Transcranial magnetic stimulation, deep brain stimulation, and other forms of neuromodulation for substance use disorders: Review of modalities and implications for treatment Author: James J Mahoney 3rd1, Colleen A Hanlon2, Patrick J Marshalek3, Ali R Rezai4, Lothar Krinke5 Affiliation: <sup>1</sup> West Virginia University School of Medicine, Rockefeller Neuroscience Institute, 33 Medical Center Drive, Morgantown, WV 26505, United States of America; WVU Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV 26505, United States of America; WVU Department of Neuroscience, 64 Medical Center Drive, Morgantown, WV 26505, United States of America. Electronic address: james.mahoney@hsc.wvu.edu. <sup>2</sup> Wake Forest School of Medicine, Cancer Biology and Center for Substance Use and Addiction, 475 Vine Street, Winston-Salem, NC 27101, United States of America. <sup>3</sup> West Virginia University School of Medicine, Rockefeller Neuroscience Institute, 33 Medical Center Drive, Morgantown, WV 26505, United States of America; WVU Department of Behavioral Medicine and Psychiatry, 930 Chestnut Ridge Road, Morgantown, WV 26505, United States of America; WVU Department of Neuroscience, 64 Medical Center Drive, Morgantown, WV 26505, United States of America. <sup>4</sup> West Virginia University School of Medicine, Rockefeller Neuroscience Institute, 33 Medical Center Drive, Morgantown, WV 26505, United States of America; WVU Department of Neuroscience, 64 Medical Center Drive, Morgantown, WV 26505, United States of America; WVU Department of Neurosurgery, 64 Medical Center Drive, Morgantown, WV 26505, United States of America. <sup>5</sup> West Virginia University School of Medicine, Rockefeller Neuroscience Institute, 33 Medical Center Drive, Morgantown, WV 26505, United States of America; WVU Department of Neuroscience, 64 Medical Center Drive, Morgantown, WV 26505, United States of America; Magstim Inc., 9855 West 78 Street, Suite 12, Eden Prairie, MN 55344, United States of America. Conference/Journal: J Neurol Sci Date published: 2020 Sep 20 Other: Volume ID: 418 , Pages: 117149 , Special Notes: doi: 10.1016/j.jns.2020.117149. , Word Count: 398 Given the high prevalence of individuals diagnosed with substance use disorder, along with the elevated rate of relapse following treatment initiation, investigating novel approaches and new modalities for substance use disorder treatment is of vital importance. One such approach involves neuromodulation which has been used therapeutically for neurological and psychiatric disorders and has demonstrated positive preliminary findings for the treatment of substance use disorder. The following article provides a review of several forms of neuromodulation which warrant consideration as potential treatments for substance use disorder. PubMed, PsycINFO, Ovid MEDLINE, and Web of Science were used to identify published articles and clinicaltrials.gov was used to identify currently ongoing or planned studies. Search criteria for Brain Stimulation included the following terminology: transcranial direct current stimulation, transcranial magnetic stimulation, theta burst stimulation, deep brain stimulation, vagus nerve stimulation, trigeminal nerve stimulation, percutaneous nerve field stimulation, auricular nerve stimulation, and low intensity focused ultrasound. Search criteria for Addiction included the following terminology: addiction, substance use disorder, substance-related disorder, cocaine, methamphetamine, amphetamine, alcohol, nicotine, tobacco, smoking, marijuana, cannabis, heroin, opiates, opioids, and hallucinogens. Results revealed that there are currently several forms of neuromodulation, both invasive and non-invasive, which are being investigated for the treatment of substance use disorder. Preliminary findings have demonstrated the potential of these various neuromodulation techniques in improving substance treatment outcomes by reducing those risk factors (e.g. substance craving) associated with relapse. Specifically, transcranial magnetic stimulation has shown the most promise with several well-designed studies supporting the potential for reducing substance craving. Deep brain stimulation has also shown promise, though lacks well-controlled clinical trials to support its efficacy. Transcranial direct current stimulation has also demonstrated promising results though consistently designed, randomized trials are also needed. There are several other forms of neuromodulation which have not yet been investigated clinically but warrant further investigation given their mechanisms and potential efficacy based on findings from other studied indications. In summary, given promising findings in reducing substance use and craving, neuromodulation may provide a non-pharmacological option as a potential treatment and/or treatment augmentation for substance use disorder. Further research investigating neuromodulation, both alone and in combination with already established substance use disorder treatment (e.g. medication treatment), warrants consideration. Keywords: Deep brain stimulation; Focused ultrasound; Neuromodulation; Percutaneous nerve field stimulation; Substance use disorder; Transcranial direct current stimulation; Transcranial magnetic stimulation; Trigeminal nerve stimulation; Vagus nerve stimulation. PMID: 33002757 DOI: 10.1016/j.jns.2020.117149