Summary Despite advances in tobacco smoking cessation interventions (pharmacological and behavioral), most smokers do not succeed at quitting, creating a major public health burden. Stress is one of the most commonly reported precipitants of tobacco craving and relapse. Tobacco withdrawal is associated with escalation of negative affect symptoms; our research has found multiple stress-related physiological and hormonal alterations during withdrawal that predict relapse. Modifying these stress-related biobehavioral changes may prove useful in reducing effects of stress. Cannabidiol (CBD) is a phytocannabinoid of cannabis with low abuse liability that has received increased attention in the retail market and cannabis research. Although CBD is aggressively marketed for addressing stress, little research has been done to characterize CBD’s physiological and mood effects, their implications in managing tobacco withdrawal symptoms, and the mechanism by which CBD may influence these symptoms. Our research will address these timely issues. This application builds on our current and previous funding periods (PI: al’Absi, R01DA027232) demonstrating that stress-related hormonal changes during tobacco withdrawal predict relapse. We have shown that tobacco dependence is linked with: 1) enhanced basal hypothalamic-pituitary- adrenocortical (HPA) activity; 2) blunted cortisol response to multiple stressors; 3) disrupted opioid regulation of the stress response; 4) association of attenuated stress response and early relapse; and 5) sex differences in changes during withdrawal and predictors of relapse; hormonal responses are better predictors of relapse in men, while withdrawal symptoms and craving are stronger predictors of relapse in women. Our recent research has also documented blunted emotion regulation among cannabis users. In the new cycle, we plan to conduct a multi-site, multi-group, multi-dose, double blind, within-subject study. We will address the following specific aims: 1) Determine the acute effect of CBD on the psychobiological mechanisms of the stress response in healthy participants; 2) Examine how tobacco dependence influences the acute effect of CBD on psychobiological mechanisms of the stress response; 3) Determine the effect of CBD on tobacco withdrawal-related changes in psychobiological mechanisms of the stress response in tobacco users; 4) Explore sex differences in the psychobiological mechanisms of the stress response and acute effects of CBD in dependent tobacco users. This research is the first to examine CBD's effect during exposure to acute stress and tobacco withdrawal using relevant measures that are known to be sensitive to acute stress and to tobacco withdrawal. The research builds on important preliminary results and uses rigorous, reproducible procedures.