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Study Title and Description

Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption.



Key Questions Addressed
1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on behavior*?
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Primary Publication Information
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TitleData
Title Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption.
Author PJ Rogers,C Hohoff,SV Heatherley,EL Mullings,PJ Maxfield,RP Evershed,J Deckert,DJ Nutt,
Country
Year 2010
Numbers

Secondary Publication Information
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Extraction Form: Behavior - Design Details - INCLUDED Studies
Arms
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 20520601
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What outcome is being evaluated in this paper? Behavior
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What is the objective of the study (as reported by the authors)? 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.
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Provide a general description of the methods as reported by the authors. Information should be extracted based on relevance to the SR (i.e., caffeine related methods) The participants were 218 women and 198 men recruited from various surveys and advertisments. This was a double-blind, parallel groups, repeated-measures study. After overnight caffeine abstinence (16h), participants received one of two treatments: either 100 mg of caffeine followed 90 min later by a further 150 mg of caffeine, or placebo on both the occasions. Caffeine BP (caffeine anhydrous powder; Courtin and Warner, Lewes, East Sussex, UK) and placebo (cornflour) were administered in white, size 1 cellulose capsules (Capsuline, Pompano Beach, Florida, FL, USA). These caffeine and placebo capsules were identical in appearance, and were swallowed with 50 ml of room temperature water. Each dose was contained in a single capsule.MAPSS was used to measure anxiety, alertness, and headache. It was adapted from similar instruments used in previous studies on the effects of caffeine (Rogers et al, 2005, 2008). ANOVA, run using SPSS 12.0.1 for Windows, was used to analyze the data on anxiety, alertness, and headache. Age as a covariate and gender as a factor were included in all these analyses. In addition, for certain analyses of the effects of caffeine vs placebo on anxiety, baseline (pretreatment) anxiety score was also included as a covariate. This is similar to the approach of calculating change from baseline scores (Childs et al, 2008), and was done to control for preexisting individual differences in anxiety in these analyses. Baseline differences in anxiety as a function of consumer status and genotype group were small (see Results). For genotype data, Hardy–Weinberg equilibrium and LD analyses were performed using Haploview 4.0 (Barrett et al, 2005).
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How many outcome-specific endpoints are evaluated? 2
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What is the (or one of the) endpoint(s) evaluated? (Each endpoint listed separately) Anxiety
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List additional health endpoints (separately).
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List additional health endpoints (separately)
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Notes Endpoints are evaluated and compared for various genotypes and habitual consumption patterns within the study population.
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Clinical Clinical
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Physiological
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Other
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What is the study design? Controlled Trial
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Randomized or Non-Randomized? NCT
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What were the diagnostics or methods used to measure the outcome? Subjective
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Optional: Name of Method or short description Mood, Alertness, and Physical Sensations Scales (MAPSS)
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Caffeine (general) Caffeine (general)
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Coffee
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Chocolate
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Energy drinks
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Gum
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Medicine/Supplement
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Soda
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Tea
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Measured Measured
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Self-report
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Children
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Adolescents
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Adults Adults
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Pregnant Women
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Placebo vs. caffeine group
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What were the listed confounders or modifying factors as stated by the authors? (e.g. multi-variable components of models.  Copy from methods) Age as a covariate and gender as a factor were included in all analyses. In addition, for certain analyses of the effects of caffeine vs placebo on anxiety, baseline (pretreatment) anxiety score was also included as a covariate. Smoking was also included as a covariate in various analyses.
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Provide a general description of results (as reported by the authors). The analyses of the effects of caffeine as a function of level of habitual caffeine consumption (four consumer status groups) revealed no effects (P>0.05) involving dose/session for either anxiety, alertness, or headache, so for the results shown in Figure 1 mean values were calculated across post treatment sessions using the formula (session 1 + ((session 2 + session 3)/2))/2. Figure 1 shows that caffeine increased anxiety in N and L participants. It did not affect anxiety in either M or H participants. Headache was increased in H participants who received placebo, and increased by caffeine in L participants. At baseline there were consumer status effects for anxiety (F(3, 370) = 2.66, P = 0.048), alertness (F(3, 365) = 5.74, P = 0.001, smoking also included as a covariate), and headache (F(3, 370) = 5.05, P = 0.002). Higher habitual caffeine intake was associated with greater anxiety, lower alertness, and more headache at baseline. The placebo group in Figure 1 shows continuation and worsening of these effects. For the ADORA2A rs5751876 SNP, which has previously been found to be associated with caffeine-induced anxiety (see Introduction), there was an effect of caffeine (F(1, 366)=8.97, P=0.003), an effect of genotype (F(2, 366)=7.12, P=0.0009), and a nonsignificant caffeine by genotype interaction (F(2, 366)=2.72, P=0.067) for anxiety in session 1 (after 100 mg caffeine). Figure 3 shows that caffeine increased anxiety in the TT genotype group but not in the CC or CT genotype groups.
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Did the authors perform a dose-response analysis (or trend/related analysis)? No
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What were the authors's observations re: trend analysis?
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What were the author's conclusions? 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. 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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What were the sources of funding? This research was funded by a grant (BBS/B/01855) from the Biotechnology and Biological Sciences Research Council, UK.
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What conflicts of interest were reported? The authors declare that over the past 3 years PJR has received consulting fees from Unilever; and grants for research from Barry Callebaut, Cadbury, DSM, GSK, and Unilever. DJN has received consulting fees from Pfizer, GSK, MSD, BMS, Esteve, Novartis, Asahi, Organon, Cypress, Lilly, Janssen, Takeda, Phamacia, Therasci, Passion for Life, Hythiam, Servier, Roche, sanofi-aventis, Actelion, Lundbeck, and Wyeth; speaker’s fees from Reckitt-Benkiser and Cephalon; grants for research or clinical trial payments from MSD, GSK, Novartis, Servier, Janssen, Yamanouchi, Lundbeck, Pfizer, Wyeth, Organon, AZ, Cephalon, P1vital, MoD, and NHS; and he has worked for the UK Government’s Committee on Safety of Medicines, the Advisory Council on the Misuse of Drugs, and the British National Formulary. JD has received speaker’s fees for educational seminars from AstraZeneca, BMS, GSK, Janssen-Cilag, Pfizer, and Wyeth. The other authors declare no conflicts of interest.
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Does the exposure (dose) need to be standardized to the SR? No
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Provide calculations/conversions for the exposure based on the decision tree in the guide (for all endpoints/exposure levels of interest).
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List all the endpoint(s) followed by the dose (mg) which will be used in comparison to Nawrot.  Characterize value as LOAEL/NOAEL, etc. if possible.  Analyses of habitual consumption: Headache NOAEL = 250 mg/d Anxiety NOAEL = 250 mg/d Analyses of ADORA2A TT genotypes: Anxiety LOAEL = 100 mg/d
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. Headache and anxiety NOAELs were calculated in an analyses of the effects of caffeine as a function of level of habitual caffeine consumption in four consumer status groups (non-, low, medium, and high habitual consumption). Authors further analyzed caffeine effects within individual consumer groups and observed effects in non- and low habitual consumer groups but not medium or high habitual consumer groups. In the genotype analyses, significant increases in anxiety were seen in the ADORA2A rs5751876 SNP TT genotype group, but not the CC or CT.
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What is the importance of the study with respect to the adverseness of the outcome? Important
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