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Study Title and Description

Association between A2a receptor gene 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 A2a receptor gene polymorphisms and caffeine-induced anxiety.
Author K Alsene,J Deckert,P Sand,H de Wit,
Country
Year 2003
Numbers

Secondary Publication Information
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Extraction Form: Behavior - Design Details - INCLUDED Studies
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Design Details
Question... Follow Up Answer Follow-up Answer
Refid 12825092
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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 was designed to assess responses to an acute dose of caffeine in relation to polymorphisms in the A1 and A2a receptor genes in infrequent caffeine users.
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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) A total of 100 healthy, infrequent caffeine users, 54 men and 46 women, completed the behavioral portion of the study. Only individuals who reported a weekly caffeine consumption of less than 300 mg, including the intake of coffee, tea, caffeinated sodas, and other dietary sources of caffeine, were accepted. Caffeine consumption was based on estimates of 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 (Durrant, 2002). Eligibility was determined via a telephone interview and a brief in-person psychiatric interview. The psychiatric interview consisted of questions relating to current anxiety, depression, and psychosis, and it was conducted by an individual knowledgeable in DSM-IV diagnosis (APA, 2000). Subjects were excluded if they had any history of substance abuse or dependence, if they reported high levels of anxiety or depression, any history of psychosis, or use of more than 300 mg of caffeine per week. Cigarette smokers were not accepted because smoking has been shown to reduce the half-life of caffeine (Hart et al, 1976). Subjects were also excluded if they had high blood pressure or used any medication on a daily basis. Drugs Subjects participated in two sessions, separated by at least 2 days, in which they received either placebo or caffeine (150 mg freebase). Caffeine and placebo were administered in random order and under double-blind conditions. Caffeine was administered in the form of caffeine citrate because it is more bioavailable than anhydrous caffeine. The caffeine citrate (300 mg) is equivalent to about 150 mg caffeine freebase, and this dose has been shown to produce subjective, physiological, and behavioral effects (Lader, 1969; Gupta, 1993; Gupta et al, 1994; White et al, 1980). The caffeine capsules were white and contained caffeine citrate (Mallinckrodt Baker, Inc., Paris, KY) with dextrose filler. Placebo capsules contained dextrose alone. For blinding purposes, subjects were informed that they would receive a commonly used drug that could be a stimulant, sedative, or placebo. Sessions Before the study began, volunteers attended a short orientation session in which they read and signed the consent form. The study was approved by the University of Chicago’s Institutional Review Board. Subjects were instructed to abstain from taking any recreational drugs, including alcohol, nicotine, and caffeine, for 24 h before the sessions. They were also instructed to abstain from eating after midnight the night before the sessions. Sessions were conducted from 08.30 to 12.00 h noon with a minimum of 2 days between the sessions. Sessions for women were scheduled without regard to menstrual cycle phase as it has been shown that the pharmacokinetics of caffeine are not significantly altered during the menstrual cycle (Kamimori et al, 1999). Upon arrival in the laboratory, subjects provided breath and urine samples to confirm their compliance with abstinence instructions. They were given a light meal (bagel with cream cheese) to reduce stomach irritation from the caffeine capsule. Then they completed baseline (precapsule) mood questionnaires and measures. At 09.10 h, 30 min after consuming the bagel, they ingested a capsule with 150 ml of orange juice. Physiological, subjective, and behavioral measures were obtained 20, 40, 60, and 120 min after capsule administration. Physiological measurements included heart rate, blood pressure, and temperature. Subjective measurements included ratings of drug effects and mood (see below). Behavioral measurements consisted of two measures of psychomotor performance (see below). Subjective and behavioral tasks were administered via computer. Volunteers were allowed to watch emotionally neutral movies and read during the sessions when measurements were not being taken. On a separate visit, subjects provided a blood sample for genotyping and completed personality questionnaires.
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How many outcome-specific endpoints are evaluated? 3
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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 Primary objective was anxiety; other secondary moods measured included elation, vigor, stimulated, interested, content, drowsy, hungry, elated, sedated, nauseous
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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? 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 Visual analogue scale (VAS) and Profile of Mood States (POMS)
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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.) subjects received either a placebo (dextrose, no caffeine) or 300 mg caffeine citrate, equivalent to 150 mg pure 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) N/A
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Provide a general description of results (as reported by the authors). When the data from all 94 volunteers were examined together, caffeine produced its prototypic effects. On the subjective measurements, caffeine significantly (P<0.05) increased scores on Anxiety (VAS and POMS) and decreased scores on Depression (POMS) and Fatigue (POMS).
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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? The primary finding of this study was that acute anxiogenic responses to caffeine were associated with two linked polymorphisms in the A2a adenosine receptor gene. Based on previous reports indicating variability in anxiogenic responses to caffeine (Chait, 1992; Evans and Griffiths, 1991) and studies indicating that the adenosine receptor regulates anxiety, we hypothesized that polymorphisms in the A1 and A2a adenosine receptor gene may account for inter-individual variations in anxiety after administration of caffeine. Consistent with the hypothesis, we found that individuals with the linked 1976T/T and the 2592 Tins/Tins variants in the A2a adenosine receptor gene reported greater increases in anxiety after caffeine intake than did individuals in either of the other two genotypic groups. The three genotypic groups did not differ on other subjective measures of caffeine effects, including self-report measures of feeling stimulated or global ratings of drug effects. They also did not differ in physiological responses to caffeine (eg heart rate) or in the behavioral effects as measured by the psychomotor tasks. Thus, the genotypes were specifically related to the subjective experience of anxiety after caffeine, and not to other, more global measures of caffeine’s effects. The genotypes were not associated with variability in baseline ratings of anxiety, or ratings of anxiety after placebo, suggesting that the observed relations were related to the pharmacological effects of caffeine. We did not find any evidence for an association between A1 adenosine receptor gene polymorphisms and caffeine-induced anxiety.
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What were the sources of funding? This research was supported by DA02812 and Innovative Medizinische Forschung (IMF).
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What conflicts of interest were reported? N/A
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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 - LOAEL = 150 mg Depression - NOAEL = 150 mg Fatigue - NOAEL = 150 mg No information provided on any of the other adverse endpoints.
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Notes regarding selection/listing of endpoints and exposures/doses to be compared to Nawrot. single dose Caffeine significantly decreased depression and fatigue. Significant increase in anxiety on VAS and POMS.
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What is the importance of the study with respect to the adverseness of the outcome? Important
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