlled phase II trials in three countries. They enrolled 68 patients (82.4 percent men) with cocaine use disorder. Thirty-one of them received mavoglurant at a dose of up to 200 milligrams (individually titrated over the first two weeks) twice daily for 98 days; the remaining 37 received a placebo.
When assessing the number of days with cocaine use by self-reporting on a retrospective time scale, the post-hoc probability of reducing cocaine use was at least 99 percent for a between-group difference of less than 0 percent and at least 36.6 percent for a difference of less than 10 percent (p = 0.021). Moreover, the proportion of days with cocaine use in the main group significantly decreased over the course of treatment (p = 0.042 in the second month and p = 0.003 in the third). Mavoglurant also reduced cocaine use as measured by urine tests for its metabolite benzoylecgonine (p = 0.025) and alcohol use in self-reports on a retrospective time scale (p = 0.072).
By the end of the trial, 90.9 percent of participants in the main group achieved clinical improvement on the CGI scale, compared to 46.6 percent in the control group. Self-reported abstinence from cocaine use in the last three weeks of treatment was complete, with 41.4 percent versus 16.7 percent (p = 0.027) and 27.6 percent versus 8.3 percent (p = 0.040). Similar abstinence from alcohol was 31.0 percent versus 11.1 percent. Hair analysis for cocaine and alcohol metabolites (benzoylecgonine, norcocaine, cocaethylene, and ethyl glucuronide) confirmed a more pronounced reduction with the active drug. The adverse event profile was comparable in the main and control groups.
Thus, in multicenter, but relatively small and short-term trials, the mGluR5 antagonist mavoglurant significantly reduced cocaine and alcohol use in patients with cocaine use disorder. The clinical significance of this effect will need to be clarified in larger, longer-term trials.
Previously, American researchers showed that the availability of mGluR5 to its ligand in several brain regions can serve as a biomarker of suicidal tendencies in post-traumatic stress disorder.
