Project Summary/Abstract Substance use disorders (SUDs) are a significant public health problem. There is a need for novel substance use prevention strategies for adolescents, particularly developmentally-informed interventions rooted in basic science findings. Significant basic research indicates parent stress as a risk factor for adolescent substance use. A separate body of research finds that mindfulness interventions reduce stress in adults. Taken together, mindfulness interventions may reduce parent stress and prevent increases in substance use in adolescence. However, few randomized controlled trials (RCTs) have evaluated mindfulness interventions for parents and none have tested neurobiological mechanisms. Through our NIDA-funded R34 (Pilot and Feasibility) award, we developed and conducted a pilot RCT of a parenting-focused mindfulness intervention, the Parenting Mindfully (PM) intervention, in 100 highly-stressed parents of adolescents. We found that PM reduced parent stress, increased adaptive and mindful parenting behavior, decreased parent emotional and cortisol stress reactivity in our laboratory parent-adolescent interaction task (PAIT), and prevented increases in adolescent substance use and psychopathology symptoms to 1 year follow-up, as compared to a Parent Education (PE) control. In a sub-sample of 20 mothers, PM also decreased mothers? anterior insula reactivity and increased amygdala to dorsolateral prefrontal cortex connectivity, which predicted more adaptive parenting. The proposed study will take the next step by conducting a large RCT of PM with a longer follow-up and more rigorous PE control and by fully testing neurobiological mechanisms. 300 highly-stressed parents of early adolescents (age 12-14) will be randomly assigned to receive the PM or PE intervention. Before, during, and after the interventions, and at 6 month, 1 year, and 2 year follow- ups (into middle adolescence), we will collect questionnaire, clinical interview, and biological measures of parent stress, parenting, adolescent substance use and substance use problems, and adolescent (and parent) SUD and psychopathology symptoms. At pre- and post-intervention, observed adaptive and mindful parenting behaviors and parent emotional and cortisol stress reactivity will be measured in the PAIT task. 150 mothers will complete fMRI sessions at pre- and post- examining emotion-related neurobiological mechanisms. We will examine: 1. Efficacy of PM in preventing increases in adolescent substance use and symptoms; 2. Parent stress and parenting as mechanisms of PM on adolescent substance use; 3. Parent emotion-related fMRI responses and connectivity as neurobiological mechanisms of PM. This will be the first RCT of a stand- alone mindfulness intervention for parents of adolescents and the first to test neurobiological mechanisms. The study will provide an effective intervention to both reduce parent stress and prevent youth substance use and will identify neurobiological mechanisms to target and strengthen PM and other parenting interventions.