Globally, the rates of substance use and psychiatric disorders continue to escalate, and in the U.S., both disordertypes have become a public health crisis. Concerningly, however, psychological, behavioral, and pharmacological interventions for both disorder-types are failing to keep up with the demands for treatment. Additionally, even with treatment, the long-term prognosis for both disorder-types is equally guarded, with each expected to reduce the lifespan of those affected by an average of 10 years. These observations raise the question of whether substance use disorders and psychiatric disorders share some unknown predisposing factor—one that, if identified and treated— would markedly increase the therapeutic success rate for both disorder-types. One such factor, and one that would be highly treatable, is neuronal hyperexcitability. According to the multi-circuit neuronal hyperexcitability (MCNH) hypothesis of psychiatric disorders, an inherent hyperexcitability of the neurological system causes normal thoughts and emotions to be abnormally amplified and persistent. This can lead to obsessive thoughts and behaviors, which are fundamental characteristics of addiction disorders and obsessive- ompulsive disorder; it can lead to elevated levels of anxiety and depression, which are almost universal in substance use and psychiatric disorders; and it can lead to the use of illicit drugs in an effort to either reduce or offset the uncomfortable emotions that pathologically hyperactive neural circuits can create. This article will discuss the neuropsychiatric means by which an inherent hyperexcitability of the neurological system could be driving both substance use and its related psychiatric disorders. It will also discuss why this common neurophysiological abnormality has been so difficult to identify and provide a rationale for reducing neuronal excitability as a means of both treating and preventing a wide range of substance use and psychiatric disorders.