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Young adults who experienced child abuse and neglect (CAN) are at significant risk for callous-unemotional traits and substance use problems. Research shows that compromised self-regulation may increase risk for these maladaptive outcomes. In the present cross-sectional study, we examined the moderating role of self-regulation, indexed by heart rate variability reactivity, in the indirect link between CAN and alcohol and other drug use problems via callous-unemotional traits. We utilized a sample of mostly female undergraduate students (N = 130, 81% Female; Mage = 20.72). We hypothesized that (a) CAN and alcohol or other drug use problems would be associated indirectly via elevations in callous-unemotional traits, and (b) that this indirect association would be exacerbated by elevated heart rate variability reactivity. Results indicated that increased callous-unemotional traits underlain in the link between CAN and alcohol or other drug use problems. Further, this indirect link was exacerbated among youth with elevated heart rate variability reactivity. These findings have significant implications for prevention by demonstrating that physiological self-regulation is important to target in substance use prevention among collegiate samples. [ABSTRACT FROM AUTHOR]