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Study Title and Description

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects.



Key Questions Addressed
1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on cardiovascular outcomes?
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Primary Publication Information
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TitleData
Title Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects.
Author SC Sigmon,RI Herning,W Better,JL Cadet,RR Griffiths,
Country
Year 2009
Numbers

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Cardiovascular Design
Design Details
Question... Follow Up Answer Follow-up Answer
What outcome is being evaluated in this paper? Cardiovascular
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What is the objective of the study (as reported by the authors)? Caffeine withdrawal, acute caffeine effects, caffeine tolerance, and net beneficial effects of chronic caffeine administration were investigated using cerebral blood flow velocity, quantitative EEG and subjective effects.
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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) Participants: Participants were recruited through newspaper advertisements and notices on bulletin boards in the community. Applicants were screened for eligibility by telephone and then in person. The screening included a medical, psychiatric, dietary and drug use history. Vital signs including blood pressure, heart rate, respiration and body temperature were taken. Participants were eligible for inclusion in the study if they were: 18 to 55 years old, within +/- 20% of ideal body weight and consumed a minimum of 50 mg of caffeine daily (based on a seven-day food diary). Individuals were excluded if they: reported a history of a significant psychiatric disorder (e.g., bipolar disorder, psychotic disorder, schizophrenia); had abnormal blood pressure or heart rate; had a physical condition contraindicating the consumption of caffeine; reported a history of seizures or head injury with loss of consciousness; reported using illicit drugs recently or currently taking any prescription medication except for oral contraceptives; provided a urine sample at screening that tested positive for illicit drugs. Participants were told that the purpose of the study was to evaluate the effects of ingredients normally found in foods, beverages and over-the-counter medications on mood and physiology. To divert attention away from caffeine, they were told that they could receive any of the following compounds in capsules: chlorogenic acids, diterpines, caffeine, tannin, theobromine, theophylline, diphenhydramine or placebo (no drug). Study design: The 7-week outpatient study used a double-blind, within-subject cross-over design to examine the effects of acute caffeine and placebo administration under conditions of caffeine maintenance (400 mg per day) and placebo maintenance. Eight participants received the placebo maintenance phase first, after which they received the caffeine maintenance phase; eight received the caffeine maintenance phase first, after which they received the placebo maintenance phase. Each maintenance phase lasted approximately 21 days and involved twice-daily consumption of capsules containing either placebo or caffeine. Within each maintenance phase, subjects participated in two challenge sessions (a caffeine and a placebo challenge session). Order of challenge sessions was mixed within and across subjects. Participants were maintained on placebo or caffeine for a minimum of 14 days before the first challenge session. Each challenge session consisted of oral administration of either caffeine (200 mg b.i.d.) or placebo (b.i.d.), followed by collection of subjective and physiological measures (described below). Thus, there were a total of four challenge sessions from the two phases, with two challenges per phase: 1) in order to examine cerebral blood flow and EEG during chronic caffeine administration, one challenge session involved approximately two weeks of caffeine maintenance followed by a challenge day on which the participant received caffeine (caff/caff); 2) in order to examine the effects of acute caffeine withdrawal on these measures, a challenge session involved caffeine maintenance followed by a challenge day on which the participant received placebo (caff/plac); 3) in order to provide an assessment during chronic placebo administration, a challenge session involved placebo maintenance followed by a challenge day on which the participant received placebo (plac/plac) and 4) in order to examine the effects of acute caffeine administration on these measures, a fourth challenge session involved placebo maintenance followed by a challenge day on which the participant received caffeine (plac/caff). Participants came to the laboratory three times per week throughout the study to provide saliva samples, complete subjective measures, and to take the afternoon capsule under the observation of the research staff. At each study visit, participants were required to bring with them their container of capsules so that research staff could count the remaining pills to monitor compliance with the capsule ingestion schedule. At one visit per week, participants received a new container of capsules for the upcoming week and returned the empty container. During the caffeine maintenance phase, they ingested a capsule containing 200 mg caffeine anhydrous twice daily, once between 8 and 9 AM in the morning and then again between 2 and 3 PM, for a total daily caffeine dose of 400 mg. During the placebo maintenance phase, participants ingested a placebo capsule twice daily (8-9 AM and 2-3 PM). For the eight subjects who received the caffeine maintenance phase first, caffeine content in the daily capsules was gradually reduced during the first 3 days of the subsequent placebo maintenance phase to minimize caffeine withdrawal symptoms when switching from the caffeine to placebo maintenance condition.
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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) Cerebral blood flow
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List additional health endpoints (separately). 2 Blood pressure
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List additional health endpoints (separately).3
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List additional health endpoints (separately).4
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List additional health endpoints (separately).5
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List additional health endpoints (separately).6
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Clinical, physiological, other Physiological
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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? Objective
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Optional: Name of Method or short description Cerebral blood flow velocity was measured with participants sitting in a reclined position in a quiet room. The cerebral blood flow velocity was determined using a temporal window (zygomatic arch) for four arteries (right and left middle (MCA) cerebral arteries, right and left anterior (ACA) cerebral arteries) using pulsed Transcranial Doppler Sonography (Nicolet, Model TC2000). Mean velocity (VM: cm/s), systolic velocity (VS: cm/s), diastolic velocity (VD: cm/s), and pulsatility index (PI=(VS-VD)/VM) were determined for each artery. The blood flow measurements were taken approximately 60 minutes after the afternoon capsule administration.
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Caffeine (general) Caffeine (general)
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Coffee, Chocolate, energy drink, gum, medicine/supplement, soda, tea, other?
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Measured or self reported? Measured
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Children, adolescents, adults, or pregnant included? Adults
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Placebo group. All subjects eventually received either caffeine or placebo treatment.
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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) A condition (caff/plac, caff/caff, plac/plac, plac/caff) by side (right vs. left) repeated measures analysis of variance was performed using SAS PROC MIXED on blood flow velocity measures. Because of equipment failure, cerebral blood flow data were missing in one condition from each of two subjects; however, the data from the other three conditions for these participants were included in these analyses. PROC MIXED was chosen because this analytical model is capable of modeling repeated measures designs with missing values. While there were several significant main effects of side, there were no significant condition x side interactions. Because side differences were not the primary focus of the present study, data were collapsed across side. Post-hoc comparisons (Fisher's LSD) were conducted to compare the acute caffeine withdrawal condition to the other control conditions used in the study. These post-hoc comparisons were limited to the variables showing significant effects of condition. More specifically, five post-hoc tests were conducted: 3 comparing the caff/plac (acute abstinence) condition to each of the other three conditions (caff/caff, plac/plac, plac/caff). The fourth posthoc test compared the acute abstinence condition (caff/plac) to a combined control, in which the means of the two chronic maintenance conditions (caff/caff and plac/plac) were combined. The fifth test compared the chronic caffeine to the chronic placebo condition. Adjustments for sphericity were done using Huynh-Feldt corrections.
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What conflicts of interest were reported? Conflicts were not discussed.
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Refid 19241060
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What were the sources of funding? This research was supported in part by research grant R01 DA-03890 and training grant T32-DA07209 from the National Institute on Drug Abuse.
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Results & Comparisons

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