Diphenhydramine acts as a reversible, competitive antagonist-and more precisely, an inverse agonist-at the histamine H₁ receptor, thereby stabilizing the inactive receptor conformation and preventing histamine-mediated vasodilation, increased capillary permeability, and sensory nerve activation.[5]
Because the molecule readily penetrates the central nervous system, blockade of H₁ receptors in cortical and subcortical arousal pathways diminishes wake-promoting histaminergic signaling, producing dose-dependent somnolence and impairment of attention, memory, and psychomotor speed.[6]
At anticholinergic doses it also antagonizes muscarinic M₁ receptors, potentiating drying of secretions, mydriasis, tachycardia, and decreased gastrointestinal motility; cytochrome P450 isoenzymes (primarily CYP2D6 and 1A2) mediate hepatic N-demethylation, explaining pharmacokinetic variability and drug-drug interaction potential.[7]
Experimental psychometric studies using double-blind crossover designs confirm measurable decrements in sustained attention and reaction time within 0.5-3.5 h after intravenous administration of 50 mg, correlating with cortical H₁ receptor occupancy.[8]
Contemporary reviews emphasize that first-generation agents such as diphenhydramine are inverse agonists rather than simple antagonists and note emerging data on gene-dose effects, transporter interactions, and tolerance development, all of which should temper prolonged off-label use for insomnia.[9]