Genetics of caffeine and brain-related outcomes - a systematic review of observational studies and randomized trials

Context Although the stimulant and anxiogenic properties of caffeine are widely accepted, research on its specific effects on the brain remains controversial. Growing evidence shows that interindividual differences in caffeine response may be partly due to variations in genes such as CYP1A2 and ADORA2A, which have been used to identify individuals as fast or slow caffeine metabolizers and as having a high or low caffeine sensitivity, respectively. Objective The objective of this review was to identify, evaluate, and discuss current evidence on the associations between common genetic variants, caffeine consumption, and brain-related outcomes in humans. Data Sources PubMed and Embase databases were searched for relevant reports based on a predetermined search strategy. Data Extraction Reports of observational and experimental studies on healthy adults who underwent (a) genetic analysis for polymorphisms in genes associated with caffeine metabolism and effects and (b) measurements of brain-related effects such as anxiety, insomnia, and cognitive performance associated with the consumption of caffeine (habitual intake or supplementation) were included. Data Analysis Of the 22 records included, 15 were randomized controlled trials, 6 were cross-sectional studies, and 1 was a genome-wide association study. The main outcomes identified were cognitive performance (n = 9), anxiety (n = 7), and sleep disturbance/insomnia (n = 6). Polymorphisms in the CYP1A2 gene were associated with cognitive function, while variations in the ADORA2A gene were associated with anxiety and sleep disturbance. Conclusion The present review has provided evidence that variability in the CYP1A2 and the ADORA2A genes may modulate the association between caffeine and brain-related outcomes. Future studies are warranted to investigate the specific polymorphisms implicated in each brain outcome, which cognitive functions are particularly related to caffeine (simple vs complex), whether there are gender differences in anxiety effects, and how habitual caffeine intake may influence the acute effects of caffeine. Systematic review registration PROSPERO registration no. CRD42021257556.

Automated summary

This review examines the effects of caffeine on genetic polymorphisms and brain-related outcomes. The results suggest that the CYP1A2 gene is associated with cognitive function, while the ADORA2A gene is associated with anxiety and sleep disturbances. Future studies should further investigate specific genetic polymorphisms involved in each brain outcome, the different effects of caffeine on cognitive function, gender differences in anxiety effects, and how habitual caffeine intake influences the acute effects of caffeine.