1. Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children: Behavior Outcome
Dr. Harris Lieberman
Military Nutrition Division, US Army Research Institute of Environmental Medicine
and
Dr. Charles O’Brien
Department of Psychiatry, University of Pennsylvania

2. Disclosure Harris Lieberman: Charles O’Brien:
Member of the ILSI North America Caffeine Systematic Review Team (uncompensated)
Government Liaison ILSI North America Caffeine Working Group (uncompensated)
The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or reflecting the views of the Army or the Department of Defense. Any citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement of approval of the products or services of these organizations. In the conduct of research involving human subjects, the investigators adhered to the policies for protection of human subjects as prescribed by DOD Instruction , and the research was conducted in adherence with the provisions of 32 CFR Part 219.
Charles O’Brien:
Member of the ILSI North America Caffeine Systematic Review Team
ILSI North America provided an honorarium and travel to attend this meeting.

3. Adverse behavioral effects
Population, Exposure, Comparator, Outcome (PECO) Questions for the Behavior Outcome
For [population], is caffeine intake above [dose], compared to intakes [dose] or less, associated with adverse effects on behavior health outcomes?
Example: For healthy adults, is caffeine intake above 400 mg/day, compared to intakes of 400 mg/day or less, associated with adverse effects on behavior health outcomes?
Population
Healthy
Adults
Pregnant Women
Adolescents
Children
Exposure
> 400 mg/day
> 300 mg/day
> 2.5 mg/kg-day
Comparator
≤ 400 mg/day
≤ 300 mg/day
≤ 2.5 mg/kg-day
Outcome
Adverse behavioral effects P E C O

4. Characterization of Data for Behavior Outcome
Data Type
Characterization
Number of studies
81 included; 123 excluded (no quantitative value of caffeine – “association studies”; other exclusionary criteria such as unhealthy study population or no data on adverse effects)
Study types
Randomized controlled trials; some cross-sectional and cohort studies; a single case-control study
Populations
Adults, adolescents, children (no data available on pregnant women)
Exposure
Primarily controlled exposure to some form of pure caffeine, though some provided measured doses of coffee, energy drinks or another source
Others quantified dietary intake (e.g., food frequency questionnaires) – coffee, soda, tea, chocolate
~2/3 specifically evaluated caffeine
Categorical groupings (e.g., <1 cup/day, >3 cups/day) or specific quantification
Outcome (Endpoints)
Adverse Mood States (Anxiety, Anger and Confusion, Depression); Sleep (Objective and Subjective measures); Withdrawal; Headache; Risk-taking

5. Behavior End Points (All Potentially Adverse)
Mood – Adults
Increased anxiety
Increased anger
Increased confusion
Increased depression
Mood – Children and Adolescents
Headache – Adults
Headache – Children and Adolescents

6. Behavior End Points – All Potentially Adverse (cont’d)
Sleep – Adults
Subjective (self-report questionnaires) – increased fatigue, drowsiness
Objective – decreased sleep duration and/or quality assessed by polysomnography (EEG) or wrist activity monitoring
Sleep – Children and Adolescents
Problematic and Risk-Taking Behavior – Adults
Substance abuse
Smoking
Disorderly behavior
Risk-taking
Problematic and Risk-Taking Behavior – Children

7. Through a Different Lens Other than “Safety and Toxicology”
Caffeine is frequently consumed for its behavioral effects
Increased alertness
Decreased sleepiness
European Food Safety Authority (EFSA) Panel concluded consumption of caffeine increased alertness and attention in doses of at least 75 mg caffeine in the general adult population.

8. The Behavioral Data
81 studies included after eliminating 123 (only 5 on children and adolescents, none on pregnant women)
Only 6 were dose-response studies
19 used doses of 400 mg or above (the comparator for adults)
Most not conducted for studying ‘adverse events’ per se
Many were conducted to test behavioral hypotheses
Does caffeine in moderate doses found in foods increase alertness?
Does caffeine given before bedtime interfere with sleep?

9. Results Mood – Adults Mood – Children and Adolescents Anxiety
Findings across studies very variable, over ½ below 400 mg were negative
Concluded: caffeine can produce a small increase in anxiety above and below 400 mg/day
For future research, dose-response studies should be conducted
Anger and Confusion
Generally no effects below or above comparator
Depression
No negative effects below or above comparator
Mood – Children and Adolescents
Insufficient data overall – two studies available are both negative

10. Results (cont’d) Headache – Adults Headache – Children and Adolescents
Difficult, complex area; some studies suggest:
Caffeine withdrawal can sometimes cause headache
Caffeine administration during withdrawal can mitigate headache
Conclusion based on 15 studies – caffeine doses below 400 mg comparator are not associated with headache
Headache – Children and Adolescents
Insufficient evidence

11. Results (cont’d) Sleep – Adults Sleep – Children and Adolescents
“Subjective” effects on alertness, fatigue
No adverse effects below comparator (a decrease in fatigue)
At very high doses (1200 mg/day) increase in fatigue due to disruption of sleep
Objective measures of sleep with polysomnography (EEG) or wrist activity monitor (a decrease in sleep duration/quality)
Caffeine administration above or below 400 mg comparator can disrupt sleep especially when given later in the day
Sleep – Children and Adolescents
Insufficient data
Problematic and Risk-Taking Behavior (substance abuse, etc.)
Insufficient data – adults and children

12. Evaluation of Individual Study Quality (Risk of Bias)
Overall “probably low” risk of bias for studies in adults; few qualified studies in children and adolescents which were generally of lower quality
Limited by exposure characterization (Q8, Q11) and Outcome Assessment (Q9)
+2: Definitely low
+1: Probably low
-1: Probably high
-2: Definitely high

13. Behavior: Weight of Evidence (WoE) Conclusion
Adults: When the weight of evidence was considered, with particular emphasis on level of adversity, 400 mg caffeine/day was found to be an acceptable intake that is not associated with significant concern regarding adverse behavioral effects.
There were some adverse noted effects below the comparator:
Anxiety and sleep may be affected below the comparator depending on dose, time of administration, history of caffeine intake, genetics, etc.
There is moderate to high level of confidence in the body of evidence supporting this conclusion
Children and adolescents: the evidence base was insufficient to develop a conclusion
No data on pregnant women
From manuscript:
Overall, the Nawrot et al. (2003) conclusions for the safe levels of daily caffeine intake for healthy adults are generally supported by this body of evidence. There are sufficient data from
RCTs that lower doses of caffeine may negatively affect some aspects of behavior (particularly anxiety) and sleep for adults; however, these changes are often low in magnitude and/or are more
apparent in sensitive subpopulations.
Of the 81 included studies, the data in children and adolescents were limited to just 5 studies, which together evaluated mood, headache, and sleep. As such, it was determined that the
evidence base was insufficient to render a conclusion regarding appropriateness of the comparator (2.5 mg caffeine/day) for potential impacts of caffeine consumption on behavior
outcomes in these populations.

14. Anxiety (Adults)
The evidence demonstrates that caffeine has adverse effects on anxiety both above and below the comparator of 400 mg caffeine/day in healthy adult populations
At intakes above the comparator, up to 1200mg/day, reported adverse effects are more consistent
Studies reporting effects that were often
Low in magnitude
Only in sensitive sub-populations (ADORA2A polymorphisms)
Moderate level of confidence in the body of evidence
From manuscript:
Taken together, some but not all evidence, primarily from RCTs involving single/short term caffeine exposure and subjective measures of anxiety, suggests that the comparator of 400
mg/day can lead to increases, albeit small, in measures of anxiety in adults. Evidence suggests that some of the variability in findings may be due to individual variation in the response to
caffeine. Much of the variation in response, including the magnitude and sensitivity of its effects, may be attributed to other factors such as genotype (e.g., ADORA2a receptor TT genotype
polymorphisms), consumer status (e.g., studies that involve participants with genetic predispositions or participants who do not regularly consume caffeine tend to report effects
below the comparator), and subjectivity inherent to the evaluation of anxiety (e.g., POMS). This later point being notable when considering the level of adversity of the reported changes in
anxiety –the often-small changes observed were considered to be of low magnitude. These findings highlight the need for additional research to further characterize population-based
sensitivities based on genotype and consumption status.

15. Sleep (Adults)
Evidence supports that 400 mg caffeine/day in healthy adult populations is an acceptable intake that is not associated with significant concern regarding subjective measures of sleep
Most studies indicate that caffeine improves measures of fatigue
One study at the high end (1200 mg/day for 7 days) observed adverse effects related to cumulative loss of sleep
Evidence suggests that 400 mg caffeine/day in healthy adult populations is associated with adverse effects on objective measures of sleep
Most studies indicate that timing of the dose is important and that sleep disruption occurs most frequently when administered close to bedtime.
High level of confidence in the evidence base
From manuscript:
Subjective; Based on the studies reviewed, the majority demonstrate that the comparator of 400 mg caffeine/day is acceptable as an intake generally not associated with concern regarding adverse effects on sleep. There were a few cases in which prolonged dosing was associated with increased fatigue; the magnitude of these changes was difficult to assess. Caffeine’s mode of
action in the central nervous system (CNS) helps, in part, explain why most caffeine doses tested in these studies may indeed provide some benefit on this endpoint by reducing perceived fatigue;
however, higher doses may disrupt sleep and lead to an increase in fatigue when consumed over the course of several days (see Bonnet and Arand, 2003a, and Section on objective
effects).
Objective: With respect to the data obtained via objective measures of sleep in adults, results indicate that 400 mg caffeine/day is likely too high as an intake, in that it would be expected to disrupt sleep when administered with the intention to do so. Specifically, ingestion of caffeine even at doses below the comparator can lead to delayed sleep onset and decreases in sleep quality and
efficiency, but this is particularly the case when caffeine is consumed near bedtime. Overall, caffeine at doses both above and below the comparator may provide short-term benefits to
improve perceived fatigue but, depending on the dose and timing, may also disrupt sleep, leading to increased fatigue the following day.

16. Behavior in Children and Adolescents
Relatively little data available for each of the major behavioral endpoints
Only one study provided data above the comparator
No major adverse effects seen in children or adolescents at doses near or less than 2.5 mg/kg
Many non-quantitative (i.e. association studies) available in the literature could not be used
Few studies available to effectively evaluate the comparator of 2.5 mg/kg/day in this population
Lower quality evidence base due to issues with study design, indirectness and reverse causation
More research is required, particularly in the key areas of sleep and risk-taking behavior
From manuscript:
Of the 81 included studies, the data in children and adolescents were limited to just 5 studies, which together evaluated mood, headache, and sleep. As such, it was determined that the
evidence base was insufficient to render a conclusion regarding appropriateness of the comparator (2.5 mg caffeine/day) for potential impacts of caffeine consumption on behavior
outcomes in these populations.

17. Clinical Considerations in Weigh-of-Evidence (WoE) Conclusions
Relationship  of caffeine to anxiety disorders, caffeine and addiction, caffeine withdrawal.
Caffeine and sleep disorders.
Caffeine and children (strongly need more studies).
Caffeine and cardiac disease, hypertension.
Effects of caffeine on performance, cognitive, motor, at what dose?

18. Anxiety (Adults)
The evidence demonstrates that caffeine has adverse effects on anxiety both above and below the comparator of 400 mg caffeine/day in healthy adult populations
At intakes above the comparator, up to 1200mg/day, reported adverse effects are more consistent
Studies reporting effects that were often
Low in magnitude
Only in sensitive sub-populations (ADORA2A polymorphisms)
Moderate level of confidence in the body of evidence
From manuscript:
Taken together, some but not all evidence, primarily from RCTs involving single/short term caffeine exposure and subjective measures of anxiety, suggests that the comparator of 400
mg/day can lead to increases, albeit small, in measures of anxiety in adults. Evidence suggests that some of the variability in findings may be due to individual variation in the response to
caffeine. Much of the variation in response, including the magnitude and sensitivity of its effects, may be attributed to other factors such as genotype (e.g., ADORA2a receptor TT genotype
polymorphisms), consumer status (e.g., studies that involve participants with genetic predispositions or participants who do not regularly consume caffeine tend to report effects
below the comparator), and subjectivity inherent to the evaluation of anxiety (e.g., POMS). This later point being notable when considering the level of adversity of the reported changes in
anxiety –the often-small changes observed were considered to be of low magnitude. These findings highlight the need for additional research to further characterize population-based
sensitivities based on genotype and consumption status.

19. Sleep (Adults)
Evidence supports that 400 mg caffeine/day in healthy adult populations is an acceptable intake that is not associated with significant concern regarding subjective measures of sleep
Most studies indicate that caffeine improves measures of fatigue
One study at the high end (1200 mg/day for 7 days) observed adverse effects related to cumulative loss of sleep
Evidence suggests that 400 mg caffeine/day in healthy adult populations is associated with adverse effects on objective measures of sleep
Most studies indicate that timing of the dose is important and that sleep disruption occurs most frequently when administered close to bedtime.
High level of confidence in the evidence base
From manuscript:
Subjective; Based on the studies reviewed, the majority demonstrate that the comparator of 400 mg caffeine/day is acceptable as an intake generally not associated with concern regarding adverse effects on sleep. There were a few cases in which prolonged dosing was associated with increased fatigue; the magnitude of these changes was difficult to assess. Caffeine’s mode of
action in the central nervous system (CNS) helps, in part, explain why most caffeine doses tested in these studies may indeed provide some benefit on this endpoint by reducing perceived fatigue;
however, higher doses may disrupt sleep and lead to an increase in fatigue when consumed over the course of several days (see Bonnet and Arand, 2003a, and Section on objective
effects).
Objective: With respect to the data obtained via objective measures of sleep in adults, results indicate that 400 mg caffeine/day is likely too high as an intake, in that it would be expected to disrupt sleep when administered with the intention to do so. Specifically, ingestion of caffeine even at doses below the comparator can lead to delayed sleep onset and decreases in sleep quality and
efficiency, but this is particularly the case when caffeine is consumed near bedtime. Overall, caffeine at doses both above and below the comparator may provide short-term benefits to
improve perceived fatigue but, depending on the dose and timing, may also disrupt sleep, leading to increased fatigue the following day.

20. Future Research Needs
More research necessary on children and adolescents; particularly with regards to caffeine’s effects on sleep and risk-taking behavior.
More consideration for/or better understanding of the effects of caffeine withdrawal on these endpoints.
No data available on pregnant women.
Better understanding of the effects of caffeine on anxiety and sleep in sensitive subpopulations, individuals with polymorphisms (e.g. ADORA2A).