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Project: Systematic review of the adverse behavioral effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children

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Title Systematic review of the adverse behavioral effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children
Description To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10,000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field.
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Methodology Problem formulation was based on providing an update of Nawrot et al. (2003), “Effects of caffeine on human health,” [PMID 12519715]. No comprehensive studies of similar scope have been published in the peer-reviewed literature, and thus the overall objective is to conduct an update to Nawrot et al. that applies the rigor of a systematic review. This review is one of five systematic reviews being conducted simultaneously (other endpoints include acute toxicity and adverse effects on reproduction/development, cardiovascular, and bone and calcium balance outcomes. Exposure and comparators were thus based on levels determined by Nawrot et al., (2003). Searches: The searches were conducted using: PubMed, EMBASE, and the Cochrane Database of Systematic Review. The restrictions will be articles published in English between 2001 and June 8, 2015. EMBASE searches were exclusive of MEDLINE and restricted to selected journals (430 journals were selected based on relevance). The Cochrane library was searched between Jan 2001 and June 2015 for review articles. Search strategies were informed and reviewed by a librarian. Types of studies included: All study types (excluding case studies) characterizing a quantitative exposure to caffeine and an adverse bone and calcium balance endpoint will be included. Both exposure and response must be evaluated at the individual level. Reviews will not be included in the systematic assessment (unless original data, such as a meta analysis, were conducted), but selected reviews will be consulted for context. Include: studies reporting parameters or effects associated with adverse effects within a benefit/therapy study. Exclude: Studies assessing only beneficial or therapeutic endpoints or outcomes following exposure to caffeine. Participants/ population: Populations: healthy adults, healthy pregnant women, healthy adolescents (aged 12-19), healthy children (aged 3-12). Exposure: = 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). Comparator: < 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). *Applies to both adolescents and children. Include: Studies evaluating a healthy population; this will include athletes, military, and pregnant women, unless otherwise noted as unhealthy. Healthy in this context was defined as subjects who were not specifically described as hospitalized, diagnosed with disease, and/or receiving medical treatment for a disease at the time of the study. Include: Studies that evaluate the effects of caffeine exposure in humans. This included studies in which healthy individuals were included as a control group (or similar) as part of a study on unhealthy populations (only information from the healthy individuals would be carried forward). Include: crossover balance studies could with a control period rather than a control group. Exclude: Studies evaluating unhealthy populations with no healthy control arm; this includes asthmatics and smoking populations. Exclude: Studies that describe effects of caffeine exposure in animal species or in vitro studies. Exclude: Case studies with no comparison group.
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Funding Source This Systematic Review of the adverse behavioral effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children was sponsored by the North American Branch of the International Life Sciences Institute (ILSI) Caffeine Working Group. Unrestricted grants from the American Beverage Association (ABA) and the National Coffee Association (NCA) were also received.
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Key Questions

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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Associated Extraction Forms

Title Created by Key Questions Addressed Form Notes
Behavior - Design Details - INCLUDED Studies Ray DeVirgiliis 1

Associated Studies (each link opens a new tab)

Title Author Year
Naturalistic effects of five days of bedtime caffeine use on sleep, next-day cognitive performance, and mood E. K. Keenan, B. Tiplady, C. M. Priestley and P. J. Rogers 2014
Subjective state, blood pressure, and behavioral control changes produced by an "energy shot" C. A. Marczinski, A. L. Stamates, J. Ossege, S. F. Maloney, M. E. Bardgett and C. J. Brown 2014
Mood and Psychomotor Tremor Changes following Acute Caffeine Consumption in Moderate and Minimal Caffeine Consumers H. R. Sands, L. A. Downey, R. P. Wilson, L. R. Abbott, B. Tysse and A. C. Parrott 2015
Gender differences in subjective and physiological responses to caffeine and the role of steroid hormones J. L. Temple and A. M. Ziegler 2011
Effects of alcohol, coffee, and tobacco, alone or in combination, on physiological parameters and anxiety in a young population C. Vinader-Caerols, S. Monleon, C. Carrasco and A. Parra 2012
Risk factors for sleep bruxism in the general population. MM Ohayon,KK Li,C Guilleminault, 2001
Caffeine antagonism of alcohol-induced driving impairment. A Liguori,JH Robinson, 2001
Smoking relapse after 2 years of abstinence: findings from the VA Normative Aging Study. EA Krall,AJ Garvey,RI Garcia, 2002
Effects of caffeine on performance of low intensity tasks. WH Scott,KM Coyne,MM Johnson,CG Lausted,M Sahota,AT Johnson, 2002
Central and peripheral effects of sustained caffeine use: tolerance is incomplete. J Watson,I Deary,D Kerr, 2002
Effects of caffeine on mood and performance: a study of realistic consumption. CF Brice,AP Smith, 2002
The moderating effect of anxiety sensitivity on caffeine-induced hypoalgesia in healthy women. E Keogh,N Chaloner, 2002
Caffeine reinforces flavour preference in caffeine-dependent, but not long-term withdrawn, caffeine consumers. EM Tinley,MR Yeomans,PJ Durlach, 2003
Coffee increases state anxiety in males but not in females. P Botella,A Parra, 2003
Insomnia, metabolic rate and sleep restoration. MH Bonnet,DL Arand, 2003
Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. K Alsene,J Deckert,P Sand,H de Wit, 2003
Effects of acute exercise on the soleus H-reflex and self-reported anxiety after caffeine ingestion. RW Motl,RK Dishman, 2004
Situational insomnia: consistency, predictors, and outcomes. MH Bonnet,DL Arand, 2003
Effects of dietary caffeine on mood when rested and sleep restricted. JE James,ME Gregg, 2004
Caffeine as a risk factor for chronic daily headache: a population-based study. AI Scher,WF Stewart,RB Lipton, 2004
Sleep duration and caffeine consumption in a French middle-aged working population. M Sanchez-Ortuno,N Moore,J Taillard,C Valtat,D Leger,B Bioulac,P Philip, 2005
Caffeine deprivation state modulates coffee consumption but not attentional bias for caffeine-related stimuli. LD Stafford,MR Yeomans, 2005
Green tea consumption in everyday life and mental health. M Shimbo,K Nakamura,H Jing Shi,M Kizuki,K Seino,T Inose,T Takano, 2005
Psychostimulant and other effects of caffeine in 9- to 11-year-old children. SV Heatherley,KM Hancock,PJ Rogers, 2006
Challenging sleep in aging: the effects of 200 mg of caffeine during the evening in young and middle-aged moderate caffeine consumers. C Drapeau,I Hamel-Hébert,R Robillard,B Selmaoui,D Filipini,J Carrier, 2006
Effects of caffeine in overnight-withdrawn consumers and non-consumers. AP Smith,G Christopher,D Sutherland,
Effects of caffeine are more marked on daytime recovery sleep than on nocturnal sleep. J Carrier,M Fernandez-Bolanos,R Robillard,M Dumont,J Paquet,B Selmaoui,D Filipini, 2007
Night-time thoughts in high and low worriers: reaction to caffeine-induced sleeplessness. S Omvik,S Pallesen,B Bjorvatn,J Thayer,IH Nordhus, 2007
Stress-related sleep disturbance and polysomnographic response to caffeine. CL Drake,C Jefferson,T Roehrs,T Roth, 2006
Differential responsiveness to caffeine and perceived effects of caffeine in moderate and high regular caffeine consumers. AS Attwood,S Higgs,P Terry, 2007
A translational, caffeine-induced model of onset insomnia in rats and healthy volunteers. LM Paterson,SJ Wilson,DJ Nutt,PH Hutson,M Ivarsson, 2007
Caffeine challenge test in panic disorder and depression with panic attacks. AE Nardi,FL Lopes,AM Valença,RC Freire,AB Veras,VL de-Melo-Neto,I Nascimento,AL King,MA Mezzasalma,GL Soares-Filho,WA Zin,
Effects of repeated doses of caffeine on performance and alertness: new data and secondary analyses. P Hewlett,A Smith, 2007
Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. PJ Rogers,JE Smith,SV Heatherley,CW Pleydell-Pearce, 2008
The effects of L-theanine, caffeine and their combination on cognition and mood. CF Haskell,DO Kennedy,AL Milne,KA Wesnes,AB Scholey, 2008
Influence of caffeine ingestion on perceived mood states, concentration, and arousal levels during a 75-min university lecture. P Peeling,B Dawson, 2007
Prevalence and associated factors for episodic and chronic daily headache in the Colombian population. M Rueda-Sánchez,LA Díaz-Martínez, 2008
Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. E Childs,C Hohoff,J Deckert,K Xu,J Badner,H de Wit, 2008
Fourteen well-described caffeine withdrawal symptoms factor into three clusters. S Ozsungur,D Brenner,A El-Sohemy, 2009
Caffeine, cognitive failures and health in a non-working community sample. AP Smith, 2009
Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. SC Sigmon,RI Herning,W Better,JL Cadet,RR Griffiths, 2009
High dietary caffeine consumption is associated with a modest increase in headache prevalence: results from the Head-HUNT Study. K Hagen,K Thoresen,LJ Stovner,JA Zwart, 2009
Effects on sleep stages and microarchitecture of caffeine and its combination with zolpidem or trazodone in healthy volunteers. LM Paterson,DJ Nutt,M Ivarsson,PH Hutson,SJ Wilson, 2009
Adolescents living the 24/7 lifestyle: effects of caffeine and technology on sleep duration and daytime functioning. CJ Calamaro,TB Mason,SJ Ratcliffe, 2009
Panic disorder and social anxiety disorder subtypes in a caffeine challenge test. AE Nardi,FL Lopes,RC Freire,AB Veras,I Nascimento,AM Valença,VL de-Melo-Neto,GL Soares-Filho,AL King,DM Araújo,MA Mezzasalma,A Rassi,WA Zin, 2009
Caffeine expectancies influence the subjective and behavioral effects of caffeine. PT Harrell,LM Juliano, 2009
Relationship of blood pressure, behavioral mood state, and physical activity following caffeine ingestion in younger and older women. PJ Arciero,MJ Ormsbee, 2009
Sex differences in reinforcing value of caffeinated beverages in adolescents. JL Temple,AM Bulkley,L Briatico,AM Dewey, 2009
Coffee, tea and caffeine intake and the risk of severe depression in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. A Ruusunen,SM Lehto,T Tolmunen,J Mursu,GA Kaplan,S Voutilainen, 2010
Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. PJ Rogers,C Hohoff,SV Heatherley,EL Mullings,PJ Maxfield,RP Evershed,J Deckert,DJ Nutt, 2010
Insomnia symptoms in older adults: associated factors and gender differences. I Jaussent,Y Dauvilliers,ML Ancelin,JF Dartigues,B Tavernier,J Touchon,K Ritchie,A Besset, 2011
Effects of caffeine on repeated sprint ability, reactive agility time, sleep and next day performance. KJ Pontifex,KE Wallman,BT Dawson,C Goodman, 2010
Caffeinated coffee does not acutely affect energy intake, appetite, or inflammation but prevents serum cortisol concentrations from falling in healthy men. A Gavrieli,M Yannakoulia,E Fragopoulou,D Margaritopoulos,JP Chamberland,P Kaisari,SA Kavouras,CS Mantzoros, 2011
Caffeine choice prospectively predicts positive subjective effects of caffeine and d-amphetamine. SC Sigmon,RR Griffiths, 2011
The effect of energy drinks on cortisol levels, cognition and mood during a fire-fighting exercise. SI Sünram-Lea,J Owen-Lynch,SJ Robinson,E Jones,H Hu, 2012
Caffeine expectancies but not caffeine reduce depletion-induced aggression. TF Denson,M Jacobson,W von Hippel,RI Kemp,T Mak, 2012
Coffee, caffeine, and risk of depression among women. M Lucas,F Mirzaei,A Pan,OI Okereke,WC Willett,ÉJ O'Reilly,K Koenen,A Ascherio, 2011
Storm in a coffee cup: caffeine modifies brain activation to social signals of threat. JE Smith,AD Lawrence,A Diukova,RG Wise,PJ Rogers, 2012
ADORA2A Gene variation, caffeine, and emotional processing: a multi-level interaction on startle reflex. K Domschke,A Gajewska,B Winter,MJ Herrmann,B Warrings,A Mühlberger,K Wosnitza,E Glotzbach,A Conzelmann,A Dlugos,M Fobker,C Jacob,V Arolt,A Reif,P Pauli,P Zwanzger,J Deckert, 2012
Development of the caffeine withdrawal symptom questionnaire: caffeine withdrawal symptoms cluster into 7 factors. LM Juliano,ED Huntley,PT Harrell,AT Westerman, 2012
Beverages containing soluble fiber, caffeine, and green tea catechins suppress hunger and lead to less energy consumption at the next meal. BE Carter,A Drewnowski, 2012
Effects of caffeine on session ratings of perceived exertion. LG Killen,JM Green,EK O'Neal,JR McIntosh,J Hornsby,TE Coates, 2013
Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses. A Yoto,M Motoki,S Murao,H Yokogoshi, 2012
Faster but not smarter: effects of caffeine and caffeine withdrawal on alertness and performance. PJ Rogers,SV Heatherley,EL Mullings,JE Smith, 2013
Energy drink consumption and its association with sleep problems among U.S. service members on a combat deployment - Afghanistan, 2010. , 2012
Coffee, hunger, and peptide YY. JA Greenberg,A Geliebter, 2012
The effects of caffeine abstinence on sleep: a pilot study. SC Ho,JW Chung, 2013
A moderate dose of caffeine ingestion does not change energy expenditure but decreases sleep time in physically active males: a double-blind randomized controlled trial. PB Júdice,JP Magalhães,DA Santos,CN Matias,AI Carita,PA Armada-Da-Silva,LB Sardinha,AM Silva, 2013
Green tea and coffee consumption is inversely associated with depressive symptoms in a Japanese working population. NM Pham,A Nanri,K Kurotani,K Kuwahara,A Kume,M Sato,H Hayabuchi,T Mizoue, 2014
Caffeine can decrease subjective energy depending on the vehicle with which it is consumed and when it is measured. HA Young,D Benton, 2013
The impact of alcohol and energy drink consumption on intoxication and risk-taking behavior. A Peacock,R Bruno,FH Martin,A Carr, 2013
Neuromuscular responses to incremental caffeine doses: performance and side effects. JG Pallarés,VE Fernández-Elías,JF Ortega,G Muñoz,J Muñoz-Guerra,R Mora-Rodríguez, 2013
Effect of different amounts of coffee on dietary intake and appetite of normal-weight and overweight/obese individuals. A Gavrieli,E Karfopoulou,E Kardatou,E Spyreli,E Fragopoulou,CS Mantzoros,M Yannakoulia, 2013
Coffee, caffeine, and risk of completed suicide: results from three prospective cohorts of American adults. M Lucas,EJ O'Reilly,A Pan,F Mirzaei,WC Willett,OI Okereke,A Ascherio, 2014
Effects of caffeine and menthol on cognition and mood during simulated firefighting in the heat. Y Zhang,G Balilionis,C Casaru,C Geary,RE Schumacker,YH Neggers,MD Curtner-Smith,MT Richardson,PA Bishop,JM Green, 2014
Energy drink consumption is associated with anxiety in Australian young adult males. GS Trapp,K Allen,TA O'Sullivan,M Robinson,P Jacoby,WH Oddy, 2014
Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. C Drake,T Roehrs,J Shambroom,T Roth, 2013
The association between caffeine and cognitive decline: examining alternative causal hypotheses. K Ritchie,ML Ancelin,H Amieva,O Rouaud,I Carrière, 2014
Caffeinated sugar-sweetened beverages and common physical complaints in Icelandic children aged 10-12 years. AL Kristjansson,ID Sigfusdottir,MJ Mann,JE James, 2014
The use of energy drinks in sport: perceived ergogenicity and side effects in male and female athletes. JJ Salinero,B Lara,J Abian-Vicen,C Gonzalez-Millán,F Areces,C Gallo-Salazar,D Ruiz-Vicente,J Del Coso, 2014

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