Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety

Neuropsychopharmacology. 2008 Nov;33(12):2791-800. doi: 10.1038/npp.2008.17. Epub 2008 Feb 27.


Caffeine produces mild psychostimulant and sometimes anxiogenic effects by antagonizing adenosine at A(1) and A(2A) receptors, and perhaps through interactions with other transmitter systems. Adenosine receptors are colocalized and functionally interact with dopamine receptors in the brain. Thus, functional polymorphisms in the genes for either adenosine or dopamine receptors may affect responses to caffeine. In this study, we examined associations between self-reported anxiogenic effects of caffeine and variation in the genes for A(2A) (ADORA2A) and DRD(2) (DRD2) receptors. Healthy male and female individuals (n=102), who consumed less than 300 mg caffeine per week, ingested capsules containing 0, 50, 150, and 450 mg caffeine under double-blind conditions in four separate experimental sessions. Subjective anxiety was measured before and at repeated times after capsules were consumed. At the 150 mg dose of caffeine, we found a significant association between caffeine-induced anxiety (Visual Analog Scales, VAS) and ADORA2A rs5751876 (1976C/T), rs2298383 (intron 1a) and rs4822492 (3'-flank), and DRD2 rs1110976 (intron 6). Caffeine-induced anxiety (VAS) was also associated with two-loci interactions of selected ADORA2A and DRD2 polymorphisms. The lowest dose of caffeine did not increase ratings of anxiety while the highest dose increased anxiety in the majority of subjects. These findings provide support for an association between an ADORA2A polymorphism and self-reported anxiety after a moderate dose of caffeine. It is likely that other ADORA2A and DRD2 polymorphisms also contribute to responses to caffeine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine / metabolism
  • Adolescent
  • Adult
  • Anxiety Disorders / chemically induced*
  • Anxiety Disorders / genetics
  • Anxiety Disorders / physiopathology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Brain Chemistry / drug effects
  • Brain Chemistry / genetics
  • Caffeine / toxicity*
  • DNA Mutational Analysis
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genetic Variation / genetics
  • Genotype
  • Humans
  • Male
  • Phosphodiesterase Inhibitors / pharmacology
  • Polymorphism, Genetic*
  • Receptor, Adenosine A2A / drug effects*
  • Receptor, Adenosine A2A / genetics
  • Receptors, Dopamine D2 / drug effects*
  • Receptors, Dopamine D2 / genetics
  • Self-Assessment
  • Young Adult


  • Phosphodiesterase Inhibitors
  • Receptor, Adenosine A2A
  • Receptors, Dopamine D2
  • Caffeine
  • Adenosine
  • Dopamine