Beyond flavor: dietary vanillyl alcohol, a D₂ receptor antagonist promoting sleep.

Sleep disturbances have become a prevalent public health challenge globally, spurring the demand for safe, naturally derived food-based interventions as alternatives to synthetic agents. Vanillyl alcohol (VA), a widely distributed bioactive compound in edible plants and a key constituent of Vanilla planifolia and the traditional sedative herb Gastrodia elata, is extensively used as a food additive for its characteristic vanilla aroma. Despite its long-term use in dietary and traditional contexts, the molecular mechanism underlying its potential sleep-regulating effects remains unclear. Given the critical role of dopamine receptor D2 (D2) in sleep-wake modulation, we systematically investigated the sleep-promoting activity of VA using a cross-disciplinary approach integrating in vitro biochemical assays, in silico simulations, and in vivo validation in D2-knockdown and chemically induced insomnia mouse models. Our results demonstrated that VA significantly prolonged total sleep time and shortened sleep latency in insomnia mice, which was dependent on D2-mediated signaling pathways. Mechanistically, VA interacted with D2R to inhibit its activity, thereby rebalancing the levels of key sleep-related neurotransmitters in the brain. This work not only elucidates the scientific basis for the traditional use of VA-containing foods in alleviating sleep disturbances but also positions VA as a promising naturally derived food ingredient for the development of sleep-promoting functional foods and dietary strategies. Collectively, our findings provide novel insights into the neuro-nutritional effects of food bioactives and offer a translational approach for addressing sleep disorders through dietary intervention.