Cognitively-enhanced tDCS of the dorsolateral prefrontal cortex to reduce craving in opioid use disorder - The opioid epidemic remains a major public health crisis in the US, with relapse rates and overdose-related fatalities continuing to rise. However, the development and testing of viable interventions, and the investigation of their underlying neural mechanisms, in individuals with opioid use disorder (OUD) have remained limited. Core symptoms of addiction include craving and heightened reactivity to drug cues, both linked to impairments in prefrontal cortical function, particularly reduced inhibitory control. Here, we propose a phased, randomized, double-blind clinical trial using transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (dlPFC), delivered to patients with OUD in their natural treatment setting, to reduce craving and cue reactivity. The study will also include feasibility testing for self-administration, a key step toward future home- based use of this battery-powered portable device that can be used safely, remotely, and repeatedly. In our completed SBIR-funded Phase-1 and 2 clinical trials in inpatients with cocaine use disorder, we demonstrated that 15 sessions of real (vs. sham) right dlPFC tDCS reduced craving, particularly when combined with cognitive reappraisal (CR), an evidence-based learning strategy that improves treatment outcomes and engages the dlPFC, including in our fMRI studies in OUD. The present study extends the tDCS work to OUD, a population with limited longitudinal neurostimulation data to date. In the UG3 phase, we will randomize 60 inpatients with OUD into a 2×2 between-subjects design: real or sham tDCS, with or without concurrent CR. Participants will receive 15 sessions over five weeks and complete assessments at baseline, post-treatment, and at 1- and 3- month follow-ups. These include self-reported craving and fMRI to assess neural activation during a validated inhibitory control task (Stop Signal Reaction Time, SSRT). All participants will also receive training in self- administered tDCS to assess feasibility for remote use. Transition to the UH3 phase will be contingent on meeting two predefined UG3 milestones, namely significant: 1) craving reduction, and 2) increased right dlPFC activation during SSRT, both with real-tDCS compared to sham. Upon milestone verification, the UH3 phase will replicate UG3 procedures with a new cohort of 60 inpatients. To enhance generalizability and examine dose-response effects, an additional 30 participants will be enrolled into exploratory arms: 15 outpatients and 15 treatment- resistant individuals the latter receiving higher-dose tDCS (3 mA) guided by individualized electric field modeling. We hypothesize that combining tDCS with CR will synergistically enhance dlPFC function, reducing craving and cue reactivity. This project is also designed to identify biomarkers predictive of outcomes. If successful, this work will support FDA approval of a novel scalable neuromodulatory intervention with direct implications for addiction treatment and recovery in real-world settings. Ultimately, it aims to empower patients with OUD through a targeted, self-administered brain-based therapy that can be deployed where and when it is most needed.
