Original Article

Neuropsychopharmacology (2010) 35, 1973–1983; doi:10.1038/npp.2010.71; published online 2 June 2010

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

Peter J Rogers1, Christa Hohoff2, Susan V Heatherley1, Emma L Mullings1, Peter J Maxfield3, Richard P Evershed3, Jürgen Deckert4 and David J Nutt5

  1. 1Department of Experimental Psychology, University of Bristol, Bristol, UK
  2. 2Department of Psychiatry, University of Münster, Münster, Germany
  3. 3School of Chemistry, University of Bristol, Bristol, UK
  4. 4Department of Psychiatry, University of Würzburg, Würzburg, Germany
  5. 5Department of Neuropsychopharmacology and Molecular Imaging, Imperial College London, Hammersmith Hospital Campus, London, UK

Correspondence: Professor PJ Rogers, Department of Experimental Psychology, University of Bristol, 12a Priory Road, Bristol BS8 1TU, UK. Tel: +440 117 928 8584; Fax: +440 117 928 8588; E-mail: peter.rogers@bristol.ac.uk

Received 2 November 2009; Revised 3 March 2010; Accepted 15 April 2010; Published online 2 June 2010.



Caffeine, a widely consumed adenosine A1 and A2A receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine. Participants were 162 non-/low (NL) and 217 medium/high (MH) caffeine consumers. In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100mg caffeine and again after another 150mg caffeine given 90min later, or after placebo on both occasions. Caffeine intake was prohibited for 16h before the first dose of caffeine/placebo. Results showed greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake (indeed coffee intake was higher), in the rs5751876 TT genotype group, and a reduced anxiety response in MH vs NL participants irrespective of genotype. Apart from the almost completely linked ADORA2A SNP rs3761422, no other of eight ADORA2A and seven ADORA1 SNPs studied were found to be clearly associated with effects of caffeine on anxiety, alertness, or headache. Placebo administration in MH participants decreased alertness and increased headache. Caffeine did not increase alertness in NL participants. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.


caffeine; adenosine; polymorphism; anxiety; alertness; headache



These links to content published by NPG are automatically generated

Extra navigation