The Caffeinated Brain Part 3: The Effect of Caffeine on Electroencephalography (EEG) During Wakefulness-A Systematic and Mechanistic Review.

Introduction: Caffeine is a widely consumed psychoactive compound whose central pharmacological effects are mediated primarily through antagonism of adenosine receptors. Wakeful EEG provides a temporally sensitive method for examining caffeine-related changes in oscillatory activity and vigilance-related brain states. This systematic review synthesized evidence concerning the effects of acute and habitual caffeine exposure on non-ERP EEG measures during wakefulness. Materials and Methods: The review followed PRISMA 2020 guidelines. PubMed/MEDLINE, Scopus, Web of Science, Embase, PsycINFO, and the Cochrane Library were searched from database inception to 30 May 2026. Eligible studies included human participants exposed to caffeine, coffee, or caffeine-containing interventions and reported EEG outcomes during wakeful resting-state or task-related conditions. Risk of bias was assessed using RoB 2 for randomized trials and ROBINS-I for non-randomized studies. Findings were synthesized narratively because of substantial methodological heterogeneity. Results: Forty-eight studies were included. Resting-state spectral EEG was the dominant paradigm, although studies also examined task-related activity, prolonged wakefulness, sleep deprivation, withdrawal, driving-related drowsiness, coherence, nonlinear complexity, EEG microstates, and multimodal EEG-fMRI measures. Reductions in alpha power or amplitude were among the more frequently reported findings following acute caffeine administration, while attenuation of theta, delta, or other slow-frequency activity was particularly evident under conditions of sleep pressure, prolonged wakefulness, withdrawal, fatigue, or reduced vigilance. However, neither effect was universal. Beta findings were heterogeneous, and changes in alpha frequency, total EEG power, coherence, asymmetry, complexity, and microstates were less consistently examined. The direction and magnitude of EEG responses varied according to caffeine dose, habitual intake and withdrawal status, baseline vigilance, eye condition, task demands, participant characteristics, scalp region, frequency-band definition, and EEG methodology. Evidence concerning coherence, asymmetry, nonlinear complexity, microstates, and multimodal EEG-fMRI outcomes was preliminary. Conclusions: The available evidence does not establish a single reproducible EEG signature or validated electrophysiological biomarker of caffeine response. Reductions in alpha power and attenuation of slow-frequency activity during states of elevated sleep pressure or caffeine withdrawal were among the more frequently reported findings, but substantial methodological and state-dependent heterogeneity limits their specificity and generalizability. EEG changes should also not be interpreted as direct indicators of improved cognitive performance, because electrophysiological and behavioral effects were not consistently concordant across studies.