Diphenhydramine, a first-generation antihistamine, was approved by the US Food and Drug Administration (FDA) in 1946 for the treatment of allergies and in 1982 was authorized for over-the-counter (OTC) sales.1 Since that time, many millions of patients with allergies have benefited from its therapeutic efficacy. However, diphenhydramine’s benefits are offset by substantial neurologic and anticholinergic adverse reactions.