Circulating orexin changes during withdrawal are associated with nicotine craving and risk for smoking relapse.

We examined the extent to which orexin measured during smoking and the early phase of abstinence was related to craving, withdrawal, stress hormones, and risk for smoking relapse in men and women. Considering its role in modulating nicotine-related reward, we predicted that a reduction in circulating orexin during withdrawal would be associated with increased craving and risk for smoking relapse. Two hundred and eighty five participants provided biological samples and self-report information to identify predictors of smoking relapse. All participants attended two laboratory sessions, which were before and after a period of required abstinence from smoking. After quitting, participants also attended four weekly sessions to track smoking relapse. Only smokers who relapsed within the follow-up period exhibited reduced orexin levels during the initial withdrawal period; ACTH, but not craving nor cortisol, increased across the abstinence period for successful abstainers but not for relapsers. Sex differences in orexin and craving or withdrawal associations also emerged. Adding sex, HPA hormones, and self-reported measures of craving and withdrawal as potential mediators had minimal effects on the above abstinence and orexin effects. These results provide the first evidence that circulating orexin may be a useful marker of risk for relapse; and sex, adrenal hormones, and self-reported craving and withdrawal were not mediators of this effect. The results point to a promising pathway to investigate objective biological markers for craving and smoking relapse and highlight the complexity of the neurobiology of relapse.