Treating cocaine and opioid use disorder with transcranial magnetic stimulation: A path forward.

Developing new, effective treatments for substance use disorders (SUDs), especially cocaine and opioid use disorders (CUD and OUD), are of immense importance. These are chronic, relapsing brain diseases characterized by dysregulated circuits manifesting from neuroplastic change brought on by repeated exposure to substances of abuse. A potential treatment is therapeutically inducing neuroplastic change in targeted dysregulated circuits. One such intervention, repetitive transcranial magnetic stimulation (rTMS) has gained traction over the past two decades as a method of noninvasively stimulating cortical structures in order to induce subcortical neuroplastic change. By doing so, rTMS ameliorates symptoms that are consequent of dysregulations in disease-related circuits, such as craving, and reduces drug use. Although rTMS has been successfully applied as a treatment for other clinical disorders, progress toward treatment applications for SUDs has been stymied by what we dub "known unknowns". These are fundamental lines of research within the rTMS-SUD field that have yet to be systematically understood which could help to optimize TMS as an intervention for SUDs. Because progress in treatment for CUD and OUD is imperative given the widespread severity of OUD and the lack of treatment for CUD, it is necessary to critically reflect on the ways in which rTMS research for these disorders can most effectively move forward to help patients. We articulate six "known unknowns" and outline a direction of research to address each. Briefly, the "known unknowns" in the field are: 1) Cortical target selection, 2) subcortical circuit engagement, 3) optimizing rTMS sequences, 4) rTMS as an adjuvant to existing interventions, 5) manipulating brain state, and 6) selecting outcome measures. We also outline research design approaches to address these "known unknowns" in the rTMS-SUDs field. Unification of efforts across research laboratories is necessary to develop empirically validated treatments that will benefit patients in a timely fashion.