The brochure 'Coffee and the Brain' discusses the effects of coffee and caffeine on headache, cognition, and cognitive aging, summarizing numerous scientific studies. It provides information on how caffeine can act as an analgesic, affect cognitive functions, and potentially impact age-related cognitive decline. Additionally, the document highlights the relationship between caffeine consumption, headache types, and cognitive performance while encouraging readers to stay informed through their newsletter and website.

1. Coffee
and the brain

2. Colophon
Publishing
Coffee and Health Information Bureau
Design and printing
Stimio Communicatie & Presentatie, Tiel, The Netherlands
Copyright
© April 2011, Coffee and Health Information Bureau, Rijswijk, The Netherlands
Availability
The brochure ‘Coffee and the brain‘ can be downloaded free of charge from
www.koffieengezondheid.nl. From here, you can also download the brochure
‘Coffee, heart and blood vessels’ (2007) and ‘Coffee, stomach, intestines
and liver’ (2009) or you can register for the email newsletter. This free Dutch
newsletter keeps you updated on the most recent scientific information on
coffee and health and is published 4 times a year.
Coffee and Health Information Bureau
(Voorlichtingsbureau voor Koffie en Gezondheid)
P.O. Box 161, 2280 AD Rijswijk
Tel. : + 31 (0)70 - 3365163
Fax : + 31 (0)70 - 3365167
E-mail: info@koffieengezondheid.nl
Website: www.koffieengezondheid.nl

3. ‘Coffee and the brain’- Contents
Page
Introduction 5-6
1 Coffee, caffeine and headache
Headache 7
Caffeine and headache 8-9
Caffeine withdrawal, fasting and weekend headache 9-13
Headache and fluid balance 13
References 14
2 Coffee, caffeine en cognition
Cognitive function 15-16
Caffeine and the brain 16-17
Coffee and alertness 17-19
Coffee and attention, concentration and memory 20-21
Coffee and qualification caffeine effect 21-22
Coffee and mood 23-24
Coffee and sleep 24
References 26-27
3 Coffee and cognitive aging
Cognitive aging, MCI and dementia 29
Coffee and acute effects on cognitive aging 29-30
Coffee and long term effects on cognitive aging 30-31
Coffee and Alzheimer’s disease 31-32
Coffee and Parkinson’s disease 32-33
References 34
Study of coffee and health 35
Coffee and the brain | 3

4. 4|

5. Introduction
Coffee is not only appreciated for its taste and aroma, but also for its effect on
the mental performance. It’s widely known that coffee can help to stay alert, but
how much coffee do you have to drink before you notice any effect and what is
known about the mechanism? What is the effect of coffee on headache, does it
alleviate the symptoms or not? Coffee adds to cognition, but could coffee coun-
teract age-related cognitive decline? This brochure deals with common ques-
tions about coffee in relation to the effect on the brain and provides a summary
of results of innumerable scientific studies.
The Coffee and Health Information Bureau (Voorlichtingsbureau voor Koffie
en Gezondheid) sought assistance from scientists who are well known for their
knowledge and experience in this research area. We would like to take this op-
portunity to thank them for their excellent contribution and cooperation in the
preparation of this brochure.
- Dr. Astrid Nehlig (research director, Faculté de Médécine, French National
Institute for Health and Medical Research, INSERM, Strasbourg, France)
- Dr. Monicque Lorist (associate professor, Faculteit der Gedrags- en
Maatschappijwetenschappen, Rijksuniversiteit Groningen, The Netherlands)
- Dr. Jan Snel (associate professor UHD psychofysiology, Universiteit van
Amsterdam, The Netherlands)
Coffee and the brain | 5

6. Research on the effects of coffee and/or caffeine on cognitive aging is highly
relevant and very timely due to the aging of the population. Some topics do not
have yet an unequivocal answer, because the amount of research is currently
insufficient. The Information Bureau will continue to closely monitor scientific
developments and inform you on new studies in our email newsletter and on
our website www.koffieengezondheid.nl.
If after reading of this brochure you still have questions or comments, we will be
pleased to hear from you. You can also order Dutch copies of the brochure free
of charge or download the Dutch or English version at www.koffieengezond-
heid.nl.
Coffee and Health Information Bureau
(Voorlichtingsbureau voor Koffie en Gezondheid)
6|

7. 1 Coffee, caffeine and headache
1 What is headache?
Headaches occur as a response to daily life situations like stress, fatigue, lack
of sleep, hunger or weather changes. Despite the fact that headaches are
extremely common, almost 90% of men and 95% of women have at least one
headache a year, they are not fully understood. Neither the skull nor the brain is
sensitive to pain, however, both are surrounded by pain-sensitive membranes.
Abnormalities in these membranes or nearby muscles, blood vessels, or nerves,
either alone or in combination, are thought to be the source of most headache
pain. Also changes in estrogen level can make headaches worse (Harvard Health
Publications, 2010)
2 What are the common types of headache?
The International Classification of Headache Disorders (ICHD) separates primary
headache disorders from the secondary headache disorders. The former include,
most importantly, migraine, tension type headache and cluster headache. The
latter is attributed to causative disorders like a head or neck trauma, a vascular
disorder, a substance (e.g. medication overuse), substance withdrawal (e.g.
caffeine) or a disorder of homeostasis (e.g. fasting) (IHS, 2004; Olesen, 2004).
Tension type headache and migraine are the most common types of headache;
however, mixed headaches do occur.
Coffee and the brain | 7

8. 3 Can caffeine consumption relief headache symptoms?
Caffeine may act as analgesic for headache and the use of caffeine as constitu-
ent of analgesics dates back to 1875. Nowadays caffeine is an essential com-
ponent of numerous widely consumed medications for the relief of headache
symptoms (Shapiro, 2008; Nehlig, 2004). A meta-analysis of 30 clinical trials
indicates that adding caffeine to an analgesic agent reduces the dosage needed
of that analgesic agent by 40% to achieve equivalent analgesia (Laska, 1984).
A further meta-analysis of randomized controlled trials of simple analgesics
taken with or without caffeine indicates that addition of caffeine promotes a
significant headache relief (Zhang, 2001). Studies on the efficacy and safety
of over the counter (OTC) headache combination analgesics were reviewed in
2010 (Anneken, 2010). Treatment of migraine and tension-type headache,
was shown more effective using a combination of acetylsalicyclic acid (ASA),
acetaminophen and caffeine (100-150 mg) than monotherapy with either of
these substances. Adding caffeine was associated with an increased analgesic
effect, which is often unachievable via increased dosages of mono-analgesics
because of their flat dose-effect relationships. Moreover, mixed analgesics co-
formulated with caffeine provide the same efficacy using a lower analgesic dose,
thus potentially reducing dose dependent adverse effects.
4 Can you get a headache of too much caffeine?
Conflicting results have been found in population studies evaluating the
association between high caffeine consumption and the prevalence of headache
and chronic frequent headache (CFH), in particular. CFH is the collective term
for primary headaches occurring on more than 14 days per month for at least
3 months. In a general population study in the Netherlands, CHF was associated
with overuse of analgesics, psychiatric disorders, smoking, sleeping problems,
a history of head and neck trauma and low educational level, but not with
8|

9. caffeine use (Wiendels, 2006). In this study, the average intake of caffeine was
7 consumptions a day, including coffee, tea, ice tea and cola. However, in a
large cross sectional study in Norway, high caffeine consumption (> 540 mg/d)
was associated with increased prevalence of infrequent headache, whereas
chronic headache was less likely among individuals with high caffeine consump-
tion (Hagen, 2009). According to the authors these results may indicate that
high caffeine consumption changes chronic headache into infrequent headache
due to the analgesic properties of caffeine, or that chronic headache sufferers
tend to avoid the intake of caffeine. This is in line with the conclusion of the
review by Shapiro (2008), stating that caffeine can exert potent pharmacologic
effects that can generate or alleviate headache, depending on the site of action,
dosage and timing of exposure.
5 Can you get a headache if you stop drinking coffee?
Abrupt cessation of regular caffeine consumption may result in headache
among sensitive individuals. The headache generally resolves within a few days
or at most one week after consumption stopped. In addition, the headache
disappears when caffeine consumption is resumed (Nehlig, 2004; Scher, 2004).
Caffeine withdrawal headache are not experienced by all individuals; prevalence
figures vary between 0.4% and 50% (Shapiro, 2008). Caffeine withdrawal head-
ache can be easily prevented by reducing caffeine consumption gradually in the
days before cessation of consumption, for instance in case of (religious) fasting
or a surgical procedure.
Coffee and the brain | 9

10. 6 Are fasting headaches related to caffeine consumption?
Fasting of food is an important precipitating factor of headache and the
probability of onset increases directly with the duration of fasting. Fasting
headache is one of the most common forms of secondary headache, but much
remains to be explained about the underlying patho-physiological mechanisms.
Hypoglycemia (low blood glucose level) and caffeine withdrawal are suggested
as potential triggers, although fasting headache may occur even when there
is no hypoglycemia and in individuals who do not normally consume caffeine
(Torelli, 2009).
Headaches after fasting before and after surgical procedures are found to be
related to habitual caffeine consumption (Nehlig, 2004). A study of prolonged
fasting suggests that other factors like abstinence from water or foods, genetic
background or cultural factors may contribute more strongly to fasting induced
headache, but not fully exclude caffeine as a factor (Shapiro, 2008).
7 What is meant by 'weekend headache'?
Some people experience headaches in particularly on weekend mornings.
Different explanations are proposed for this so called weekend headache
(Couturier, 1992; Nehlig, 2004; Shapiro, 2004). It might be related to the
change in stress level, or sudden disappearance of stress during the weekend.
Change in the pattern of sleep, often longer than usual, has also been suggest-
ed as an important cause. Other possible causes are increased consumption of
alcohol at the beginning of the weekend, or missing breakfast because of sleep-
ing late. Weekend headaches are also linked to a delay (sleep later) or avoidance
of caffeine consumption during weekend mornings (see also question 5).
10 |

11. Coffee intake
Caffeine is naturally present in coffee, tea and cocoa, and added in small quanti-
ties to some soft drinks. Consumption of coffee varies largely between countries.
In Europe the consumption of coffee ranges from 1.5 to 11.9 kg coffee per
person per year. The highest consumption occurs in Scandinavia (Finland 11.9
kg coffee/person/year), and the lowest consumption in Poland (1.5 kg coffee/
person/year) (International Coffee Organization, 2010).
The amount of caffeine per cup of coffee varies with the type of coffee used
(Arabica or Robusta), the brewing method (e.g. drip filter, instant, espresso,
boiled) and the brewing strength (in the Netherlands on average 7 grams per
cup). The table on page 12 summarizes average values of caffeine per product.
8 Can weekend headache be prevented and if yes how?
If someone is prone to weekend headache, there are several steps to prevent
or diminish the headaches.
• Identify triggers (see question 6 and 7) so these can be avoided.
• In case of habitual caffeine consumption, include a cup of coffee for
breakfast during the weekends.
• Keep a regular schedule that includes a full night’s rest, balanced meals
and exercise during the weekends (Harvard Health Publications, 2010).
Coffee and the brain | 11

14. References
• American Psychiatric Association (1994, 2000). Diagnostic and Statistical Manual of Mental
Disorders, 4th ed. (DSM-IV-TR) APA Press, Washington DC.
• Anneken K e.a. (2010). Efficacy of fixed combinations of acetylsalicyclic acid, acetaminophen and
caffeine in the treatment of idiopathic headache: a review. Eur J Neurol, 17: 534-540.
• Armstrong LE e.a. (2007). Fluid, Electrolyte, and Renal Indices of Hydration During 11 Days of
Controlled Caffeine Consumption. Int J Sport Nutr Exerc Met, 15: 252-265.
• Couturier EGM (1992). Weekend attacks in migraine patients: caused by caffeine withdrawal?
Cephalalgia, 12: 99-100.
• Dutch Nutrition Center (2011), www.voedingscentrum.nl.
• Hagen K e.a. (2009). High dietary caffeine consumption is associated with a modest increase in
headache prevalence: results from the Head-HUNT Study. J Headache Pain, 10: 153-159.
• Harvard Health Publications (2010). A Harvard Medical School Special Health Report. Headaches
Relieving and preventing migraine and other headaches.
• IHS - Headache Classification Subcommittee of the International Headache Society (2004). The
International Classification of Headache Disorders. Cephalalgia, 24, S1: 1-160.
• Institute of Medicine of National Academies; Food and Nutrition Board. Dietary Reference Intake for
Water, Potassium, Sodium, Chloride and Sulfate. The National Academic Press (2004). www.nap.edu.
• International Coffee Organization (2010). Monthly Coffee Market Report, Oct. 2010. www.ico.org.
• Kolasa KM e.a. (2009). Hydration and Health Promotion. Nutrition Today, 44: 190-201.
• Laska EM e.a. (1984). Caffeine as an analgesic adjuvant. JAMA 251: 1711-1718.
• Nehlig A (2004). Caffeine and Headache: Relationship with the effects of caffeine on cerebral
blood flow. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton,
Florida: 175-186.
• Nehlig A e.a. (2010). SPECT assessment of brain activation induced by caffeine: no effect on areas
involved in dependence. Dialogues Clin Neurosci, 12: 255-263.
• Olesen J and Steiner TJ (2004). The international classification of headache disorders, 2nd edn
(ICDH-II). J Neurol Neurosurg Psychiatry, 75: 807-808.
• Ruxton CHS (2008). The impact of caffeine on mood, cognitive function, performance and
hydration: a review of benefits and risks. Nutr Bull, 33: 15-25.
• Satel S (2006). Is caffeine addictive? A review of the literature. Am J Drug Alcohol Abuse,
32: 493-502.
• Scher AI e.a. (2004). Caffeine as a risk factor for chronic daily headache. A population based study.
Neurology, 63: 2022-2027.
• Shapiro RE (2008). Caffeine and Headaches. Current Pain Headache Rep, 12: 311-315.
• Torelli P e.a. (2009). Fasting Headache: A review of the literature and new hypotheses. Headache,
49: 744-752.
• Wiendels NJ e.a. (2006). Chronic frequent headache in the general population: prevalence and
associated factors. Cephalalgia, 26: 1434-1442.
• World Health Organization (WHO, 1994). The ICD-10 classification of mental and behavioral
disorders. WHO, Geneva.
• Zhang WY e.a. (2001). A benefit-risk assessment of caffeine as an analgesic adjuvant. Drug Saf,
24: 1127-1142.
14 |

15. 2 Coffee, caffeine and cognition
1 What is cognitive function?
The word ‘cognition’ comes from the Latin word ‘cognoscere’ which means
‘to know’ or ‘to recognize’ (Nehlig, 2010). Cognitive function is a general term
that is used to describe a great variety of different brain mediated functions and
processes. These brain functions allow us to perceive, evaluate, store, manipulate
and use information from external sources, like our environment, and internal
sources, like experience, memory and thoughts, and respond to that informa-
tion (Schmitt, 2005). Cognitive functions can be clustered in six main domains:
executive functions, memory functions, attention functions, perceptual functions,
psychomotor functions and language skills (see schematic representation on
page 16). These distinct functions often act together to produce actual cogni-
tive performance output. For example, efficient storage of new information in
the long-term memory cannot occur without proper attention for the relevant
information, adequate perceptual processing, and the executive learning strate-
gies. Besides, cognitive functioning is mediated by a number of other factors
which are not considered to be cognitive functions themselves. A key mediator is
the level of central arousal, which can be roughly described as the level of mental
energy. Mood state (sad, happy) is also known to modulate cognitive function, as
well as motivation and physical well-being.
Coffee and the brain | 15

17. In doses normally consumed, caffeine blocks inhibitory A1 and A2A receptors,
and hence increases central nervous system activity (Nehlig, 1992; Fredholm,
1999; Daly, 2004; Fisone, 2004; Tieges, 2007).
3 What is the effect of coffee or caffeine on alertness?
It is well-known that caffeine ingestion leads to dose dependent increased
energetic arousal, which reflects alertness and mental energy (Nehlig, 2010).
However, the relationship between the level of arousal and task performance is
not a linear one, but follows an inverted U-curve: performance decrements can
occur due to under- and over-arousal (Schmitt, 2005). Furthermore, the optimal
arousal level is thought to vary between different cognitive tasks (Van Boxtel,
2004).
Some of the most sensitive functions for increased arousal are reaction time and
vigilance. There is a large number of scientific studies showing that consump-
tion of caffeinated foods and beverages is associated with increased alertness,
improvements of reaction time and vigilance performance. Most of this research
includes computer tests which have the advantage of a standardized presenta-
tion and accurate and detailed response capture. The level of performance is
usually measured in terms of speed (e.g. simple reaction time) and accuracy
(the amount of correct information), free recall of information or selective visual
tasks. The stimulating effect of caffeine consumption on alertness and perform-
ance efficiency was demonstrated for a variety of tasks (Lorist, 1994, 1996;
Ruijter, 1999, 2000; Smit, 2000, 2005a; Smith, 2005b; Haskell, 2005; Hewlett,
2007; Olson, 2010). EEG data support the stimulating effect of caffeine on the
brain (Lorist, 2003).
Coffee and the brain | 17

18. How is caffeine metabolized in the body?
After drinking a cup of coffee, caffeine is rapidly and efficiently absorbed from
the gastro intestinal tract and peak plasma concentrations are reached between
15 and 120 minutes. Caffeine is distributed throughout the body and easily
enters the brain. The half life of caffeine amounts 2.5 to 4.5 hours but can vary
considerably depending on endogenous factors such as physiology and genet-
ics, and exogenous factors such as lifestyle. For example, caffeine half-life can
be reduced by about 50% in smokers compared to non-smokers. Caffeine is
metabolized in the liver and its break down products are excreted through the
kidney (Nehlig, 1992; Fredholm, 1999).
4 When is the effect of caffeine most noticeable?
The impact of caffeine on increased alertness is more marked for individuals
with low arousal levels. However, improved performance has also been observed
when reduced alertness is not involved (Smith, 2002; Snel, 2004). Sleepiness
leads to deterioration in performance and is associated with an increased risk
of error and injury. For instance shift work is a major cause of sleepiness as it
requires being awake at times which are different from those dictated by our
body-clock. A review of 13 trials shows that caffeine can reduce the number of
errors and improve cognitive performance in shift workers and also in persons
suffering from jet lag (Ker, 2010). In addition, caffeine or coffee consump-
tion has been shown to counter-act fatigue induced by a night with sleep-
deprivation (Lorist, 1994), and to reduce the post lunch dip (Robelin, 1998),
to improve nocturnal driving performance whereas napping did not (Sagaspe,
2007) and is associated with improved alertness and reduced risk for accidents
at work (Smith, 2005a).
18 |

19. In the same way, for short stopovers (1-2 days) during trips with time zone
differences, judicious naps combined with caffeine and short-term hypnotics
appear to be the best way to maintain alertness and sleep (Arendt, 2009).
5 How much coffee do I have to drink to become more alert
and achieve a better performance?
The benefit of caffeine in typical servings of coffee (60-100 mg of caffeine) on
alertness was demonstrated in several studies. Even lower doses have been
demonstrated to increase alertness, such as 40 mg caffeine per serving (Smit,
2000), 32 mg per serving (Lieberman, 2001) or doses as low as 12.5 mg
caffeine (Smit, 2000). However, the effect of low doses of caffeine was observed
predominantly in those people who are not accustomed to taking caffeine.
Higher caffeine intakes, as those found in more than one or two cups of
coffee do not necessarily result in additional increases in alertness (Smit, 2000;
Quinlan, 2000). It is thought that the relationship between the level of arousal
and task performance follows an inverted U-curve: performance decrements
can occur due to under- and over-arousal (Schmitt, 2005). In general, beneficial
behavioral effects of caffeine are found with doses comparable to those found in
habitual coffee consumption levels (Smith, 2002).
Coffee and the brain | 19

20. 6 How can drinking coffee contribute to attention
and concentration?
Concentration is usually related with improved selective attention, meaning
that the mind is focusing narrowly on the task at hand. Focusing of attention
can be improved by caffeine as shown in several selective attention task studies.
Subjects had to focus on the task and neglect distracters. The results suggested
an increased performance in selection of relevant information (Smith, 1999;
Ruijter, 2000; Lorist, 2003; Snel, 2004). Recently caffeine was shown to improve
participant’s ability to efficiently use stored information and inhibit the influence
of action-irrelevant information (Brunyé, 2010).
7 What is the effect of coffee or caffeine on memory?
Memory is one aspect of cognition which includes encoding, consolidation and
retrieval of information. Memory can be divided according to the duration of
memory: short-term memory, which is transient and limited in capacity and
long-term memory, which includes the vast store of knowledge and the record
of prior events, for potentially unlimited duration. Working-memory refers to
short-term memory and other processing mechanisms that are assumed to be
necessary in order to keep things in mind while performing complex tasks such
as reasoning, comprehension and learning. Memory is not located in a single
part of the brain, but involves a widely distributed network located in different
brain structures (Cowan, 2008; Baddeley, 2010).
Low doses of caffeine enhance working memory performance, while higher
doses are found to decrease it, possibly due to over-stimulation. Comparable
results are shown in a study with low-load memory tasks versus high load
memory tasks (Nehlig, 2010). Caffeine was shown to facilitate low-difficulty
performance in low load memory tasks. High-load and complicated tasks
20 |

21. induced increased arousal by itself, and caffeine could lead to over-arousal.
Thus caffeine appears to rather improve working memory performance under
conditions that otherwise produce low arousal. There are not many studies
on the effects of caffeine on long-term memory. In elderly caffeine could help
attenuating age-related arousal decrements to reduce the decline in memory
performance during the day (Ryan, 2002; Nehlig, 2010). However, the effects of
caffeine on memory are inconsistent. Discrepancies between studies may be due
to the memory assessment method (recall or recognition), time frame (immedi-
ate versus delayed), sex and age of the subjects.
8 Does caffeine have a real impact on cognitive functioning,
or does it just alleviate withdrawal symptoms, in other words,
restore cognitive functioning to baseline levels?
It has been suggested that the positive effects of caffeine really reflect removal
or negative effects of caffeine withdrawal (James, 2005). However, this view
cannot account for effects observed in non-consumers or deprived individuals
(Smith, 2002). Several studies suggested a real impact of caffeine on mood and
performance, irrespective of an overnight caffeine withdrawal. No difference in
mood and performance has been shown between habitual caffeine consumers
after an overnight caffeine withdrawal and non-caffeine consumers. Moreover,
caffeine challenge enhanced mood and performance and the effects increased
with the caffeine dose (Haskell, 2005; Smith, 2005b, 2006). Further, a study
of the effects of caffeine following a day of normal consumption showed that
caffeine had similar effects in those who had abstained from caffeine for more
than 6 hours and those who had consumed caffeine up to the time of testing
(Hewlett, 2007).
Coffee and the brain | 21

22. 9 Can a cup of coffee affect my mood?
Enjoying a cup of coffee for its taste and smell, talking with family, friends or
colleagues during a coffee break might be part of the benefit coffee can have on
our mood.
Mood states are generally assessed using validated self-rating scales with a vari-
ety of mood terms like happy, sad, depressed, pleasant, calm and contented.
22 |

23. Despite the variability in mood definitions, research has provided a fairly consist-
ent picture of effects of caffeine on mood state. In low to moderate dosages
(20-200 mg), caffeine has been quite constantly shown to improve mood state
(Smith, 2004; Casas, 2004; Smith, 2005b; Olson, 2010). People report that
they feel energetic, imaginative, efficient, self confident and alert after caffeine
consumption. They feel more able to concentrate and motivated to work but
also more willing to socialize (Fredholm, 1999). In a recent prospective follow
up study coffee consumption was associated with a decreased risk of depression
(Ruusunen, 2010).
10 Can caffeine consumption cause anxiety?
In general it appears that low doses of caffeine tend to improve the mood states
and that high caffeine doses are associated with negative affective change, like
restlessness and jitteriness. Individual differences in caffeine sensitivity very likely
play a substantial role in determining the mental and physical response to
caffeine (Smith, 2004). In addition, a genetic variation on the adenosine
receptor A2A is associated with sensitivity to caffeine effects on anxiety (Alsene,
2003).
Anxiety is rarely seen with the average range of caffeine consumption, but
the literature suggests that extremely high doses of caffeine may increase
anxiety (Smith, 2002). Moreover, caffeine is a substance that is normally
considered as ‘self-regulating’, meaning that most people know when they took
enough coffee and usually stop drinking before negative effects will emerge
(Tieges, 2007).
Coffee and the brain | 23

24. 11 Can caffeine/coffee consumption interfere with sleep?
Caffeine can increase wakefulness and has been shown to counter-act fatigue
induced by a night with sleep-deprivation (see also question 4). In a French
study on sleep duration and caffeine consumption in a middle aged working
population no effect on sleep duration was found up to a habitual use of 7 cups
of coffee or 600 mg of caffeine equivalent (Sanchez-Ortuno, 2005). Regular
consumption of caffeine can result in some degree of tolerance, reducing
the effects on sleep (Bonnet, 2005). Other research indicated that drinking
caffeinated beverages in the evening may interfere with the onset of sleep in
caffeine sensitive subjects. Differences in caffeine pharmacokinetics have been
reported for sleep sensitive and non-sensitive subjects (Bchir, 2006). Caffeine
elimination was slower in subjects with sleep disturbances; they had half lives for
caffeine between 6.5 and 8 hours. The average half life for caffeine amounts 2.5
to 4.5 hours (see frame on page 18). Significant plasma caffeine concentrations
may persist during the night when caffeine is consumed in the late afternoon.
In addition, a genetic variation on the adenosine receptor A2A is associated with
caffeine sleep sensitivity and a habitual caffeine consumption (Cornelis, 2007;
Retey, 2007). In case of insomnia caffeine abstinence or avoiding caffeine
consumption in the afternoon and evening might be one of the factors to
consider, next to regular exercise, sleeping in a quiet and comfortable
environment and avoiding TV watching in the bedroom and strenuous activities
shortly before going to bed.
24 |

25. Is it safe to consume caffeine?
Caffeine is one of the most investigated components in our diet. Based on
extensive reviews of scientific literature there is general consensus that 400
mg caffeine per day (about 4-5 cups of coffee) are not associated with adverse
health effects in adults. Women who are pregnant, lactating or planning to
become pregnant are recommended to limit their caffeine consumption to
200-300 mg per day (about 2-3 cups of coffee). Caffeine intake in children
should be limited to 2.5 mg caffeine per kg bodyweight per day (Nawrot,
2003; Higdon, 2006; Fredholm, 1999).
Coffee and the brain | 25

26. References
• Alsene K e.a. (2003). Association between A2a receptor gene polymorphisms and caffeine-induced
anxiety. Neuropsychopharmacology, 28(9): 1694-702.
• Arendt (2009). Managing jet lag: Some of the problems and possible new solutions. Sleep Med Rev,
13(4): 249-56.
• Baddeley A (2010). Working memory. Curr Biol, 20(4): R136-140.
• Bchir F e.a. (2006). Differences in pharmacokinetics and electroencephalographic responses to
caffeine in sleep-sensitive and non-sensitive subjects. CR Biologies, 329: 512-519.
• Bonnet MH e.a. (2005). The use of stimulants to modify performance during sleep loss: A review by
the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep,
28(9): 1163-1187.
• Brunyé TT e.a. (2010). Caffeine modulates attention network function. Brain and Cognition,
72(2): 181-189.
• Casas M (2004). Effects of Coffee and Caffeine on Mood and Mood Disorders. In Nehlig A (ed)
Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton, Florida: 73-83.
• Cornelis MC e.a. (2007). Genetic polymorphism of the adenosine A2A receptor is associated with
habitual caffeine consumption. Am J Clin Nutr, 86: 240–244.
• Cowan N (2008). What are the differences between long-term, short-term, and working memory?
Prog Brain Res, 169: 323-338.
• Daly JW e.a. (2004). Mechanism of Action of Caffeine on the Nervous System. In Nehlig A (ed)
Coffee, Tea, Chocolate and the Brain; CRC Press LLC, Boca Raton, Florida: 1-11.
• Fisone G e.a. (2004). Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci,
61(7-8): 857-872.
• Fredholm B e.a. (1999). Actions of caffeine in the brain with special reference to factors that
contribute to its widespread use. Pharmacology Rev, 51(1): 83-133.
• Haskell CF e.a. (2005). Cognitive and mood improvements of caffeine in habitual consumers and
habitual non-consumers of caffeine. Psychopharmacology, 179: 813-825.
• Hewlett P and Smith A (2007). Effects of repeated doses of caffeine on performance and alertness:
new data and secondary analyses. Hum Psychopharmacology, 21: 167-180.
• Higdon JV and Frei B (2006). Coffee and health: a review of recent human research. Critical Reviews
in Foods Science and Nutrition, 56(2): 101-123.
• James JE and Rogers PJ (2005). Effects of caffeine on performance and mood: withdrawal reversal is
most plausible explanation. Psychopharmacology, 182: 1-8.
• Ker K e.a. (2010). Caffeine for the prevention of injuries and errors in shift workers (Review).
The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. www.thecochranelibrary.
• Lieberman HR (2001). The effects of Ginseng, Ephedrine, and Caffeine on cognitive performance,
mood and energy. Nutrition Reviews, 59: 91-102.
• Lorist MM and Tops M (2003). Caffeine, fatigue and cognition. Brain and Cognition, 53: 82-84.
• Lorist MM e.a. (1994). Influence of caffeine on information processing stages in well rested and
fatigued subjects. Psychopharmacology, 113: 411–421.
• Lorist MM e.a. (1996). Acute effects of caffeine on selective attention and visual search processes.
Psychophysiology, 33: 354-361.
• Nawrot P e.a. (2003). Effects of caffeine on health. Food Additives and Contaminants, 20(1): 1-30.
• Nehlig A e.a. (1992). Caffeine and the central nervous system: Mechanisms of action, biochemical,
metabolic, and psycho stimulant effects. Brain Research Reviews, 17: 139-170.
• Nehlig A (2010). Is Caffeine a Cognitive Enhancer? J Alzheimers Dis, 20, S1: 85-94.
26 |

27. • Olson CA e.a. (2010). Effects of Adenosine Antagonists, Quercetin and Caffeine, on Vigilance and
Mood. J Clin Psychopharmacology, 30(5): 537-578.
• Quinlan PT e.a. (2000). The acute physiological and mood effects of tea and coffee: the role of caf-
feine level. Pharmacol Biochem Behav, 66(1): 19-28.
• Retey JV e.a. (2007). A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes
to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther, 81: 692–698.
• Robelin M and Rogers PJ (1998). Mood and psychomotor performance effects of the first, but not of
subsequent, cup of coffee equivalent doses of caffeine consumed after overnight caffeine abstinence.
Behav Pharmacol, 9(7): 611-618.
• Ruijter J (1999). The influence of different doses of caffeine on visual task performance. Journal of
Psychophysiology, 13: 37-48.
• Ruijter J e.a. (2000). The effects of caffeine on visual selective attention to color: An ERP study.
Psychophysiology, 37: 427-439.
• Ruusunen A e.a. (2010). Coffee, tea and caffeine intake and the risk of severe depression in
middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Public Health
Nutrition, 1-6.
• Ryan L e.a. (2002). Caffeine reduces time-of-day effects on memory performance in older adults.
Psychological Science, 13: 68-71.
• Sagaspe P (2007). Aging and nocturnal driving: better with coffee or a nap? A randomized study.
Sleep, 30(12): 1808-1813.
• Sanchez-Ortuno M e.a. (2005). Sleep duration and caffeine consumption in a French middle-aged
working population. Sleep Medicine, 6: 247-251.
• Schmitt JAJ e.a. (2005). General methodological considerations for the assessment of nutritional
influences on human cognitive functions. Eur J Nutr, 44: 459-464.
• Smit HR and Rogers PJ (2000). Effects of low doses of caffeine on cognitive performance, mood and
thirst in low and higher caffeine consumers. Psychophymacology, 152: 167-173.
• Smith A (2002). Effects of caffeine on human behaviour. Food and Chemical Toxicology,
40:1243-1255.
• Smith AP e.a. (1993). Investigation of the Effects of Coffee on Alertness and Performance during the
day and night. Neuropsychobiology, 27: 217-223.
• Smith AP e.a. (1999). Effects of low dose of caffeine given in different drinks on mood and
performance. Human Psychopharm Clin Exp, 14: 473-482.
• Smith AP (2005a). Caffeine at work. Hum Psychopharmacol. 20(6): 441-445.
• Smith AP e.a. (2005b). Effects of repeated doses of caffeine and mood and performance of alert and
fatigued volunteers. J Psychopharmacol, 19(6): 620-626.
• Smith AP e.a. (2006). Effects of caffeine in overnight withdrawn consumers and non-consumers.
Nutritional Neuroscience, 9: 63-71.
• Smith BD e.a. (2004). Arousal and behaviour: Biopsychological Effects of Caffeine. In A. Nehlig (ed).
Coffee, Tea, Chocolate, and the Brain; CRC Press LLC, Boca Raton, Florida: 35-52.
• Snel J e.a. (2004). Coffee, Caffeine, and Cognitive Performance. In A. Nehlig (Ed.). Coffee, Tea,
Chocolate, and the Brain. Boca Raton, FL: CRC Press: 53-71.
• Tieges Z (2007). Caffeine and cognitive control: Behavioural and electrophysiological studies.
Thesis: ISBN 987-90-9022340-7.
• Van Boxtel MPJ and Schmitt JAJ (2004). Age-Related Changes in the Effects of Coffee on Memory
and Cognitive Performance. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC,
Boca Raton, Florida: 85-96.
Coffee and the brain | 27

28. 28 |

29. 3 Coffee and cognitive aging
1 What is the difference between normal cognitive decline,
mild cognitive impairment (MCI) and dementia?
By late adulthood, people typically experience some deterioration in cogni-
tive abilities as part of the normal course of aging. Abilities, such as memory,
reasoning and processing speed, all seem to decline, on average, with age
(Corley, 2010). People with mild cognitive impairment (MCI) suffer from more
severe memory impairments beyond that would be expected according to age
(Roberts, 2009). People with MCI are at higher risk of progressing to dementia
and Alzheimer’s disease, which in turn is the leading cause of dementia. With
dementia, people lose their cognitive abilities to an extent that they are unable
to carry out normal activities and relationships. In addition to memory losses
also behavior and personality changes can occur.
2 What are the acute effects of coffee in elderly people?
It’s well known that caffeine ingestion leads to dose dependent increased ener-
getic arousal, which reflects alertness and mental energy (Nehlig, 2010). Caffeine
is a mild stimulant and its cognitive enhancing effects are more pronounced in
individuals with low arousal levels, for instance due to sleep deprivation, fatigue or
prolonged mental activity (see chapter 2, questions 3 and 4). Since mental energy
and speed of information processing diminish with age, elderly in particular could
benefit from the cognitive effects of caffeine. The vast majority of knowledge on
the acute behavioral effects of caffeine is based on experiments with young or
middle-aged subjects. Although caffeine appears to be metabolized similarly in
young and old individuals, only few studies have investigated the acute cognitive
effects of caffeine in elderly. The results indicate that caffeine may restore arousal
Coffee and the brain | 29

30. levels and hence facilitate cognitive functioning (Van Boxtel, 2004). This effect is
even more pronounced in situations of prolonged mental activity, since elderly
have less compensatory capacity (spare energy sources). Moreover, research
suggests that caffeine intake can ameliorate the decline in memory performance
during the day in older adults (Ryan, 2002). There is some, although very limited,
evidence suggesting that older people may benefit more from relatively higher
dosage (Van Boxtel, 2004). It is suggested to be an interesting topic for further
research since caffeine intake typically increases in early adulthood and declines
with older age.
3 Could caffeine counteract age-related cognitive decline?
There is a growing number of epidemiological studies suggesting that
coffee consumption is associated with better cognitive performance later in life.
In a large cross- sectional study of 9,003 British adults a dose-response trend
between habitual coffee consumption and cognitive abilities was measured;
the oldest men and women seemed to benefit most from a higher caffeine in-
take (Jarvis, 1993). Higher caffeine intake was not associated to better cognition
after 6 years in 1,376 individuals studied in the Netherlands (Van Boxtel, 2003).
In a prospective population study in France, higher caffeine consumption was
associated with less memory decline in women but not in men. The association
was stronger with increasing age and higher caffeine doses (> 300 mg per day)
(Ritchie, 2007). Similar results were found in a study by Johnson-Kozlow (2002).
In a longitudinal prospective cohort study with 676 older men in Finland, Italy
and the Netherlands, coffee intake was associated with lower levels of cognitive
decline 10 years later in life, with 4.3 times less decline in men consuming 3
cups a day in comparison with non-consumers (Van Gelder, 2007).
30 |

31. In a Scottish study, a general trend was shown for individuals who drink more
coffee and less tea to have better cognitive health at age 70 (Corley, 2010). So
far, results indicate that habitual coffee and or caffeine intake seems to be as-
sociated with less cognitive decline in elderly.
4 Does caffeine intake protect from dementia and
Alzheimer’s disease?
There are currently no cures and only limited treatment options for Alzheimer’s
disease. Research focused on prevention of Alzheimer disease suggested that
coffee and caffeine might have a protective effect on the likelihood of develop-
ing Alzheimers’s disease (Rosso, 2008). In a meta-analysis of two case-control
studies and two cohort studies on coffee consumption and the risk of Alzhe-
imer’s disease a protective effect of coffee consumption was found (Barranco
Quintana, 2007). In the pooled estimate the risk was 0.73 (i.e. 27% lower) for
coffee-users versus non-coffee users. In a Finnish cohort study with an average
follow-up of 21 years, coffee drinking at midlife was associated with a decreased
risk of dementia and Alzheimer’s disease and dementia later in life. There are
several indications that caffeine, and perhaps other components in coffee as
well, play a neuroprotective role in the aging brain through a combination of
actions, including anti-inflammatory effects by blockade of both A1 and A2A
receptors. Caffeine has been suggested to increase transcription factors which
enhance cell proliferation and prevent cell death. Moreover, caffeine has been
shown to reduce the negative effects of ␤-amyloid, whose accumulation is the
pathological signature of Alzheimer disease (Rosso, 2008). Caffeine consump-
tion was shown to be dose-dependently related with less white matter lesions in
elderly women, which is an indication of less ␤-amyloid accumulation (Ritchie,
2010). These biological findings indicate that the relationship between caffeine
and cognitive decline found in epidemiological research is highly likely to be a
true causal relationship and not a spurious association (Ritchie, 2010).
Coffee and the brain | 31

32. Polyphenols in coffee have been hypothesized to neutralize free radicals that can
cause damage to neurons and other cells and have also anti-inflammatory prop-
erties. There are still a lot of questions to be answered before a conclusion on
the potential protective effect of coffee and or caffeine can be drawn, however
the results so far are encouraging.
5 What causes Parkinson’s disease and what is the effect
of coffee?
Parkinson’s disease is suggested to be a multifactorial disease, although the precise
cause for Parkinson’s disease remains still undetermined. Complex interactions
between neurotoxins and neuroprotective agents with genetic factors are thought
to be responsible for the development and progression of the disease (Morelli,
2010). Genetic factors seem to be important in early-onset cases of Parkinson’s
disease, while environmental and lifestyle factors are probably more relevant in
the development of Parkinson’s disease at older ages (Costa, 2010). Among these
lifestyle factors, coffee/caffeine is of particular interest in light of caffeine’s safety
and widespread consumption. Caffeine has been demonstrated to be neuropro-
tective in various experimental models of Parkinson’s disease (Xu, 2010; Morelli,
2010; Kachroo, 2010), probably via blocking A2A receptors in the brain. The
knowledge on the plausible biological mechanism based on the pharmacological
actions of caffeine strengthens the inverse association between coffee drinking and
Parkinson’s disease found in epidemiological research (Costa, 2010).
32 |

33. 6 Is coffee consumption a protective factor for Parkinson’s
disease?
The first study to indicate the possible effects of drinking coffee and reducing
the risk of Parkinson disease was published as early as 1968 (Nefzger, 1968).
More than 30 years later, a meta-analysis including 8 case-control and 5 cohort
studies demonstrated that the relative risk of Parkinson’s disease was 30% lower
for coffee drinkers, in comparison to non-coffee drinkers (Hernan, 2002).
A recent systemic review and meta-analysis of 26 studies (7 cohorts, 2 nested
case-controls, 16 case-controls and 1 cross-sectional study) on caffeine and
the risk of Parkinson’s disease confirmed the strength of the inverse association
(Costa, 2010). A 25% reduction in risk of Parkinson’s disease among caffeine
consumers was demonstrated. The results also indicate a linear dose-response
relation, with higher intakes of caffeine being associated with lower risk of
Parkinson’s disease. Moreover, coffee consumption is significantly associated
with a reduced Parkinson’s disease mortality in men (Ascherio, 2004); the effect
in women was dependent on post menopausal estrogens use. In women
consuming 4 cups or more coffee per day compared to women not consum-
ing coffee the risk reduced by 53% among never users and increased by 30%
among users (Ascherio, 2004). These differences could partly reflect a varia-
tion in the genetic expression of one enzyme metabolizing caffeine, CYP1A2
rs762551 (Palacios, 2010).
Coffee and the brain | 33

34. References
• Ascherio A e.a. (2004). Coffee consumption, Gender, and Parkinsons’s disease mortality in the Can-
cer prevention Study II Cohort: The Modifying Effects of Estrogen. Am J Epidemiol 160(10): 977-984.
• Barranco Quintana JL e.a. (2007). Alzheimer’s disease and coffee: a quantitative review.
Neurol Res, 29: 91-95.
• Corley J e.a. (2010). Caffeine consumption and cognitive function at age 70: The Lothian Birth
Cohort 1936 Study. Psychosom Med, 72: 206-214.
• Costa J e.a. (2010). Caffeine Exposure and the Risk of Parkinson’s Disease: A Systemic Review and
Meta-Analysis of Observational Studies, 20: S221-S238.
• Hernan MA (2002). A meta-analysis of Coffee Drinking, Cigarette Smoking, and the Risk of
Parkinson’s Disease. Ann Neurol, 52: 276-284.
• Jarvis MJ (1993). Does caffeine intake enhance absolute levels of cognitive performance?
Psychopharmacology, 110(1-2): 45-52.
• Johnson-Kozlow M e.a. (2002). Coffee consumption and cognitive function among older adults.
Am J Epidemiol, 156: 842-850.
• Kachroo A e.a. (2010). Caffeine protects against combined paraquat and maneb-induced
dopaminergic neuron degeneration. Exp Neurol, 223: 657-661.
• Morelli M and Simola N (2010). Can dietary substances protect against Parkinson’s disease?
The case of caffeine. Exp Neurol, 225(2): 246-249.
• Nefzger MD e.a. (1968). A retrospective study of smoking in Parkinson’s disease. Am J Eidemiol,
88: 149-158.
• Nehlig A (2010). Is Caffeine a Cognitive Enhancer? J Alzheimer’s Disease 20, S1: 85-94.
• Palacios N e.a. (2010). Polymorphisms of caffeine metabolism and estrogen receptor genes and risk
of Parkinson's disease in men and women. Parkinsonism Relat Disord, 16(6): 370-375.
• Ritchie K e.a. (2007). The neuroprotective effects of caffeine. A prospective population study.
Neurology, 69: 536-545.
• Ritchie K e.a. (2010). Caffeine, cognitive functioning, and white matter lesions in the elderly:
establishing causality from epidemiological evidence. J Alzheimers Dis, 20 S1: 161-166.
• Roberts JL e.a. (2009). Subject memory Complaints and Awareness of Memory Functioning in Mild
Cognitive Impairment: A Systematic Review. Demet Geriatr Cogn Disord, 28: 95-109.
• Rosso A e.a. (2008). Caffeine: Neuroprotective Functions in Cognition and Alzheimer’s Disease.
Am J Alzheimers Dis Other Dem, 23(5): 417-422.
• Ryan L e.a. (2002). Caffeine reduces time-of-day effects on memory performance in older adults.
Psychological Science, 13(1): 68-71.
• Van Boxtel MPJ e.a. (2003). The effects of habitual caffeine use on cognitive change:
a longitudinal perspective. Pharmacol Biochem Behav, 75: 921-927.
• Van Boxtel MPJ and Schmitt JAJ (2004). Age-Related Changes in the Effects of Coffee on Memory
and Cognitive Performance. In Nehlig A (ed) Coffee, Tea, Chocolate and the Brain; CRC Press LLC,
Boca Raton, Florida: 85-96.
• Van Gelder B e.a. (2007). Coffee consumption is inversely associated with cognitive decline in elderly
European men: the FINE Study. Eur J Clin Nutr, 61(2): 226-232.
• Xu K e.a. (2010). Neuroprotection by caffeine: Time course and role of its metabolites in the MPTP
model of Parkinson Disease. Neuroscience, 167(2): 475-481.
34 |

35. Study of coffee and health
Every type of research has its own evidential value and limitations.
Most of the studies reported in this brochure can be differentiated into:
1. Meta-analysis: A literature study of various studies (intervention studies, cohort
studies and/or patient control studies) of the relationship between coffee con-
sumption behaviour and a biomarker or (medical) condition, with the aim of
obtaining a more precise outcome.
2. Cohort study (prospective): In this brochure in the case of this type of study large
groups of people have been monitored (prospectively) over a longer period. In
this context at the start of the study differences in coffee consumption between
people who have and have not developed a (medical) condition during the
study are examined. The pattern of coffee consumption of the participants has
therefore not been influenced by the condition.
3. Cross-sectional study: This is a study in which one monitors simultaneously
(smaller) cohorts which follow each other in time. For example a group in the
age range 31-45 and a group in the age range 45-60 are then examined simul-
taneously. In this case at the start of the study differences in coffee consumption
have been examined between people who did and people who did not acquire
the (medical) condition during the study. In this manner a good picture can be
obtained of the association between for example coffee consumption and the
development of a condition between the ages of 30 and 60.
4. Patient-control study: In the case of this type of study the differences in coffee
consumption patterns are investigated in groups of people who have and have
not developed the (medical) condition. In this case therefore questions are
asked after the event about previous coffee consumption behaviour. A disad-
vantage of this type of study may be that the coffee consumption pattern of
the people who have that condition has been modified or is assessed differently
than in the case of people who do not have the condition.
5. Intervention study: In the case of this type the effect of the substance to be
investigated on a group of people is measured and compared with a control
group, which is not given the substance. Intervention studies in the area of
coffee research are usually relatively short and the group size is limited.
Coffee and the brain | 35

36. Coffee brain
and the
KO F F I E E N G E Z O N D H E I D www.koffieengezondheid.nl