Diphenhydramine Interactions

Diphenhydramine (a sedating antihistamine) and valerian root both depress the central nervous system, through histaminergic and GABAergic pathways respectively. Taken together their sedative effects add up, increasing drowsiness, next-day impairment, and fall risk.

Diphenhydramine and melatonin both promote sleepiness through different mechanisms (H1 antihistamine blockade and MT1/MT2 receptor activation). Used together they have an additive sedating effect, which can mean heavier-than-expected drowsiness, lingering next-day grogginess, slower reaction time, and a higher fall risk, especially in older adults.