Background: The characterization of an individual’s hypothalamic-pituitary-adrenal axis stress response is a main research topic in neuropsychobiology since alterations have been causally linked to several disease states. Over the last years, several studies focused on the identification of sources of inter- and intraindividual variability, but there is still a paucity of experimental data on the effect of different pharmaceuticals on cortisol responses to acute psychological stress. Therefore, in this randomized double-blind placebo-controlled study, we investigated the effect of treatment with two popular and clinically used pharmaceuticals on stress-related cortisol responses, namely acetylsalicylic acid (aspirin), a known prostaglandin synthesis inhibitor, and the beta-blocker propranolol (Inderal), a nonselective beta-receptor antagonist. Methods: For 5 days, 73 healthy subjects (50 men, 23 women; mean age 47.3 ± 7.7 years) received either a daily oral dose of 100 mg aspirin, 80 mg propranolol (Inderal), aspirin + propranolol, or placebo. After treatment, subjects were confronted with the Trier Social Stress Test, a widely-used standardized psychosocial stress protocol. Cortisol responses were measured by six saliva samples taken before and after the stress exposure. Results: Subjects showed a significant cortisol increase after stress (p < 0.0001). The four treatment groups did not differ in their cortisol responses (group effect p > 0.44; interaction p > 0.97). Additionally, controlling for gender, age, smoking status, body mass index, mean arterial blood pressure or pre-stress cortisol levels yielded similar results in the total sample as well as in the male or female subgroups, respectively. Conclusion: Neither short-term treatment with aspirin nor propranolol altered the acute free cortisol response to psychological stress in healthy adults.

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