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bioRxiv · 10.1101/2025.11.23.689943

The renin angiotensin system in cognitive flexibility: Effects of single-dose losartan on task-switching in healthy volunteers

Prasad, D.·Feltham, G.·De Giorgi, R.·Costi, S.·Fox, E.·Gillespie, A. L.·Reinecke, A.
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Abstract

IntroductionCognitive flexibility, defined as the ability to shift mental strategies when environmental demands change, may influence psychological well-being and psychiatric treatment outcomes. Emerging research increasingly implicates the renin angiotensin system (RAS) in cognition, yet its role in cognitive flexibility is inadequately understood. MethodsWe conducted a double-masked trial with N=60 healthy adults aged 18-50. Participants were randomly assigned to receive a single 50 mg dose of losartan, an angiotensin II receptor blocker, or placebo. Following a waiting period, participants completed a task-switching paradigm as a measure of cognitive flexibility, which required dynamically categorizing arrows based on location or direction. Statistical analyses were conducted to determine group (losartan vs. placebo), task (location vs. direction), and switch (switching vs. repeating a task) effects on reaction time (RT) and accuracy independently. A composite bin score was also computed, integrating both RT and accuracy data. ResultsAll participants displayed the expected switch costs. While participants on losartan exhibited numerically superior RTs and accuracy, losartan did not significantly improve task-switching performance relative to placebo. This was confirmed by the bin score analysis, which indicated no benefit of losartan when RT and accuracy were considered together. An exploratory probe suggested that losartan improved accuracy on direction switch trials, indicating a potential drug effect under specific cognitive conditions. ConclusionOverall, we found no significant benefits of losartan on task-switching in healthy adults. Our results may be explained by ceiling effects in our sample, which could have hindered the detection of group differences, or possibly reflect a negligible role for the RAS in cognitive flexibility.

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Prasad, D., Feltham, G., De Giorgi, R., Costi, S., Fox, E., Gillespie, A. L., Reinecke, A.. 2025-11-26. The renin angiotensin system in cognitive flexibility: Effects of single-dose losartan on task-switching in healthy volunteers. https://doi.org/10.1101/2025.11.23.689943

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