Proprietary: This proposal includes trade secrets and other proprietary or confidential information of Highland Instruments and is being provided for use by the National Institutes of Health (NIH) for the sole purpose of evaluating this SBIR proposal. No other rights are conferred. This proposal and the trade secrets and other proprietary or confidential information contained herein shall further not be disclosed in whole or in parts, outside of NIH without Highland Instrument's permission. This restriction does not limit the NIH's right to use information contained in the data if it is obtained from another source without restriction. This legend applies to the Abstract, Specific Aims, Research Plan (all components), Commercialization Plan, and Human Subject's Sections of this proposal. Abstract. OUD is the primary cause of substance abuse related overdoses, resulting in a significant rise in mortality rates, with over 80,000 deaths in 2021 [1][2]. Overall, the alarming increase in opioid use, addiction, and overdose has led to a national epidemic [3]. Current pharmacological therapies to treat addiction [4, 5] are inadequate due to limited efficacy and adverse events [6]. Non-Invasive Brain Stimulation (NIBS) has shown promise in treating some forms of addiction [7-14]. NIBS is thought to induce changes in brain activity that revert maladaptive plasticity associated with addiction [15-17]. However, past NIBS studies have shown limited efficacy in treating opioid addiction [7, 8]. Highland Instrument's Electrosonic Stimulation (ESStim) is an improved NIBS technology that combines independently controlled electromagnetic and ultrasonic fields [18- 20]. The combined fields focus and boost neurostimulation currents via tuned electromechanical coupling in neural tissue. ESStim was shown to be safe and effective in the treatment of OUD in our Fast Track Phase I feasibility studies [21, 22]. As part of our Phase II work, we are conducting a double-blinded, multi-center, placebo-controlled study to investigate ESStim for OUD treatment. Based on FDA guidance, received as part of the FDA Q-sub process that was completed as part of our Phase II grant activities (see R44DA049685 RPPR Summer 2023), we propose to update our Phase II study protocol via this Supplement. As part of this vital work, and as guided by the FDA, ESStim will be administered to 100 participants (50 Active, 50 SHAM) to the left dorsolateral prefrontal cortex (DLPFC) for 20 min/day across 4x five-day cycles interspersed with 6- week follow-up periods over 6-months. We will administer a battery of clinical/safety, drug use, electrophysiology, behavioral, and psychosocial assessments in the OUD patients, evaluated over 6 months. As guided by the FDA, the primary endpoint for our trial will assess participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use during timeline followback inte...