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Randomized Controlled Trial
, 35 (9), 1973-83

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

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Randomized Controlled Trial

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

Peter J Rogers et al. Neuropsychopharmacology.

Abstract

Caffeine, a widely consumed adenosine A(1) and A(2A) 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.

Figures

Figure 1
Figure 1
Effects of caffeine on anxiety, alertness, and headache as a function of level of habitual caffeine consumption (corresponding to the non- (N), low (L), medium (M) and high (H) consumer groups described in Table 2). The data are for session 1 (after 100 mg caffeine) pooled with sessions 2 and 3 (after a second dose, 150 mg, of caffeine). Note that smoking was included as a covariate in the analysis of the data for alertness (see text for rationale). **P<0.01 and *P<0.05 for caffeine vs placebo within consumer group (Bonferroni t).
Figure 2
Figure 2
Genomic organization and linkage disequilibrium (LD) structure of the ADORA2A gene (NM_000675), and the ADORA1 (NM_000674) gene. SNP positions relative to the 5′ promoter region, exons (numbered consecutively; ADORA2A coding exons are 4 and 5, and ADORA1 coding exons are 5 and 6) and introns are shown by arrows. Shades of gray represent extent of LD (black denotes D′=1) and numbers in boxes give R2 values (>0.5 denotes high LD, >0.9 denotes nearly complete LD in bold).
Figure 3
Figure 3
Effect of 100 mg caffeine (session 1 data, see text) on anxiety as a function of ADORA2A rs5751876 genotype group. **P<0.01 for caffeine vs placebo within TT genotype group (Bonferroni t).
Figure 4
Figure 4
Effect of caffeine on anxiety as a function of habitual level of caffeine consumption and ADORA2A rs5751876 genotype group (with baseline anxiety included as a covariate). The data are for session 1 (after 100 mg caffeine) pooled with sessions 2 and 3 (after a second dose, 150 mg, of caffeine). NL, non- and low consumers; MH, medium and high consumers. Top panel: CC and CT genotype groups combined. Bottom panel: TT genotype group. **P<0.01 and *P<0.05 for caffeine vs placebo within consumer and genotype group (Bonferroni t).
Figure 5
Figure 5
Habitual caffeine consumption as a function of ADORA2A rs5751876 genotype group. ‘Other' sources of caffeine were cola, energy drinks, and chocolate. *P<0.05 (adjusted for multiple tests).

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