Abstract
INTRODUCTION: Cognitive function is closely linked to brain energy metabolism and may be compromised by aging, metabolic stress, and neuropsychiatric disease. Ketone bodies can serve as an alternative cerebral fuel and may also exert signaling effects relevant to cognition. Exogenous ketones (EK) offer a practical means of increasing circulating ketone concentrations without dietary carbohydrate restriction. However, the overall effect of EK supplementation on cognitive performance in humans has not been systematically quantified. METHODS: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Web of Science, and Embase were searched through October 2025 for randomized controlled trials investigating the effects of EK on cognitive outcomes in healthy adults or individuals with neuropsychiatric conditions. Data extraction and quality assessment were performed independently by multiple reviewers using the PEDro scale. Standardized mean differences (SMD) were calculated using random-effects models. Subgroup and meta-regression analyses examined the influence of ketone formulation, intervention duration, dose, population type, and presence of acute cognitive stressors. RESULTS: 38 studies comprising 41 protocols (1,602 participants) were included in the systematic review, with 29 protocols (1,117 participants) eligible for meta-analysis. EK supplementation was associated with a statistically significant improvement in cognitive performance compared with placebo (SMD = 0.29, 95% CI 0.16–0.41; p < 0.001). Sub-group analyses did not show statistically significant differences between the type of supplementation (p = 0.083), study duration (acute vs. intermediate; p = 0.11), population type (healthy vs. Alzheimer’s disease; p = 0.077), or the presence of acute cognitive stressors (p = 0.89). Meta-regression revealed a positive association between daily EK dose and cognitive improvement. DISCUSSION: EK supplementation is associated with modest improvements in cognitive performance across diverse populations and study designs. These findings support EK as a flexible nutritional strategy for cognitive support and warrant further investigation in well-powered, long-term trials to clarify optimal dosing, formulation, and clinical applicability. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023471727, CRD42023471727.