There is growing evidence from preclinical studies for an involvement of orexins (ORX) in the regulation of stress, affectivity and addictive behavior. The aim of our study was to gather corresponding clinical data and to elucidate the relationships between alcohol withdrawal stress, ORX plasma concentration and psychopathology. A consecutive sample of thirty-four alcohol-dependent inpatients was included in the study. Blood was drawn at onset of withdrawal and following 2 weeks of controlled abstinence in order to assess ORX, ACTH and cortisol plasma concentrations. In parallel, we assessed clinically relevant psychological distress symptoms applying the Brief Symptom Inventory (BSI). We found a significant positive correlation between ORX and global distress indices of the BSI (p ≤ 0.05). In a regression model, ORX concentration during acute withdrawal explained 24% of the variance of symptom severity (p<0.01). No association with craving, ACTH or cortisol plasma concentration was detected. Our results suggest an involvement of ORX in the affective dysregulation seen commonly in alcohol dependent patients during alcohol withdrawal. Moreover, the effects on global distress indices as well as the earlier studied effects on reinstatement of drug seeking behaviors may point on an involvement of ORX in impaired brain stress systems.

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