Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance

Arch Intern Med. 1997 Nov 10;157(20):2350-6.


Background: The classic, first-generation histamine1-receptor antagonists used to treat allergic disorders frequently cause sedation. In contrast, sedation is reduced or absent after administration of recommended doses of second-generation histamine1-receptor antagonists. We measured the initial and steady-state effects of diphenhydramine, a first-generation antihistamine, and loratadine, a second-generation antihistamine, by means of a comprehensive battery of psychometric tests that mirror real-world tasks.

Methods: Healthy volunteers (N = 98) were randomly assigned in a double-blind fashion to receive loratadine (n = 33), diphenhydramine (n = 32), or placebo (n = 33). A computerized test battery was administered at baseline, on day 1 after administration of the initial dose, and on days 3 and 5.

Results: After the initial dose, subjects taking diphenhydramine demonstrated poorer cognitive performance than subjects taking loratadine or placebo on tasks of divided attention, working memory, speed, and vigilance. Subjects taking diphenhydramine also reported greater fatigue and sleepiness and lower levels of motivation, and rated the quality of their performance as lower than subjects taking loratadine or placebo. On day 3, subjects taking diphenhydramine continued to show more fatigue and lower motivation, and rated the quality of their test performance as poorer than subjects taking loratadine or placebo. There were no differences between loratadine and placebo after the initial dose or steady-state (day 5) dosing for any measure of cognitive or psychomotor test performance, mood, or sedation.

Conclusions: Patients taking diphenhydramine may be at risk of lapses and significant errors that may lead to potential hazards and decreased work productivity.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Affect / drug effects*
  • Cognition / drug effects*
  • Diphenhydramine / adverse effects
  • Diphenhydramine / pharmacology*
  • Double-Blind Method
  • Female
  • Histamine H1 Antagonists / adverse effects
  • Histamine H1 Antagonists / pharmacology*
  • Humans
  • Hypnotics and Sedatives / pharmacology*
  • Loratadine / adverse effects
  • Loratadine / pharmacology*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Psychomotor Performance / drug effects*
  • Reference Values
  • Time Factors
  • Volunteers


  • Histamine H1 Antagonists
  • Hypnotics and Sedatives
  • Loratadine
  • Diphenhydramine