Bifunctional Modulation of NMDA and Opioid Receptors in Ketamine Reinforcement and Misuse: Implications for Substance Use Disorder Treatment

Certain medications carry a risk by providing therapeutic benefits at the expense of misuse potential. Ketamine is increasingly being used for the treatment of depression, and studies indicate that it may also have utility for substance use disorder (SUD) treatment. However, it has recreational appeal and known misuse potential. Driven by the ongoing expansion of its use in clinical settings, concerns for misuse of ketamine are escalating. In this review, we summarize neurochemical, molecular, and brain circuit mechanisms associated with ketamine reinforcement and misuse potential and discuss their relevance toward its potential for SUD treatment. We focus on ketamine's direct actions on opioid and glutamatergic systems, highlighting recent discoveries on its interactions with mu opioid receptors (MORs) and NMDA receptors (NMDARs) in addiction-relevant brain circuits. We propose that ketamine's reinforcing properties and misuse potential stem from its bifunctional engagement with these receptors, with its (S)-ketamine enantiomer, compared with (R)-ketamine, being ketamine's primary risk driver. We contextualize this bifunctional NMDAR/MOR mechanism within ketamine's known efficacy for treatment of depression and other mental health conditions, including its potential for SUD treatment. We conclude that the brain mechanisms contributing to ketamine reinforcement, its recreational appeal, and its misuse potential are intertwined with its antidepressant properties and potential for SUD treatment.