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This study examines how work stress affects the misuse of prescription drugs to augment mental performance without medical necessity (i.e., cognitive enhancement). Based on the effort-reward imbalance model, it can be assumed that a misalignment of effort exerted and rewards received increases prescription drug misuse, especially if employees overcommit. To test these assumptions, we conducted a prospective study using a nationwide web-based sample of the working population in Germany ( N = 11,197). Effort, reward, and overcommitment were measured at t  1 and the 12 month frequency of prescription drug misuse for enhancing cognitive performance was measured at a one-year follow-up ( t  2 ). The results show that 2.6% of the respondents engaged in such drug misuse, of which 22.7% reported frequent misuse. While we found no overall association between misuse frequency and effort, reward, or their imbalance, overcommitment was significantly associated with a higher misuse frequency. Moreover, at low levels of overcommitment, more effort and an effort-reward imbalance discouraged future prescription drug misuse, while higher overcommitment, more effort, and an imbalance increased it. These findings suggest that a stressful work environment is a risk factor for health-endangering behavior, and thereby underlines the importance of identifying groups at risk of misusing drugs.

Effort–Reward Imbalance at Work and Prescription Drug Misuse—Prospective Evidence from Germany