“No Thanks, Coffee Keeps Me Awake”: Individual Caffeine Sensitivity Depends on ADORA2A Genotype

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Each aspect of sleep is a highly complex phenotype and little is currently known about their molecular bases. Nevertheless, genetic studies in model organisms have uncovered sleep regulatory mechanisms and distinct neurochemical processes that are conserved from Drosophila to rodents to humans.¹ Although no dedicated “sleep genes” have been identified (if they exist), the adenosine neuromodulator/receptor system is believed to play an important role in sleep and sleep-wake regulation. Support for this hypothesis comes from the finding that the wake-promoting effects of caffeine, the major stimulant in the world, are mediated by antagonistic interaction with adenosine A₁ and A_2A receptors.^2,3

Since people drink coffee, it is well-known that some individuals are sensitive to its stimulant effects whereas some others are not. The behavioral actions of caffeine in humans were first studied scientifically 100 years ago by Harry Levi Hollingworth.⁴ Hollingworth's studies set a new standard in psychopharmacological research because for the first time, they included double-blind and placebo-controlled experimental design. With respect to sleep disturbances, he concluded that “a few individuals show complete resistance to the effects of small doses of caffeine” (p. 100). Until recently, the biological reasons for these inter-individual differences remained unknown. Now we know they have a basis in genetics.