EFSA supporting publication 2015:EN-561
EXTERNAL SCIENTIFIC REPORT
Extensive literature search as preparatory work for the safety assessment
for caffeine1
Sarah Bull2, Terry Brown3, Karin Burnett4, Lini Ashdown2, Lesley Rushton5
2
Ricardo-AEA Ltd - 3 Cranfield University - 4 Independent consultant - 5 Imperial College London
ABSTRACT
Previous studies on the safety of caffeine have been published by the Scientific Committee on Food (SCF) in
1983, 1999 and 2003. In the latter assessment, the SCF concluded that caffeine would not exacerbate the adverse
effects of alcohol.
A recent study carried out by the Committee on toxicity of chemicals in food consumer products and the
environment (COT) looked at any new data published since the SCF report and advised on the potential for
interactions between caffeine and alcohol. Limited data prevented them assessing the effect of caffeine on the
acute toxicity of alcohol. Overall, the committee concluded that, based on the current balance of evidence, there
is no harmful toxicological or behavioural interaction between caffeine and alcohol. However, they stated that
this opinion should be reviewed if new evidence emerges.
In 2013, the European Food Safety Authority (EFSA) was asked to evaluate potential adverse health effects that
may arise following consumption either alone or in combination with alcohol and/or other substances such as
energy drinks. Therefore, the objective of this project is to provide EFSA with an evidence base related to the
adverse effects of caffeine, either alone or in combination with alcohol and/or other substances found in energy
drinks in various population groups.
© Copyright notice of the author(s), 2015
KEY WORDS
caffeine, energy drinks, alcohol, adverse health effects, performance
DISCLAIMER
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried
out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the author(s),
awarded following a tender procedure. The present document is published complying with the transparency principle to
which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety
Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present
document, without prejudice to the rights of the authors.
1
Question No EFSA-Q-2013-00419
Any enquiries related to this output should be addressed to nda@efsa.europa.eu
Suggested citation: Bull S. et al., 2015. Extensive literature search as preparatory work for the safety assessment for caffeine.
EFSA supporting publication 2015:EN-561, 98 pp.
Available online: www.efsa.europa.eu/publications
© European Food Safety Authority, 2015
Extensive literature search for caffeine
SUMMARY
Previous studies on the safety of caffeine have been published by the Scientific Committee on Food
(SCF) in 1983, 1999 and 2003. In the latter assessment, the SCF concluded that caffeine would not
exacerbate the adverse effects of alcohol.
A recent study carried out by the Committee on Toxicity (COT) looked at any new data published
since the SCF report and advised on the potential for interactions between caffeine and alcohol.
Limited data prevented them assessing the effect of caffeine on the acute toxicity of alcohol. Overall,
the committee concluded that, based on the current balance of evidence, there is no harmful
toxicological or behavioural interaction between caffeine and alcohol. However, they stated that this
opinion should be reviewed if new evidence emerges.
In 2013, the European Food Safety Authority (EFSA) was asked to evaluate potential adverse health
effects that may arise following consumption either alone or in combination with alcohol and/or other
substances such as energy drinks. Therefore, the objective of this project is to provide EFSA with an
evidence base related to the adverse effects of caffeine consumption, alone or in combination with
alcohol and/or substances found in energy drinks in various population groups.
A tiered approach was implemented to search, select, evaluate and assess data. Study retrieval was
carried out in a strategic manner using predefined search terms. Study selection was then carried out,
first classifying the articles according to the endpoint, then by carrying out a primary screen on titles
of the articles retrieved and lastly by screening the abstracts. Endpoints that showed no or inverse
correlations with caffeine were not further considered, i.e. performance related endpoints, type II
diabetes, various cancers, Parkinson’s and stroke. 2382 full articles were collected on appropriate
adverse endpoints, including cardiovascular effects, reproductive outcomes, cancer,
neurological/central nervous system effects, bone effects, glaucoma and insulin sensitivity, following
exposure to caffeine alone, or in combination with alcohol or other substances in energy drinks.
Secondary screening/methodological evaluation was carried out on all articles to evaluate the
methodological quality of such papers, using the Newcastle Ottawa Scale (NOS) score for
observational studies, or the Cochrane Collaboration for intervention studies. At all stages of the
protocol articles were screened against inclusion/exclusion criteria and excluded if appropriate.
Finally, data for all articles were collated in data abstraction forms and a narrative provided for each
endpoint following exposure to caffeine, either alone or in combination with alcohol and/or other
substances such as energy drinks.
EFSA supporting publication 2015:EN-561
2
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
TABLE OF CONTENTS
Abstract .................................................................................................................................................... 1
Summary .................................................................................................................................................. 2
Table of contents ...................................................................................................................................... 3
Background as provided by EFSA ........................................................................................................... 5
Terms of reference as provided by EFSA ................................................................................................ 5
Introduction and Objectives ..................................................................................................................... 6
Materials and Methods ............................................................................................................................. 8
1. Study retrieval.................................................................................................................................. 8
1.1.
Search strategy ........................................................................................................................ 8
1.2.
Selection of information sources............................................................................................. 8
2. Study selection................................................................................................................................. 8
2.1.
Development of eligibility criteria for study selection ........................................................... 8
2.2.
Primary screening on titles and abstracts ................................................................................ 9
2.3.
Secondary screening – assessment of methodological quality ............................................. 10
2.3.1. Epidemiology studies ....................................................................................................... 11
2.3.2. Intervention studies........................................................................................................... 11
2.4.
Recording data ...................................................................................................................... 11
2.5.
Data abstraction .................................................................................................................... 11
2.6.
Data retrieval ......................................................................................................................... 12
2.6.1. Question a) Papers on adverse effects of caffeine ............................................................ 12
2.6.2. Question b) Papers on adverse effects of caffeine in combination with alcohol .............. 13
2.6.3. Question c) Papers on adverse effects of caffeine in combination other substances in
energy drinks ................................................................................................................................. 13
2.6.4. Question d) Papers on adverse effects of caffeine in combination with other substances
in energy drinks and alcohol .......................................................................................................... 14
2.7.
Health endpoints ................................................................................................................... 14
2.8.
Adverse health effects of caffeine......................................................................................... 14
2.8.1. Breast-fed infants consuming caffeine via mother’s milk ................................................ 14
2.8.2. Children possibly divided by age group ........................................................................... 14
2.8.2.1. General toxicity........................................................................................................ 14
2.8.2.2. Cardiovascular effects .............................................................................................. 14
2.8.2.3. Neurological/CNS effects ........................................................................................ 14
2.8.2.4. Summary .................................................................................................................. 15
2.8.3. Pregnant and lactating women .......................................................................................... 15
2.8.3.1. Low birth weight/restricted foetal growth ............................................................... 15
2.8.3.2. Spontaneous abortion ............................................................................................... 16
2.8.3.3. Foetal or infant death ............................................................................................... 17
2.8.3.4. Neurological/CNS/psychological effects ................................................................. 17
2.8.3.5. Summary .................................................................................................................. 18
2.8.4. Adults and adolescents ..................................................................................................... 18
2.8.4.1. General toxicity........................................................................................................ 18
2.8.4.2. Cardiovascular effects.............................................................................................. 18
2.8.4.3. Cancer ...................................................................................................................... 21
2.8.4.4. Neurological/CNS effects ........................................................................................ 23
2.8.4.5. Insulin sensitivity ..................................................................................................... 24
2.8.4.6. Glaucoma ................................................................................................................. 24
2.8.4.7. Urinary incontinence ................................................................................................ 25
2.8.4.8. Bone effects and calcium balance ............................................................................ 25
2.8.4.9. Summary .................................................................................................................. 26
2.8.5. Adults and adolescents performing endurance exercise ................................................... 27
2.8.5.1. Performance ............................................................................................................. 27
EFSA supporting publication 2015:EN-561
3
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.8.5.2. Cardiovascular effects.............................................................................................. 27
2.8.5.3. Summary .................................................................................................................. 27
2.9.
Adverse health effects of intake of caffeine in combination with alcohol ............................ 27
2.9.1. Adults and adolescents ..................................................................................................... 28
2.9.1.1. Reproductive effects ................................................................................................ 28
2.9.1.2. Cardiovascular effects .............................................................................................. 28
2.9.1.3. Alcohol consumption and intoxication .................................................................... 28
2.9.1.4. Risk taking ............................................................................................................... 29
2.9.1.5. Neurological/CNS effects ........................................................................................ 29
2.9.1.6. Summary .................................................................................................................. 30
2.9.2. Adults and adolescents performing endurance exercise ................................................... 30
2.9.2.1. Cardiovascular effects.............................................................................................. 30
2.9.2.2. Summary .................................................................................................................. 30
2.10. Adverse health effects of intake of caffeine in combination with other substances in socalled “energy drinks”........................................................................................................................ 30
2.10.1. Children possibly divided by age group ........................................................................... 30
2.10.2. Pregnant women ............................................................................................................... 30
2.10.3. Lactating women .............................................................................................................. 30
2.10.4. Adults and adolescents ..................................................................................................... 30
2.10.4.1. Performance ............................................................................................................. 30
2.10.4.2. Kidney effects .......................................................................................................... 31
2.10.4.3. Miscellaneous effects ............................................................................................... 31
2.10.4.4. Summary .................................................................................................................. 31
2.10.5. Adults and adolescents performing endurance exercise ................................................... 31
3. Data evaluation .............................................................................................................................. 32
3.1.
Cancer Effects ....................................................................................................................... 32
3.2.
Cardiovascular Effects .......................................................................................................... 32
3.3.
Neurological/CNS effects ..................................................................................................... 33
3.4.
Reproductive effects ............................................................................................................. 33
3.5.
Other health effects ............................................................................................................... 34
3.6.
Data from authoritative bodies.............................................................................................. 34
3.6.1. Germany ........................................................................................................................... 34
3.6.2. UK .................................................................................................................................... 35
3.6.3. Belgium ............................................................................................................................ 35
3.6.4. Norway ............................................................................................................................. 36
3.6.5. Finland .............................................................................................................................. 36
3.6.6. US ..................................................................................................................................... 37
3.6.7. France ............................................................................................................................... 37
3.6.8. Canada .............................................................................................................................. 37
3.6.9. New Zealand ..................................................................................................................... 37
3.6.10. Hong Kong ....................................................................................................................... 38
3.6.11. Miscellaneous ................................................................................................................... 38
Conclusion.............................................................................................................................................. 38
References .............................................................................................................................................. 39
Abbreviation ........................................................................................................................................... 51
Annex – Complete Protocol ................................................................................................................... 52
EFSA supporting publication 2015:EN-561
4
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
BACKGROUND AS PROVIDED BY EFSA
The safety of caffeine was evaluated by the Scientific Committee on Food (SCF) in 1983, 1999 and
2003 in the context of opinions on the safety of caffeine, taurine and glucuronolactone in so-called
“energy drinks” (Scientific Committee on Food 2003, 1983, 1999). In 2008, the EFSA Panel on
Flavourings, Processing Aids and Materials in Contact with Food (CEF) performed an assessment of
xanthin alkaloids used as flavouring substances but did not conclude owing to the lack of data. In
2013, the European Commission will ask EFSA to re-evaluate the safety of caffeine either consumed
alone or in combination with alcohol and/or other substances from all sources, independent from its
intended uses, for specified population groups.
TERMS OF REFERENCE AS PROVIDED BY EFSA
For the fulfilment of the tasks of this assignment it is expected that the Contractor conducts an
extensive literature search related to adverse health effects of caffeine either consumed alone or in
combination with alcohol and/or other substances in specific population groups as defined in section
1.2 (above). The Contractor will provide EFSA with an evidence report summarising the data
retrieved.
Relevant literature for the objective described in section 1.2 a) are primary studies in humans reporting
on the (dose-response) relationship between quantitative intakes of caffeine from different sources
(e.g. coffee, tea, chocolate, cola-type beverages, energy drinks, supplements, medicines) and adverse
health effects which control for effects of other constituents in these foods which might have an
impact on the adverse health outcome, case reports in humans in which the amount of caffeine
consumed is reported and safety assessments of caffeine conducted by national risk assessment bodies.
Relevant literature for the objective described in section 1.2 b) c) and d) are primary studies in humans
reporting on the (dose-response) relationship between quantitative intakes of caffeine and alcohol
and/or other substances, as the case may be, and adverse health effects which control for effects of
other constituents than the ones under investigation in these foods and which might have an impact on
the adverse health outcome, case reports in humans in which the amount of caffeine, alcohol and/or
other substances consumed is reported and safety assessments conducted by national risk assessment
bodies in relation to the combination under investigation.
This contract was awarded by EFSA to: Ricardo-AEA, Gemini Building, Fermi Avenue, Harwell, UK
Contractor: Ricardo-AEA, UK
Contract: Extensive literature search as preparatory work for the safety assessment of caffeine.
Contract number: RC/EFSA/NUTRI/2013/01
EFSA supporting publication 2015:EN-561
5
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
INTRODUCTION AND OBJECTIVES
The overall objective of the project was to perform an extensive literature search and to provide
EFSA with an evidence report summarising the data retrieved related to:
a) adverse health effects of caffeine intake in specific population groups
Relevant population groups are:
•
Breast-fed infants consuming caffeine via mother’s milk
•
Children possibly divided by age group
•
Pregnant women
•
Lactating women
•
Adults and adolescents
•
Adults and adolescents performing endurance exercise
b) adverse health effects of intake of caffeine in combination with alcohol in specific population
groups
Relevant population groups are:
•
Adults and adolescents
•
Adults and adolescents performing endurance exercise
c) adverse health effects of intake of caffeine in combination with other substances in so-called
“energy drinks” in specific population groups
Relevant population groups are:
•
Children possibly divided by age group
•
Pregnant women
•
Lactating women
•
Adults and adolescents
•
Adults and adolescents performing endurance exercise
d) adverse health effects of intake of caffeine in combination with other substances in so-called
“energy drinks” and alcohol in specific population groups
Relevant population groups are:
•
Adults and adolescents
•
Adults and adolescents performing endurance exercise
These data may serve as a basis to assess the safety of caffeine either consumed alone or in
combination with alcohol and/or other substances.
EFSA supporting publication 2015:EN-561
6
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Specific objectives:
•
The Contractor should carry out comprehensive literature searches to identify and retrieve all
related information/data published in peer-reviewed journals and by national risk assessment
bodies in relation to the overall objectives of the contract.
•
The Contractor should collate the data retrieved.
•
Relevant data should be further analysed and an evidence report should be prepared. The
information should be transferred in a concise way to EFSA including the full list of
references considered pertinent. References not considered pertinent should be listed and
reasoning should be provided why these references were not considered relevant. The report
should be accompanied by an EndNote library containing the related references.
EFSA supporting publication 2015:EN-561
7
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
MATERIALS AND METHODS
The complete protocol for this extensive literature search is attached as an annex to this report.
1.
1.1.
STUDY RETRIEVAL
Search strategy
Search terms have been developed to gather data on the four topic areas outlined in the tender
documents, namely adverse health effects of caffeine alone; caffeine in combination with alcohol;
caffeine in combination with other substances found in energy drinks; and caffeine in combination
with other substances found in energy drinks and alcohol.
For question a) caffeine, this related to coffee, tea, chocolate, cola-type drinks, energy drinks (when
other constituents were not mentioned), supplements, gum and medicines.
For question b) caffeine and alcohol, this related to the above mentioned caffeinated items consumed
in combination with alcohol.
For question c) caffeine in combination with other substances in so-called “energy drinks”, this related
to energy drinks containing caffeine, taurine and/or glucuronolactone.
For question d) caffeine in combination with other substances in so-called “energy drinks” and
alcohol, this related to energy drinks containing caffeine, taurine and/or glucuronolactone and alcohol.
Because energy drinks were considered as a source of caffeine in the tender documents, there is some
cross over between question a and c, where adverse effects of energy drinks are described.
Broad search terms were used to capture as many publications as possible and that were appropriate to
the database being interrogated, namely Scopus, Web of Science and PubMed. Various sensitivity
analyses were carried out by the Information Scientist to ensure that articles were indeed being
captured and if necessary, search terms were amended. All searches were carried out in English. All
titles and abstracts retrieved from the literature search were imported into Endnote and RefWorks
bibliographic software and the duplicates removed. This library was accessible to all team members.
The search strategies including search terms used for the different databases were recorded on an
information source form. We also interrogated references from key papers and included any relevant
publications not retrieved from the literature search.
1.2.
Selection of information sources
As mentioned above, literature databases Scopus, Web of Science and PubMed were used to search
the scientific literature for relevant data.
2.
Study selection
2.1.
Development of eligibility criteria for study selection
Identification of the eligibility criteria is critical in the validity of the ELR. The Project Lead Expert,
Epidemiologist and Information Scientist identified the study population (P), the intervention or
exposure (I or E), a comparator (C) and outcome (O) and consulted with other members of the team
when appropriate.
EFSA supporting publication 2015:EN-561
8
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
The description of the populations was given in the technical specifications, namely breast-fed infants,
children, pregnant and lactating women, adolescents and adults performing exercise. A more
prescriptive description of these populations, as described by the EFSA Food consumption database6,
was followed, namely;




Infants: up to and including 11 months
Children: from 36 months up to and including 9 years of age
Adolescents: from 10 up to and including 17 years of age
Adults: from 18 up to and including 64 years of age
All study types were included: case series, cross-sectional, case-control and cohort. Intervention
studies were considered, including both randomised and non-randomised trials. Only adverse health
effects were considered as the health endpoint.
2.2.
Primary screening on titles and abstracts
Titles and abstracts of all references retrieved, after duplicates were removed, were first categorised
according to the endpoint i.e. reproductive effects, cardiovascular effects, cancer, diabetes,
Parkinson’s disease, Alzheimer’s disease, stroke, neurological/central nervous system (CNS) effects
kidney effects, glaucoma/intraocular pressure, bone effects and insulin sensitivity. All studies were
independently screened against an inclusion/exclusion criteria checklist (Table 1). The
inclusion/exclusion criteria were developed by team members and agreed by EFSA. Articles that did
not appear to meet the inclusion criteria were excluded from further analysis.
Whilst classifying each article, the overall outcome of the paper was assigned one of three outcomes
(effect, no effect, inverse effect) based on the abstract of the paper. Due to the large numbers of
articles retrieved and the remit of the project i.e. to investigate adverse health effects following
caffeine consumption, following discussion with EFSA it was decided to exclude publications that
reported no or an inverse effect, i.e. diabetes, Parkinson’s disease, Alzheimer’s disease and stroke.
The full text of articles that passed all the above primary screening stages was retrieved ready for
secondary screening.
6
EFSA Food consumption database. http://www.efsa.europa.eu/en/efsajournal/doc/2097.pdf
EFSA supporting publication 2015:EN-561
9
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Table 1:
Inclusion and exclusion criteria used during primary screening
Inclusion criteria
Exclusion criteria
Articles in English language
Articles in other languages
Articles published from 1997 to present
Articles published prior to 1997
Articles concerning caffeine alone (as coffee, tea, chocolate,
cola-type beverages, energy drinks, supplements, medicines,
energy shots, caffeinated chewing gum, caffeinated sport bar,
caffeinated sport gel, monster, red bull, rockstar)7
Articles concerning caffeine (as coffee, tea, chocolate, colatype beverages, energy drinks, supplements, medicines,
energy shots, caffeinated chewing gum, caffeinated sport bar,
caffeinated sport gel, monster, red bull, rockstar) in
combination with alcohol 8
Articles related to caffeine in combination with other
beverages or substances i.e. cocaine
Articles related to caffeine (as coffee, tea, chocolate, colatype beverages, energy drinks, supplements, medicines,
energy shots, caffeinated chewing gum, caffeinated sport bar,
caffeinated sport gel, monster, red bull, rockstar) in
combination with other substances in energy drinks
(specifically guarana, taurine and glucuronolactone) 9
Articles related to caffeine in combination with other
beverages or substances, or relating to alcohol alone
Articles related to caffeine in combination with other
beverages or substances, relating to energy drinks alone
or constituents of energy drinks alone
Articles related to caffeine (as coffee, tea, chocolate, colatype beverages, energy drinks, supplements, medicines,
energy shots, caffeinated chewing gum, caffeinated sport bar,
caffeinated sport gel, monster, red bull, rockstar) in
combination with other substances in energy drinks
(specifically guarana, taurine and glucuronolactone) and
alcohol 10
Articles relating to the relevant population group
Articles related to caffeine in combination with other
beverages or substances, or relating to alcohol or
constituents of energy drinks alone
Articles relating to human studies
Studies in experimental animal species or in vitro
studies
Studies related to oral exposure
Articles related to other routes of exposure i.e.
inhalation or dermal studies
Systematic reviews
Other reviews (e.g. narrative reviews)
Scientific articles, reviews, reports and letters that report reworking of data
Commentaries, letters, editorials or other publication
types
2.3.
Articles relating to other population groups i.e. groups
suffering from a severe disease
Secondary screening – assessment of methodological quality
The team independently reviewed the full manuscripts by comparing each one against the criteria
shown in the secondary screening tool in order to assess the methodological quality of the studies. For
the cancer endpoint, meta-analyses were used instead of primary papers as they covered most primary
articles found in the literature searches.
The secondary screening tool was adapted for the different types of studies retrieved such as
epidemiology studies, intervention studies or meta-analyses. Secondary screening was carried out in
parallel with data abstraction.
7
Question a) adverse health effects of caffeine
Question b) adverse health effects of caffeine in combination with alcohol
9
Question c) adverse health effects of caffeine in combination with other substances in energy drinks
10
Question d) adverse health effects of caffeine in combination with other substances in energy drinks and alcohol
8
EFSA supporting publication 2015:EN-561
10
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.3.1.
Epidemiology studies
The methodological quality of all non-randomised epidemiology studies passing the primary screening
(on titles and abstracts) was assessed by using the using the Newcastle Ottawa Scale (NOS). The tool
can either be used as a checklist or scale, and separate scales exist for cohort and case-control studies.
It contains eight items, categorised into three dimensions, including selection, comparability and,
depending on study type, outcome (cohort studies) or exposure (case-control studies). To carry out the
NOS, a coding manual was provided to each team member assessing the articles that provided
guidance on how to complete the form appropriately, thereby aiding in the consistency and quality
control of assessments.
We considered a study awarded seven or more stars as a high quality study as there is no agreed
qualitative scale of, for example, low, medium or high using the NOS. However, all studies that pass
through the primary screening process were included in the draft review, irrespective of their NOS
score.
For consistency, all NOS scores were reviewed by an epidemiologist.
2.3.2.
Intervention studies
The study quality of intervention studies was evaluated by using the Cochrane Collaboration ‘Risk of
Bias’ (methodological quality) tool to assess the risk of bias in randomized controlled trials. To
complete the tool, the Cochrane guidance was provided to each team member assessing the articles
and provides assistance on how to complete the form appropriately, thereby aiding in the consistency
and quality control of assessments.
For consistency, all Cochrane Collaboration scores were reviewed by an epidemiologist.
2.4.
Recording data
At all stages of the screening process the number of publications that were excluded from further
analysis were recorded in the data selection form. The reason why records were excluded during
primary screening on abstracts was recorded in Endnote.
2.5.
Data abstraction
In parallel with the secondary screening all articles were systematically reviewed by a team member
and relevant data was extracted and captured in an EXCEL-based data abstraction forms. To aid in the
transparency of the review, these data abstraction forms will be included as an appendix in the final
report. If there are a large number they will be presented in a separate document.
For quality assurance, 10 per cent of the studies were checked by another reviewer to ensure
consistency. If discrepancies arose, such differences were discussed between team members to achieve
a consensus view and if necessary, a third member of the team also reviewed the manuscript.
EFSA supporting publication 2015:EN-561
11
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
RESULTS
2.6.
Data retrieval
2.6.1.
Question a) Papers on adverse effects of caffeine
A total of 11,319 papers were found relating to the adverse effect of caffeine (after duplicates were
removed), from which 9,208 were excluded on titles according the exclusion criteria, leaving 2,111
studies that were further screened for inclusion by carrying out primary screening on the abstracts.
Following such screening, a total of 142 papers were included and underwent secondary screening to
assess methodological quality and data abstraction. Of the 142 papers, 0 articles were found relating to
infants, 2 articles were found on children, 26 on pregnant and lactating women, 108 on adults and
adolescents and 7 on adults and adolescents performing endurance exercise.
For children, we found papers on general toxicity and cardiovascular effects (1) and neurological
effects (1). For pregnant and lactating women we retrieved 3 papers on foetal infant death, 10 papers
on low birth weight, 11 on spontaneous abortion and 2 papers on psychological effects. We also
retrieved 28 papers on cardiovascular effects in adults and adolescents, 44 papers on cancer, 7 on bone
and calcium effects, 4 on glaucoma, 3 on insulin sensitivity, 2 on incontinence and 18 on neurological
effects, as well as 2 papers on general toxicity. Lastly, 3 papers were retrieved relating to
cardiovascular effects following endurance exercise in adults and adolescents, and 4 on performance
itself.
Articles were excluded for several reasons. Despite specifying English in the search terms, several
papers (67) written in a non-English language were still identified hence were discarded. A number of
papers were also rejected based on the other exclusion criteria due to articles:

being published prior to 1997 (82)

relating to caffeine in combination with other beverages or substances including alcohol and
drugs of abuse (90)

relating to caffeine in combination with other beverages or substances, or relating to alcohol
alone (13)

relating to other population groups i.e. groups suffering from a severe disease (48)

presenting data in experimental animal species or in vitro studies (6)

not having an abstract (384)

reporting data on an endpoint that was not considered an adverse effect, such as an increase in
performance (375)

reporting data on caffeine in combination with other chemicals, including alcohol and drugs of
abuse (90)

reporting data on caffeine in combination with other factors such as smoking (45)

reporting on different endpoints such Parkinson’s, type II diabetes, stroke (256)

reporting the therapeutic effects of caffeine (22)
EFSA supporting publication 2015:EN-561
12
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Articles were also excluded if caffeine was not mentioned in the abstract (232), if articles were
duplicated (80), was a primary cancer paper (171) or a narrative review (85).
References not considered pertinent are listed in Endnote and reasoning why these references are not
considered relevant is provided. The report is accompanied by the EndNote library containing the
related references.
There was some overlap in the articles retrieved for the other questions, as the search also picked up
many papers related to adverse effects of caffeine in combination with alcohol or other substances in
energy drinks, which were also picked up in the searches for questions b) and c) hence were excluded
from further analysis for question a).
2.6.2.
Question b) Papers on adverse effects of caffeine in combination with alcohol
A total of 2,009 papers were found relating to the adverse effect of caffeine and alcohol (after
duplicates were removed), from which 1,762 were excluded according the exclusion criteria, leaving
247 studies that were further screened for inclusion by carrying out primary screening on the abstracts.
Following such screening, 27 articles (26 on adults and 1 on adults and adolescents performing
exercises) were included and underwent secondary screening. We retrieved 13 papers on alcohol
consumption and intoxication in adults and adolescents, 4 on cardiovascular effects, 2 on
neurological/CNS effects, 6 on risk taking and 1 on reproductive effects. One paper was retrieved on
adults and adolescents performing endurance exercise.
References not considered pertinent are listed in Endnote and reasoning why these references are not
considered relevant is provided. The report is accompanied by the EndNote library containing the
related references.
As with question a), many papers were excluded due to reporting data on the topics listed above. In
addition, papers were also excluded due to reporting the effects of caffeine alone (such papers would
be included in question a), or for alcohol alone. When papers relating to caffeine alone were retrieved,
they were cross referenced with those captured for question a) to ensure as many papers were retrieved
as possible.
2.6.3.
Question c) Papers on adverse effects of caffeine in combination other substances in
energy drinks
A total of 114 papers were found relating to the adverse effect of caffeine and other substances in
energy drinks (after duplicates were removed), from which 90 were excluded according the exclusion
criteria, leaving 24 studies (including those added from searches or from analysing various reports
from authoritative bodies) that will be further screened for inclusion by carrying out primary screening
on the abstracts. Following screening on abstracts, 6 articles were further evaluated and included in the
study, all of which related to adults and adolescents.
References not considered pertinent are listed in Endnote and reasoning why these references are not
considered relevant is provided. The report is accompanied by the EndNote library containing the
related references.
Papers were excluded mainly due to reporting data solely on caffeine or energy drinks containing
caffeine (which were already covered in question a)), reporting data on other substances outside the
remit of this project i.e. glucose or data relating to the use and consumption of energy drinks.
EFSA supporting publication 2015:EN-561
13
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.6.4.
Question d) Papers on adverse effects of caffeine in combination with other substances
in energy drinks and alcohol
A total of 63 papers were found related to the effects of caffeine, other substances in energy drinks and
alcohol (after duplicates were removed). However, most papers were rejected due to only reporting the
adverse effects of caffeine or energy drinks and alcohol and no papers addressed the potential adverse
effects of caffeine, other substances in energy drinks and alcohol. Such papers would have already
been picked in in the search for question b), seeing as energy drink per se was named in the technical
specification as a source of caffeine.
2.7.
Health endpoints
Following the extensive literature search a number of different health endpoints were identified,
including reproductive effects, cardiovascular effects, cancer, diabetes, Parkinson’s disease,
Alzheimer’s disease, stroke, neurological/CNS effects, kidney effects, glaucoma/intraocular pressure,
bone effects and insulin sensitivity). Following a brief evaluation of the abstracts of all papers,
following discussion with EFSA several endpoints i.e. diabetes, Parkinson’s disease, Alzheimer’s
disease, stroke, were discounted as data showed no correlation, or an inverse correlation with caffeine.
2.8.
Adverse health effects of caffeine
112 articles relating to the adverse effects of caffeine in the different population groups were included
in the study.
2.8.1.
Breast-fed infants consuming caffeine via mother’s milk
No data were retrieved.
2.8.2.
Children possibly divided by age group
Three papers were found on the effects of caffeine on children (aged from 36 months up to and
including 9 years of age).
2.8.2.1.
General toxicity
Acute caffeine has been reported to cause severe emesis, tachycardia, central nervous system effects,
agitation and diuresis whereas chronic exposure has been associated with gastrointestinal system
effects, hepatotoxicity, nephrotoxicity, respiratory effects, neurological effects (agitation, seizures),
psychotic disorders, cardiovascular disorders (tachycardia, cardiac dysrhythmias, hypertension, heart
failure) and muscle effects in children (Nawrot et al., 2003, Seifert et al., 2011).
2.8.2.2.
Cardiovascular effects
High doses (data not given) of caffeine could potentially exacerbate cardiac conditions for which
stimulants are contraindicated, including ion channelopathies and hypertrophic cardiomyopathy in
children and young adults, due to the risk of hypertension, syncope, arrhythmias and sudden death
(Seifert et al., 2011).
2.8.2.3.
Neurological/CNS effects
The potential link between excessive caffeine intake and headaches was investigated in children and
adolescents (age range 6-18). Subjects reporting daily or near daily headaches consumed 192.88 mg
caffeine per day, in the form of cola drinks, amounting to 1414.5 mg (1350.1-2700.3 mg/week).
Gradual withdrawal of caffeinated led to complete cessation of headaches in 33 of the 36 subjects.
Three adolescents reported intermittent episodic migraine instead of daily headache, although not
frequent enough to require treatment. Overall, the authors concluded that a high daily caffeine intake
may be linked with daily headache in children and adolescents (Hering-Hanit and Gadoth 2003).
EFSA supporting publication 2015:EN-561
14
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.8.2.4.
Summary
Overall, reviews cited by various authoritative bodes have associated the intake of caffeine by children
with a number of adverse health effects affecting the gastrointestinal system, liver, kidney, respiratory
system, central nervous system, cardiovascular system as well as causing psychological disorders.
However, few epidemiological papers published on children between the age of 3 and 9 years
between1997-2013 were identified. Most studies focussed on older children (ages 10 years old and
above), hence were considered as adolescents, according the EFSA Food consumption database.
2.8.3.
Pregnant and lactating women
29 articles relating to reproductive effects following caffeine consumption were included in the study,
covering low birth weight and restricted foetal growth, spontaneous abortion and foetal or infant death.
Important confounders for these health outcomes include smoking, alcohol consumption, prepregnancy weight, height and parity. Some studies presented did not adjust for such factors.
2.8.3.1.
Low birth weight/restricted foetal growth
Mothers of small for gestational age (SGA) infants had higher mean intake of caffeine (281 mg/day) in
the third trimester compared with those delivering non-SGA infants (212 mg/day).
The risk of SGA births was increased with increasing caffeine consumption in the total population of
infants and with male infants, as unadjusted odds ratios (ORs) were 1.9 (95% confidence intervals (CI)
1.0-3.7) after 110-204.9 mg/day; 2.3 (95% CI 1.2-4.4) after 205-309.9 mg/day and 2.7 (95% CI 1.55.2) after >310 mg/day. No relationship was seen for female foetuses. ORs adjusted for possible
confounders, in particular cigarettes, smoking, low pre-pregnancy weight, low education and previous
birth of an SGA infant, show a slightly increased risk for a mother to give birth to an SGA infant
associated with a high caffeine intake in the third trimester. If stratified by gender, this increased risk
was only found for males (adjusted OR 2.5 95% CI 1.4-4.8) but not for females (adjusted OR 1.0 95%
CI 0.5-1.7) (Vik et al., 2003). Similarly, serum paraxanthine levels in the third trimester were
significantly higher among women who gave birth to SGA infants (752 ng/ml) compared to those who
did not (653 ng/ml), but this association was only seen in women who smoked. There was no
association between caffeine and fetal growth in non-smoking women. Adjustment for maternal age,
pre-pregnant weight, education, parity, ethnicity and number of cigarettes smoked did not significantly
alter the results (Klebanoff et al., 2002). In contrast, a significant reduction in birth weight after an
average caffeine intake of >71 mg/day was reported, after adjustment for gestational age, infant sex,
parity, maternal height and weight, only in infants born to non-smoking mothers (Vlajinac et al.,
1997).
Following adjustment for maternal age, weight, height, ethnicity, parity, sex, gestational age at
delivery, smoking status and alcohol intake, caffeinated coffee consumption throughout pregnancy
was also associated with an increased risk of restricted fetal growth in a dose dependent manner (100199 mg/day; OR 1.2 (95% CI 0.9-1.6), 200-299 mg/day; 1.5 (95% CI 1.1-2.1) and for >300 mg/day
OR 1.4 (95% CI 1.0-2.0) for compared with <100 mg/day (Care Study Group 2008). In addition,
women (classified as drinking coffee or not) who drank caffeinated coffee after adjustment for age,
parity, race, height, education, prenatal care, smoking, tea/cola consumption had an adjusted OR of 1.3
(95% CI 1.0-1.7) for preterm delivery, although those drinking decaffeinated and caffeinated coffee
had a higher risk (OR 2.3 95% CI 1.3-4.0) (Eskenazi et al., 1999).
In contrast, various authors reported that drinking caffeinated coffee was not associated with low birth
weight (Bracken et al., 2003, Clausson et al., 2002, Eskenazi et al., 1999, Jarosz et al., 2012, Santos et
al., 1998), SGA (Eskenazi et al., 1999, Parazzini et al., 2005), foetal growth (Klebanoff et al., 2002),
gestational age (Clausson et al., 2002), premature birth (Jarosz et al., 2012), preterm births and
intrauterine growth retardation (Bracken et al., 2003, Santos et al., 1998).
EFSA supporting publication 2015:EN-561
15
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.8.3.2.
Spontaneous abortion
Several studies reported an association between higher caffeine intake (>300 mg/day) and spontaneous
abortion. Higher coffee drinking before and during early pregnancy was associated with an increased
risk of spontaneous abortion as the OR were 1.23 (95% CI 0.91-1.64) for 1 cup/day, 1.34 (95% CI
1.04-1.73) for 2-3 cups/day and 1.47 (95% CI 1.07-2.02) for > 4 cups/day before pregnancy, and 1.22
(95% CI 0.93-1.60) for 1 cup/day, 1.75 (95% CI 1.23-2.29) for 2-3 cups/day and 3.98 (95% CI 2.556.21) for >4 cups/day during pregnancy, following adjustment for age, education, previous live births
and miscarriages, alcohol consumption, smoking, nausea intensity (Parazzini et al., 1998). Other
studies showed that ingestion of caffeine may increase the risk of spontaneous abortion in a dosedependent manner (100-299 mg/day adjusted OR 1.3 (95 % CI 0.9-1.8); 300-499 mg/day OR 1.4 (95
% CI 0.9-2.0) and >500 mg/day OR 2.2 (95 % CI 1.3-3.8) after adjusting for caffeine intake, smoking
status, age, number of previous pregnancies, history of spontaneous abortion, consumption of alcohol,
and presence or absence of nausea, vomiting and fatigue (Cnattingius et al., 2000).
Greenwood et al., (2010) also concluded that greater caffeine intake (>300 mg/day) in the form of tea
or coffee was associated with increases in late miscarriage and stillbirth as adjusted OR (adjusting for
maternal age, parity, alcohol intake and amount smoked measured by salivary cotinine) increased to
2.2 (95% CI 0.7-7.1) for 100-199 mg/day, 1.7 (95% CI 0.4-67.1 for 200-299 mg/day and 5.1 (95% CI
1.6-16.4) for >300 mg/day compared to those consuming < 100 mg/day (Greenwood et al., 2010).
Similarly, high caffeine consumption during pregnancy (>300 mg/day), in particular coffee
consumption, was identified as an independent risk factor for increased risk of miscarriage, as adjusted
ORs (for maternal age, severity of nausea and gestational age) were 1.94 (95% CI 1.04-3.63) for 301–
500 mg/day and 2.18 (95% CI 1.08-4.40) for >500 mg/day, although there was no evidence that prepregnancy caffeine consumption affected the risk (Giannelli et al., 2003).
An association between caffeine (caffeinated coffee, tea, soft drinks and hot chocolate) during
pregnancy and increased risk of miscarriage was demonstrated in a dose-dependent manner. After
adjusting for potential confounders including maternal age, race, education, household income, marital
status, previous miscarriage, smoking, alcohol consumption, Jacuzzi use, magnetic field exposure, and
nausea and vomiting , the adjusted hazard ratio for <200 mg/day was 1.42 (95% CI 0.93-2.15) and
>200 mg/day was 2.23 (95% CI 1.34-3.69) (Weng et al., 2008). Odds ratios of 3.045 (95% CI 1.247.29) and 16.106 (95% CI 6.55-39.62) for 151-300.9 mg/day and >301 mg/day, respectively, were
reported in a similar study, not taking into account confounding factors. When confounders such as
cigarette smoking, alcohol consumption, exposure to toxicants, nausea/vomiting were adjusted for,
each caffeine intake of 100 mg/day was associated with an increased OR of 2.724 (95% CI 2.7152.733) (Stefanidou et al., 2011).
Fernandes et al., (1998) carried out a meta-analysis to investigate the relationship between caffeine
consumption and spontaneous abortion and abnormal foetal growth. A small but statically significant
increase in risk of spontaneous abortion and low birth-weight babies was also reported in pregnant
women consuming >150 mg caffeine per day (although authors stated that the contribution of these
result of maternal age, smoking, ethanol use and other confounders could not be excluded (Fernandes
et al., 1998).
An increased risk of repeated miscarriage among non-smoking women with high caffeine intake (>300
mg/day OR 2.7 (95% CI 1.1-6.2)), adjusting for maternal age, previous pregnancy history, induced
abortions, myoma, time to conceive, alcohol intake and folate levels, whereas there was no such
association among smokers was reported. A multivariate analysis showed that caffeine intake (brewed,
boiled, instant coffee; loose tea, tea bags or herbal tea; cocoa, chocolate, soft drinks or medications)
was associated with a non-significant dose-dependent increase in risk of miscarriage (0-99 mg/day OR
1; 100-299 mg/day OR 1.6 (95% CI 0.7-0.33); >300 mg/day 1.8 (95% CI 0.8-3.9)). Overall authors
concluded that the main life-style-related risk factors for repeated miscarriage were smoking and high
EFSA supporting publication 2015:EN-561
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
caffeine intake during pregnancy (George et al., 2006). In contrast, neither the total caffeine (>300
mg/day) nor individual caffeinated drinks consumed during the first trimester of pregnancy was
associated with an appreciable increased risk of spontaneous abortion (Fenster et al., 1997). Other
authors also reported that caffeine consumption (in the form of coffee, tea, soda) before or during
pregnancy were not associated with becoming pregnant or increased risk of miscarriage, after
adjusting for confounders (Pollack et al., 2010, Savitz et al., 2008).
2.8.3.3.
Foetal or infant death
Caffeine intake has been associated with sudden infant death syndrome as the relative risk (RR)
increased with high levels of caffeine consumption in a dose dependent manner in both the first and
third trimester. Odds ratios were adjusted for confounders including selection variables,
sociodemographic details, pregnancy details, infant details and postnatal factors. Mothers consuming
>400 mg/day (equivalent to >4 cups of coffee per day) during the first trimester had an increased RR
(after adjusting for confounders) as ORs were 1.30 (95% CI 0.92 to 1.82) in the first trimester; 1.46
(95% CI 1.05 to 2.05) during the third trimester and 1.65 (95% CI 1.15 to 2.36) throughout pregnancy.
Authors stated that it was apparent that more sudden infant death syndrome mothers consumed heavy
caffeine than controls (28.1 vs 14.0% respectively) (Ford et al., 1998).
Similarly, caffeine intake during pregnancy was significantly associated with fetal mortality, and a
dose-dependent increase in mortality was observed as only >300 mg/day was shown to be associated
with increased risk of fetal death (adjusted OR 2.33 (95% CI 1.23-4.41)) compared to lower caffeine
intakes (1-59 mg/day, OR 0.74 (95% CI 0.42-1.31), 60-149 mg/day, OR 0.93 (95% CI 0.51-1.67) and
150-299 mg/day, OR 1.22 (95% CI 0.69-2.17). Data were adjusted for maternal and partner’s
education, history of abortions and/or fetal deaths, vomiting/nausea during the first trimester and
attendance for prenatal care (Matijasevich et al., 2006).
In contrast, after adjusting for smoking, alcohol, parity, maternal age, marital status, years of
education, occupational status and body mass index, Wisborg et al., (2003) concluded that drinking
coffee during pregnancy was not associated with infant death, even at high doses of caffeine (>8
cups/day, adjusted OR 1.6 (95% CI 0.7-3.6) although they did show an increased risk of stillbirths that
increased in a dose-dependent manner (1-3 cups/day, adjusted OR 0.6 (95% CI 0.3-1.1), 4-7 cups/day,
OR 1.4 (95% CI 0.8-2.5) and >8 cups/day OR 2.2 (95% CI 1.0-4.7) (Wisborg et al., 2003).
2.8.3.4.
Neurological/CNS/psychological effects
An investigation into the effect of caffeine during pregnancy problems behaviour in 5-6 year old
children showed that exposure to coffee, tea and cola (highest dose group >425 mg/day) around the
16th week of gestation was not associated with hyperactivity/inattention problems, or suboptimal
prosocial behaviour. Data were adjusted for maternal age, ethnicity, education, anxiety, cohabitant
status, smoking, alcohol, gender, family size and gestational age (Loomans et al., 2012).
The association between intrauterine exposure to caffeine, in the form of coffee, tea or soft drinks, and
inattention/over-activity in 18 month old children, suggestive of attention deficit/hyperactivity
disorder (ADHD) was also investigated. After adjusting for various confounders in 3 models such as
gender (model 1), maternal characteristics, age, education, marital status, symptoms of anxiety ⁄
depression, smoking and alcohol intake), (model 2) and birth weight and head circumference (model
3), exposure to caffeine at week 17 of gestation had a small effect on inattention and overactivity
combined, and exposure at 17 and 30 weeks affected overactivity, when investigated separately from
inattention, compared to controls. Authors also reported that such effects were only observed
following exposure to soft drinks rather than coffee or tea and suggested that particular components of
such drinks may account for a greater risk rather than caffeine itself (Bekkhus et al., 2010).
EFSA supporting publication 2015:EN-561
17
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.8.3.5.
Summary
Overall, a number of studies have reported that the consumption of caffeine may increase the risk of
small-for-gestational age babies, although evidence is inconclusive; may increase the risk of
spontaneous abortion; and increase the risk of sudden infant death syndrome, foetal and infant death.
Most, although not all studies adjusted for confounding factors such as smoking, alcohol consumption,
prepregnancy weight, height and parity.
2.8.4.
Adults and adolescents
76 articles relating cardiovascular effects, cancer, bone effects, glaucoma, insulin sensitivity,
incontinence and neurological effects were included in the study. Important confounders for these
health outcomes include smoking, alcohol consumption, height, weight, body mass index and age.
2.8.4.1.
General toxicity
Caffeine toxicity in adults has been associated with a number of adverse health effects such as
nervousness, irritability, insomnia, sensory disturbances, diuresis, arrhythmia, tachycardia, elevated
respiration and gastrointestinal disturbances (Nawrot et al., 2003). In adults, no adverse effects are
expected following exposure to <400 mg/day. Exposure to 1-3 mg/kg or 12.5-100 mg/day has positive
effects on performance, whereas 4-12 mg/kg caffeine has been correlated with anxiety and jitteriness
(Seifert et al., 2011). Acute clinical toxicity has been observed at 1 g and fatalities have been seen at 510 g (Seifert et al., 2011).
A review of the health risks of energy drinks reported CNS effects (alertness, decreased fatigue,
improved concentration) following 85-250 mg and undesirable effects (restlessness, nervousness,
insomnia and tremors) at 250-500 mg. At 15-30 mg/kg, symptoms may also include muscle spasms,
myocardial irritability, myocardial arrhythmias, vomiting and seizures, based on the report from Rath
and colleagues (Guilbeau 2012, Rath 2012).
2.8.4.2.
Cardiovascular effects
Blood pressure and hypertension
Several studies have been conducted to investigate the effect of caffeine on blood pressure in both
normotensive and hypertensive subjects.
Following a randomised control trial (RCT), after adjusting for age, blood pressure was increased in
normotensive men and women following caffeine consumption (80 mg 3x/day for 6 days and 250 mg
on 7th day), with systolic blood pressure increasing by 4 mm Hg and diastolic blood pressure by 3 mm
Hg (Farag et al., 2010). Ad lib consumption of coffee or tea also was reported to raise blood pressure
of adults (4 mm Hg for systolic blood pressure and 3 mm Hg for diastolic blood pressure (Lane et al.,
1998). Similarly, 500 mg caffeine significantly increased average blood pressure during the working
day and evening, by 4/3 mm Hg, and amplified the increase in blood pressure associated with high
levels of stress in habitual coffee drinkers, after data were adjusted for subject, time of day, posture,
physical activity and perceived stress (Lane et al., 2002).
Hypertensive subjects were identified as five hypertensive risk groups, namely optimal, normal, highnormal, stage 1 and diagnosed hypertension, classified as systolic and diastolic blood pressure. After
caffeine consumption (3.3 mg/kg or a fixed dose of 250 mg) systolic and diastolic blood pressure was
increased in all groups. Statistical analyses (ANCOVA) showed that the largest blood pressure
response was observed in hypertensive men, followed by those classified as stage 1, high-normal
groups, optimal then normal groups. Multiple regression analysis controlled for factors such as age
and body mass index. Following the increase in blood pressure, 19% of the high-normal, 15% of the
stage 1, and 89% of the diagnosed hypertensive groups, fell into the hypertensive range (systolic blood
EFSA supporting publication 2015:EN-561
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
press; >140 mm Hg; diastolic blood pressure; >90 mm Hg). Subjects in the optimal and normal groups
remained normotensive (Hartley et al., 2000).
Sustained hypertension that required treatment was developed more frequently in coffee drinkers
compared with non-drinkers (53.1 vs 43.9%). The adjusted hazard ratio (HR) of moderate (1-3
cups/day) and heavy (>4 cups/day) drinkers was 1.25, 95% CI 1.06-1.44 compared to non-drinkers.
Data were adjusted for age, sex, life-style factors, parental hypertension, duration of hypertension,
body mass index and change in body weight. Authors concluded that a non-linear relationship was
found between coffee consumption and sustained hypertension in hypertensive subjects (Palatini et al.,
2007).
There seem to be no gender differences in hypertensive effects in relation to caffeine. Both men and
women had similar increased blood pressure responses to 3.3 mg/kg caffeine compared to the control
group. In women, systolic and diastolic blood pressures were increased by 4.5 and 3.3 mm Hg,
respectively, and men, 4.1 and 3.8 mm Hg, respectively (Hartley et al., 2004).
There appeared to be conflicting data regarding age-related blood pressure responses. Systolic blood
pressure was increased in both young men (Farag et al., 2010) and women (Arciero and Ormsbee
2009, Farag et al., 2010) following 80 mg 3x/day caffeine followed by 250 mg, or 5 mg/kg caffeine,
respectively. However, differences in diastolic blood pressure may exist as an increase was only
reported in young and old women, and in young but not old men (Farag et al., 2010), whereas other
studies showed an increase in younger, but not older women (Arciero and Ormsbee 2009).
In contrast, blood pressure response was augmented to a greater extent in older rather than younger
women following acute caffeine ingestion (5 mg/kg) and less physically active younger women were
more vulnerable to the pressor response to caffeine than more active younger women (Arciero and
Ormsbee 2009). Caffeine intake was also reported to potentially increase blood pressure in
adolescents, especially African Americans. Those consuming >100 mg/day had a higher systolic blood
pressure compared to those consuming 0-50 mg/day (mean difference 6 mm Hg (95 % CI 2.3-9.7)) or
50-100 mg/day (7.1 mm Hg (95% CI 3.4-10.7)) after gender and body mass index were controlled for
(Savoca et al., 2004, Savoca et al., 2005).
The habitual consumption of caffeine plays a role in the hypertensive effects observed following
consumption. After adjusting for age, subject, time of day, posture, physical activity and perceived
stress, caffeine significantly increased average blood pressure by 2-4 mm Hg during the working day
on a daily basis in some habitual coffee drinkers (Farag et al., 2005, Lane et al., 2002). In contrast,
habitual coffee consumption was associated with lower blood pressure (-0.6 mm Hg for systolic blood
pressure and -0.4 mm Hg for diastolic blood pressure) with and without adjustment for alcohol use,
smoking, body mass index, glucose tolerance and green tea intake (Wakabayashi et al., 1998).
Because decaffeinated coffee also increases blood pressure in non-habitual drinkers, authors
concluded that ingredients other than caffeine must be responsible for cardiovascular activation (Corti
et al., 2002).
The association between caffeine consumption and hypertension does not always show a linear dose
response relationship. Using categorical analysis, an inverse U-shaped association between caffeine
(coffee; 14.8-608.1 mg/day) consumption and incident hypertension in women was reported.
Compared with participants in the lowest quintile of caffeine consumption (0-45 mg/day), those in the
third quintile (144-297 mg/day) had a 13% and 12% increased risk of hypertension, respectively (RR)
1.13 (95% CI 1.08-1.18) and 1.12 (95% CI 1.06-1.18 for two nurse cohorts, respectively). When
looking at individual caffeinated beverages, habitual coffee consumption was not associated with
increased risk of hypertension as an increased risk was associated with increased consumption of
sugared or diet cola (Winkelmayer et al., 2005). According to the authors, data from cross-sectional
studies also suggested an inverse linear or U-shaped association of habitual coffee use with blood
EFSA supporting publication 2015:EN-561
19
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
pressure in different populations and prospective studies suggest a protective effects of high coffee
intake (≥ 4 cups/day) against hypertension (Geleijnse 2008).
In contrast, Mesas et al., (2011) carried out a recent meta-analyses and reported that 100-300 mg
caffeine intake produced an acute increase in blood pressure but did not support an association
between long term coffee consumption and hypertension (Mesas et al., 2011). Similarly, 3.3 mg/kg
caffeine did not significantly increase blood pressure in normotensive subjects (Hartley et al., 2000).
Cardiovascular disease
Various studies have been carried out to investigate the relationship between caffeine consumption
and cardiovascular disease, defined as diseases of the heart and blood vessels.
Compared to coffee non-drinkers, men who consumed moderate-to-high (>200 ml coffee/day) coffee
consumption had increased inflammation markers (interleukin-6, tumour necrosis factor , serum
amyloid), after adjusting for interactions between coffee consumption and age, sex, smoking, body
mass index, physical activity and other covariates. Authors concluded that a relationship may exist
between caffeine and inflammatory process, which in turn, that may lead to cardiovascular disease
(Zampelas et al., 2004).
No significant correlation between regular coffee consumption (>2-6 cups/day) and mortality due to
cardiovascular disease were found in men (Jazbec et al., 2003, Lopez-Garcia et al., 2011) or women
(Jazbec et al., 2003, Lopez-Garcia et al., 2011, Lopez-Garcia et al., 2008). Some positive effects of
coffee on general mortality were shown, but not on cardiovascular disease mortality in women, after
data were adjusted for age, smoking, diastolic blood pressure, well-being, ulcer and region (Jazbec et
al., 2003), whereas Lopez-Garcia et al., (2008) failed to show such an association. After data were
adjusted for age, smoking and other cardiovascular disease and cancer risk factors, regular coffee
consumption was not associated with an increased mortality in either men or women.
Consumption of coffee, green tea and total caffeine intake was associated with a reduced risk of
mortality from cardiovascular disease. Compared to those who consumed < 1 cup/week, the hazard
ratio adjusted for age and body mass index for those drinking 1-6 cups/week, 1-2 cups/day or >3
cups/day were 0.71 (95% CI 0.53-0.96), 0.84 (95% CI 0.64-0.99) and 1.17 (95% CI 0.77 – 1.76)
(Mineharu et al., 2011).
Myocardial infarction
Data from a cohort study of 1971 42-60 year old men showed that heavy coffee consumption (>814 ml
coffee) increased the acute risk of acute myocardial infarction or coronary death, independent of the
brewing methods (rate ratios adjusted for age, smoking, exercise ischemia, diabetes, income and
serum insulin levels, were 0.84 (95% CI 0.41-1.72) for light (<375 ml), 1.22 (95% CI 0.90-1.64) for
moderate (376-813ml) and 1.43 (95% CI 1.06-1.94) for heavy (814ml) drinkers (Happonen et al.,
2004). Filtered coffee was positively associated with the risk of first acute myocardial infarction in
men (OR 1.73 95% CI 1.05-2.84) for > 4 times per day), but not women, after adjusting for current
smoking, postsecondary education, hypertension and sedentary lifestyle (Nilsson et al., 2010).
Similarly, findings from a cohort study of patients with incident cases of non-fatal myocardial
infarction indicated that coffee intake may trigger myocardial infarction, especially in those with
light/occasional intake of coffee (<1 cup/day; RR 4.14 95% CI 2.03– 8.42; 2–3 cups/day; RR 1.60
95% CI 1.16 –2.21; >4 cups/day RR 1.06 95% CI 0.69 –1.63). Data were stratified by habitual intake
of coffee and by risk factors for underlying cardiovascular disease (Baylin et al., 2006).
Various studies did not show a correlation between caffeine and myocardial infarction. A case-control
study reported the OR for drinking >4 cups/day after adjusting for coronary risk factors was 0.84 (95%
EFSA supporting publication 2015:EN-561
20
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
CI 0.49-1.42) compared to >1-3 cups (0.91 95% CI 0.58-1.45), 2-7 cups/week (0.78 95% CI 0.481.26) or <1 cup/week (1). Coronary risk factors included sex, smoking, hypertension medication,
family history, diabetes, aspirin use, body mass index, physical activity, calories from saturated fat,
total calorie intake and alcohol intake (Sesso et al., 1999).
Later case-control studies also concluded that that coffee consumption does not increase myocardial
infarction risk and that coffee consumption of >5 cups/week was non-significantly inversely
associated with myocardial infarction risk among older Swedish women, after adjustment for age,
coronary heart disease risk factors and dietary variables (0-4 cups/week (Rosner et al., 2007). Other
studies also found no association between coffee consumption (>4 cups) and cardiovascular risk
including myocardial infarction (Floegel et al., 2012) and Mukamal reported no overall association
between coffee (>14 cups/week) or cola consumption (> 7 servings/week) with survival after acute
myocardial infarction (Mukamal et al., 2004).
2.8.4.3.
Cancer
Forty-four references were identified that investigated the association between caffeine and cancer.
However, when reviewing the abstracts it was observed that a number meta-analyses and pooled
analyses had been carried out over the past ten years, and that systematic literature reviews (SLR) had
been carried out in support of the revision of the World Cancer Research Fund’s (WCRF) (World
Cancer Research Fund 2007) that also included meta-analyses. It was agreed with the contractor that
this safety assessment could concentrate on such studies in favour of reviewing all individual papers.
Any paper published after the latest meta/pooled-analysis was reviewed to assess whether it reported
any findings that significantly differed from the pooled estimates.
Yu et al., (2011) carried out a large meta-analysis that reviewed 59 studies, consisting of 40
independent cohorts published before 2011, that met the inclusion criteria. These criteria were: have a
prospective cohort design, report RR or HR and their corresponding 95% CIs of cancer relating to
every category of coffee intake, and provide the frequency of coffee intake. Compared with
individuals who did not or seldom drank coffee, the pooled RR of cancer was 0.87 (95% CI 0.82-0.92)
for regular coffee drinkers, 0.89 (95% CI 0.84-0.93) for low to moderate coffee drinkers, and 0.82
(95% CI 0.74-0.89) for high drinkers. Authors report that overall an increase in consumption of 1 cup
of coffee per day was associated with a 3% reduced risk of cancers (RR=0.97, 95% CI 0.96-0.98) and
that coffee drinking was associated with a reduced risk of buccal and pharyngeal (RR=0.419),
oesophageal (RR=0.55), pancreatic (RR=0.82), hepatocellular (RR=0.54), colorectal (RR=0.89),
breast (RR=0.94), bladder (RR=0.83), prostate (RR=0.79), endometrial (RR=0.74) and leukaemic
(RR=0.64) cancers.
Other meta-analyses and pooled analyses have also reported no association or an inverse association
between caffeine and risk of brain & glioma (Dubrow et al., 2012, Holick et al., 2010, Michaud et al.,
2010), colorectal (Bakker et al., 2006, Norat et al., 2010, Tavani and La Vecchia 2004), endometrial
(Bandera et al., 2006, Bravi et al., 2009, Je and Giovannucci 2012, Norat et al., 2012), hepatocellular
& liver (Bos et al., 2006, Bravi et al., 2007, Larsson and Wolk 2007), oral & oropharyngeal, (Alberg et
al., 2006, Galeone et al., 2010, Hartman et al., 2006) , ovarian (Agnoli et al., 2006, Steevens et al.,
2007), pancreatic (Forman et al., 2007, Genkinger et al., 2012, Norat et al., 2011), prostate (Bekkering
et al., 2006a, Park et al., 2010), oesophageal (Hartman et al., 2007), stomach (Botelho et al., 2006,
Forman et al., 2006), renal cell cancer (Lee et al., 2007, Mayer et al., 2006) and breast cancer (Agnoli
et al., 2005, Jiang et al., 2013, Norat et al., 2008, Tang et al., 2009).
Bladder cancer
The WCRF systematic review reported that adjusted results from cohort and case-control studies
exclude any substantial association between increasing coffee consumption and the risk of bladder
EFSA supporting publication 2015:EN-561
21
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
cancer (Bekkering et al., 2006b). The study included had adjusted their results for various
confounders, including age, smoking, gender, other dietary sources of caffeine, education, occupation
and alcohol. However, it was not clear whether the review made any further adjustments.
A pooled analysis of 10 European bladder cancer case-control studies was conducted between 1976
and 1996 (Sala et al., 2000). In total there were 564 cases (205 men; 359 women) and 2,929 controls
(1358 men; 1571 women) aged 30 to 79 years; all were non-smokers. Hospital controls (n=1,112)
were diagnosed with various diseases. Coffee consumption was categorised by number of cups per day
(0; 1-2; 3-5; 6-9; ≥10) and duration in years (0-10; 11-30; 31-43; 44-72). Overall, there was no excess
risk in coffee drinkers compared to people who never drank coffee (RR 1.0 95% CI 1.0-1.3). The risk
did not increase with dose or duration, although a significant excess risk was observed in those
drinking ≥10 cups per day (RR 1.8 95% CI 1.0-3.3). However, the pooled results depended on the type
of controls, with an overall excess risk observed for studies using hospital controls (RR 1.4, 95% CI
1.0-1.8), and a dose-response relationship observed overall and for men. There was no heterogeneity
between the studies and no confounding from smoking, although other confounders may have
influenced the results that the authors believed should be considered in any future study. Selection bias
may have influenced the results because of the difference between population and hospital controls. In
addition the different methods used to assess exposure may have influenced the results; the
categorisation of exposure in American compared to European studies is different because there is no
standard cup size. The chemical composition of a beverage also needs to be considered.
Zeegers et al., (2001) carried out a systematic review in 2001 and reported coffee was unlikely to be
associated with bladder cancer in women, whereas a 26% elevation of risk was seen in men.
The association between caffeine consumption and risk of bladder cancer was also investigated by
Zhou et al., (2012) who carried out a systematic review of the literature (1971-2011) in which 23 casecontrol (7,690 cases; 13,507 controls) and 5 cohorts (700 cases; 229,099 participants) were identified.
However, 2 of the studies that Sala et al., (2000) included in their analysis were not considered.
For case-control studies included in the meta-analysis, which controlled for smoking, a significant
excess risk was observed in all exposure categories when compared to the reference category. The
pooled RRs among non-smokers were also in excess, and on average about 15% higher, indicating an
apparent stronger effect in this group compared to non-smokers. A dose-response analysis, adjusted
for smoking, an increased risk of 1.10 (95% CI=1.07-1.15) for each 2-cups/day increase (Zhou et al.,
2012). For non-smokers pooled RRs increased with increasing number of cups consumed per day,
although it was not indicated whether this trend was significant or not. Zhou et al., (2012) reported
similar relationships among US and European studies and between studies where controls were
hospital- or population-based. However, no relationship was seen among women.
Cohort studies identified in the meta-analysis showed a much smaller increased risk of 1.01, (95%
CI=0.87-1.17) for each 2-cups/day increase, but no dose-response relationship (Zhou et al., 2012).
Other articles from the literature search were identified but not reviewed (Geoffroy-Perez and Cordier
2001, Kurahashi et al., 2009, Woolcott et al., 2002).
Lung cancer
The SLR for the WCRF report for lung cancer identified 3 cohort studies that could be included in a
dose-response meta-analysis, the summary random effect RR for these studies was 1.06 (95% CI 0.611.86) per drink per week. For 11 case-control studies a summary OR of 1.007 (95% CI 0.989-1.027)
was obtained (Alberg et al., 2006).
EFSA supporting publication 2015:EN-561
22
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Tang et al., (2010) searched the literature from 1966 to January 2009, and identified 5 prospective
studies and 8 case-control studies involving 5,347 cases and 104,911 non-cases. Studies that assessed
the association between high coffee consumption and lung cancer risk gave an overall RR of 1.27
(95% CI 1.04-1.54), with no indication of publication bias but significant heterogeneity across the
studies. The latter was accounted for by removing two studies which increased the pooled RR to 1.42
(95% CI 1.23-1.65), thereby removing the heterogeneity. Sub-group analysis by study design indicated
a statistically significant 57% increased risk of developing lung cancer among prospective studies
while no significant association among case-control studies. Analysis by study population indicated a
statistically significant increased risk in American and Japanese studies but not in European. The
overall results in smokers indicated a non-significant positive association between high coffee
consumption and lung cancer risk, and borderline significant inverse association in non-smokers.
Dose-response analysis reported that an increment of coffee consumption of 2 cups/day was
statistically significant associated with an 11% increased risk (Tang et al., 2010).
Other articles from the literature search were identified but not reviewed (Baker et al., 2005, De
Stefani et al., 2011).
2.8.4.4.
Neurological/CNS effects
Common adverse effects that may arise following CNS stimulation, including insomnia, anxiety,
depression, irritability, dizziness, nervousness and tremors (Nawrot et al., 2003, Thomson and Schiess
2010).
Several studies have reported that caffeine increase sleep latency and quality of sleep (Adan et al.,
2008, Carrier et al., 2007, Drake et al., 2006, Drapeau et al., 2006, Kelly et al., 1997, LaJambe et al.,
2005, Orbeta et al., 2006), although some authors did not see such a correlation (Sanchez-Ortuno et
al., 2005, Youngberg et al., 2011).
Ingestion of 100 mg caffeine was reported to cause a lower somnolence compared to those drinking
decaffeinated coffee (Adan et al., 2008) and to increase stage 1 sleep (LaJambe et al., 2005). 200 mg
caffeine increased sleep latency, increased stage 1, and reduced stage 2 and slow-wave sleep compared
to the placebo condition in young and middle aged adults, after controlling for the effects of age,
habitual caffeine consumption and sleep variables (Drapeau et al., 2006) and in sleep deprived adults
(Carrier et al., 2007). Higher doses of caffeine (300 mg) impaired sleep maintenance by reducing total
sleep time and increasing wake time, and reduced sleep depth by increasing stage 1 sleep and reducing
slow-wave sleep (Drapeau et al., 2006). Sleep latency was also prolonged by consumption of 3 mg/kg
caffeine in adults who were vulnerable to stress-related sleep disturbance, although authors suggested
that such vulnerability may be related to a physiological factor (Drake et al., 2006).
The association between sleep duration and daily caffeine intake was explored in a working population
in France. No significant relationship was seen between total sleep time and daily caffeine intake of
less than 8 cups per day, although time in bed was reduced as caffeine intake increased. Authors
concluded that that habitual use of up to 7 cups of coffee/day (600 mg/day caffeine) was not
associated with decreased duration of sleep (Sanchez-Ortuno et al., 2005). Similarly, plasma caffeine
concentrations were not significantly correlated with polysomnographic measures of sleep
disturbance, following consumption of <4 cups/day coffee (Youngberg et al., 2011).
Caffeine has also been reported to be associated with anxiety and depression. Gau et al., (2004) carried
out a study to investigate correlates of morning and evening sleep wake patterns in children and young
adolescents between 10-16 years of age. After data were controlled for age, pubertal development,
school grade levels, body mass index, sleep disturbances, sleepiness, mood status and the use of coffee
and alcohol, coffee was significantly associated with Morningness/Eveningness (M/E) score (a higher
score indicates a tendency to be a morning type, a lower score indicates an evening type) and is
EFSA supporting publication 2015:EN-561
23
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
potentially associated with daytime sleepiness, early insomnia, fear of sleeping in darkness,
bedwetting, depression and anxiety. Those who were evening-types may also need to drink coffee to
reduce their daytime sleepiness and maintain daytime function (Gau et al., 2004). Caffeine was also
reported to increase alertness and anxiety when administered as a single large dose of 200 mg or 250
mg (Brice and Smith 2002, Smith et al., 2012) or four doses of 65 mg caffeine to adult males (Brice
and Smith 2002), and correlated to depression and anxiety in adult smokers consuming 100-400 mg
(Dosh et al., 2010). Consumption of coffee (150 and 300 mg/day) also increased anxiety in males, but
not females, when compared to the placebo group (Botella and Parra 2003).
Depression, but not anxiety, correlated to caffeine use in 10-12 and 15-17 year old adolescents
respectively, which was potentially mediated by withdrawal effects. Luebbe and Bell (2009)
concluded that at the level of exposure seen in the study (13.82-15.24 mg/kg for 10-12 and 15-17 year
olds, respectively), the development of dependence may occur as well as physiological and
psychological effects that could be related to depression and anxiety (Luebbe and Bell 2009).
A case study of two children ages 11 – 13 years suggested a correlation between tics and the
consumption of caffeine in the form of caffeinated drinks and chocolate. Davis and Osorio (1998)
suggested the amount of caffeine was correlated with the frequency and intensity of tics. Two to four
caffeinated drinks per day was correlated with frequent intense tics, which disappeared when caffeine
was eliminated from the diet. Re-introduction of three to seven drinks per week correlated with the
reappearance of tics. Authors concluded that caffeine may precipitate tics in susceptible children
(Davis and Osorio 1998).
Tremor has also been suggested to arise following caffeine administration, in a dose dependent
manner. A single dose of caffeine (3 mg/kg) was reported to increase tremor in young adult males but
there was no effect following administration of 1 mg/kg (Miller et al., 1998).
2.8.4.5.
Insulin sensitivity
Caffeine exposure (3 mg/kg loading dose followed by a continuous infusion of 0.6 mg/kg/hr) caused a
decrease in insulin sensitivity by 15 % in healthy volunteers compared with the placebo. Keijzers et
al., (2002) stated that magnitude of such a change in insulin sensitivity could be clinically relevant. A
later study showed that caffeinated coffee (5 mg/kg bw) consumed with a high glycaemic index meal
did not result in a decreased insulin sensitivity, although blood glucose was higher following
caffeinated coffee, compared to water of decaffeinated coffee but also reported data to show that
consuming caffeine with breakfast significantly impaired blood glucose management and decreased
insulin sensitivity by 30-40 %, hence authors concluded that caffeinated coffee may play a role in
glycaemic management (Moisey et al., 2010). Caffeine ingestion (5 mg/kg bw) was also reported to
decrease insulin sensitivity in obese male adults (Petrie et al., 2004).
2.8.4.6.
Glaucoma
Caffeinated coffee was adversely associated with the risk of primary open-angle glaucoma in a large
cohort study. Compared to those drinking <150 mg/day the pooled multivariate risk ratios were 1.05
(95 % CI 0.89-1.25), 1.19 (95 % CI 0.99-1.43), 1.13 (95% CI, 0.89–1.43) and 1.17 (95% CI, 0.90 –
1.53) for 150 to 299 mg/day, 300 to 449 mg/day, 450 to 559 mg/day, and 600 mg/day, respectively,
adjusted for age, family history, African-America heritage, hypertension, diabetes, body mass index,
smoking, physical activity, alcohol intake and caloric intake. However, the multivariate analysis of
primary open-angle glaucoma across categories of caffeinated beverages showed subjects drinking >5
cups had a significantly increased risk (age-adjusted RR 1.61, 95 % CI 1.00-2.59). No associations
were made with decaffeinated coffee. Including the consumption of coffee and tea in the same model
resulted in some changes in the relative risk. However the same adverse associations remained
between caffeinated coffee and glaucoma. Kang et al., (2008) concluded that caffeine was not
associated with an increased risk of primary open-angle glaucoma.
EFSA supporting publication 2015:EN-561
24
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
The association between caffeine and caffeinated drinks and the risk of exfoliation glaucoma or
suspected exfoliation glaucoma was investigated (Pasquale et al., 2012). After adjusting for age
(months), family history of glaucoma, ancestry (Scandinavian Caucasian, southern European
Caucasian, other Caucasian, other ancestry), hypertension, diabetes, high cholesterol, myocardial
infarction, body mass index, smoking, geographical tier of residence (northern, middle, southern tier),
cumulatively updated alcohol intake and total caloric intake, there was a trend towards a positive
association between total caffeine intake and risk of exfoliation glaucoma or suspected exfoliation
glaucoma, although was not statistically significant (RR 1.43 95% CI 0.98-2.08 for >500 mg/day
compared to those drinking <125 mg/day). Further adjusting data for total fluid intake did not affect
the results. When considering specific caffeinated beverages, subjects who consumed > 3 cups of
caffeinated coffee per day had a 1.66-fold greater risk of exfoliation glaucoma or suspected exfoliation
glaucoma compared to those who did not consume coffee (RR 1.66 95% CI 1.09-2.54). Associations
were stronger in women with a family history of glaucoma (RR 2.95 95% CI 1.16-7.46) compared to
those with no family history (RR 1.16 95% CI 0.72-1.88). Drinking other caffeinated products such as
soft drinks, tea or chocolate was not associated with a risk of exfoliation glaucoma or suspected
exfoliation glaucoma. Pasquale et al., (2012) concluded that heavier coffee consumption was
positively associated with risk of exfoliation glaucoma or suspected exfoliation glaucoma.
Coffee was also correlated to increased intraocular pressure in patients open-angle glaucoma
(Chandrasekaran et al., 2005). Participants with open-angle glaucoma who reported regular
consumption of coffee (>200 mg caffeine/day) had a borderline significantly higher intraocular
pressure compared to those who drank <200 mg caffeine per day or those who did not drink coffee,
after adjusting for age, sex and systolic blood pressure, although after multivariate adjustment this
association did not reach significance. Caffeine consumption was not associated to increased
intraocular pressure in subjects without open-angle glaucoma or with ocular hypertension. Overall, the
Chandrasekaran et al., (2005) concluded that coffee could increase intraocular pressure in older people
with open-angle glaucoma.
Avisar et al., (2002) investigated the effect of caffeine on intraocular pressure in patients with
normotensive glaucoma or ocular hypertension was also investigated. Following ingestion of 180 mg
of caffeine, both groups of patients showed a statistically significant increase in intraocular pressure.
Authors recommended that patients with normotensive glaucoma or ocular hypertension should avoid
drinking caffeinated coffee with more than 180 mg caffeine (Avisar et al., 2002).
2.8.4.7.
Urinary incontinence
Data from a large prospective cohort study reported a significantly increased risk of weekly urinary
incontinence in women consuming >450 mg (RR 1.19 95 % CI 1.06-1.34) compared to those
consuming <150 mg, after data were adjusted for parity, BMI, cigarette smoking, race, diabetes, total
fluid intake, and physical activity. There was a significant dose-response trend as data showed an
increase in risk with increasing intakes. Such a risk was related to incident urinary incontinence (RR
1.34 95 % CI 1.00-1.80) when comparing ingestion of >450 mg and <150 mg, but not stress or mixed
incontinence (Jura et al., 2011). In contrast, no association between levels of caffeine and urinary
incontinence progression over two years was observed (OR 0.87 95 % CI 0.7-1.08 comparing >450
mg and <150 mg). Data were adjusted for potential risk factors such as age, parity, body mass index,
smoking, race and total fluid intake as well as physical activity, menopausal status, postmenopausal
hormone use, diabetes and diuretic use (Townsend et al., 2012).
2.8.4.8.
Bone effects and calcium balance
Various studies have reported the association between caffeine intake and bone mineral density
(Hallstrom et al., 2010, Rapuri et al., 2001) whereas others failed to show such a correlation
(Demirbag et al., 2006, Grainge et al., 1998, Lloyd et al., 1997, Lloyd et al., 1998, Nawrot et al.,
2003).
EFSA supporting publication 2015:EN-561
25
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Elderly post-menopausal women having a high daily caffeine intake (>300 mg) had a higher rate of
bone loss in the spine (1.19±1.08), as indicated by a reduced bone mineral density, compared to
subjects with low (<300 mg) caffeine intake (-1.90±0.97) after adjusting for smoking, alcohol use,
calcium intake, age, height, weight, 25-hydroxyvitamin D concentrations. In addition, in subjects who
consumed >300 mg/day, the rate of bone loss was significantly greater in the spine in subjects with the
recessive tt vitamin D genotype compared with those with the dominant genotype. In subjects drinking
<300 mg/day, rates of bone loss did not differ significantly at any of the skeletal sites measured and
did not differ between the different genotypes (Rapuri et al., 2001).
Hallstrom et al., (2010) carried out a prospective study of 359 men and 358 women in which a 7-day
food diary was assessed and two years later bone mineral density measured. Age and multivariable
(height, weight, total caloric intake, vitamin D intake, vitamin A intake, calcium intake, alcohol intake,
intake of tea, smoking and levels of leisure physical activity) adjusted data show that men consuming
>4 cups of coffee per day had a 4% lower bone mineral density in the proximal femur compared with
those consuming 0-2 cups per day. No reduction was observed in women. Authors concluded that high
coffee consumption (>4 cups/day) could contribute to a reduction in bone mineral density of the
proximal femur in elderly men (Hallstrom et al., 2010).
Earlier studies also investigated caffeine as a risk factor for bone loss in postmenopausal women. No
correlation was seen between caffeine intake (>8 cups/day) and any loss of bone mineral density
(Lloyd et al., 1997). No strong correlation between caffeine consumption in 30 year old subjects and
femoral neck and whole body bone mineral density was also reported, although bone mineral density
tended to increase with increasing caffeine consumption, which was of borderline significance
(Grainge et al., 1998).
Some negative associations between caffeine intake and bone density have been observed, although
such associations disappeared when confounders such as calcium intake were adjusted for in some
studies. Overall, authors concluded that caffeine consumption was not associated with significant
decreases in bone density in adolescent women, young women 20–30 years of age, premenopausal
women, peri-menopausal women, postmenopausal women or men (Nawrot et al., 2003).
Waugh et al., (2009) carried out a systematic review of the literature in 2009, covering 1990-2006, to
identify risk factors for low bone mineral density in healthy women aged 40-60 years and concluded
that there was good to fair evidence that caffeine intake was not a risk factor (Waugh et al., 2009).
2.8.4.9.
Summary
A number of cohort and intervention studies have been carried out to investigate the potential effect
of caffeine on the cardiovascular system. In adults and adolescents, studies have reported an increase
in blood pressure and heart rate in normotensives and hypertensives, although effects were short term.
However, caffeine appeared to have no positive correlation with mortality from cardiovascular disease
and myocardial infarction.
The results reported on cancer were predominantly from a large number of well conducted metaanalyses and pooled-analyses, which do not indicate that caffeine is a risk factor in cancer aetiology,
with the exception of bladder and lung cancers. However, care must be taken when interpreting the
results of studies of these cancers because even though they may have been adjusted for smoking there
are other more significant risk factors, including occupational, that it was not made clear whether they
were taken into account.
In terms of neurological/CNS effects, various studies have reported restlessness, insomnia and tremors
at high intake levels, and vomiting, muscle spasms and seizures at lower levels. Sleep latency was also
increased following caffeine consumption, as was the risk of anxiety and depression.
EFSA supporting publication 2015:EN-561
26
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
From a number of other studies, caffeine was correlated to decreased insulin sensitivity, although
results were inconclusive, increase risk of glaucoma and increased intraocular pressure, increased risk
of urinary incontinence in women and decreased bone mineral density in the elderly.
2.8.5.
Adults and adolescents performing endurance exercise
6 articles related to potential adverse effects of caffeine following exercise in adults and adolescents.
2.8.5.1.
Performance
The ergogenic effect of caffeine during endurance exercise has been extensively examined in young
adults. The majority of experimental studies have investigated the effect of a single dose of caffeine
taken prior to exercise, following a period where the subject refrained from caffeine consumption for
up to 7 days. The meta-analysis of Doherty and Smith (2005) reported that during constant load
exercising, rating of perceived exertion was reduced by 5.6% following caffeine consumption when
compared to placebo, whilst there was an 11.6% improvement of test performance.
Few of the references reviewed reported any significant adverse health effects during the exercise
trials performed. This may be due to the fact that part of the inclusion criteria for the subjects was that
they had to be healthy and disease-free, and in a significant majority of the studies they were athletes.
In one study subjects were recruited but subsequently excluded from the study because they were
reported to be “sensitive” to caffeine (Yeragani et al., 2005) although a definition of ‘sensitive’ was
not given. In the study of Bell et al., (1998) four subjects vomited during the exercise trial involving
combined caffeine and ephedrine treatment, and their results were not presented. However, it was not
clear whether the vomiting was due to the caffeine or the ephedrine (Bell et al., 1998). Astorino et al.,
(2012) investigated the effect of caffeine on cycling performance in endurance-trained adults. Four
subjects reported feelings of increased energy, one reported feelings of anxiety, two had the onset of
mild tremor and 2 reported nausea.
2.8.5.2.
Cardiovascular effects
Namdar et al., (2006) reported a non-significant trend to increase mean resting myocardial blood flow
after caffeine ingestion. However, bicycle exercise-induced hyperaemic myocardial blood flow
decreased significantly by 13% (p<0.05), resulting in a decrease in physiological myocardial flow
reserve (MFR) of 22%. The authors stated these findings may not have a clinical importance in
healthy volunteers but may raise safety questions in patients with reduced MFR as seen in coronary
artery disease. In a subsequent study, MFR decreased significantly in coronary artery disease patients,
the decrease being significantly greater than that in fit controls (Namdar et al., 2009).
A significant increase in heart rate, mean arterial pressure and rate-pressure product and systolic (but
not diastolic) blood pressure was also reported in resistance trained men following strenuous exercise
and caffeine ingestion (6 mg/kg) compared with the placebo (Astorino et al., 2007).
2.8.5.3.
Summary
Whilst the effects of caffeine on performance were well studied, only a few studies were identified
that reported adverse effects of caffeine in adults and adolescents performing endurance exercise.
Myocardial blood flow reserve was decreased during exercise following caffeine. Others studies
reported vomiting, nausea, tremor and anxiety following caffeine consumption prior to exercise.
2.9.
Adverse health effects of intake of caffeine in combination with alcohol
28 articles relating to the adverse effects of caffeine and alcohol were included in the study.
EFSA supporting publication 2015:EN-561
27
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.9.1.
Adults and adolescents
26 papers were found that related to caffeine and alcohol in adults and adolescents.
2.9.1.1.
Reproductive effects
One article was found that looked at the effects of alcohol and caffeine on fertility. Hakim et al.,
(1998) reported that alcohol, but not caffeine, reduced the probability of conception. The consumption
of both alcohol and caffeine decreased the conception rate. Alcohol consumed with light caffeine
consumption (<100 mg caffeine) lowered the conception rate to 16.6 % and decreased the odds of
conception to 0.44 (95 % CI 0.23-0.86) and alcohol with heavier caffeine consumption (>100 mg)
further reduced conception rate to 10.5 % (OR 0.26 (95% CI 0.13-0.52), after adjusting for age and
number of occurrences of sexual intercourse per month (Hakim et al., 1998).
2.9.1.2.
Cardiovascular effects
Following an effort test, heart rate at the ventilator threshold, but not maximal threshold, was higher
after consumption of alcohol and alcohol+energy drink, compared with energy drinks alone or
controls, although there was no difference between these two groups (177±11 vs 170±9 for alcohol
and alcohol+energy drink, respectively). Oxygen uptake was unaffected by alcohol or energy drinks
(Ferreira et al., 2004). In additional, consumption of energy drinks and alcohol slowed the postexercise recovery in heart rate and heart rate variability compared to exercise alone, although no
arrhythmias were observed following consumption (Wiklund et al., 2009).
An increased risk of acute myocardial infarction was associated with consumption of alcohol (amount
not specified) and caffeine (>3 cups/day OR 1.5 95% CI 1.0-2.2) compared to drinking alcohol
(amount not specified) and <3 cups/day caffeine (OR 1), alcohol alone (> 3 drinks per day (OR 0.5
(95% CI 0.3-0.8)) or caffeine alone (>3 cups/day OR 2.2 95% CI 1.3-3.7). Authors suggested that the
co-consumption of alcohol and heavy coffee drinking was positively associated with the risk of
myocardial infarction (Tavani et al., 2001).
Cleary et al., (2012) reported case studies in which subjects presented to hospitals following
consumption of alcohol and energy drinks. Four patients presented with sinus tachycardia (heart rate
greater than 100 beats/min), although none required medication as the tachycardia generally resolved
quickly, although one patient was admitted due to the sustained tachycardia (Cleary et al., 2012).
2.9.1.3.
Alcohol consumption and intoxication
In general, alcohol consumption was greater in terms of amounts consumed, frequency and
intoxication when mixed with energy drinks (Brache and Stockwell 2011, O'Brien et al., 2008,
Thombs et al., 2010). Other studies also reported subjects drink more alcohol when combined with
energy drinks (Peacock et al., 2012, Price et al., 2010)
Various case studies indicated that mixing alcohol and caffeine masks the effects of alcohol, resulting
in higher consumption (Arria et al., 2010, Arria et al., 2011, Attwood et al., 2012, Ferreira et al., 2006,
Marczinski and Fillmore 2006, Marczinski et al., 2013, Price et al., 2010). According to some authors
this may potentially lead to alcohol-related adverse health effect or risk of alcohol dependence,
compared with drinking alcohol alone.
Consuming energy drinks mixed with alcohol increased the odds of getting intoxicated, after adjusting
for potential confounders. Subjects had a 3-fold increased chance of getting highly intoxicated and 4fold increased chance of intending to drive home, compared to those who did not consume alcohol and
energy drinks (Thombs et al., 2011, Thombs et al., 2010).
EFSA supporting publication 2015:EN-561
28
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Consumption of energy drinks (2-4 mg/kg caffeine) and alcohol (0.6-1.0 mg.kg), compared to alcohol
alone, reduced subjective symptoms of intoxication (headache, weakness, motor coordination
impairment), but had no effect on alcohol-related performance (Ferreira et al., 2006, Marczinski and
Fillmore 2006). According to the authors this may lead to subjects may misinterpreting their level in
intoxication, leading them to consume more alcohol. Similarly, co-administration of energy drinks
(3.57 ml/kg) and alcohol (0.65 g/kg) reduced perception of mental fatigue and enhanced feelings of
stimulation, leading to a high risk scenario in that individuals perceived better functionality than
reality according to Marczinski et al. (2012).
Following consumption of alcohol alone (0.6 g/kg), caffeine alone (2.0 mg.kg) and alcohol/caffeine
combined, Attwood et al., (2012) reported that caffeine did not affect absolute levels of perceived
intoxication, enabling the individual to drink for a longer period of time. Changes in intoxication were
assessed qualitatively rather than quantitatively.
Based on a number of case studies in which adolescents and young adults presented in an emergency
department following consumption of caffeinated alcoholic beverages, Cleary et al., (2012) reported
patients were agitated, intoxicated, somnolent or lethargic.
2.9.1.4.
Risk taking
The effect of co-ingestion of energy drinks and alcohol on risk taking behaviour was also assessed
(Brache and Stockwell 2011, Miller 2008, O'Brien et al., 2008, Thombs et al., 2010).
Subjects drinking energy drinks and alcohol has an increased chance of being hurt or injured, even
after adjusting for the amount of alcohol consumed, as well as student gender, age, race, fraternity or
sorority status, athlete status, and within-campus clustering (adjusted OR 2.25 95% CI 1.70-2.96),
requiring medical treatment (OR 2.17, 95% CI 1.24-3.80), riding home with a driver who had been
drinking (OR 2.20, 95 % CI 1.81-2/68), being taken advantage sexually (OR 1.77, 95% CI 1.23-2.55)
or taking advantage of others (OR 2.18, 95% CI 1.34-3.55) although effects were only compared with
those drinking non-alcoholic energy drinks. In terms of driving after drinking alcoholic energy drinks,
the risk of driving was greater following consumption of energy drinks and alcohol, compared with
non-alcoholic energy drinks (adjusted OR 2.96) (O'Brien et al., 2008). Similarly ORs adjust for age,
sex, heavy episodic drinking and risk taking propensity were also presented by Brache et al. for being
hurt or injured (adjusted OR 1.38, 95% CI 1.02-1.88), riding home with a driver who had been
drinking (OR 1.36, 95 % CI 1.03-1.80), fighting (OR 1.26 95% CI 0.98-1.61) or driving home after
drinking (OR 1.45, 95% CI 1.03-2.05) (Brache and Stockwell 2011). Drinking energy drinks mixed
with alcohol also increased the risk of intention of driving upon leaving the bar district four-fold,
compared to drinking alcohol alone (Thombs et al., 2010).
The odds of physiological effects (walking difficulties, nausea) and psychological effects (confusion,
sadness) were decreased after drinking energy drinks and alcohol compared to alcohol alone as the
stimulatory effects from the energy drinks increased alertness and reduced alcohol-induced sedative
effects. Despite this, the odds of participating in 26 risky activities were significantly lower after
consuming energy drinks and alcohol when compared to the effects of alcohol alone (Peacock et al.,
2012). In contrast, Marczinski et al., (2012) reported that alcohol (0.65 g/kg) and energy drinks (3.57
mg.kg) increased risk taking behaviour due to reducing fatigue and enhancing stimulation, leading to a
false perception of motor coordination.
2.9.1.5.
Neurological/CNS effects
Dikici et al., (2013) reported ischemic stroke and epileptic seizure in a 37 year old man following
consumption of 750 mL an energy drink mixed with vodka (amount not reported) (Dikici et al., 2013).
Cleary et al., (2012) also reported a case study in which a patient was admitted to hospital due to
having multiple seizures following consumption of alcohol and energy drinks (Cleary et al., 2012).
EFSA supporting publication 2015:EN-561
29
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
2.9.1.6.
Summary
Several papers have been published that investigated the effects of caffeine and alcohol, many in the
form of energy drinks mixed with alcohol. Such drinks have been associated with increased heart rate,
post-exercise arrhythmias and an increased risk of acute myocardial infarction. The combination of
caffeine and alcohol has also been associated with an increased risk taking behaviour and the amount
of alcohol consumed.
2.9.2.
Adults and adolescents performing endurance exercise
One paper was found relating the adverse effects of caffeine and alcohol following endurance
exercise.
2.9.2.1.
Cardiovascular effects
Consumption of energy drinks (240 mg caffeine) and alcohol (0.4 g/kg) influenced both the postexercise recovery in heart rate and heart rate variability in terms of delaying heart rate recovery, and
small ECG changes were found that may be related to the consumption of energy drinks and alcohol.
Although no clinically significant arrhythmias were reported in the study authors concluded that risk
of arrhythmias is increased after physical exercise and such a risk could be accentuated with the intake
of energy drinks and alcohol, as this causes a blunted cardiac autonomic control (Wiklund et al.,
2009).
2.9.2.2.
Summary
Few data were identified that investigated the adverse effects of caffeine mixed with alcohol following
endurance exercise. Although no cardiac arrhythmias were reported, heart rate recover and small ECG
changes were reported.
2.10.
Adverse health effects of intake of caffeine in combination with other substances in socalled “energy drinks”
6 articles relating to the adverse effects of caffeine in combination with other substances found in
energy drinks were included in the study. In accordance to the technical specification, studies relating
to energy drinks were largely considered as a source of caffeine, hence were assessed under section a).
2.10.1.
Children possibly divided by age group
No data were retrieved. All publications retrieved that related to children reported data in children over
the age of 10 years old, hence were considered as adolescents for the purpose of this report.
2.10.2.
Pregnant women
No data were retrieved.
2.10.3.
Lactating women
No data were retrieved.
2.10.4.
Adults and adolescents
Six papers on the effect of caffeine and other substances in energy drinks were assessed.
2.10.4.1.
Performance
Various authors investigated the effect of caffeine and taurine on reaction times (Aggarwal et al.,
2011, Giles et al., 2012, Horne and Reyner 2001, Peacock et al., 2013).
EFSA supporting publication 2015:EN-561
30
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Peacock et al., (2013) carried out a double blind placebo-controlled crossover study, where
participants (19 healthy non-smoking, right handed female undergraduates, aged 19-22 years of age)
received two-capsule combinations in a counterbalanced order: placebo/placebo, (cornflour capsules),
taurine (1000 mg)/placebo, caffeine (80 mg)/placebo or caffeine/taurine. Treatment doses
corresponded to those found in 250 mL of an energy drink. Following administration, behavioural
tests were carried out (visual oddball task and a stimulus degradation task). Co-administration of
caffeine with taurine tended to attenuate the effects of caffeine on reaction times, although these
effects were task-dependent according to the authors (Peacock et al., 2013).
In contrast, caffeine and taurine decreased simple and choice reaction times compared with caffeine
alone (386.21±14.76 vs 390.76±12.90) or taurine alone (386.21±14.76 vs 393.37±13.62) (Giles et al.,
2012). Horne and Reyner (2001) also reported that caffeine and taurine decreased reaction time.
2.10.4.2.
Kidney effects
Schoffl et al., (2011) presented a case study in which a 17 year old boy suffered renal failure after
consuming 3 L energy drink in combination of 1 L vodka, equating to 4600 mg taurine, 780 mg
caffeine and 380 g alcohol. Authors reported that the joint effect of caffeine and taurine reduced the
effect of alcohol.
2.10.4.3.
Miscellaneous effects
The minimum caffeine level to cause symptoms was 200 mg (4 mg/kg) which caused jitteriness in a
13 year old, and the maximum level was 1622 mg (35.5 mg/kg) in a 14 year old. One adult had a
myocardial infarction (Seifert et al., 2011).
An extensive review of the literature to investigate the health effects of energy drinks on children,
adolescents and young adults was carried out (Seifert et al., 2011). It was reported that adverse effects
of caffeine included nervousness, irritability, anxiety, insomnia, tachycardia, palpitations, upset
stomach, vomiting, abdominal pain, rigidity, hypokalaemia, altered consciousness, paralysis,
hallucinations, increased intracranial pressure, cerebral oedema, seizures, rhabdomyolysis,
supraventricular and ventricular tachyarrhythmias; guarana was generally considered safe by the FDA;
taurine was generally considered safe by the FDA. Authors noted that Germany, Ireland and New
Zealand has track energy drink-related incidents and reported outcomes such as confusion, nausea and
vomiting, abdominal pain, agitation, liver and kidney damage, respiratory disorders, agitation,
seizures, psychotic conditions, rhabdomyolysis, tachycardia, cardiac dysrhythmias, hypertension, heart
failure and death (Seifert et al., 2011).
2.10.4.4.
Summary
Few papers were identified that related that specifically to caffeine and other substances found in
energy drinks, namely taurine and glucuronolactone. Articles relating to energy drinks were
considered under section a) of this report. Conflicting data on the effect of caffeine and taurine on
reaction time were reported as some authors reported an increase in reaction time, whereas others
showed a decrease.
2.10.5.
Adults and adolescents performing endurance exercise
No data were retrieved.
EFSA supporting publication 2015:EN-561
31
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
3.
Data evaluation
For caffeine alone, 11,319 papers were originally identified, from which 9,208 papers were excluded
after primary screening of titles, according to pre-defined exclusion criteria. 2,111 articles underwent
screening on abstracts, again using the exclusion criteria, of which 142 articles were deemed
appropriate for use in the literature review and subsequently underwent methodological assessment
and data abstraction.
Regarding caffeine and alcohol, 2,009 papers were originally identified, and 1,762 were excluded
according to exclusion criteria. The abstract of the remaining 247 studies were evaluated and 27
papers selected for further review.
114 articles were initially retrieved relating to caffeine in combination with other substances in energy
drinks. 90 were excluded on titles, leaving 24 studies to be evaluated. Following further exclusions, 6
articles were retained and assessed.
For caffeine in combination with alcohol and other substances in energy drinks, 63 papers were
retrieved but all were excluded due to reporting the adverse effects following consumption of caffeine
or energy drinks and alcohol, as studies were already included in question b).
3.1.
Cancer Effects
The information gathered for this review was obtained from a number of meta-analyses and pooled
analyses of the association between caffeine consumption and individual cancers. Each study has a
rigorous methodology, and the combination of a number of studies provides a greater weight-ofevidence than an individual study alone.
Caffeine intake alone has been reported:

In adults:
o
To increase the risk of bladder cancer, especially among individuals who drink large
quantities of coffee
o
To increase the risk of lung cancer, especially in individuals who drink large
quantities
o
To not increase the risk of any other cancer, even at high consumption levels
However, these results must be considered carefully because it is not known whether all potential
confounders, especially occupational, were adjusted for in the analysis carried out by studies included
each meta-analysis.
3.2.
Cardiovascular Effects
Caffeine intake alone has been reported:

In children:
o

To exacerbate cardiac conditions
In adults and adolescents:
o
To increase blood pressure and heart rate in normotensives and hypertensives,
although these effects were short-term
EFSA supporting publication 2015:EN-561
32
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
o
To increase the levels of inflammatory markers in the blood
o
To have no effect on mortality
o
To reduce myocardial blood flow reserve during exercise
o
To both increase and decrease the risk of acute myocardial infarction AMI
Caffeine & alcohol intake has been reported:

3.3.
In adults and adolescents:
o
To increase heart rate, although this effect is short-term
o
To increase post-exercise arrhythmias
o
To increase the risk of AMI
Neurological/CNS effects
Caffeine intake alone has been reported:

In children:
o

In pregnancy and lactating women:
o

To increase the risk of headaches, which is significantly reduced when caffeine is
withdrawn
Consumption during pregnancy is not associated with behavioural problems in
children
In adults and adolescents:
o
To increase restlessness, nervousness, insomnia, and tremors at high intake levels
o
To increase the incidence of symptoms such as muscle spasms, myocardial
irritability/arrhythmias, vomiting and seizures at low intake levels
o
To increase sleep latency and decrease sleep quality
o
To increase the risk of anxiety and depression
Caffeine & alcohol intake has been reported:

3.4.
In case studies to increase the risk of seizures for consumption
Reproductive effects
Caffeine intake during pregnancy has been reported:

To increase the risk of small-for-gestational age babies, although evidence is inconclusive

To increase the risk of spontaneous abortion
EFSA supporting publication 2015:EN-561
33
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine

To increase the risk of sudden infant death syndrome, foetal and infant death
Caffeine & alcohol intake has been reported:

3.5.
To decrease conception rate
Other health effects
In adults and adolescents caffeine intake alone has been reported to:

Decrease insulin sensitivity, although the evidence is inconclusive

Increase the risk of glaucoma and increase intraocular pressure

Increase the risk of urinary incontinence in women, with a dose-response being reported

Decrease bone mineral density in the elderly, the evidence in working age adults is
inconclusive
Caffeine & alcohol intake has been reported:

to increase the amount of alcohol consumed, leading to increased intoxication and risk taking
behaviour.
3.6.
Data from authoritative bodies
3.6.1.
Germany
In 2008 the Federal Institute for risk assessment (BfR) assessed the more recent human data related to
energy drinks, following a suspicion expressed in the BfR expert opinion in March 2002 in that ‘the
safety of energy drinks is to be questioned in the circumstances in which they are possibly drunk by
some consumers’ (Federal Institute for risk assessment 2008). Energy drinks were described as having
caffeine up to a max of 320 mg/L, taurine up to 4000 mg/L, inosite up to 200 mg/L and
glucuronolactone up to 2400 mg/L. Based on new research, recent human data were presented on the
possible health risks posed following consumption of energy drinks, focussing on dysrhythmia,
seizures, kidney failure and fatalities.
BfR also assessed energy drinks when mixed with alcohol. Results from a survey of German poison
information and treatment centres on adverse health effects caused by energy drinks included seizures,
tachycardia (increased heart rate), cardiac dysrhythmia, rhabdomyolysis (decline of skeletal muscle
cells), agitation, hypertonia (high blood pressure), respiratory disorders and psychotic conditions
although it was stated that interpretation of such finding was difficult because alcohol, medicines and
drugs were also taken in combination with energy drinks.
As part of the 2008 study a literature search was carried out and information was sought from the
Swedish National Food Agency regarding the health effects following consumption of energy drinks.
Various case studies were presented relating to fatalities following consumption of energy drinks, with
or without alcohol. Adverse effects such as cardiac and central nervous system effects were implicated
in many of the retrieved articles.
Overall, BfR stated that "In addition to the currently prescribed labelling on a high caffeine content
(Directive 2002/67/EC), it is recommended, on the grounds of preventive health protection, that
information should be provided on the packaging of energy drinks that:
EFSA supporting publication 2015:EN-561
34
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine

adverse effects cannot be ruled out when larger amounts of these beverages are consumed in
conjunction with intensive physical activity or with intake of alcoholic beverages;

beverages of this kind, particularly when consumed in larger amounts, are not recommended
for children, pregnant women, lactating women or individuals who are sensitive to caffeine
(those who have arrhythmias or mental disorders)
Subsequently, BfR also assessed the health risks related to excessive energy shots in 2009 (Federal
Institute for risk assessment 2009). Energy shots contain higher concentrations of caffeine and taurine
compared with energy drinks, containing between 50-200 mg caffeine and taurine 200-1000 mg per
portion. BfR stated that energy shorts pose no risk to health if consumed in accordance to the
suggested intake levels. However, in light of the opinion that consumers may not always adhere to the
proper use, BfR assessed energy shorts to be unsafe in terms of Article 14(1) of Regulation (EC) No
178/2002.
3.6.2.
UK
The Committee of Toxicity of Chemicals in Food, Consumer Products and the Environment (COT)
produced a statement on the reproductive effects of caffeine in 2008, based on epidemiology studies
and the most recently published scientific research (Committee on toxicity of chemicals in food
consumer products and the environment 2008). The Committee concluded that exposure to caffeine
during pregnancy is associated with an increased risk of foetal growth restriction although a causal
relationship could not be assumed definitively. In addition, it was not possible to identify a threshold
level of caffeine below which there was no increased risk from the available data. An intake of 200
mg/day or lower seems likely to be associated with an increased risk but if a causal relationship does
indeed exist, the absolute increase of foetal growth restriction from <200 mg/day caffeine would be
less than 2% of infants. The Committee also concluded that a positive association between caffeine
intake and miscarriage may exist, although uncertainties in the data exist. Finally, the association
between caffeine consumption and pre-term birth and congenital malformations was inconclusive.
The EU Scientific Committee on Food (SCF) opinion cited by Food Standards Agency, who noted that
5 mg/kg bw caffeine (300 mg for a 60 kg adult) could result in transient changes such as increased
arousal, nervousness or anxiety (Food Standards Agency). Following the COT advice, the Food
Standards Agency in UK recommended that pregnant women should limit their daily caffeine intake to
ideally below 200 mg/day (Food Standards Agency 2008, Food Standards Agency).
A later statement was issued by the COT in 2012 relating to the interaction of caffeine and alcohol and
their combined effects on health and behaviour (Committee on toxicity of chemicals in food consumer
products and the environment 2012).
3.6.3.
Belgium
In 2009, the Superior Health Council (SHC) received a request for advice from the FPS Public Health,
Food Chain Safety and Environment regarding the use of caffeine in foodstuffs, including food
supplements and soft drinks. Included in the advice was a description of adverse effects and risks
following ingestion of caffeine (Superior Health Council 2012). The SHC used the extensive literature
review by Nawrot et al., (2003), as the basis of their advice, and reported that evidence showed an
intake of 400 mg/day in adults was not linked to any adverse health effects including general toxicity,
cardiovascular effects, altered behaviour, increased incidence of cancer, effects on male fertility or
bone status and/or calcium balance, provided that calcium intake is sufficient. The Council considered
pregnant women or women of childbearing age to be a sensitive group in which the intake of caffeine
should not exceed 300 mg/day, or even 200 mg/day. Children were also considered to be an at risk
group as they are liable to suffer behavioural or central nervous system effects hence their intake
should not exceed 2.5 mg/kg bw/day.
EFSA supporting publication 2015:EN-561
35
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
3.6.4.
Norway
The Norwegian Scientific Committee for Food Safety (VKM) assessed new information on
ingredients in so-called ‘energy drinks’ in 2009, following an initial review carried out in 2005. In the
opinion of 2005, the VKM concluded that there was too limited knowledge on combined effects of
components of energy drinks, especially caffeine and taurine, to exclude negative health effects related
to intake of such drinks. In the later assessment VKM could not rule out the potential combined effects
of caffeine and taurine on the cardiovascular system, especially in susceptible individuals, since this
had not been properly investigated. They also concluded that there is no a priori reason to expect
combined effects of D-glucoronolactone and caffeine or taurine (Norwegian Scientific Committee for
Food Safety 2009).
VKM also commented on the combined effects of alcohol, exercise and energy drinks in 2009 and
reported results from a small study by Wiklund et al, 2009, in which intake of energy drinks and
alcohol with exercise caused a temporary decrease in heart rhythm variability among 10 subjects.
However, they concluded that it was not possible to determine whether such effects are related to
energy drinks or the simultaneous exposure to alcohol or exercise (Norwegian Scientific Committee
for Food Safety 2009).
A hazard identification and characterisation for caffeine was also carried out by VKM, based on the
Nordic Council of Ministers recently published risk assessment of caffeine among children and
adolescents in Nordic countries (Meltzer et al., 2008). Due to the clearance of caffeine being slower in
foetus’s, children and pregnant women, adverse health effects may occur at lower caffeine
concentrations. The estimated lethal dose of caffeine in adults is approximately 140 - 170 mg/kg bw
(corresponding to approximately 60 - 100 cups of coffee) but children, a dose of 3 g caffeine was fatal.
High exposures to caffeine in adults may induce adverse effects including nervousness, anxiety,
restlessness, insomnia, tremors and hyperesthesia, although such effects occur at doses far higher than
those commonly consumed. Few data on adverse effects of caffeine in children are available. Anxiety
was reported to be induced at a dose from 2.5 mg/kg bw, and a significantly lower heart rate and
higher blood pressure was reported in young girls and boys, although moderate doses of caffeine (5
mg/kg bw) did not affect metabolism at low-moderate intensities of exercise. Another study indicated
that children and adolescents with a high daily consumption of caffeine in the form of cola drinks may
develop caffeine-induced headache. Overall, lowest observed adverse effect levels in adults and
children were reported (Norwegian Scientific Committee for Food Safety 2009).
3.6.5.
Finland
The Finnish Food Safety Authority Evira reported the toxic dose of caffeine to be 20 mg/kg (120 mg
for a 60 kg adult) and cited the EU Scientific Committee on Foods opinion (1999), stating that ‘the
proportion of caffeine from energy drinks in comparison with the total consumption of caffeine in
unlikely to be harmful to adults, apart from pregnant women, as it is assumed that energy drinks
replace other caffeine sources. However, for children, daily additional exposure may cause temporary
behavioural changes such as restlessness and nervousness. The Committee states that pregnant women
must be advised to reduce their caffeine consumption’ (Finnish Food Safety Authority Evira 2010).
Subsequently, the Finnish Food Safety Authority Evira also took part in the risk assessment project to
assess exposure of children and adolescents to caffeine in Nordic countries (Meltzer et al., 2008). They
reported that even small amounts of caffeine were shown to have adverse effects, such as increase in
caffeine tolerance, withdrawal symptoms, anxiety and jitteriness, the latter being two effects being
observed with daily doses exceeding 125 mg (Finnish Food Safety Authority Evira 2011).
EFSA supporting publication 2015:EN-561
36
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
3.6.6.
US
In 2011, Milanez prepared a review of the adverse effects of caffeine for the Food and Drug
Administration (Milanez 2011) and assessed the effect of caffeine on a variety of health endpoints.
Authors reported that consumption of caffeine was associated with anxiety (0.7-3 mg/kg);
cardiovascular effects such as hypertension and bradycardia (1.4 mg/kg); fetal toxicity and bone
effects (3 mg/kg); reproductive toxicity (4 mg/kg); irritability, nausea, palpitations, panic attacks (47 mg/kg); seizures, tachycardia and rhabdomyolysis (7-17 mg/kg).
3.6.7.
France
French Agency for food, environmental and occupational health and safety (ANSES) did a recent
review of the risk associated with so called ‘energy drinks’ (French Agency for food 2013). The
concluded that heart failure may occur in individuals with genetic predispositions, and heart rhythm
disorders may occur following consumption of energy drinks in association with physical exercise,
high alcohol consumption and sensitivity to caffeine. Other cardiovascular, psycho-behavioural or
neurological effects also were observed after intake of large quantities of caffeine. The report
addressed the effect of caffeine and other constituents of energy drinks (i.e. taurine) on performance
during physical exercise but did not investigate the potential risks of energy drinks and alcohol in
amateurs or highly trained sportspeople. They did note that due to the diuretic effects, caffeine in
energy drinks may exacerbate water and electrolyte loss, and may alter body heat regulation during
exercise in hot climates, potentially increasing the risk of heat stroke.
3.6.8.
Canada
Heath Canada issued a reminder that healthy adults should limit their caffeine intake to <400 mg/day,
pregnant or breast feeding women should drink no more than 300 mg/day and children should not
drink more than 45 mg – 2.5 mg/kg bw/day (45 mg for 4-6 year olds; 62.5 mg for 7-9 year olds; 85 mg
for 10-12 year olds; 2.5 mg/kg bw/day for 13 year olds and older)(Health Canada 2013).
The Institut National de Sante Publique du Quebec stated that daily consumption of caffeine in excess
of recommended limits could lead to nausea, vomiting convulsions or serious heart problems, as well
as headaches, palpitations, agitation, irritability, restlessness, muscular jolts, tremors and
gastrointestinal discomfort. They also stated that children and adolescents are more likely to
experience undesirable effects and those with chronic illnesses may be more sensitive to caffeine.
Overall, they concluded that there was not enough evidence to conclude that energy drinks were a
public health risk. (Institut National de Sante Publique du Quebec 2013).
Rotstein also assessed the potential health risks of energy drinks and reported that consumption of
energy drinks after exercise may delay the return to a resting heart rate, that the combined
consumption of energy drinks and alcohol may pose a risk to health as intoxication may occur more
quickly, leading to more risky behaviour, such as excessive alcohol consumption. Authors concluded
that two servings of energy drinks per day would not be exposed to pose a risk to the adult population,
based on the safety of non-caffeine ingredients and the fact that caffeine intake would not exceed
Health Canada’s recommended daily intake (Rotstein et al., 2013).
3.6.9.
New Zealand
A older study carried out in New Zealand reported that a precise link between caffeine and
cardiovascular disease has not been established as there was little evidence that typical doses of
caffeine consumed in the diet causes hypertension. In contrast, dietary doses may lead to withdrawal
effects and physical dependence in adults. In terms of behavioural effects, caffeine increased anxiety
in children and adults at 3 mg/kg bw/day and reduces the ability to sleep at 1.4 mg/kg bw/day (Smith
et al., 2000).
EFSA supporting publication 2015:EN-561
37
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
The more recent risk profile study carried out by Smith cited a moderate daily intake of up to 400
mg/day (5.7 mg/kg bw/day for a 70 kg adult) was unlikely to result in adverse effects although
reported that caffeine was associated with acute effects such as stimulation of the central nervous
system (dizziness, rapid heartbeat, irritability, anxiety, tremors and insomnia), irritation of the
gastrointestinal tract (diarrhoea, nausea and/or vomiting) or cardiovascular effects (rapid heartbeat and
high blood pressure). Caffeine intake was also associated with a slight deterioration in calcium balance
and bone mineral density, but there is limited evidence for caffeine as a carcinogen. Authors also
reported that consumption during pregnancy has been associated with an increased risk of foetal
growth restriction (Thomson and Schiess 2010).
3.6.10.
Hong Kong
The Centre for Food Safety in Hong Kong cited the EU SCF opinion, in that adverse effects caused by
energy drinks may be due to interactions between constituents in energy drinks and alcohol and
exercise as effects were seen on the CNS (alcohol intoxication), kidney (increased water and sodium
loss) and cardiovascular system (heart rate and blood pressure), and suggest that such effects could
pose a risk to consumers (Centre for Food Safety 2012).
3.6.11.
Miscellaneous
The European Food Information Council stated that there was no evidence that caffeine is a risk factor
for cancer, a view supported by the World Cancer Research Fund, nor coronary heart disease, or
arrhythmia , although did cite two studies that that indicated coffee may trigger nonfatal myocardial
infarction (European Food Information Council 2007).
CONCLUSION
An evidence report is presented containing a summary of data related to the adverse effect of caffeine
when consumed alone, with alcohol, or with other substances in energy drinks, as well as a mixture of
caffeine, alcohol and other substances in energy drinks. All data have been collected from scientific
papers and web databases using strategic search terms appropriate to the database being interrogated.
EFSA supporting publication 2015:EN-561
38
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
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41
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
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EFSA supporting publication 2015:EN-561
42
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
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by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
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by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
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The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Waugh EJ, Lam MA, Hawker GA, McGowan J, Papaioannou A, Cheung AM, Hodsman AB, Leslie
WD, Siminoski K, Jamal SA and Perimenopause BMDGSoOC, 2009. Risk factors for low bone
mass in healthy 40-60 year old women: a systematic review of the literature. Osteoporos Int, 20, 121.
Weng X, Odouli R and Li DK, 2008. Maternal caffeine consumption during pregnancy and the risk of
miscarriage: a prospective cohort study. American Journal of Obstetrics and Gynecology, 198,
279.e271-279.e278.
Wiklund U, Karlsson M, Ostrom M and Messner T, 2009. Influence of energy drinks and alcohol on
post-exercise heart rate recovery and heart rate variability. Clin Physiol Funct Imaging, 29, 74-80.
Winkelmayer WC, Stampfer MJ, Willett WC and Curhan GC, 2005. Habitual caffeine intake and the
risk of hypertension in women. Journal of the American Medical Association, 294, 2330-2335.
Wisborg K, Kesmodel U, Bech BH, Hedegaard M and Henriksen TB, 2003. Maternal consumption of
coffee during pregnancy and stillbirth and infant death in first year of life: prospective study. BMJ
(Clinical research ed.), 326, 420.
Woolcott CG, King WD and Marrett LD, 2002. Coffee and tea consumption and cancers of the
bladder, colon and rectum. European journal of cancer prevention : the official journal of the
European Cancer Prevention Organisation (ECP), 11, 137-145.
World Cancer Research Fund, 2007. Food, Nutrition, Physical Activity and the Prevention of Cancer:
A Global Perspective. . WCRF, London.
Yeragani VK, Krishnan S, Engels HJ and Gretebeck R, 2005. Effects of caffeine on linear and
nonlinear measures of heart rate variability before and after exercise. Depression and anxiety, 21,
130-134.
Youngberg MR, Karpov IO, Begley A, Pollock BG and Buysse DJ, 2011. Clinical and physiological
correlates of caffeine and caffeine metabolites in primary insomnia. Journal of clinical sleep
medicine : JCSM : official publication of the American Academy of Sleep Medicine, 7, 196-203.
Yu X, Bao Z and Dong J, 2011. Coffee consumption and risks of cancers: a meta-analysis of cohort
studies. BMC Cancer, 11, 96.
Zampelas A, Panagiotakos DB, Pitsavos C, Chrysohoou C and Stefanadis C, 2004. Associations
between coffee consumption and inflammatory markers in healthy persons: the ATTICA study.
The American Journal of Clinical Nutrition, 80, 862-867.
Zeegers MP, Dorant E, Goldbohm RA and van den Brandt PA, 2001. Are coffee, tea, and total fluid
consumption associated with bladder cancer risk? Results from the Netherlands Cohort Study.
Cancer causes & control : CCC, 12, 231-238.
Zhou Y, Tian C and Jia C, 2012. A dose-response meta-analysis of coffee consumption and bladder
cancer. Preventive medicine, 55, 14-22.
EFSA supporting publication 2015:EN-561
50
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
ABBREVIATION
ADHD
Attention deficit/hyperactivity disorder
ANSES
French Agency for food, environmental and occupational health and safety
BfR
Federal Institute for risk assessment
CEF
EFSA Panel on Flavourings, Processing Aids and Materials in Contact with
CI
Confidence intervals
CNS
Central nervous system
COT
Committee on toxicity of chemicals in food consumer products and the
environment
EFSA
European Food Safety Authority
HR
Hazard ratio
M/E
Morningness/Eveningness score
MFR
Myocardial flow reserve
NOS
Newcastle Ottawa Scale
OR
Odds ratio
RCT
Randomised control trial
RPE
Rating of perceived exertion
RR
Relative risk
SCF
Scientific Committee on Food
SGA
Small for gestational age
SHC
Superior Health Council
SLR
Systematic literature reviews
VKM
Norwegian Scientific Committee for Food Safety
WCRF
World Cancer Research Fund
EFSA supporting publication 2015:EN-561
51
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search for caffeine
Annex – Complete Protocol
EFSA supporting publication 2015:EN-561
52
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively
by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender
procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be
considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the
issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search as
preparatory work for the safety
assessment of caffeine
Start-up contract – definitive protocol
Report for European Food Safety Authority
Ricardo-AEA/R/ED58662
Issue Number 1
Date 7/6/2013
EFSA supporting publication 2015:EN-561
liii
The present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the
author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender procedure. The
present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output
adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the
conclusions reached in the present document, without prejudice to the rights of the authors.
Extensive literature search as preparatory work for the safety assessment of caffeine
Customer:
Contact:
European Food Safety Authority
Sarah Bull
Ricardo-AEA Ltd
Gemini Building, Harwell, Didcot, OX11 0QR
Customer reference:
RC/EFSA/NUTRI/2013/01
t: 01235 753078
Confidentiality, copyright & reproduction:
Ricardo-AEA is certificated to ISO9001 and ISO14001
This report is the Copyright of European
Food Safety Authority and has been
prepared by Ricardo-AEA Ltd under contract
to European Food Safety Authority dated
21/02/2013. The contents of this report may
not be reproduced in whole or in part, nor
passed to any organisation or person without
the specific prior written permission of the
commercial manager. Ricardo-AEA Ltd
accepts no liability whatsoever to any third
party for any loss or damage arising from any
interpretation or use of the information
contained in this report, or reliance on any
views expressed therein.
e: sarah.bull@ricardo-aea.com
Author:
Sarah Bull
Approved By:
Jon Gibbard
Date:
th
12 June 2013
Signed:
Ricardo-AEA reference:
Ref: ED58662- Issue Number 1
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i
Extensive literature search as preparatory work for the safety assessment of caffeine
Executive summary
During recent years, the sale of energy drinks has significantly grown, as has mixing such drinks with
alcoholic beverages. These energy drinks contain levels of caffeine, equivalent to those found in
coffee. Previous studies on the safety of caffeine have been published by the Scientific Committee on
Food (SCF) in 1983, 1999 and 2003. In the latter assessment, the SCF concluded that caffeine would
not exacerbate the adverse effects of alcohol. Moreover, at low blood alcohol levels caffeine may
improve the performance of carrying out simple tasks11.
A recent study carried out by the UK-Committee on Toxicity (COT) looked at any new data published
since the SCF report and advised on the potential for interactions between caffeine and alcohol. Some
studies showed that caffeine can ameliorate the effects of alcohol on motor and memory reaction time,
although other studies failed to show such a correlation. Limited data also prevented them assessing
the effect of caffeine on the acute toxicity of alcohol. Overall, the committee concluded that, based on
the current balance of evidence, there is no harmful toxicological or behavioural interaction between
caffeine and alcohol. However, they stated that this opinion should be reviewed if new evidence
emerges12.
In 2013, the European Food Safety Authority (EFSA) was asked to re-evaluate any potential adverse
health effects that may arise following the consumption of caffeine, either alone or in combination
with alcohol and/or other substances such as energy drinks. Therefore, the objective of this project is
to provide EFSA with an evidence base related to the adverse effects of caffeine, either alone or in
combination with alcohol and/or energy drinks in various population groups.
SCF
2003.Opinion
of
the
SceintificCommitt
on
Food
on
additional
information
on
‘energy
drinks’.http://ec.europa.eu/food/fs/sc/scf/out169_en.pdf
12
COT 2012.COT statement on the interaction of caffeine and alcohol and their combined effects on health and behaviour.
http://cot.food.gov.uk/pdfs/cotstatementcaffalco201204.pdf
11
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Extensive literature search as preparatory work for the safety assessment of caffeine
Table of contents
1 Background ........................................................................................................................................... 1
2 Terms of reference................................................................................................................................. 1
3 Acknowledgements ............................................................................................................................... 1
4 Introduction and objectives ................................................................................................................... 2
4.1
Introduction ............................................................................................................................. 2
4.2
Objectives ............................................................................................................................... 2
4.2.1 Overall objectives ............................................................................................................... 2
4.2.2 Specific objectives .............................................................................................................. 3
5 Proposal for the extensive literature search process .............................................................................. 4
5.1
Methodology for study retrieval ............................................................................................. 4
5.1.1 Selection of search strategies .............................................................................................. 4
5.1.2 Selection of information sources ........................................................................................ 4
6 Proposal for the study selection process ................................................................................................ 5
6.1
Development of eligibility criteria for study selection ........................................................... 5
6.2
Removal of duplicated records ............................................................................................... 5
6.3
Primary screening on titles...................................................................................................... 5
6.4
Primary screening on abstracts ............................................................................................... 7
6.5
Secondary screening ............................................................................................................... 7
6.5.1 Epidemiology studies ......................................................................................................... 7
6.5.2 Intervention studies............................................................................................................. 9
6.6
Recording of data .................................................................................................................. 10
7 Proposal for extracting data from the included studies ....................................................................... 12
7.1
Data abstraction .................................................................................................................... 12
7.1.1 Epidemiology studies ....................................................................................................... 12
7.1.2 Intervention studies........................................................................................................... 13
8 Proposal for assessing the methodological quality of the included studies ......................................... 16
8.1
Assessing bias ....................................................................................................................... 16
8.2
Epidemiology studies ............................................................................................................ 16
8.3
Intervention studies ............................................................................................................... 16
9 Proposal for synthesising the data from the included studies .............................................................. 17
10 Results ............................................................................................................................................... 18
10.1
Selection of search strategies ................................................................................................ 18
10.1.1 Year of article publication ................................................................................................ 18
10.1.2 Selection of subject areas in scientific databases ............................................................. 18
10.1.3 Selection of search terms .................................................................................................. 19
10.2
Number of records retrieved ................................................................................................. 24
10.2.1 Question a) Papers on adverse effects of caffeine ............................................................ 12
10.2.2
Question b) Papers on adverse effects of caffeine in combination with alcohol ..... 13
10.2.3
Question c) Papers on adverse effects of caffeine in combination other substances
in energy drinks ....................................................................................................... 13
10.2.4
Question d) Papers on adverse effects of caffeine in combination with other
substances in energy drinks and alcohol.................................................................. 14
11 Foreseen timetable ............................................................................................................................. 37
Appendix 1 ............................................................................................................................................. 38
Appendix 2 ............................................................................................................................................. 41
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Extensive literature search as preparatory work for the safety assessment of caffeine
1.
BACKGROUND
The safety of caffeine was evaluated by the Scientific Committee on Food (SCF) in 1983, 1999 and
2003 in the context of opinions on the safety of caffeine, taurine and glucuronolactone in so-called
‘energy drinks’.
In 2008, the EFSA Panel on Flavourings, Processing Aids and Materials in Contact with Food (CEF)
performed an assessment of xanthin alkaloids used as flavouring substances but did not make any
conclusions due to the lack of data. In 2013, the European Commission asked the European Food
Safety Authority (EFSA) to re-evaluate the safety of caffeine either consumed alone or in combination
with alcohol and/or other substances from all sources, independent from its intended uses, for
specified population groups.
Therefore the aim of this project is to perform an extensive literature search (ELS) to provide an
evidence base that will form the basis of the re-evaluation of the safety of caffeine, either alone or in
combination with alcohol or energy drinks in various population groups.
2.
TERMS OF REFERENCE
Extensive literature search as preparatory work for the safety assessment of caffeine as provided by
EFSA in the Tender specifications for project RC/EFSA/NUTRI/2013/01.
3.
ACKNOWLEDGEMENTS
This contract was awarded by EFSA to: Ricardo-AEA.
Contract title: Extensive literature search as preparatory work for the safety assessment of caffeine.
RC/EFSA/NUTRI/2013/01.
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Extensive literature search as preparatory work for the safety assessment of caffeine
4.
INTRODUCTION AND OBJECTIVES
4.1.
Introduction
This report summarises our progress to date in terms of the definition of search strategies to answer
the questions posed by EFSA (Section 5.1) and describes the inclusion/exclusion criteria used to
exclude studies from further analysis (Section 6.3). We also present the number of studies retrieved
during such searches, the number of articles retained after duplicates have been removed, and the
number of studies left after primary screening on their titles (Section 6.3). This number of records is
indicative of the data available for more extensive review. Finally, we propose methodologies for data
extraction (Section0), data analysis (Section 8) and data synthesis (Section 9) that could be used
during the follow-up contract. Section 10 presents the results of the extensive literature searches,
removal of duplicates and primary screening by title and abstract, including numbers of articles found,
excluded and included from each search.
4.2.
4.2.1.
Objectives
Overall objectives
The aim of this start-up assignment is firstly to propose and undertake a methodology for an extensive
literature search (ELS) of the studies relating to the adverse health effects of caffeine, either alone or
in combination with other substances found in energy drinks and/or alcohol. This is followed by a
proposal for study selection for potential inclusion in the ELS. The second aim is to provide a proposal
for data extraction, for assessing quality of studies and data synthesis, all of which will be carried out
in a follow-up study if deemed appropriate by EFSA.
This assignment will cover the four topic areas related to:
a) Adverse health effects of caffeine intake in specific population groups:
Relevant population groups include, but is not limited to:
 Breast-fed infants consuming caffeine via mother’s milk
 Children divided by age group, where possible
 Pregnant women
 Lactating women
 Adults and adolescents
 Adults and adolescents performing all kind of physical exercise
b) Adverse health effects of intake of caffeine in combination with alcohol in specific
population groups:
Relevant population groups include:
 Lactating women
 Adults and adolescents
 Adults and adolescents performing all kind of physical exercise
c) Adverse health effects of intake of caffeine in combination with other substances in socalled energy drinks in specific population groups:
Relevant population groups include:
 Children divided by age group, where possible
 Pregnant women
 Lactating women
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Extensive literature search as preparatory work for the safety assessment of caffeine


Adults and adolescents
Adults and adolescents performing all kind of physical exercise
d) Adverse health effects of intake of caffeine in combination with other substances in socalled energy drinks and alcohol in specific population groups:
Relevant population groups include:
 Adults and adolescents
 Adults and adolescents performing all kind of physical exercise
4.2.2.
Specific objectives
The Contractor should carry out a comprehensive literature search in order to retrieve all information
related to the topics in peer-reviewed journals, by national risk assessment bodies and in grey literature
in relation to the overall objectives of the contract.
Once data have been retrieved, the Contractor should collate such data.
All relevant data should be further analysed and an evidence report should be prepared.
The information should be transferred in a concise way to EFSA including the full list of references
considered pertinent. References not considered pertinent should be listed and reasoning should be
provided why these references were not considered relevant. The report should be should be
accompanied by an EndNote library containing the related references.
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Extensive literature search as preparatory work for the safety assessment of caffeine
5.
PROPOSAL FOR THE EXTENSIVE LITERATURE SEARCH PROCESS
5.1.
5.1.1.
Methodology for study retrieval
Selection of search strategies
As part of this start-up contract, the Project Lead Expert, Epidemiologist and Information Scientist
have discussed and identified a list of search terms that are appropriate to retrieve published literature
relating to the adverse effects of caffeine. Search terms have been developed to gather data on the four
topic areas outlined in the tender documents, namely adverse health effects of caffeine alone, or in
combination with alcohol, other substances found in energy drinks or alcohol and energy drinks.
Broad search terms were used that were appropriate to the database being interrogated and to capture
as many publications as possible.
This literature search was carried out by the Information Scientist, in collaboration with various team
members. Various sensitivity analyses were carried out by the Information Scientist to ensure that
articles were indeed being captured and if necessary, search terms were amended (see section 10.3.1).
The search strategies and information such as the search terms used for the different databases were
recorded on an information source form (Table 15- Table 18).
All searches were carried out in English and all titles and abstracts retrieved from the literature search
were stored in a centralised location using Endnote bibliographic software. This library was accessible
to all team members.
5.1.2.
Selection of information sources
The project team has access to a number of scientific and bibliographic databases such as Scopus,
PUBMED and Web of Knowledge, as well as information from other sources.
Scopus is the world’s largest abstract and citation database, covering MEDLINE amongst other
databases. It contains over 20,500 titles from 5,000 publishers worldwide.
PUBMED comprises >22 million citations for biomedical literature, covering biomedicine and health,
life, behavioural and chemical sciences.
Web of Knowledge covers also science and social sciences. Within Web of Knowledge Cranfield
University has access to MEDLINE, Biosis previews and Web of Science. To avoid duplication with
other databases such as Scopus, MEDLINE was excluded from Web of Knowledge searches.
Although there is some duplication between the databases in that they all cover MEDLINE all are
deemed necessary due to them covering other databases. This is evidenced by the numbers of papers
retrieved by each database. For example, when searching for papers for question c (caffeine and other
substances in energy drinks), we retrieved 69 articles from SCOPUS, 19 from Web of Science, 7 from
Biosis Preview and 43 from PUBMED.
In this start-up contract, the literature search was confined to the bibliographic databases named above.
In the follow-up study, literature searches to identify and retrieve all related information/data
published by national risk assessment bodies both in Europe as well as Canada (Institute of Medicine
(IoM)), USA (Food and Drug Administration (FDA)) and Australia/New Zealand(Food Standards
Australia New Zealand (FSANZ)). A search of the grey literature will be also carried out.
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Extensive literature search as preparatory work for the safety assessment of caffeine
6.
6.1.
PROPOSAL FOR THE STUDY SELECTION PROCESS
Development of eligibility criteria for study selection
Identification of the eligibility criteria is critical in the validity of the ELR. The Project Lead Expert,
Epidemiologist and Information Scientist identified the study population (P), the intervention or
exposure (I or E), a comparator (C) and outcome (O) and consulted with other members of the team
when appropriate.
The description of the populations is given in the specifications, namely breast-fed infants, children, pregnant
and lactating women, adolescents and adults performing exercise. All study types will be included: case series,
cross-sectional, case-control and cohort. Intervention studies will also be included, both randomised and nonrandomised trials. All outcomes, in terms of adverse health effects will be investigated, as EFSA have not
specified any specific outcome.
6.2.
Removal of duplicated records
As part of the start-up contract, duplicate records were removed by the Information Scientist, in terms
of the same publication retrieved from different databases. Where there were multiple publications
stemming from the same study, all will be retained through primary screening and the full articles will
be retrieved. All will be included providing that either the outcomes or the population analysed
differed. If not, the most recent, relevant publication was used.
6.3.
Primary screening on titles
During the start-up contract, the titles of all references retrieved, after duplicates were removed, were
initially screened against an inclusion/exclusion criteria checklist (Table 1). The derivation of this list
of criteria was discussed within team members and agreed with EFSA.
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Extensive literature search as preparatory work for the safety assessment of caffeine
Table 1: Inclusion and exclusion criteria used during primary screening
Inclusion criteria
Exclusion criteria
Articles in English language
Articles in other languages
Articles published from 1997 to present
Articles published prior to 1997
Articles concerning caffeine alone (as coffee, tea, chocolate,
cola-type beverages, energy drinks, supplements, medicines,
energy shots, caffeinated chewing gum, caffeinated sport
bar, caffeinated sport gel, monster, red bull, rockstar)13
Articles concerning caffeine (as coffee, tea, chocolate, colatype beverages, energy drinks, supplements, medicines,
energy shots, caffeinated chewing gum, caffeinated sport
bar, caffeinated sport gel, monster, red bull, rockstar) in
combination with alcohol 14
Articles related to caffeine in combination with other
beverages or substances i.e. cocaine
Articles related to caffeine (as coffee, tea, chocolate,
cola-type beverages, energy drinks, supplements,
medicines, energy shots, caffeinated chewing gum,
caffeinated sport bar, caffeinated sport gel, monster,
red bull, rockstar) in combination with other
substances in energy drinks (specifically guarana,
15
taurine and glucuronolactone)
Articles related to caffeine in combination with other
beverages or substances, or relating to alcohol alone
Articles related to caffeine in combination with other
beverages or substances, relating to energy drinks
alone or constituents of energy drinks alone
Articles related to caffeine (as coffee, tea, chocolate, colatype beverages, energy drinks, supplements, medicines,
energy shots, caffeinated chewing gum, caffeinated sport
bar, caffeinated sport gel, monster, red bull, rockstar) in
combination with other substances in energy drinks
(specifically guarana, taurine and glucuronolactone) and
alcohol 16
Articles relating to the relevant population group
Articles related to caffeine in combination with other
beverages or substances, or relating to alcohol or
constituents of energy drinks alone
Articles relating to human studies
Studies in experimental animal species or in vitro
studies
Studies related to oral exposure
Articles related to other routes of exposure i.e.
inhalation or dermal studies
Systematic reviews
Other reviews (e.g. narrative reviews)
Scientific articles, reviews, reports and letters that report reworking of data
Commentaries, letters, editorials or other publication
types
Articles relating to other population groups i.e. groups
suffering from a severe disease
This primary screening removed records in irrelevant topic areas. In situations where it was unclear
whether the record was of relevance to the study, the article was retained for further screening. In
some cases, the record may be inappropriate for inclusion of one question but relevant for another. In
such cases the article was retained where appropriate. For example, when searching for question d)
articles were found that related to caffeine and alcohol alone. These papers were cross referenced with
those already identified for question b) to ensure that as many articles were retrieved as possible.
On completion of this primary screening of titles, in the results section we present EFSA with:
 the total number of studies identified (after duplicates were removed)
 the number of studies that will go forward to the primary screening on abstracts (after
irrelevant titles were removed)
We will also present the initial list of publications retrieved and the list of articles after primary
screening on titles in Endnote format. Such titles will then undergo primary screening on abstracts.
13
Question a) adverse health effects of caffeine
Question b) adverse health effects of caffeine in combination with alcohol
15
Question c) adverse health effects of caffeine in combination with other substances in energy drinks
16
Question d) adverse health effects of caffeine in combination with other substances in energy drinks and
alcohol
14
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Extensive literature search as preparatory work for the safety assessment of caffeine
These articles give an indication about the amount of data available for analysis during the follow-up
contract.
6.4.
Primary screening on abstracts
As part of the follow-up contract, abstracts of articles that pass through the first primary screening
stage will be assessed against the same inclusion/exclusion criteria as described above, and excluded if
appropriate. This abstract screening will be useful in cases where the title is ambiguous or does not
give required information on which to base a decision, such as what test species was used or whether
caffeine, energy drinks or alcohol health are described in the study. Examples of titles that required the
examination of the abstract in order to make a decision are shown in Table 2.
Table 2. Examples of articles examined during primary screening on abstracts
Example
Reason for including/excluding
Green tea (-)-epigallocatechin-3-gallate inhibits HGF-induced
progression in oral cavity cancer through suppression of
HGF/c-Met.
From the title it was unclear whether the study was carried
out in animals or humans. This paper relates to effects seen
in mice and in vitro. Will be excluded from further
screening.
This article reports coffee being inversely associated
with advanced beta-cell autoimmunity in offspring
exposed during pregnancy in humans. Will be
retained for secondary screening.
Maternal food consumption during pregnancy and risk of
advanced beta-cell autoimmunity in the offspring
A national study of sleep-related behaviours of nurse
anaesthetists: personal and professional implications
This article discusses effect of stimulants other than
coffee. Will be excluded from further screening.
Dietary patterns and risk of adenocarcinoma of the lung
in males: a factor analysis in Uruguay
This article presents data that milk/coffee is positively
associated with risk of adenocarcinoma of the lung in
humans. Will be retained for secondary screening.
Substance abuse and movement disorders: complex
interactions and comorbidities
This article presents data on various drugs of abuse,
not including caffeine. Will be excluded from further
screening.
Induction of regulatory t cells by green tea polyphenol
EGCG
This article presented both in vitro and in vivo data
following exposure to EGCG. Will be excluded from
further screening.
The full text of articles that pass the primary screening stages will be retrieved by the Information
Scientist and will be fully reviewed by the team members during the secondary screening stage. For
records in which it was not clear from the abstract whether the article met the inclusion criteria, the
full text was retrieved and reviewed for the necessary information.
6.5.
Secondary screening
The team will independently review all full manuscripts by comparing each one against the criteria
shown in the secondary screening tool, which will be completed for all articles. This secondary
screening tool will be adapted for the different types of studies retrieved such as epidemiology studies
(Table 3) or intervention studies (Table 4). Secondary screening will be carried out at the same time as
data abstraction.
6.5.1.
Epidemiology studies
The quality of non-randomised epidemiology studies is an important component of a thorough
systematic review/meta-analysis of such studies, with low quality studies potentially leading to a
distortion of the summary effect estimate. Therefore a methodological appraisal of all studies passing
the primary screening (on titles and abstracts) will be carried out by using the Newcastle-Ottawa
(Quality Assessment) Scale (NOS).
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Extensive literature search as preparatory work for the safety assessment of caffeine
The NOS was proposed by Wells et al. (2009)17 to assess the quality of published non-randomised
studies. The tool can either be used as a checklist or scale, and separate scales exist for cohort and
case-control studies. It contains eight items, categorised into three dimensions, including selection,
comparability and, depending on study type, outcome (cohort studies) or exposure (case-control
studies). An example of the NOS for a case-control study is shown in Table 3.
For each item a series of response options is provided. A star system is used to allow a semiquantitative assessment of study quality, such that the highest quality studies are awarded a maximum
of one star for each item with the exception of the item related to comparability that allows the
assignment of two stars. The NOS ranges between zero up to nine stars. Although details of the NOS
have not been published in a peer-reviewed journal, a number of studies have shown the scale to be
reliable and valid18,19,20. We will consider a study awarded seven or more stars as a high quality study
because standard criteria have not been established14. However, all studies that pass through the
primary screening process will be included in the final review, irrespective of their NOS score.
To aid in consistency and quality control, a guide to completing the NOS for case-control studies is
available for all epidemiologists carrying out such assessments and is given in appendix 1.
Table 3: Worked example of NOS for a case-control study
EFSA SYSTEMATIC REVIEW
EXTENSIVE
LITERATURE
PREPARATORY
WORK
FOR
ASSESSMENT OF CAFFEINE
EFSA REFERENCE
ABSTRACT
RC/EFSA/NUTRI/2013/01
SEARCH
AS
THE
SAFETY
Benko CR (2011).
Potential link between caffeine
consumption and pediatric depression: A case-control study.
BMC
Pediatrics,
11,
73
(http://www.biomedcentral.com/1471-2431/11/73)
9 April 2013
NO
YES
NA
Terry Brown
DATE REVIEWED
RECORD INCLUDED IN ELR
REASON FOR EXCLUSION
REVIEWER
Case-control Studies: Laurence et al., (2012)
Selection
1. Is the case definition
adequate
2. Representativeness of the
cases
3. Selection of controls
4. Definition of controls
a)
b)
c)
a)
b)
a)
b)
c)
a)
b)
Yes, with independent validation
Yes, e.g. record linkage or based on self-reports
No description
Consecutive or obviously representative series of cases
Potential for selection biases or not stated
Community controls
Hospital controls
No description
No history of disease (endpoint) 
No description of source




Comparability
1. Comparability of cases and
controls on the basis of the
design or analysis
a) Study controls for ___________ (select the most important
factor) 
b) Study controls for any additional factor (this criteria could
be modified to indicate specific control for a second
important factor) 


Exposure
17
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. (2009). The Newcastle-Ottawa Scale (NOS) for assessing the
quality if nonrandomized studies in meta-analysis. Available from: URL: http;//www.ohri.ca/programs/clinical_epidemiology/oxford.htm
18
Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al. (2003). Evaluating non-randomised intervention studies.Health
Technology Assessment, 7(27), iii-173.
19
Li W, Ma D, Liu M, Liu H, Feng S, Hao, et al. (2008). Association between metabolic syndrome and risk of stroke: a meta-analysis of
cohort studies. Cerebrovascular Diseases, 25(6), 539-547.
20
Myung SK, Ju W, McDonnell DD, Lee YJ, Kazinets G, Cheng CT, et al. (2009). Mobile phone use and risk of tumors: a meta-analysis.
Journal of Clinical Oncology, 27, 5565-5572.
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
8
Extensive literature search as preparatory work for the safety assessment of caffeine
1. Ascertainment of exposure
a)
b)
c)
d)
e)
a)
b)
2. Same method of
ascertainment for cases
and controls
3. Non-response rate
Secure record
Structured interview where blind to case/control status
Interview not blinded to case/control status
Written self-report or medical record only
No description
Yes
No
a) Same rate for both groups
b) Non-respondents described
c) Rate difference and no designation




TOTAL
9
After completing the secondary screening on the selected articles, the results from each reviewer will
be compared for consistency and to highlight any discrepancies. Any differences will be discussed to
achieve a consensus between reviewers and, if necessary, a third member of the team will also review
the abstracts.
6.5.2.
Intervention studies
For intervention studies, the Cochrane Collaboration21 uses a ‘Risk of Bias’ (methodological
quality) tool that review authors are expected to use for assessing the risk of bias in
randomized controlled trials. This involves consideration of six features:

Random sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective reporting and

Other sources of bias
Items are assessed by:

Providing a description of what happened in the study; and

Providing a judgment on the adequacy of the study with regard to the item.
The judgment is formulated by answering a pre-specified question, such that an answer of
‘Yes’ indicates low risk of bias, and answer of ‘No’ indicates high risk of bias, and an answer
of ‘Unclear’ indicates unclear or unknown risk of bias (Table 4).
Table 4: Worked example of secondary screening tool: intervention studies
EFSA
REVIEW
SYSTEMATIC
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK FOR THE
SAFETY ASSESSMENT OF CAFFEINE
EFSA REFERENCE
RC/EFSA/NUTRI/2013/01
ABSTRACT
Ferreira SE et al. (2004). Does an energy drink modify the effects of alcohol in a
maximal
effort
test?
Alcoholism: Clinical and Experimental Research, 28(9), 1408-1412
(http://www.ncbi.nlm.nih.gov/pubmed/15365313)
21
http://www.cochrane-handbook.org
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
9
Extensive literature search as preparatory work for the safety assessment of caffeine
9 April 2013
DATE REVIEWED
RECORD
ELR
INCLUDED
IN
YES
REASON FOR EXCLUSION
NA
REVIEWER
Terry Brown
Domain
NO
Support of judgement
Yes/
No
Selection bias
Random
generation
sequence
Allocation concealment
Support of judgement: Describe the method used to generate the allocation sequence in
sufficient detail to allow an assessment of whether it should produce comparable groups.
Review authors judgement: Selection bias (biased allocation to interventions) due to
inadequate generation of a randomised sequence
Support of judgement: Describe the method used to conceal the allocation sequence in
sufficient detail to determine whether intervention allocations could have been foreseen
in
advance
of,
or
during,
enrolment.
Review authors judgement: Selection bias (biased allocation to interventions) due to
inadequate concealment of allocations prior to assignment
Y
Y
Performance bias
Blinding of participants
and personnel
Support of judgement: Describe all measures used, if any, to blind study participants and
personnel from knowledge of which intervention a participant received. Provide any
information relating to whether the intended blinding was effective.
Review authors judgement: Performance bias due to knowledge of the allocated
interventions by participants and personnel during the study
Y
Support of judgement: Describe all measures used, if any, to blind outcome assessors
from knowledge of which intervention a participant received. Provide any information
relating
to
whether
the
intended
blinding
was
effective.
Review authors’ judgement: Detection bias due to knowledge of the allocated
interventions by outcome assessors.
Y
Support of judgement: Describe the completeness of outcome data for each main
outcome, including attrition and exclusions from the analysis. State whether attrition and
exclusions were reported, the numbers in each intervention group (compared with total
randomised participants), reasons for attrition/exclusions where reported, and any reinclusions
in
analyses
performed
by
the
review
authors.
Review authors judgement: Attrition bias due to amount, nature or handling of
incomplete data.
Y
Support of judgement: State how the possibility of selective outcome reporting was
examined
by
the
review
authors,
and
what
was
found.
Review authors judgement: Reporting bias due to selective outcome reporting.
Y
Support of judgement: State any important concerns about bias not addressed in the
other domains in the tool. If particular questions/entries were pre-specified in the
review’s protocol, responses should be provided for each question/entry.
Review authors judgement: Bias due to problems not covered elsewhere in the table.
N
Detection bias
Blinding of outcome
assessment
Attrition bias
Incomplete
data
outcome
Reporting bias
Selective reporting
Other bias
Other sources of bias
6.6.
Recording of data
At all stages of the screening process the number of publications that are excluded from further
analysis will be recorded in the data selection form (Table 5). Articles may be excluded following
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
10
Extensive literature search as preparatory work for the safety assessment of caffeine
secondary screening if the results presented or the analysis was deemed inadequate, i.e. if the article
was a conference abstract or letter.
Table 5: Worked example of the data selection form
EFSA EXTENSIVE LITERATURE
REVIEW
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK
FOR THE SAFETY ASSESSMENT OF CAFFEINE
EFSA REFERENCE
RC/EFSA/NUTRI/2013/01
Date
15 May 2013
Information scientist
Lini Ashdown
No. of records retrieved
14273 / 2510 / 138 / 34
Question a / b / c / d
Total no. of records retrieved
16955
Duplicates removal
Date
16 May 2013
Reviewer/s
Lini Ashdown
No. of records excluded
2954 / 501 / 24 / 6
Question a / b / c / d
Total no. of records excluded
3485
Primary screening
Date
17-20 April 2013
Reviewer/s
Sarah Bull, Terry Brown
Numbers of records excluded (titles)
10402 / 1895 / 100 / 28
Question a / b / c / d
Total no. of records excluded (titles)
Numbers of records excluded (abstracts)
12425
tbc in follow up of records excluded (titles)
Question a / b / c / d
Total no. of records excluded (abstracts)
tbc in follow up
Secondary screening
Date
tbc in follow up
Reviewer/s
Terry Brown, Sarah Bull, Karin Burnett
Numbers of records excluded
tbc in follow up
Total no. of full records obtained
tbc in follow up
Total no. of full records excluded
tbc in follow up
Total no. of records used for SR
tbc in follow up
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
11
Extensive literature search as preparatory work for the safety assessment of caffeine
7.
PROPOSAL FOR EXTRACTING DATA FROM THE INCLUDED STUDIES
7.1.
Data abstraction
In parallel with the secondary screening all articles will be systematically reviewed by a team member
and relevant data will be extracted and captured in an EXCEL-based data abstraction forms (Table 6 –
Table 7). The forms will be piloted by two of the reviewers on a subset of the literature to ensure all
relevant data are collected. If necessary the form will be refined. To aid in the transparency of the
review, these data abstraction forms will be included as an appendix in the final report. If there are a
large number they will be presented in a separate document. The data abstraction forms proposed in
this protocol provides an example of the type of information that should be retrieved from the
publication. However, such forms may be adapted according to the requirements of EFSA for the final
report.
This procedure also acts as a quality control for the reviewers themselves to ensure critical information
is not missed. As the data extraction task typically will be distributed across several members of the
team, the team will discuss this data extraction stage prior to it being carried out and is critical to
ensure consistency between reviewers. For quality assurance, 10 per cent of the studies will be
checked by another reviewer to ensure consistency. If discrepancies arise, such differences will be
discussed between team members to achieve a consensus view and if necessary, a third member of the
team will also review the manuscript.
7.1.1.
Epidemiology studies
For an epidemiology study, we will extract information on study characteristics such as:
 study type/design
 study population characteristics
 chemical/s under investigation
 exposure assessment methods
 health outcomes
 summary of the most relevant data outlined in the results section
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
12
Extensive literature search as preparatory work for the safety assessment of caffeine
Table 6: Worked example of data abstraction form for epidemiology studies
EFSA
SYSTEMATIC
REVIEW
EFSA REFERENCE
ABSTRACT
DATABASE REFERENCE
ID:
DATE REVIEWED
REVIEWER
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK FOR THE
SAFETY ASSESSMENT OF CAFFEINE
RC/EFSA/NUTRI/2013/01
Benko CR (2011). Potential link between caffeine consumption and pediatric
depression: A case-control study.
BMC Pediatrics, 11, 73 (http://www.biomedcentral.com/1471-2431/11/73)
EPI-0001
Reference
13th April 2013
Terry Brown
Benkoet al. (2011)
Study Type
Case-Control
Study Population (country, size,
sex, age)
Brazil; 34 Cases, 17 Controls; Cases defined as children with suspected learning
difficulties, mood disorders, attention problems, and hyperactive behaviour. Mean
age 9.9 years
Caffeine consumption, from drinking coffee, cola or tea
Chemicals under investigation
Exposure assessment
frequency, route)
Dose metric
(duration,
Health outcome
Greater than 3 cups per day
Never, Sometimes, Often, Always
Nutrition
Behaviour
Children Depressive Inventory (CDI)
Inventory
(NBI)
Follow-up
Results
Details of study quality
Risk of bias
Comments
Participants with CDI scores ≥ 15 also had high NBI scores (mean=52) suggestive of
relationship between depressive symptoms and environmental factors
Cases had significantly higher NBI scores than controls
Caffeine consumption was associated with depressive symptoms, but not sugar
Children who reported never drinking caffeine showed significantly lower depressive
symptoms. Significantly greater number classified as “often” or “always” showed
CDI ≥ 15. i.e. depressive symptoms
Small study
Only controlled for sugar consumption, possibility of other factors being involved.
Further research required to investigate whether or not this association is due to a
cause and effect relationship.
Cohort study members had nearly ubiquitous exposure to most PFCs examined
For all studies we will also comment on the quality of the study.
7.1.2.
Intervention studies
For an intervention study, a condensed version of the data collection form developed by the Cochrane
Collaboration22 will be used. We will extract information on study characteristics, such as:
 Study eligibility (study type, participants, types of intervention/ outcome measures,
etc.);
 Population and setting (population description, location, inclusion/exclusion criteria);
 Methods (aim of study, design, start and end dates, duration, etc.);
 Risk of bias assessment (blinding of participants and personnel, allocation
concealment, etc.);
 Participants (total, demographics, withdrawals and exclusions, etc.);
 Intervention groups (treatment duration and timing, etc.);
 Outcomes (time points measured/reported, definition, etc.)
 Results (dichotomous and continuous outcome, statistical analyses, etc.); and
22
http://handbook.cochrane.org/
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
13
Extensive literature search as preparatory work for the safety assessment of caffeine

Applicability of results (Table 7).
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
14
Extensive literature search as preparatory work for the safety assessment of caffeine
Table 7: Worked example of data abstraction form for intervention studies
EFSA
REVIEW
SYSTEMATIC
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK FOR THE
SAFETY ASSESSMENT OF CAFFEINE
EFSA REFERENCE
RC/EFSA/NUTRI/2013/01
ABSTRACT
Ferreira SE et al. (2004). Does an energy drink modify the effects of alcohol in a
maximal
effort
test?
Alcoholism: Clinical and Experimental Research, 28(9), 1408-1412
(http://www.ncbi.nlm.nih.gov/pubmed/15365313)
DATABASE
ID:
REFERENCE
EPI-0002
DATE REVIEWED
13th May 2013
REVIEWER
Terry Brown
Reference
Ferreira et al. (2004)
Study eligibility
Double-blind intervention study; males
Population and setting
Healthy volunteers attended laboratory; presented normal laboratory and clinical
exams, had no history of psychiatric disorders, and displayed a normal ergometer test
with an ECG, moderate alcohol consumption, moderate energy drink consumption
Methods
Ingestion of energy drink alters breath alcohol concentration, subjective perception of
alcohol intoxication, or performance in tests of motor coordination and visual reaction
time; double-blind study of 2 groups; 150 mins. Duration;
Risk of bias assessment
Volunteers randomly assigned to 2 groups and blind to what they received; unsure
whether personnel were blinded
Participants
26; male; age 23±3; BMI 22.7±1.6; wt. 69±8; ht. 174±8
Interevention groups
Group
1
(n=12):
0.6g/kg
alcohol;
3.57mL/kg
Group 2 (n=14): 1.0g/kg alcohol; 3.57mL/kg energy drink
Outcomes
Breath alcohol concentration; subjective feelings of alcoholic intoxication; motor
coordination; visual reaction time
Results
Ingestion of alcohol plus energy drink significantly reduced subjects’ perception of
headaches, weakness, dry mouth, and impairment of motor coordination
Ingestion of energy drink did not significantly reduce the deficits caused by alcohol
on objective motor coordination and visual reaction time. Did not alter breath alcohol
concentration in either group.
Applicability of results
None given
Comments
None
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
energy
drink
15
Extensive literature search as preparatory work for the safety assessment of caffeine
8.
8.1.
PROPOSAL FOR ASSESSING THE METHODOLOGICAL QUALITY OF THE INCLUDED STUDIES
Assessing bias
The types of bias being assessed under such protocols include selection, performance, detection,
attrition and reporting bias. As negative effects are less likely to be published than positive findings,
publication bias is a key concern in most ELRs.
The method of choice to assess publication bias is the funnel plot. However, this would require
abstracting data from each paper and entering it into relevant statistical software for analysis. This is a
time-consuming process and because of time and budget constraints this will not be
undertaken. Therefore, a qualitative assessment of publication bias will be undertaken by observing
how many studies are published that present positive results compared to those that present negative
results.
8.2.
Epidemiology studies
We will evaluate the study quality of epidemiological studies using the NOS (Table 3).
For the NOS, a coding manual will be provided to each team member assessing the articles and
provides guidance on how to complete the form appropriately, thereby aiding in the consistency and
quality control of assessments (appendix 1).
8.3.
Intervention studies
We will evaluate to study quality of intervention studies using the Cochrane Collaboration ‘Risk of
Bias’ tool (Table 4). For the tool, the Cochrane guidance will be provided to each team member
assessing the articles and provides assistance on how to complete the form appropriately, thereby
aiding in the consistency.
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
16
Extensive literature search as preparatory work for the safety assessment of caffeine
9.
PROPOSAL FOR SYNTHESISING THE DATA FROM THE INCLUDED STUDIES
Data synthesis involves the collation, combination and summary of the findings of individual
studies included in the literature review. Synthesis can be done quantitatively using formal
statistical techniques such as meta-analysis (which is not the objective of this work), or if
formal pooling of results is inappropriate, through a narrative approach. As well as drawing
results together, synthesis will consider the strength of evidence, explore whether any
observed effects are consistent across studies, and investigate possible reasons for any
inconsistencies. This will enable reliable conclusions to be drawn from the assembled body
of evidence.
The synthesis will draw on the evaluation procedures described above and the information
abstracted from papers considered for inclusion in the ELR. This purely descriptive process
will be explicit and rigorous. A narrative synthesis will be employed, the characteristic of
which will be to adopt a textual approach that provides an analysis of the relationships within
and between studies and an overall assessment of the robustness of the evidence.
A narrative synthesis is more subjective process than meta-analysis, therefore the approach
will be rigorous and transparent to reduce the potential for bias. The synthesis process will
adapt the approach developed by the Centre for Reviews and Dissemination23. The weightof-evidence24 will then be assessed in providing a final assessment and any
recommendations for future work that may be required to identify any gaps in the knowledge
there may be. The structure of the narrative will be discussed with EFSA at the start of the
follow-up contract, should it be awarded.
Overall, it is envisaged that the final report for this project will consist of:
 Endnote files for questions a, b, c and d containing the original number of articles
retrieved, and the number of articles retained following primary screening on titles
and abstracts
 Summary evidence tables of data for questions a, b, c and d. These will contain the
pertinent information on each study. The content of such tables will be discussed with
EFSA at the start of the follow-up contract, should it be awarded.
 A narrative of results, drawing together any similarities or differences of observed
effects across studies.
CRD (2009). CRD’s Guidance for Undertaking Reviews in Health Care: Systematic Reviews. University of York: Centre for Reviews and
Dissemination.
24
Weed DL (2005). Weight of evidence: a review of concepts and methods. Risk Analysis, 25(6), 1545-1557.
23
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
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Extensive literature search as preparatory work for the safety assessment of caffeine
10. RESULTS
10.1. Selection of search strategies
10.1.1. Year of article publication
On request of EFSA at the kick off meeting, the date of article publication was not specified in the
searches hence articles from all years, from 1935 to the present were captured. Due to the vast amount
of data retrieved, the publication year has been amended to cover from 1997 to the present.
10.1.2. Selection of subject areas in scientific databases
Scopus operates in a tiered system in which subject areas may first be selected. We initially chose to
use the Life Sciences, Health Sciences and Social Sciences subject areas, then excluded areas that
were deemed unnecessary (Table 8).
Table 8: Example of selection of subject areas in Scopus
Included categories
Medicine (medi)
 Pharmacology,
Toxicology and
Pharmaceutics (phar)

Neuroscience (neur)


Health Professions
(heal)
 Nursing (nurs)

Biochemistry, Genetics
and Molecular Biology
(bioc)
 Immunology and
Microbiology (immu)
 Psychology (psyc)
Multidisciplinary (mult)
Agricultural and
Biological Sciences
(agri)
Excluded categories
Chemical

Physics and
Engineering
Astronomy(phys)
(ceng)

Chemistry (chem)


Earth and
Planetary
Sciences (eart)

Environmental
Science (envi)

Engineering
(engi)

Decision sciences
(deci)

Energy (Ener)

Social science
(soci)

Arts and
humanities (arts)

Economics,
econometrics and
finance (econ)

Materials Science
(mat sci)

Veterinary (vete)

Mathematics
(math)

Material Science
(Mate)

Dentistry (dent)

Business (busi)

Computer
Science (comp)
* excluded from searches
In Web of Knowledge, again, specific subject/research areas were selected that were most appropriate
to the topic being researched (Table 9).
For both databases, a sensitivity analysis was carried out by using the search terms in individual
research areas. Results showed that no, or irrelevant articles, were retrieved from the excluded
research areas in both Scopus and Web of Knowledge, giving confidence that the most appropriate
areas were selected (data not shown).
Table 9: Example of selection of subject areas in Web of Knowledge

Toxicology

Included categories
Respiratory system
 Biochemistry molecular 
biology

Public environmental

Genetics heredity
Ref: Ricardo-AEA/R/ED58662/Issue Number 1

Gastroenterology

Pharmacology
pharmacy
Reproductive biology
18
Extensive literature search as preparatory work for the safety assessment of caffeine
occupational health
hepatology

Cell biology

Immunology

Physiology


Neurosciences
neurology

Developmental biology

Obstetrics gynaecology 

Hematology

Oncology

Cardiovascular system
cardiology

Behavioural sciences

Psychology

Anaesthesiology


Anthropology

Food science
technology

Science technology

General internal
medicine


Orthopaedics

Plant sciences

Engineering

Sociology

Philosophy

Education educational 
research

Ophthalmology

Optics

Social issues

Physics

Materials science

Chemistry

Mathematical
computational biology

Agriculture

Information science

Vet sciences

Microscopy

Urban sciences

Women apos studies

Criminology

Medical informatics

Entomology

History

Virology

Parasitology

Religion

Cultural studies

Research

Imaging science

Medical ethics

Audiology speech

Communication

Meteorology

Film radio television

Nuclear science

Medical laboratory
technology

Demography

Cell biology

Dentistry oral surgery 
medicine
Rehabilitation

Emergency medicine

Biophysics

Computer science

Ethnic studies

Business economics

Government law

Zoology

Integrative
complementary
medicine

Energy fuels

Rheumatology

Allergy
Excluded categories
 Nutritional dietetics
Endocrinology
metabolism
Paediatrics
Urology nephrology
Microbiology

Psychiatry
Geriatrics gerontology

Mathematics

Surgery

Dermatology

Linguistics

Radiology
Social sciences other 
topics
Legal medicine
10.1.3. Selection of search terms
As part of the literature search, various sensitivity analyses were carried out to ensure that as many
relevant records as possible were captured by the search terms. For example, the following sensitivity
analyses were carried out:
 ‘supplement’ or ‘medicine’, as mentioned in the technical specifications, did not
capture any additional relevant articles, hence were not added to the search terms.
 ‘female’, ‘male’, ‘woman’, ‘women’, ‘man’ and ‘men’ were added to search terms as
the initial searches using terms such as ‘human’ failed to capture many relevant
articles. In PUBMED, ‘human’ is a specific filter choice that was selected. In Web of
Science, as well as including search terms described, we also included exclusion
terms such as NOT ‘rat*, mouse or mice’ to focus on retrieving only human studies.
 ‘Physical exercise’, as requested by EFSA, did not capture any additional articles as
‘exercise’ was already included in the search terms, hence only ‘exercise’ was
retained.
 ‘Guarana containing foods, including drinks and supplements’ as requested by EFSA,
did not capture any papers so ‘guarana’ alone was used as the search term
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
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Extensive literature search as preparatory work for the safety assessment of caffeine





Alternatives for ‘Energy drink’ such as ‘energy shot’, ‘taurine’, ‘glucuronolactone’,
Monster, Red Bull and Rockstar, as suggested by EFSA, we all investigated.
‘Monster’ and ‘Red Bull’ both retrieved a number of articles, although had some cross
over with articles retrieved by using search term ‘energy drink’. ‘Rockstar’ and ‘energy
shot’ did not capture any articles. However, they were all retained in the search terms
for completeness.
Other energy drinks (Amp, Relentless, Rehab) were also investigated but did not
capture any relevant articles hence were not included in the search terms.
‘Caffeinated sports bar and gels’, as requested by EFSA, not capture any additional
papers. On further investigation, searches using such search terms alone also did not
retrieve any articles so they were not included in the search terms.
‘Cola and cola-like beverages’ as mentioned in the technical specifications, was
removed from the search terms in Web of Sciences as it captured articles on cancer
and colon rather than articles relating to cola-like beverages. Articles on cola were
captured under the ‘caffeine’ search term.
‘Adverse effect’, ‘health effect’, ‘*toxi*’, ‘endurance’, ‘exercise’, ‘performance’,
‘behaviour’, ‘attention’, ‘psych*’, ‘cancer’, ‘cardio*’, ‘birth defect’, ‘fertility’,
‘reproductive’, ‘interaction’, ‘safety’, ‘side effects’, and ‘dose-response’ were all
included to cover as many adverse effects as possible. Such search terms were
obtained following the interrogation of other reviews or following comments from
EFSA.
Following these different analyses, the keywords or MESH Terms use to retrieve articles from
Scopus on question a), b), c) and d) are presented in Table 10. Similarly search terms used for
Web of Science, Biosis Previews and PubMed are presented in Table 11 and Table 12.
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
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Extensive literature search as preparatory work for the safety assessment of caffeine
Table 10: Scopus search terms
Search terms
Question a)
(TITLE-ABS-KEY(caffein* OR coffee OR tea OR chocolate OR cola OR {energy shot} OR {red bull} OR monster OR rockstar OR
{energy drink}) AND TITLE-ABS-KEY({breast milk} OR baby OR babies OR infant* OR child* OR adolescent* OR adult* OR
pregnan* OR lactating OR female OR male OR woman OR women OR man OR men) AND TITLE-ABS-KEY({physical exercise} OR
{side effect} OR {dose response} OR safety OR dance OR dancing OR sport OR {adverse effect} OR {health effect} OR *toxi* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR {birth defect} OR fertility OR
reproductive OR interaction)
Question b)
(TITLE-ABS-KEY((caffein* OR coffee OR tea OR chocolate OR cola OR {energy shot} OR {red bull} OR monster OR rockstar OR
{energy drink} AND alcohol)) AND TITLE-ABS-KEY((adult OR adolescent OR female OR male OR wom?n OR man OR men) AND
NOT (baby OR babies OR child* OR infant*)) AND TITLE-ABS-KEY({physical exercise} OR {side effect} OR {dose response} OR
safety OR dance OR dancing OR sport OR {adverse effect} OR {health effect} OR *toxi* OR endurance OR exercise OR performance OR
behaviour OR attention OR psych* OR cancer OR cardio* OR {birth defect} OR fertility OR reproductive OR interaction)
Question c)
(TITLE-ABS-KEY((caffein* OR coffee OR tea OR chocolate OR cola OR {energy shot} OR {red bull} OR monster OR rockstar OR
{energy drink}) AND (guarana OR taurine OR glucuronolactone)) AND TITLE-ABS-KEY((child* OR adult* OR adolescent* OR
pregnan* OR lactating OR female OR male OR wom?n OR man OR men) AND NOT (baby OR babies OR infant*)) AND TITLE-ABSKEY({physical exercise} OR {side effect} OR {dose response} OR safety OR dance OR dancing OR sport OR {adverse effect} OR
{health effect} OR *toxi* OR endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR
{birth defect} OR fertility OR reproductive OR interaction)
Question d)
(TITLE-ABS-KEY((caffein* OR coffee OR tea OR chocolate OR cola OR {energy shift} OR {red bull} OR monster OR rockstar OR
{energy drink}) AND alcohol AND (guarana OR taurine OR glucuronolactone)) AND TITLE-ABS-KEY((adult OR adolescent OR female
OR male OR wom?n OR man OR men) AND NOT (baby OR babies OR child* OR infant*)) AND TITLE-ABS-KEY({physical exercise}
OR {side effect} OR {dose response} OR safety OR dance OR dancing OR sport OR {adverse effect} OR {health effect} OR *toxi* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR {birth defect} OR fertility OR
reproductive OR interaction)
Table 11: Web of science search terms
Search terms
Question a)
TS=(caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster OR rockstar OR "energy drink*") AND
TS=("breast milk" OR baby OR babies OR infant* OR child* OR adolescent* OR adult* OR female OR male OR pregnan* OR lactating
OR woman OR women OR man OR men) AND TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR
dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR performance OR behaviour OR
attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction)
Question b)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster OR rockstar OR "energy drink*") AND
alcohol) AND TS=((adult* OR adolescent* OR female OR male OR woman OR women OR man OR men) NOT (baby OR babies OR
child* OR infant*)) AND TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR sport OR
"adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR performance OR behaviour OR attention OR psych* OR
cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction)
Question c)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull" OR monster OR rockstar OR "energy drink" ) AND
(guarana OR taurine OR glucuronolactone)) AND TS=((child* OR adult* OR adolescent* OR pregnan* OR lactating OR female OR male
OR woman OR women OR man OR men) NOT (baby OR babies OR infant*)) AND TS=("physical exercise" OR "side effect" OR "dose
response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR
interaction)
Question d)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull"OR monster OR rockstar OR "energy drink") AND
(guarana OR taurine OR glucuronolactone) AND alcohol) AND TS=((adult* OR adolescent* OR pregnan* OR lactating OR female OR
male OR woman OR women OR man OR men) NOT (child* OR baby OR babies OR infant*)) AND TS=("physical exercise" OR "side
effect" OR "dose response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxic* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR
reproductive OR interaction)
Table 12: Biosis Previews search terms
Search terms
Question a)
(caffein*[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster OR rockstar OR
"energy drink*"[Title/Abstract]) AND (("breast milk" OR baby OR babies OR infant* OR child* OR adolescent* OR adult* OR female
OR male OR pregnan* OR lactating OR woman OR women OR man OR men[MeSH Terms])) OR ("breast milk" OR baby OR babies OR
infant* OR child* OR adolescent* OR adult* OR female OR male OR pregnan* OR lactating OR woman OR women OR man OR
men[Title/Abstract]) AND (("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR sport OR
"adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR performance OR behaviour OR attention OR psych* OR
cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction[MeSH Terms])) OR ("physical exercise" OR "side
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Extensive literature search as preparatory work for the safety assessment of caffeine
effect" OR "dose response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance
OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR
reproductive OR interaction[Title/Abstract])
Question b)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster OR rockstar OR "energy drink*") AND
alcohol) AND TS=((adult* OR adolescent* OR female OR male OR woman OR women OR man OR men) NOT (baby OR babies OR
child* OR infant*)) AND TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR sport OR
"adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR performance OR behaviour OR attention OR psych* OR
cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction)
Question c)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull" OR monster OR rockstar OR "energy drink" ) AND
(guarana OR taurine OR glucuronolactone)) AND TS=((child* OR adult* OR adolescent* OR pregnan* OR lactating OR female OR male
OR woman OR women OR man OR men) NOT (baby OR babies OR infant*)) AND TS=("physical exercise" OR "side effect" OR "dose
response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR
interaction)
Question d)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull"OR monster OR rockstar OR "energy drink")
AND (guarana OR taurine OR glucuronolactone) AND alcohol) AND TS=((adult* OR adolescent* OR pregnan* OR lactating
OR female OR male OR woman OR women OR man OR men) NOT (child* OR baby OR babies OR infant*)) AND
TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR sport OR "adverse effect*"
OR "health effect*" OR *toxic* OR endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer
OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction)
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
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Extensive literature search as preparatory work for the safety assessment of caffeine
Table 13: PUBMED search terms
Search terms
Question a)
(((caffeine OR coffee OR tea OR chocolate[Title/Abstract])) AND alcohol[Title/Abstract] OR (caffeine[MeSH Terms]) AND
alcohol[MeSH Terms]) AND ((adult* OR adolescent* OR female OR male OR woman OR women OR man OR men) NOT
(baby OR babies OR child* OR infant*)[Title/Abstract])) OR ((adult* OR adolescent* OR female OR male) NOT (baby OR
babies OR child* OR infant*)[MeSH Terms]) AND ((adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise
OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive
OR interaction[MeSH Terms])) OR (adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR behaviour
OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction[Title/Abstract])
Question b)
((caffein*[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR cola OR "energy shot*" OR "red bull" OR monster
OR rockstar OR "energy drink*") AND (alcohol[MeSH Terms]) OR alcohol[Title/Abstract]) AND (((adult* OR adolescent* OR
female OR male OR woman OR women OR man OR men[MeSH Terms])) NOT (baby OR babies OR child* OR infant*[MeSH
Terms]) OR ((adult* OR adolescent* OR female OR male OR woman OR women OR man OR men[Title/Abstract])) NOT
(baby OR babies OR child* OR infant*[Title/Abstract])) AND (("physical exercise" OR "side effect" OR "dose response" OR
safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR
interaction[MeSH Terms])) OR ("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR
sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR performance OR behaviour OR
attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction[Title/Abstract])
Question c)
(caffeine[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR cola OR "energy shot*" OR "red bull" OR monster
OR rockstar OR "energy drink*"[Title/Abstract]) AND (((guarana OR taurine OR glucuronolactone[MeSH Terms])) OR (guarana
OR taurine OR glucuronolactone[Title/Abstract]) OR ((guarana OR taurine OR glucuronolactone[MeSH Terms])) OR (guarana
OR taurine OR glucuronolactone[Title/Abstract])) AND (((child* OR adult* OR adolescent* OR pregnan* OR lactating OR
female OR male OR woman OR women OR man OR men[MeSH Terms])) NOT (baby OR babies OR infant*[MeSH Terms])
OR ((child* OR adult* OR adolescent* OR pregnan* OR lactating OR female OR male OR woman OR women OR man OR
men[Title/Abstract])) NOT (baby OR babies OR infant[Title/Abstract])) AND (("physical exercise" OR "side effect" OR "dose
response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR
exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR
reproductive OR interaction[MeSH Terms])) OR ("physical exercise" OR "side effect" OR "dose response" OR safety OR
dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR performance
OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR
interaction[Title/Abstract])
Question d)
((caffeine[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR cola OR "energy shot*" OR "red bull" OR monster
OR rockstar OR "energy drink*"[Title/Abstract]) AND ((guarana OR taurine OR glucuronolactone[MeSH Terms])) OR (guarana
OR taurine OR glucuronolactone[Title/Abstract]) AND (alcohol[MeSH Terms]) OR alcohol[Title/Abstract]) AND (((adult* OR
adolescent* OR female OR male OR woman OR women OR man OR men[MeSH Terms])) NOT (baby OR babies OR child*
OR infant*[MeSH Terms]) OR ((adult* OR adolescent* OR female OR male OR woman OR women OR man OR
men[Title/Abstract])) NOT (baby OR babies OR child* OR infant*[Title/Abstract]) AND (("physical exercise" OR "side effect"
OR "dose response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR
fertility OR reproductive OR interaction[MeSH Terms])) OR ("physical exercise" OR "side effect" OR "dose response" OR
safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR
interaction[Title/Abstract])
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
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Extensive literature search as preparatory work for the safety assessment of caffeine
10.2. Number of records retrieved
Once records were retrieved from the different databases, duplicates were removed and titles
underwent primary screening to remove irrelevant articles, based on exclusion and inclusion criteria.
Examples of titles that were excluded based on such criteria are shown in Table 14.
The information source forms below show the number of articles retrieved from the different
databases on the adverse health of caffeine alone (Table 15), or in combination with alcohol (Table
16), other substances in energy drinks (Table 17) or other substances in energy drinks and alcohol
(Table 18). Articles have been retrieved from 1997 to the present.
Table 14: Examples of articles excluded during primary screening
Exclusion criteria
Example
Articles in other languages
Papers identified in French, Italian etc
Articles related to caffeine in
combination with other beverages or
25
substances i.e. cocaine
Is the consumption of coffee and methylxanthine derivatives a health hazard?
Articles related to alcohol alone
26
The ‘twinkie defense’: the relationship between carbonated non-diet soft
drinks and violence perpetration among Boston high school students
Brain hemodynamic changes in preterm infants after caffeine and
theophylline treatment
Delirium following ingestion of marijuana present in chocolate cookies
Impact of caffeine and protein on postexercise muscle glycogen
synthesis
Moderate alcohol intake during pregnancy and risk of foetal death
Influence of alcohol on gastrointestinal motility: Lactulose breath
hydrogen testing in orocecal transit time in chronic alcoholics, social
drinkers and teetotaler subjects
A 21-year longitudinal analysis of the effects of prenatal alcohol
exposure on young adult drinking
Articles related to other substances
27
in energy drinks alone
Cardiovascular adverse reactions associated with Guarana: Is there a causal
effect?
Articles related to beneficial effects
Caffeine potentiates or protects against radiation-induces DNA and
chromosomal damage in human lymphocytes depending on
temperature and concentration
Articles relating
population group
relevant
A complementary care study combining flaxseed oil, caffeine, fasting,
and exercise in women diagnosed with advanced ovarian cancer:
Findings from a case study
Effect of caffeine administered intravenously on intracoronaryadministered adenosine-induced coronary hemodynamics in patients
with coronary artery disease
Influence of alcohol on gastrointestinal motility: Lactulose breath
hydrogen testing in orocecal transit time in chronic alcoholics, social
drinkers and teetotaler subjects
Chemoprevention of human prostate cancer by oral administration of
green tea catechins in volunteers with high-grade prostate
intraepithelial neoplasia: A preliminary report from a one-year proof-ofprinciple study
animal
Caffeine and theophylline metabolism in newborn and adult
hepatocytes: comparison with adult rat hepatocytes
Caffeine induces apoptosis in human neuroblastoma cell line SK-N-MC
Intravenous caffeine elevates plasma CCK levels in health adults and
vervet monkeys
to
the
Studies in experimental
species or in vitro studies
Articles related to other routes of
Acute ventilator response to green coffee dust extract
25
Question a) adverse health effects of caffeine
Question b) adverse health effects of caffeine in combination with alcohol
27
Question c) adverse health effects of caffeine in combination with other substances in energy drinks
26
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
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Extensive literature search as preparatory work for the safety assessment of caffeine
exposure i.e. inhalation or dermal
studies
Effects of intravenous caffeine administration to health males during
sleep
Effect of caffeine administered intravenously on intracoronaryadministered adenosine-induced coronary hemodynamics in patients
with coronary artery disease
Commentaries, letters, editorials or
other publication types
JAMA patients page – energy drinks
Research continues to serve up heart perks for coffee drinkers
For each study question, the total number of papers found, the number of duplicates removed and the
number of papers excluded during the primary screening on titles are presented in Figures 1 to 4
below.
10.2.1. Question a) Papers on adverse effects of caffeine
A total of 11,319 papers were found relating to the adverse effect of caffeine (after duplicates were
removed), from which 9,208 were excluded according the exclusion criteria, leaving 2,111 studies
(including those added from searches or from analysing various reports from authoritative bodies) that
will be further screened for inclusion by carrying out primary screening on the abstracts (Table 15).
Articles were excluded for several reasons. Despite specifying English in the search terms, several
papers written in a non-English language were still identified hence were discarded. A significant
quantity of papers were also rejected based on the other exclusion criteria due to reporting data on:
 experimental animals species such mice, rats, monkeys and guinea pigs
 in vitro studies
 studies relating to theophylline or clozapine
 other drugs of abuse such as MDMA, cocaine or cannabis
 caffeine in combination with other chemicals, including alcohol and drugs of abuse
 effects of aspirin and paracetamol
In addition, there was some overlap in the articles retrieved for the other questions, as the search also
picked up many papers related to adverse effects of caffeine in combination with alcohol or other
substances in energy drinks, which were also picked up in the searches for questions b) and c) hence
were excluded from further analysis for question a).
10.2.2. Question b) Papers on adverse effects of caffeine in combination with alcohol
A total of 2,009 papers were found relating to the adverse effect of caffeine and alcohol (after
duplicates were removed), from which 1,762 were excluded according the exclusion criteria, leaving
247 studies (including those added from searches or from analysing various reports from authoritative
bodies) that will be further screened for inclusion by carrying out primary screening on the abstracts
(Table 16).
As with question a), many papers were excluded due to reporting data on the topics listed above. In
addition, papers were also excluded due to reporting the effects of caffeine alone (such papers would
be included in question a), or for alcohol alone. When papers relating to caffeine alone were retrieved,
they were cross referenced with those captured for question a) to ensure as many papers were retrieved
as possible.
10.2.3. Question c) Papers on adverse effects of caffeine in combination other substances in energy
drinks
A total of 114 papers were found relating to the adverse effect of caffeine and other substances in
energy drinks (after duplicates were removed), from which 90 were excluded according the exclusion
criteria, leaving 24 studies (including those added from searches or from analysing various reports
from authoritative bodies) that will be further screened for inclusion by carrying out primary screening
on the abstracts (Table 17).
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
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Extensive literature search as preparatory work for the safety assessment of caffeine
Papers were excluded mainly due to reporting data solely on caffeine or energy drinks containing
caffeine (which were already covered in question a)) or data relating to the use and consumption of
energy drinks.
10.2.4. Question d) Papers on adverse effects of caffeine in combination with other substances in
energy drinks and alcohol
A total of 63 papers were found related to the effects of caffeine, other substances in energy drinks and
alcohol (after duplicates were removed). However, most papers were rejected due to only reporting the
adverse effects of caffeine or energy drinks and alcohol and no papers addressed the potential adverse
effects of caffeine, other substances in energy drinks and alcohol (Table 18). Such papers would have
already been picked in in the search for question b), seeing as energy drink per se was named in the
technical specification as a source of caffeine.
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Extensive literature search as preparatory work for the safety assessment of caffeine
Table 15: Information source form – question a) adverse health effects of caffeine
EFSA SYSTEMATIC REVIEW
EFSA REFERENCE
INFORMATION SCIENTIST
STUDY QUESTION
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK FOR THE SAFETY
ASSESSMENT OF CAFFEINE
RC/EFSA/NUTRI/2013/01
LINI ASHDOWN
Question a) adverse health effects of caffeine
Scopus
(TITLE-ABS-KEY(caffein* OR coffee OR tea OR chocolate OR cola OR {energy shot} OR
{red bull} OR monster OR rockstar OR {energy drink}) AND TITLE-ABS-KEY({breast milk}
OR baby OR babies OR infant* OR child* OR adolescent* OR adult* OR pregnan* OR
lactating OR female OR male OR woman OR women OR man OR men) AND TITLE-ABSKEY({physical exercise} OR {side effect} OR {dose response} OR safety OR dance OR
dancing OR sport OR {adverse effect} OR {health effect} OR *toxi* OR endurance OR
exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR
{birth defect} OR fertility OR reproductive OR interaction) AND NOT TITLE-ABS-KEY(rat*
OR mouse OR mice)) AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR
mult OR medi OR nurs OR vete OR dent OR heal OR mult OR arts OR busi OR deci OR econ
OR psyc OR soci) AND (EXCLUDE(SUBJAREA, "AGRI") OR EXCLUDE(SUBJAREA,
"CHEM") OR EXCLUDE(SUBJAREA, "ENVI") OR EXCLUDE(SUBJAREA, "SOCI") OR
EXCLUDE(SUBJAREA,
"VETE")
OR
EXCLUDE(SUBJAREA,
"DENT")
OR
EXCLUDE(SUBJAREA,
"CENG")
OR
EXCLUDE(SUBJAREA,
"ENGI")
OR
EXCLUDE(SUBJAREA,
"ARTS")
OR
EXCLUDE(SUBJAREA,
"MATH")
OR
EXCLUDE(SUBJAREA,
"BUSI")
OR
EXCLUDE(SUBJAREA,
"PHYS")
OR
EXCLUDE(SUBJAREA,
"DECI")
OR
EXCLUDE(SUBJAREA,
"ECON")
OR
EXCLUDE(SUBJAREA,
"MATE")
OR
EXCLUDE(SUBJAREA,
"COMP")
OR
EXCLUDE(SUBJAREA, "EART") OR EXCLUDE(SUBJAREA, "ENER")) AND (LIMITTO(PUBYEAR, 2013) OR LIMIT-TO(PUBYEAR, 2012) OR LIMIT-TO(PUBYEAR, 2011)
OR LIMIT-TO(PUBYEAR, 2010) OR LIMIT-TO(PUBYEAR, 2009) OR LIMITTO(PUBYEAR, 2008) OR LIMIT-TO(PUBYEAR, 2007) OR LIMIT-TO(PUBYEAR, 2006)
OR LIMIT-TO(PUBYEAR, 2005) OR LIMIT-TO(PUBYEAR, 2004) OR LIMITTO(PUBYEAR, 2003) OR LIMIT-TO(PUBYEAR, 2002) OR LIMIT-TO(PUBYEAR, 2001)
OR LIMIT-TO(PUBYEAR, 2000) OR LIMIT-TO(PUBYEAR, 1999) OR LIMITTO(PUBYEAR, 1998) OR LIMIT-TO(PUBYEAR, 1997))
May 2013
5660
Web of science
TS=(caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster OR
rockstar OR "energy drink*") AND TS=("breast milk" OR baby OR babies OR infant* OR
child* OR adolescent* OR adult* OR female OR male OR pregnan* OR lactating OR woman
OR women OR man OR men) AND TS=("physical exercise" OR "side effect" OR "dose
response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*"
OR *toxi* OR endurance OR exercise OR performance OR behaviour OR attention OR psych*
OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction) NOT
TS=(rat* OR mouse OR mice)
Refined by: [excluding] Research Areas=( NUTRITION DIETETICS OR TRANSPORTATION
OR BUSINESS ECONOMICS OR MARINE FRESHWATER BIOLOGY OR DENTISTRY
ORAL SURGERY MEDICINE OR TROPICAL MEDICINE OR EDUCATION
EDUCATIONAL RESEARCH OR ACOUSTICS OR HEALTH CARE SCIENCES SERVICES
OR INTEGRATIVE COMPLEMENTARY MEDICINE OR COMMUNICATION OR FOOD
SCIENCE TECHNOLOGY OR MEDICAL LABORATORY TECHNOLOGY OR
COMPUTER SCIENCE OR EVOLUTIONARY BIOLOGY OR GOVERNMENT LAW OR
GENERAL INTERNAL MEDICINE OR REHABILITATION OR LINGUISTICS OR
SURGERY OR AREA STUDIES OR EMERGENCY MEDICINE OR BIOMEDICAL
SOCIAL SCIENCES OR CHEMISTRY OR ENGINEERING OR FAMILY STUDIES OR
PATHOLOGY OR HISTORY OR WOMEN S STUDIES OR LITERATURE OR
DERMATOLOGY OR MYCOLOGY OR RADIOLOGY NUCLEAR MEDICINE MEDICAL
IMAGING OR SPECTROSCOPY OR CRIMINOLOGY PENOLOGY OR ENTOMOLOGY
OR SOCIAL SCIENCES OTHER TOPICS OR GEOGRAPHY OR PHYSIOLOGY OR
ANTHROPOLOGY OR MATERIALS SCIENCE OR AGRICULTURE OR BIOPHYSICS OR
MATHEMATICAL COMPUTATIONAL BIOLOGY OR ENVIRONMENTAL SCIENCES
ECOLOGY OR ANESTHESIOLOGY OR OPHTHALMOLOGY OR ARTS HUMANITIES
OTHER TOPICS OR INFECTIOUS DISEASES OR AUDIOLOGY SPEECH LANGUAGE
PATHOLOGY OR BIOTECHNOLOGY APPLIED MICROBIOLOGY OR BIODIVERSITY
CONSERVATION OR GENETICS HEREDITY OR LEGAL MEDICINE OR
MATHEMATICS OR RESEARCH EXPERIMENTAL MEDICINE OR NUCLEAR SCIENCE
TECHNOLOGY OR CELL BIOLOGY OR PHYSICS OR ORTHOPEDICS OR POLYMER
SCIENCE OR RHEUMATOLOGY OR SOCIAL ISSUES OR GERIATRICS
GERONTOLOGY OR SOCIOLOGY OR TELECOMMUNICATIONS OR LIFE SCIENCES
BIOMEDICINE OTHER TOPICS OR OTORHINOLARYNGOLOGY OR URBAN STUDIES
OR VETERINARY SCIENCES OR PARASITOLOGY OR VIROLOGY OR SCIENCE
TECHNOLOGY OTHER TOPICS ):
May 2013
1470
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Extensive literature search as preparatory work for the safety assessment of caffeine
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
TOTAL NUMBER RETRIEVED
NUMBER
OF
DUPLICATES
REMOVED
NUMBER
UNDERGOING
PRIMARY SCREENING - TITLES
NUMBER
UNDERGOING
PRIMARY
SCREENING
ABSTRACTS
Biosis Previews (1997 – 2008)
TS=(caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster OR
rockstar OR "energy drink*") AND TS=("breast milk" OR baby OR babies OR infant* OR
child* OR adolescent* OR adult* OR female OR male OR pregnan* OR lactating OR woman
OR women OR man OR men) AND TS=("physical exercise" OR "side effect" OR "dose
response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*"
OR *toxi* OR endurance OR exercise OR performance OR behaviour OR attention OR psych*
OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR interaction) NOT
TS=(rat* OR mouse OR mice)
Refined by: [excluding] Research Areas=( CELL BIOLOGY OR PHYSICS OR NUTRITION
DIETETICS OR MARINE FRESHWATER BIOLOGY OR OPHTHALMOLOGY OR
RHEUMATOLOGY OR EDUCATION EDUCATIONAL RESEARCH OR LIFE SCIENCES
BIOMEDICINE OTHER TOPICS OR INSTRUMENTS INSTRUMENTATION OR
DENTISTRY ORAL SURGERY MEDICINE OR BIODIVERSITY CONSERVATION OR
ENGINEERING OR FOOD SCIENCE TECHNOLOGY OR VETERINARY SCIENCES OR
EVOLUTIONARY BIOLOGY OR HEMATOLOGY OR PHILOSOPHY OR ENTOMOLOGY
OR HISTORY OR SURGERY OR OTORHINOLARYNGOLOGY OR SCIENCE
TECHNOLOGY OTHER TOPICS OR DERMATOLOGY OR ANATOMY MORPHOLOGY
OR GERIATRICS GERONTOLOGY OR BUSINESS ECONOMICS OR MATHEMATICAL
COMPUTATIONAL BIOLOGY OR COMMUNICATION OR GENETICS HEREDITY OR
ANESTHESIOLOGY OR GOVERNMENT LAW OR HEALTH CARE SCIENCES
SERVICES OR INTEGRATIVE COMPLEMENTARY MEDICINE OR PARASITOLOGY OR
LINGUISTICS OR LEGAL MEDICINE OR MEDICAL LABORATORY TECHNOLOGY OR
CHEMISTRY OR PALEONTOLOGY OR PHYSIOLOGY OR PATHOLOGY OR
REHABILITATION OR ENVIRONMENTAL SCIENCES ECOLOGY OR RADIOLOGY
NUCLEAR MEDICINE MEDICAL IMAGING OR AUDIOLOGY SPEECH LANGUAGE
PATHOLOGY OR GENERAL INTERNAL MEDICINE OR ANTHROPOLOGY OR
FORESTRY OR AGRICULTURE OR ALLERGY OR MATERIALS SCIENCE OR
INFECTIOUS DISEASES OR SOCIOLOGY OR METEOROLOGY ATMOSPHERIC
SCIENCES )
May 2013
1082
Pubmed
(caffein*[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR
"red bull" OR monster OR rockstar OR "energy drink*"[Title/Abstract]) AND (("breast milk"
OR baby OR babies OR infant* OR child* OR adolescent* OR adult* OR female OR male OR
pregnan* OR lactating OR woman OR women OR man OR men[MeSH Terms])) OR ("breast
milk" OR baby OR babies OR infant* OR child* OR adolescent* OR adult* OR female OR
male OR pregnan* OR lactating OR woman OR women OR man OR men[Title/Abstract]) AND
(("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR
sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*"
OR fertility OR reproductive OR interaction[MeSH Terms])) OR ("physical exercise" OR "side
effect" OR "dose response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR
"health effect*" OR *toxi* OR endurance OR exercise OR performance OR behaviour OR
attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR
interaction[Title/Abstract]) Filters: Publication date from 1997/01/01 to 2013/12/31; Humans:
May 2013
6361
14573
2954
11319
2111
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
28
Extensive literature search as preparatory work for the safety assessment of caffeine
Table 16: Information source form – question b) adverse effects of caffeine in
combination with alcohol
EFSA SYSTEMATIC REVIEW
EFSA REFERENCE
INFORMATION SCIENTIST
STUDY QUESTION
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK FOR THE SAFETY
ASSESSMENT OF CAFFEINE
RC/EFSA/NUTRI/2013/01
LINI ASHDOWN
Question b) adverse effects of caffeine in combination with alcohol
Scopus
(TITLE-ABS-KEY((caffein* OR coffee OR tea OR chocolate OR cola OR {energy shot} OR
{red bull} OR monster OR rockstar OR {energy drink} AND alcohol)) AND TITLE-ABSKEY((adult OR adolescent OR female OR male OR wom?n OR man OR men) AND NOT
(baby OR babies OR child* OR infant*)) AND TITLE-ABS-KEY({physical exercise} OR {side
effect} OR {dose response} OR safety OR dance OR dancing OR sport OR {adverse effect} OR
{health effect} OR *toxi* OR endurance OR exercise OR performance OR behaviour OR
attention OR psych* OR cancer OR cardio* OR {birth defect} OR fertility OR reproductive OR
interaction) AND NOT TITLE-ABS-KEY(rat* OR mouse OR mice)) AND SUBJAREA(mult
OR agri OR bioc OR immu OR neur OR phar OR mult OR medi OR nurs OR vete OR dent OR
heal OR mult OR arts OR busi OR deci OR econ OR psyc OR soci) AND
(EXCLUDE(SUBJAREA,
"AGRI")
OR
EXCLUDE(SUBJAREA,
"SOCI")
OR
EXCLUDE(SUBJAREA,
"ENVI")
OR
EXCLUDE(SUBJAREA,
"CHEM")
OR
EXCLUDE(SUBJAREA,
"DENT")
OR
EXCLUDE(SUBJAREA,
"MATH")
OR
EXCLUDE(SUBJAREA,
"DECI")
OR
EXCLUDE(SUBJAREA,
"CENG")
OR
EXCLUDE(SUBJAREA,
"ECON")
OR
EXCLUDE(SUBJAREA,
"ARTS")
OR
EXCLUDE(SUBJAREA,
"ENGI")
OR
EXCLUDE(SUBJAREA,
"PHYS")
OR
EXCLUDE(SUBJAREA,
"BUSI")
OR
EXCLUDE(SUBJAREA,
"COMP")
OR
EXCLUDE(SUBJAREA, "ENER") OR EXCLUDE(SUBJAREA, "MATE")) AND (LIMITTO(PUBYEAR, 2013) OR LIMIT-TO(PUBYEAR, 2012) OR LIMIT-TO(PUBYEAR, 2011)
OR LIMIT-TO(PUBYEAR, 2010) OR LIMIT-TO(PUBYEAR, 2009) OR LIMITTO(PUBYEAR, 2008) OR LIMIT-TO(PUBYEAR, 2007) OR LIMIT-TO(PUBYEAR, 2006)
OR LIMIT-TO(PUBYEAR, 2005) OR LIMIT-TO(PUBYEAR, 2004) OR LIMITTO(PUBYEAR, 2003) OR LIMIT-TO(PUBYEAR, 2002) OR LIMIT-TO(PUBYEAR, 2001)
OR LIMIT-TO(PUBYEAR, 2000) OR LIMIT-TO(PUBYEAR, 1999) OR LIMITTO(PUBYEAR, 1998) OR LIMIT-TO(PUBYEAR, 1997)):
May 2013
849
Web of science
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster
OR rockstar OR "energy drink*") AND alcohol) AND TS=((adult* OR adolescent* OR female
OR male OR woman OR women OR man OR men) NOT (baby OR babies OR child* OR
infant*)) AND TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR
dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxic* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR
cardio* OR "birth defect*" OR fertility OR reproductive OR interaction) NOT TS=(rat* OR
mouse OR mice)
Refined by: [excluding] Research Areas=( NUTRITION DIETETICS OR FOOD SCIENCE
TECHNOLOGY OR REHABILITATION OR GENETICS HEREDITY OR SCIENCE
TECHNOLOGY OTHER TOPICS OR RHEUMATOLOGY OR TRANSPORTATION OR
WOMEN S STUDIES OR CELL BIOLOGY OR HEALTH CARE SCIENCES SERVICES OR
CHEMISTRY OR PHYSIOLOGY OR CRIMINOLOGY PENOLOGY OR ENGINEERING
OR BIOTECHNOLOGY APPLIED MICROBIOLOGY OR ENTOMOLOGY OR
DERMATOLOGY OR GOVERNMENT LAW OR GENERAL INTERNAL MEDICINE OR
EDUCATION EDUCATIONAL RESEARCH OR INFECTIOUS DISEASES OR MEDICAL
LABORATORY TECHNOLOGY
OR
LEGAL MEDICINE
OR
RESEARCH
EXPERIMENTAL MEDICINE OR OPHTHALMOLOGY OR SURGERY OR
OTORHINOLARYNGOLOGY OR ANTHROPOLOGY OR PARASITOLOGY OR
BUSINESS ECONOMICS OR PATHOLOGY OR DENTISTRY ORAL SURGERY
MEDICINE OR RADIOLOGY NUCLEAR MEDICINE MEDICAL IMAGING OR
ENVIRONMENTAL SCIENCES ECOLOGY OR RELIGION OR GERIATRICS
GERONTOLOGY OR INTEGRATIVE COMPLEMENTARY MEDICINE OR SOCIAL
ISSUES OR BIOCHEMISTRY MOLECULAR BIOLOGY OR LIFE SCIENCES
BIOMEDICINE OTHER TOPICS OR SOCIAL SCIENCES OTHER TOPICS OR NURSING
OR ORTHOPEDICS OR SOCIOLOGY OR EMERGENCY MEDICINE )
May 2013
314
Biosis Previews (1997 – 2008)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot*" OR "red bull" OR monster
OR rockstar OR "energy drink*") AND alcohol) AND TS=((adult* OR adolescent* OR female
OR male OR woman OR women OR man OR men) NOT (baby OR babies OR child* OR
infant*)) AND TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR
dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxic* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
29
Extensive literature search as preparatory work for the safety assessment of caffeine
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
TOTAL NUMBER RETRIEVED
NUMBER
OF
DUPLICATES
REMOVED
NUMBER
UNDERGOING
PRIMARY SCREENING - TITLES
NUMBER
UNDERGOING
PRIMARY
SCREENING
ABSTRACTS
cardio* OR "birth defect*" OR fertility OR reproductive OR interaction) NOT TS=(rat* OR
mouse OR mice)
Refined by: [excluding] Research Areas=( SCIENCE TECHNOLOGY OTHER TOPICS OR
DENTISTRY ORAL SURGERY MEDICINE OR ENVIRONMENTAL SCIENCES
ECOLOGY OR PHYSIOLOGY OR MATHEMATICAL COMPUTATIONAL BIOLOGY OR
ANTHROPOLOGY OR LIFE SCIENCES BIOMEDICINE OTHER TOPICS OR
HEMATOLOGY OR ORTHOPEDICS OR LEGAL MEDICINE OR GERIATRICS
GERONTOLOGY OR OPHTHALMOLOGY OR SURGERY OR BIOCHEMISTRY
MOLECULAR BIOLOGY OR INFECTIOUS DISEASES OR ANATOMY MORPHOLOGY
OR SOCIOLOGY OR BUSINESS ECONOMICS OR FOOD SCIENCE TECHNOLOGY OR
CELL BIOLOGY OR ENTOMOLOGY OR MEDICAL LABORATORY TECHNOLOGY OR
DERMATOLOGY OR HISTORY OR PATHOLOGY OR GENERAL INTERNAL MEDICINE
OR HEALTH CARE SCIENCES SERVICES OR REHABILITATION OR RADIOLOGY
NUCLEAR MEDICINE MEDICAL IMAGING OR RHEUMATOLOGY OR GENETICS
HEREDITY ):
May 2013
210
Pubmed
((caffein*[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR cola OR "energy
shot*" OR "red bull" OR monster OR rockstar OR "energy drink*") AND (alcohol[MeSH
Terms]) OR alcohol[Title/Abstract]) AND (((adult* OR adolescent* OR female OR male OR
woman OR women OR man OR men[MeSH Terms])) NOT (baby OR babies OR child* OR
infant*[MeSH Terms]) OR ((adult* OR adolescent* OR female OR male OR woman OR
women OR man OR men[Title/Abstract])) NOT (baby OR babies OR child* OR
infant*[Title/Abstract])) AND (("physical exercise" OR "side effect" OR "dose response" OR
safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR
cardio* OR "birth defect*" OR fertility OR reproductive OR interaction[MeSH Terms])) OR
("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR
sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*"
OR fertility OR reproductive OR interaction[Title/Abstract]) Filters: Publication date from
1997/01/01 to 2013/12/31; Humans:
May 2013
1137
2510
501
2009
247
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
30
Extensive literature search as preparatory work for the safety assessment of caffeine
Table 17: Information source form – Question c) adverse effects of caffeine in
combination with other substances in energy drinks
EFSA SYSTEMATIC REVIEW
EFSA REFERENCE
INFORMATION SCIENTIST
STUDY QUESTION
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK FOR THE SAFETY
ASSESSMENT OF CAFFEINE
RC/EFSA/NUTRI/2013/01
LINI ASHDOWN
Question c) adverse effects of caffeine in combination with other substances in energy
drinks
Scopus
(TITLE-ABS-KEY((caffein* OR coffee OR tea OR chocolate OR cola OR {energy shot} OR
{red bull} OR monster OR rockstar OR {energy drink}) AND (guarana OR taurine OR
glucuronolactone)) AND TITLE-ABS-KEY((child* OR adult* OR adolescent* OR pregnan*
OR lactating OR female OR male OR wom?n OR man OR men) AND NOT (baby OR babies
OR infant*)) AND TITLE-ABS-KEY({physical exercise} OR {side effect} OR {dose response}
OR safety OR dance OR dancing OR sport OR {adverse effect} OR {health effect} OR *toxi*
OR endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer
OR cardio* OR {birth defect} OR fertility OR reproductive OR interaction) AND NOT TITLEABS-KEY(rat* OR mouse OR mice)) AND SUBJAREA(mult OR agri OR bioc OR immu OR
neur OR phar OR mult OR medi OR nurs OR vete OR dent OR heal OR mult OR arts OR busi
OR deci OR econ OR psyc OR soci) AND (EXCLUDE(SUBJAREA, "AGRI") OR
EXCLUDE(SUBJAREA,
"CHEM")
OR
EXCLUDE(SUBJAREA,
"ENVI")
OR
EXCLUDE(SUBJAREA, "SOCI") OR EXCLUDE(SUBJAREA, "ARTS")) AND (LIMITTO(PUBYEAR, 2013) OR LIMIT-TO(PUBYEAR, 2012) OR LIMIT-TO(PUBYEAR, 2011)
OR LIMIT-TO(PUBYEAR, 2010) OR LIMIT-TO(PUBYEAR, 2009) OR LIMITTO(PUBYEAR, 2008) OR LIMIT-TO(PUBYEAR, 2007) OR LIMIT-TO(PUBYEAR, 2006)
OR LIMIT-TO(PUBYEAR, 2005) OR LIMIT-TO(PUBYEAR, 2004) OR LIMITTO(PUBYEAR, 2003) OR LIMIT-TO(PUBYEAR, 2002) OR LIMIT-TO(PUBYEAR, 2001)
OR LIMIT-TO(PUBYEAR, 2000) OR LIMIT-TO(PUBYEAR, 1998) OR LIMITTO(PUBYEAR, 1997)):
May 2013
69
Web of science
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull" OR monster OR
rockstar OR "energy drink" ) AND (guarana OR taurine OR glucuronolactone)) AND
TS=((child* OR adult* OR adolescent* OR pregnan* OR lactating OR female OR male OR
woman OR women OR man OR men) NOT (baby OR babies OR infant*)) AND TS=("physical
exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR sport OR
"adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR performance
OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility
OR reproductive OR interaction) NOT TS=(rat* OR mouse OR mice)
Refined by: [excluding] Research Areas=( NUTRITION DIETETICS OR BIOCHEMISTRY
MOLECULAR BIOLOGY OR EDUCATION EDUCATIONAL RESEARCH OR
BIOTECHNOLOGY APPLIED MICROBIOLOGY OR EMERGENCY MEDICINE OR
CHEMISTRY OR FOOD SCIENCE TECHNOLOGY OR HEALTH CARE SCIENCES
SERVICES OR INTEGRATIVE COMPLEMENTARY MEDICINE OR ORTHOPEDICS OR
NURSING OR GENERAL INTERNAL MEDICINE ):
May 2013
19
Biosis Previews (1997 – 2008)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull" OR monster OR
rockstar OR "energy drink" ) AND (guarana OR taurine OR glucuronolactone)) AND
TS=((child* OR adult* OR adolescent* OR pregnan* OR lactating OR female OR male OR
woman OR women OR man OR men) NOT (baby OR babies OR infant*)) AND TS=("physical
exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR sport OR
"adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR performance
OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility
OR reproductive OR interaction) NOT TS=(rat* OR mouse OR mice)
Refined by: [excluding] Research Areas=( MATHEMATICAL COMPUTATIONAL
BIOLOGY OR NUTRITION DIETETICS OR PHYSIOLOGY OR BIOCHEMISTRY
MOLECULAR BIOLOGY ):
7
Pubmed
(caffeine[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR cola OR "energy
shot*" OR "red bull" OR monster OR rockstar OR "energy drink*"[Title/Abstract]) AND
(((guarana OR taurine OR glucuronolactone[MeSH Terms])) OR (guarana OR taurine OR
glucuronolactone[Title/Abstract]) OR ((guarana OR taurine OR glucuronolactone[MeSH
Terms])) OR (guarana OR taurine OR glucuronolactone[Title/Abstract])) AND (((child* OR
adult* OR adolescent* OR pregnan* OR lactating OR female OR male OR woman OR women
OR man OR men[MeSH Terms])) NOT (baby OR babies OR infant*[MeSH Terms]) OR
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
31
Extensive literature search as preparatory work for the safety assessment of caffeine
Date accessed
Number of records retrieved
TOTAL NUMBER RETRIEVED
NUMBER
OF
DUPLICATES
REMOVED
NUMBER
UNDERGOING
PRIMARY SCREENING - TITLES
NUMBER
UNDERGOING
PRIMARY
SCREENING
ABSTRACTS
((child* OR adult* OR adolescent* OR pregnan* OR lactating OR female OR male OR woman
OR women OR man OR men[Title/Abstract])) NOT (baby OR babies OR
infant[Title/Abstract])) AND (("physical exercise" OR "side effect" OR "dose response" OR
safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*" OR *toxi* OR
endurance OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR
cardio* OR "birth defect*" OR fertility OR reproductive OR interaction[MeSH Terms])) OR
("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing OR
sport OR "adverse effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*"
OR fertility OR reproductive OR interaction[Title/Abstract]) Filters: Publication date from
1997/01/01 to 2013/12/31; Humans:
May 2013
43
138
24
114
24
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
32
Extensive literature search as preparatory work for the safety assessment of caffeine
Table 18: Information source form – Question d) adverse effects of caffeine in
combination with other substances in energy drinks and alcohol
EFSA SYSTEMATIC REVIEW
EFSA REFERENCE
INFORMATION SCIENTIST
STUDY QUESTION
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
Information source
Search terms
Date accessed
Number of records retrieved
EXTENSIVE LITERATURE SEARCH AS PREPARATORY WORK FOR THE SAFETY
ASSESSMENT OF CAFFEINE
RC/EFSA/NUTRI/2013/01
LINI ASHDOWN
Question d) adverse effects of caffeine in combination with other substances in energy
drinks and alcohol
Scopus
(TITLE-ABS-KEY((caffein* OR coffee OR tea OR chocolate OR cola OR {energy shift} OR
{red bull} OR monster OR rockstar OR {energy drink}) AND alcohol AND (guarana OR
taurine OR glucuronolactone)) AND TITLE-ABS-KEY((adult OR adolescent OR female OR
male OR wom?n OR man OR men) AND NOT (baby OR babies OR child* OR infant*)) AND
TITLE-ABS-KEY({physical exercise} OR {side effect} OR {dose response} OR safety OR
dance OR dancing OR sport OR {adverse effect} OR {health effect} OR *toxi* OR endurance
OR exercise OR performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR
{birth defect} OR fertility OR reproductive OR interaction) AND NOT TITLE-ABS-KEY(rat*
OR mouse OR mice)) AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR
mult OR medi OR nurs OR vete OR dent OR heal OR mult OR arts OR busi OR deci OR econ
OR psyc OR soci) AND (EXCLUDE(SUBJAREA, "AGRI") OR EXCLUDE(SUBJAREA,
"ARTS") OR EXCLUDE(SUBJAREA, "SOCI")) AND (EXCLUDE(SUBJAREA, "AGRI") OR
EXCLUDE(SUBJAREA, "ARTS") OR EXCLUDE(SUBJAREA, "SOCI")):
May 2013
16
Web of science
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull"OR monster OR
rockstar OR "energy drink") AND (guarana OR taurine OR glucuronolactone) AND alcohol)
AND TS=((adult* OR adolescent* OR pregnan* OR lactating OR female OR male OR woman
OR women OR man OR men) NOT (child* OR baby OR babies OR infant*)) AND
TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing
OR sport OR "adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*"
OR fertility OR reproductive OR interaction) NOT TS=(rat* OR mouse OR mice)
Refined by: [excluding] Research Areas=( FOOD SCIENCE TECHNOLOGY OR GENERAL
INTERNAL MEDICINE OR HEALTH CARE SCIENCES SERVICES OR
BIOTECHNOLOGY APPLIED MICROBIOLOGY OR NUTRITION DIETETICS OR
EDUCATION EDUCATIONAL RESEARCH OR ORTHOPEDICS OR EMERGENCY
MEDICINE ):
May 2013
8
Biosis Previews (1997 – 2008)
TS=((caffein* OR coffee OR tea OR chocolate OR "energy shot" OR "red bull"OR monster OR
rockstar OR "energy drink") AND (guarana OR taurine OR glucuronolactone) AND alcohol)
AND TS=((adult* OR adolescent* OR pregnan* OR lactating OR female OR male OR woman
OR women OR man OR men) NOT (child* OR baby OR babies OR infant*)) AND
TS=("physical exercise" OR "side effect" OR "dose response" OR safety OR dance OR dancing
OR sport OR "adverse effect*" OR "health effect*" OR *toxic* OR endurance OR exercise OR
performance OR behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*"
OR fertility OR reproductive OR interaction) NOT TS=(rat* OR mouse OR mice):
May 2013
1
Pubmed
((caffeine[MeSH Terms]) OR (caffein* OR coffee OR tea OR chocolate OR cola OR "energy
shot*" OR "red bull" OR monster OR rockstar OR "energy drink*"[Title/Abstract]) AND
((guarana OR taurine OR glucuronolactone[MeSH Terms])) OR (guarana OR taurine OR
glucuronolactone[Title/Abstract]) AND (alcohol[MeSH Terms]) OR alcohol[Title/Abstract])
AND (((adult* OR adolescent* OR female OR male OR woman OR women OR man OR
men[MeSH Terms])) NOT (baby OR babies OR child* OR infant*[MeSH Terms]) OR ((adult*
OR adolescent* OR female OR male OR woman OR women OR man OR men[Title/Abstract]))
NOT (baby OR babies OR child* OR infant*[Title/Abstract]) AND (("physical exercise" OR
"side effect" OR "dose response" OR safety OR dance OR dancing OR sport OR "adverse
effect*" OR "health effect*" OR *toxi* OR endurance OR exercise OR performance OR
behaviour OR attention OR psych* OR cancer OR cardio* OR "birth defect*" OR fertility OR
reproductive OR interaction[MeSH Terms])) OR ("physical exercise" OR "side effect" OR "dose
response" OR safety OR dance OR dancing OR sport OR "adverse effect*" OR "health effect*"
OR *toxi* OR endurance OR exercise OR performance OR behaviour OR attention OR psych*
OR cancer OR cardio* OR "birth defect*" OR fertility OR reproductive OR
interaction[Title/Abstract]) Filters: Publication date from 1997/01/01 to 2013/12/31; Humans:
May 2013
9
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
33
Extensive literature search as preparatory work for the safety assessment of caffeine
TOTAL NUMBER RETRIEVED
NUMBER
OF
DUPLICATES
REMOVED
NUMBER
UNDERGOING
PRIMARY SCREENING - TITLES
NUMBER
UNDERGOING
PRIMARY
SCREENING
ABSTRACTS
34
6
28
0
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
34
Extensive literature search as preparatory work for the safety assessment of caffeine
Figure 1: Number of articles retrieved for questions a) adverse health effects of
caffeine
Figure 2: Number of articles retrieved for question b) adverse health effects of caffeine
and alcohol
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
35
Extensive literature search as preparatory work for the safety assessment of caffeine
Figure 3: Number of articles retrieved for questions c) adverse health effect of caffeine
and substances in energy drinks
Figure 4: Number of articles retrieved for question d) adverse health effect of caffeine,
substances in energy drinks and alcohol
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
36
Extensive literature search as preparatory work for the safety assessment of caffeine
11. FORESEEN TIMETABLE
The foreseen timetable for the follow-up contract is shown in Figure 5 and the human resources need
to perform the task outlined in the specification document.
Figure 5: Gantt chart indicating the foreseen timetable for the follow-up contract
Month 1
Month 2
Month 3
Month 4
Month 5
Follow-up contract
Draft evidence report
1 (S) + 19 (J)
Interim telephone meeting
0.5 (J)
Final evidence report
22 (J) = 22 working days for a junior expert
1 (S) + 2.5 (J)
2 (S) = 2 working days for a senior expert
Work and delivery of draft
Teleconference with EFSA
Delivery of final report
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
37
Extensive literature search as preparatory work for the safety assessment of caffeine
APPENDIX 1
CODING MANUAL FOR CASE-CONTROL STUDIES
1) Is the Case Definition Adequate?
a) Requires some independent validation (e.g. >1 person/record/time/process to extract
information, or reference to primary record source such as x-rays or medical/hospital records)
b) Record linkage (e.g. ICD codes in database) or self-report with no reference to primary
record
c) No description
2) Representativeness of the Cases
a) All eligible cases with outcome of interest over a defined period of time, all cases in a
defined catchment area, all cases in a defined hospital or clinic, group of hospitals, health
maintenance organisation, or an appropriate sample of those cases (e.g. random sample)
b) Not satisfying requirements in part (a), or not stated.
3) Selection of Controls
This item assesses whether the control series used in the study is derived from the same population as
the cases and essentially would have been cases had the outcome been present.
a) Community controls (i.e. same community as cases and would be cases if had outcome)
b) Hospital controls, within same community as cases (i.e. not another city) but derived from a
hospitalised population
c) No description
4) Definition of Controls
a) If cases are first occurrence of outcome, then it must explicitly state that controls have no
history of this outcome. If cases have new (not necessarily first) occurrence of outcome, then
controls with previous occurrences of outcome of interest should not be excluded.
b) No mention of history of outcome
COMPARABILITY
1) Comparability of Cases and Controls on the Basis of the Design or Analysis
A maximum of 2 stars can be allotted in this category
Either cases and controls must be matched in the design and/or confounders must be adjusted
for in the analysis. Statements of no differences between groups or that differences were not
statistically significant are not sufficient for establishing comparability. Note: If the odds ratio
for the exposure of interest is adjusted for the confounders listed, then the groups will be
considered to be comparable on each variable used in the adjustment.
There may be multiple ratings for this item for different categories of exposure (e.g. ever vs.
never, current vs. previous or never)
Age = , Other controlled factors =
EXPOSURE
1) Ascertainment of Exposure
Allocation of stars as per rating sheet
2) Non-Response Rate
Allocation of stars as per rating sheet
CODING MANUAL FOR COHORT STUDIES
Ref: Ricardo-AEA/R/ED58662/Issue Number 1
38
Extensive literature search as preparatory work for the safety assessment of caffeine
1) Representativeness of the Exposed Cohort
Item is assessing the representativeness of exposed individuals in the community, not the
representativeness of the sample of women from some general population. For example, subjects
derived from groups likely to contain middle class, better educated, health oriented women are likely
to be representative of postmenopausal estrogen users while they are not representative of all women
(e.g. members of a health maintenance organisation (HMO) will be a representative sample of
estrogen users. While the HMO may have an under-representation of ethnic groups, the poor, and
poorly educated, these excluded groups are not the predominant usersusers of estrogen).
Allocation of stars as per rating sheet
2) Selection of the Non-Exposed Cohort
Allocation of stars as per rating sheet
3) Ascertainment of Exposure
Allocation of stars as per rating sheet
4) Demonstration That Outcome of Interest Was Not Present at Start of Study
In the case of mortality studies, outcome of interest is still the presence of a disease/incident, rather
than death. That is to say that a statement of no history of disease or incident earns a star.
COMPARABILITY
1) Comparability of Cohorts on the Basis of the Design or Analysis
A maximum of 2 stars can be allotted in this category
Either exposed and non-exposed individuals must be matched in the design and/or
confounders must be adjusted for in the analysis. Statements of no differences between
groups or that differences were not statistically significant are not sufficient for establishing
comparability. Note: If the relative risk for the exposure of interest is adjusted for the
confounders listed, then the groups will be considered to be comparable on each variable used
in the adjustment.
There may be multiple ratings for this item for different categories of exposure (e.g. ever vs.
never, current vs. previous or never)
Age = , Other controlled factors =
OUTCOME
1) Assessment of Outcome
For some outcomes (e.g. fractured hip), reference to the medical record is sufficient to satisfy the
requirement for confirmation of the fracture. This would not be adequate for vertebral fracture
outcomes where reference to x-rays would be required.
a) Independent or blind assessment stated in the paper, or confirmation of the outcome by
reference to secure records (x-rays, medical records, etc.)
b) Record linkage (e.g. identified through ICD codes on database records)
c) Self-report (i.e. no reference to original medical records or x-rays to confirm the outcome)
d) No description.
2) Was Follow-Up Long Enough for Outcomes to Occur
An acceptable length of time should be decided before quality assessment begins (e.g. 5 yrs. for
exposure to breast implants)
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Extensive literature search as preparatory work for the safety assessment of caffeine
3) Adequacy of Follow Up of Cohorts
This item assesses the follow-up of the exposed and non-exposed cohorts to ensure that losses are not
related to either the exposure or the outcome.
Allocation of stars as per rating sheet
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Extensive literature search as preparatory work for the safety assessment of caffeine
APPENDIX 2
Preliminary peer review of search strategy presented by the contractor for the assessment of
caffeine – Comments discussed at the kick of meeting
M-2013-0067, EFSA-Q-2013-00200
Ricardo-AEA ref RC/EFSA/NUTRI/2013/01
We went through the contractor proposal; we analysed in detail the Appendix 2 and we have the
following remarks:
Search strategy proposed using the Scopus database:

The time span is too limited, we suggest to include all years;

The inclusion and or exclusion of subject areas should be selected according to the scientific
area (please check the use of ‘vete’ and ‘arts’ and ‘busi’). Due to the fact that the toxicology
aspect is not considered the veterinary subject area should not be included, as example;

We suggest to follow the four overall objectives summarised at point 1.2 page 1 and 2 of the
technical specification. This would allow to identify the relevant evidence set on the basis of
the specific population and the health effect substances linked to the indicated substances;

Regarding points c) and d) of the objectives we suggest to delete the single ingredients of the
‘energy drinks’ and considering only the major ingredients as ‘taurine’ NB at the kick off
meeting the inclusion of ‘glucoronolactone’ was also requested.
Search strategy proposed for Web of Knowledge (WoK) we have the same remarks as Scopus
search at point 3; furthermore is suitable to indicate the single databases included in WoK.
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Extensive literature search as preparatory work for the safety assessment of caffeine
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