Cytokine-associated emotional and cognitive disturbances in humans

Arch Gen Psychiatry. 2001 May;58(5):445-52. doi: 10.1001/archpsyc.58.5.445.


Background: Infectious, autoimmune, and neurodegenerative diseases are associated with profound psychological disturbances. Studies in animals clearly demonstrate that cytokines mediate illness-associated behavioral changes. However, the mechanisms underlying the respective psychological alterations in humans have not been established yet. Therefore, we investigated the effects of low-dose endotoxemia, a well-established and safe model of host-defense activation, on emotional, cognitive, immunological, and endocrine parameters.

Methods: In a double-blind, crossover study, 20 healthy male volunteers completed psychological questionnaires and neuropsychological tests 1, 3, and 9 hours after intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) or saline in 2 experimental sessions. Blood samples were collected hourly, and rectal temperature and heart rate were monitored continuously.

Results: Endotoxin had no effects on physical sickness symptoms, blood pressure, or heart rate. Endotoxin caused a mild increase in rectal temperature (0.5 degrees C), and increased the circulating levels of tumor necrosis factor alpha (TNF-alpha), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. After endotoxin administration, the subjects showed a transient significant increase in the levels of anxiety (effect size [ES] = 0.55) and depressed mood (ES = 0.66). Verbal and nonverbal memory functions were significantly decreased (ES = 0.55 to 0.64). Significant positive correlations were found between cytokine secretion and endotoxin-induced anxiety (r = 0.49 to r = 0.60), depressed mood (r = 0.40 to r = 0.75), and decreases in memory performance (r = 0.46 to r = 0.68).

Conclusions: In humans, a mild stimulation of the primary host defense has negative effects on emotional and memory functions, which are probably caused by cytokine release. Hence, cytokines represent a novel target for neuropsychopharmacological research.

Publication types

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

MeSH terms

  • Adult
  • Affective Symptoms / immunology
  • Affective Symptoms / physiopathology*
  • Blood Pressure / drug effects
  • Blood Pressure / immunology
  • Body Temperature Regulation / drug effects
  • Body Temperature Regulation / immunology
  • Cognition Disorders / immunology
  • Cognition Disorders / physiopathology*
  • Cytokines / immunology
  • Cytokines / physiology*
  • Drug Design
  • Emotions / drug effects
  • Endotoxemia / immunology
  • Endotoxemia / physiopathology
  • Endotoxins / pharmacology
  • Heart Rate / drug effects
  • Heart Rate / immunology
  • Humans
  • Male
  • Memory / drug effects
  • Psychotropic Drugs / therapeutic use


  • Cytokines
  • Endotoxins
  • Psychotropic Drugs