Prefrontal Cortical Changes With Mindfulness-Oriented Recovery Enhancement in Opioid Use Disorder

Importance: Despite decades of clinical implementation of medications for opioid use disorder (OUD), overdose mortality rates remain high, underscoring a critical need for interventions that target the brain mechanisms underlying addiction. Objective: To assess the neural mechanisms of Mindfulness-Oriented Recovery Enhancement (MORE) and their associations with clinical outcomes, including craving and abstinence duration. Design, Setting, and Participants: This randomized clinical trial was conducted from November 2020 to September 2024 among individuals with OUD recruited from an inpatient rehabilitation facility in New York and randomized to MORE or psychoeducational supportive therapy (PST). Data were analyzed from October 2024 to August 2026. Interventions: Treatment with MORE (comprising training in mindfulness, drug cue reappraisal, and savoring positive experiences) or PST (active control condition) across 8 weekly 2-hour group sessions. Main Outcomes and Measures: Outcomes included treatment-related changes in functional magnetic resonance imaging (fMRI) blood oxygen level-dependent signal (primary), abstinence length (secondary), and cue-induced craving (secondary). Results: Drug cue reactivity task analyses included 59 participants (MORE, n = 24; 5 women [20.8%]; mean [SD] age, 43.6 [11.3] years; PST, n = 35; 8 women [22.9%]; mean [SD] age, 42.8 [10.0] years). Movie-watching and follow-up analyses were conducted in subsets of 37 (MORE, n = 18; PST, n = 19) and 38 participants (MORE, n = 13; PST, n = 25), respectively. Compared with PST, MORE reduced drug-biased activity in the middle frontal gyrus and other brain areas, including the precuneus, during downregulation of responses to drug cues relative to upregulation of responses to natural reward cues (even when controlling for passive cue viewing; z > 3.1; P < .05). The shift from drug to natural reward responses in the lateral and ventromedial prefrontal cortex (PFC) was associated with lower cue-induced craving exclusively in the MORE group (z > 3.1; P < .05). Relative to PST, MORE also reduced medial PFC synchronization to naturalistic drug-related movie scenes (q = 0.019) and significantly extended abstinence duration at follow-up (approximately 4 months posttreatment; χ2 = 6.7; P = .04; Cohen w = 0.19). Conclusions and Relevance: This neuroimaging randomized clinical trial demonstrates that MORE may restructure function in PFC nodes of the reward, salience, and control networks, positioning it as a biologically grounded adjunct to pharmacotherapy for OUD. Trial Registration: ClinicalTrials.gov Identifier: NCT04112186.