October 2020 Issue
CPE Monthly: Coffee’s Impact on Cognitive Function
By Lacey Durrance, MS, RD
Vol. 22, No. 8, P. 52
Suggested CDR Performance Indicators: 8.1.4, 8.3.6, 10.4.2, 10.4.3
CPE Level 2
Interest in the potential health benefits of coffee compounds is growing, especially concerning their impact on cognitive function. A good deal of research has shown that coffee, and its constituents chlorogenic acid (CGA) and caffeine, positively could impact cognitive function.
This continuing education course reviews coffee’s effects on cognition, how its impact varies based on consumption patterns, its physiological and neurophysiological effects, and consumption recommendations.
Consumption Patterns and Recommendations
Coffee is one of the most widely consumed and popular beverages in the world.1 Different brewing methods allow for different coffee preparations, including the drip method, percolation, pressurization to make espresso, and instant coffee made by mixing granules with hot water. While coffee is commonly used to start the day between 9 and 11 AM, consumption also peaks in the afternoon (1 to 3 PM) and decreases gradually into the evening. Consumption is also lower on weekends than weekdays.2 Common reasons for drinking coffee include taste, energy, relief from warm or cold weather, and social connection. About 63% of Americans report having coffee each day.3
Guidelines for coffee intake are dependent on the daily recommendations for caffeine and given in milligrams of caffeine per day. Currently, the 2015–2020 Dietary Guidelines for Americans support that as much as 400 mg/day of caffeine is safe for most healthy individuals, equating to three to five cups of coffee at 8 oz per serving.4 This lowers to 200 to 300 mg/day during pregnancy and 300 mg/day when breast-feeding; caffeine could cause spontaneous abortion when crossing the placenta in pregnancy due to potential impacts on endogenous hormone regulation, and it’s expressed in breastmilk during lactation.5-7 In Europe, safe levels are similar to the United States, with the addition of a “safe consumption in one sitting” guideline of 200 mg.8 Common side effects of caffeine toxicity include increased heart rate, anxiety, poor sleep, and potential increases in blood pressure. For those prone to anxiety or panic attacks, these conditions can be intensified. However, symptoms don’t always occur with the same dose or severity, so staying within the daily recommended values will limit these effects for the average person.9
More than a thousand compounds have been identified in coffee, including caffeine, chlorogenic acids, and tannins.1 Per the USDA’s FoodData Central, one 8-oz cup of coffee contains 11% DV for riboflavin, 6% DV for pantothenic acid, 95 mg caffeine, and 2 kcal. Comparatively, 1 oz of espresso contains 3 kcal, 8% DV for niacin, 6% DV for magnesium, 63 mg caffeine, and minimal riboflavin and pantothenic acid.10,11
Caffeine accounts for about 1% of the weight of coffee beans.1
An average 8-oz cup of coffee contains around 80 to 100 mg caffeine, and a 1-oz shot of espresso contains around 65 mg caffeine.4 Decaf coffee contains 2 to 15 mg caffeine per 8-oz serving.12 Most espresso drinks, such as cappuccinos and lattes, are, depending on the size, typically made with more than one shot of espresso, resulting in a higher caffeine content. Caffeine content also can range drastically depending on the origin of the coffee, the type of roast (such as robusta vs arabica), the brew method (eg, espresso, drip, or percolation), and the grounds-to-water ratio used in brewing. When specialty coffees were tested, the caffeine content of either drip coffee or espresso varied not only from store to store but also within the same store from day to day. For example, 16 oz of Starbucks Breakfast Blend ranged from 259.2 mg caffeine to 564.4 mg caffeine over a six-day period.13
CGAs are the main class of phenolics found in coffee and contain no caffeine themselves. Specific CGAs in coffee include caffeoylquinic acid, feruloylquinic acid, and dicaffeoylquinic acid.14 They’ve been studied for their potential to impact mood and cognition in both caffeinated and decaffeinated coffees. CGAs typically comprise ~10% of the weight of coffee beans.1
As CGAs are metabolized, their metabolites circulate in the body and have the potential for impact on brain function. The most common polyphenol in coffee from this group is 5-caffeoylquinic acid. In the stomach, it’s hydrolyzed to caffeic acid and quinic acid before absorption by the gastrointestinal tract and metabolized to glucuronide and sulphate metabolites.15
CGAs also are found in tea, blueberries, and sunflower seeds, with lower amounts seen in Chinese parsley, potatoes, tomatoes, apples, pears, tobacco, and eggplant.16 Beverages made from vegetables and fruits also contain CGAs, though these aren’t consumed nearly as much as coffee.17 CGA concentrations have been shown to be highest in light-roasted coffee compared with medium- or dark-roasted coffee, and the robusta species has been shown to contain more CGAs than arabica varieties.18,19 As CGAs are in numerous foods and function as antioxidants, their possible cardioprotective and neuroprotective benefits have been an ongoing focus of research.20
Tannins are found in coffee in varying amounts. There’s been some concern about the effects of tannins on iron availability, as they’ve been shown to potentially inhibit iron’s absorption by binding it in the intestinal lumen. However, long-term studies haven’t shown significant changes in iron status when consuming tannins. While absorption can be reduced when tannins are consumed in isolation, such as in tea or coffee, they don’t appear to impact iron bioavailability when consumed as part of a complex meal. This is thought to be due to the inclusion of iron enhancers, such as ascorbic acid within a meal, rather than only iron inhibitors.21,22
The effects of coffee on the body and brain originate from numerous compounds, including caffeine and CGAs. Caffeine has a half-life of around three to five hours, so effects can be seen as soon as 15 minutes after consumption and may continue for hours, depending on the amount of coffee consumed and one’s individual metabolic rate of coffee’s compounds. Caffeine blood levels peak around 30 minutes post consumption, with 99% of caffeine absorption occurring in 45 minutes, while other coffee compounds can peak anywhere between 30 to 60 minutes and four to six hours after ingestion.1,8 Peak CGA concentrations have been shown to occur at 40 minutes post consumption.23
Coffee and Adenosine
The main physiological reactions to caffeinated coffee are due to caffeine’s impacts on the central nervous system through an antagonistic effect on adenosine, specifically adenosine receptors. Adenosine regulates the body in many ways. Within the central nervous system, it dilates cerebral vessels, aids in regulating cerebral blood flow, and regulates neurotransmitter release.24,25 Of importance for energy production, it combines with phosphate to form adenosine triphosphate.
Caffeine inhibits the adenosine receptors A1 and A2A to subsequently decrease cerebral blood flow and oxygenation to the brain, upregulate various neurotransmitters, and constrict blood vessels.1,26 The A1 receptor is involved in neural activation, while the A2A receptor is related to vascular and physiological effects.8,26 While caffeine causes vascular changes due to its inhibition of adenosine, caffeine’s impacts on the brain are thought to stem from a neuronal effect, including the changes in neurotransmitter production, rather than a vascular one.27,28
Physiological changes from antagonism include increases in systolic, diastolic, and arterial blood pressure; vasoconstriction of cerebral blood vessels; reduction of cerebral blood flow; and changes in cerebral oxygenated hemoglobin and deoxygenated hemoglobin.26 Thirty minutes after a dose of coffee containing 200 mg caffeine, 12 male participants showed a 10% and 15% increase in systolic and diastolic blood pressure, respectively.24 The same dosage also has been shown to decrease cerebral blood flow by approximately 30%.29
Cognition and Coffee’s Effects
Cognition typically is measured through computerized assessment batteries, such as the Computerised Mental Performance Assessment System, for numerous cognitive functions including memory, attention, recall, processing speed, and logical reasoning. Examples of cognitive domains commonly tested include emotional processing, short-term memory, storage in long-term memory, retrieval from long-term memory, sustained attention, perceptual speed, cognitive flexibility, and susceptibility to cognitive interference within these test batteries. A commonly used test for cognitive flexibility is the Stroop Test, where color names are presented in different colors. The words are either presented where the name of a color and the color of its ink are the same or the name of a color and the color of its ink are different. For example, the word “red” would be written in any color other than red to make an incongruent pair. The participant has to say the color of the ink, not the color the word states, as fast and accurately as they can. They’re then scored for reaction time, number of errors, and total responses.26 One study included an assessment of driving ability using a driving simulation to test adherence to road rules, staying on track, and following directions.1 Some studies also implemented electrophysiological testing.25
Mood has been measured using self-reported ratings for various descriptors, including alert, overall mood, tense, mental fatigue, relaxed, tired, jittery, calm, and content. In the studies examining mood, participants measured mood by rating their current status for each descriptor on a scale.
When assessing cognitive changes, it’s important to separate treatments using caffeinated coffee vs decaffeinated coffee, as well as coffee that contains CGAs vs noncoffee caffeine sources that wouldn’t contain these nutrients.
Caffeinated Coffee vs Placebo
Caffeinated coffee reduces self-reported tiredness, tenseness, and mental fatigue while increasing feelings of alertness and overall mood.23 Compared with placebo, caffeinated coffee has been shown to increase alertness, vigilance, accuracy, and mood, and improve reaction time, mental fatigue, and tiredness 30 minutes after a 100-mg dose.1,28 Cropley and colleagues found that coffee containing 167 mg caffeine was correlated with increased sustained attention, boosted alertness, and reduced delayed recall functioning compared with decaffeinated coffee in older males.23
Caffeine vs Placebo
Participants who consumed 200 mg caffeine after a study session showed no differences in recognition memory, but significant differences were found in memory consolidation due to improved recall 24 hours after the initial study session, compared with placebo.29 The same caffeine dosage was associated with an increase in correct responses on a shifting attention test and shorter response times during a braking driving test. In the shifting attention test, the placebo group provided 52.2 ± 6.4 correct responses, while the group given 200 mg caffeine produced 55 ± 5.7 correct responses, a 5% difference. In the driving test, braking times decreased from 0.89 ± 0.12 seconds in the placebo group to 0.84 ± 0.08 seconds in the caffeine group, an average 5% reduction.30 Even a smaller dose of 75 mg caffeine was associated with an increase in reaction time and overall mood, a decrease in cerebral oxygenated hemoglobin, and an increase in deoxygenated hemoglobin, the latter of which is thought to indicate neural activation.28
Decaffeinated vs Caffeinated Coffee
Decaffeinated coffee also has been shown to improve mood and alertness. Compared with placebo, decaf coffee was associated with improved attention and reduced tiredness, though not as much as caffeinated coffee.1 These results signify potential positive effects of compounds other than caffeine, such as CGAs.
Differences in CGA Content
Cropley and colleagues found that high- CGA decaf coffee was associated with improved alertness and decreased mental fatigue more than regular-CGA decaf coffee in 20 males aged 53 to 79, supporting a potential dose-response relationship with CGAs.23 However, CGAs in supplement form didn’t show the same beneficial impact as an equal amount of CGAs in decaf coffee.1-3 Therefore, further exploration is necessary to learn more about other compounds in coffee and their role in cognition, as well as their possible synergistic effect with CGAs that may lead to greater benefits than when taking the compound alone.
Chronic vs Acute Users
It’s been proposed that chronic users of caffeinated coffee may experience withdrawal symptoms, such as reduced alertness, in studies requiring caffeine abstinence, and that these could impact study outcomes if not accounted for as confounding variables. However, when comparing habitual users with nonusers of caffeine, caffeine has been shown to increase alertness similarly.1 Unfortunately, the definitions classifying nonusers, habitual users, and low and high users varies from study to study. For example, Haskell and colleagues defined habitual nonconsumers as those who didn’t drink tea or coffee and consumed less than 50 mg/day of caffeine; habitual consumers were defined as drinking tea and/or coffee and more than 50 mg/day of caffeine.28 Of “habitual drinkers,” consuming more than 300 mg/day usually is the threshold to differentiate high and low users.31 Dodd and colleagues, on the other hand, defined habitual drinkers as those who consumed more than 150 mg/day of caffeine and
nonhabitual drinkers as those who consumed less than 60 mg/day.26
As A1 receptors can be upregulated with chronic caffeine use, those who habitually consume caffeine could build up a tolerance to some of its effects over time, leading to questions of caffeine’s ability to continue to impact cognition.26 However, one study found that simple reaction time, digit vigilance, numeric working memory reaction time, alertness, and sentence verification accuracy still were increased when habitual consumers ingested caffeine, and these consumers’ scores were better than nonconsumers’ for spatial memory. Most of these benefits were seen at a 150-mg dose, while some occurred after only a 75-mg dose.28 Both habitual and nonhabitual users experienced decreased ratings of tiredness and mental fatigue following a 75-mg dose. In one study, variances between nonhabitual users and habitual users showed that reaction times were significantly faster in habitual users, even though both groups improved following caffeine.26
While basal differences in heart rate and blood pressure haven’t been observed between users and nonusers, caffeine intake was associated in one study with an increase in systolic blood pressure among nonusers, but not in habitual users. This may support the notion that habituation attenuates caffeine’s negative effects on blood pressure.32
Metabolic Differences Among Users
Caffeine from coffee is absorbed in the stomach and small intestine and then metabolized by the liver with the aid of the cytochrome P450 enzyme system.9 Its metabolic byproducts are excreted in the urine. Many studies have included baseline and posttreatment saliva testing to ensure compliance with caffeine abstinence and effective absorption and metabolism of caffeine into the body. It’s important to note that variability exists in absorption and metabolism of caffeine and CGAs across individuals, and thus the amounts that end up in the brain. This is in part due to a polymorphism in the CYP1A2 isoform of cytochrome P450. Other polymorphisms in enzymes and brain targets for caffeine also can vary from person to person.8
Coffee and Thermogenesis
Research is mixed on the effects of caffeinated coffee and/or caffeine on energy expenditure. Studies generally have used small sample sizes and large doses of caffeine. Caffeine stimulates the sympathetic nervous system, an important regulator of energy expenditure, which may lead to an increase in resting energy expenditure (REE). One study of 12 young men found that 200 mg caffeine increased resting metabolic rate by 7% ± 4%; however, the study was small and limited to one sex and age range.33 Another small study of eight participants showed that adding coffee that included 4 mg/kg body weight of caffeine (272 mg for a 150-lb reference person) to a 736-kcal meal increased the thermic effect by 10% compared with decaffeinated coffee, while consumption of 100 mg caffeine in a single dose increased basal metabolic rate by 3% to 4% for 150 minutes post consumption.34-36 Dulloo and colleagues found that thermogenesis from caffeine could occur throughout the day if caffeine was consumed every two hours, six times per day (up to 600 mg throughout the day, which is well over the recommended daily caffeine intake). This level of consumption was associated with an insignificant 8% to 11% REE increase—150 kcal in lean subjects and 79 kcal in “postobese” subjects, defined as those who were once obese but were within a normal weight range at the time of the study.36 Based on these results, caffeine’s thermogenic effects are likely to be short-lived, insignificant, reversed as caffeine is cleared from the body, and different based on weight history.
Duration of Impacts and Dosing
Most studies on cognitive impacts tested participants at baseline and again at 30 to 45 minutes post consumption, so effects on cognition past this timeframe are unknown. Only one study tested memory function 24 hours post consumption.29 In studies on thermogenesis, any increases in metabolic rate have been shown to return to normal rates at around 120 to 150 minutes post consumption.35,37
Cognitive changes have been seen with a caffeine dose as low as 75 mg, with more impact after a dose of around 200 mg. It seems that 200 mg is the minimum dose associated with memory consolidation effects, while improvements in reaction time, working memory, mood, and alertness were seen at 75 mg. Participants also experienced decreased self-reported tiredness and mental fatigue following a 75-mg dose.28,29
Those who are pregnant or breast-feeding, smoke cigarettes, experience high blood pressure, and take certain drugs are at risk of negative impacts from caffeine.
Pregnant or Breast-Feeding
Those who are pregnant or breast-feeding need to use caution when consuming caffeinated coffee. During pregnancy, caffeine’s metabolism slows, prolonging its half-life. The half-life is longest during the third trimester, lasting 11.5 to 18 hours compared with the normal 2.5 to five hours. In addition, the fetus and placenta can’t metabolize caffeine, which can lead to caffeine accumulation in the fetus; as such, recommendations for maximum caffeine intake per day are set at 200 mg to 300 mg during pregnancy.8 During lactation, caffeine is excreted with breastmilk, which can cause symptoms of overalertness in infants. The safe level for caffeine consumption during lactation is 300 mg per day.5,6
Cigarette smokers experience an increase in caffeine metabolism, with clearance double that of nonsmokers due to an increase in liver enzyme activity. Smoking cessation can slow caffeine metabolism by 36% compared with nonsmokers; thus, during the first few weeks of smoking cessation, caffeine intake may need to be lower than that of nonsmokers due to increased sensitivity.8 Smoking behaviors should be assessed to determine the potential for increased caffeine potency in those who have recently quit smoking.
High Blood Pressure
Individuals with hypertension should consume caffeine with caution, as it can lead to increases in blood pressure. Blood pressure responses to caffeine are individualized based on sensitivity and dose response. In a study of 24 healthy subjects, 75 mg caffeine had no effect on blood pressure 30 minutes post consumption.26 In another study of healthy males, researchers observed 5% and 10% greater increases in systolic and diastolic blood pressure, respectively, compared with controls after consumption of 200 mg caffeine.24
Food and Drug Interactions
Because caffeine uses the cytochrome P450 enzyme system during metabolism, it can impact other drugs using that system. When both caffeine and these drugs compete for metabolism through the cytochrome P450 enzyme, caffeine can prevent these drugs from being metabolized.9 Grapefruit juice has been shown to reduce caffeine clearance by 23% as it inhibits one of the P450 system enzymes.8
Known medication interactions with caffeine include allopurinol, antimycotic drugs, cardiovascular drugs, central nervous system drugs, H2 receptor antagonists, idrocilamide, methylxanthines, nonsteroidal anti-inflammatory drugs, oral contraceptives, estrogen replacement therapy, proton pump inhibitors, quinolones, psoralens, and phenylpropanolamine.9 Caffeine can increase or decrease the effects of these drugs, inhibit their absorption, or reduce caffeine’s clearance from the body. Oral contraceptives and cardiovascular medications have been shown to slow the clearance of caffeine from the body by potentially doubling caffeine’s half-life.8 Dietary and supplemental caffeine intake should be considered when assessing food-drug interaction risks.
According to the National Coffee Association’s annual survey, the consumption of espresso, cold brew, and blended drinks is on the rise.3 Those drinking coffee for energy also may use other energy-boosting beverages, supplements, or even drugs. When discussing daily food logs or 24-hour recalls with patients, an emphasis on items such as energy drinks and supplements may be needed to accurately assess total caffeine intake.
While the FDA requires added caffeine to be listed in a product’s ingredient list, coffee contains intrinsic caffeine and so wouldn’t qualify under this rule unless a coffee product has additional caffeine in its recipe. Caffeine content doesn’t legally have to be listed on food labels, as caffeine isn’t a nutrient, though companies can choose to disclose the caffeine content, as many soda and energy drink manufacturers have done.38
Cardiac issues, psychotropic medications, history of neurological or psychiatric disorders, and clinically high blood pressure were common exclusion criteria in many of the studies assessed.23 Due to these restrictions, it’s unknown how coffee could impact cognition in these populations.
There are several confounding variables and sources of potential bias in results of studies discussed in this course. Tiers of self-reported caffeine intake are inconsistent across studies, with varying definitions for “nonusers,” “low users,” and “heavy users.” Furthermore, self-reporting, which was used for not only caffeine intake but also factors such as mood in many studies, is known to have low validity due to forgetfulness of respondents and lack of serving size knowledge. In addition, most studies didn’t adjust results for cigarette smoking, which affects caffeine metabolism.
Sample sizes were consistently within a range of eight to 70 participants, with most on the lower end of that range. Some studies only included one sex and age range, while others were more equally distributed. Larger and more diverse sample sizes could show different results.
The quantity of coffee, type of brew method, and amount of water used varied across studies, and some sourced caffeine from supplements rather than coffee or espresso. Caffeine dosage differed across both caffeinated and decaffeinated preparations. Furthermore, while most coffee consumers order specialty drinks at coffee shops or make their own at home, the coffees tested were extremely standardized and didn’t mimic the realistic variable nature of coffee brewing at home or in retail.
Many consumers add various sweeteners and/or creamers to coffee drinks. Whole milk hasn’t been shown to impact the bioavailability of the phenolic acids, such as CGAs, in instant coffee, but it’s unknown how other milk or creamer products or caloric or noncaloric sweeteners could alter the bioavailability of coffee compounds.23 Foods consumed at the same time as coffee, or caffeine being consumed within a food or beverage, also can change bioavailability.8 In addition, cognitive improvements associated with caffeine were negated when caffeine was combined with L-theanine, supporting a strong potential for a modulatory effect on cognitive outcomes due to other compounds.26
Putting It Into Practice
Both caffeinated and decaffeinated coffee have been shown to have cognitive impacts. Most notably, caffeinated coffee has shown improvements in alertness, attention, mood, processing speed, and reaction time, while decaffeinated coffee has been shown to improve both alertness and mood. Clients seeking neurostimulation safely can use coffee to improve these cognitive functions within the safe daily recommended levels for caffeine. However, the improvements noted in many studies may not be noticeable in day-today activities, such as braking times or reductions in mental fatigue. While alertness and mental fatigue improved after 75 or 150 mg of caffeine, it’s unknown how these improvements translate into behavior changes, productivity, or other actions, as no specific improvement data were given. While cognitive changes are statistically significant, they may not be significant enough to translate into true day-to-day impacts on behavior. Before recommending coffee to clients to improve cognition, more research must determine the extent of behavior change one can expect and provide more support for coffee’s positive relationship with cognitive function. RDs can remind clients of the wealth of research showing that lifestyle changes, including consuming fruits and vegetables, adequate sleep, proper hydration, and stress management can improve the body’s—and brain’s—health and performance.
— Lacey Durrance, MS, RD, is a nutrition lecturer at Clemson University and freelance writer. Durrance holds a Master of Science in nutrition and Master of Science in psychology. She instructs a research-based college course, “The Impacts of Coffee on Cognition and Metabolism.”
After completing this continuing education course, nutrition professionals should be better able to:
1. Examine the current research surrounding coffee’s impact on cognition.
2. Assess the effect coffee has on cognitive performance at varying dosages of caffeine.
3. Identify the safe dosage recommendations for coffee per day in various populations.
4. Distinguish three ways coffee metabolism can be affected.
CPE Monthly Examination
1. Caffeine’s half-life is slowed by which of the following?
a. Consumption on an empty stomach
b. Cigarette smoking
c. Oral contraceptives
d. The time of day it’s consumed
2. Caffeinated coffee and decaffeinated coffee both have been shown to affect which of the following components of cognition?
b. Processing speed
c. 24-hour recall
d. Auditory processing
3. Caffeinated coffee typically contains about what amount of caffeine per 8 oz?
a. 50 mg
b. 100 mg
c. 150 mg
d. 200 mg
4. Caffeinated coffee is __ % caffeine by weight and __ % chlorogenic acids.
a. 5, 15
b. 10, 1
c. 3, 15
d. 1, 10
5. What is the daily recommended maximum for caffeine per day in healthy adults?
a. 200 mg
b. 400 mg
c. 600 mg
d. 800 mg
6. During pregnancy, safe daily caffeine levels are reduced to what amount?
a. 0 mg
b. 50 to 100 mg
c. 200 to 300 mg
d. 300 to 400 mg
7. What’s the main class of phenols found in coffee?
d. Chlorogenic acids
8. Caffeinated coffee stimulates the nervous system and is associated with subsequent physiological effects through its inhibition of which of the following?
9. Caffeine is metabolized by the cytochrome P450 enzyme system, which is impacted by which of the following foods?
10. What are the labeling regulations for caffeine content on food products?
a. All caffeine, intrinsic or extrinsic/added, is under voluntary disclosure.
b. Intrinsic caffeine doesn’t have to be labeled, but any extrinsic/added caffeine must be included within the ingredients list.
c. If a food product contains caffeine, it must be disclosed.
d. Caffeine levels must be labeled only if they exceed the safe daily limit of 400 mg.
1. Haskell-Ramsay CF, Jackson PA, Forster JS, Dodd FL, Bowerbank SL, Kennedy DO. The acute effects of caffeinated black coffee on cognition and mood in healthy young and older adults. Nutrients. 2018;10(10):E1386.
2. Caffeine and metabolism. Coffee & Health website. https://www.coffeeandhealth.org/topic-overview/caffeine-and-metabolism/. Updated February 28, 2019.
3. NCA national coffee data trends 2019. National Coffee Association website. https://nationalcoffee.blog/2019/03/09/national-coffee-drinking-trends-2019/. Published March 9, 2019.
4. US Department of Health & Human Services. Dietary Guidelines for Americans 2015–2020: Eighth Edition. http://health.gov/dietaryguidelines/2015/guidelines/. Published January 7, 2016.
5. Morgan S, Koren G, Bozzo P. Is caffeine consumption safe during pregnancy? Can Fam Physician. 2013;59(4):361-362.
6. Restricting caffeine intake during pregnancy. World Health Organization website. https://www.who.int/elena/titles/caffeine-pregnancy/en/. Updated February 11, 2019.
7. Hahn KA, Wise LA, Rothman KJ, et al. Caffeine and caffeinated beverage consumption and risk of spontaneous abortion. Hum Reprod. 2015;30(5):1246-1255.
8. Nehlig A. Interindividual differences in caffeine metabolism and factors driving caffeine consumption. Pharmacol Rev. 2018;70(2):384-411.
9. Carrillo JA, Benitez J. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinet. 2000;39(2):127-153.
10. Beverages, coffee, brewed, espresso, restaurant-prepared. US Department of Agriculture, Agricultural Research Service, FoodData Central website. https://fdc.nal.usda.gov/fdc-app.html#/food-details/171891/nutrients. Updated April 1, 2019.
11. Beverages, coffee, brewed, prepared with tap water. US Department of Agriculture, Agricultural Research Service, FoodData Central website. https://fdc.nal.usda.gov/fdc-app.html#/food-details/171890/nutrients. Updated April 1, 2019.
12. Spilling the beans: how much caffeine is too much? US Food and Drug Administration website. https://www.fda.gov/consumers/consumer-updates/spilling-beans-how-much-caffeine-too-much. Updated December 12, 2018.
13. McCusker RR, Goldberger BA, Cone EJ. Caffeine content of specialty coffees. J Anal Toxicol. 2003;27(7):520-522.
14. Camfield DA, Silber BY, Scholey AB, Nolidin K, Goh A, Stough C. A randomised placebo-controlled trial to differentiate the acute cognitive and mood effects of chlorogenic acid from decaffeinated coffee. PLoS One. 2013;8(12):e82897.
15. Tajik N, Tajik M, Mack I, Enck P. The potential effects of chlorogenic acid, the main phenolic components in coffee, on health: a comprehensive review of the literature. Eur J Nutr. 2017;56(7):2215-2244.
16. Chlorogenic acid. The Marshall Protocol Knowledge Base website. https://mpkb.org/home/food/chlorogenic_acid. Updated February 28, 2019.
17. Liang N, Kitts DD. Role of chlorogenic acids in controlling oxidative and inflammatory stress conditions. Nutrients. 2015;8(1):E16.
18. Jung S, Kim MH, Park JH, Jeong Y, Ko KS. Cellular antioxidant and anti-inflammatory effects of coffee extracts with different roasting levels. J Med Food. 2017;20(6):626-635.
19. Caprioli G, Cortese M, Sagratini G, Vittori S. The influence of different types of preparation (espresso and brew) on coffee aroma and main bioactive constituents. Int J Food Sci Nutr. 2015;66(5):505-513.
20. Heitman E, Ingram DK. Cognitive and neuroprotective effects of chlorogenic acid. Nutr Neurosci. 2017;20(1):32-39.
21. Delimont NM, Haub MD, Lindshield BL. The impact of tannin consumption on iron bioavailability and status: a narrative review. Curr Dev Nutr. 2017;1(2):1-12.
22. Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br J Nutr. 1999;81(4):289-295.
23. Cropley V, Croft R, Silber B, et al. Does coffee enriched with chlorogenic acids improve mood and cognition after acute administration in healthy elderly? A pilot study. Psychopharmacology (Berl). 2012;219(3):737-749.
24. Sasaki H, Hirasawa A, Washio T, Ogoh S. Acute effect of coffee drinking on dynamic cerebral autoregulation. Eur J Appl Physiol. 2016;116(5):879-884.
25. Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine receptors: expression, function and regulation. Int J Mol Sci. 2014;15(2):2024-2052.
26. Dodd FL, Kennedy DO, Riby LM, Haskell-Ramsay CF. A double-blind, placebo-controlled study evaluating the effects of caffeine and L-theanine both alone and in combination on cerebral blood flow, cognition, and mood. Psychopharmacology (Berl). 2015;232(14):2563-2576.
27. Heilbronner U, Hinrichs H, Heinze HJ, Zaehle T. Caffeine differentially alters cortical hemodynamic activity during working memory: a near infrared spectroscopy study. BMC Res Notes. 2015;8:520.
28. Haskell CF, Kennedy DO, Wesnes KA, Scholey AB. Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine. Psychopharmacology. 2005;179(4):813-825.
29. Borota D, Murray E, Keceli G, et al. Post-study caffeine administration enhances memory consolidation in humans. Nat Neurosci. 2014;17(2):201-203.
30. Konishi Y, Hori H, Ide K, et al. Effect of single caffeine intake on neuropsychological functions in healthy volunteers: a double-blind placebo-controlled study. PLoS One. 2018;13(10):e0202247.
31. Hursel R, Viechtbauer W, Dulloo AG, et al. The effects of catechin rich teas and caffeine on energy expenditure and fat oxidation: a meta-analysis. Obes Rev. 2011;12(7):e573-e581.
32. Zimmermann-Viehoff F, Thayer J, Koenig J, Herrmann C, Weber CS, Deter HC. Short-term effects of espresso coffee on heart rate variability and blood pressure in habitual and non-habitual coffee consumers — a randomized crossover study. Nutr Neurosci. 2016;19(4):169-175.
33. Koot P, Deurenberg P. Comparison of changes in energy expenditure and body temperatures after caffeine consumption. Ann Nutr Metab. 1995;39(3):135-142.
34. Acheson KJ, Zahorska-Markiewicz B, Pittet P, Anantharaman K, Jéquier E. Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals. Am J Clin Nutr. 1980;33(5):989-997.
35. Westerterp-Plantenga M, Diepvens K, Joosen AM, Bérubé-Parent S, Tremblay A. Metabolic effects of spices, teas, and caffeine. Physiol Behav. 2006;89(1):85-91.
36. Dulloo AG, Geissler CA, Horton T, Collins A, Miller DS. Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers. Am J Clin Nutr. 1989;49(1):44-50.
37. Júdice PB, Magalhães JP, Santos DA, et al. A moderate dose of caffeine ingestion does not change energy expenditure but decreases sleep time in physically active males: a double-blind randomized controlled trial. Appl Physiol Nutr Metab. 2013;38(1):49-56.
38. Sorkin BC, Camp KM, Haggans CJ, et al. Executive summary of NIH workshop on the use and biology of energy drinks: current knowledge and critical gaps. Nutr Rev. 2014;72(Suppl 1):1-8.