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Study Title and Description

Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety.



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 between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety.
Author E Childs,C Hohoff,J Deckert,K Xu,J Badner,H de Wit,
Country
Year 2008
Numbers

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There are currently no secondary publications defined for this study.


Extraction Form: Behavior - Design Details - INCLUDED Studies
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 18305461
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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)? In this study, we aimed to replicate and extend our previous finding that certain ADORA2A SNPs are associated with self-reported anxiety after 150 mg caffeine. We tested the association in a separate group of subjects and also investigated these effects at other doses of caffeine (0, 50, and 450 mg). Furthermore, we examined associations between self-reported anxiety after caffeine and additional genetic variations in ADORA2A and DRD2. As in the previous study, we assessed association in volunteers who consumed less than 300 mg caffeine (approximately three cups) per week to minimize the influences of tolerance or dependence. We hypothesized that variation in ADORA2A rs5751876 (1976C/T) would predict self-reported anxiety after 150 mg caffeine. We also predicted that genetic variation in DRD2 would affect anxiety after 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) Male (N=51) and female (N=51) light, or non-caffeine consumers, aged 18–35 years, were recruited, without regard to race or ethnicity, from the University and surrounding community. Eligible participants attended a brief in-person psychiatric interview and physical examination including an electrocardiogram. Exclusion criteria included a current or prior diagnosis of Major Axis I DSM-IV disorder, any history of psychosis, daily smoking (Hart et al, 1976), less than a high-school education, lack of fluency in English, a body mass index outside of 19–26 kg/m2, night shift work, high blood pressure, abnormal electrocardiogram, daily use of any medications, and in women, use of birth control pills, pregnancy, or breast feeding. Participants were queried about all dietary sources of caffeine upon which estimates of caffeine intake were based (50 mg per 12 oz serving of caffeinated soft drinks, 60 mg per 8 oz serving of tea, 100 mg per 8 oz serving of coffee, and 10 mg per bar of chocolate). Subjects kept a detailed diary of food and beverage consumption for 2 weeks prior to testing to confirm their initial self-reports. Participants’ ethnicity was determined by self-report. Before the study began, participants attended a short orientation session in which they read and signed the consent form, were familiarized with the experimental procedures, and completed personality and drug use questionnaires. The consent form stated that the study would investigate the effects of drugs upon mood and performance. For blinding purposes, volunteers were advised that they might receive one of several classes of drugs, including stimulants, tranquilizers, or inactive placebos. The study utilized a four-session, double-blind, placebo-controlled, within-subject design. Each subject received placebo, 50, 150, or 450 mg caffeine in random order during four test sessions conducted at least 72 h apart. Sessions were conducted from 0900 to 1300 h. Subjects refrained from eating from midnight on the night previous to sessions and were given a light snack on arrival in the laboratory at 0900 h. Before ingesting the capsule, urine tests were conducted to detect recent drug use and breath samples collected to verify that they were alcohol free. No subjects tested positive. Subjects then completed pre-capsule subjective measures (Profile of Mood States (POMS), Visual Analog Scales (VAS); see below). At 0930 h, subjects ingested a capsule containing placebo or caffeine (50, 150, or 450 mg). Subjective measures were obtained again 30, 60, and 90 min after capsule administration. Subjects also completed behavioral tasks and physiological data were obtained (heart rate, blood pressure) that are not included in this analysis. The focus of this report is subjective anxiety, which was assessed using POMS (McNair et al, 1971) and VAS (Folstein and Luria, 1973). The POMS is a 72-item adjective checklist on which subjects report their current mood on a 5-point scale from ‘not at all’ (0) to ‘extremely’ (4). The adjectives comprising the anxiety scale included tense, shaky, on edge, panicky, relaxed, restless, uneasy, nervous, and anxious. The VAS consisted of a 100mm horizontal line labeled with ‘not at all anxious’ at one end (score of 0) and ‘extremely anxious’ at the other (score of 100). Subjects were instructed to place a mark indicating how anxious they felt at that moment. Caffeine was administered as caffeine citrate as it is more bioavailable than anhydrous caffeine. Caffeine citrate (Mallinckrodt Baker Inc., Paris, KY) was obtained from the University Hospital Pharmacy. Caffeine citrate doses are equivalent to approximately half the caffeine freebase dose. All data are expressed in mg of freebase caffeine. Doses of caffeine were administered in opaque gelatin capsules with dextrose as filler. Placebo capsules contained only dextrose. Subjective effects of caffeine for each subject were calculated as a peak change score for each separate session that is, 0, 50, 150, and 450 mg caffeine. The pre-capsule baseline was subtracted from the maximum response exhibited during 90 min after capsules were administered. The effect of order of dose presentation upon subjective responses was examined by two-factor (dose × order) analysis of variance (ANOVA) for repeated measures upon peak change scores.
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How many outcome-specific endpoints are evaluated? 1
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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 measured using POMS and VAS
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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? RCT
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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 The POMS is a 72-item adjective checklist on which subjects report their current mood on a 5-point scale from ‘not at all’ (0) to ‘extremely’ (4). The adjectives comprising the anxiety scale included tense, shaky, on edge, panicky, relaxed, restless, uneasy, nervous, and anxious. The VAS consisted of a 100mm horizontal line labeled with ‘not at all anxious’ at one end (score of 0) and ‘extremely anxious’ at the other (score of 100). Subjects were instructed to place a mark indicating how anxious they felt at that moment.
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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 controlled (dextrose, 0 mg caffeine) compared to 50 mg, 150 mg, 450 mg caffeine
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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) ADORA2A and DRD2 polymorphisms
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Provide a general description of results (as reported by the authors). Caffeine had its expected effects on subjective state and vital signs, when all subjects were considered together. These effects have been reported in detail elsewhere (Childs and de Wit, 2006). Only the highest dose (450 mg) significantly increased ratings of anxiety (VAS; Figure 3).
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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? In the group as a whole, caffeine (0, 50, 150, or 450 mg) produced its expected effects (Childs and de Wit, 2006), and only the highest dose increased self-reported anxiety.
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What were the sources of funding? This research was supported by NIDA (DA02812) and the General Clinical Research Center (USPHS MO1RR000555).
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What conflicts of interest were reported? All authors reported no biomedical financial interests or potential 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.  Anxiety - NOAEL = 150 mg/day ; LOAEL = 450 mg/day Anxiety - LOAEL = 150 mg/day for the ADORA2A TT genotype
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. overall, effects seen above levels seen in Nawrot; however certain genotypes were associated with significant increases in anxiety after 150 mg
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What is the importance of the study with respect to the adverseness of the outcome? Important
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