Veterans experience chronic pain at greater rates than the rest of society and are more likely to receive long-term opioid therapy (LTOT), which, at high doses, is theorized to induce maladaptive neuroplastic changes that attenuate self-regulatory capacity and exacerbate opioid dose escalation. Mindfulness meditation has been shown to modulate frontal midline theta (FMT) and alpha oscillations that are linked with marked alterations in self-referential processing. These adaptive neural oscillatory changes may promote reduced opioid use and remediate the neural dysfunction occasioned by LTOT. In this study, we used electroencephalography (EEG) to assess the effects of a mindfulness-based, cognitive training intervention for opioid misuse, mindfulness-oriented recovery enhancement (MORE), on alpha and theta power and FMT coherence during meditation. We then examined whether these neural effects were associated with reduced opioid dosing and changes in self-referential processing. Before and after 8 weeks of MORE or a supportive psychotherapy control, veterans receiving LTOT (N = 62) practiced mindfulness meditation while EEG was recorded. Participants treated with MORE demonstrated significantly increased alpha and theta power (with larger theta power effect sizes) as well as increased FMT coherence relative to those in the control condition-neural changes that were associated with altered self-referential processing. Crucially, MORE significantly reduced opioid dose over time, and this dose reduction was partially statistically mediated by changes in frontal theta power. Study results suggest that mindfulness meditation practice may produce endogenous theta stimulation in the prefrontal cortex, thereby enhancing inhibitory control over opioid dose escalation behaviors.Fig. 1SPECTRAL EEG CHANGES DURING A LABORATORY-BASED MINDFULNESS MEDITATION PRACTICE SESSION BEFORE AND AFTER 8 WEEKS OF MINDFULNESS-ORIENTED RECOVERY ENHANCEMENT (MORE) OR A SUPPORTIVE GROUP (SG) PSYCHOTHERAPY CONTROL CONDITION.: Topoplots are interpolated to cover the entire headspace. dB = decibels.Fig. 2THETA COHERENCE CHANGES DURING A LABORATORY-BASED MINDFULNESS MEDITATION PRACTICE SESSION BEFORE AND AFTER 8 WEEKS OF MINDFULNESS-ORIENTED RECOVERY ENHANCEMENT (MORE) OR A SUPPORTIVE GROUP (SG) PSYCHOTHERAPY CONTROL CONDITION.: Red colors indicate positive coherence while blue colors indicate negative coherence. Saturation of color as well as line thickness represent the strength of coherence between nodes. ROIs are grouped via node color. n.u. = normalized units.Fig. 3Path model indicating that the effect of mindfulness-oriented recovery enhancement (MORE) versus a supportive group (SG) psychotherapy control condition on reducing opioid dose was statistically mediated by increasing frontal theta power mindfulness meditation.Fig. 4Scatterplots depicting associations between treatment-related changes in frontal theta power and a self-transcendence (measured by the Nondual Awareness Dimensional Assessment) and b change in body boundaries (measured by the perceived body boundaries scale), among Veterans treated with mindfulness-oriented recovery enhancement (MORE) or a supportive group (SG) psychotherapy condition.