- Epidemiological and mechanistic studies raised the possibility that cognitive function may be affected by brain responses to insulin. We systematically reviewed and analyzed existing clinical trials that assessed the potential beneficial effects of intranasal insulin administration on cognitive functions. Interventional studies measuring changes in cognitive functions in response to intranasal insulin were retrieved and included if they were in English and assessed cognitive functions before and after treatment. Cohen's effect size was calculated to allow comparison between studies. Eight studies (328 participants) were analyzed. No significant side effects of intranasal insulin administration were reported. Seven studies included healthy subjects' response to intranasal insulin, and three evaluated the cognitive effect among patients with minimal cognitive impairment or overt Alzheimer's disease. In healthy people, Cohen's effect size calculations suggest that only 160 IU/d intranasal insulin induced potential beneficial effects. Although females, when compared head-to-head, exhibited greater improvements in cognitive tests than men, the composite analysis of all included studies did not support this trend. Among cognitively impaired patients, only lower doses of insulin were assessed, and 20 IU revealed potential beneficial effects on cognitive functions. This was significant in a single study assessing long-term intranasal insulin administration, whereas acute administration of 20 IU intranasal insulin tended to show a beneficial effect on immediate recall in Apo ε4(-), but not Apo ε4(+), patients. The current limited clinical experience suggests potential beneficial cognitive effects of intranasal insulin. Analyses provide clinical considerations for future research aimed at elucidating whether intranasal insulin may be used to improve cognitive functions.