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

Author(s): Peter J Rogers, Christa Hohoff, Susan V Heatherley, Emma L Mullings, Peter J Maxfield, Richard P Evershed, Jürgen Deckert, David J Nutt


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 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. Caffeine intake was prohibited for 16 h 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.


by Peter Rogers
Previous research has found individual differences in susceptibility to the anxiety-increasing effect of caffeine, and some studies have linked this to a variant of the gene that codes for the adenosine A2A receptor (various effects of caffeine are caused by it blocking the action of endogenous adenosine at this receptor). Our study compared the effects of caffeine in people who rarely or never consume caffeine-containing products (coffee, tea, cola etc) with its effects in frequent caffeine consumers. We conducted tests on nearly 400 individuals who abstained from caffeine for 16 hours before being given either caffeine or a placebo. We also measured the frequency of the anxiety-susceptible genotype in the two populations (frequent and infrequent consumers). Contrary to our hypothesis, this frequency did not differ, so it appears that this susceptibility to caffeine-induced does not deter caffeine consumption. Other results of the study suggest that this is because the anxiety effect of caffeine is rather small (even in susceptible individuals and even after a dose of caffeine equivalent to 1.5 cups of ground coffee), and frequent consumption leads to a reduction in the anxiety effect of caffeine (tolerance), again even in genetically susceptible individuals.

A further finding from the study was that frequent caffeine consumers deprived of caffeine overnight and given placebo felt much less alert than infrequent consumers given placebo. Caffeine restored alertness of the infrequent caffeine consumers to the same level as infrequent consumers given placebo, but not above this level. This fits with other evidence supporting the so-called ‘withdrawal reversal hypothesis.’ That is, although as frequent caffeine consumers we feel more alert after consuming caffeine, this is actually caffeine just brining us back to normal.