Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption
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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.
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ADORA2A polymorphisms operate more at the pharmacodynamic level-specifically, an individual's sensitivity to the blockade of adenosine A2A receptors.
“Unlike *CYP1A2*, which primarily influences pharmacokinetics, *ADORA2A* polymorphisms operate more at the pharmacodynamic level—specifically, an individual’s sensitivity to the blockade of adenosine A2A receptors.”
From Pre-Exercise Caffeine as a Modulator of Exercise-Induced Acute Cardiometabolic Responses: A Narrative Review (2026) · cites this paper as [98]
The Introduction (page unavailable) describes caffeine as an adenosine A2A receptor antagonist, and the Results and Discussion (page unavailable) link ADORA2A variants to differences in caffeine-induced anxiety. The paper does not establish that the variants alter sensitivity to receptor blockade specifically, nor does it address the comparison with CYP1A2 pharmacokinetics. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn adults, tolerance to the anxiogenic effect of caffeine develops with frequent consumption, even in genetically susceptible individuals.
“In adults, tolerance to the anxiogenic effect of caffeine develops with frequent consumption, even in genetically susceptible individuals (Rogers et al., 2010).”
From Scientific Opinion on the safety of caffeine (2015) · cites this paper as Rogers et al., 2010
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- Authors
- Rogers, P. J., Hohoff, C., Heatherley, S. V., Mullings, E. L., Maxfield, P. J., Evershed, R. P., Deckert, J., & Nutt, D. J.
- Affiliations
- University of Bristol (GB)
- University of Münster (DE)
- University of Würzburg (DE)
- Hammersmith Hospital (GB)
- Corresponding author
- Rogers, Peter J
- Venue
- Neuropsychopharmacology
- Published
- 2010-06-02
- Volume
- 35
- Issue
- 9
- Pages
- 1973-1983
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3055635
- OpenAlex
- W2133998876
- Cited by
- 212
- References
- 37
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 13 · 2021: 19 · 2020: 16 · 2019: 10 · 2018: 16 · 2017: 17 · 2016: 11 · 2015: 11 · 2014: 14 · 2013: 11 · 2012: 20
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion)
- HAL (submittedVersion, other-oa)
- SHURA (Sheffield Hallam University Research Archive) (Sheffield Hallam University) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BBS/B/01855)
- Topics
- Health Sciences › Medicine › Pharmacology › Coffee research and impacts
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- caffeine, anxiogenic effects, alertness, adenosine A2A receptor, adenosine A1 receptor, adenosine receptors, single nucleotide polymorphisms, caffeine tolerance, headache, coffee consumption, genetic susceptibility
- MeSH terms
- Adult, Central Nervous System Stimulants, Anxiety, Arousal, Caffeine, Dose-Response Relationship, Drug, Double-Blind Method, Female, Genotype, Headache, Humans, Male, Middle Aged, Polymorphism, Genetic, Psychomotor Performance, Reaction Time, Saliva, Substance Withdrawal Syndrome, Xanthines, Linkage Disequilibrium, Receptor, Adenosine A1, Receptor, Adenosine A2A, Young Adult
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