Glutamatergic Agents for the Treatment of Cocaine Use Disorder

Purpose of Review Disruptions in glutamate hemostasis have been implicated in cocaine use disorder (CUD). This manuscript reviews novel agents that influence glutamate neurotransmission with respect to their potential for the treatment of CUD. Among glutamatergic receptors/transporters, we focused on NMDA and AMPA/kainate receptors, mGluR1/5, mGluR2/3, and xCT and GLT-1 transporters. Recent Findings This review suggests that beta-lactam antibiotics, propentofylline, metabotropic glutamate-receptor-5 antagonists, and ketamine may alter neuroplastic processes related to chronic cocaine use. Among novel agents targeting glutamatergic systems, arguably the agent with the most preclinical and clinical support is ketamine, although the route of administration and potential for misuse are limitations. The beta-lactam antibiotics clavulanic acid and ceftriaxone have significant preclinical support, but ceftriaxone has limitations relating to the route of administration and safety profile. Among other agents with promising preclinical data, there exists ongoing (e.g., mavoglurant and clavulanic acid) or completed (e.g., clavulanic acid) clinical trials. Summary Given the potential of targeting glutamatergic systems, further study is needed of these agents. Gaps and limitations when it comes to translation of preclinical work to clinical settings are being reduced and addressed with promising candidates such as ketamine, newer beta-lactam agents with better safety profiles, and ongoing trials with agents targeting metabotropic glutamate receptors.