research report on caffeine

Many of us can’t imagine starting the day without a cup of coffee. One reason may be that it supplies us with a jolt of caffeine, a mild stimulant to the central nervous system that quickly boosts our alertness and energy levels. [1] Of course, coffee is not the only caffeine-containing beverage. Read on to learn more about sources of caffeine, and a review of the research on this stimulant and health.

Absorption and Metabolism of Caffeine

The chemical name for the bitter white powder known as caffeine is 1,3,7 trimethylxanthine. Caffeine is absorbed within about 45 minutes after consuming, and peaks in the blood anywhere from 15 minutes to 2 hours. [2] Caffeine in beverages such as coffee, tea, and soda is quickly absorbed in the gut and dissolves in both the body’s water and fat molecules. It is able to cross into the brain. Food or food components, such as fibers, in the gut can delay how quickly caffeine in the blood peaks. Therefore, drinking your morning coffee on an empty stomach might give you a quicker energy boost than if you drank it while eating breakfast.

Caffeine is broken down mainly in the liver. It can remain in the blood anywhere from 1.5 to 9.5 hours, depending on various factors. [2] Smoking speeds up the breakdown of caffeine, whereas pregnancy and oral contraceptives can slow the breakdown. During the third trimester of pregnancy, caffeine can remain in the body for up to 15 hours. [3]

People often develop a “caffeine tolerance” when taken regularly, which can reduce its stimulant effects unless a higher amount is consumed. When suddenly stopping all caffeine, withdrawal symptoms often follow such as irritability, headache, agitation, depressed mood, and fatigue. The symptoms are strongest within a few days after stopping caffeine, but tend to subside after about one week. [3] Tapering  the amount gradually may help to reduce side effects.

Sources of Caffeine

Caffeine is naturally found in the fruit, leaves, and beans of coffee , cacao, and guarana plants. It is also added to beverages and supplements. There is a risk of drinking excess amounts of caffeinated beverages like soda and energy drinks because they are taken chilled and are easy to digest quickly in large quantities.

• Coffee. 1 cup or 8 ounces of brewed coffee contains about 95 mg caffeine. The same amount of instant coffee contains about 60 mg caffeine. Decaffeinated coffee contains about 4 mg of caffeine. Learn more about coffee .
• Espresso. 1 shot or 1.5 ounces contains about 65 mg caffeine.
• Tea. 1 cup of black tea contains about 47 mg caffeine. Green tea contains about 28 mg. Decaffeinated tea contains 2 mg, and herbal tea contains none. Learn more about tea .
• Soda. A 12-ounce can of regular or diet dark cola contains about 40 mg caffeine. The same amount of Mountain Dew contains 55 mg caffeine.
• Chocolate (cacao) . 1 ounce of dark chocolate contains about 24 mg caffeine, whereas milk chocolate contains one-quarter of that amount.
• Guarana. This is a seed from a South American plant that is processed as an extract in foods, energy drinks, and energy supplements. Guarana seeds contain about four times the amount of caffeine as that found in coffee beans. [4] Some drinks containing extracts of these seeds can contain up to 125 mg caffeine per serving.
• Energy drinks. 1 cup or 8 ounces of an energy drink contains about 85 mg caffeine. However the standard energy drink serving is 16 ounces, which doubles the caffeine to 170 mg. Energy shots are much more concentrated than the drinks; a small 2 ounce shot contains about 200 mg caffeine. Learn more about energy drinks .
• Supplements. Caffeine supplements contain about 200 mg per tablet, or the amount in 2 cups of brewed coffee.

Recommended Amounts

In the U.S., adults consume an average of 135 mg of caffeine daily, or the amount in 1.5 cups of coffee (1 cup = 8 ounces). [5] The U.S. Food and Drug Administration considers 400 milligrams (about 4 cups brewed coffee) a safe amount of caffeine for healthy adults to consume daily. However, pregnant women should limit their caffeine intake to 200 mg a day (about 2 cups brewed coffee), according to the American College of Obstetricians and Gynecologists.

The American Academy of Pediatrics suggests that children under age 12 should not consume any food or beverages with caffeine. For adolescents 12 and older, caffeine intake should be limited to no more than 100 mg daily. This is the amount in two or three 12-ounce cans of cola soda.

Caffeine and Health

Caffeine is associated with several health conditions. People have different tolerances and responses to caffeine, partly due to genetic differences. Consuming caffeine regularly, such as drinking a cup of coffee every day, can promote caffeine tolerance in some people so that the side effects from caffeine may decrease over time. Although we tend to associate caffeine most often with coffee or tea, the research below focuses mainly on the health effects of caffeine itself. Visit our features on coffee , tea , and energy drinks for more health information related to those beverages.

Caffeine can block the effects of the hormone adenosine, which is responsible for deep sleep . Caffeine binds to adenosine receptors in the brain, which not only lowers adenosine levels but also increases or decreases other hormones that affect sleep, including dopamine, serotonin, norepinephrine, and GABA. [2] Levels of melatonin, another hormone promoting sleep, can drop in the presence of caffeine as both are metabolized in the liver. Caffeine intake later in the day close to bedtime can interfere with good sleep quality. Although developing a caffeine tolerance by taking caffeine regularly over time may lower its disruptive effects, [1] those who have trouble sleeping may consider minimizing caffeine intake later in the day and before going to bed.

In sensitive individuals, caffeine can increase anxiety at doses of 400 mg or more a day (about 4 cups of brewed coffee). High amounts of caffeine may cause nervousness and speed up heart rate, symptoms that are also felt during an anxiety attack. Those who have an underlying anxiety or panic disorder are especially at risk of overstimulation when overloading on caffeine.

Caffeine stimulates the heart, increases blood flow, and increases blood pressure temporarily, particularly in people who do not usually consume caffeine. However, strong negative effects of caffeine on blood pressure have not been found in clinical trials, even in people with hypertension, and cohort studies have not found that coffee drinking is associated with a higher risk of hypertension. Studies also do not show an association of caffeine intake and atrial fibrillation (abnormal heart beat), heart disease , or stroke. [3]

Caffeine is often added to weight loss supplements to help “burn calories.” There is no evidence that caffeine causes significant weight loss. It may help to boost energy if one is feeling fatigued from restricting caloric intake, and may reduce appetite temporarily. Caffeine stimulates the sympathetic nervous system, which plays a role in suppressing hunger, enhancing satiety, and increasing the breakdown of fat cells to be used for energy. [6] Cohort studies following large groups of people suggest that a higher caffeine intake is associated with slightly lower rates of weight gain in the long term. [3] However, a fairly large amount of caffeine (equivalent to 6 cups of coffee a day) may be needed to achieve a modest increase in calorie “burn.” Additional calories obtained from cream, milk, or sweetener added to a caffeinated beverage like coffee or tea can easily negate any calorie deficit caused by caffeine.

Caffeine can cross the placenta, and both mother and fetus metabolize caffeine slowly. A high intake of caffeine by the mother can lead to prolonged high caffeine blood levels in the fetus. Reduced blood flow and oxygen levels may result, increasing the risk of miscarriage and low birth weight. [3] However, lower intakes of caffeine have not been found harmful during pregnancy when limiting intakes to no more than 200 mg a day. A review of controlled clinical studies found that caffeine intake, whether low, medium, or high doses, did not appear to increase the risk of infertility. [7]

Most studies on liver disease and caffeine have specifically examined coffee intake. Caffeinated coffee intake is associated with a lower risk of liver cancer, fibrosis, and cirrhosis. Caffeine may prevent the fibrosis (scarring) of liver tissue by blocking adenosine, which is responsible for the production of collagen that is used to build scar tissue. [3]

Studies have shown that higher coffee consumption is associated with a lower risk of gallstones. [8] Decaffeinated coffee does not show as strong a connection as caffeinated coffee. Therefore, it is likely that caffeine contributes significantly to this protective effect. The gallbladder is an organ that produces bile to help break down fats; consuming a very high fat diet requires more bile, which can strain the gallbladder and increase the risk of gallstones. It is believed that caffeine may help to stimulate contractions in the gallbladder and increase the secretion of cholecystokinin, a hormone that speeds the digestion of fats.

Caffeine may protect against Parkinson’s disease. Animal studies show a protective effect of caffeine from deterioration in the brain. [3] Prospective cohort studies show a strong association of people with higher caffeine intakes and a lower risk of developing Parkinson’s disease. [9]

Caffeine has a similar action to the medication theophylline, which is sometimes prescribed to treat asthma. They both relax the smooth muscles of the lungs and open up bronchial tubes, which can improve breathing. The optimal amount of caffeine needs more study, but the trials reviewed revealed that even a lower caffeine dose of 5 mg/kg of body weight showed benefit over a placebo. [10] Caffeine has also been used to treat breathing difficulties in premature infants. [3]

Caffeine stimulates the release of a stress hormone called epinephrine, which causes liver and muscle tissue to release its stored glucose into the bloodstream, temporarily raising blood glucose levels. However, regular caffeine intake is not associated with an increased risk of diabetes . In fact, cohort studies show that regular coffee intake is associated with a lower risk of type 2 diabetes , though the effect may be from the coffee plant compounds rather than caffeine itself, as decaffeinated coffee shows a similar protective effect. [3] Other observational studies suggest that caffeine may protect and preserve the function of beta cells in the pancreas, which are responsible for secreting insulin. [11]

Signs of Toxicity

Caffeine toxicity has been observed with intakes of 1.2 grams or more in one dose. Consuming 10-14 grams at one time is believed to be fatal. Caffeine intake up to 10 grams has caused convulsions and vomiting, but recovery is possible in about 6 hours. Side effects at lower doses of 1 gram include restlessness, irritability, nervousness, vomiting, rapid heart rate, and tremors.

Toxicity is generally not seen when drinking caffeinated beverages because a very large amount would need to be taken within a few hours to reach a toxic level (10 gm of caffeine is equal to about 100 cups of brewed coffee). Dangerous blood levels are more often seen with overuse of caffeine pills or tablets. [3]

Did You Know?

• Caffeine is not just found in food and beverages but in various medications. It is often added to analgesics (pain relievers) to provide faster and more effective relief from pain and headaches. Headache or migraine pain is accompanied by enlarged inflamed blood vessels; caffeine has the opposite effect of reducing inflammation and narrowing blood vessels, which may relieve the pain.
• Caffeine can interact with various medications. It can cause your body to break down a medication too quickly so that it loses its effectiveness. It can cause a dangerously fast heart beat and high blood pressure if taken with other stimulant medications. Sometimes a medication can slow the metabolism of caffeine in the body, which may increase the risk of jitteriness and irritability, especially if one tends to drink several caffeinated drinks throughout the day. If you drink caffeinated beverages daily, talk with your doctor about potential interactions when starting a new medication.

Energy Drinks

• Clark I, Landolt HP. Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials. Sleep medicine reviews . 2017 Feb 1;31:70-8. *Disclosure: some of HPL’s research has been supported by Novartis Foundation for Medical-Biological Research.
• Institute of Medicine (US) Committee on Military Nutrition Research. Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US); 2001. 2, Pharmacology of Caffeine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223808/
• van Dam RM, Hu FB, Willett WC. Coffee, Caffeine, and Health.  NEJM .  2020 Jul 23; 383:369-378
• Moustakas D, Mezzio M, Rodriguez BR, Constable MA, Mulligan ME, Voura EB. Guarana provides additional stimulation over caffeine alone in the planarian model. PLoS One . 2015 Apr 16;10(4):e0123310.
• Drewnowski A, Rehm CD. Sources of caffeine in diets of US children and adults: trends by beverage type and purchase location. Nutrients . 2016 Mar;8(3):154.
• Harpaz E, Tamir S, Weinstein A, Weinstein Y. The effect of caffeine on energy balance. Journal of basic and clinical physiology and pharmacolog y. 2017 Jan 1;28(1):1-0.
• Bu FL, Feng X, Yang XY, Ren J, Cao HJ. Relationship between caffeine intake and infertility: a systematic review of controlled clinical studies.  BMC Womens Health . 2020;20(1):125.
• Zhang YP, Li WQ, Sun YL, Zhu RT, Wang WJ. Systematic review with meta‐analysis: coffee consumption and the risk of gallstone disease. Alimentary pharmacology & therapeutics . 2015 Sep;42(6):637-48.
• Hong CT, Chan L, Bai CH. The Effect of Caffeine on the Risk and Progression of Parkinson’s Disease: A Meta-Analysis. Nutrients . 2020 Jun;12(6):1860.
• Welsh EJ, Bara A, Barley E, Cates CJ. Caffeine for asthma.  Cochrane Database Syst Rev . 2010;2010(1):CD001112.
• Lee S, Min JY, Min KB. Caffeine and Caffeine Metabolites in Relation to Insulin Resistance and Beta Cell Function in US Adults. Nutrients . 2020 Jun;12(6):1783.

Last reviewed July 2020

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• Published: 01 April 2024

Estimate the prevalence of daily caffeine consumption, caffeine use disorder, caffeine withdrawal and perceived harm in Iran: a cross-sectional study

• Fatemeh Abdoli 1   na1 ,
• Mohammadreza Davoudi 1 , 2   na1 ,
• Fereshte Momeni 2 ,
• Farhang Djafari 3 ,
• Behrooz Dolatshahi 2 ,
• Samaneh Hosseinzadeh 4 ,
• Hajar Aliyaki 2 &
• Zahra Khalili 2  

Scientific Reports volume  14 , Article number:  7644 ( 2024 ) Cite this article

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Metrics details

• Comorbidities

One of the informal diagnoses in DSM-5 is Caffeine Use Disorder (CUD). CUD and high levels of caffeine consumption could impact mental health conditions. This study aimed to estimate the prevalence of CUD, caffeine consumption, caffeine-related harms, and related psychiatric symptoms in Iran. A cross-sectional survey with a convenience sample of 1228 adults were conducted in Iran. Caffeine consumption was assessed across 20 products in Iran. Caffeine Use Disorder Questionnaire (CUDQ), Caffeine Withdrawal Symptoms Questionnaire (CWSQ), 14-item Caffeine-related Harm Screening (CHS), and Symptom Checklist-25 (SCL-25) were used in the present study. We used SPSS (desktop version 26.0) to analyze the data using descriptive statistics, chi-square, and the least significant difference (LSD) post hoc test. The daily average caffeine consumption was 146.67 mg. The prevalence of CUD and caffeine withdrawal (C.W.) were estimated at 19.5% and 46.62%, respectively. Also, 12.9% of responders received CUD and C.W.s simultaneously. The prevalence of CUD was higher in men than females (25.08% vs. 13.93%). 95% of participants (n = 1166) reported using at least one caffeine product yesterday. Moreover, the most reported caffeine-related harms were the desire for sugar (42.9%), insomnia (39.3%), and caffeine dependence (38.3%). Age significantly correlates with CUD (− 0.07) and daily caffeine intake (0.08). Moreover, all SCL-90 subscales had a significant correlation with daily caffeine intake. Finally, responders at younger ages reported higher levels of CUD and caffeine consumption than older adults( P  < 0.05). High rates of C.W. and CUD in the Iranian population suggest that it is necessary to develop evidence-based treatments.

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Introduction

Caffeine is the most commonly consumed psychoactive substance worldwide 1 . Caffeine consumption increases alertness and concentration 2 , cognitive performance 3 , and physical strength 4 .

The evidence indicates the effectiveness of this substance on Alzheimer’s, Parkinson’s, and persistent depression 5 , 6 . Also, some epidemiological studies showed that consuming caffeine products at normal levels can protect against dementia, non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes 7 , 8 .

However, caffeine consumption is associated with potential adverse physical and psychological effects. For example, caffeine is contraindicated for those with gastrointestinal problems, urinary incontinence, insomnia, and anxiety, and its use during pregnancy is associated with weakness 9 .

Caffeine in higher doses can cause symptoms of failure and intoxication (such as digestive discomfort, insomnia, and restlessness 10 . Additionally, excessive caffeine consumption leads to symptoms that overlap with many psychiatric disorders. Excessive caffeine consumption is associated with exacerbation of psychotic symptoms and aggression, increased incidence of stroke, and worsening of anxiety symptoms and sleep disorders 11 , 12 , 13 . Also, some caffeine users become dependent on this substance and show symptoms of withdrawal and deprivation 13 .

In this regard, the diagnosis of Caffeine Use Disorder (CUD) is mentioned in DSM-5, in part III (as a suggestion for further study). Recent studies have shown that in different countries, between 8 and 20 percent of people have a caffeine consumption disorder. CUD, especially in sensitive individuals, can cause symptoms of "caffeinism." Symptoms of this condition include anxiety, restlessness, nervousness, grouch, insomnia, excitement, psychomotor agitation, and inappropriate flow of thought and speech 14 .

High doses (greater than 300 mg) of caffeine regularly have been shown to delay recovery in bipolar patients and cause mood swings and anxiety 15 , 16 . Caffeine consumption disorder can even cause manic episodes and psychotic symptoms in those who have not previously suffered from these disorders 17 , 18 .

One country that exports tea (one of the most common caffeinated substances) is Iran. Due to the legal ban on the consumption of alcoholic beverages, caffeinated substances are the only available option for serving in parties and other life situations. Despite these cases, no study has investigated use patterns and the prevalence of CUD. Also, the prevalence of psychiatric disorders related to it is still unknown 18 , 19 .

Awareness of these cases can help diagnose, treat, and intervene to withdraw CUD and improve individual and social interventions by identifying related risk factors. Therefore, as a cross-sectional study, the current study aims to investigate the prevalence of CUD and its relationship with psychiatric symptoms and demographic features in the Iranian population.

Study design

The study is cross-sectional and descriptive-analytical. The ethics code of this research (IR.USWR.REC.1401.037) was received from the Tehran University of Welfare and Rehabilitation Sciences in May 2022.

Participants and process

This research data was collected between June and August 2022 through Paper-and-Pencil questionnaires in Tehran, Iran. In the first step, an announcement about the study prepared and shared on the most common social media in Iran (include Instagram, Telegram, and Tiktok). In the advertisement, researchers of the current study provided some information about the study and its process. They then asked volunteers to go to an address based on their accessibility from four places: Nezam Mafi Rehabilitation Center (located in the west of Tehran), Rofeyde Rehabilitation Hospital (located in the north), Razi Psychiatric Hospital (located in the south), and Asma Rehabilitation Center (located in the east). All of these centers are affiliated with the University of Social Welfare and Rehabilitation Sciences, Tehran, Iran, which provided ethical approval and supervision for the study. In each center, one of the authors of the current study worked as a psychologist and was ready to gather data.

In the current study, participants were asked to respond to the caffeine they consumed based on a checklist for the previous day. We chose the last day to prevent recalling bias and memory problems.

Also, they responded to a demographic checklist, the caffeine use disorder questionnaire, the caffeine withdrawal symptoms questionnaire, the 14-item caffeine-related Harm screening, and the symptom checklist-25.

Before the main study, we conducted a pilot test with 25 psychology students to evaluate the comprehensibility and clarity of the questionnaire. Their feedback allowed us to refine and improve the questionnaire, addressing any potential ambiguities that could lead to recall bias.

This research was survey research based on quota sampling. According to the following formula, the sample size estimated was 1473. However, we added 8% to that to reduce potential bias in the self-report scale, so the final sample size was 1589 participants.

n is the required sample size.

Z is the Z-score corresponding to the desired confidence level, which we consider 99% (Z = 2.576).

p represents the estimated prevalence of psychiatric disorders in the population. According to a study conducted in New Zealand, which showed a prevalence of 20% for caffeine use disorder, we consider 0.2 for p 20 .

d is the desired margin of error, which we considered 0.03.

Translation and cross-cultural adaptation process

The current study was the first utilization of the Caffeine Use Disorder Questionnaire (CUDQ) and Caffeine Withdrawal Symptoms Questionnaire (CWSQ) scales within the Persian context. The authors used the American Psychological Association (APA) translation and cross-cultural adaptation criteria.

Forward translation

Both questionnaires, originally in English, were translated into Persian (Iranian language) by two psychologists proficient in English. They generated Form X for each scale. Additionally, two English teachers with over 15 years of experience (without knowledge of psychology) created Form Y for both scales.

Translation synthesis

After the initial translations, a meeting was convened with the all translators to consolidate their versions into a unified questionnaire labeled as Z for each scale.

Backward translation

Two translators from England, proficient in Persian but lacking training in behavioral sciences and access to the Caffeine Use Disorder Questionnaire (CUDQ), Caffeine Withdrawal Symptoms Questionnaire (CWSQ), or comparable measures, translated the synthesized Persian version back into English. The resulting final forms are designated as F forms.

Expert committee

A committee of two writers and translators with expertise in methodology, psychometrics, epidemiology, and biostatistics was formed to compare the back-translated versions with the original questionnaires. Identifying and rectifying translation errors, their goal was to enhance the comprehensibility and appropriateness of the pre-final Persian versions for a broader Persian audience.

Pilot testing

In a preliminary study, 60 psychology students assessed the comprehensibility and clarity of the Persian versions. They were instructed to utilize the tool and highlight any ambiguous items in their responses. Subsequently, the final versions were prepared based on their feedback.

Demographic information questionnaire and caffeine consumption checklist : This questionnaire was designed to collect individual information regularly and determine caffeine use patterns and the amount of caffeine consumption. This checklist is a researcher-made checklist under the guidance of mentors and advisors. At first, to measure the amount and type of consumption of each caffeinated product, with the help of a nutritionist, a university professor in the field of psychology, an expert in the field of addiction, and a marketer in the field of sales of caffeinated products, a checklist of caffeinated products that are available in Iran was prepared. Demographic questions included information on age, gender, socioeconomic status, employment status, and marital status using standardized questions. Also, the questioned person specified the number of times of consumption of each caffeinated product in the questionnaire based on day, week, month, or year. The frequency of caffeine consumption in this questionnaire is in the form of a spectrum that started from “I do not eat” and continued to “once a year.” The participant could indicate the amount of daily consumption (if any) in the form of an open-ended question. In this questionnaire, 20 caffeinated substances common in Iran were asked. According to to previous studies, low consumption is defined as less than 200 mg/day, moderate consumption is considered in the range of 200–400 mg/day, and high consumption is defined as exceeding 400 mg/day 20 .

Caffeine use disorder questionnaire (CUDQ): This questionnaire was designed by Ágoston, Urban, Richman, and Demetrovics in 2018 21 . This questionnaire is a 10-item scale based on the nine criteria proposed for CUD in DSM-5, which is accompanied by an additional item related to the suffering caused by the symptoms and the severity of the symptoms of caffeine consumption during the last 12 months. It is measured on a 4-point Likert scale (0 = never, 3 = always). To meet the criteria for CUD, participants must endorse at least the first three items. Cronbach's alpha of this questionnaire was measured outside of Iran in research by Booth, Saxton, and Rodda, which is equal to 0.82 20 . In this research, this questionnaire was implemented as a pilot. A total of 152 community members completed the questionnaire at the beginning of the research, and its internal consistency was equal to 0.770. Also, 30 people completed the questionnaire again in two weeks, and its test–retest value was 0.94 with a 95% confidence interval.

Caffeine withdrawal symptoms questionnaire (CWSQ): This questionnaire was designed by Juliano, Huntley, Harrell, and Westerman in 2012 22 . This scale measures five withdrawal symptoms within 24 h after a sudden reduction in caffeine consumption on a yes–no basis). Cronbach's alpha is reported as 0.78. In the present research, to check the repeatability of this questionnaire, 30 people answered the questions twice in two weeks. Its test–retest value was equal to 0.98 with a confidence interval of 95%.

14-item caffeine-related harm screening (CHS): This questionnaire was designed by Booth, Saxton, and Rodda in 2020 20 . This tool measures the amount of damage in the last 12 months with the answer (yes/no). The items measure the following: physiological harms (e.g., headache, insomnia, fatigue, stomach discomfort), psychological factors (e.g., feeling dependent), and other harms such as high cost and tooth stains, which do not necessarily lead to clinical disorders. The internal consistency of this questionnaire was evaluated, and its Cronbach's alpha was equal to 0.86. In the present research, first, this questionnaire was translated with the help of several experts. To check the repeatability of this questionnaire, 30 people answered the questions twice in two weeks. Its test–retest value was equal to 0.90 with a confidence interval of 95%.

Symptom checklist-25 (SCL-25) : This checklist was designed by Najarian and Davoudi in 2001 23 . This questionnaire is a 25-item self-report scale that is a shortened form of the SCL-90, most of which is taken directly from the Hopkins Symptom Checklist. This checklist is a unique collection for evaluating psychological symptoms and psychological distress that measures nine different psychological dimensions, including physical complaints, obsessions, and compulsions, sensitivity in mutual relationships, depression, anxiety, aggression, phobia, paranoid thoughts, and psychosis, five-point scale from zero (none) to four (severe) 24 . In Najarian’s research (2001), it was observed that this checklist has a significant correlation with its original form (SCL-90), and as a result, it is a valid tool for measuring the symptoms of mental disorders.

Statical analysis

All analyses were conducted using the Statistical Package for the Social Sciences (SPSS) software, version 26. Tests related to continuous variables, such as independent t-groups and one-way analysis of variance (ANOVA), were employed to describe the data. For discrete variables, the chi-square test was utilized. Additionally, the least significant difference (LSD) post hoc test was applied to compare quantitative scores between different groups.

Ethical approval

The ethics committee of the University of Social Welfare and Rehabilitation Sciences, Tehran, Iran (IR.USWR.REC.1401.037), approved this study. Moreover, written informed consent was achieved from all patients before the research procedures were operated. In addition, we informed them that they could leave the project whenever they wanted without any consequences. All procedures were carried out in compliance with the ethical rules and regulations or the Helsinki Declaration.

Participant's characteristic

One thousand five hundred eighty-nine participants consented to take part in the survey. Given the focus of the paper, we excluded participants who did not complete the following measurement tools: caffeine consumption checklist (n = 77), CUD (n = 179), caffeine withdrawal (n = 29), and caffeine-related harm (n = 76). A total of n = 1228 respondents (77.28% of the initial sample) were included for analysis. As shown in Table 1 , respondents were in middle age (median = 34, range 17–59), and nearly half of the sample were female.

The results showed that the average caffeine consumption in the Iranian population was 146.67 mg. The prevalence of CUD and caffeine withdrawal was 19.5% and 46.62%, respectively. Also, 12.9% of participants showed a simultaneous diagnosis of CUD and caffeine withdrawal. Moreover, the results showed that there are significant age differences between different categories of caffeine consumption (low, medium, and high doses) (F = 6.81, P  < 0.01). LSD results showed that the group consuming high caffeine doses was significantly younger. However, there is no significant difference in age between low-dose and medium-dose users.

Sociodemographic differences in CUD severity and daily caffeine consumption

Table 2 shows the diversity of caffeine consumption in different age groups, genders, and education levels. Also, using the quantitative version of the CUD scale, CUD severity has been compared in different subgroups. All caffeine users responded to the CUD severity scale (based on Likert; see procedures section for more information). Table 2 shows that men's daily caffeine consumption rate is significantly higher than women. However, CUD severity was not significantly different between women and men. Also, the chi-square test results showed that the prevalence of CUD in women (25.08%) is significantly higher than in men (13.93%).

We used the International Encyclopedia of the Social & Behavioral Sciences guidelines, and Geifman et al. proposed age stages to define the age in categorical data 25 , 26 .

The results showed a significant difference in daily caffeine consumption between different age groups. LSD results showed that young adults reported significantly higher levels of caffeine consumption than the other two groups. Also, there was no significant difference in caffeine consumption between Adulthood and Middle age. Also, there were differences between different age groups in CUD severity. There was no significant difference in CUD severity between young adults and adulthood. However, young adults showed higher levels of CUD severity than middle age. Regarding CUD diagnosis, there was a significant difference between different age groups.

Caffeine consumption by product

Among the 1228 participants, 1166 (95%) reported consuming at least one caffeinated substance the previous day. In Fig.  1 , the consumption amount of each caffeinated substance on the last day is listed separately by consumption. As shown in this figure, brewed tea is the most used caffeinated substance in Iran, with a rate of 85.7%. Caffeinated toffee, biscuits, and dark chocolate were placed in the next positions.

The percentage of caffeine consumption on the previous day by the participants.

Prevalence of experienced caffeine-related harms

Regarding self-reported symptoms of the harms of caffeine consumption, 1220 people responded to the caffeine harms questionnaire. Of these subjects, 1062 (87%) experienced at least one symptom related to perceived harm from caffeine. As shown in Table 3 , the most common symptoms were increased desire to consume sugary substances, insomnia, and caffeine dependence, respectively.

Associations between CUD and clinical variables

The results showed that the prevalence of caffeine consumption disorder and caffeine withdrawal was 19.5% and 46.62%, respectively. Table 2 examines the correlation between clinical variables and the intensity of caffeine consumption. As shown in Table 3 , age significantly correlates with the daily amount of caffeine consumption (positively) and CUD (negatively). Also, with the increase in daily consumption, the severity of CUD was significantly increased in people who received a diagnosis of CUD. Among the psychiatric symptoms, depression had no significant relationship with the amount of caffeine consumption. However, a significant and linear relationship was found between the severity of CUD and depression. Regarding other variables, Table 4 provides detailed information.

This study aims to investigate caffeine use patterns, CUD, CWSs, caffeine-related harm, and their relationship with psychiatric symptoms, taking into account a wide range of demographic information among Adults in Iran. Among the participants, 19.5% met the criteria for CUD, 46.62% met the criteria for CWS, and 87% had reported at least one caffeine-related harm in the past year.

The highest average consumption among the daily products was related to tea, toffee, biscuit, and dark chocolate, consumed by 85.7, 21.9, 20.8, and 20.4 percent of the participants, respectively. Also, 18.7% of participants consume > 400 mg/day caffeine. In Iran, tea is cultivated in the country’s northern regions, including Lahijan, which has reduced the cost of tea production in Iran. In addition, tea consumption has long been considered the leading custom of getting together, and few people in Iran do not drink a cup of tea in the morning 27 . Although many people often mention its taste as the reason for consumption, the preference for the bitter and certainly bad taste of caffeine is probably due to the positive effects of this psychoactive substance and its association with mood changes caused by its consumption 28 .According to the results, the age of the participants who had the highest amount of caffeine consumption (> 400 mg/day) was lower than the other groups and, unlike the study of Frary, Johansson and Wang 29 , the correlation between age and caffeine consumption was negative. This issue can be because, nowadays, younger people usually consume caffeine from different sources and new products such as energy drinks, dark chocolate, and carbonated drinks. Furthermore, with age, due to some physical issues such as blood sugar, caffeine consumption will generally be limited to tea and coffee. The young generation, like students and athletes, consumes caffeine to feel alert, increase sociability, increase physical energy, improve mood, and reduce stress. Energy drinks, a new popular caffeinated beverage, are also often consumed to boost energy or combat insufficient sleep 30 . Of course, marketing some caffeinated products, such as energy drinks, soft drinks, and ready-to-drink alcoholic beverages, which often target specific populations such as young adults and teenagers, is not without influence 30 , 31 .

Although nutritional knowledge may influence caffeine consumption 32 , beliefs, experiences, and information from peers may change how consumers interpret their feelings 33 .

As mentioned, among participants, 19.5% met the criteria for caffeine use disorder. This finding is consistent with the results of the research conducted by Booth, Saxton, and Rodda (20%) in 2020 in New Zealand 20 , But these results are higher than the results of Sweeney et al.'s research (8%) 13 and Ágoston’s research (13.5%) 21 . At first, People who consume caffeine in a problematic way may be unaware of its physical and psychological consequences or cannot attribute the side effects they experience to caffeine consumption. Also, it has been shown in some research 34 that health-related students reduce their caffeine consumption after being aware of the consequences of this substance. Other people may use caffeine as a coping mechanism and an addictive pattern to face their existing conditions, leading to excessive consumption of these products 35 . In this regard, considering the opinion of addiction experts is an important supplement to evaluate the clinical significance of CUD.

Continuous consumption of even less than 100 mg of caffeine, or 3–7 days of high doses of caffeine, can also lead to caffeine withdrawal syndrome, so that even a short abstinence, such as missing a cup of coffee or tea in the morning, can lead to significant unpleasant effects, that drinking even low doses of caffeine suppresses these symptoms 36 . Since about 86% of the participants consumed a caffeinated product daily, it seems normal that 46.62% met the criteria for CWSs. These results are similar to those of a New Zealand study 20 , in which 30 percent of participants had experienced caffeine withdrawal symptoms.

Among participants, 87 percent reported at least one caffeine-related harm in the past year. These results are similar to those of a New Zealand study 20 , in which 85 percent of participants had experienced at least one caffeine-related harm in the past year. According to the results, the participants' most experienced caffeine-related harm was increased sugar cravings (42.9%) and sleep difficulties (39.3%). Although consumption in low to moderate doses leads to pleasant sensations, higher doses taken at once or for short periods can cause or exacerbate restlessness, insomnia, nervousness, and anxiety 37 . Furthermore, most evidence shows that caffeine alone increases the adverse effects of glucose metabolism and reduces insulin sensitivity 38 . Caffeine’s reputation as a stimulant that can compensate for fatigue-related deficits means that the substance is often consumed by tired people, even though caffeine itself has been implicated in causing fatigue in the first place 39 . The “coffee cycle” phenomenon can partially explain this: feeling tired in the morning causes more caffeine consumption, which is associated with disruption of subsequent sleep patterns 40 .

The results of Bergin and Kendler’s study in 2012 showed that generalized anxiety disorder, phobia, and major depressive disorder have common genetic factors with caffeine consumption, and their genetic correlation was estimated at 0.48, 0.25, and 0.38, respectively 41 ; in this research correlation between CUD severity and anxiety, phobia, and depression symptoms was 0.34, 0.33 and 0.26 respectively. Hearn and his colleagues also observed in 2020 that the daily consumption of caffeine among the general population is significantly higher than that of the patient population, but the rate of poisoning caffeine doses was higher among the clinical population 42 . Such research can lead us to conclude that significant common genetic and environmental factors between psychiatric disorders and caffeine phenotypes may help us in the etiology of the coexistence between these phenotypes.

Limitations and future directions

According to the review of research evidence in Iran, this was the first study that specifically investigated caffeine consumption patterns and their relationship with the signs and symptoms of mental disorders. In addition, in this research, demographic variables have been widely studied, which can be very effective in the transparency of the issue.

However, the use of self-report tools and the cross-sectional nature of the present study are among the limitations of this research. Due to the increased costs, taking a blood test to measure caffeine accurately was impossible, so self-report scales alone may affect how people respond. Therefore, using other methods to obtain information from participants can help increase the generalizability and validity of the findings. This study was conducted during the outbreak of COVID-19, which may have affected the amount of caffeine consumption due to the remote working of many jobs. Also, since sampling was done in public places, many people may have been quarantined at home due to the spread of COVID-19. Since this research had examined a wide range of variables, if it was conducted online, due to its length, the possibility of completing the questionnaire was very low, so the research was conducted on pencil paper. However, when the questionnaire was administered, some people refused to answer because it was too long, and the number of returned questionnaires was incomplete. The exclusion of individuals aged 60 years and older may limit the generalizability of the findings to the broader population, and caution should be exercised in generalizing the results. This age-related exclusion was implemented to minimize potential biases associated with prevalent health conditions in the elderly.

The high rate of CUD and CWSs in the present sample highlights the need for education and treatments related to caffeine consumption. However, it should be noted that although there are different types of caffeinated products, and there are also different expectations regarding the effects of these beverages, it seems that each of these products may have different roles in causing CUD 21 . Therefore, more research should be done on caffeinated products separately. In addition, demographic variables (such as gender and social economic status) and caffeine use patterns (time of use, number of servings, etc.) can determine the prevalence of CUD and CWSs and their relationship with another research.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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The Substance Abuse and Dependence Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran, supported this research.

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Substance Abuse and Dependence Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Fatemeh Abdoli & Mohammadreza Davoudi

Department of Clinical Psychology, School of Behavioral Sciences, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Mohammadreza Davoudi, Fereshte Momeni, Behrooz Dolatshahi, Hajar Aliyaki & Zahra Khalili

Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran

Farhang Djafari

Biostatistics Department, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Samaneh Hosseinzadeh

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F.A., M.D. and F.M. contributed to the study conception and design. Material preparation, data collection and analysis were performed by F.D., B.D. and F.A. The first draft of the manuscript was written by F.A. and M.D.; which all other authors commented on previous versions of the manuscript. The final revision of data analysis performed by S.H., and H.A., and Z.K. All authors read and approved the final manuscript.

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Abdoli, F., Davoudi, M., Momeni, F. et al. Estimate the prevalence of daily caffeine consumption, caffeine use disorder, caffeine withdrawal and perceived harm in Iran: a cross-sectional study. Sci Rep 14 , 7644 (2024). https://doi.org/10.1038/s41598-024-58496-8

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International society of sports nutrition position stand: caffeine and exercise performance

• Nanci S. Guest   ORCID: orcid.org/0000-0002-1745-862X 1 ,
• Trisha A. VanDusseldorp 2 ,
• Michael T. Nelson 3 ,
• Jozo Grgic 4 ,
• Brad J. Schoenfeld 5 ,
• Nathaniel D. M. Jenkins 6 ,
• Shawn M. Arent 7 , 8 ,
• Jose Antonio 9 ,
• Jeffrey R. Stout 10 ,
• Eric T. Trexler 11 ,
• Abbie E. Smith-Ryan 12 ,
• Erica R. Goldstein 10 ,
• Douglas S. Kalman 13 , 14 &
• Bill I. Campbell 15  

Journal of the International Society of Sports Nutrition volume  18 , Article number:  1 ( 2021 ) Cite this article

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Following critical evaluation of the available literature to date, The International Society of Sports Nutrition (ISSN) position regarding caffeine intake is as follows:

Supplementation with caffeine has been shown to acutely enhance various aspects of exercise performance in many but not all studies. Small to moderate benefits of caffeine use include, but are not limited to: muscular endurance, movement velocity and muscular strength, sprinting, jumping, and throwing performance, as well as a wide range of aerobic and anaerobic sport-specific actions.

Aerobic endurance appears to be the form of exercise with the most consistent moderate-to-large benefits from caffeine use, although the magnitude of its effects differs between individuals.

Caffeine has consistently been shown to improve exercise performance when consumed in doses of 3–6 mg/kg body mass. Minimal effective doses of caffeine currently remain unclear but they may be as low as 2 mg/kg body mass. Very high doses of caffeine (e.g. 9 mg/kg) are associated with a high incidence of side-effects and do not seem to be required to elicit an ergogenic effect.

The most commonly used timing of caffeine supplementation is 60 min pre-exercise. Optimal timing of caffeine ingestion likely depends on the source of caffeine. For example, as compared to caffeine capsules, caffeine chewing gums may require a shorter waiting time from consumption to the start of the exercise session.

Caffeine appears to improve physical performance in both trained and untrained individuals.

Inter-individual differences in sport and exercise performance as well as adverse effects on sleep or feelings of anxiety following caffeine ingestion may be attributed to genetic variation associated with caffeine metabolism, and physical and psychological response. Other factors such as habitual caffeine intake also may play a role in between-individual response variation.

Caffeine has been shown to be ergogenic for cognitive function, including attention and vigilance, in most individuals.

Caffeine may improve cognitive and physical performance in some individuals under conditions of sleep deprivation.

The use of caffeine in conjunction with endurance exercise in the heat and at altitude is well supported when dosages range from 3 to 6 mg/kg and 4–6 mg/kg, respectively.

Alternative sources of caffeine such as caffeinated chewing gum, mouth rinses, energy gels and chews have been shown to improve performance, primarily in aerobic exercise.

Energy drinks and pre-workout supplements containing caffeine have been demonstrated to enhance both anaerobic and aerobic performance.

Introduction

Caffeine is the world’s most widely consumed psychoactive substance and naturally occurs in dozens of plant species, including coffee, tea and cocoa. Caffeine is ingested most frequently in the form of a beverage such as coffee, soft drinks and tea, although the consumption of many functional beverages, such as energy drinks, has been on a steady rise in the past two decades [ 1 ]. In Western countries, approximately 90% of adults consume caffeine on a regular basis, with dietary caffeine consumption of U.S. adult men and women estimated at approximately 200 mg/day in a 2009–2010 survey [ 2 , 3 , 4 ]. In young adults and exercising individuals, there has also been a rise in the consumption of other caffeine-containing products, including energy drinks [ 1 , 3 ], ‘pre-workout supplements’, chewing gum, energy gels and chews, aerosols, and many other novel caffeinated food products [ 5 ]. Caffeine-containing products have a range of doses per serving, from 1 mg in milk chocolate up to > 300 mg in some dietary supplements [ 6 ].

Caffeine and its effects on health have been a longstanding topic of interest, and caffeine continues to be a dietary compound of concern in public health, as indicated by extensive investigations [ 7 , 8 , 9 , 10 ]. At the same time, caffeine has become ubiquitous in the sporting world, where there is keen interest in better understanding the impact of caffeine on various types of exercise performance. Accordingly, caffeine has dominated the ergogenic aids and sport supplement research domain over the past several decades [ 11 , 12 , 13 ].

Caffeine in sport: a brief history

In the early days (1900s) of modern sport, concoctions of plant-based stimulants, including caffeine and other compounds such as cocaine, strychnine, ether, heroin and nitroglycerin, were developed secretly by trainers, athletes and coaches, in what appears to be evidence for early day ergogenic aids designed to provide a competitive advantage [ 14 ]. The use of various pharmaceutical cocktails by endurance athletes continued until heroin and cocaine became restricted to prescriptions in the 1920s, and further when the International Olympic Committee (IOC) introduced anti-doping programs in the late 1960s [ 15 ].

Some of the earliest published studies on caffeine came from two psychologists and colleagues William Rivers and Harald Webber, at Cambridge University, who both had an interest in disentangling the psychological and physiological effects of substances like caffeine and alcohol. Rivers and Webber, using themselves as subjects, investigated the effects of caffeine on muscle fatigue. The remarkable well-designed studies carried out from 1906 to 1907 used double-blinded placebo-controlled trials and standardization for diet (i.e. caffeine, alcohol), and were described in a 1907 paper in the Journal of Physiology [ 16 ]. Significant research on the effects of caffeine on exercise performance with more subjects, different sports, and exploring variables such as the effects between trained and untrained individuals, began and continued through the 1940s [ 14 , 17 ]. However, it was the series of studies investigating the benefits of caffeine in endurance sports in the Human Performance Laboratory at Ball State University in the late 1970s, led by David Costill [ 18 , 19 ] and others [ 20 ], that sparked a generation of research on the effects of caffeine in exercise metabolism and sports performance.

Caffeine sources

Along with naturally occurring sources, such as coffee, tea and cocoa, caffeine is also added to many foods, beverages and novelty products, such as jerky, peanut butter, and candy, in both synthetic (e.g. powder) and natural (e.g. guarana, kola nut) forms. Synthetic caffeine is also an ingredient in several over-the-counter and prescription medications, as it is often used in combination with analgesic and diuretic drugs to amplify their pharmacological potency [ 21 ].

Approximately 96% of caffeine consumption from beverages comes from coffee, soft drinks and tea [ 22 ]. Additionally, there are varying levels of caffeine in the beans, leaves and fruit of more than 60 plants, resulting in great interest in herbal and other plant-based supplements [ 23 , 24 , 25 , 26 ]. Caffeine-containing energy drink consumption [ 27 , 28 , 29 , 30 , 31 ] and co-ingestion of caffeine with (e.g. “pre-workouts”), or in addition to, other supplements (e.g. caffeine + creatine) is also popular among exercising individuals [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. To date, the preponderance of caffeine and exercise performance literature has utilized anhydrous caffeine (in a capsule) [ 40 , 41 , 42 , 43 , 44 , 45 , 46 ] for simpler dose standardization and placebo creation. There is also a growing body of literature studying the effects of using alternate delivery methods of caffeine during exercise [ 5 ] such as coffee [ 18 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ], energy drinks, herbal formulas [ 57 ] and ‘pre-workout’ formulas, among others. A review of alternate caffeine forms may be found in the Alternative caffeine sources section and Tables  4 , 5 , 6 , 7 and 8 .

Caffeine legality in sport

Anti-doping rules apply to most sports, especially in those where athletes are competing at national and international levels. The IOC continues to recognize that caffeine is frequently used by athletes because of its reported performance-enhancing or ergogenic effects [ 109 ]. Caffeine was added to the list of banned substances by the IOC in 1984 and the World Anti-Doping Agency (WADA) in 2000. A doping offense was defined as having urinary caffeine concentrations exceeding a cut-off of 15 μg/ml. In 1985, the threshold was reduced to 12 μg/ml [ 110 ]. The cut-off value was chosen to exclude typical amounts ingested as part of common dietary or social coffee drinking patterns, and to differentiate it from what was considered to be an aberrant use of caffeine for the purpose of sports performance enhancement [ 111 ].

The IOC and WADA removed the classification of caffeine as a “controlled” substance in 2004, leading to a renewed interest in the use of caffeine by athletes. However, caffeine is still monitored by WADA, and athletes are encouraged to maintain a urine caffeine concentration below the limit of 12 μg/ml urine which corresponds to 10 mg/kg body mass orally ingested over several hours, and which is more than triple the intake reported to enhance performance [ 112 , 113 ]. Interestingly, caffeine is also categorized as a banned substance by the National Collegiate Athletic Association (NCAA), if urinary caffeine concentration exceeds 15 μg/ml, which is greater than the “monitored substance” level set for WADA [ 114 ], and also well above amounts that are deemed ergogenic.

A comparison of caffeine concentrations obtained during in-competition doping control from athletes in several sports federations pre− 2004 versus post-2004, indicated that average caffeine concentrations decreased in 2004 after removal from the prohibited substance list [ 110 ]. Reports on over 20,000 urine samples collected and analyzed after official national and international competitions between 2004 and 2008, and again in 2015 using 7500 urine samples found overall prevalence of caffeine use across various sports to be about 74% in the 2004 to 2008 time period and roughly 76% in 2015. The highest use of caffeine was among endurance athletes in both studies [ 115 , 116 ]. Urinary caffeine concentration significantly increased from 2004 to 2015 in athletics, aquatics, rowing, boxing, judo, football, and weightlifting; however, the sports with the highest urine caffeine concentration in 2015 were cycling, athletics, and rowing [ 116 ].

Caffeine pharmacokinetics

Caffeine or 1,3,7-trimethylxanthine, is an odorless white powder that is soluble in both water and lipids and has a bitter taste. It is rapidly absorbed from the gastrointestinal tract, mainly from the small intestine but also in the stomach [ 117 ]. In saliva, caffeine concentration reaches 65–85% of plasma levels, and is often used to non-invasively monitor compliance for ingestion or abstinence of caffeine [ 118 ]. Caffeine is effectively distributed throughout the body by virtue of being sufficiently hydrophobic to allow easy passage through most, if not all biological membranes, including the blood-brain barrier [ 119 ]. When caffeine is consumed it appears in the blood within minutes, with peak caffeine plasma concentrations after oral administration reported to occur at times (T max ) ranging from 30 to 120 min [ 43 , 120 , 121 , 122 ]. The absolute bioavailability of caffeine is very high and reaches near 100% as seen in studies reporting areas under the plasma concentration-time curves (AUC) [ 120 ]. Once caffeine is absorbed, there appears to be no hepatic first-pass effect (i.e. , the liver does not appear to remove caffeine as it passes from the gut to the general circulation), as evidenced by similar plasma concentration curves when administered by either oral or intravenous routes [ 123 ]. Caffeine absorption from food and beverages does not seem to be dependent on age, gender, genetics or disease, or the consumption of drugs, alcohol or nicotine. However, the rates of caffeine metabolism and breakdown appear to differ between individuals through both environmental and genetic influences [ 3 , 124 , 125 ].

Over 95% of caffeine is metabolized in the liver by the Cytochrome P450 1A2 (CYP1A2) enzyme, a member of the cytochrome P450 mixed-function oxidase system, which metabolizes and detoxifies xenobiotics in the body [ 126 ]. CYP1A2 catalyzes the demethylation of caffeine into the primary metabolites paraxanthine (1,7-dimethylxanthine), theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine), which account for approximately 84, 12, and 4%, of total caffeine elimination, respectively [ 127 , 128 ]. These three caffeine metabolites undergo further demethylations and oxidation to urates in the liver with about 3–5% remaining in caffeine form when excreted in the urine [ 129 , 130 ]. While the average half-life (t 1/2 ) of caffeine is generally reported to be between 4 and 6 h, it varies between individuals and even may range from 1.5 to 10 h in adults [ 120 ]. The wide range of variability in caffeine metabolism is due to several factors. The rate of caffeine metabolism may be inhibited or decreased with pregnancy or use of hormonal contraceptives [ 125 ], increased or induced by heavy caffeine use [ 131 ] cigarette smoking [ 132 ] or modified in either direction by certain dietary factors [ 133 ] and/or variation in the CYP1A2 gene, which will be discussed later [ 125 , 132 , 133 , 134 ].

Several studies have also shown that the form of caffeine or its vehicle for entry into the body can modify the pharmacokinetics [ 58 , 81 , 119 , 122 ]. One small trial ( n  = 3) evaluated T max for a variety of beverages that all included 160 mg of caffeine but in different volumes of solution, and reported that T max occurs at 0.5, 0.5, and 2 h for coffee, tea and cola, respectively [ 135 ]. In another study involving seven participants, caffeine plasma concentrations peaked rapidly at 30 min for capsule form, whereas caffeine absorption from cola and chocolate was delayed and produced lower plasma concentrations that peaked at roughly 90–120 min after consumption. This study also did not control for volume of administered solution (capsules and chocolate ingested with 360 ml water and 800 ml cola) [ 122 ]. Liguori et al. [ 136 ] evaluated a 400 mg dose of caffeine in 13 subjects and reported salivary caffeine T max values of 42, 39 and 67 min, for coffee, sugar-free cola and caffeine capsules, respectively. However, fluid volume was again not standardized (coffee – 12 oz., sugar-free cola – 24 oz., capsules – volume of administered fluid not reported). The impact of temperature or rate of ingestion of caffeine has also been investigated, amidst concerns that cold energy drinks might pose a danger when chugged quickly, compared to sipping hot coffee. One study [ 121 ] compared five conditions that included: slow ingestion (20 min) of hot coffee, and fast (2-min) or slow (20-min) ingestion for both cold coffee and energy drinks. Similar to other caffeine pharmacokinetic studies [ 122 , 135 ], White et al. [ 121 ] reported that although the rate of consumption, temperature, and source (coffee vs. energy drink) may be associated with slight differences in pharmacokinetic activity, these differences are small.

Chewing gum formulations appear to alter pharmacokinetics, as much of the caffeine released from the gum through mastication can be absorbed via the buccal cavity, which is considered faster due to its extensive vascularization, especially for low molecular weight hydrophobic agents [ 137 ]. Kamimori et al. [ 58 ] compared the rate of absorption and relative caffeine bioavailability from chewing gum compared to a capsule form of caffeine. Although caffeine administered in the chewing gum formulation was absorbed at a significantly faster rate, the overall bioavailability was comparable to the capsuled 100 and 200 mg caffeine dose groups. These pharmacokinetic findings are useful for military and sport purposes, where there is a requirement for rapid and maintained stimulation over specific periods of time. Chewing gum may also be advantageous due to reduced digestive requirements, where absorption of caffeine in other forms (capsule, coffee etc.) may be hindered by diminished splanchnic blood flow during moderate to intense exercise. Finally, there is a growing prevalence of caffeinated nasal and mouth aerosols administered directly in the mouth, under the tongue or inspired may affect the brain more quickly through several proposed mechanisms [ 5 ], although there are only a few studies to date to support this claim. The administration of caffeine via aerosol into the oral cavity appears to produce a caffeine pharmacokinetic profile comparable to the administration of a caffeinated beverage [ 81 ]. Nasal and mouth aerosols will be discussed further in another section.

Mechanism of Action (MOA)

Although the action of caffeine on the central nervous system (CNS) has been widely accepted as the primary mechanism by which caffeine alters performance, several mechanisms have been proposed to explain the ergogenic effects of caffeine, including increased myofibrillar calcium availability [ 138 , 139 ], optimized exercise metabolism and substrate availability [ 45 ], as well as stimulation of the CNS [ 140 , 141 , 142 ]. One of the earlier proposed mechanisms associated with the ergogenic effects of caffeine stemmed from the observed adrenaline (epinephrine)-induced enhanced free-fatty acid (FFA) oxidation after caffeine ingestion and consequent glycogen sparing, resulting in improved endurance performance [ 18 , 45 , 143 ]. However, this substrate-availability hypothesis was challenged and eventually dismissed, where after several performance studies it became clear that the increased levels of FFAs appeared to be higher earlier in exercise when increased demand for fuel via fat oxidation would be expected [ 141 , 144 , 145 ]. Furthermore, this mechanism could not explain the ergogenic effects of caffeine in short duration, high-intensity exercise in which glycogen levels are not a limiting factor. Importantly, several studies employing a variety of exercise modalities and intensities failed to show a decrease in respiratory exchange ratio (RER) and/or changes in serum FFAs, which would be indicative of enhanced fat metabolism during exercise when only water was ingested [ 144 , 146 , 147 , 148 ]. Ingestion of lower doses of caffeine (1–3 mg/kg of body mass), which do not result in significant physiological responses (i.e. RER, changes in blood lactate, glucose), also appear to deliver measurable ergogenic effects, offering strong support for the CNS as the origin of reported improvements [ 43 , 149 , 150 ]. As such, focus has shifted to the action of caffeine during exercise within the central and peripheral nervous systems, which could alter the rate of perceived exertion (RPE) [ 151 , 152 , 153 , 154 ], muscle pain [ 151 , 155 , 156 , 157 ], and possibly the ability of skeletal muscle to generate force [ 151 ].

Caffeine does appear to have some direct effects on muscle which may contribute to its ergogenicity. The most likely pathway that caffeine may benefit muscle contraction is through calcium ion (Ca 2+ ) mobilization, which facilitates force production by each motor unit [ 138 , 139 , 150 , 158 ]. Fatigue caused by the gradual reduction of Ca 2+ release may be attenuated after caffeine ingestion [ 139 , 159 ]. Similarly, caffeine may work, in part, in the periphery through increased sodium/potassium (Na + /K + ) pump activity to potentially enhance excitation-contraction coupling necessary for muscle contraction [ 160 ]. Caffeine appears to employ its effects at various locations in the body, but the most robust evidence suggests that the main target is the CNS, which is now widely accepted as the primary mechanism by which caffeine alters mental and physical performance [ 141 ]. Caffeine is believed to exert its effects on the CNS via the antagonism of adenosine receptors, leading to increases in neurotransmitter release, motor unit firing rates, and pain suppression [ 151 , 155 , 156 , 157 , 161 ]. There are four distinct adenosine receptors, A 1 , A 2A , A 2B and A 3 , that have been cloned and characterized in several species [ 162 ]. Of these subtypes, A 1 and A 2A, which are highly concentrated in the brain, appear to be the main targets of caffeine [ 163 ]. Adenosine is involved in numerous processes and pathways, and plays a crucial role as a homeostatic regulator and neuromodulator in the nervous system [ 164 ]. The major known effects of adenosine are to decrease the concentration of many CNS neurotransmitters, including serotonin, dopamine, acetylcholine, norepinephrine and glutamate [ 163 , 164 , 165 ]. Caffeine, which has a similar molecular structure to adenosine, binds to adenosine receptors after ingestion and therefore increases the concentration of these neurotransmitters [ 163 , 165 ]. This results in positive effects on mood, vigilance, focus, and alertness in most, but not all, individuals [ 166 , 167 ].

Researchers have also characterized aspects of adenosine A 2A receptor function related to cognitive processes [ 168 ] and motivation [ 169 , 170 ]. In particular, several studies have focused on the functional significance of adenosine A 2A receptors and the interactions between adenosine and dopamine receptors, in relation to aspects of behavioral activation and effort-related processes [ 168 , 169 , 170 , 171 ]. The serotonin receptor 2A (5-HT2A) has also been shown to modulate dopamine release, through mechanisms involving regulation of either dopamine synthesis or dopaminergic neuron firing rate [ 172 , 173 ]. Alterations in 5-HTR2A receptors may therefore affect dopamine release and upregulation of dopamine receptors [ 174 , 175 ]. A possible mechanism for caffeine’s ergogenicity may involve variability in 5-HTR2A receptor activity, which may modulate dopamine release and consequently impact alertness, pain and motivation and effort [ 141 ]. 5-HTR2A receptors are encoded by the HTR2A gene, which serves as a primary target for serotonin signaling [ 176 ], and variations in the gene have been shown to affect 5-HTR2A receptor activity [ 177 , 178 ]. This may therefore modulate dopamine activity, which may help to elucidate some of the relationships among neurotransmitters, genetic variation and caffeine response, and the subsequent impact on exercise performance.

Muscle pain has been shown to negatively affect motor unit recruitment and skeletal muscle force generation proportional to the subjective scores for pain intensity [ 179 , 180 ]. In one study, progressively increased muscle pain intensity caused a gradual decrease in motor firing rates [ 179 ]. However, this decrease was not associated with a change in motor unit membrane properties demonstrating a central inhibitory motor control mechanism with effects correlated to nociceptive activity [ 179 ]. Other studies also indicate that muscle force inhibition by muscle pain is centrally mediated [ 181 ]. Accordingly, caffeine-mediated CNS mechanisms, such as dopamine release [ 182 ], are likely imputable for pain mitigation during high-intensity exercise [ 155 , 156 , 157 , 181 , 183 , 184 , 185 , 186 ]. Although there appears to be strong evidence supporting the analgesic effects of caffeine during intense exercise, others have found no effect [ 185 , 187 ].

The attenuation of pain during exercise as a result of caffeine supplementation may also result in a decrease in the RPE during exercise. Two studies [ 183 , 184 ] have reported that improvements in performance were accompanied by a decrease in pain perception as well as a decrease in RPE under caffeine conditions, but it is unclear which factor may have contributed to the ergogenic effect. Acute caffeine ingestion has been shown to alter RPE, where effort may be greater under caffeine conditions, yet it is not perceived as such [ 12 , 152 , 153 , 154 ]. A meta-analysis [ 12 ] identified 21 studies using mostly healthy male subjects (74%) between the ages of 20 and 35 years and showed a 5.6% reduction in RPE during exercise following caffeine ingestion. An average improvement in performance of 11% was reported across all exercise modalities. This meta-analysis established that reductions in RPE explain up to 29% of the variance in the improvement in exercise performance [ 12 ]. Others have not found changes in RPE with caffeine use [ 187 ]. A more recent study by Green et al. [ 188 ] also showed that when subjects were instructed to cycle at specific RPE (effort) levels under caffeine conditions, the higher perceived intensity did not necessarily result in greater work and improved performance in all subjects equally. The authors noted that individual responses to caffeine might explain their unexpected findings.

In the last decade, our understanding of CNS fatigue has improved. Historically, it is well- documented that “psychological factors” can affect exercise performance and that dysfunction at any step in the continuum from the brain to the peripheral contractile machinery will result in muscular fatigue [ 189 , 190 ]. The role of the CNS and its ‘motor drive’ effect was nicely shown by Davis et al. [ 191 ] who examined the effect of caffeine injected directly into the brains of rats on their ability to run to exhaustion on a treadmill. In this controlled study, rats were injected with either vehicle (placebo), caffeine, 5′-N-Ethylcarboxamido adenosine (NECA), an adenosine receptor agonist, or caffeine NECA together. Rats ran 80 min in the placebo trial, 120 min in the caffeine trial and only 25 min with NECA. When caffeine and NECA were given together, the effects appeared to cancel each other out, and run time was similar to placebo. When the study was repeated with peripheral intraperitoneal (body cavity) injections instead of brain injections, there was no effect on run performance. The authors concluded that caffeine increased running time by delaying fatigue through CNS effects, in part by blocking adenosine receptors [ 191 ]. Caffeine also appears to enhance cognitive performance more in fatigued than well-rested subjects [ 192 , 193 , 194 ]. This phenomenon is also apparent in exercise performance [ 195 ] both in the field [ 196 ] and in the lab [ 60 , 63 , 149 ].

The placebo effect

The placebo effect is a beneficial outcome that cannot be attributed to a treatment or intervention but is brought about by the belief that one has received a positive intervention. For example, an individual may ingest a capsule with sugar or flour (a small amount of non-active ingredient) but believes that he/she ingested caffeine and experiences improvements in performance because of this belief [ 197 ]. The nocebo effect is directly opposite to this in that a negative outcome occurs following the administration of an intervention or lack of an intervention (e.g. knowingly ingesting a placebo) [ 198 ]. For example, the nocebo may be a substance without medical effects, but which worsens the health status of the person taking it by the negative beliefs and expectations of the patient. Similarly, the nocebo may be a ‘caffeine placebo’, where an individual’s performance is worse based on the belief that they did not ingest caffeine.

Several studies have provided evidence for placebo effects associated with caffeine ingestion [ 199 , 200 , 201 ] or other “beneficial” interventions [ 202 ] during exercise. An example of this was reported in a study [ 200 ] where well-trained cyclists exhibited a linear dose–response relationship in experimental trials from baseline to a moderate (4.5 mg/kg) and high dose (9 mg/kg) of caffeine respectively. Athletes improved as the perceived caffeine doses increased; however, a placebo was used in all interventions. Similarly, Saunders et al. [ 201 ] found that correct identification of caffeine appears to improve cycling performance to a greater extent than the overall effect of caffeine, where participants who correctly identified placebo showed possible harmful effects on performance. Therefore, readers are encouraged to consider whether studies that have explored the effects of caffeine on exercise have examined and reported the efficacy of the blinding of the participants.

Caffeine and endurance exercise

Less than a 1% change in average speed is enough to affect medal rankings in intense Olympic endurance events lasting ~ 45 s to 8 min [ 203 ]. In other events, such as the men’s individual road race, the difference between the top three medalists was < 0.01% [ 204 ]. At the highest level of sports, competitors will be near their genetic potential, will have trained intensively, followed prudent recovery protocols, and will have exploited all strategies to improve their performance—the use of an ergogenic aid, when legal, safe and effective, is an alluring opportunity.

Caffeine has consistently been shown to improve endurance by 2–4% across dozens of studies using doses of 3–6 mg/kg body mass [ 13 , 195 , 205 , 206 , 207 ]. Accordingly, caffeine is one of the most prominent ergogenic aids and is used by athletes and active individuals in a wide variety of sports and activities involving aerobic endurance. Caffeine has been shown to benefit several endurance-type sports including cycling [ 60 , 206 , 208 ], running [ 91 , 209 , 210 ] cross-country skiing [ 211 ] and swimming [ 212 ].

Much of the caffeine-exercise body of literature has focused on endurance-type exercise, as this is the area in which caffeine supplementation appears to be more commonly used and likely beneficial in most, but not all, athletes [ 11 , 12 , 13 ]. For example, the caffeine concentration in over twenty thousand urine samples obtained for doping control from 2004 to 2008 was measured after official national and international competitions [ 110 , 115 ]. The investigations concluded that roughly 74% of elite athletes used caffeine as an ergogenic aid prior to or during a sporting event, where endurance sports are the disciplines showing the highest urine caffeine excretion (and therefore prevalence) after competition [ 110 , 115 ].

A recent meta-analysis reporting on 56 endurance time trials in athletes (79% cycling), found the percent difference between the caffeine and placebo group ranged from − 3.0 to 15.9% [ 195 ]. This wide range in performance outcomes highlights the substantial inter-individual variability in the magnitude of caffeine’s effects as reported. These inter-individual differences might be due to the methodological differences between the studies, habitual caffeine intake of the participants, and/or partly due to variation in genes that are associated with caffeine metabolism and caffeine response [ 213 ].

A recent systematic review was carried out on randomised placebo-controlled studies investigating the effects of caffeine on endurance performance and a meta-analysis was conducted to determine the ergogenic effect of caffeine on endurance time-trial performance [ 205 ]. Forty-six studies met the inclusion criteria and were included in the meta-analysis. This meta-analysis found that caffeine has a small but significant effect on endurance performance when taken in moderate doses (3–6 mg/kg) as well as an overall improvement following caffeine compared to placebo in mean power output of 2.9 ± 2.2% and a small effect size of 0.22 ± 0.15. Time-trial completion time showed improvements of 2.3 ± 2.6% with a small effect size of 0.28 ± 0.12. However, there was some variability in outcomes with responses to caffeine ingestion, with two studies reporting slower time-trial performance, and five studies reporting lower mean power output during the time–trial [ 205 ].

In summary, caffeine has been consistently shown to be effective as an ergogenic aid when taken in moderate doses (3–6 mg/kg), during endurance-type exercise and sport. Dozens of endurance studies are highlighted through this review is various sections, showing consistent yet wide-ranging magnitudes of benefit for endurance performance under caffeine conditions.

Caffeine and muscular endurance, strength and power

Strength and power development through resistance exercise is a significant component of conditioning programs for both fitness and competitive sport. The most frequently consumed dose of caffeine in studies using strength tasks with trained or untrained individuals usually ranges from 3 to 6 mg/kg body mass (with 2 mg to 11 mg representing the entire range), ingested in the form of pills or capsules 30 to 90 min before exercise. In resistance exercise, strength is most commonly assessed using 1 repetition maximum (1RM) [ 214 ], or different isometric and isokinetic strength tests [ 215 ]. Muscular endurance assesses the muscle’s ability to resist fatigue and is an important quality in many athletic endeavors (e.g., swimming, rowing). Muscular endurance may be tested with repetitions of squats, maximal push-ups, bench press exercises (load corresponding to 60–70% of 1RM) to momentary muscular failure, or by isometric exercises such as the plank or static squat [ 216 , 217 ].

Although several studies exploring the effects of caffeine on strength performance have been published since the 2010 ISSN caffeine position stand [ 40 ], some uncertainty surrounding the benefits of caffeine in activities involving muscular endurance, strength and power remains.

Caffeine was shown to be ergogenic for muscular endurance in two meta-analyses reporting effect sizes ranging from 0.28 to 0.38 (percent change range: 6 to 7%) [ 158 , 218 ]. However, others have shown that it enhances strength but not muscular endurance [ 219 , 220 ], and when studies have examined multiple strength-muscular endurance tasks, there were benefits across the board [ 67 , 221 ], none at all [ 98 , 222 ], or even impairments in muscular endurance with caffeine use [ 222 , 223 ]. Ingesting caffeine prior to a muscular endurance task is likely to delay muscular fatigue, but these effects are not consistent among all studies.

Three meta-analyses explored the acute effects of caffeine on strength, and all reported ergogenic effects [ 158 , 224 , 225 ]. However, the effects in these meta-analyses were small, ranging from 0.16 to 0.20 (percent change: 2 to 7%). Such small improvements in muscular strength likely have the greatest practical meaningfulness for athletes competing in strength-based sports, such as powerlifting and weightlifting (athletes which already seem to be among the highest users of caffeine [ 110 ]).

Power output is often measured during a single-bout sprinting task using the Wingate test, which generally consists of ‘all-out’ cycling for 30 s performed at specific external loads (e.g., 7.5% of body mass). Power output is also assessed during different protocols of intermittent-sprinting and repeated-sprints often with the Wingate cycling test as well as assessments during running [ 226 ] or swimming repeated sprints [ 212 ].

The data for repeated sprint and power performance using Wingate data has been mixed. In an older study, 10 male team-sport athletes performed 18, 4-s sprints with 2-min active recovery [ 227 ]. Here, caffeine ingestion (6 mg/kg) enhanced mean power output and sprint work by 7 and 8.5%, respectively [ 227 ]. A more recent study examining the effects of acute caffeine ingestion on upper and lower body Wingate performance in 22 males did not report significant findings when measuring lower body mean and peak power using the Wingate test [ 228 ]. An older study by Greer et al. [ 229 ] also failed to report caffeine benefits on power output during a 30-s high-intensity cycling bout using the Wingate test. One meta-analysis reported that caffeine ingestion enhances mean and peak power during the Wingate test [ 230 ], although the effect sizes of 0.18 (+ 3%) and 0.27 (+ 4%), respectively are modest. In contrast, another meta-analysis that examined the effects of caffeine on muscle power as assessed with the Wingate test for three of the studies, and repeated sprints for a maximum of 10-s for the fourth, did not report benefits from ingestion of caffeine [ 231 ]. An average caffeine dose of 6.5 mg/kg of body mass was used across the four studies with no improvements in muscle power under caffeine conditions (effect size = 0.17, p  = 0.36) compared to placebo trials, although the data collected spanned only 5 years [ 231 ]. A study by Lee et al. [ 232 ] reported that caffeine ingestion enhanced sprint performance involving a 90-s rest interval (i.e., intermittent-sprinting) but did not benefit repeated-sprints with a 20-s rest interval. This might suggest that the rest interval between sprints may modulate the ergogenic effects of caffeine. Indeed, a recent meta-analysis that focused on the effects of caffeine on repeated-sprint performance reported that total work, best sprint, and last sprint performance was not affected by caffeine ingestion [ 226 ].

Several studies have also shown substantial variability in outcomes. For example, one study [ 63 ] found that only 13 of 20 cyclists improved their performance with ~ 3–4 mg/kg of caffeine, while the remaining participants either worsened or did not alter their performance. Similarly, Woolf et al. [ 233 ] found that 5 mg/kg of caffeine improved overall peak power performance on the Wingate Test in 18 elite or professional athletes. However, 4 (28%) of the participants did not improve their performance with caffeine. Average power, minimum power, and power drop were not significantly different between treatments, but 72% of the participants obtained a greater peak power during the caffeine trial than during the placebo trial. There was also no overall improvement in average power or fatigue index, despite 13 (72%), and 9 (50%) of the participants, respectively, improving their performance. In summary, caffeine ingestion may be beneficial to enhance single and intermittent-sprint performance, while caffeine’s effects on repeated-sprint performance are inconsistent and require further research to draw stronger conclusions on the topic.

Ballistic movements (such as throws and jumps) are characterized by high motor unit firing rates, brief contraction times, and high rates of force development [ 234 ]. Many studies have explored the effects of caffeine on jumping performance [ 225 , 235 ]. The body of evidence has indicated that caffeine supplementation increases vertical jump height during single and repeated jumps; however, the magnitude of these effects is rather modest, with effect sizes ranging from 0.17 to 0.22 (2 to 4%) [ 225 , 235 ]. Besides jumping, several studies have explored the effects of caffeine on throwing performance. These studies reported that: (a) caffeine ingestion enhanced maximal shot put throwing distance in a group of 9 nine inter-collegiate track and field athletes [ 65 ]; and (b) caffeine ingestion at a dose of 6 mg/kg of body mass administered 60 min pre-exercise increased maximal medicine ball throwing distance [ 236 ]. Overall, the current body of evidence indicates that caffeine supplementation may be useful for acute improvements in ballistic exercise performance in the form of jumps and throws. However, more research is needed to explore the effects of caffeine on different throwing exercise tests, as this has been investigated only in a few studies.

Generally, the primary sports-related goal of strength and power-oriented resistance training programs is to move the force-velocity curve to the right, indicating an ability of the athlete to lift greater loads at higher velocities [ 237 ]. Several studies have explored the effects of caffeine on movement velocity and power in resistance exercise using measurement tools such as linear position transducers [ 238 ]. These studies generally report that caffeine ingestion provides ergogenic effects of moderate to large magnitudes, with similar effects noted for both mean and peak velocity, and in upper and lower-body exercises [ 67 , 221 , 239 ]. Even though this area merits further research to fill gaps in the literature, the initial evidence supports caffeine as an effective ergogenic aid for enhancing velocity and power in resistance exercise.

Caffeine and sport-specific performance

Even though caffeine ingestion may enhance performance in the laboratory, there has been a paucity of evidence to support that these improvements transfer directly to sport-specific performance. To address this issue, several studies have also explored the effects of caffeine on sport-specific exercise tasks using sport simulation matches. Many studies conducted among athletes competing in team and individual sports, report that caffeine may enhance performance in a variety of sport tasks. However, there are also several studies that report no effects as outlined below:

Basketball – increased jump height, but only in those with the AA version of the CYP1A2 gene [ 240 ], increased number of free throws attempted and free throws made, increased number of total and offensive rebounds [ 241 ], but did not improve sprint time [ 240 ], nor dribbling speed [ 242 ]

Soccer – increased total distance covered during the game, increased passing accuracy, and jumping height [ 94 , 243 , 244 ], but the consumption of a caffeinated energy drink did not enhance performance in the “T test” in female soccer players [ 245 ], nor during match play in young football players [ 246 ]

Volleyball – increased number of successful volleyball actions and decreased the number of imprecise actions [ 247 , 248 ], although caffeine did not improve physical performance in multiple sport-specific tests in professional females [ 249 ], nor performance in volleyball competition [ 250 ]

Football - did not improve performance for anaerobic exercise tests used at the NFL Combine [ 251 ]

Rugby – increased the number of body impacts, running pace, and muscle power during jumping [ 252 , 253 ], but did not impact agility [ 254 ]

Field hockey – increased high-intensity running and sprinting [ 255 ], and may offset decrements in skilled performance associated with fatigue [ 256 ]

Ice-hockey - has limited impact on sport-specific skill performance and RPE, but may enhance physicality during scrimmage [ 257 ]

Combat sports – increased number of offensive actions and increased the number of throws [ 258 ]

Cross-country skiing – reduced time to complete a set distance [ 259 ] and improved time to task failure [ 211 ]

In summary, although reviews of the literature show that caffeine ingestion is, on average , ergogenic for a wide range of sport-specific tasks, its use might not be appropriate for every athlete. Specifically, the use of caffeine needs to be balanced with the associated side-effects and therefore experimentation is required in order to determine the individual response before assessing whether the benefits outweigh the costs for the athlete. Athletes should gauge their physical response to caffeine during sport practice and competition in addition to monitoring mood state and potentially disrupted sleep patterns.

Interindividual variation in response to caffeine

There is a lack of research examining potential interindividual differences in strength or anaerobic power-type exercise, but this is not the case for endurance exercise. In the myriad of studies examining caffeine on endurance performance, the benefits of caffeine do not appear to be influenced by sex, age, VO 2 max, type of sport, or the (equivalent) dose of caffeine [ 13 , 195 , 260 ]. Nevertheless, there appears to be substantial interindividual variability in response to caffeine under exercise conditions, which may be attributed to several factors outlined below.

Genetic variants affect the way we absorb, metabolize, and utilize and excrete nutrients, and gene-diet interactions that affect metabolic pathways relevant to health and performance are now widely recognized [ 261 ]. In the field of nutrigenomics, caffeine is the most widely researched compound with several randomized controlled trials investigating the modifying effects of genetic variation on exercise performance [ 75 , 208 , 262 , 263 ].

Numerous studies have investigated the effect of supplemental caffeine on exercise performance, but there is considerable inter-individual variability in the magnitude of these effects [ 11 , 13 , 44 ] or in the lack of an effect [ 264 , 265 ], when compared to placebo. Due to infrequent reporting of individual data it is difficult to determine the extent to which variation in responses may be occurring. The performance of some individuals is often in stark contrast to the average findings reported, which may conclude beneficial, detrimental, or no effect of caffeine on performance. For example, Roelands et al. [ 265 ] reported no ergogenic effect of caffeine in a study involving trained male cyclists. The authors concluded that inter-individual differences in response to caffeine might be responsible for the lack of overall performance improvement, as 50% of subjects improved while 50% worsened, in the caffeine compared to the placebo trial.

These inter-individual differences appear to be partly due to variations in genes such as CYP1A2 and possibly ADORA2A , which are associated with caffeine metabolism, sensitivity and response [ 213 ]. Over 95% of caffeine is metabolized by the CYP1A2 enzyme, which is encoded by the CYP1A2 gene and is involved in the demethylation of caffeine into the primary metabolites paraxanthine, theophylline and theobromine [ 127 ]. The -163A > C (rs762551) single nucleotide polymorphism (SNP) has been shown to alter CYP1A2 enzyme inducibility and activity [ 132 , 134 ], and has been used to categorize individuals as ‘fast’ or ‘slow’ metabolizers of caffeine. In the general population, individuals with the AC or CC genotype (slow metabolizers) have an elevated risk of myocardial infarction [ 266 ], hypertension and elevated blood pressure [ 267 , 268 ], and pre-diabetes [ 269 ], with increasing caffeinated coffee consumption, whereas those with the AA genotype show no such risk. Additionally, regular physical activity appears to attenuate the increase in blood pressure induced by caffeine ingestion, but only in individuals with the AA genotype [ 268 ].

The largest caffeine, genetics and exercise study to date [ 208 ] examined the effects of caffeine and CYP1A2 genotype on 10-km cycling time trial performance in competitive male athletes (both endurance and power sports) after ingestion of placebo, and caffeine doses of 2 mg (low dose) or 4 mg (moderate dose) per kg body mass. There was a 3% improvement in cycling time with the moderate dose in all subjects, which is consistent with previous studies using similar doses [ 13 , 206 ]. However, there was a significant caffeine-gene interaction; improvements in performance were seen at both caffeine doses, but only in those with the AA genotype who are ‘fast metabolizers’ of caffeine. In that group, a 6.8% improvement in cycling time was observed at 4 mg/kg, which is greater than the 2–4% mean improvement seen in several other studies using cycling time trials and similar doses [ 13 , 201 , 206 , 207 , 270 , 271 , 272 ]. Among those with the CC genotype (i.e., “slow metabolizers”), 4 mg/kg caffeine impaired performance by 13.7%, whereas no difference was observed between the placebo and 2 mg/kg caffeine trials. In those with the AC genotype there was no effect of either dose [ 208 ]. The findings are consistent with a previous study [ 263 ] that observed a caffeine-gene interaction indicating improved time trial cycling performance following caffeine consumption only in those with the AA genotype.

In contrast, previous studies either did not observe any impact of the CYP1A2 gene in caffeine-exercise studies [ 273 , 274 ], or reported benefits only in slow metabolizers [ 75 ]. There are several reasons that may explain discrepancies in study outcomes. These include smaller samples sizes with few and/or no subjects in one genotype [ 75 , 273 , 274 ], as well as shorter distances or different types of performance test (power versus endurance) [ 75 ] compared to the aforementioned trials, which reported improved endurance after caffeine ingestion in those with the CYP1A2 AA genotype [ 208 , 263 ]. The effects of genotype on performance might be the most prominent during training or competition of longer duration or an accumulation of fatigue (aerobic or muscular endurance) [ 149 ], where caffeine appears to provide its greatest benefits, and where the adverse effects to slow metabolizers are more likely to manifest [ 195 , 260 ]. Indeed, in a study of performance in elite basketball players [ 240 ], only in those with the AA genotype caffeine improved repeated jumps which requires maintaining velocity at take-off repeatedly as an athlete fatigues throughout a game (muscular endurance) - even though there was no caffeine-genotype interaction effect for this outcome. However, caffeine similarly improved performance in those with the both AA and C-genotypes during a simulated basketball game [ 240 ]. In a cross-over design of 30 resistance-trained men, caffeine ingestion resulted in a higher number of repetitions in repeated sets of three different exercises, and for total repetitions in all resistance exercises combined, which resulted in a greater volume of work compared to placebo conditions, but only in those with the CYP1A2 AA genotype [ 262 ]. Although more research is warranted, there is a growing body of evidence to support the role of CYP1A2 in modifying the effects of caffeine ingestion on aerobic or muscular endurance-type exercise, which helps to determine which athletes are most likely to benefit from caffeine.

The ADORA2A gene is another genetic modifier of the effects of caffeine on performance. The adenosine A 2A receptor, encoded by the ADORA2A gene, has been shown to regulate myocardial oxygen demand and increase coronary circulation by vasodilation [ 275 , 276 ]. The A 2A receptor is also expressed in the brain, where it has significant roles in the regulation of glutamate and dopamine release, with associated effects on insomnia and pain [ 277 , 278 ]. The antagonism of adenosine receptors after caffeine ingestion is modified by the ADORA2A gene, which may allow greater improvements in dopamine transmission and lead to norepinephrine and epinephrine release due to increased neuronal firing [ 168 ] in some genotypes versus others. Dopamine has been associated with motivation and effort in exercising individuals, and this may be the mechanism by which differences in response to caffeine are manifested [ 141 , 168 , 169 ].

Currently, only one small pilot study has examined the effect of the ADORA2A gene (rs5751876) on the ergogenic effects of caffeine under exercise conditions [ 279 ]. Twelve female subjects underwent a double-blinded, crossover trial comprising two 10-min cycling time trials following caffeine ingestion or placebo. Caffeine benefitted all six subjects with the TT genotype, but only one of the six C allele carriers. Further studies are needed to confirm these preliminary findings and should include a large enough sample to distinguish any effects between the different C allele carriers (i.e. CT vs. CC genotypes) and potential effects related to sex.

The ADORA2A rs5751876 genotype has also been implicated, by both objective and subjective measures, in various parameters of sleep quality after caffeine ingestion in several studies [ 280 , 281 , 282 , 283 ]. Adenosine promotes sleep by binding to its receptors in the brain, mainly A 1 and A 2A receptors, and caffeine exerts an antagonist effect, blocking the receptor and reversing the effects of adenosine and promoting wakefulness [ 280 ]. This action, as well as the potency of caffeine to restore performance (cognitive or physical) in ecological situations, such as highway-driving during the night [ 284 ], supports the notion that the adenosine neuromodulator/receptor system is significantly involved in sleep–wake regulation. This action of caffeine may also serve athletes well under conditions of jetlag, and irregular or early training or competition schedules. Psychomotor speed relies on the ability to respond, rapidly and reliably, to randomly occurring stimuli which is a critical component of, and characteristic of, most sports [ 285 ]. Genetic variation in ADORA2A has been shown to be a relevant determinant of psychomotor vigilance in the rested and sleep-deprived state and modulates individual responses to caffeine after sleep deprivation [ 282 ]. Those with the CC genotype of ADORA2A rs5751876 consistently performed on a higher level on the sustained vigilant attention task than T-allele -carriers; however, this was tested in ADORA2A haplotypes that included combinations of 8 SNPs. This work provides the basis for future genetic studies of sleep using individual ADORA2A SNPs.

As mentioned, the ADORA2A genotype has also been implicated in sleep quality and increases in sleep disturbance [ 283 ]. Consistent with the “adenosine hypothesis” of sleep where the accumulation of adenosine in the brain increases sleep propensity, caffeine prolongs time to fall asleep, decreases the deep stages of non-rapid-eye movement (nonREM) sleep, reduces sleep efficiency, and alters the waking and sleep electroencephalogram (EEG) frequencies, which reliably reflect the need for sleep [ 286 , 287 , 288 ]. Increased beta activity in nonREM sleep may characterize individuals with insomnia when compared with healthy good sleepers [ 289 ]. A functional relationship between the ADORA2A genotype and the effect of caffeine on EEG beta activity in nonREM sleep has previously been reported [ 281 ], where the highest rise was in individuals with the CC genotype, approximately half in the CT genotype, whereas no change was present in the TT genotype. Consistent with this observation, the same study found individuals with the CC and TC genotypes appeared to confer greater sensitivity towards caffeine-induced sleep disturbance compared to the TT genotype [ 281 ]. This suggests that a common variant in ADORA2A contributes to subjective and objective responses to caffeine on sleep.

Caffeine, genetics and anxiety

In elite athletes, 50% face mental health issues sometime during their career [ 290 ]. Given that anxiety may be normalized in elite sports even at clinical levels, factors that contribute to anxiety should be mitigated whenever possible. Anxiety may be caused by stress-related disorders (burnout), poor quality sleep patterns (often related to caffeine intakes) and possibly as a response to caffeine ingestion due to genetic variation, even at low levels [ 109 ].

As previously mentioned, caffeine blocks adenosine receptors, resulting in the stimulating effects of caffeine [ 213 ]. A common variation in the ADORA2A (adenosine A 2A receptor) gene contributes to the differences in subjective feelings of anxiety after caffeine ingestion [ 291 , 292 ], especially in those who are habitually low caffeine consumers [ 293 ]. This may be particularly relevant to athletes who possess the TT variant of rs5751876 in the ADORA2A gene. These individuals are likely to be more sensitive to the stimulating effects of caffeine and experience greater increases in feelings of anxiety after caffeine intake than do individuals with either the CT or CC variant [ 291 , 292 , 293 ].

Sport psychologists commonly work with athletes to help them overcome anxiety about performance during competitions. Anxiety before or during athletic competitions can interfere not only in performance, but also in increased injury risk [ 294 ]. Athletes who are more prone to performance anxiety may exacerbate their risk for feelings of anxiety depending on their caffeine use and which variant of the ADORA2A gene they possess. Monitoring the actions of caffeine in those individuals who are susceptible, may alleviate some of the related feelings of anxiety with caffeine use. Given that anxiety may disrupt concentration and sleep and negatively impact social interactions, athletes with higher risks and prevalence for anxiety, may want to limit or avoid caffeine consumption (if caffeine is a known trigger) during times where they are feeling anxious or stressed, such as at sporting competitions or social gatherings or other work and school events.

The importance of both sleep and caffeine (as an ergogenic aid) to athletes highlights the importance of optimizing rest and recovery through a better understanding of which athletes may be at greater risk of adverse effects of caffeine on mood and sleep quality, possibly due to genetic variation. This information will allow athletes and coaching staff to make informed decisions on when and if to use caffeine when proximity to sleep is a factor. These considerations will also be in conjunction with the possibility that an athlete will benefit from caffeine in endurance-based exercise as determined in part, by their CYP1A2 genotype, albeit with a clear need for future research.

Habitual caffeine intake

The quantification of habitual caffeine intake is difficult, which is problematic for studies aiming to compare performance outcomes following caffeine ingestion in habitual versus non-habitual caffeine users. This concern is highlighted by reports showing large variability in the caffeine content of commonly consumed beverages, e.g. ~ 8- to 9-fold differences in caffeine content have been reported in coffee beverages purchased from similar retail shops [ 295 ] and in pre-workout supplements [ 296 ]. Self-reported intakes may therefore be unreliable. Newly discovered biomarkers of coffee consumption may be more useful for quantifying intakes in the future, but currently, these are not widely available [ 297 ]. Different protocols for the length of the caffeine abstinence period preceding data collection is also a relevant factor in determining variability in performance outcomes. For example, in shorter caffeine abstinence periods e.g., 12–48 h, reversal of caffeine withdrawal effects by acute caffeine supplementation may have positive effects on performance, i.e. alleviating the negative symptoms of withdrawal, which in itself may improve performance [ 298 ]. These effects may be more pronounced in those genetically predisposed to severe withdrawal effects [ 299 ]. However, in one study 3 mg/kg caffeine significantly improved exercise performance in trained cyclists ( n  = 12), irrespective of whether a 4-day withdrawal period was imposed on habitual caffeine users [ 300 ]. Another study also reported increased endurance in habitual caffeine users ( n  = 6) regardless of a 0, 2- or 4-day abstinence period. The authors concluded that improved performance under caffeine conditions at 6 mg/kg is not related to prior caffeine habituation in recreational athletes [ 301 ]. Although genes have been associated with habitual caffeine intake using GWAS research [ 302 , 303 ], it is important to highlight that these associations are not directly applicable to determining differences in performance outcomes in response to acute caffeine doses for regular or habitual caffeine users versus non-habitual users. The “caffeine habits” of individuals are more likely related to their personal experience with adverse effects such as feel jittery, experiencing tachycardia or insomnia. Furthermore, associations between genes and habitual caffeine intake do not elucidate potential mechanisms by which caffeine intake behaviors may influence subsequent performance following caffeine supplementation [ 304 , 305 ]. In animal model studies, regular consumption of caffeine has been associated with an upregulation of the number of adenosine receptors in the vascular and neural tissues of the brain [ 306 ]. Although, this did not appear to modify the effects of caffeine in one study [ 307 ], in another, chronic caffeine ingestion by mice caused a marked reduction in locomotor exploratory activity [ 308 ]. Changes in adenosine receptor number or activity have not been studied in humans.

There does not appear to be a consistent difference in the performance effects of acute caffeine ingestion between habitual and non-habitual caffeine users, and study findings remain equivocal. In one study, habitual stimulation from caffeine resulted in a general dampening of the epinephrine response to both caffeine and exercise; however, there was no evidence that this impacted exercise performance [ 309 ]. Another study [ 310 ] examined the effect of 4 weeks of caffeine supplementation on endurance performance in 18 low-habitual caffeine consumers who were randomly assigned to ingest caffeine or placebo for 28 days. Four weeks of caffeine ingestion resulted in increased tolerance to acute caffeine supplementation in previously low habitual caffeine consumers, with the ergogenic effect of acute caffeine supplementation no longer apparent [ 310 ]. These results are in contrast with a recent study in which 20 days of consecutive supplementation with caffeine maintained an ergogenic effect, even though the effect size attenuated over time [ 311 ]. More recently, a double-blind, crossover, counterbalanced study was performed [ 312 ], where 40 endurance-trained male cyclists were allocated into tertiles according to their daily caffeine intake: low (58 ± 29 mg), moderate (143 ± 25 mg), and high consumers (351 ± 139 mg). Participants completed three trials in which they performed simulated cycling time-trials under three conditions: caffeine (6 mg/kg), placebo, and no supplement (control). Caffeine ingestion improved performance as compared to placebo and control, with no influence of habitual caffeine intake. Additionally, no correlation was observed between habitual caffeine intake and absolute changes in a ~ 30 min cycling time-trial performance with caffeine [ 312 ]. However, a limitation of this study is the short 24-h caffeine withdrawal period in all groups which may have resulted in performance improvements due to the reversal of caffeine withdrawal effects, rather than impact of acute-on-chronic caffeine administration and the effects of habituation to caffeine on exercise performance [ 298 , 313 ]. In addition, habitual caffeine intake was estimated using a food frequency questionnaire, which might be a limitation given the already mentioned variation of caffeine in coffee and different supplements.

There is wide variability in caffeine content of commonly consumed items, and as such, an objective measure (e.g., caffeine or metabolite levels) might be considered to reported caffeine intakes [ 297 , 313 ]. Based on these observations, the assumption that habitual and nonhabitual caffeine consumers will or will not respond differently to caffeine supplementation during exercise, requires further study.

Caffeine timing

The most common timing of caffeine supplementation is 60 min before exercise. This timing is used given that it is believed that 60 min post-ingestion, plasma levels of caffeine are at maximal values [ 314 ]. However, caffeine appears to be most beneficial during times or in sports where there is an accumulation of fatigue, i.e., exercise over a longer continuous or intermittent duration [ 64 ]. Therefore, ingestion of caffeine during exercise (mid/later stages) may be more beneficial than ingestion beforehand for some individuals depending upon the length of the event. A recent review [ 195 ] reported that the effect size of caffeine benefits increase with the increasing duration of the time trial event, meaning that timing caffeine intake closer to a time of greater fatigue, i.e., later in the race, may be most beneficial. This supports the notion that endurance athletes (with longer races) may benefit most from caffeine for performance enhancement since they have the greatest likelihood of being fatigued. This also supports findings in other investigations that show ingesting caffeine at various time points including late in exercise may be most beneficial [ 196 ].

For example, an early study [ 196 ] aimed to understand whether or not there were benefits to a common practice among endurance athletes, such as those participating in marathons and triathlons, which is to drink flat cola toward the end of an event. When researchers investigated the ingestion of a low dose of caffeine toward the end of a race (e.g., in the form of flat cola) it was found to have comparable effects as ingesting higher doses, such as ~ 5 or 6 mg/kg, ingested ~ 60 min before the race. The study also demonstrated that the effect was due to the caffeine and not the carbohydrate, which may also aid performance as fuel stores become depleted [ 196 ].

More recently, caffeine gum ingestion enhanced cycling performance when it was administered immediately prior to exercise, but not when administered 1 or 2 h beforehand. This may have been due to the faster absorption with caffeinated gum consumption, and due to the continued increase in plasma caffeine concentrations during the cycling time trial, when athletes may become fatigued (i.e. 30 + minutes into exercise), as the trials also included a 15 min steady-state cycling bout prior to the time trial [ 60 ]. Similarly, in a lab setting, a study of athletes completing 120 min of steady-state cycling followed by a time trial under conditions of placebo and caffeine, found that the ingestion of both low and moderate doses of caffeine later in exercise were beneficial [ 149 ]. However, there was significant interindividual variability, highlighting the need for athletes to experiment with their own strategies as far as dosing and timing are concerned.

The optimal timing of caffeine ingestion may depend on the source of caffeine. As stated earlier, some of the alternate sources of caffeine such as caffeine chewing gums may absorb more quickly than caffeine ingested in caffeine-containing capsules [ 60 ]. Therefore, individuals interested in supplementing with caffeine should consider that timing of caffeine ingestion will likely be influenced by the source of caffeine.

Training status

Training status may mediate the magnitude of caffeine’s ergogenic effect, but studies have reported mixed results. Although a 2010 meta-analysis [ 158 ] did not find differences ( p  = 0.08) in caffeine’s ability to enhance muscle endurance in untrained subjects versus trained subjects, these results were not derived from direct comparisons between trained and untrained subjects. Currently, only a few investigations [ 96 , 210 , 315 , 316 , 317 , 318 ] have included both trained and untrained subjects in their study design.

In a study of elite and occasional swimmers [ 318 ], it was reported that 250 mg of supplemental caffeine was ergogenic only for competitive swimmers and not recreational swimmers. A limitation of this study is that the swimming exercise task differed between the trained and untrained participants. Specifically, the study utilized 1600-m swimming for the trained swimmers and 400-m for the untrained swimmers, which is a likely explanation for these findings. However, some have also postulated that this is because athletes perform more reliably on a given task than nonathletes, and increased test-retest reliability might prevent type II errors [ 319 ]. In contrast to the above evidence regarding the importance of training status, other research has shown that training status does not moderate the ergogenic effects of caffeine on exercise performance. One study [ 210 ] showed similar performance improvements (1.0 and 1.1%) in 15 well-trained and 15 recreational runners performing an outdoor 5 km time trial after 5 mg/kg caffeine intake compared to the placebo trial. Similarly, Astorino et al. [ 96 ] found that overall, acute caffeine intake improved 10 km time-trial performance in both endurance-trained athletes and active men, with no differences seen between groups. Likewise, an investigation concluded that there was no ergogenic effect of caffeine at a dose of 5 mg/kg on time to exhaustion in either endurance trained or untrained men [ 315 ].

More recently, a small study by Boyett et al. [ 317 ] investigated the interactions of 6 mg/kg caffeine on training status and time of day in 20 male subjects. Subjects completed four experimental trials consisting of a 3-km cycling time trial performed in randomized order for each combination of time of day (morning and evening) and treatment. They reported that both untrained and trained subjects improved performance with caffeine supplementation in the morning; however, only the untrained subjects improved when tested in the evening. Although there were some limitations to this study, these observations indicate that trained athletes are more likely to experience ergogenic effects from caffeine in the morning, while untrained individuals appear to receive larger gains from caffeine in the evening than their trained counterparts. This may further complicate the training status data with a possible temporal effect [ 317 ]. The concentration of adenosine receptors (the primary target of caffeine) do appear to be higher in trained compared to untrained individuals, but this has only been reported in animal studies [ 320 ]. Boyett et al. [ 317 ] speculated that the higher concentration of adenosine receptors may increase tissue sensitivity to any given concentration of adenosine.

Although some studies comparing training status of subjects support the notion [ 318 ] that training influences response to caffeine during exercise, most do not [ 96 , 210 , 315 ] and this was also the finding in a subsequent meta-analysis [ 158 ]. It is possible that the only difference between trained and untrained individuals is that trained individuals likely have the mental discipline to exercise long or hard enough to benefit more from the caffeine stimulus, which might provide an explanation for why in some studies, trained individuals respond better to caffeine [ 314 ]. Currently, it seems that trained and untrained individuals experience similar improvements in performance following caffeine ingestion; however, more research in this area is warranted.

Caffeine and sleep

The impacts of caffeine on sleep and behavior after sleep deprivation are widely reported [ 321 ]. Sleep is recognized as an essential component of physiological and psychological recovery from, and preparation for, high-intensity training in athletes [ 322 , 323 ]. Chronic mild to moderate sleep deprivation in athletes, potentially attributed to caffeine intakes, may result in negative or altered impacts on glucose metabolism, neuroendocrine function, appetite, food intake and protein synthesis, as well as attention, learning and memory [ 323 ]. These factors can all influence an athlete’s nutritional, metabolic, and endocrine status negatively and hence potentially affect energy levels, muscle repair, immunity, body composition, memory and learning and result in diminished athletic performance [ 324 , 325 ].

Objective sleep measures using actigraphy or carried out in laboratory conditions with EEG have shown that caffeine negatively impacts several aspects of sleep quality such as: sleep latency (time to fall asleep), WASO (wake time after sleep onset), sleep efficiency and duration [ 321 ]. Studies in athletes have also shown adverse effects in sleep quality and markers for exercise recovery after a variety of doses of caffeine ingestion [ 326 , 327 , 328 ]. Although caffeine is associated with sleep disturbances, caffeine has also been shown to improve vigilance and reaction time and improved physical performance after sleep deprivation [ 282 , 329 , 330 , 331 , 332 ]. This may be beneficial for athletes or those in the military who are traveling or involved in multiday operations, or sporting events and must perform at the highest level under sleep-deprived conditions [ 192 , 194 , 330 , 332 ].

Even though caffeine ingestion may hinder sleep quality, the time of day at which caffeine is ingested will likely determine the incidence of these negative effects. For example, in one study that included a sample size of 13 participants, ingestion of caffeine in the morning hours negatively affected sleep only in one participant [ 333 ]. However, ingestion of caffeine in the late afternoon (18:00 h) resulted in insomnia effects among 6 participants. These results are likely explained by the half-life of caffeine, which is generally around 4 to 6 h (even though it varies between individuals). Unfortunately, athletes and those in the military are unlikely to be able to make adjustments to the timing of training, competition and military exercises or the ability to be combat ready. However, to help avoid negative effects on sleep, athletes may consider using caffeine earlier in the day whenever possible. Pronounced individual differences have also been reported where functional genetic polymorphisms have been implicated in contributing to individual sensitivity to sleep disruption [ 280 , 281 ] and caffeine impacts after sleep deprivation [ 282 ] as discussed in the Interindividual variation in response to caffeine: Genetics section of this paper.

Side-effects associated with caffeine intake

As with any supplement, caffeine ingestion is also associated with certain side-effects. Some of the most commonly reported side-effects in the literature are tachycardia and heart palpitations, anxiety [ 281 , 291 ], headaches, as well as insomnia and hindered sleep quality [ 239 , 326 ]. For example, in one study, caffeine ingestion before an evening Super Rugby game resulted in a delay in time at sleep onset and a reduction in sleep duration on the night of the game [ 327 ]. Caffeine ingestion is also associated with increased anxiety; therefore, its ingestion before competitions in athletes may exacerbate feelings of anxiety and negatively impact overall performance (see caffeine and anxiety section). Increased jitters/anxiety/arousal associated with caffeine ingestion also needs to be considered within the specific demands of each sport, and even the position within a given sport. For example, athletes competing in sports that heavily rely on the skill component (e.g., tennis players, biathlon shooting) would likely not benefit from caffeine-induced jitters and arousal. However, athletes in sports that depend more on physical capabilities, such as strength and endurance (e.g., football lineman), might actually benefit from increased jitters and arousal before games. These aspects are less explored in research but certainly warrant consideration in the practical context to optimize the response to caffeine supplementation. The primary determinant in the incidence and severity of side-effects associated with caffeine ingestion is the dose used. Side-effects with caffeine seem to increase linearly with the dose ingested [ 239 ]. Therefore, they can be minimized—but likely not fully eliminated—by using smaller doses, as such doses are also found to be ergogenic and produce substantially fewer side-effects [ 112 ]. In summary, an individual case-by-case basis approach is warranted when it comes to caffeine supplementation, as its potential to enhance performance (benefit) needs to be balanced with the side-effects (risk).

Caffeine and cognitive performance

In addition to exercise performance, caffeine has also been studied for its contribution to athletes of all types (including Special Forces operators in the military) who are routinely required to undergo periods of sustained cognitive function and vigilance due to their job requirements (Table  1 ). A 2016 review [ 344 ] concluded that caffeine in doses from 32 to 300 mg (for a 75 kg individual) enhanced specific aspects of cognitive performance, such as attention, vigilance, and reaction time. Spriet [ 112 ] also concluded that lower doses of caffeine (approximately 200 mg) improved cognitive processes associated with exercise including vigilance, alertness, and mood. Hogervorst et al. [ 82 ] studied 24 well-trained cyclists that were randomized to 3 groups: (1) consumed a bar containing 45 g of carbohydrate and 100 mg of caffeine; (2) an isocaloric non-caffeine performance bar; or, (3) a placebo beverage (non-caloric flavored water) immediately before performing a 2.5-h ride followed by a time to exhaustion trial. They found that caffeine in a carbohydrate-containing performance bar significantly improved both endurance performance and complex cognitive ability during and after exercise [ 82 ]. Antonio et al. [ 345 ] assessed the effects of an energy drink on psychomotor vigilance in a small cohort of 20 exercise-trained men and women. The acute consumption of 300 mg of caffeine in a commercially available energy drink produced a significant improvement in psychomotor vigilance mean reaction time in these subjects compared to the placebo trial. This matches a 2001 IOM report [ 346 ] that the effects of caffeine supplementation include increased attention and vigilance, complex reaction time, and problem-solving and reasoning.

One confounding factor on cognitive effects of caffeine is the role of sleep. Special Forces military athletes conduct operations where sleep deprivation is common. A series of different experiments [ 42 , 329 , 330 , 332 , 334 , 335 , 346 , 347 ] have examined the effects of caffeine in real-life military conditions. In three of the studies [ 329 , 330 , 334 ], soldiers performed a series of tasks such as a 4 or 6.3 km run and a marksmanship test, which is a task that requires fine motor coordination and steadiness, observation/reconnaissance, and requires long periods of no movement coupled with alertness and psychomotor vigilance over several days, where opportunities for sleep became more infrequent. Caffeine was provided at doses ranging from 600 to 800 mg in the form of chewing gum, owing to its practicality, i.e., rapid absorption and portability [ 58 ]. The investigators found that vigilance was either maintained or enhanced under the caffeine conditions (vs. placebo), in addition to improvements in run times and obstacle course completion [ 329 , 330 , 334 ]. Similarly, Lieberman et al. [ 42 ] examined the effects of caffeine on cognitive performance during sleep deprivation in U. S. Navy Seals. During this investigation, there were multiple doses of caffeine ingested, 100 mg, 200 mg, or 300 mg, in capsule form. Once again, results were also significant for the assessments related to vigilance and reaction time in both the 200 and 300 mg caffeine intervention, suggesting smaller successive doses of caffeine are more beneficial than large boluses, for improving focus and vigilance.

The positive effects of caffeine on cognitive function were further supported by work from Kamimori et al. [ 332 ] where 20 special forces operators were randomly assigned to receive four 200-mg doses of caffeine or placebo during a period of low sleep over three successive days. The caffeine intervention maintained psychomotor speed, improved event detection, increased the number of correct responses to stimuli, and increased response speed during logical reasoning tests. Under similar conditions of sleep deprivation, Tikuisis et al. [ 335 ] demonstrated that the cognitive component of a shooting task (i.e., target detection) benefited from caffeine. These studies [ 42 , 329 , 330 , 332 , 334 , 335 , 346 , 347 ] demonstrate the effects of caffeine on vigilance and reaction time in a sleep deprived state, in a distinct and highly trained population, usually with repeated ‘lower’ doses, ~ 200 mg of caffeine ingestion. When subjects are not sleep deprived, the effects of caffeine on cognition appear to be less effective. For example, Share et al. [ 336 ] did not show any difference in shooting accuracy, reaction time, or target tracking times among the three intervention trials using 2 escalating doses of caffeine at 2 mg/kg and 4 mg/kg.

In addition to the ability of caffeine to counteract the stress from sleep deprivation, it may also play a role in combatting other stressors. Gillingham et al. [ 339 ] showed that in 12 reservists who ingested 5 mg/kg body mass of caffeine or placebo 1 h pre- and post-strenuous exercise, that caffeine ingestion mediated stress from sleep deprivation cited above. However, these benefits were not observed during more complex operations [ 339 ]. With a different stressor (a simulated firefight), no cognitive effect was seen with a caffeine dose of 400 mg [ 340 ]. Crowe et al. [ 341 ] examined the effects of caffeine (6 mg/kg dose) on cognitive parameters (visual reaction time and number recall tests) via two maximal 60-s bouts of cycling over three conditions (caffeine, placebo, control). Again, no cognitive benefit was observed.

Other studies [ 244 , 338 , 342 , 343 ] support the effects of caffeine on the cognitive aspects of sport performance, even though with some mixed results [ 348 , 349 ]. Foskett et al. [ 244 ] determined that a moderate dose (6 mg/kg) of caffeine enhanced the fine motor skills in soccer players as measured by improved ball passing accuracy and control. This was supported by Stuart et al. [ 342 ] who examined the effects of the same dose of caffeine (6 mg/kg) and found a 10% improvement in ball-passing accuracy. Equivocal results were reported for distance covered, agility, and accuracy in a review of 19 studies where caffeine ingestion before exercise was between 3 and 6 mg/kg [ 348 ]. Data on reactive agility time is split, with one study demonstrating a benefit [ 343 ] and another one [ 349 ] did not showing any benefit, despite using the same dose of caffeine (6 mg/kg). Finally, caffeine (5 mg/kg) was shown to enhance cognitive performance after an upper-body Wingate test, which may be beneficial in sports or occupational activities where there is a need for anaerobic performance concurrent with decision making (e.g. firefighting, military related tasks, wheelchair basketball) [ 338 ].

The exact mechanism of how caffeine enhances cognition in relation to exercise is not fully elucidated and appears to work through both peripheral and central neural effects [ 350 ]. In a study by Lieberman et al. [ 42 ], 8 h after caffeine administration, caffeine continued to enhance motor learning and short-term memory via performance of repeated acquisition. Repeated acquisition are behavioral tests in which subjects are required to learn new response sequences within each experimental session [ 351 ]. The researchers [ 42 ] speculated that caffeine exerted its effects from an increased ability to sustain concentration, as opposed to an actual effect on working memory. Other data [ 352 ] were in agreement that caffeine reduced reaction times via an effect on perceptual-attentional processes (not motor processes). This is in direct contrast to earlier work that cited primarily a motor effect [ 353 ]. Another study with a sugar free energy drink showed similar improvements in reaction time in the caffeinated arm; however, they attributed it to parallel changes in cortical excitability at rest, prior, and after a non-fatiguing muscle contraction [ 354 ]. The exact cognitive mechanism(s) of caffeine have yet to be elucidated.

Based on some of the research cited above, it appears that caffeine is an effective ergogenic aid for individuals either involved in special force military units or who may routinely undergo stress including, but not limited to, extended periods of sleep deprivation. Caffeine in these conditions has been shown to enhance cognitive parameters of concentration and alertness. It has been shown that caffeine may also benefit sport performance via enhanced passing accuracy and agility. However, not all of the research is in agreement. It is unlikely that caffeine would be more effective than actually sleeping, i.e. you cannot ‘outcaffeinate’ poor sleep.

Environmental influences on response to caffeine

Physical activity and exercise in extreme environments are of great interest as major sporting events (e.g. Tour de France, Leadville 100, Badwater Ultramarathon) are commonly held in extreme environmental conditions. Events that take place in the heat or at high altitudes bring additional physiological challenges (i.e., cardiovascular strain, thermoregulation, diuresis) for athletes, which may be potentially compounded if caffeine is consumed prior to and/or during training or competition in such environments [ 355 ]. Nonetheless, caffeine is widely used by athletes as an ergogenic aid when exercising or performing in extreme environmental situations. The current understanding of caffeine’s impact on exercise performance is based largely on the findings of analyses conducted in controlled, temperate environments, whereas data collected on the ergogenic effect of caffeine consumption by individuals performing in the heat or at altitude are limited and have resulted in inconsistent findings.

The ability to perform prolonged exercise is impaired in hot and/or humid environments [ 355 , 356 ]. The use of caffeine in conjunction with exercise in the heat has been proposed to increase the risk for various heat-related illnesses with particular concerns regarding caffeine’s effect on body temperature and hydration status [ 357 ]. Ely et al. [ 358 ] concluded that caffeine dosages as high as 9 mg/kg did not substantially alter body heat balance during endurance exercise performance at 40 °C. Further, a recent study demonstrated that while caffeine ingestion increased blood lactate and heart rate during exercise in the heat (42 °C and 20% relative humidity), endurance capacity and thermoregulation were unaffected in both male and female participants [ 359 ]. Although caffeine may induce mild fluid loss, the majority of research has confirmed that caffeine consumption does not significantly impair hydration status, exacerbate dehydration, or jeopardize thermoregulation (i.e., body temperature regulation) when exercising in the heat [ 360 , 361 ].

Several trials have observed no benefit of acute caffeine ingestion on cycling and running performance in the heat (Table  2 ) [ 265 , 362 , 364 ]. However, Ganio and colleagues [ 365 ] found caffeine (2 dosages of 3 mg/kg) to be similarly ergogenic under both cool (12 °C) and warm (33 °C) environmental conditions. Likewise, others [ 366 ] have reported a non-significant, yet notable, improvement in cycling time trial performance in the heat (35 °C and 25% relative humidity) after caffeine consumption (3 mg/kg) compared with placebo ingestion. While caffeine’s effect on performance in the heat remains somewhat unclear to date, positive support exists for dosages between 3 and 6 mg/kg. Further, there does not appear to be sufficient evidence to interdict the use of caffeine by individuals who exercise in heat if consumed in dosages of 9 mg/kg or less.

It is well established that caffeine improves performance and perceived exertion during exercise at sea level [ 260 , 314 , 368 , 369 ]. Despite positive outcomes at sea level, minimal data exist on the ergogenic effects or side effects of caffeine in conditions of hypoxia, likely due to accessibility of this environment or the prohibitive costs of artificial methods. To date, only four investigations (Table  3 ) have examined the effects of caffeine on exercise performance under hypoxic conditions [ 211 , 370 , 371 , 372 ]. In an initial study by Berglund and colleagues [ 370 ], caffeine (6 mg/kg) significantly improved 21 km time trial performance 2300 m above sea level in 14 well-trained cross-country skiers. Likewise, [ 371 ] positive outcomes were reported after caffeine (4 mg/kg) ingestion on endurance performance in acute hypoxic conditions of 4300 m above sea level. Specifically, significant improvements in time to exhaustion in eight young adults cycling at 80% of their altitude specific VO 2max was reported. More recently, 13 skiers were examined at an altitude of 2000 m above sea level and it was reported that caffeine (4.5 mg/kg) significantly improved time to exhaustion while double poling during cross-country skiing at 90% of altitude-specific VO 2max [ 211 ]. In a more recent double-blind, randomized, counterbalanced cross-over investigation [ 372 ], seven adult males significantly improved time to exhaustion by 12% following consumption of 4 mg/kg caffeine. Overall, results to date appear to support the beneficial effects of caffeine supplementation that may partly reduce the negative effects of hypoxia on the perception of effort and endurance performance [ 211 , 370 , 371 , 372 ].

Alternate caffeine sources

Sources other than commonly consumed coffee and caffeine tablets have garnered interest, including caffeinated chewing gum, mouth rinses, aerosols, inspired powders, energy bars, energy gels and chews, among others. While the pharmacokinetics [ 18 , 373 , 374 , 375 , 376 ] and effects of caffeine on performance when consumed in a traditional manner, such as coffee [ 47 , 49 , 55 , 153 , 368 , 377 , 378 ] or as a caffeine capsule with fluid [ 55 , 203 , 379 , 380 ] are well understood, curiosity in alternate forms of delivery (as outlined in pharmacokinetics section) have emerged due to interest in the speed of delivery [ 81 ]. A recent review by Wickham and Spriet [ 5 ] provides an overview of the literature pertaining to caffeine use in exercise, in alternate forms. Therefore, here we only briefly summarize the current research.

Caffeinated chewing gum

Several investigations have suggested that delivering caffeine in chewing gum form may speed the rate of caffeine delivery to the blood via absorption through the extremely vascular buccal cavity [ 58 , 381 ]. Therefore, caffeine via chewing gum may be absorbed via two passageways: the buccal mucosa in the oral cavity and/or gut absorption due to the swallowing of caffeine-containing saliva [ 58 , 381 , 382 ]. Kamimori and colleagues [ 58 ] compared the rate of absorption and relative caffeine bioavailability from caffeinated chewing gum and caffeine in capsule form. The results suggest that the rate of drug absorption from the gum formulation was significantly faster. In the groups ingesting 100 and 200 mg, both gum and capsule formulations provide near comparable plasma caffeine concentrations to the systemic circulation. These findings suggest that there may be an earlier onset of pharmacological effects from caffeine delivered through the gum formulation. Further, while no data exist to date, it has been suggested that increasing absorption via the buccal cavity may be preferential over oral delivery if consumed closer to or during exercise, as splanchnic blood flow is often reduced [ 383 ], potentially slowing the rate of caffeine absorption.

To date, five studies [ 59 , 60 , 61 , 62 , 63 ] have examined the potential ergogenic impact of caffeinated chewing gum on aerobic performance, commonly administered in multiple sticks (Table  4 ). To note, all studies have been conducted using cycling interventions, with the majority conducted in well-trained cyclists. Results from these investigations suggest that caffeinated chewing gum delivered in total dosages ranging 200–300 mg, closer to initiation of exercise or during a prolonged endurance event may be most beneficial, specifically for individuals with a higher training status. However, more research is needed, especially in physically active and recreationally training individuals.

Four studies [ 64 , 66 , 68 , 384 ] have examined the effect of caffeinated chewing gum on more anaerobic type activities (Table  4 ). Specifically, Paton et al. [ 64 ] administered 3 mg/kg caffeinated gum to male cyclists during repeat sprint cycling, resulting in greater attenuation of fatigue, compared to a placebo. The reduced fatigue in the caffeine trials equated to a 5.4% performance enhancement in power during sprints, in favor of caffeinated gum. A study [ 384 ] assessing 100 mg caffeinated chewing gum on shot-put performance during an early morning trial resulted in overall improvements in shot-put distance thrown compared to a placebo. Caffeinated gum consumption also positively influenced performance in two out of three soccer-specific (Yo-Yo Intermittent Recovery Test and CMJ) tests used in the assessment of performance in soccer players [ 66 ]. A recent study also explored the effects of 300 mg of caffeine provided in caffeine chewing gum and found that its consumption 10 min pre-exercise resulted in ergogenic effects on jumping performance, isokinetic peak torque, upper body movement velocity and whole-body power output during a rowing test [ 68 ]. These results suggest that caffeine chewing gums may provide ergogenic effects across a wide range of exercise tasks. To date, only Bellar et al. [ 384 ] has examined chewing gum with caffeine on cognitive function, specifically reporting improved alertness as assessed by a psychomotor vigilance test. Future studies may consider comparing the effects of caffeine in chewing gums to caffeine ingested in capsules.

Caffeine mouth rinsing

Caffeine mouth rinsing (CMR; 5–20 s in duration) may have the potential to enhance exercise performance due to the activation of sensorimotor brain cortices [ 79 ]. Specifically, the mouth contains bitter taste sensory receptors that are sensitive to caffeine [ 385 ]. It has been proposed that activation of these bitter taste receptors may activate neural pathways associated with information processing and reward within the brain [ 385 , 386 , 387 ]. Physiologically, caffeinated mouth rinsing may also reduce gastrointestinal distress potential that may be caused when ingesting caffeine sources [ 388 , 389 ].

Few investigations on aerobic [ 69 , 74 , 75 , 76 , 390 ] and anaerobic [ 72 , 73 , 78 ] changes in performance, as well as cognitive function [ 70 , 71 ] and performance [ 77 ], following CMR have been conducted to date (Table  5 ). One study [ 390 ] demonstrated ergogenic benefits of CMR on aerobic performance, reporting significant increases in distance covered during a 30-min arm crank time trial performance. Likewise, in a separate study [ 74 ], a 5 s CMR (containing 32 mg of caffeine dissolved in 125 ml water) improved 30 min cycling performance, without concurrent increases in ratings of perceived exertion or heart rate. With regard to anaerobic trials, other researchers [ 72 ] have also observed improved performance, where recreationally active males significantly improved their mean power output during repeated 6-s sprints after rinsing with a 1.2% caffeine solution. A follow-up study [ 73 ] reported that recreationally active males who were deemed ‘glycogen depleted’ increased mean and peak power during the 3rd sprint of repeat cycling, as well as decreased perception of pain during the 4th and 5th sprints following a 10 s rinse of a 2% caffeine rinse. While CMR has demonstrated positive outcomes for cyclists, another study [ 78 ] in recreationally resistance-trained males did not report any significant differences in the total weight lifted by following a 1.2% caffeine rinse. CMR appears to be ergogenic in cycling to include both longer, lower-intensity and shorter high-intensity protocols. The findings on the topic are equivocal likely because caffeine provided in this source does not increase caffeine plasma concentration and increases in plasma concentration are likely needed to experience an ergogenic effect of caffeine [ 69 ]. Details of these studies, as well as additional studies may be found in Table  5 .

Caffeinated nasal sprays and inspired powders

The use of caffeinated nasal sprays and inspired powders are also of interest. Three mechanisms of action have been hypothesized for caffeinated nasal sprays. Firstly, the nasal mucosa is permeable, making the nasal cavity a potential route for local and systemic substance delivery; particularly for caffeine, a small molecular compound [ 11 , 12 , 30 , 31 ]. Secondly, and similar to CMR, bitter taste receptors are located in the nasal cavity. The use of a nasal spray may allow for the upregulation of brain activity associated with reward and information processing [ 391 ]. Thirdly, but often questioned due to its unknown time-course of action, caffeine could potentially be transported directly from the nasal cavity to the CNS, specifically the cerebrospinal fluid and brain by intracellular axonal transport through two specific neural pathways, the olfactory and trigeminal [ 392 , 393 ].

In two separate trials [ 79 , 80 ], the effects of caffeinated nasal sprays containing 15 mg of caffeine per mL were examined. No significant improvements were reported in either anaerobic and aerobic performance outcome measures despite the increased activity of cingulate, insular, and sensory-motor cortices [ 79 ]. Laizure et al. [ 81 ] compared the bioavailability and plasma concentrations of 100 mg caffeine delivered via an inspired powder (AeroShot) and an oral solution. Both were found to have similar bioavailability and comparable plasma concentrations with no differences in heart rate or blood pressure (Table  6 ).

Caffeinated gels

While caffeinated gels are frequently consumed by runners, cyclists and triathletes, plasma caffeine concentration studies have yet to be conducted and only three experimental trials have been reported. Cooper et al. [ 83 ] and Scott et al. [ 84 ] examined the effects of carbohydrate-caffeinated gels, which both included 100 mg caffeine dosages alongside 25 g and 21.6 carbohydrate, respectively. In the study by Cooper et al. the consumption of caffeinated gels 60 min pre-exercise did not enhance intermittent sprint performance. In contrast, Scott et al. utilized a shorter time period from consumption to the start of the exercise (i.e., 10 min pre-exercise) and found significant improvements in 2000-m rowing performance after consumption of caffeinated gels. Another recent study utilized caffeine gels and found that 300 mg of caffeine, provided 10 min pre-exercise increased vertical jump performance, strength, and power in a sample of 17 resistance-trained men [ 67 ]. These results tentatively suggest that timing of consumption is important when it comes to caffeinated gels with ergogenic effects found when consuming caffeine gels 10 min but not 60 min before exercise. However, these ideas are based on results from independent studies and therefore, future studies may consider exploring the optimal timing of caffeine gel ingestion in the same group of participants. More details on these studies may be found in (Table  7 ).

Caffeinated bars

Similar to caffeinated gels, no studies measured plasma caffeine concentration following caffeinated bar consumption; however, absorption and delivery likely mimic that of coffee or caffeine anhydrous capsule consumption. While caffeinated bars are commonly found in the market, research on caffeinated bars is scarce. To date, only one study [ 82 ] (Table  7 ) has examined the effects of a caffeine bar on exercise performance. Specifically, participants that consumed a carbohydrate-bar containing 100 mg of caffeine significantly improved their time to exhaustion during cycling compared to a carbohydrate bar and placebo with no differences found in ratings of perceived exertion, average heart rate and relative exercise intensity. Furthermore, cyclists significantly performed better on complex information processing tests following the time trial to exhaustion after caffeine bar consumption when compared to the carbohydrate only trial. As there is not much data to draw from, future work on this source of caffeine is needed.

Caffeine in combination with other ingredients

Caffeine and creatine.

A review by Trexler and Smith-Ryan comprehensively details research on caffeine and creatine co-ingestion [ 32 ]. With evidence to support the ergogenic benefits of both creatine and caffeine supplementation on human performance—via independent mechanisms—interest in concurrent ingestion is of great relevance for many athletes and exercising individuals [ 32 ]. While creatine and caffeine exist as independent supplements, a myriad of multi-ingredient supplements (e.g., pre-workouts) containing both caffeine and creatine are available. It has been reported that the often-positive ergogenic effect of acute caffeine ingestion prior to exercise is unaffected by creatine when a prior creatine loading protocol had been completed by participants [ 394 , 395 ]. However, there is some ambiguity with regard to the co-ingestion of caffeine during a creatine-loading phase (e.g., co-ingestion of coffee and creatine) [ 396 , 397 , 398 , 399 ]. Studies available to date suggest that high-dose chronic caffeine (> 9 mg/kg) and creatine co-ingestion should be employed cautiously, as counteracting mechanisms on Ca2+ clearance and release, and muscle relaxation time have been hypothesized [ 396 , 398 ]. While favorable data exist on muscular performance outcomes and adaptations in individuals utilizing multi-ingredient supplements (e.g., pre-workouts), these results may be confounded by other ingredients (e.g., beta-alanine, citrulline malate, amino acids) in the supplement [ 34 , 95 , 400 , 401 ]. Until future investigations are available, it may be prudent to consume caffeine and creatine separately, or avoid high caffeine intakes when utilizing creatine for muscular benefits [ 402 ].

Caffeine and carbohydrate

To date, investigations examining the co-ingestion of carbohydrate and caffeine compared with carbohydrate alone prior to and/or during exercise have produced inconsistent results [ 196 , 264 , 403 , 404 , 405 ]. This is likely due to the heterogeneity of experimental protocols that have been implemented and examined. Nonetheless, a 2011 systematic review and meta-analysis of 21 investigations [ 406 ] concluded the co-ingestion of carbohydrate and caffeine significantly improved endurance performance when compared to carbohydrate alone. However, it should be noted that the magnitude of the performance benefit that caffeine provides is less when added to carbohydrate (i.e., caffeine + carbohydrate vs. carbohydrate) than when isolated caffeine ingestion is compared to placebo [ 404 ]. Since the 2011 publication [ 406 ], results remain inconclusive, as investigations related to sport-type performance measures [ 83 , 250 , 407 , 408 , 409 , 410 , 411 ], as well as endurance performance [ 84 , 367 , 412 ] continue to be published. Overall, to date it appears caffeine alone, or in conjunction with carbohydrate is a superior choice for improving performance, when compared to carbohydrate supplementation alone.

While the majority of training or performing individuals would choose to supplement with caffeine prior to exercise or during competition, interest in caffeine’s effect on muscle glycogen repletion during the post-exercise period has garnered interest. Few studies to date have investigated the effect of post-exercise caffeine consumption on glucose metabolism [ 413 , 414 ]. While the delivery of exogenous carbohydrate can increase muscle glycogen alone, Pedersen et al. [ 413 ] report faster glycogen repletion rates in athletes who co-ingested caffeine (8 mg/kg body mass) and carbohydrate (4 g/kg body mass), compared to carbohydrate alone (4 g/kg body mass). In addition, it has been demonstrated that co-ingestion of caffeine with carbohydrate after exercise improved subsequent high-intensity interval-running capacity compared with ingestion of carbohydrate alone. This effect may be due to a high rate of post-exercise muscle glycogen resynthesis [ 415 ]. The data to date indicate that caffeine may potentiate glycogen resynthesis when high dosages of caffeine (~ 8 mg/kg body mass) are consumed during the recovery phase of exercise; though, when adequate carbohydrate is provided post-exercise, caffeine may not provide any glycogen-resynthesizing benefit [ 414 ]. Practically, caffeine ingestion in close proximity to sleep, coupled with the necessity to speed glycogen resynthesis, should be taken into consideration, as caffeine before bed may cause sleep disturbances.

Caffeine within brewed coffee

The genus of coffee is Coffea , with the two most common species Coffea arabica (arabica coffee) and Coffea canephora (robusta coffee) used for global coffee production. While coffee is commonly ingested by exercising individuals as part of their habitual diet, coffee is also commonly consumed pre-exercise to improve energy levels, mood, and exercise performance [ 11 , 40 ]. Indeed, a recent review on coffee and endurance performance, reported that that coffee providing between 3 and 8.1 m/kg of caffeine may benefit endurance performance, such as time trial performance or time to exhaustion [ 11 ]. To date, research has only examined coffee’s effects on cycling and running exercise performance. Specifically, Higgins et al. [ 11 ] highlight that significant improvements over control conditions were found with doses up to 8.1 mg/kg; however, performance benefits were similar to 3 mg/kg servings. Since the release of the Higgins et al. review, three additional studies have been published, examining the effects of coffee on exercise performance. Specifically, Niemen et al. [ 416 ] assessed the impact of high chlorogenic acid coffee on performance. Cyclists were asked to consume coffee or placebo (300 ml/day) for 2 weeks prior to completing a 50-km time-trial. Chlorogenic acid coffee provided 1066 mg chlorogenic acid plus 474 mg caffeine, while the placebo consisted of 187 mg chlorogenic acid and 33 mg caffeine. Fifty-km cycling time performance and power did not differ between trials. Participant’s heart rate and ventilation were higher with chlorogenic acid coffee during the time-trial, potentially provoking the non-significant performance outcomes. Regarding resistance exercise performance, only two studies [ 55 , 56 ] have been conducted to date. One study [ 56 ] reported that coffee and caffeine anhydrous did not improve strength outcomes more than placebo supplementation. On the other hand, Richardson et al. [ 55 ] suggested that coffee consumption may improve lower-body muscular endurance performance similarly as isolated caffeine ingestion. The results between studies differ likely because it is challenging to standardize the dose of caffeine in coffee as differences in coffee type and brewing method may alter caffeine content [ 417 ]. Even though coffee may enhance performance, due to the difficulty of standardizing caffeine content most sport dietitians and nutritionists use anhydrous caffeine with their athletes due to the difficulty of standardizing caffeine content.

Caffeine containing energy drinks and pre-workouts

Consumption of energy drinks has become more common in the last decade, and several studies have examined the effectiveness of energy drinks as ergogenic aids (Table  8 ). Souza and colleagues [ 418 ] completed a systematic review and meta-analysis of published studies that examined energy drink intake and physical performance. Studies including endurance exercise, muscular strength and endurance, sprinting and jumping, as well as sport-type activities were reviewed. Dosages of caffeine ranged from 40 to 325 mg among the studies, with the majority of drinks also containing taurine. While it was concluded that energy drink consumption increased performance in the aforementioned performance activities, the ergogenic effect was not solely attributed to the amount of caffeine administered, but improved also as a result of taurine content (dosages ranged 71 to 3105 mg) [ 418 ]. This is similar to data from another study, reporting that Red Bull (500 ml serving; 160 mg of caffeine/2.25 mg/kg), also containing taurine, glucose, glucuronolactone, and B vitamins, improved 5-km run performance in recreationally athletes [ 91 ]. It has been suggested that the additional taurine to caffeine containing energy drinks or pre-workout supplements, as well as the addition of other ergogenic supplements such as beta-alanine, B-vitamins, and citrulline, may potentiate the effectiveness of caffeine containing beverages on athletic performance endeavors [ 419 ]. However, other suggest that the ergogenic benefits of caffeine containing energy drinks is likely attributed to the caffeine content of the beverage [ 420 ]. For a thorough review of energy drinks, consider Campbell et al. [ 419 ]. Table  8 provides a review of research related to energy drinks and pre-workout supplements.

Caffeine in its many forms is a ubiquitous substance frequently used in military, athletic and fitness populations which acutely enhance many aspects of exercise performance in most, but not all studies.

Supplementation with caffeine has been shown to acutely enhance many aspects of exercise, including prolonged aerobic-type activities and brief duration, high-intensity exercise. Caffeine is ergogenic when consumed in doses of 3–6 mg/kg body mass. The most commonly used timing of caffeine supplementation is 60 min pre-exercise. The optimal timing of caffeine ingestion likely depends on the source of caffeine. Caffeine’s effects seem to be similar in both trained and untrained individuals. Studies that present individual participant data commonly report substantial variation in caffeine ingestion responses. Inter-individual differences may be associated with habitual caffeine intake, genetic variations, and supplementation protocols in a given study. Caffeine may be ergogenic for cognitive function, including attention and vigilance. Caffeine may improve cognitive and physical performance in some individuals under conditions of sleep deprivation. Caffeine at the recommended doses does not appear significantly influence hydration, and the use of caffeine in conjunction with exercise in the heat and at altitude is also well supported. Alternative sources of caffeine, such as caffeinated chewing gum, mouth rinses, and energy gels, have also been shown to improve performance. Energy drinks and pre-workouts containing caffeine have been demonstrated to enhance both anaerobic and aerobic performance. Individuals should also be aware of the side-effects associated with caffeine ingestion, such as sleep disturbance and anxiety, which are often linearly dose-dependent.

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N.S.G conceived and outlined the sections to be included in the manuscript, provided the initial draft and oversaw all critical edits and revisions. T.A.V authored multiple sections and participated in final editing and revisions. M.T.N, J. G and B.J.S provided expertise and contributed to the one or more sections of the manuscript. N.D.M.J, S.M.A, J. A, J.R.S, E.T.T, A.E.S-R, E.R.G, and D.S.K provided valuable comments and suggested minor edits to the manuscript. B.I.C. oversaw the writing process, and all authors reviewed and gave final approval of the version to be published.

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N.S.G consults for and is on the scientific advisory board of Nutrigenomix, a genetic testing company. T.A.V is on the scientific advisory board for Dymatize Nutrition, a manufacturer of sports supplements; has received research grants related to dietary supplements. B.J.S is on the scientific advisory board for Dymatize Nutrition, a manufacturer of sports supplements. S.M.A has received grants to evaluate the effects of dietary supplements, including caffeine and caffeine-derivatives, serves or has served on scientific advisory boards for sport nutrition companies, has been a paid consultant for a coffee company, and holds patents for an ingredient used in a performance coffee product. J. A is the CEO of the ISSN. The ISSN has received grants from sports supplement companies that sell caffeine-based products. E.T.T earns income as a writer and practitioner within the fitness industry. A.E.S-R has received research grants related to dietary supplements and is a science advisor to Ladder Sport. D.S.K declares that in part, he works for a contract research company that conducts research and human clinical trials for industries including dietary supplements, medical foods, beverages, foods, pharmaceuticals and medical devices. He also sits on the Scientific Advisory Board for Dymatize Nutrition (BellRing Brands) B.I.C is on the scientific advisory board for Dymatize Nutrition, a manufacturer of sports supplements. M.T.N, J. G, N.D.M.J, J.R.S, E.R.G, report no competing interests or conflicts of interest.

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Guest, N.S., VanDusseldorp, T.A., Nelson, M.T. et al. International society of sports nutrition position stand: caffeine and exercise performance. J Int Soc Sports Nutr 18 , 1 (2021). https://doi.org/10.1186/s12970-020-00383-4

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RECONSIDERING CAFFEINE :

AN AWAKE AND ALERT NEW LOOK AT

AMERICA’S MOST COMMONLY CONSUMED DRUG

DAVID M. MRAZIK

CLASS OF 2004

APRIL 27 TH , 2004

This paper is submitted in satisfaction of both the Food and Drug Law course requirement and the third year written work requirement.

Caffeine is one of the most pervasively ingested addictive substances in the United States, yet astoundingly little attention is paid to its ubiquitous presence. This Paper examines caffeine, the substance, from many perspectives. First, it discusses caffeine with particular regard to its chemical properties; its presence in foods, beverages, and medications both naturally and as an additive; and its known impacts on human biological and psychological functioning. Relevant medical investigations of caffeine’s therapeutic properties and its toxicology are included in order to better evaluate the benefits, the risks, and the relative safety of prolonged caffeine consumption. In light of more recent medical findings, the Paper finds that caffeine poses fewer serious health risks than previously thought, and the potential for damage to the vast majority of the consumer public is minimal.

The Paper also addresses issues of FDA regulation of caffeine, including a discussion of current regulation and classification of the substance both as a food product and as a drug product, as well as questioning the usefulness of greater consumer warning labels and promotion of improved public awareness of caffeine’s various health effects. Due to both the paucity of long-term caffeine health studies and the conflicts among those studies, the Paper contends that heightened FDA regulatory scrutiny of American caffeine consumption is an unnecessary expenditure of limited resources. The Paper finds caffeine poses no material danger to the consumer, and dismisses the claims of prior authors to that effect as generally overstated. Finally, the Paper poses a hypothetical analysis of caffeine as both a new food additive and a new drug, in order to illustrate the FDA’s modern regulatory process and demonstrate greater confidence in the safety of consumer caffeine use.

I. INTRODUCTION: CAFFEINE – THE AMERICAN CRUTCH

Picture this: a group of people are seated and quietly reading the morning newspaper in the nearby corner “Starbucks” coffee shop while sipping a “Grande Latte.” [1] Elsewhere, a team of frenetic business executives dash to the closest street vendor to grab a quick cup of black coffee or a “Diet Coke” to wake up for the next morning business meeting. [2] In dormitory rooms on college campuses everywhere, students sit staring at computer screens while drinking a wide variety of caffeinated beverages, or even ingesting OTC drugs like “Vivarin” to stay awake and finish the occasional all-night assignment. [3] In a quiet teahouse, people debate philosophy over a cup of Assam or Darjeeling black tea. Whether used as a day-starter, a work finisher, or a recreational excuse for conversation, substances containing caffeine have developed a certain contemporary cachet in American society, though they have been available for centuries. [4]

On the other hand, ever-increasing consumer vigilance regarding individual health causes many people to wonder about the addictive and potentially dangerous properties of caffeinated products. For a drug so commonly used, little attention is paid to the chemical itself, its abundant sources both in nature and in synthetics, the quantity of caffeine ingested on a daily basis, and the real effects of caffeine use (both short and long term). These issues are now discussed in detail.

II. UNDERSTANDING CAFFEINE: THE DRUG AND ITS EFFECTS

A. Caffeine: The Chemical and its Sources

Caffeine is now thought to be “the most widely used psychoactive drug in the world.” [5] Some studies estimate that 90% or more of this country’s population uses caffeine, whether through foods, beverages, or prescription and over-the-counter medicines. [6] The most common sources of caffeine for Americans include brewed coffee, brewed tea, typical cola drinks, milk and dark chocolate, and over-the-counter medications like “Anacin” and “Vivarin.” [7]

Caffeine is an alkaloid, or nitrogen-containing substance, bearing the chemical formula C 8 H 10 N 4 O 2 . [8] It belongs to the family of chemicals known as methylxanthines, which also includes the closely related chemicals theophylline and theobromine. [9] In its pure form, caffeine “occurs as odorless, white, fleecy masses, glistening needles or powder.” [10] As with all methylxanthines, caffeine has low solubility and is therefore often combined with a wide variety of compounds to form complexes, such as the double salt sodium benzoate, for purposes of enhanced solubility in consumer goods like soft drinks. [11]

Caffeine and the other methylxanthines are found in nature “in plants widely distributed geographically.” [12] Tea, which is prepared from the leaves of the plant Thea sunensis , naturally contains all three of the aforementioned methylxanthines and is consumed by at least half of the entire world population. [13] Cocoa and chocolate are produced “from the seeds of Theobroma cacao ”; both contain caffeine and theobromine, and both are used the world over. [14] The most obvious and important source of American caffeine intake, coffee, is produced from the Coffea arabica plant. [15] Prior to the deliberate insertion of additional caffeine during production, many sodas contain a natural form of caffeine “because of their content of extracts of the nuts of Cola acuminata .” [16] While it occurs abundantly in nature from a wide variety of sources, caffeine is also “created synthetically and by extraction from cocoa, coffee bean or tea leaf waste,” which allows for its inclusion in a greater variety of consumer products. [17]

B. Caffeine Dosages: Quantity in Consumer Products

It is difficult to arrive at a recommended ordinary consumption quantity, or a standard “dose,” since caffeine is present in various consumer goods at widely differing levels. Some sources suggest that one-hundred milligrams, whether delivered into the bloodstream by liquid or solid, is useful as a base-line single dosage. [18] Though caffeine content can differ markedly even within a product category, (for example, the amount of caffeine present in “real-world coffee” can range from seventy-five to two-hundred-fifty milligrams per serving), the rough quantity of caffeine in the most commonly ingested products is well known. [19]

A standard six ounce cup of drip-brewed coffee contains roughly one-hundred milligrams of caffeine, whereas a similarly sized cup of brewed tea contains roughly seventy milligrams. [20] Espresso, a common ingredient in many of today’s popular specialty coffee drinks, contains closer to one-hundred milligrams of caffeine per liquid ounce. [21] A conventional twelve ounce can of soda contains approximately fifty milligrams of caffeine, though specialty sodas such as “Jolt Cola” contain closer to seventy milligrams. [22] Milk chocolate contains roughly six milligrams of caffeine per ounce. [23] In the most common over-the-counter drugs, “Anacin” and “Excedrin” tablets contain thirty-two milligrams of caffeine each, while “Vivarin” contains two-hundred milligrams per tablet. [24]

More noteworthy than the specific quantity of caffeine in conventional consumer products is the quantity of each product ingested on a daily basis. While the customary six ounce cup of coffee may contain one-hundred milligrams of caffeine, the ordinary serving sizes of “Starbucks” coffees are twelve, sixteen, and twenty ounces each. [25] More than half of all adult Americans “drink an average of three and a half cups of coffee a day, in addition to tea, cola, chocolate and over-the-counter caffeine-containing drugs.” [26] If potential problems with adult caffeine consumption are an issue to be considered, the caffeine intake of children is even more important, because “the potency of caffeine on a human body depends on the body’s weight.” [27] Some sources suggest that “[t]he highest exposure to caffeine from soft drinks on a mg/ kg / day basis is among young children,” especially children under the age of six. [28]

C. Caffeine Consumption I: Therapeutic Uses and Positive Mechanics

Since so many people are consuming so much caffeine on a daily basis, the short and long-term beneficial effects of such usage merit significant discussion. [29] Caffeine has a variety of pharmacological effects on organ systems and neural functions, “though the level and duration of the effect varies among bodies.” [30] It is absorbed into the bloodstream following ingestion via the lining of the stomach and the small intestine, and reaches peak levels in the circulation of the bloodstream between fifteen and forty-five minutes after consumption. [31] Caffeine stimulates the central nervous system, reaching its maximum effect between thirty and sixty minutes after absorption; this is accompanied by a temporary increase in metabolic function. [32] It also relaxes smooth muscle, particularly bronchial muscle, which accounts for its inclusion in a wide variety of asthma medications. [33]

Initially, caffeine’s therapeutic application to small children was difficult; infants have incredible difficulty metabolizing caffeine until at least three to five months of age, while younger infants may be entirely unable to process it, and generally excrete it unchanged. [34] However, caffeine has found new popularity “in the treatment of the prolonged apnea that is sometimes observed in preterm infants.” [35] Though the long-term effects of caffeine administration on infant growth and development are not entirely known, no negative correlations between infant development and caffeine use have been detected as yet. [36]

Caffeine has long been employed medically “as a mild diuretic,” meaning it increases the body’s ability to produce urine; this is precisely the rationale behind its inclusion in certain medications for menopausal women who are suffering from water retention. [37] Caffeine also acts as a stimulant for the cardiovascular system, though “[t]he actions of the methylxanthines on the circulatory system are complex and sometimes antagonistic, and the resulting effects largely depend on the conditions prevailing at the time of their administration.” [38] Higher concentrations of caffeine have been known to produce tachycardia and other cardiac arrhythmias, but the risk of this in normal healthy individuals is minimal. [39]

These pharmacological effects last only as long as caffeine remains in the bloodstream; as time progresses following ingestion and absorption, the liver metabolizes the caffeine. [40] It is then excreted from the body through a number of channels, including urine, saliva, semen, and even breast milk. [41] While a number of factors, among which are pregnancy, liver disease, body weight, concurrent medications, and natural metabolic rate all influence the body’s ability to break down caffeine, “its average half-life is three and one half hours,” meaning that the average person will eliminate half of the amount of ingested caffeine within that time span. [42] Fortunately, caffeine is “quickly and completely removed from the brain and, unlike other central nervous system stimulants or alcohol, its effects are short lived.” [43] Additionally, “caffeine does not affect concentration or higher mental functions, and hence caffeinated drinks are often consumed in the course of work.” [44]

Put simply, people predominantly use caffeine to help them wake up in the morning, so that they will feel more alert and less tired. The chemical process behind this feeling of increased alertness, however, is actually quite complex, and requires a brief discussion of the body’s sleep mechanics. In order for a person to fall asleep, adenosine is created in the brain, which then binds itself to specialized adenosine receptors. [45] This normal binding process causes drowsiness, through adenosine’s slowing down of nerve cell activity. [46] Adenosine binding also simultaneously causes blood vessels in the body to dilate, presumably to increase the oxygen flow to and from the brain during the various stages of the sleep cycle. [47]

Caffeine interferes with the body’s natural tendencies to feel tired and sleep by engaging in adenosine replacement; to a nerve cell, caffeine’s xanthine structure appears similar to adenosine, allowing the substituted binding process to occur. [48] However, caffeine chemically stimulates nerve cell activity rather than slowing it down, causing the familiar feeling of “lift.” [49] Caffeine also causes the constriction of cranial blood vessels in lieu of the dilation caused by adenosine; this is precisely the rationale for its inclusion in a variety of over-the-counter pain relievers. [50] “Pain relievers that contain caffeine appear to provide somewhat more relief than caffeine-free products.” [51]

Once caffeine has caused the brain’s neuron firing to increase rather than decrease, the pituitary gland stimulates the adrenal gland’s release of epinephrine (adrenaline) in response to the increased activity. [52] Therefore, many of the “lifting” effects felt after ingesting a caffeinated substance are actually secondary central nervous system effects stemming from the body’s increased adrenaline production; dilated pupils, increased respiratory capacity, elevated heart rate, and muscle tightening are all natural results of the release of adrenaline. [53] It is noteworthy that the body’s adrenaline production following significant caffeine intake is much like an emergency “fight or flight” response to a crisis; the body is able to generate improved short-term mental and physical performance largely due to its being “fooled” into a state of emergency. [54]

The interaction between caffeine and dopamine is perhaps more important, and helps to explain caffeine’s addictive nature. Dopamine is a neurotransmitter that activates the brain’s pleasure center. [55] As with amphetamines, caffeine absorption causes a reduction in the rate of dopamine reuptake, increasing the body’s overall dopamine level. [56] Though the effects are much milder with caffeine than with amphetamines or strong narcotics like cocaine and heroin, the dopamine reuptake inhibiting mechanism is thought to be much the same. [57] This contributes to caffeine’s addictiveness; as the body receives neural signals indicating pleasure from the intake of caffeine, it wants to maintain these mildly pleasurable feelings. [58]

D. Caffeine Consumption II: Addiction

The primary complaint of most consumers against caffeine is addictiveness. In the context of adrenaline and dopamine production, caffeine causes the body to experience artificial sensations of lift and pleasure. [59] In the short-term, the body benefits from caffeine as it “restores mental alertness or wakefulness during fatigue or drowsiness,” and helps the body remain active when rest is not an option. [60] However, the levels of adrenaline and dopamine in the body are both diminished as the majority of the substance is metabolized, leading to fatigue and depression, and a greater desire to have another dose instead of experiencing a mood crash. [61] In the long-run, therefore, caffeine consumption can be a difficult cycle to break, especially when considering its short-term benefits. [62]

The FDA has previously noted that “chronic ingestion of caffeine in larger than recommended doses can lead to ‘habituation,’ which is a mild form of addiction.” [63] Though significantly milder and less damaging in effect than other related forms of addiction, recurrent caffeine use can cause psychological dependence in the user. [64] Physical and psychological dependence are marked by several characteristics, including “tolerance, withdrawal, persistent desire, or unsuccessful attempts to reduce consumption and persistent use despite adverse psychological or physical consequences.” [65]

Tolerance and withdrawal are the most commonly reported indicators of caffeine habituation, and can take place after ceasing to consume daily dosages of two-hundred-fifty milligrams or less. [66] Tolerance can occur rapidly based on the stimulant properties of caffeine, suggesting that mild withdrawal symptoms may occur even if caffeine has only been ingested for a short period of time. [67] Withdrawal symptoms can include “throbbing headaches, drowsiness, nausea, lethargy, irritability, nervousness, and depression,” and the onset of these symptoms can be as early as eighteen hours after the last intake. [68] A withdrawal headache, commonly called a “caffeine headache,” is actually indicative of a hypersensitivity to adenosine; the sensitivity causes a decline in blood pressure, an opening of the brain’s blood vessels, and increased intracranial pressure leading to some sensations of pain and throbbing. [69] Individuals wishing to reduce their caffeine dependency are better off doing so by gradually reducing their daily intake, as withdrawal symptoms are diminished by a gradual step-down. [70]

Though habituation in any form arguably poses some risk, the negative effects of caffeine are widely disputed; the available caffeine literature is marked by a continual disagreement among sources regarding the potential long-term addictiveness (and therefore dangerousness) of the drug. [71] While some sources contend that caffeine can be a serious and compelling addiction, the American Psychiatric Association disagrees to the extent that it has omitted caffeine from its listing of addicting stimulants. [72] In a letter from the National Soft Drink Association, the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION article entitled “Caffeine Dependence Syndrome” was heavily criticized for its conclusions regarding dependency. [73] The letter disputes the accuracy of the study based on its sample population, but more importantly distinguishes caffeine use from other addictions because “steadily increasing doses are not associated with caffeine ingestion.” [74] Since caffeine is at least mildly addictive and has some potential for unpleasant withdrawal effects, consumers should be aware and exercise greater vigilance before consuming caffeinated products.

E. Caffeine Consumption III: Other Possible Toxicology

Irrespective of its remedial properties and its potential to cause habituation, caffeine is still poisonous given a large enough dosage. Though fatalities from caffeine use are rare, they have occurred in the past; sixteen fatalities were attributed to caffeine toxicity in the period between 1959 and 1987. [75] The LD 50 , or “lethal dose fifty percent,” is the basis of all toxicological measurement. [76] It refers to the quantity of a particular substance that kills fifty percent of a sample population, and is colloquially known as the “semi-lethal dose.” [77] Caffeine’s LD 50 is ten grams; put in terms of six ounce cups of coffee (each containing an estimated one-hundred milligrams of caffeine), fatality may result if approximately one-hundred cups of coffee are ingested within a very short period of time. [78]

This type of fatality is extremely unlikely. Besides the fact that enormous quantities of caffeine are required to reach fatal toxic levels, and such quantities must be ingested rapidly, the most commonly used caffeine-containing substances such as coffee and soda would cause significant gastric irritation, acid secretion, nausea, and vomiting, irrespective of their caffeine content if ingested at those volumes. [79] More importantly, these effects would likely take place long before the fatal toxicity could be reached. [80]

Even in non-lethal doses, large quantities of caffeine can cause potentially significant health problems, including conditions that may be considered “long-term poisoning.” [81] According to an article in the JOURNAL OF FORENSIC SCIENCE , a one-thousand milligram dose of caffeine, or one-tenth of the LD 50 , has been known to cause convulsions, uncomfortably rapid breathing, tachycardia, hyperglycemia, and ketonuria. [82] Continual caffeine intake at lower levels can also cause borderline toxic responses – restlessness, disturbed sleep, irritability, muscle tension, cardiac arrhythmia, persistent nervousness, or sporadic reactions similar to anxiety attacks. [83]

Incidences of significant or borderline toxic responses to caffeine are not frequent enough to be considered problematic [84] ; however, there are “rare persons who are so sensitive to caffeine that even a single cup of coffee will cause a response bordering on the toxic.” [85] Certain groups are also more generally susceptible to the effects of caffeine; because of its correlation with body weight, children are often disproportionately affected by smaller doses of caffeine. [86] Similarly, some elderly people have been known to experience a disproportionate interruption of the sleep cycle simply from ingesting caffeinated medications. [87]

Pregnant women are also generally advised to avoid caffeine, for a variety of reasons. Though it has not been linked to “pre-term labor, low birth weight, or birth defects,” physicians generally suggest that pregnant women abstain from caffeine intake due to the suspicion of an increased likelihood for miscarriage and intra-uterine growth retardation. [88] Because of the potential for caffeine transmission through breast milk, women who are planning to breast feed a child are similarly encouraged to avoid caffeine. [89]

Sleep deprivation caused by caffeine is worthy of separate mention. While the obvious “wake up” benefit of a morning cup of coffee is well known, the cost associated with this benefit is the potential for delayed negative effect on adenosine absorption. [90] Adenosine is critical to deep, restful sleep; the later in the day an individual consumes caffeine, the longer the adenosine replacement will take place and conflict with ordinary restful sleep cycles. [91] For example, using caffeine’s estimated three and a half hour half-life, a single one-hundred milligram dose of the drug taken at four o’clock p.m. will be at half strength at seven thirty. In general, more caffeine consumed later in the day will be increasingly likely to cause sleep disturbances; this further fuels the need for caffeine to facilitate the body’s awakening the following morning. [92]

Caffeine also poses a potential problem when considered in concert with other prescription drug therapies and physician diagnoses. Goodman & Gilman’s chapter on methylxanthines notes

the xanthine beverages present a medical problem in that a large fraction of the population consumes enough caffeine to produce substantial effects on a number of organ systems. Hence, the physician should give due consideration to the possible contribution of caffeine to the presenting signs and symptoms of patients, as well as to its potential interaction with any contemplated therapeutic regimen. [93]

Considering its known stimulating effects, those patients who could frustrate existing medical conditions through its use should avoid caffeine intake. For example, people with abnormal heart function, including tachycardia and arrhythmia, should avoid caffeine because it could unnecessarily stimulate cardiac function. [94] Similarly, people with existing sleep disorders should avoid the interruptive effects of adenosine replacement. Finally, patients with gastrointestinal dysfunction of any kind, including gastro-esophageal reflux disease and peptic ulcers, should limit intake or omit caffeine entirely from daily consumption. [95]

F. Caffeine: The Problem of Disputed Science

Though caffeine is generally considered to be a safe product provided it is taken in small quantities, it may still be considered a poisonous substance regardless of the amount ingested. [96] Some sources are more concerned about its ready availability to the public, fearing untold long-term risk of overuse. [97] Many sources, however, defend the use of caffeine, claiming that much of the previous study research implicating it in a variety of health problems was poorly done or at best inconclusive. [98]

Several of the presumed linkages between caffeine use and significant health problems have recently been debunked as a result of new laboratory information. [99] For example, a famous 1980 study posited a link between caffeine use and fibrocystic breast disease; the correlation was later summarily dismissed. [100]

The supposed connection was suggested by a surgeon’s study, in 1980, which relied on interviews with a small number of women but included no objective examination of their breast tissue. Since then, the few well-designed studies have found no association. [101]

Medical studies of caffeine continue to evolve and conflict; this makes definitive causal connections between caffeine and individual health concerns increasingly more difficult to establish.

A clear example of the conflicts among caffeine data involves the perceived correlation between caffeine use and bone fragility, particularly in post-menopausal women. According to an older Harvard-based study of more than one-hundred-thousand nurses, caffeine intake has a negative correlation with the body’s ability to retain calcium, potentially altering bone density and increasing the likelihood of bone fracture and osteoporosis. [102] However, a recent evaluation of bone density data refutes the presumed linkage between caffeine use and calcium retention, and suggests that there is no verifiable independent link between bone fragility and the use of caffeine-containing substances. [103] Therefore significant concern about the issue is thought to be unfounded. [104]

Elevated risk of heart disease is a second important example of conflicting data in caffeine studies, especially since heart disease is now the largest cause of death in the United States. [105] While “some studies linked caffeine consumption to an increased risk of heart disease, particularly in men,” [106] more recent research reflects no such negative correlation between caffeine intake and heart disease. [107]

Cardiovascular disease (CVD)... has been the subject of extensive medical and scientific research for several decades. While researchers have differed in their conclusions over time, new evidence in 1999 strongly indicates that consumption of coffee and caffeine does not contribute to CVD, finding neither caffeinated nor decaffeinated coffee associated with the risk of stroke – even for those drinking more than four cups of coffee a day. [108]

A 1994 review of the relevant medical literature similarly concluded that, “[t]he largest and better studies suggest that coffee is not a major risk factor for coronary disease.” [109] Numerous other studies reflecting similar findings have been done in the past fifteen years, indicating that the espoused link between caffeine consumption and heart disease is probably spurious. [110]

At one time, caffeine was erroneously thought to be potentially carcinogenic; due to its diuretic properties, caffeine was believed to be linked to increased likelihood of bladder cancer. [111] However, a new wealth of study data now not only suggests that caffeine has no links to the promotion of cancer growths, the data also shows that caffeine-containing substances may actually combat certain types of cancer formation. [112] Though more information is needed to link caffeine to combating cancer, sufficient data exists to remove caffeine from consideration as a carcinogen. [113]

Several other presumed health linkages of lesser severity have also recently been called into question. For example, caffeine intake was once thought to be highly correlated with spikes in blood pressure, elevated serum cholesterol levels, and the exacerbation of existing cardiac conditions, including arrhythmia. [114] New data suggests that each of these health linkages is suspect. For instance, while caffeine certainly does correlate to a short-term spike in blood pressure to a xanthine-naïve body, such effect is “transient,” and “[n]o changes in blood pressure appear to occur in regular users of caffeine.” [115] Furthermore, serum lipid and cholesterol levels do not show any increase in coffee prepared “by drip machines and percolators.” [116]

Admittedly, physicians generally remain cautious and encourage patients suffering from mild cardiac dysfunction to avoid excessive caffeine intake; there is little incentive not to follow this precautionary measure. [117] However, a 1991 article reviewing medical studies on coffee and caffeine in conjunction with arrhythmias and tachycardia found that a daily dose of five-hundred milligrams of caffeine, or the rough equivalent of five standard cups of coffee, “does not increase the frequency or severity of cardiac arrhythmias or ventricular tachycardia in healthy people or those with CVD.” [118] Thus, even health problems once considered to be obviously correlated with caffeine use are now being substantially called into question, or dismissed entirely.

G. Caffeine Alternatives: Balancing Costs and Benefits

The long-popular American slogan, “everything in moderation,” applies just as well to caffeine as it does to almost any other food, drug, or activity. In very large doses, caffeine is admittedly a poison. In small doses and in rare circumstances, caffeine can potentially cause health problems, though the scope of these problems and the level of medical concern both continue to change with new research developments. This is, practically speaking, no different from any other food or drug item in daily life; too much of virtually anything can be toxic. However, even considering its addictiveness, caffeine is seemingly harmless the vast majority of the time, for the vast majority of people concerned. [119]

Even still, the market has produced alternatives to, and substitutes for, caffeine. In the early 1980s, after the market produced a “health craze,” soda companies began producing numerous decaffeinated colas; these sodas continue to be widely available today. [120] Nowadays, decaffeinated options are made available for consumers virtually everywhere teas and coffees are sold. For those consumers concerned with caffeine content in over-the-counter pain relievers, numerous replacement drugs do not have caffeine as an ingredient. [121]

One particular new source of concern is the American public’s recent infatuation with herbal remedies and supplements; many stimulants, including Ma Huang ( Ephedra sunensis ), Ginseng ( Panax quinquefolium ), and Guarana ( Paullinia cupana ), have become exceedingly common in the market, both as over-the-counter supplements and in food and beverage products, particularly energy drinks. [122] Besides the short and long-term health effects specific to each natural substance, some products like Ma Huang are variations of Ephedrine (recently pulled from the market by the FDA), [123] and others contain large quantities of caffeine and synthetic caffeine substitutes. [124]

The FDA faces a separate regulatory challenge in dealing with these products, many of which do not present the natural caffeine content of the product’s ingredients for greater consumer awareness. [125] Fortunately, due to much of the recent study data’s suggestion that caffeine is not nearly as dangerous as once thought, [126] the proliferation of caffeinated substances in the marketplace is not of great concern; individual consumers can readily avoid consuming toxic quantities of caffeine through moderation, with little effort. [127]

III. CAFFEINE AND THE FDA: THE REGULATORY FRAMEWORK

The United States maintains one of the world’s safest supplies of food and drugs, thanks in large measure to the “interlocking monitoring system that watches over food production and distribution.” [128] The Food and Drug Administration (FDA) is one of the focal points of this monitoring system, and has broad responsibilities regarding the oversight of foods, drugs, and other medical products. [129] The main regulatory authority for the FDA’s work “originated with the Federal Food, Drug, and Cosmetic Act of 1938” (FDCA), though the powers and responsibilities of the FDA have been updated through legislation several times since its passage. [130] The FDA “regulates over $1 trillion worth of products, which account for 25 cents of every dollar spent annually by American consumers.” [131]

A. Caffeine and the FDA: A Brief History of Dual Regulation

In general, FDA regulation requires that new drugs demonstrate that they are safe and efficacious for consumer use before companies market them to the public. [132] By statute, a drug is defined as any article “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.” [133] FDA regulation also ensures that the foods consumed by Americans on a daily basis are generally “safe and wholesome,” and that all of the food and drug products available to the public are “labeled truthfully with the information that people need to use them properly.” [134] Statute defines food as any article “used for food or drink”; [135] courts have further defined food in terms of “its function as food, rather than in terms of its source, biochemical composition or ingestibility.” [136]

Due to its content in such a wide variety of products, caffeine poses interesting regulatory challenges for the FDA, which “regulates caffeine extensively as a drug and a food.” [137] This kind of dual regulation is not at all uncommon; due to fact that the FDCA “has not been interpreted to require the definitions of food and drug to be mutually exclusive,” [138] the FDA instead tends to regulate substances that appear both in foods and drugs based on the advertising of the products. [139]

At first glance, it may seem odd that the same substance can be regulated ‘inconsistently,’ sometimes as a drug and other times as a food. For example, it may seem odd that chewing gum can be a drug simply because it contains caffeine and is advertised as a ‘natural energy booster.’ But this oddity is not limited to caffeine.... [140]

Moreover, definitions of articles adopted by the FDA are granted “substantial deference by courts.” [141]

Several factors generally apply to the FDA’s classification of a caffeine-containing product as either a food or a drug, the most important of which are: (1) whether the product is intended to be used for the diagnosis or treatment of disease; (2) whether it is intended to affect the body’s structure or its function; and most importantly - (3) the specific intent of the vendor. [142] Vendor intent “may be derived or inferred” based on the product’s “labeling, promotional material, advertising, and any other relevant source.” [143] Another common factor in the FDA’s calculus is whether or not the product is recognized in “official compendia”; [144] however, while the courts generally grant extraordinary deference to the FDA’s classification decisions, the courts are not in universal agreement about the application of this last factor. [145]

B. Caffeine and the FDA I: Regulation as a Food

The FDA’s choice in regulating caffeine either as a food or as a drug has important ramifications for the leniency or severity of the regulation imposed. [146] In general, the FDA’s caffeine regulation is much less severe when applied to foods rather than drugs, though the level of leniency varies depending on whether caffeine is added to foods or occurs naturally. [147] Manufacturers of foods, dietary supplements, soft drinks, and many other ingestible consumer products generally prefer classification of their products as foods rather than as drugs, in order to benefit from the leniency of food regulation. [148] A spokesman for the FDA noted that

different regulations apply to drugs and foods. These differences include the labeling of the product, requirements for premarketing approval, practices required during manufacturing, the records that must be maintained during production and manufacturing, and the way in which the substance is dispensed. [149]

With respect to each of the factors above, compliance with food regulation is both easier and less costly than compliance with corresponding drug regulation. [150]

Much of the FDA’s past discussion of caffeine-containing foods revolved around the GRAS, or “generally regarded as safe,” status of caffeine. Under statute, the FDA recognizes a wide variety of substances that satisfy GRAS; these substances include salt, pepper, vinegar, monosodium glutamate, common essential oils, spices, natural extracts, and artificial colors and flavors. [151] Caffeine as added to cola products has been a component of the GRAS list since 1961; [152] its use continues to be generally regarded as safe subject to a drug tolerance requirement of 0.02 percent by weight, and provided that it is added to sodas “in accordance with good manufacturing practice.” [153]

The adherence to “good manufacturing practice” means that: (1) “the quantity of a substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritional, or other technical effect in food”; (2) “the quantity... that becomes a component of food” through processing or manufacturing “and which is not intended to accomplish any physical or other technical effect in the food itself, shall be reduced to the extent reasonably possible”; and (3) “the substance is of appropriate food grade and is prepared and handled as a food ingredient.” [154]

By the FDA’s estimation, soda manufacturers have thus far complied with these manufacturing requirements; therefore, caffeine is exempt from the provisions of the 1958 Food Additives Amendment and its successor provisions through retention of GRAS status. [155] In the 1980s, however, GRAS status was somewhat in doubt:

In 1980, the FDA proposed to delete caffeine from the GRAS list, to declare that no prior “sanction” existed, and to restrict the use of caffeine in food to its 1980 levels until further studies could be conducted. It was prompted to issue the proposal by animal test results that suggested a link between caffeine and birth defects and raised concerns about caffeine’s potential teratogenecity. [156]

In 1987, following a finding that a 0.02 percent by weight requirement would be sufficient to protect the public from injury, [157] the FDA took strides in the opposite direction and instead proposed to grant a “prior exception” for caffeine as a soft drink additive. [158] To date, however, the 1987 proposal has not been acted upon, and caffeine remains on the GRAS list. [159]

Aside from GRAS status, the most obvious aspect of caffeinated food regulation is the requirement that caffeine appear in the list of ingredients when it is used as a food additive. [160] Interestingly, this regulation tends to apply primarily to soft drinks, and is not required in products that have natural caffeine content but no added caffeine. Moreover, the FDA does not require specific disclosure of the quantity of caffeine in food products, though some sources supply such information voluntarily. [161] While natural sources of caffeine, including coffees, teas, and chocolates go largely unregulated and unnoticed by the FDA, [162] the same cannot be said for caffeine-containing substances regulated as drugs.

C. Caffeine and the FDA II: Regulation as a Drug

Whether used as one of the world’s first all natural energy drinks for shepherds and nomads, a religious zealot’s device for maintaining all-night prayer, a sixteenth-century European panacea, or a modern miracle “wake-up” drug, caffeine has been used throughout the centuries for its stimulant effect. [163] In the United States today, however, pharmaceutical companies, food and beverage makers, and particularly over-the-counter producers of “energy products” are all subject to a wide variety of regulation, and cannot therefore market caffeine with reckless abandon. [164]

The FDA strictly controls the drug market and requires extensive showings of safety and effectiveness before it will allow caffeine (or any other drug) to be used as a drug ingredient. It does so ‘to protect consumers and enable them to know what they’re buying.’ [165]

In order to regulate the behavior of American drug companies, the FDA publishes numerous documents involving product requirements and instructions; the two main types of documents are Regulations and Guidances. [166] The two document types differ in important ways: “Regulations are legally binding requirements found in Title 21 of the Code of Federal Regulations and must be followed,” whereas Guidances “represent the FDA’s current thinking and recommendations” but are nonbinding and subordinate to Regulations. [167] In order for any drug to be introduced into the market, it must conform to all codified FDA regulations regarding safety and effectiveness. [168]

Once a company has submitted a drug for approval, the FDA will then review the company’s application and issue a monograph classifying the drug. [169] A drug must receive a Category I monograph from the FDA before it can be marketed to the public; this means the FDA views the new product as safe, effective, and not misbranded. [170] A Category II classification means that the FDA must withhold market approval; by contrast, a Category III classification requires the petitioning company to obtain more data and submit for further FDA scrutiny prior to a final classification as either a Category I or Category II drug. [171]

Since technical information is essential to the process of drug approval, the FDA relies heavily on the independent expertise of advisory panels and committees. [172] The general role of an advisory panel is “to provide independent advice that will contribute to the quality of the agency’s regulatory decision-making and lend credibility to the product review process.” [173] This helps the FDA make better-informed decisions, while giving outside field experts the opportunity “to comment on whether adequate data supports approval, clearance, or licensing of a medical product for marketing,” or suggest that additional information or labeling of a new product is necessary. [174] However, the most important fact about advisory panels is that their findings are nonbinding; “while committee decisions and final votes are very important to the FDA, the final regulatory decision rests with the agency.” [175]

In practice, the FDA has no problem disregarding the positive findings of an advisory panel. When caffeine was proposed as an addition to antacids in hangover medications in 1991, an advisory panel was convened regarding this proposal. [176] Following the advisory panel’s decision that the inclusion of caffeine would be safe and effective, the FDA disregarded the panel’s findings. [177] The agency concluded that

although moderate doses of caffeine did not generally cause gastrointestinal problems, the population likely to ingest hangover medicine already suffered from gastrointestinal irritation and might be harmed by caffeine’s stimulation of gastric secretions of hydrochloric acid. [178]

The agency therefore demonstrates that it adheres to a strict consumer safety policy regarding drug approval: the FDA can classify potentially useful drugs as unsafe solely on the basis that consumer usage of those drugs may ultimately be unsafe. [179]

The FDA has also demonstrated that failing any one of the three main approval criteria (safety, effectiveness, and proper labeling for stated purpose), is a sufficient rationale for the agency to withhold marketing approval. One clear example of this strict enforcement involves cold and allergy medications:

For example, the FDA has prevented the use of caffeine in cold, cough, allergy, bronchodilator and antiasthmatic drug products because it concluded that caffeine was either unsafe or ineffective in combination with phenylpropanolamine and/or ephedrine or pseudoephedrine or in combination with any cold, cough, allergy, bronchodilator, or antiasthmatic ingredient, and either unsafe or ineffective (in combating lethargy) in cold preparations not containing antihistamines. [180]

It is interesting to note that the FDA does approve the use of theophylline, the methylxanthine closely related to caffeine, in bronchodilators because of its relaxing effects on smooth muscle; however, the quantity of caffeine required to make it an effective bronchodilator is considered close enough to its toxic quantity for the FDA to consider its use unsafe or ineffective. [181]

In reviewing caffeinated weight loss products like “Dexatrim,” the FDA, after advisory panel review, decided that both caffeine and caffeine citrate had no valuable weight loss effects for consumers; this prompted FDA intervention in 1991. [182] The agency both removed caffeinated weight loss products from the market and threatened further regulatory action against manufacturers if they refused to remove caffeine from their weight loss products within one year. [183] Even though caffeine intake has in the past been attributed to increased athletic function and metabolism, the FDA prefers to err on the side of caution and does not allow the public to overmedicate unnecessarily. [184]

Setting aside the numerous instances in which the FDA has intervened in the consumer drug market to prevent unnecessary or unsafe caffeine use, a number of caffeinated drug products have been FDA-approved and are readily used by consumers.

FDA has approved the use of caffeine in a number of over-the-counter (OTC) drug products. For example, it has found caffeine to be safe and effective as an ingredient in stimulant drug products, used to ‘restore mental alertness or wakefulness during fatigue or drowsiness’.... In addition, the FDA has approved the use of caffeine in menstrual drug products, recognizing that it is a diuretic and a stimulant which can help women suffering from water weight gain and fatigue during their menstrual or pre-menstrual periods. Finally, after years of study and review, the FDA has recognized the effectiveness of caffeine as an analgesic adjuvant in aspirin and aspirin/acetaminophen products. [185]

Caffeinate is often “widely employed” in the treatment of many ordinary types of headache and fatigue, and is even used in combination with an “ergot alkaloid in the treatment of migraine.” [186]

Once the FDA has approved the existence and production of a new caffeinated drug, it continues to monitor consumer safety through strict labeling requirements. [187] Contrary to caffeine food labeling requirements, which only require the presence of caffeine on the ingredients list if it is an additive (i.e. sodas), caffeine in drugs must be listed qualitatively on the label, and with significant stimulant warnings. [188] The regulation specifies that

The labeling of the product contains the following warnings under the heading ‘warnings’: (1) The recommended does of this product contains about as much caffeine as a cup of coffee. Limit the use of caffeine-containing medications, foods, or beverages while taking this product because too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heart beat. (2) For occasional use only. Not intended for use as a substitute for sleep. If fatigue or drowsiness persists or continues to recur, consult a physician [or doctor]. (3) Do not give to children under 12 years of age. [189]

Furthermore, in 1999, the FDA approved a new monograph (generally effective in April 2001) with more detailed labeling requirements for over-the-counter drugs. [190]

Among the new over-the-counter labeling provisions are requirements that the labels “adhere to standardized headings and subheadings, presented in a specified order,” as well as graphical restrictions including “minimum requirements for type size, graphical highlights, leading (space between two lines of text), kerning (spacing between letters),” and use of “connecting terms” previously required under the Code of Federal Regulations. [191] The updated regulation is intended to “further the safe and effective use of these drug products for consumers by making labels easier to read and understand.” [192]

The FDA’s continuing concerns regarding the labeling and warnings on caffeinated drugs are part of the agency’s dedication to further minimizing consumer health risks. For example, one of the reasons the FDA mandates standardized and legible drug content data is so that consumers can avoid using too much caffeine in combination with other products, therefore both making consumers aware of likely side effects and reducing the potential for negative consequences from these side effects. [193]

Perhaps the most important addition to the existing over-the-counter drug regulations is the codification of active ingredient listing requirements including the specific quantity of ingredients used. Prior to the 1999 final rule on over-the-counter labeling requirements, the FDA did not require manufacturers to list the quantities of active ingredients on their labels. [194] Some sources posit that such regulation was, in the past, unnecessary due to massive voluntary disclosure of active ingredient information; “under another voluntary program begun in 1974, the member companies... have been including the quantities of active ingredients on OTC drug labels.” [195] The Nonprescription Drug Manufacturers Association, a trade organization that encompasses the vast majority of all over-the-counter drug sales in the United States, was the impetus for this general practice of voluntary disclosure. [196]

As part of the 1999 reforms, and partly due to the tremendous increase in the publicly available number of herbal remedies, energy boosting supplements, and other new over-the-counter drug products, the FDA issued regulations that codified the previous voluntary practice of active ingredient quantity labeling. [197] Under the “Active Ingredients” section of the final rule, the FDA notes that

Section 201.66(c)(2) requires the heading “Active Ingredient(s),” followed by the established name and the quantity of each active ingredient per dosage unit. For products marketed without a discrete dosage unit, such as topical OTC drug products, the proportion of each active ingredient must be stated instead of the quantity, unless otherwise specified in an applicable monograph or approved drug application. This provision incorporates a recent amendment to section 502(e) of the act under FDAMA... to require that the quantity... of each active ingredient appear in the labeling of all OTC drug products intended for human use. [198]

This means that consumers can now be certain to know exactly how much caffeine they consume when using over-the-counter drugs. While there is still “a significant discrepancy in caffeine content across OTC drugs,” consumers are “made aware of it and are warned against excessive consumption.” [199]

Another way the FDA maintains control over caffeinated drugs after market approval is through dosage limits; for example, while certain analgesics use caffeine both as an adjuvant and a stimulant, the FDA planned to limit the amount of caffeine to “64 or 65 mg per dose irrespective of the amount of analgesic in the dose.” [200] The low dosage was the “demonstrated minimum effective caffeine dose, and was chosen based on agency concerns about the potential of caffeine to foster analgesic misuse.” [201] Because the FDA perceives caffeine habituation as a problem, albeit a reasonably minor one, drugs that incorporate caffeine must still do so at doses that are clinically effective while not unnecessarily or deliberately causing addictive psychotropic responses. [202]

Even in drug products in which the FDA generally allows caffeine to be used in small amounts, such as aspirin or acetaminophen pain relievers, approval does not extend unequivocally to any similar class of drug seeking to include caffeine. Further, even if permission is granted to produce and market a new drug, there is still strict FDA supervision of marketing claims made on behalf of caffeine-containing drugs. [203] For example, in 1997, Bristol-Myers Squibb attempted market a new caffeine-containing drug similar to a commonly used pain reliever called “Norflex,” which contains the active ingredient orphenadrine citrate. [204]

Norflex (orphenadrine citrate) is used “to relieve the pain and discomfort associated with musculoskeletal injuries and conditions.” [205] In its attempt to market its new tablet combining orphenadrine citrate, aspirin, and caffeine, Bristol-Myers Squibb and its subsidiaries released promotional materials claiming this new tablet was “AB Rated, Therefore Bioequivalent to Norflex.” [206] However, the FDA demanded immediate removal of all promotional material, stating that “Norflex contains only a single active agent, namely, orphenadrine citrate.... thus these products are not AB rated and are not bioequivalent.” [207] The FDA was primarily concerned about the potential for interaction effects that could result from the use of the additional active ingredients caffeine and aspirin combined with orphenadrine citrate. [208] Thus, even after approval, the FDA maintains a vigilant watch over the caffeine-containing consumer drug pool in order to minimize the potential for negative health consequences among consumers.

IV. THE FUTURE OF CAFFEINE REGULATION: REEXAMINING THE FDA APPROACH

Recognizing the American public’s curious infatuation with caffeine, the FDA, through its regulation of both foods and drugs, has been trying to keep the public informed about caffeine and protected from any adverse effects. In the 1980s, after data suggested a correlation between caffeine and birth defects, the FDA was hard at work, issuing press releases, consumer warnings, and labeling requirements as part of its educational campaign. [209] As with any food or drug, as the FDA perceives consumer health concerns, it intervenes to correct problems through issuance of regulations and through direct contact with manufacturers. [210] If no way can be found to release and market a particular product such that it will be safe and effective for consumer use, the FDA issues an order to pull the product from the market entirely. [211]

A. More FDA Regulation: No Additional Need, No Productive Purpose

To date, the FDA has not seen fit to issue a general ban on the inclusion of caffeine in foods and drugs because such a ban is unwarranted. Since caffeine has been used safely for so long in so many foods and beverages, a simple risk-benefit calculus would lead to the general conclusion that “consumers be permitted to make their own judgments about risks on the basis of complete and accurate information about the hazards involved.” [212] With the dearth of long-term caffeine study data raising alarm, and the prevalence of caffeine in the consumer products market, the FDA should remain on guard for future indications of dangerous health correlations. However, following the recent passage of uniform over-the-counter drug labeling requirements, [213] there is no further market intervention that would be necessary or desirable on the part of the FDA.

Some sources have suggested that there is a problem with caffeine regulation as applied to foods, asserting that caffeine content labeling on foods is the next logical step in FDA consumer protection. [214] The basic argument for this position is that consumers cannot make informed choices about their daily caffeine intake if the specific amount of caffeine is only listed on certain drug products. [215] The argument also notes that “caffeine quantities vary significantly in foods,” and generalizes that consumers may be misled if, for example, a single serving of chocolate can contain anywhere from six to twenty-five milligrams of caffeine. [216]

Any argument that favors the extension of caffeine quantity labeling to foods is fundamentally flawed. While it might be beneficial to know the exact amount of caffeine in any given food, this is not always possible. A new coffee study suggests (among other things) that “java’s caffeine jolt varies naturally,” and that “there are many variables that contribute to caffeine content from cup to cup, such as the type of bean, roasting and brewing methods, and grind.” [217] This variance is further exacerbated by recent findings that “the caffeine content of specialty coffee beverages varies widely from day to day as well as from coffee shop to coffee shop.” [218]

While the study data suggests that American caffeine consumption may be on the rise, researchers contend that “coffee drinkers might have to live with uncertainty when it comes to how much caffeine” they take in from their daily coffee. [219] This same logic applies to all other natural sources of caffeine in foods; if the caffeine content in a serving of chocolate can vary anywhere from six to twenty-five milligrams, it would be an unjustifiable burden on manufacturers to have them give a best guess at the caffeine content on an individual item. Further, the quantity of caffeine added to products like soda, while not listed explicitly on the label, is easily enough obtained since content data is published by soft drink manufacturers. [220]

Fortunately, the FDA has long held to a policy of rarely including consumer health warnings on foods, and doing so only in such instances deemed absolutely necessary. [221] The fact that caffeine has been safely consumed for so long, coupled with the agency’s fear of consumer analysis paralysis, suggests that further regulatory intervention is both impractical and undesirable. [222]

B. New Scientific Information Means Diminished Concern

The advancement of new scientific data regarding the positive and neutral health impacts of caffeine prompted the FDA’s public affairs staff to summarize some of the administration’s previous concerns about caffeine. [223]

In 1980, FDA was confronted with various studies that aroused concern about the possible association of caffeine in the human diet with numerous health problems. Of immediate concern was the study that demonstrated caffeine's potential for causing birth defects in animals. Was there a danger to humans? The agency said that it didn't know. So, it chose to lean on the side of caution by warning pregnant women and, at the same time, asking industry and the scientific community to do more studies on caffeine's health effects. These have now been done, and they generally have produced less worrisome results. For that reason, and because FDA determined that some of the earlier studies were faulty, inconclusive, or contradicted by later findings, the concern about caffeine has lessened. [224]

A change in the regulatory posture of caffeine is unsurprising, as the FDA continues to monitor and update the level of regulation on consumer products based on the continued development of laboratory data. [225] What is surprising, however, is the continued outpouring of new data suggesting potential positive health effects of caffeine use. For example, the National Parkinson Foundation has researched the posited inverse relationship between caffeine intake and Parkinson disease for years, but with “equivocal” results at best. [226] However, a thirty-year follow-up case review published in the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION indicates that “higher coffee and caffeine intake is associated with a significantly lower incidence of Parkinson disease.” [227] While it is certainly not the last word on this newly-established caffeine correlation, it serves as proof-positive that time and medical data can and have significantly diminished the necessary level of public health concern with regard to caffeine use. Another example of conflicting caffeine data that has been reconsidered recently involves correlations between caffeine intake and health risks for women who are either seeking to become pregnant, or who are already pregnant or nursing. A small 1988 study suggested that low to moderate caffeine consumption might decrease female fertility; however, the scientists involved “acknowledged that delayed conception could be due to other factors they did not consider, such as exercise, stress, or other dietary habits.” [228] Further study data has since prompted the International Food Information Council (IFIC) to dismiss the presumed link between caffeine and infertility. [229] The IFIC and the Organization of Teratology Information Services (OTIS) further investigated correlations between caffeine intake and risks of birth defects, low birth weight, and caffeine transfer to infants through breast milk; the results demonstrate that, though high levels of caffeine intake are potentially dangerous to infants during gestation and breast feeding, low to moderate levels of caffeine intake are less problematic than previously thought. [230] The wave of recent positive caffeine study data has even caused some health professionals and consumers to wonder if coffee is “the new health food.” [231] Besides posited correlations between caffeine intake and reduced risk of Parkinson disease, a recent Harvard study also suggests that persistent caffeine use might also reduce the risk of type-2 diabetes. [232]

After analyzing data on 126,000 people for as long as 18 years, Harvard researchers calculate that compared with not partaking in America’s favorite morning drink, downing one to three cups of caffeinated coffee daily can reduce diabetes risk by single digits. But having six cups or more each day slashed men’s risk by 54% and women’s by 30% over java avoiders. [233]

While these (and other similar) findings would benefit from more research, the overarching trend in caffeine data over the last five to ten years is positive; “overall... coffee is far more healthful than it is harmful... the evidence is very strong that regular coffee consumption reduces risk of Parkinson’s disease and for that, it’s directly related to caffeine.” [234] The proliferation of scientific information available through the internet has a large upside for consumers: useful findings of new medical studies (including the ones discussed herein) can reach the consumer public faster than ever before. Internet services such as “MSN Health” and “WebMD” even have newsletter services, such that health product consumers can make more informed product purchasing decisions as a result of newly available information. [235] For caffeine users, this translates to increased awareness of product effects, such that people can better regulate their diets to suit their individual health needs. [236]

C. Residual Skepticism and Incomplete Scientific Information The availability of new caffeine health data does not mean that the FDA should rest on its regulatory laurels. The Parkinson disease, pregnancy, and diabetes studies together illustrate that with the increase in the number of scientific experiments conducted and the dramatic expansions of available scientific data and information, the FDA and the American public (as consumers of health information) must be cautious not to jump too quickly to health-related conclusions. The Parkinson study admits that “the study design is such as to prevent the researchers from concluding, definitively, that coffee or caffeine directly protect against development of Parkinson disease.” [237] It instead recognizes that “the possibility that caffeine may have a protective effect against developing Parkinson disease must be investigated further.” [238] The FDA admits that the risks associated with caffeine use have been at least overstated in the past; [239] even so, sources at the FDA continue to encourage consumer wariness, fearing unknown future potential effects from long-term exposure.

However, FDA is also saying that while there is a basis for being less concerned about caffeine's impact on health, some questions remain unanswered. The agency continues to stress that caffeine is a chemical stimulant that affects the central nervous system. It is a widely used food additive to which some people are more sensitive than others. It could have other, still unknown, effects. But determining what these effects are is not a simple matter, as some studies have indicated, since other factors - such as smoking, alcohol consumption, poor diet, and drug use - also can affect human health. From a regulatory standpoint, FDA will continue to monitor caffeine use in foods and how much of it people consume. Meanwhile, consumers probably should adhere to some age-old advice: moderation makes good sense. [240]

Many consumers also decry the lack of caffeine content data on food products such as sodas, fearing the addictive properties of the drug are more dangerous than the FDA recognizes. [241]

Besides the obvious potential problems with new scientific data, including consumer over-reliance and incomplete or uncertain conclusions, caffeine and other drug data can be taken out of context or manipulated in such a way as to cause an artificial sense of consumer security or unnecessary fear of drug products. For example, a recent alarmist email message was sent to thousands of consumers regarding phenylpropanolamine, a common product in cough and cold medicines, weight control drugs, and decongestants. [242] Among other claims, the email letter suggested that “all drugs containing phenylpropanolamine are being recalled,” and that consumers should “stop taking anything containing this ingredient” because it “has been linked to increased hemorrhagic stroke... among women ages 18-49 in the three days after starting use of medication.” [243]

While it is true that the FDA is seriously concerned over the inclusion of phenylpropanolamine in common over-the-counter products, particularly after a Yale research study linked it to increased risk of hemorrhagic stroke, [244] the FDA already took the necessary regulatory measures in the year 2000. [245] Further, the email letter grossly overstates the linkage between phenylpropanolamine and immediate health risk. [246]

The “drug hoax” as described is not included to suggest that FDA and other consumer health warnings should be taken lightly; rather, it serves to illustrate the downside of the information age. With the explosion of internet technology, consumers live in an age in which scientific information is more readily available than ever before, and this has consumer awareness benefits. [247] With this new ease of access to data comes a corresponding responsibility to carefully consider the sources and validity of available information, the overarching concern being that the quality of health related statements relied upon by consumers is oftentimes dubious. Provided that consumers stick to reputable sources of information, however, increased connectivity can lead to better health decision-making. [248]

D. A Hypothetical Scenario Considered: Caffeine as a New Food Additive or Drug

Though the policy of consumer moderation is still an entirely sensible approach, this Paper generally contends that, in the face of newer and better data, caffeine is much safer than older studies and reviews have suggested. This finding, however, prompts an interesting hypothetical consideration: since caffeine is and has been so pervasive in the marketplace (naturally, as a food additive, and in drugs), it has not been forced to undergo the more complex and time consuming contemporary processes of food additive or drug approval. It is worthwhile, then, to hold caffeine up to current regulatory process and scrutiny, in order to better demonstrate that previous health concerns regarding caffeine were inflated.

1. Caffeine as a Newly-Proposed Food Additive

A company must first petition the FDA for approval before marketing a new food additive. [249] A food additive petition “must provide convincing evidence that the proposed additive performs as it is intended.” [250] Usually, part of the relevant data comes from animal studies “using large doses of the additive for long periods” to satisfactorily demonstrate that the substance “would not cause harmful effects at expected levels of human consumption.” [251] The FDA considers many factors, including “the composition and properties of the substance, the amount likely to be consumed, its probable long-term effects and various safety factors” when weighing its approval decisions. [252] Since one-hundred percent safety is not practical for any substance, the FDA must instead determine if the proposed new additive is safe enough “under the proposed conditions of use,” and “based on the best scientific knowledge available.” [253]

Now, assume the existence of a new soda company, “Hypo-Cola,” in a consumer world that is entirely familiar with the GRAS list and with the proper process for soda manufacturing, but that is caffeine naïve. First, the Hypo-Cola company petitions the FDA to have its new additive, the methylxanthine chemical caffeine, approved for consumer use. [254] As a potential new food additive, the FDA wants to know caffeine’s intended purpose, as well as the company’s rationale for including it in its new soft drink.

This is the first potential snag in the regulatory process; without GRAS list status, and without a world in which caffeine use is assumed to be both natural and commonplace, Hypo-Cola likely has some difficulty explaining the need for caffeine’s inclusion in sodas. While the National Soft Drink Association claims both that “caffeine has a classic bitter taste that enhances other flavors,” and that “small amounts of caffeine are added to soft drinks as part of the flavor profile,” [255] Hypo-Cola has to convince the FDA of the validity of those claims while minimizing the significance of the chemical’s stimulant properties, or else risk more cumbersome drug regulation.

Getting caffeine approved as a flavor additive may be slightly more difficult in light of a recent Johns Hopkins University study, which found that “only two out of 25 hard-core cola drinkers were able in a blind taste test to detect whether a soda sample contained caffeine.” [256] While the size and format of the study are disputed by the National Soft Drink Association, [257] the results might cause the FDA to take a closer look at caffeine’s inclusion in new soft drinks, and the potential for mandatory labeling requirements. However, since “vendor intent” is a strong indicator of whether a substance will be considered a food or a drug, [258] and since there is not sufficient evidence to suggest ulterior motivation on the part of soda manufacturers, Hypo-Cola can likely proceed with the FDA approval process. [259]

The FDA then considers the chemical properties of the new additive, potential consumer use of the product (including the amount likely to be consumed), and the likelihood of long-term consumer health risks. Hypo-Cola has to provide evidence sufficient to satisfy the FDA’s consumer safety concerns. [260] Assuming the company has mustered all relevant study data, including sufficient animal laboratory data to show that the stimulant effects of caffeine are generally harmless, and further assuming that Hypo-Cola will be using a small enough amount of caffeine so as not to injure public health, [261] the FDA might approve the use of caffeine as a new soft drink flavoring additive.

If a new additive is approved, the FDA “issues regulations that may include the types of foods in which it can be used, the maximum amounts to be used, and how it should be identified on food labels.” [262] As applied to Hypo-Cola, this means that the company places caffeine on the list of ingredients, though not necessarily the specific amount used. [263] Once the product is released and marketed for consumer use, FDA officials continue to monitor the level of American consumption of the new additive and the results of any new product safety research; this is to assure that the use of the product continues to be within safe limits. [264] The FDA will take no affirmative steps to ban or further limit caffeine as a food additive so long as the long-term study data continue to show no major harmful effects of its intake. [265]

2. Caffeine as a Newly-Proposed Drug

While the food additive approval process may be somewhat more complicated today than it was in the past, “drug development in the United States has undergone many changes in the past 25 years,” and few people “fully realize the complexities involved in developing a new drug.” [266] In fact, the drug development process occurs in several stages:

Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development. [267]

Of every five-thousand to ten-thousand new drug compounds that will be subjected to the FDA approval process, only an average of one “will proceed through development to Food and Drug Administration approval.” [268]

Further, recent estimates suggest that “developing a new drug requires approximately 10 to 15 years”; this process costs an estimated 897 million dollars. [269] Though the temporal and monetary costs associated with new drug development are high, the FDA has recurring interests in accurate “statistical methods for handling subgroups in the design and analysis of clinical trials,” as well as in “methods to assure data integrity,” such that the agency can be sure that new compounds released to market are safe and effective for human consumption. [270]

Though the FDA admits it has limited knowledge regarding the drug development process, and has many different pressures to weigh when considering the safety of a newly created drug, it is still responsible for creating the standards by which consumer health is protected; this means a more costly and time-consuming process for drug manufacturers. [271]

In setting standards, FDA functions amid a number of tensions. There is the desire of many people, including much of the academic community, to have more information about a drug before it has been approved. There are special interest groups... who want to be represented in studies to attain information specific to them. Consumer protection advocates want to have drugs worked-up well and thoroughly evaluated for safety and efficacy before getting on the market. On the other hand, there are economic pressures to get drugs on the market as soon as possible, and these are highly valid. [272]

With that as the general regulatory backdrop, now assume the existence of a new drug manufacturer, “Hypo-Stim.”

Hypo-Stim has discovered a new methylxanthine compound called caffeine. The company suspects that the drug will be a good mild stimulant, though it may have other potential uses. Hypo-Stim therefore wants to test the product, in hopes that it can eventually garner FDA approval for marketing. [273] The process begins with preclinical research; “after a promising compound is identified, much work occurs before human exposure, usually in vitro and with animal testing.” [274]

The general goal of preclinical research and testing is to weed out potentially dangerous compounds as much as possible prior to human clinical trials, therefore minimizing risk exposure for human test subjects later on. [275] Also, preclinical trials give the drug sponsor or manufacturer the initial opportunity to test whether the new substance will be commercially viable, prior to the FDA having to interrupt production or marketing. [276] Preclinical trials involve the use of numerous kinds of studies:

Usual types of studies that are performed include safety pharmacology studies (to assess drug effect on vital organ systems, such as the cardiovascular system, the respiratory system, and the central nervous system), single-dose acute toxicity studies, repeated-dose toxicity studies, local tolerance studies, at least part of the genotoxicity studies (bacterial reverse mutation test and chromosomal damage test), and possibly carcinogenicity studies. [277]

Since caffeine usage has been linked to alterations in central nervous system, cardiovascular system, and (though less so) to respiratory system functioning, [278] Hypo-Stim will likely have to engage in a large battery of expensive preclinical trials, in order to satisfactorily demonstrate that the quantitative effect on those body systems is insufficient to trigger health concerns in humans. Further, caffeine’s LD 50 will be recorded in laboratory research; this data will influence whether the company considers going forward with clinical testing. [279]

Though caffeine does stimulate several of the body’s major organ systems, study data in the last twenty-five years has shown that these effects are generally mild provided that toxic quantities are not ingested. [280] Therefore, Hypo-Stim can likely proceed out of the preclinical phase and into clinical trials. However, “once the decision is made from preclinical testing that use of the medical product appears promising and clinical testing should proceed,” an IND, or Investigational New Drug application, must be filed by the drug’s sponsor with the FDA “before research studies begin with a new compound in human subjects.” [281] The drug sponsor, in this case Hypo-Stim, is the “person who takes responsibility for and initiates a clinical investigation.” [282]

The initiation of the IND process is where the FDA’s regulatory role really begins:

FDA’s role in the development of a new drug begins when the drug’s sponsor (usually the manufacturer or potential marketer) having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system. [283]

This really means that all of Hypo-Stim’s expensive and time-consuming preclinical testing was just to see if the drug could possibly pass initial FDA scrutiny, and undergo later stages of clinical testing.

While the primary purpose of the IND application process is to grant a legal exemption from interstate shipping requirements, [284] a new IND “now consists of multiple sections summarizing the general investigational plan, Investigator’s Brochure (summarizing available safety and efficacy information in animals and humans, when available), protocol(s) for planned studies, chemistry/manufacturing/control information, and pharmacology/toxicology and other information.” [285] Unless the FDA decides to issue a clinical hold on the new drug, [286] “the IND goes into effect and development work may proceed,” though “additional information is then submitted periodically to the IND by the sponsor.” [287] This means that Hypo-Stim’s IND will include detailed summaries of all the caffeine preclinical laboratory findings, LD 50 toxicity data, as well as explanation of caffeine’s positive stimulant properties.

Assuming the FDA finds the data sufficient to proceed with clinical trials (barring findings that the drug is either ineffective or unsafe), Hypo-Stim can begin its human scientific investigation in earnest. Clinical approval is likely to occur because caffeine’s level of toxicity is very mild when comparing toxic quantities to the amount required to achieve basic stimulant effects. The clinical development work process generally has three distinct phases, the first of which involves somewhere between twenty and eighty “healthy adult volunteers” and requires roughly twelve to eighteen months to complete. [288] The basic rationale of Phase I study is to discover how safe the drug is as increasing dosages are applied and side effects emerge. [289] As applied to Hypo-Stim’s caffeine testing, Phase I will likely yield mixed but positive results. It is noted that caffeine causes feelings of alertness at mild dosages, and those effects can be sustained with additional intake; on the other hand, the study data likely reflects possible side effects of nervousness and agitation. [290]

Since the side effects of caffeine are generally mild and often result only at elevated dosages, Phase II studies are likely to follow. Phase II research usually involves one-hundred to three-hundred patients “with the disease or condition under study”; these studies often take more than two years. [291] While this research functions as an additional measure of short-term safety, its primary function is as an effectiveness screen. [292] For Hypo-Stim, this means that studies are conducted predominantly on sleep-deprived patients, in order to demonstrate caffeine’s effectiveness as a wake-up agent. [293] Again, barring unforeseen problems with toxicity or severe side effects, Hypo-Stim can proceed to Phase III.

Research studies in Phase III tend to be the largest and most time consuming; they generally involve thousands of patients, though the number varies depending on the disease or condition under study, and can take upwards of three years to complete. [294] Since more information is already available about the drug at this point, the primary goal is to garner a large sample set with conclusive safety and effectiveness findings in order to proceed with the final stages of FDA approval. [295] Hypo-Stim is unlikely to experience a shortage of available Americans needing a boost in the morning, and is further unlikely to uncover any surprise negative correlations between caffeine intake and human health risk.

The company is therefore ready to proceed with its New Drug Application (NDA); “when the sponsor has collected sufficient information from preclinical and clinical studies to provide the FDA with data for analysis of the safety and efficacy of the study drug, they submit an application for marketing.” [296] The NDA process is also very involved; it requires extensive information regarding proposed labeling, manufacturing methods and controls, human drug interaction data, and all relevant preclinical and clinical research information. [297] More importantly, Hypo-Stim will have to provide an “integrated safety summary, an integrated summary of the benefits and risks of the drug, statistical analyses, pediatric information, case report forms and tabulations, patent information, and financial disclosure information.” [298] In other words, the company has to have all cards on the table; all information regarding estimated effective dose, side effects, possible dangerous interactions, and necessary warnings must be disclosed so that the FDA can review the drug according to its mandate. [299]

While this hypothetical NDA takes place without the benefit of centuries of safe consumer caffeine use, the new drug will likely be approved, though perhaps with stricter initial labeling requirements and warnings. There is insufficient scientific evidence to support correlations between caffeine and severe health risks; further, though caffeine can cause borderline toxic responses in the occasional individual, the data shows that moderate use (and even heavy use) generally results in only mild side effects. [300] The FDA review process includes “medical, biopharmaceutical, [and] statistical... reviews to study and validate the sponsor’s conclusions.” [301] The FDA may request additional research and information if the agency is unsatisfied by the material submitted; it may further perform inspections “to verify the data” and the integrity of “sponsor manufacturing facilities.” [302] The FDA may also consult with an expert review committee, though the findings of the committee are non-binding. [303]

Assuming Hypo-Stim spends the time and money to pass caffeine through the entire FDA review process, a few details remain. The FDA will likely negotiate with Hypo-Stim regarding specific product labeling, but more importantly will decide “whether postmarketing work will be required.” [304]

Once a medical product receives marketing approval, there are several reasons why additional clinical studies may be needed, such as Phase IV commitments required of or agreed to by the sponsor, pharmacoeconomic studies to assess cost/benefit, investigator-initiated studies, and quality-of-life studies. [305]

Assuming caffeine does not require any such reexamination, Hypo-Stim can finally begin to market its drug to the public, subject to the continued watch of the FDA.

The agency may have concerns about study data reflecting caffeine’s addictiveness; however, the habituation is sufficiently mild that it should not significantly impede the company’s marketing of the new drug. Since there is no known serious problem with caffeine use in moderate doses, any additional concerns the FDA has can be addressed through product labeling and FDA Guidances. If long-term health study data continues to be generally favorable, caffeine will continue to be approved for use as a valid drug product.

V. CONCLUSION: CAFFEINE – THE NEW AND IMPROVED AMERICAN CRUTCH

The hypothetical food additive and drug discussions are not meant to supercede a sensible policy of moderated intake. [306] To paraphrase an old American saying, “too much of a good thing can be bad for your health.” This statement is valid with regard to almost anything, and caffeine intake is probably no exception. Though the FDA cannot absolutely guarantee that every consumer will exercise moderation of caffeine intake, the same could be said for any widely available food and over-the-counter drug product.

Fortunately, the FDA arguably has much less to worry about with regard to caffeine regulation nowadays than it did in 1980 when negative caffeine correlations were first being asserted. The majority of medical studies conducted in the intervening period generally tend to demonstrate that moderate use of caffeine, both in foods and in drugs, poses no significant health risks to most consumers, representing a turnaround from earlier findings. Further, research is beginning to show (with gradually increasing levels of persuasiveness) that caffeine intake at varying higher levels is linked to a number of potential health benefits.

While it is admittedly too early to assume that a heavy daily intake of “Starbucks” will help prevent the onset of diseases such as Parkinson’s and type-2 diabetes, the FDA cannot ignore the positive correlations being drawn between caffeine consumption and human health. More importantly, given the demanding amount of time and money required to supervise the creation of new food additives and drugs, the FDA need not waste additional precious regulatory resources on a substance that has been safely ingested for hundreds, if not thousands of years. There is no additional need for FDA regulation of caffeine with respect to food or drug products.

[1] “Starbucks” refers to the Starbucks Corporation, and “Grande Latte” is a proprietary designation.

[2] “Diet Coke” is a trademarked product of the Coca Cola Corporation.

[3] “Vivarin” is a trademarked over-the-counter caffeine pill.

[4] See Goodman & Gilman’s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, NINTH EDITION , McGraw-Hill Health Professions Division (1996), at 672 (“The basis for the popularity of all the caffeine-containing beverages is the ancient belief that they have stimulant and antisoporific actions that elevate mood, decrease fatigue, and increase capacity for work. For example, legend credits the discovery of coffee to a prior of an Arabian convent. Shepherds reported that goats that had eaten the berries of the coffee plant gamboled and frisked about all through the night instead of sleeping. The prior, mindful of the long nights of prayer that he had to endure, instructed the shepherds to pick the berries so that he might make a beverage from them”). See also “Caffeine and Women’s Health,” INTERNATIONAL FOOD INFORMATION COUNCIL PUBLICATIONS (Aug. 2002), available at http://ific.org/publications/brochures/caffwomenbroch.cfm; (“As long ago as 2,700 B.C. the Chinese Emperor Shen Nung sipped hot brewed tea. Coffee’s origins date back to 575 A.D. when in Africa beans were used as money and consumed as food”).

[5] Goodman & Gilman, supra note 4 at 571. See also Prothro, supra note 5 at 66: (“Caffeine is one of the most widely used psychoactive substances in the United States and the world today”). See generally Jerome H. Jaffe, “Psychoactive Substance Use Disorders,” in COMPREHENSIVE TEXTBOOK OF PSYCHIATRY , 642, 683 (1989).

[6] See Brain, supra note 14.

[7] See Id .

[8] Prothro, Gwendolyn, “ The Caffeine Conundrum: Caffeine Consumption and Regulation in the United States ,” 27 CUMB. L. REV. 65, 66 (1996/1997).

[9] See “Wikipedia, the Free Encyclopedia – Caffeine,” available at http://en.wikipedia.org/wiki/Caffeine.

[11] Goodman & Gilman, supra note 4 at 673.

[12] Id. at 672.

[13] Id . (“ Thea sunensis , a bush native to southern China and now extensively cultivated in other countries”).

[14] Id . A separate but relevant subject of study involves the combination and interaction effects of the methylxanthines as a group; since products like tea and cocoa contain multiple methylxanthines, an elevated (or perhaps conflicting) set of effects could be observed.

[15] See Id .

[16] Id . See also “What is Caffeine,” GLOSSARY OF FOOD RELATED TERMS , available at http://ozans.4mg.com/glossary.htm: (“Caffeine is a naturally-occurring substance found in the leaves, seeds or fruits of over 63 plant species worldwide”).

[17] See Prothro, supra note 5 at 66. See also Marshall Brain, “How Caffeine Works,” available at http://health.howstuffworks.com/caffeine1.htm: (“The chief source of pure caffeine is the process of decaffeinating coffee and tea”).

[18] See “Wikipedia,” supra note 6.

[20] Brain, supra note 14.

[21] “Wikipedia,” supra note 6.

[23] See generally Brain, supra note 14.

[25] Sizing information corresponds to the Starbucks Corporation’s usage of the terminology “Tall,” “Grande,” and “Venti,” which are twelve, sixteen, and twenty ounce sizes respectively.

[26] Prothro, supra note 5 at 68. Citing Ed Blonz, “The Buzz About Caffeine,” Better Homes and Gardens, May 1995, at 50.

[27] Id. at 70.

[28] 45 FED. REG. 69,817, 69,820 (1980). Cited in Prothro, supra note 5 at 68.

[29] See Brain, supra note 14: (“More than half of all American adults consume more than 300 milligrams (mg) of caffeine every day, making it America’s most popular drug by far”).

[30] Prothro, supra note 5 at 67.

[31] See Id .

[33] Goodman & Gilman, supra note 4 at 677: (“Preparations are employed to relax bronchial smooth muscle in the treatment of asthma and to relieve dyspnea in the treatment of chronic obstructive pulmonary disease”).

[34] See Alejandro Lopez-Ortiz, “Frequently Asked Questions About Coffee and Caffeine,” available at http://www.lib.ox.ac.uk/internet/news/faq/archive/caffeine-faq.html. Cited in Prothro, supra note 5 at 67.

[35] Goodman & Gilman, supra note 4 at 677.

[36] See Id .

[37] Brain, supra note 14. See generally “Wikipedia,” supra note 6. See also Goodman and Gilman, supra note 4 at 677: (“Caffeine, in probably subtherapeutic amounts, is incorporated into a number of over-the-counter preparations used for analgesia or to produce diuresis”).

[38] See Goodman & Gilman, supra note 4 at 674: (“In addition to effects on the vagal and vasomotor centers in the brain stem, there is an array of more or less direct actions on vascular and cardiac tissues, in combination with indirect peripheral actions that are mediated by catecholamines and possibly by the rennin-angiotensin system. Therefore, the observation of a single function, for example, the blood pressure, is deceiving because the drugs may act on a variety of circulatory factors in such a way that the blood pressure may remain essentially unchanged”).

[40] See generally Goodman & Gilman, supra note 4.

[41] See Lopez-Ortiz, supra note 34.

[42] Prothro, supra note 5 at 67. See also Lopez-Ortiz, supra note 34; the half-life of caffeine in the body of a pregnant woman can be as much as eighteen to twenty hours, while caffeine ingested concurrently with nicotine produces faster metabolism and a shorter half-life of three hours or so.

[43] “Wikipedia,” supra note 6.

[45] See generally Goodman & Gilman, supra note 4.

[46] See generally Brain, supra note 14.

[47] See Id .

[48] See Id .

[49] Brain, supra note 14.

[50] See Id . (“You can see that caffeine also causes the brain’s blood vessels to constrict, because it blocks adenosine’s ability to open them up. This effect is why some headache medicines like Anacin contain caffeine - if you have a vascular headache, the caffeine will close down the blood vessels and relieve it”). In other words, caffeine reduces intracranial pressure to relieve vascular headaches.

[51] “Caffeine in Pain Relievers,” Consumer Rep. on Health, July 1995, at 76.

[52] See Brain, supra note 14.

[53] See Id . See also Goodman & Gilman, supra note 4 at 674: (“Persons ingesting caffeine or caffeine-containing beverages usually experience less drowsiness, less fatigue, and a more rapid and clearer flow of thought.... As the does of caffeine or theophylline is increased, signs of progressive CNS stimulation are produced...”).

[54] See Id .

[55] Brain, supra note 14.

[58] See Id .

[59] Id . See generally Goodman & Gilman, supra note 4.

[60] See Kathleen Doheny, “Smell the Coffee – Just Don’t Drink Too Much,” L.A. Times, Jan. 9, 1996, at E1.

[61] See generally Brain , supra note 14.

[62] Brain, supra note 14.

[63] 53 FED. REG . 6100, 6103 (1988).

[64] See “Wikipedia,” supra note 6. See also Eric C. Strain, et al., “Caffeine Dependence Syndrome: Evidence from Case Histories and Experimental Evaluations,” 272 JAMA 1043 (1994): (“caffeine exhibits the features of a typical psychoactive substance of dependence”).

[65] See Wallace B. Pickworth, “Caffeine Dependence,” Lancet, Apr. 29, 1995, at 1066, cited in Prothro, supra note 5 at 73.

[66] Doheny, supra note 60.

[67] Goodman & Gilman, supra note 4 at 572.

[68] See Prothro, supra note 5 at 73. But see Goodman & Gilman, supra note 4 at 572: (“Although a withdrawal syndrome can be demonstrated, few caffeine users report loss of control of caffeine intake or significant difficulty in reducing or stopping caffeine, if desired”).

[69] See “Wikipedia,” supra note 6.

[70] See Doheny, supra note 60.

[71] A notable discrepancy between sources exists when discussing the severity of caffeine’s addictiveness, particularly with regard to frequency and severity of withdrawal symptoms following cessation of caffeine intake. Based on the descriptions of caffeine’s medical effects in Goodman & Gilman, it is a reasonable conclusion that the known dangers of caffeine have been overstated in numerous other sources.

[72] See Goodman & Gilman, supra note 4 at 572: (“Thus caffeine is not listed in the category of addicting stimulants”), citing a 1994 APA report.

[73] Richard H. Adamson & Howard R. Roberts, “Letter: Caffeine Dependence Syndrome,” 273 JAMA 1418 (1995). The potential bias of this source is considerable, though the points raised against the previous study are noteworthy.

[74] See Id .

[75] See Prothro, supra note 5 at 69.

[76] See “Wikipedia, the Free Encyclopedia – LD 50 ,” available at http://en.wikipedia.org/wiki/LD50.

[77] See Id .

[78] See Prothro, supra note 5 at 69. See also “Wikipedia,” supra note 6.

[79] See Goodman & Gilman, supra note 4 at 678.

[80] See Id. : (“It has been long known <and perhaps forgotten> that beverages made from roasted grain containing no caffeine stimulate acid secretion in human beings as much as does coffee. Decaffeinated coffee is only slightly less potent than the natural product in enhancing the secretion of gastrin and acid, and both are about twice as effective as is an equivalent amount of caffeine”).

[81] See Id. : (“Overindulgence in xanthine beverages may lead to a condition that might be considered one of long-term poisoning”).

[82] P.L. Morrow, “Caffeine Toxicity: A Case of Child Abuse by Drug Ingestion,” 32 J. FORENSIC SCI. 1801, 1803 (1987).

[83] See Prothro, supra note 5 at 70. See generally Brain, supra note 14. See generally Goodman & Gilman, supra note 4.

[84] See generally “Caffeine Health – What to Worry About,” available at http://www.coffeeforums.com.

[85] See Goodman & Gilman, supra note 4 at 678.

[86] Prothro, supra note 5 at 70: (“And children often display symptoms of attention deficit / hyperactivity disorder when they consume caffeine.... Because the potency of caffeine on a human body depends on the body’s weight, children are far more sensitive to caffeine than adults – a single soft drink <containing 30-46 mg of caffeine> affects a young child the way two cups of coffee <130-230 mg of caffeine> affect an adult”).

[88] Id. , citing Isabel Fortier et al., “Relation of Caffeine Intake During Pregnancy to Intrauterine Growth Retardation and Preterm Birth,” 137 AM. J. EPIDEMIOLOGY 931, 931-40 (1993).

[89] Id . According to some sources, caffeine may correlate with greater difficulty among women in conceiving children, though further exploration of this linkage is required; See e.g. Doheny, supra note 60. But see “Caffeine CERHR Study,” (Aug. 2003), available at http://cerhr.niehs.nih.gov/genpub/topics/caffeine-ccae.html, stating that (“numerous studies have examined the effects of caffeine intake on fertility and pregnancy. Most studies found that moderate caffeine intake does not affect fertility or increase the chance of having a miscarriage or a baby with birth defects; some studies did find a relationship between caffeine intake and fertility or miscarriages. However, most of those studies were judged to be inadequate because they did not consider other lifestyle factors that could contribute to infertility or miscarriages. The Organization of Teratology Information Services (OTIS) stated that there is no evidence that caffeine causes birth defects in humans. Groups such as OTIS and Motherisk agree that low caffeine intake (<150 mg/day or 1-1/2 cups of coffee) will not likely increase a woman’s chance of having a miscarriage or a low birth weight baby. Motherisk recommends that caffeine intake by pregnant women not exceed 150 mg/day whereas OTIS stated that moderate caffeine intake of 300 mg/day (equivalent to about 3 cups of coffee) does not seem to reduce fertility in women or increase the chances of having a child with birth defects or other problems. Caffeine can enter breast milk, and high amounts can cause the baby to become wakeful and agitated. The American Academy of Pediatrics recommends that nursing women limit caffeine intake, but states that no harm is likely to occur in a nursing child whose mother drinks one cup of coffee a day. OTIS recommends that pregnant and nursing women drink plenty of water, milk, and juice and not substitute those fluids with caffeinated beverages”).

[90] See Brain, supra note 14.

[91] See Id .

[92] See Id .

[93] Goodman & Gilman, supra note 4 at 678.

[94] See Prothro, supra note 5 at 71.

[95] See generally Goodman & Gilman, supra note 4.

[96] See “Caffeine Health,” supra note 84.

[97] See Prothro, supra note 5 at 71.

[98] See generally Adamson & Roberts, supra note 73.

[99] See generally “Caffeine Health,” supra note 84.

[100] See “Questions and Answers; Caffeine and Breast Disease,” CONSUMER REP ., July 1995, at 493.

[102] Jane Brody, “Caffeine, The Doctor’s Report,” Dallas Morning News, Sept. 25, 1995, at 3C.

[103] See “Coffee, Caffeine, and Osteoporosis,” The Coffee Science Information Centre, available at http://www.cosic.org/mainissues/article/11: (“Earlier papers have suggested that caffeine may affect bone health, though these researchers stress that uncontrolled confounding factors may be responsible. The vast majority of recently published studies do not suggest caffeine as an independent risk factor for osteoporosis”).

[104] See Id .

[105] See “Understanding Coffee, Caffeine, and Cardiovascular Disease,” Coffee Science Source, available at http://www.coffeescience.org/heart.html: (“Cardiovascular disease (CVD), coronary heart disease, is the number one cause of death in America”).

[106] Prothro, supra note 5, citing Dag S. Thelle et al., “Does Coffee Raise Serum Cholesterol Level,” 308 NEW ENG. J. MED. 1454-57 (1983); Andrea Z. LaCroix et al., “Coffee Consumption and the Incidence of Coronary Heart Disease,” 315 NEW ENG. J. MED. 977-82 (1986); Lynn Rosenberg et al., “Coffee Drinking and Nonfatal Myocardial Infarction in Men Under 55 Years of Age,” 128 AM. J. EPIDEMIOLOGY 570-78 (1988); Lynn Rosenberg et al., “Coffee Drinking and Nonfatal Myocardial Infarction in Young Women: An Update,” 126 AM. J. EPIDEMIOLOGY 147-49 (1987).

[107] See “Understanding Coffee, Caffeine, and Cardiovascular Disease,” supra note 105.

[109] See Warren G. Thompson, “Coffee: Brew or Bane?” 308 AM. J. MED. SCI. 349, 349-57 (1994).

[110] See e.g. Walter C. Willet et al., “Coffee Consumption and Coronary Heart Disease in Women,” 275 JAMA 458, 458-62 (1996); utilizing a data set including 85,000 women over a ten year period, and adjusting for known risk factor variables, the authors found no link whatsoever between risk of coronary heart disease and coffee consumption in women, even for women ingesting more than six cups of coffee daily. See also Diederick E. Grobbee et al., “Coffee, Caffeine and Cardiovascular Disease in Men,” 323 NEW ENG. J. MED. 1026, 1026-32 (1990); finding no link between heart disease and caffeine consumption in a sample of over 45,000 men, whose daily caffeine intake included four or more cups of coffee.

[111] See e.g. Jean Carper, “Caffeine: The Bitter Truth,” USA Weekend Magazine, available at http://www.usaweekend.com/99_issues/991003/991003eatsmart.html: (“[t]here’s little evidence that caffeine promotes cancer, except possibly bladder cancer”).

[112] See e.g. “Other Questions About Coffee and Health – Coffee and Caffeine Content,” available at http://www.coffeescience.org/other.html: (“Decades of research and centuries of human consumption confirm the safety of coffee and caffeine.... In fact, recent scientific research carried out at the Mayo Clinic, Harvard School of Public Health, U.S. Veterans Administration and other medical centers show that coffee is not only safe but beneficial – drinking from 2 to 4 cups of coffee a day may lower the risk of colon cancer (25%), gallstones (45%), cirrhosis of the liver (80%), and Parkinson’s Disease (50-80%), among other diseases”). See also Giovannucci, “Meta-Analysis of Coffee Consumption and Risk of Colorectal Cancer,” 147 AM. J. EPIDEMIOLOGY 1043, 1043-1052 (June 1998); consolidating seventeen separate studies on colorectal cancer and caffeine consumption, and finding a 24% reduced risk among consumers of four or more cups of coffee per day. See also “Caffeine Clue to Fighting Cancer,” BBC News World Edition, available at http://news.bbc.co.uk/2/hi/health/2207153.stm; discussing a University College London study which found that: (“Chocolate, cola and coffee could form the basis of new anti-cancer drugs, scientists believe. Researchers in the UK have found that caffeine and theophylline may be effective in fighting cancer tumours [sic]”). See also Carper, supra note 111: (“Recent Japanese research suggests that caffeine alters hormones in ways that may reduce the odds of breast cancer. New research in Switzerland has found coffee drinkers have a 27% lower risk of developing colon cancer. A study at Harvard suggested four to five cups of coffee a day reduced the risk of colorectal cancer by 24%”).

[113] See “Coffee, Caffeine, and Cancer,” The Coffee Science Information Centre, available at http://www.cosic.org/mainissues/article/14/: (“In 1990, IARC, the International Agency for Research on Cancer held a monograph on Coffee, Caffeine, Tea, and Mate.... Coffee was cleared in all areas with the exception of bladder cancer where there was insufficient evidence available at that time. Several studies since have clearly shown no linkage between coffee consumption and bladder cancer”). See also “Food, Nutrition and the Prevention of Cancer: A Global Perspective,” American Institute for Cancer Research, (1997): (“Most evidence suggests that regular consumption of coffee and/or tea has no significant relationship with the risk of cancer at any site”).

[114] See “Understanding Coffee, Caffeine, and Cardiovascular Disease,” supra note 105.

[115] See Id. , citing Annette Bak and Diederick Grobbee, “Caffeine, Blood Pressure and Serum Lipids,” 53 AM. J. CLINICAL NUTRITION 971, 971-974 (1991).

[116] Id. , referring to a Scandinavian study that found small increases in serum lipids only through preparation of unfiltered boiled coffee – (“a process little used in the U.S.”).

[117] See generally Goodman & Gilman, supra note 4.

[118] See Id. , citing M. G. Meyers, “Caffeine and Cardiac Arrhythmias,” 114 ANNALS OF INTERNAL MED. 147, 147-150 (1991).

[119] See generally Thompson, supra note 109. See generally Goodman & Gilman, supra note 4.

[120] See Prothro, supra note 5 at 74, citing Toni Minarich & Janet Havter, “Elephantine Enlightenment,” Beverage World, July 1995, at 66.

[121] See e.g. “Anacin” and “Excedrin” versus other common pain relievers such as ibuprofen.

[122] A search, available at http://www.google.com, for the combined terms “Buy”, “Ginseng”, “Guarana”, and “Ma Huang” yielded more than seven thousand web pages, the vast majority of which were purchasing sites.

[123] See “Sales of Supplements Containing Ephedrine Alkaloids (Ephedra) Prohibited,” available at http://www/fda/gov/oc/initiatives/ephedra/february2004/: (“On April 12, 2004, a final rule went into effect prohibiting the sale of dietary supplements containing ephedrine alkaloids <ephedra>. Ephedra, also called Ma Huang, is a naturally occurring substance derived from plants. Its principal active ingredient is ephedrine, which when chemically synthesized is regulated as a drug. In recent years ephedra products have been extensively promoted to aid weight loss, enhance sports performance, and increase energy. But FDA has determined that ephedra presents an unreasonable risk of illness or injury. It has been linked to significant adverse health effects, including heart attack and stroke”).

[124] See e.g. “Body and Fitness,” available at http://www.bodyandfitness.com/products/health/energy.htm; one particular proprietary energy supplement sold at this source, a capsule called “Super Enermax,” contains the following ingredients: 200mg guarana, 200mg yerba mate, 100mg green tea, 50mg ginseng, 50mg kola extract, and 50mg rhodiola. Most of these additives contain some portion of natural caffeine, particularly guarana (half of the 200mg is caffeine), and yerba mate (a dried herb containing even higher levels of natural caffeine). Therefore, though the product may contain a wide variety of “natural energy-boosting ingredients,” the total caffeine content of a pill this size is several ordinary doses, and likely accounts for the vast majority of the energy boost that a consumer will experience.

[125] For example, consumers may be unaware that guarana and similar “natural” ingredients contain caffeine naturally.

[126] See generally “ Caffeine: The Problem of Disputed Science ” section above.

[127] See Prothro, supra note 5 at 75: (“As with much else in our food and drug supply, moderation is the answer and should be the message conveyed by the FDA”).

[128] See “Food Safety: A Team Approach,” FDA Backgrounder, Sep. 24, 1998, available at http://www.fda.gov/opacom/backgrounders/foodteam.html.

[129] Sharon Wyatt Moore, “An Overview of Drug Development in the United States and Current Challenges,” 96 SOUTHERN MED. J. 12, 1244 (Dec. 2003). See also “Food Safety,” supra note 128, which outlines the overall U.S. government regulatory structure with regard to control over the food and drug supply, including the interlocking roles of the U.S. Department of Health and Human Services, the U.S. Department of Agriculture, the U.S. Environmental Protection Agency, and several other agencies.

[130] Id. at 1245.

[131] “The Food and Drug Administration: An Overview,” available at http://www.cfsan.fda.gov/fdaoview.html. See also “Health Information Resource Database,” National Health Information Center, available at http://health.nih.gov/search_results.asp; explaining the broad goals of the FDA: (“The mission of the U.S. Food and Drug Administration (FDA) is to: promote the public health by promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner; with respect to such products, protect the public health by ensuring that foods are safe, wholesome, sanitary, and properly labeled; human and veterinary drugs are safe and effective; there is reasonable assurance of the safety and effectiveness of devices intended for human use; cosmetics are safe and properly labeled, and; public health and safety are protected from electronic product radiation; participate through appropriate processes with representatives of other countries to reduce the burden of regulation, harmonize regulatory requirements, and achieve appropriate reciprocal arrangements; and, as determined to be appropriate by the Secretary, carry out paragraphs (1) through (3) of The FDA Modernization Act of 1997 (PL 105-115) in consultation with experts in science, medicine, and public health, and in cooperation with consumers, users, manufacturers, importers, packers, distributors and retailers of regulated products”).

[132] See Moore, supra note 129. A brief description of the evolution and scope of FDA authority follows: (“Although earlier drug legislation existed, this Act established the authority of the FDA to require that new drugs demonstrate safety before they could be marketed. The Kefauver-Harris Drug Amendments, passed in 1962, then required new drugs to demonstrate efficacy before marketing. In the 1970s, the FDA’s scope enlarged when the Public Health Service Bureau of Radiologic Health transferred to the FDA in 1971, the regulation of biologics transferred to the FDA from the National Institutes of Health (NIH) in 1972, and Medical Device Amendments were passed in 1976, establishing new regulatory procedures for medical device manufacturers. The Food and Drug Administration Act of 1988 officially established the FDA as an agency within the Department of Health and Human Services and noted that the President appoints the Commissioner of the FDA. This was followed by the Food and Drug Administration Modernization Act of 1997 (FDAMA), providing the most wide-ranging reforms in the FDA since 1938. The purposes of the FDAMA legislation included accelerated review of drugs and medical devices and regulation of advertising of unapproved uses of approved medical products”). See also http://www.fda.gov, for more general information regarding the FDA’s regulatory purview and history.

[133] 21 U.S.C. 321(g)(1) (1994). The statute further includes any article (“other than food intended to affect the structure or any function of the body”).

[134] See “The Food and Drug Administration: An Overview,” supra note 131.

[135] 21 U.S.C. 321(f) (1994).

[136] See Prothro, supra note 5 at 76, citing Nutrilab, Inc. v. Schweiker, 713 F.2d 335, 337 (7 th Cir. 1983).

[137] See Id. at 75.

[138] See Id .

[139] See S. Rep. No. 74-361, at 4 (1935): (“If it is sold to be used both as a food and for the prevention or treatment of disease it would satisfy both definitions and be subject to the substantive requirements for both”). Cited in Prothro, supra note 5 at 75.

[140] Prothro, supra note 5 at 75, discussing: (“Buzz Gum”, a “product created by Gum Tech International... was marketed with the following labels... ‘Catch a Buzz Naturally’ and ‘Natural Energy Booster.’ Based on this labeling, the FDA concluded that the gum was intended to be used as a stimulant, a drug and not just a snack food”). See also “FDA Warning Letter Chews Up Labeling of Stimulant Gum,” Food Labeling News, Apr. 21, 1994, at 31.

[141] See American Health Prods. Co. v. Hayes, 574 F. Supp. 1498, 1501 (S.D.N.Y. 1983), aff’d per curium , 744 F.2d 912 (2d Cir. 1984). See also United States v. Neptone, holding (“the determination that Neptone is a drug rests entirely on the pattern of promotion used by claimant in the several years immediately preceding the instant seizure”).

[142] See National Nutritional Foods Ass’n v. Mathews, 557 F.2d 325, 333 (2d Cir. 1977): (“[t]he vendor’s intent in selling the product to the public is the key element in this statutory definition”).

[143] Id. at 334. See also Prothro, supra note 5 at 76-77: (“Thus, if one markets a caffeinated soft drink as just a soft drink, it will likely be regulated as a food. But if one markets it as a soft drink to help maintain ‘blood energy, muscular activity, sound teeth and gums,’ it will likely be regulated as a drug and require FDA pre-market approval”), ref . United States v. Kordel, 164 F.2d 913, 916 (7 th Cir. 1947), aff’d , 335 U.S. 345 (1948); in which the “Kola” product sarsaparilla was declared a mislabeled drug as opposed to a food because it made health claims like a drug.

[144] See Prothro, supra note 5 at 76.

[145] See e.g. Mathews, supra note 142 at 337: (“the mere inclusion in the USP (United States Pharmacopeia) and the NF (National Formulary) is an insufficient basis for drug classification”). But see United States v. Beuthanasia-D Regular, [1979 Transfer Binder] Food Drug Cosm. L. Rep. P38265 (D. Neb. 1979); holding that such inclusion is conclusive evidence of drug status. Cited in Prothro, supra note 5 at note 80.

[146] See generally http://www.fda.gov, for a more complete description of the differences between food regulation and drug regulation.

[147] See Prothro, supra note 5 at 80. See also Prothro, supra note 5 at note 106: (“In coffee, tea and chocolate, for instance, caffeine occurs naturally and is nonadded. In soft drinks, however, caffeine is a food additive; only 5% of the caffeine present is naturally occurring <from the Kola nut>”).

[148] See John Vanderveen, “Regulation of Amino Acids and Other Dietary Components Associated with Enhanced Physical Performance,” Report from the Director of the FDA’s Office of Plant and Dairy Foods and Beverages, Nov. 1992, available at http://www.books.nap.edu/books/030905088X/html/461.html.

[150] See generally Moore, supra note 129, for a more comprehensive analysis of the costs associated with drug regulation compliance.

[151] See 21 C.F.R. 182, at 456 (2003), available at http://www.cfsan.fda.gov/~lrd/FCF182.html.

[152] See 26 FED. REG. 938 (1961).

[153] See 21 C.F.R. 182, at 462 – “Subpart B—Multiple Purpose GRAS Food Substances, Sec. 182.1180,” available at http://www.cfsan.fda.gov/~lrd/FCF182.html.

[154] 21 C.F.R. 182, supra note 151 at 456. This regulation does bear the caveat that (“the inclusion of substances in the list of nutrients does not constitute a finding on the part of the Department that the substance is useful as a supplement to the diet for humans”).

[155] See 21 U.S.C. 348 (1972), for a more complete listing of the requirements of the Food Additives Amendments.

[156] Prothro, supra note 5 at 81. See also 21 U.S.C. 321(s)(4) (1972), for a description of the “prior sanction” rule that grants exemption to foods that were approved by either the FDA or the Department of Agriculture prior to 1958.

[157] See 52 FED. REG. 18,923, 18,925 (1987).

[158] See 52 FED. REG. 18,923 (1987).

[159] See 21 C.F.R. 182, supra note 153 at 462. See also Prothro, supra note 5 at 81.

[160] See “How Are Additives Approved for Use in Foods?” Food Additives FDA/IFIC Brochure (Jan. 1992), available at http://www.cfsan.fda.gov/~lrd/foodaddi.html.

[161] For example, the list of ingredients on virtually any caffeinated soda product contains caffeine as a single ingredient in the list, along with all the artificial flavors, colors, and other additives used to preserve the product. However, information about the specific quantity of caffeine in popular products is readily available on the internet. See e.g. “Caffeine Content of Soft Drinks,” National Soft Drink Association (Oct. 2003), available at http://nsda.org/WhatsIn/caffeinecontent.html. See also “Caffeine Content of Foods and Drugs,” CSPI Press Releases (July 1997), available at http://www.cspinet.org/new/cafchart.htm, for a more comprehensive listing of caffeine content in common products.

[162] See Prothro, supra note 5 at 82.

[163] See “History of Caffeine,” available at http://web1.caryacademy.org/chemistry/rushin/StudentProjects/CompoundWebSites/1998/Caffeine/history_of_caffeine.htm. See also Goodman & Gilman, supra note 4 at 672.

[164] See Prothro, supra note 5 at 77.

[165] Id . See also “Health Information Resource Database,” supra note 131, regarding the rationale behind strict FDA drug regulations.

[166] See Moore, supra note 129 at 1245.

[167] Id . Guidances also (“usually contain greater detail about specified topics and can be updated more easily”).

[168] See Prothro, supra note 5 at note 86: (“Every drug must be approved as safe and effective by the FDA before it can be introduced into interstate commerce”); See 21 U.S.C. 355(a) (1994). The Federal Food Drug and Cosmetic Act of 1938 initially imposed the drug “safety” requirement; this regulation was later updated to include drug effectiveness prior to introduction into interstate commerce. See 21 U.S.C. 355(b)(1)(a) (1994).

[169] Any company seeking new drug approval must submit applications to the FDA. An advisory review panel or committee generally reviews the application after several phases of testing. The FDA reviews the findings and final vote(s) of the advisory panel and then issues a monograph in response to the new drug application; this monograph will classify a new drug in one of three possible categories:

(1) Category I is applied if the new drug is “generally recognized as safe and effective and not misbranded”; (2) Category II is applied if the drug is not “generally recognized as safe and effective or would result in misbranding”; or (3) Category III is applied if the FDA determines that more testing data is required “on the basis of the Commissioner’s determination that the available data are insufficient to classify such conditions” under either Category I or Category II. See 21 C.F.R. 330.10(a)(6)(i)-(iii) (1995). See also Prothro, supra note 5 at note 86.

[170] Prothro, supra note 5 at note 86.

[171] See Id .

[172] See Carol Rados, “Advisory Committees: Critical to the FDA’s Product Review Process,” FDA Consumer (Jan.-Feb. 2004), available at http://fda.gov/fdac/features/2004/104_adv.html.

[175] Id . See also “Human Drug Advisory Committees,” U.S. Food and Drug Administration Center for Drug Evaluation and Research, available at http://www.fda.gov/cder/audiences/acspage/, for more information regarding the appointment and function of advisory committees.

[176] See 56 FED. REG . 66,742 (1991).

[177] See 56 FED. REG . 66,746 (1991).

[178] Prothro, supra note 5 at 78, ref . 56 FED. REG . 66,746 (1991).

[179] See also “How Are Additives Approved for Use in Foods?” supra note 160, emphasizing the importance of FDA discretion with regard to “expected levels of human consumption.” The FDA often decides to prohibit or limit use of a product based on the idea that “the amount likely to be consumed” and “various safety factors” contribute to a belief that a potentially safe product will tend to be used unsafely.

[180] Prothro, supra note 5 at 77-78, ref . 53 FED. REG. 30,522, 30,557-58 (1988).

[181] See Goodman and Gilman, supra note 4 at 677. See also “What Are the Major Classes of Asthma Medications?” FAQ: Asthma – General Information (Sep. 2000), available at http://www.radix.net/~mwg/medclass.html, for a more detailed description of the FDA’s specific approval of different classes of asthma medications.

[182] See 21 C.F.R. 310.545(a)(20) (1995).

[183] See Id . See also 21 C.F.R. 310.545(d)(2) (1995).

[184] The FDA’s decision that caffeine does not correlate sufficiently with weight loss is under new scientific investigation. See e.g. M. H. Van Soeren and T.E. Graham, “Effect of Caffeine On Metabolism, Exercise Endurance, and Catecholamine Responses After Withdrawal,” available at http://www.elitetrack.com/caffeine5.pdf: (“We conclude the mechanism through which caffeine acts as an ergogenic aid is unlikely to be through changes in available metabolic substrates or catecholamines but rather is through some direct action of caffeine on tissues as yet to be described”). Whether caffeine stimulates increased metabolic function or acts in some other way to boost body energy, potential weight loss links could be reevaluated in the future following additional testing.

[185] Prothro, supra note 5 at 78-79.

[186] See Goodman & Gilman, supra note 4 at 678.

[187] See generally http://www.fda.gov, for basic drug labeling requirements. See also Prothro, supra note 5 at 79.

[188] See 21 C.F.R. 340.50 (1995). Subsection (a) specifies that: (“the labeling of the product contains the established name of the drug, if any, and identifies the product as an ‘alertness aid’ or a ‘stimulant’”). Subsection (b) specifies the requirements for caffeinated product indications, but with the important restriction that: (“Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed...”); meaning that the FDA still pull the product from the market even if the label is technically correct if they find that consumers are being misled.

[189] 21 C.F.R. 340.50(c)(1)-(3) (1995).

[190] See generally “New FDA Labeling Requirements for Over-the-Counter Drug Products,” Release #9B-118 (Sept. 1999), available at http://www.actstesting.com/actsnews.nsf/0/860825D224E2E73285256802004637F3?open.

[191] See Id . Companies like ACTS Testing Labs (the sponsor of the site) are paid by companies to evaluate new drug labels for potential FDA compliance problems.

[192] Id . Another separate issue of ever-increasing importance is the labeling of prescription drugs. In the December 22, 2000 Federal Register, a new FDA prescription drug labeling proposal was put forth, in response to (“increasing length and complexity of labeling for new prescription drugs, and after many physicians said the current format can lead to confusion. The agency states that the information most useful to doctors is contraindications, drug interactions, side effects, and dosage and administration”). See “FDA Caters to Physicians; A Proposed Rule for Redesigning Prescription Drug Labeling Can Help Save Physician Time and Reduce Adverse Drug Events,” (Mar. 2001), available at http://devicelink.com/pmpn/archive/01/03/010.html. This further underscores the importance the FDA places on accurate and safe labeling of drugs, and the difficulties in protecting the consumer public; if expert physicians are having difficulty understanding and safely dispensing prescription medication, the FDA is even more concerned about the ramifications of consumer self-medication with readily available over-the-counter drugs.

[193] See Prothro, supra note 5 at 79-80. See also 53 FED. REG. at 6,100 and 6,103, discussing stimulant warning statements.

[194] See “Over-the-Counter Human Drugs: Labeling Requirements,” FDA Final Rule Re: 21 C.F.R. Parts 201, 330, 331, 341, 346, 355, 358, 369, and 701 (Mar. 1999), available at http://www.fda.gov/cder/otc/label/label-fr-reg.htm.

[195] See 60 FED. REG. 6,892, 6,897 (1995), cited in Prothro, supra note 5 at note 105. See also “Over-the-Counter Human Drugs: Labeling Requirements,” supra note 194: (“At that time, the agency’s regulations encouraged (but did not require) manufacturers to include the quantity per dosage unit in the labeling (330.1(j)). The vast majority of OTC drug products already include such information in their labeling”).

[196] See Id .

[197] See “Over-the-Counter Human Drugs: Labeling Requirements,” supra note 194: (“As a result of the statutory change, this final rule makes clear that the established name and quantity of each active ingredient must be included in the required information set forth in 201.66(c), in the location and format established by the agency”).

[199] See Prothro, supra note 5 at 80.

[200] See F.D.C. REP ., 3 THE TAN SHEET 19 (1995), cited in Prothro, supra note 5 at note 99.

[201] See Id. , cited in Prothro, supra note 5 at 79.

[202] See Id. : (“Habituation to caffeine is well documented in the scientific literature... caffeine in analgesic combinations at concentrations as low as 64 mg can exert some psychotropic effect”).

[203] See generally Moore, supra note 129.

[204] See Stephen Sherman, “Warning Letter to Thomas E. Costa, Vice President and Counsel, U.S. Pharmaceutical Group, Bristol-Myers Squibb Company Re: ANDA 74-817 Orphenadrine Citrate, Aspirin and Caffeine Tablets,” FDA Division of Drug Marketing, Advertising and Communications (July 1997), available at http://www.fda.gov/cder/warn/july97/orphen.pdf.

[205] See “Orphenadrine Citrate Drug Information,” Pharmacy Health (2003), available at http://www.pharmacyhealth.net/d/orphenadrine-citrate-6471.htm.

[206] See Sherman, supra note 204.

[208] See Id. : (“There is significant risk and potential danger to consumers if Apothecon’s product were used inadvertently in place of Norflex by a consumer who is allergic to aspirin or who has peptic ulcers or coagulation abnormalities.... BMS should immediately, clearly, and prominently alert health care professionals of this serious error, that its orphenadrine citrate, aspirin and caffeine tablets are not bioequivalent to Norflex, and the potential risks of using this product....”).

[209] See Prothro, supra note 5 at 82-83 for further summary.

[210] See generally “About the U.S. Food and Drug Administration,” available at http://www.fda.gov/opacom/hpview.html.

[211] See Id .

[212] Peter B. Hutt, “The Basis and Purpose of Government Regulation of Adulteration and Misbranding of Food,” 33 FOOD DRUG COSM. L. J. 505, 537 (1978).

[213] See “Over-the-Counter Human Drugs: Labeling Requirements,” supra note 194.

[214] See Prothro, supra note 5 at 83.

[215] See Id .

[216] See Id .

[217] See Jennifer Warner, “Specialty Coffee’s Caffeine Jolt Varies,” WebMD Health Archives (Oct. 23, 2003), available at http://my.webmd.com/content/article/75/89869.htm, ref . R. McCusker, 27 J. ANALYTICAL TOXICOLOGY 520, 520-522 (Oct. 2003).

[218] Id . The study refers to a comparison between “Starbucks” coffee and “Dunkin Donuts” coffee, and finds that the average medium sized coffees from Starbucks contained 259 milligrams of caffeine, as compared to 143 milligrams of caffeine for Dunkin Donuts coffee. Further, the study noted that at identical storefront locations, the caffeine content of a Starbucks medium coffee could range anywhere from 259 to 564 milligrams.

[219] See Id .

[220] See e.g. “Caffeine in Beverages,” available at http://www.nsda.org/WhatsIn/caffeinecontent.html. The National Soft Drink Association voluntarily makes caffeine content data public.

[221] See 58 FED. REG. 2850, 2872 (1993).

[222] See e.g. Lars Noah, “The Imperative to Warn: Disentangling the ‘Right to Know’ from the ‘Need to Know’ About Consumer Product Hazards,” 11 YALE J. ON REG. 293, 315-20 (1994). See also Prothro, supra note 5 at 86, admitting: (“[a] caffeine warning label would not be useful. There are simply too many labels ‘warning’ consumers. Their combined effect is overload. Consumers react either by ignoring all warnings, including ones of deadly danger, or by paying too much attention to the warnings and avoiding all products bearing such statements, including useful and beneficial products”).

[223] See Chris Lecos, “Caffeine Jitters: Some Safety Questions Remain,” FDA Public Affairs Staff, available at http://www.hoptechno.com/book4.htm.

[225] See generally http://www.fda.gov, for information regarding continuing post-approval regulation of food additives and drugs.

[226] See Abraham Lieberman, “Coffee and Parkinson Disease: Is Starbucks the Treatment?” National Parkinson Foundation (2000), available at http://www.parkinson.org/coffee.htm.

[227] Id. ; describing a May 2000 study released in the JAMA that involved 8,004 Japanese-American men over a period of 30 years. The study utilized (“Incident Parkinson disease (number of participants who developed Parkinson during the study) by amount of coffee intake (measured at study enrollment and 6-year follow-up) and by total dietary caffeine intake (measured at enrollment)...”) as its main outcome measure, and further found that: (“Age-adjusted incidence of Parkinson disease declined consistently with increased amounts of coffee intake, from 10.4/10,000 person-years in men who drank no coffee to 1.9/10,000 person-years in men who drank at least 280z/d. Similar relationships were observed with total caffeine intake and caffeine from non-coffee sources.... Other nutrients in coffee, including niacin, were unrelated to Parkinson disease incidence. The relationship between caffeine and PD was unaltered by intake of milk and sugar”). See also Tomas DePaulis, PhD research scientist for Vanderbilt University’s Institute for Coffee Studies, quoted in Sid Kirchheimer, “Coffee: The New Health Food? Plenty of Health Benefits Are Brewing in America’s Beloved Beverage,” WebMD Feature (Jan. 26 2004), available at http://content.health.msn.com/content/article/80/96454.htm?printing=true: (“In fact, Parkinson’s drugs are now being developed that contain a derivative of caffeine based on this evidence”).

[228] See “Caffeine, CERHR Study,” supra note 89.

[229] See Id. : (“Since then, larger, well-designed studies have failed to support these findings. In 1990, researchers at the Centers for Disease Control and Prevention and Harvard University examined the association between the length of time to conceive and consumption of caffeinated beverages.... The researchers found that caffeine consumption had little or no effect on the reported time to conceive in those women who had given birth. Caffeine consumption also was not a risk factor for infertility. [In] 2001, OTIS reviewed the studies examining caffeine effects on fertility and concluded that ‘low to moderate caffeine consumption (<300mg/day) does not seem to reduce a woman’s chance of becoming pregnant”).

[230] See Id. : (“Groups such as OTIS, March of Dimes, and Motherisk reviewed studies examining caffeine intake during pregnancy and are in agreement that high caffeine intake (>300mg/day, equivalent to more than 3 cups of coffee/day) should be avoided during pregnancy. There is also general agreement that low caffeine intake (<150mg/day, about 1-1/2 cups of coffee) during pregnancy is not likely to harm the unborn child. See also “Caffeine and Women’s Health,” supra note 4. See also “Caffeine in Pregnancy,” March of Dimes Quick Reference and Fact Sheets (April 2004), available at http://www.marchofdimes.com/professionals/681_1148.asp. See generally “Caffeine and Pregnancy,” Organization of Teratology Information Services (Dec. 2001), available at http://www.otispregnancy.org/pdf/caffeine.pdf.

[231] See Kirchheimer, supra note 227.

[232] See Id. , ref . Harvard School of Public Health study by Frank Hu, 140 ANNALS OF INTERNAL MED. 1, 1-8 (Jan 2004).

[234] See Id. , quoting Tomas DePaulis, PhD research scientist for Vanderbilt University’s Institute for Coffee Studies.

[235] See e.g. http://www.webmd.com, and http://www.health.msn.com; website visitors can subscribe to particular categories of health-related newsletters, such that they will be emailed new updates on their topics of choice.

[236] See Id . Thousands of visitors frequent WebMD daily; an in-site search for “caffeine” yielded 722 documents discussing different aspects of caffeine, including latest medical findings. Arguably, this means that new information is readily available to consumers.

[237] See Lieberman, supra note 226. The study also humorously notes that: (“At this time there is not enough evidence to urge you to go to Starbucks and drink 6 café-lattes a day”).

[239] See “Caffeine Jitters,” supra note 223.

[241] See e.g. Patricia Lieberman, “Label Caffeine as a Drug – Even in Soda,” New York Times Letter to the Editor, Aug. 26, 1997, available at http://www.junkscience.com/news/soda.html: (“[t]he article ignored one of the worst aspects of adding caffeine to soda. Introducing a mildly addictive drug to soft drinks encourages children to drink sugar water instead of more nutritious beverages like fruit juice and low-fat milk....The Food and Drug Administration should require that soft drinks and other foods be labeled with their caffeine content to help parents decide what their children should drink”).

[242] See “Drug Recall Hoax,” Trend Micro Security Info (2004), available at http://www.trendmicro.com/vinfo/hoaxes/hoax5.asp?HName=Drug+Recall+Hoax.

[244] See Ralph Horwitz et al., “Phenylpropanolamine & Risk of Hemorrhagic Stroke: Final Report of The Hemorrhagic Stroke Project,” (May 10, 2000), available at http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3647b1_tab19.doc.

[245] See “Phenylpropanolamine (PPA) Information Page,” CDER (2000), available at http://www.fda.gov/cder/drug/infopage/ppa/default.htm: (“The Food and Drug Administration (FDA) is taking steps to remove phenylpropanolamine (PPA) from all drug products and has requested that all drug companies discontinue marketing products containing PPA. In addition, FDA has issued a public health advisory...”).

[246] While the letter described the health risks as “URGENT,” the FDA concluded that: (“Although the risk of hemorrhagic stroke is very low, FDA recommends that consumers not use any products that contain PPA”). See “Phenylpropanolamine (PPA) Information Page,” supra note 245. See also “Drug Recall Hoax,” supra note 242.

[247] See generally “ New Scientific Information Means Diminished Concern ” section above.

[248] See e.g. http://www.webmd.com, which is a highly trafficked and well respected contemporary source of consumer health information.

[249] See “How Are Additives Approved for Use in Foods?” supra note 160.

[251] Id . The FDA also notes that: (“approximately 100 new food and color additives petitions are submitted to the FDA annually”), though most are for (“indirect additives such as packaging materials”). Further, any available human study data may be submitted to the FDA along with animal test data.

[252] Id . See generally “Food Safety: A Team Approach,” supra note 128.

[254] For purposes of this hypothetical exercise, assume that all the current laboratory data on caffeine is known to the scientific and regulatory communities.

[255] See “What’s In Soft Drinks?” National Soft Drink Association (Oct. 2003), available at http://www.nsda.org/softdrinks/History/whatsin.html.

[256] See Neil Osterweil, “Study: Caffeine May Add Zing to Cola, But It Doesn’t Add Flavor,” WebMD Medical News Archive (Aug. 14, 2000), available at http://my.webmd.com/article/27/1728_60353.htm.

[257] See Id. : (“Too few people were tested, too little science was used in the testing and too much opinion is contained in the conclusions”).

[258] See generally Mathews, supra note 142.

[259] A separate, highly contentious query involves the notion that caffeine is only included in sodas to make them more addictive. In examining the websites of every major soda company, in addition to the website of the National Soft Drink Association, the companies make it uniformly clear that they use caffeine as part of a soda’s “flavor profile.” Therefore, taste experiments like the aforementioned Johns Hopkins study, however methodologically problematic, may attract FDA focus.

[260] In other words, the company must demonstrate that the product is “safe and wholesome.” See generally “The Food and Drug Administration: An Overview,” supra note 131.

[261] See e.g. 52 FED. REG. 18,923, 18,925 (1987).

[262] See “How Are Additives Approved for Use in Foods?” supra note 160.

[263] Under the current regulatory regime, soft drink companies are not required to list the specific quantities of caffeine used on the products themselves; however, many companies and sources, including the International Food Information Council Foundation and the National Soft Drink Association, publish caffeine content data for interested consumers voluntarily. See e.g. “Caffeine Content of Soft Drinks,” supra note 161.

[264] See “How Are Additives Approved for Use in Foods?” supra note 160.

[265] See Id . The FDA also has several methods of supervising products already in the marketplace, including ARMS: (“In addition, FDA operates an Adverse Reaction Monitoring System (ARMS) to help serve as an ongoing safety check of all additives. The system monitors and investigates all complaints by individuals or their physicians that are believed to be related to specific foods; food and color additives; or vitamin and mineral supplements. The ARMS computerized database helps officials decide whether reported adverse reactions represent a real public health hazard associated with food, so that appropriate action can be taken”).

[266] See Moore, supra note 129 at 1244.

[267] Id . See generally Donna Shalala and Janet Woodcock et al., “From Test Tube to Patient: Improving Health Through Human Drugs; An FDA Center for Drug Evaluation and Research Special Report,” (Sep. 1999), available at http://www.fda.gov/cder/about/whatwedo/testtube-full.pdf.

[268] See Id .

[270] See Charles Anello, “Emerging and Recurrent Issues in Drug Development,” 18 STATIST. MED. 2301, 2301-2309 (1999).

[271] See Janet Woodcock, “An FDA Perspective on the Drug Development Process,” 52 FOOD AND DRUG L. J. 145, 145-150 (1997).

[273] Due to the complexity of the drug approval process, the hypothetical will not explore every aspect of drug approval – space and time prohibit an exhaustive treatment of this subject. The hypothetical is intended only to demonstrate some of the potential concerns the FDA would raise with caffeine if it were a new drug compound seeking approval under the current regulatory regime.

[274] See Moore, supra note 129 at 1247.

[275] Id . See also Shalala and Woodcock et al., supra note 267.

[276] See Woodcock, supra note 271.

[277] Id. , ref . F. Attarchi, “Preclinical Regulatory Requirements,” REGULATORY AFF. FOCUS 9 (Apr. 2003); and K Olejniczak et al., “Preclinical Testing Strategies,” 35 DRUG INF. J. 321, 321-36 (2001).

[278] See generally Goodman & Gilman, supra note 4.

[279] See also “Investigational New Drug (IND) Application Process,” available at http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm: (“During a drug’s early preclinical development, the sponsor’s primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies”).

[280] See e.g. “Wikipedia,” supra note 6; Brain, supra note 14; Goodman & Gilman, supra note 4.

[281] Moore, supra note 129 at 1247. See also “Investigational New Drug (IND) Application Process,” supra note 279.

[282] 21 C.F.R. 312.2(b) (2003), available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.2.

[283] “Investigational New Drug (IND) Application Process,” supra note 279.

[284] See Id. : (“Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA”).

[285] Moore, supra note 129 at 1248.

[286] See 21 C.F.R. 312.42 (2003), available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.42.

[287] Moore, supra note 129 at 1248. Once an IND has been approved, several amendments can be made to the IND under statutory provisions. For example, Protocol Amendments (each new protocol for clinical trials conducted under the U.S. IND) must be submitted to the FDA under 21 C.F.R. 312.30. Information Amendments must be submitted regarding any essential information not covered in other reports, subject to 21 C.F.R. 312.31. IND Safety Reports and Annual Reports (21 C.F.R. 312.32 and 312.33, respectively), serve to make the FDA aware of any serious or unexpected adverse events, as well as general progress reports on the development work.

[288] Id . at 1249.

[289] See Id . In addition to basic dosage and side effect measurements, Phase I generally includes studies of “pharmacokinetic and pharmacologic actions of the drug (absorption, distribution, metabolism, and elimination information).” Id .

[290] See “Frequently Asked Questions About Caffeine,” (Dec. 2001), available at http://www.coffeefaq.com/caffaq.html.

[291] Moore, supra note 129 at 1249.

[292] See Id .

[293] It should be noted that the type of Phase II testing largely depends on the intended purpose or function of the new drug; since caffeine could be widely applied to a variety of medical ailments, this hypothetical is focusing on the stimulant properties only for sake of simplicity.

[294] See Moore, supra note 129 at 1249-50.

[295] See Id. at 1250.

[297] See Id . at 1251.

[299] See “Health Information Resource Database,” supra note 131, referring to the mission of the FDA to promote safety, effectiveness, and proper labeling.

[300] All previously cited studies in the Paper are incorporated by reference herein.

[301] Moore, supra note 129 at 1251.

[302] See Id .

[303] See Rados, supra note 172.

[304] See Moore, supra note 129 at 1251.

[306] One source summarizes the rationales for the FDA review processes as follows: (“In the U.S., the review of a new drug application serves many purposes. It is a public scientific document reflecting how a regulatory agency interprets information submitted for market approval of a drug. It provides a public record which needs to be ‘correct, coherent, well-organized, and credible’. It also shows the scientific aspects of the review. The goal of an application review is to determine if the data submitted supports proposed labeling claims and whether or not there is substantial evidence of efficacy and evidence that the drug is safe”). Anello, supra note 270. Since caffeine arguably satisfies all of these ideas, there is no significant reason to assume it is unworthy of current levels of consumer intake.

Michael Pollan’s long and strange trip: shifting perspectives on food and psychedelics

“It appears to be a universal human desire. Every culture on Earth, with the exception of the Inuit in Greenland, has used some plant to change consciousness, whether it was as profound as a psychedelic experience or as routine as a caffeine experience.” says Michael Pollan. Graphic by KCRW’s Gabby Quarante.

For decades, the bond between humans and plants, encompassing food, caffeine, and magic mushrooms, has fascinated investigative journalist and author Michael Pollan.

Pollan’s early books, including The Omnivore's Dilemma and The Botany Of Desire ,  provoked a national conversation about the wonder of plants, what we eat, and where our food comes from. They also inspired the 2008 documentary Food Inc ., which peeled back the curtain on the complexities of America's food industrial complex.

More recently, Pollan’s keen interest in the plants we consume has also led him into the world of psychedelics and mind-altering plants. In How To Change Your Mind; What The New Science Of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, And Transcendence ,

Pollan explores their therapeutic potential, remarking that the outcomes in addressing certain types of depression, anxiety, and addiction are nothing short of astonishing.

“I think we will come to understand that there’s a common denominator to the kinds of disorders psychedelics address effectively,” says Pollan. “It does seem to increase the kind of the plasticity of the brain and allows us to give up old narratives that are destructive, whether behaviorally or mentally, and write some new ones.”  

Pollan’s research also allowed him to experiment with both LSD and psilocybin .

“My own psychedelic experiences, some of which were profoundly spiritual, I came to understand spirituality is essentially egolessness.… It was an experience where, when the walls of the ego come down, there's nothing between you and the world and there’s this wonderful sense of merging into something larger and greater than yourself.” 

Pollan’s most recent book, This is Your Mind on Plants , challenges our commonly held views on drugs and psychoactive plants - including our pervasive use of caffeine; “90% of people on our planet have a daily relationship with caffeine,” Pollan says, “that includes our children if we're letting them drink soda.”

In regards to Food Inc. 2 , the sequel to Oscar-nominated Food Inc . that came out last year,  Pollan revisits food conglomerates that provide us with so much of our food and discovers that the pandemic exposed even more cracks in the system:  “Something really interesting and revealing happened in America, which is that the food system fell apart,” says Pollan. “In a weird, paradoxical way, you have the split screen and on one screen were empty supermarket shelves and people buying, hoarding, whatever they could find in the supermarket, and then on the other side of the screen, you had farmers destroying their crops, spilling milk out onto the ground that they couldn't sell, and euthanizing animals, pigs, and chickens by the thousands. How could both these things be true?” 

Today, there has been a noticeable shift in how we procure our food, with many opting for farmers' markets, CSA memberships, and organic produce—a transformation described as a blossoming trend by Pollan. He says “It hasn't disturbed the giant multinational companies that are running the bulk of the food system. Their power has only grown and the risks that come with that power have also only grown.”

Though the prospect of significant change in food systems may appear bleak, Pollan injects a note of optimism by highlighting that "the food movement boasts influential allies", citing "Biden's antitrust policies" and " Cory Booker , the senator from New Jersey, who sits on the Agriculture Committee ." Senator Booker, Pollan says has “connected the dots and understands that the public health challenges of his constituents are connected to the agricultural policies that are dictating what kind of food we're growing.” 

• Michael Pollan - author - @michaelpollan

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Here's How to Take a Nap Without Ruining Your Sleep

No nap shaming here. Follow these six tips to take a midday snooze like a pro.

Ever avoid a nap because you know you'll end up like this at night? If you nap the right way, you can still get a good night's sleep. 

Sometimes a nap during the afternoon is the only way to power through the day. While napping can absolutely affect your sleep at night, if you do it the right way, you get the best of both worlds -- great daytime naps and  still sleep soundly at night. With a few napping tips and tricks up your sleeve, you can avoid that oh-so-dreadful delay in your nighttime routine .

For extra tips on getting your best quality sleep, here are  7 natural sleep aids for insomnia and how to create the perfect environment for better rest . 

Tips: How to take a nap without ruining your sleep

Cue a collective sigh of relief: You can rejoice in the fact that it is possible to enjoy an afternoon snooze and not feel like you ruined your sleep cycle for the next five days. 

While some people -- as noted above -- should generally avoid naps, with the right strategy, most people can savor an afternoon nap and still get quality shut-eye when the world goes dark. Here are seven do's and don'ts to keep in mind before your next nap. 

1. Aim to nap in the early afternoon

The earlier you can nap (once you start to feel drowsy), the better. Just like long naps, late naps can interfere with your sleep cycle and keep you up at night. Though everyone's circadian rhythm is unique, most people  experience a dip in alertness around 1 to 3 p.m.  If you can make it to a restful area within this timeframe, that's your best bet for a good nap that doesn't mess with nighttime sleep.

The room you're napping in should have minimal light. This is difficult to achieve during the day without room-darkening curtains, so definitely invest in some if you take a lot of naps.

2. Set the scene

If you're going to take a nap, you may as well optimize it. Your napping environment should be just as restful as your sleeping environment. Ideally, you'll nap in the same place you sleep. Napping in a restful environment -- with little to no light, a comfortable temperature and a  pillow that suits your sleeping style  -- can help you fall asleep faster and fully reap the benefits of a short power nap. 

3. Nap without guilt

Naps should make you feel better, not worse. Don't let your nap guilt you into working late or doing more -- you needed the extra rest for a reason. Saying things like, "If I nap now, I have to stay up later to do [insert task]," can further disrupt your sleep cycle and cause you to develop a shameful mindset around napping, as if it's something you should never do. So nap without guilt, as long as you're still fulfilling your major obligations. 

And if you still feel guilty about your afternoon snooze, remember that some cultures literally  build naps into their collective daily routine , which should be evidence enough that naps are good for you. 

4. Keep naps short

More is not better when it comes to naps. The  Mayo Clinic  advises people to  nap for just 10 to 20 minutes . That may seem ridiculously short -- pointless, even -- but research shows that naps of this length  improve alertness  without the groggy post-nap feeling most people are familiar with. Naps that are just 30 minutes long can induce " sleep inertia ," a period of impaired performance immediately after napping. 

If you nap for up to an hour or more, you might seriously impair your circadian rhythm. Plus, Fargo says, waking from longer naps can make you feel groggy and cranky because it requires you to wake from deeper sleep. This can cancel out the benefits (read: alertness) you were hoping to gain from a nap. 

5. Don't sandwich your nap with screen time

The whole point of a nap is to make you feel better, not worse. Sandwiching your nap with  screen time  can make the nap less effective, as the  psychosocial effects of screen time  (particularly social media usage) can cancel out any tranquility you gained from your nap.

If you work in a profession that requires computer use, it may not be possible to avoid screen time before your nap. But that's all the more reason to avoid screens for a few moments after your nap.  Put your phone away  and do something to extend the relaxation:  Meditate  for five minutes, stretch out your arms and legs, go for a brief walk or  eat a healthy snack . Then, get back to work or whatever task is calling your name. 

6. Don't replace your nap with caffeine

Everyone is busy, and  burnout  is at an  all-time high  -- but stress and  anxiety  about work and life keep us all going at 100 mph. It's often tempting to power through the afternoon with an extra cup of coffee, thinking you'll cross more things off of your to-do list, but your body will be better served by a power nap. 

Consuming caffeine in the afternoon is linked to nighttime wakefulness,  even if you drink your afternoon coffee six hours before you go to bed . And drinking espresso three hours before bed delays melatonin production (the hormone that makes you sleepy) by  nearly an hour . 

A short nap, however, can reduce sleepiness,  improve focus  and  increase productivity  without the dreaded caffeine crash. 

Why we feel sleepy in the afternoon

The natural dip in energy and focus that you feel after lunchtime is known as the "afternoon slump." This is part of your circadian rhythm , the biological clock inside your body that regulates your sleep cycle. It's caused by fluctuations in hormones and neurotransmitters, particularly cortisol and adenosine. 

Cortisol makes you feel awake and alert. Cortisol levels in the body are generally higher when you first wake up and decrease steadily throughout the day. However, your body produces more cortisol in response to certain stimuli, such as exercise, which is why an afternoon workout can make you feel more awake. 

Adenosine , on the other hand, makes you feel sleepy, and your body secretes more of it as the day goes on. (Fun fact: Caffeine blocks adenosine receptors on your cells , which is why it works to keep you alert.)

Aside from your natural body clock, things like nighttime sleep quality, diet, caffeine consumption, room temperature, screen time and exercise habits influence afternoon fatigue. Sleep disorders, such as sleep apnea and insomnia, also contribute to daytime sleepiness. 

Who shouldn't take a nap 

Dr. Ramiz Fargo, medical director for the Loma Linda University Sleep Disorder Center , told CNET that most people can take naps and still enjoy a healthy sleep cycle, but people who struggle with insomnia should avoid napping. 

In people who already experience nighttime wakefulness, napping can exacerbate the problem and lead to a sleep detriment in a few ways, including: 

• Fragmented sleep (frequent awakening throughout the night).
• Delayed sleep-wake phase (falling asleep later and waking later than normal).
• Irregular sleep-wake rhythm (disorganization of sleep cycle, no clear bedtime or wake time).
• Anxiety about not being able to sleep, which may delay sleep even further.

If you aren't diagnosed with a sleep disorder and you don't usually have trouble falling asleep or staying asleep at night, you can most likely nap without issue. 

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Overview of Caffeine Effects on Human Health and Emerging Delivery Strategies

Sofia m. saraiva.

1 CPIRN-UDI/IPG, Center of Potential and Innovation of Natural Resources, Research Unit for Inland Development (UDI), Polytechnic Institute of Guarda, 6300-559 Guarda, Portugal; tp.gpi@aviarasaifos (S.M.S.); tp.gpi@otnicajamlet (T.A.J.)

Telma A. Jacinto

Ana c. gonçalves.

2 CICS-UBI—Health Sciences Research Centre, University of Beira Interior, 6201-001 Covilhã, Portugal; tp.opas@sevlacnoganiloracana

Dário Gaspar

3 Department of Sport Sciences, University of Beira Interior, 6201-001 Covilhã, Portugal; moc.liamg@7rapsagoirad

Luís R. Silva

4 Department of Chemical Engineering, University of Coimbra, CIEPQPF, Rua Sílvio Lima, Pólo II—Pinhal de Marrocos, 3030-790 Coimbra, Portugal

Associated Data

Data sharing not applicable.

Caffeine is a naturally occurring alkaloid found in various plants. It acts as a stimulant, antioxidant, anti-inflammatory, and even an aid in pain management, and is found in several over-the-counter medications. This naturally derived bioactive compound is the best-known ingredient in coffee and other beverages, such as tea, soft drinks, and energy drinks, and is widely consumed worldwide. Therefore, it is extremely important to research the effects of this substance on the human body. With this in mind, caffeine and its derivatives have been extensively studied to evaluate its ability to prevent diseases and exert anti-aging and neuroprotective effects. This review is intended to provide an overview of caffeine’s effects on cancer and cardiovascular, immunological, inflammatory, and neurological diseases, among others. The heavily researched area of caffeine in sports will also be discussed. Finally, recent advances in the development of novel nanocarrier-based formulations, to enhance the bioavailability of caffeine and its beneficial effects will be discussed.

1. Introduction

Currently, special attention is being paid to natural molecules and their putative therapeutic effects to delay, or even prevent, the occurrence of many diseases and improve the health status of the population [ 1 ]. Indeed, their ingestion is widely believed to have fewer or no adverse effects on humans than most synthetic molecules, and they are also cheaper and easier to obtain [ 2 , 3 , 4 ]. Caffeine, in particular, has been the subject of intense and in-depth research on the human organism regarding its health-promoting effects and possible beneficial effects on the performance of athletes, especially through its ability to improve anaerobic and aerobic performance, muscle efficiency, and speed, and to reduce fatigue [ 5 , 6 , 7 , 8 , 9 ]. Caffeine is probably the most commonly ingested psychoactive substance in the world, found mainly in coffee, soft drinks, tea, cocoa and chocolate-like products, yerba matte leaves, guarana berries, and some pharmaceuticals [ 10 ]. It is rapidly absorbed and distributed in all human tissues, reaching maximum plasma concentrations 30–120 min after oral intake [ 9 ].

As far as we know, in vivo studies have already reported that caffeine stimulates the central nervous system by acting as an antagonist of A1 and A2 adenosine receptors, promotes adrenaline release, increases dopamine, noradrenalin, and glutamate levels, blood circulation and respiratory rate, mobilizes intracellular calcium stores, and alters fat and carbohydrates metabolism in the human body by stimulating lipolysis, thanks to its ability to inhibit phosphodiesterase enzymes [ 11 , 12 , 13 , 14 , 15 , 16 ]. In addition, caffeine also increases energy, alertness, excitement, and mood [ 17 , 18 ]. According to the European Food Safety Authority (EFSA), a habitual daily consumption of caffeine up to 400 mg (5.7 mg/kg bw per day for a 70 kg adult) by adults, and 200 mg by pregnant or breastfeeding women is considered to be safe [ 19 ]. Exceeding this dose or the sudden cessation of caffeine intake may cause anxiety, insomnia, hallucinations, hypertension and headache, gastrointestinal and sleep disturbances, diuresis, dehydration, tremors, palpitations, and cardiac arrhythmias given the stimulant effects of caffeine [ 20 , 21 , 22 , 23 ]. Regarding children and adolescents, the EFSA considers that there is insufficient information [ 19 ]. Considering caffeine’s high consumption, as well as its increasing commercial availability in pure form, and presence at high concentrations in products such as dietary supplements, the US Food and Drug Administration (FDA) and EFSA warn about the risks of its consumption at high doses [ 24 , 25 ].

Nonetheless, considering the different beneficial biological and physiological effects of caffeine, extensive studies have been conducted to determine its full health potential. In this line, caffeine encapsulation, alone or combined with other molecules, has been performed to increase its biological activities [ 26 , 27 , 28 , 29 , 30 ]. Therefore, the main objective of this review is to discuss the biological potential of caffeine for human health, highlighting its anticancer, immunological, anti-inflammatory, cardiovascular, and neurological protective effects, as well as its effects on the performance of athletes.

2. Chemical Structure and Main Natural Sources of Caffeine

Caffeine (C 8 H 10 N 4 O 2 ; Figure 1 A), also known as 1,3,7-trimethylxanthine, belongs to the group of methylxanthines, which are alkaloids [ 11 , 31 ]. Together with theobromine, its precursor ( Figure 1 B), both are synthetized by the fruits, leaves, and seeds of many plants and trees to protect them from diseases and predators [ 22 , 32 , 33 ].

Chemical structure and functional groups of caffeine ( A ) and theobromine ( B ).

Regarding their structure, both compounds are carbon- and nitrogen-based molecules composed of two purine rings, a pyrimidine ring (C5-ring), and an imidazole ring (C6-ring), both of which have two nitrogen atoms [ 34 , 35 ]. Their functional groups are an amide (a carbonyl group bonded to carbon and nitrogen atoms), an amine (at least one hydrocarbon group bonded to a nitrogen atom), and an alkene (an unsaturated hydrocarbon with a double bond between two carbon atoms) [ 34 ]. Caffeine serves as a hydrogen bond acceptor because three of its four nitrogen atoms are methylated [ 36 ].

Although caffeine and theobromine share similarities at the physical and chemical levels, caffeine has an additional methylene group and exerts stronger central nervous system effects than theobromine [ 37 , 38 ].

Regarding caffeine consumption, recent statistical data show that more than 85% of American adults consume caffeine daily (135 mg per day) [ 39 , 40 ]. In Europe, a higher caffeine consumption is observed (values ranging from 37 to 319 mg per day), especially in the Netherlands (411 mg per day), Denmark (390 mg per day), Finland (329 mg per day), Austria (300 mg per day), and Switzerland (288 mg per day) [ 19 , 41 ]. Compared to other non-European countries, Brazil and Argentina also have a high consumption of caffeine (mean values of 40 and 100 mg per day, respectively), as well as Australia (232 mg per day) and Japan (169 mg per day) [ 41 ]. In contrast, lower amounts of caffeine are consumed in China (16 mg per day), Angola (4 mg per day), and Kenya (50 mg per day) [ 41 ].

The main sources of caffeine are coffee and tea, energy beverages, sodas and soft drinks, and dark chocolate (see Table 1 ) [ 31 , 41 , 42 , 43 , 44 ]. As expected, coffee and chocolate are the most popular sources of caffeine worldwide [ 31 , 42 ]. Among the different types of coffee (beverage), American coffee is the most caffeinated (91.7–213.3 mg per 100.0 mL) [ 42 ], followed by Scotland espresso (66.0–276.0 mg per 13.0–90.0 mL) [ 31 ]. As for tea, black tea and Yerba Mate contain considerable amounts of this molecule (both around 40.0 mg per 236.0 mL) [ 41 ]. Among soft drinks, Mountain Dew Rise and Diet Coke have considerable amounts of caffeine (180.0 mg per 473.0 mL and 46.0 mg for 354.0 mL, respectively) [ 41 ]. Among energy drinks, Java Monster 300 and Rockstar XDurance present the highest caffeine contents (amounts around 300.0 mg per 443.0 and 473.0 mL, respectively), followed by Full Throttle (160.0 mg per 473.0 mL) [ 41 ]. In addition, as expected, energy shots, such as Spike Energy Double Shot and Bang Shot, are also rich in caffeine (levels of 350.0 and 300.0 mg per 125.0 and 88.0 mL, respectively) [ 41 ]. Finally, Cran Energy juice and Water Joe also have significant amounts of caffeine (70.0 mg per 295.0 and 591.0 mL, respectively) [ 41 , 45 ]. The presence of caffeine is also reported in dark chocolate (8.0 mg per 1.0 g) [ 41 ].

Major sources of caffeine and respective levels, according to their usual commercialization volumes/recommend preparations.

* Values in grams.

3. Benefits of Caffeine on Health

For our search, we used Web of Science. The search restrictions were based on language (English), year of publication from 2018 to present, and type of publication set to journal. The keywords used for the search were “caffeine” in combination with any of these other keywords: “cancer”, “anticancer”, “antitumor”, “anti-tumor”, anti-cancer”, “neurodegenerative diseases”, “autoimmune diseases”, “immunological”, “immunomodulatory”, “immune system”, “anti-inflammatory”, and “cardiovascular”. In the following subsections, we provide an overview of the latest research regarding the impact of caffeine in different illnesses such as cancer, autoimmune diseases, immunomodulation, and ocular, respiratory, neurodegenerative, and cardiovascular diseases.

3.1. Cancer

Cancer is one of the leading causes of death worldwide. It was estimated that in 2020, there were 19.3 million cancer cases, which resulted in 10.0 million cancer deaths [ 46 , 47 ]. By 2030, it is estimated that over 22 million people will develop cancer [ 47 , 48 ]. In addition, cancer is responsible for a significant economic burden on both the health care system and patients [ 48 ].

As early as 2000, Hanahan and Weinberg defined the key features (i.e., “hallmarks of cancer”) that describe the characteristics necessary to promote cancer growth and metastasis. These hallmarks are self-sufficiency in growth signals, insensitivity to antiproliferative signals, resistance to apoptosis, limitless replicative potential, the induction of angiogenesis, and the activation of tissue invasion and metastasis [ 49 ]. In 2011, the authors revised the original hallmarks and added two more cancer-promoting features (genomic instability and tumor-promoting inflammation) and two more hallmarks (deregulation of cellular energetics and avoidance of immune destruction) [ 50 ]. As the understanding of cancer underlying mechanisms of progression has grown, as have the available experimental and computational tools; early in 2022, Hanahan reviewed the previously discussed features and included new additional features of cancer, namely, (i) phenotypic plasticity, (ii) non mutational epigenic reprogramming, (iii) polymorphic microbiomes, and (iv) senescent cells [ 51 ].

The role of coffee components in suppressing some of the cancer hallmarks defined by Hanahan and Weinberg [ 52 , 53 ] has been reviewed by Gaascht et al. and Cadóna et al., while other authors have fully elucidated the effect of caffeine on the cell cycle [ 54 ]. Caffeine anticancer activity has been widely studied [ 55 ], and the below-stated findings demonstrate the capacity of caffeine to overcome some of the cancer-promoting hallmarks, such as resistance to cell death and cellular senescence, that play an important role in cancer progression [ 51 ]. Further, several works state that caffeine may induce apoptosis through numerous pathways, such as p-53-dependent and -independent, phosphatase and tensin homolog, PI3K/protein kinase B (AKT), and mammalian target of rapamycin (mTOR) pathways [ 56 ].

El Far et al. studied the effect of caffeine and other natural substances on the senescent cells of colon and breast cancers. After inducing senescence with doxorubicin, the cells were treated with various doses of caffeine (0, 5, 10, 15, 20, 30, 40, 50, and 60 mM). The IC 50 of caffeine against doxorubicin-treated HCT116 and MCF7 cells was 13.36 ± 2.29 mM and 17.67 ± 3.98 mM, respectively. The authors also examined caffeine-induced apoptosis in both senescent and proliferative cells. At concentrations of 10 and 15 mM, caffeine induced a significant increase in apoptosis in senescent HTC116 cells, and at concentrations of 5, 10, and 15 mM in senescent MCF7 cells compared with proliferative cells [ 56 ]. In another study, Machado et al. evaluated the effect of caffeine on two breast cancer cell lines (MCF-7 and MDA-MB-231). The results showed that caffeine at a concentration of 2.5 mM and 5 mM for MCF-7 and MDA-MB-231, respectively, reduced cell viability and induced apoptosis [ 57 ]. The antitumoral effects of caffeine were studied in diverse cancer in vitro models, such as glioblastoma, melanoma, and pancreatic and lung cancers [ 58 , 59 , 60 ].

The antitumoral effects of caffeine have also been evaluated in in vivo tumor models. Venkata Charan Tej and collaborators investigated the effect of caffeine on the carcinogen-induced tumor model of fibrosarcoma. After 250 days of 3-MCA inoculation, there was a dose-dependent decrease in the tumor incidence and growth rate in the groups treated with caffeine (1.030, 2.060, and 4.120 mM) [ 61 ]. The anti-tumoral effect of caffeine was related to its action on cytotoxic T lymphocytes. On one hand, caffeine led to a higher percentage of cytotoxic T cells in the tumor, and on the other hand, it decreased the expression of programmed cell death protein 1 (PD-1) on these cells. In addition, it also increased the levels of pro-inflammatory cytokines such as TNF-α and IFN-γ. These results are in line with the previously known inhibitory effect of caffeine on the adenosine-A2a receptor pathway [ 62 ], which is one of the immunosuppressive pathways involved in cancer [ 63 , 64 ]. This capacity of caffeine to modulate the immune system in the tumor surroundings alters another important hallmark (i.e., the ability to avoid immune destruction). The modulation of the PD-1, an important immune checkpoint, and consequent enhancement of the T cell responses can exert an antitumor effect. In fact, the inhibitors of this protein are one of the immunotherapies approved by the FDA [ 65 ].

The therapeutic effect of caffeine was also demonstrated for renal carcinoma. Xu et al. showed, through in silico studies, that caffeine is able to bind to glucose-6-phosphate dehydrogenase (G6PDH), which is considered a biomarker and potential therapeutic target for this type of cancer. Consistent with the above results, in this study, the use of caffeine at concentrations of up to 0.016 mM for in vitro studies and 60 and 120 mg/kg/day for in vivo studies decreased the viability and proliferation of ACHN and 786-O cancer cells both in vitro and in vivo [ 64 ]. G6PDH is an important target in cancer given that is normally upregulated in different cancers and its dysregulation can provide valuable conditions for cancer progression [ 66 ]. Further, it also has an important role in maintaining the redox balance and biosynthesis of nucleotides and lipids, which is part of another cancer hallmark (i.e., reprogramming cellular metabolism) [ 67 ].

As previously mentioned, caffeine has also been tested in combination with other drugs in order to potentiate the antitumoral effect [ 68 , 69 , 70 , 71 ]. Higuchi et al. evaluated the efficacy of oral recombinant methioninase (o-rMETase) in combination with caffeine and doxorubicin in an orthotopic xenograft mouse model of synovial sarcoma. After two weeks of treatment, the group treated with the combinatorial treatment was able to induce tumor regression. According to the authors, this can be explained by the ability of caffeine to induce mitotic catastrophe [ 72 ]. Other examples of caffeine combination with different drugs are depicted in Table 2 .

Overview of the latest research regarding caffeine anti-cancer activity.

IC 50 , half-maximal inhibitory concentration; NADH, nicotinamide adenine dinucleotide; MTT assay, (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay; Anti-PD1, anti-Programmed Cell Death Protein 1; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon gamma; G6PDH, glucose-6-phosphate dehydrogenase; NADP+, nicotinamide adenine dinucleotide phosphate; IP, intraperitoneally.

Understanding the effects of caffeine on cancer and the mechanisms underlying this effect is of extreme importance. Table 2 summarizes the most recent (from 2018) works on this topic. These studies also contribute to determining the necessary caffeine quantities to achieve a therapeutic effect and to ensure the safe use of caffeine.

3.2. Anti-Inflammatory and Immunomodulation

3.2.1. autoimmune diseases and immunomodulation.

Inflammation is usually caused by infection or damage to a tissue [ 84 ]. Caffeine has the ability to exert modulation on the immune system. The immune response can be divided into two types: (i) innate and (ii) adaptive immunity [ 85 ]. Acute inflammation is a mechanism of innate immunity, whereas chronic inflammation usually contributes to the development of various diseases, such as metabolic disorders, neurodegenerative diseases, and even cancers [ 86 , 87 ]. The effect of caffeine on the innate immune system is related to the reduction in macrophage, neutrophil, and monocyte chemotaxis [ 88 , 89 ]. As for adaptive immunity, the effect of caffeine is due to the inhibition of Th1 and Th2 cell proliferation, as well as to the alteration of B cell function and the consequent reduction in antibody production [ 89 , 90 , 91 , 92 ]. Several authors, such as Horrigan et al., Açıkalın et al., and Al Reef et al., already reviewed, in depth, the impact of caffeine on the immune system and its capacity to alleviate autoimmune diseases [ 88 , 93 , 94 ].

Considering the immunomodulatory effects of caffeine, Wang et al. evaluated its effects on multiple sclerosis. Experimental autoimmune encephalomyelitis is the standard animal model for multiple sclerosis. After inducing the disease in C57BL/6 mice, these were treated with caffeine (10, 20, or 30 mg/kg/day) in drinking water. The results showed that caffeine could reduce inflammatory cell infiltration, the degree of demyelination, and microglial in vivo. It also reduced NLRP3 and p62 protein levels. In vitro assays indicated that caffeine promoted autophagy [ 95 ]. In another study, Ghaffary et al. evaluated the potential of mesenchymal stem cells to reduce the severity of rheumatoid arthritis. Wistar rats were treated with mesenchymal stem cells that had previously been incubated with various concentrations of caffeine. The results showed that the rats treated with mesenchymal stem cells, previously treated with 0.5 mM of caffeine, presented decreased disease severity and serum levels of C-reactive protein, nitric oxide, myeloperoxidase, and TNF-α. In addition, the IL-10 serum levels and the weight of the treated rats increased [ 96 ].

3.2.2. Ocular Diseases

Adenosine receptors are also expressed by retinal endothelial and retinal pigment epithelial (RPE) cells, as well as choroid and choroidal cells [ 97 ]. Therefore, caffeine may also have beneficial effects in ocular diseases, such as choroidal neovascularization and retinal inflammation.

Retinal inflammation is involved in ocular diseases as age-related macular degeneration (AMD) and diabetic retinopathy (DR), among others. For example, AMD is characterized by elevated vitreous levels of IL-1 β [ 98 ] and plasmatic tumor necrosis receptor 2 (TNF-R2) and low levels of brain-derived neurotrophic factor (BDNF) in the aqueous humor, which negatively affect photoreceptor and retinal ganglion cells’ survival [ 99 ]. Conti et al. demonstrated that caffeine has an anti-inflammatory effect in RPE cells, decreasing the expression of IL-1 β , IL-6, and TNF- α , as well as the nuclear translocation of nuclear factor kappa B (NF- κ B). In addition, the topical instillation of caffeine in an ischemia-reperfusion injury mice model was shown to restore physiological BDNF levels and reduce the mRNA levels of IL-6 in the retina, demonstrating its potential for the treatment of retinal inflammation and degeneration [ 100 ]. The effect of caffeine on choroidal adenosine receptors, the reduction in cell migration to the injured area, and angiogenesis demonstrate the importance of caffeine in attenuating choroidal neovascularization [ 97 ]. Despite the potential of caffeine in the management of such ocular conditions, the available studies are still scarce.

3.2.3. Respiratory Diseases

Currently, there are respiratory diseases for which caffeine is used as a clinical treatment, namely, premature infant diseases such as apnea and bronchopulmonary dysplasia (BPD). BPD is a common neonatal pulmonary complication with a prevalence of 45% in preterm infants [ 101 ]. BPD is associated with a nonspecific inflammatory response involving the activation of Toll-like receptors (TLRs), NOD-like receptors (NLRs), and increased levels of pro-inflammatory cytokines (IL-1 β , IL-6, IL-8, IL-18, TNF α ) [ 102 ]. In addition, NLR3 (NOD-, LRR-, and pyrin domain-containing protein 3), a key player in the pathogenesis of BPD, is responsible for the release of pro-inflammatory cytokines (IL-1 β and IL-18) and alveolar cell death through various mechanisms [ 103 , 104 ]. Caffeine is the most commonly used medication for extreme prematurity (less than 28 weeks) and is also very commonly prescribed for very early preterm birth (28 to 32 weeks) [ 105 ]. As clinically shown, the early initiation of caffeine treatment (5 and 10 mg/kg/day) is important to achieve a successful outcome. Early treatment significantly reduced BPD incidence and mortality in low-birth-weight neonates [ 106 ]. Despite the use of caffeine and its clear benefits, the mechanisms behind the clinical benefits in these diseases are not fully understood.

In vitro studies showed that the treatment of lipopolysaccharide (LPS)-induced macrophages with caffeine caused a reduction in caspase-1 expression and the inhibition of the NLRP3 inflammasome, demonstrating its potential effect on this important target. Moreover, in vivo, the treatment of newborn mice with hypoxia-induced lung injury with caffeine was shown to significantly increase A2a receptor expression and inhibit the NLRP3 inflammasome protein and NF- κ B pathway in the lung. The effect of caffeine on these key regulators attenuated inflammatory infiltration, reduced oxidative stress, decreased alveolar cell death, and promoted alveolar development [ 107 ]. Similar results were also observed in another study; specifically, caffeine caused a decrease in NF- κ B and pro-inflammatory factor levels, increased the expression of A1, A2a, and A2b receptors, and decreased cell death in the lung [ 108 ].

Table 3 summarizes recent research findings on the anti-inflammatory effects of caffeine and its effects on autoimmune diseases.

Overview of the latest research regarding caffeine anti-inflammatory activity and impact on the immune system.

IL, interleukin; TNF- α , tumor necrosis factor alpha; IFN- γ , interferon gamma; MCP-1 (monocyte chemoattractant protein-1); STAT1, Signal Transducer and Activator of Transcription 1; Akt, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; mTOR, mammalian target of rapamycin; NLRP3, NLR family pyrin-domain-containing 3; NF- k B, nuclear factor- κ B MAPK, mitogen-activated protein kinase; IP-10, interferon gamma-induced protein 10; CCL4, CC motif chemokine ligand 4; TGF- β , transforming growth factor beta; CTGF, connective tissue growth factor; α -SMA, alpha smooth muscle actin; LPAR1, lysophosphatidic acid receptor 1; LPS, lipopolysaccharide; M-MFs, inflammation-resolving macrophages; GM-MFs, inflammation-promoting macrophages; NF κ B1, nuclear factor kappa B subunit 1; HMGB1, high mobility group box 1 protein; BDNF, brain-derived growth factor.

3.3. Neurodegenerative Diseases

By 2050, the number of dementia cases worldwide is estimated to be 36.5 million [ 127 ]. There are several neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and multiple sclerosis [ 128 , 129 ]. For example, Parkinson’s disease is triggered by the loss of neurons, which leads to a decrease in dopamine levels. In Alzheimer’s disease, there is a deposition of extracellular deposits of amyloid-beta peptides and neurofibrillary tangles [ 130 , 131 ].

Caffeine is considered the most widely consumed psychoactive stimulant in the world. This natural compound is able to cross the blood–brain barrier [ 132 , 133 ] and, according to the literature, may exert a stimulant effect on the central nervous system by modulating several molecular targets, such as the (i) antagonism of adenosine receptors, (ii) promotion of intracellular calcium mobilization, (iii) inhibition of phosphodiesterase, and (iv) inhibition of GABA A receptors. However, except for the blockade of adenosine receptors and consequent inhibition of neurotransmitter-induced signaling pathways, the other mechanisms only exert their effects at toxic concentrations of caffeine [ 132 , 134 , 135 , 136 ]. Recently, Ruggiero et al. reviewed the available literature on the protective effects of caffeine in various neurodegenerative diseases [ 137 ]. Among these studies, some emphasized the neuroprotective role of caffeine. For example, Manolo et al. showed that caffeine, at a concentration of 10 mM, is able to protect 96% of the dopaminergic neurons. The co-administration of olanzapine and caffeine did not result in neuroprotection, implying that both dopamine D2-like and A2a receptors are required for neuroprotection [ 138 ]. In an in silico study of Parkinson’s disease, the authors demonstrated that caffeine has the ability to bind to both wild-type and mutant parkin protein [ 139 ]. The mutation of parkin protein is the most common cause of Parkinson’s disease, as is the abnormal secretion and accumulation of α-synuclein [ 140 , 141 ]. This last part was detected in the following in vivo studies. Luan et al. investigated whether caffeine could protect against mutant α-synuclein-induced toxicity. Exposing mice to 1 g/L of caffeine in drinking water attenuated apoptotic neuronal cell death as well as microglia and astroglia reactivation, culminating in synucleinopathy [ 142 ]. In a similar study, Yan et al. investigated synergetic neuroprotection between caffeine and eicosanoyl-5-hydroxytryptamide. Both compounds are present in coffee and showed no effect at subtherapeutic doses, whereas their combination reduced the accumulation of phosphorylated α-synuclein, and maintained neuronal integrity and function [ 143 ]. Table 4 summarizes the most recent research on the neuroprotective effects of caffeine in neurodegenerative diseases and other conditions.

Overview of the latest research regarding caffeine in neurodegenerative diseases.

ADAM10, A disintegrin and metalloproteinase domain-containing protein 10; APP, amyloid-beta precursor protein; ROS, reactive oxygen species; LPS, lipopolysaccharides; GFAP, glial fibrillary acidic protein; SNAP25, synaptosomal-associated protein, 25kDa; N/D, non-disclosed; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; N/A, not applicable.

3.4. Cardiovascular Diseases

Cardiovascular disease (CVD), the leading cause of mortality, accounted for 17.8 million deaths worldwide between 1980 and 2017 [ 160 ]. By 2030, an estimated 23.6 million people per year will die due to CVD. Caffeine intake, particularly through the consumption of coffee, tea, and other products, has shown various cardiovascular effects. Turnbull et al. reviewed more than 300 studies regarding the effects of caffeine on cardiovascular health, published from the late 1980s to 2017. Overall, the results suggest that caffeine consumption does not increase the risk of CVD and may have a protective effect against this group of diseases [ 161 ]. However, recent studies on this topic have shown that high caffeine consumption may have the opposite effect.

A study of 347,077 people (UK Biobank) concluded that coffee consumption may modestly increase the risk of cardiovascular disease. A nonlinear association was found between long-term coffee consumption and cardiovascular disease. Individuals who consumed coffee in high doses (>6 cups/day, >450 mg caffeine/day) were more likely to develop cardiovascular disease (22%) than those who consumed less coffee (1–2 cups/day or 75–150 mg caffeine/day) [ 162 ]. In addition, the authors examined the association between coffee consumption, plasma lipids, and CVD risk in 362,571 individuals (UK Biobank). The results showed that high coffee consumption (>6 cups/day) may increase CVD risk by increasing the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (total-C), and apolipoprotein B (ApoB) [ 163 ].

However, other studies have reported the potential beneficial effects of moderate coffee consumption, in line with Turnbull et al.’s literature review [ 161 ]. For instance, a study involving 20,487 Italian participants concluded that moderate coffee consumption (3–4 cups/day) was associated with a low risk of CVD-related mortality. In addition, an inverse correlation was found between NT-proBNP levels (N-terminal fragment of the B-type natriuretic peptide, which is associated with higher stroke risk) and coffee consumption [ 164 ]. Similarly, a study of more than 500,000 participants in England reported that a caffeine intake of 121–182 mg/day from coffee (2–3 cups/day) or tea (4–6 cups/day) was associated with a low risk of coronary artery disease [ 165 ]. In addition, a US follow-up study of 23,878 participants over 16 years found that the daily caffeine consumption of about 100–200 mg or >200 mg is associated with a lower risk of CVD mortality [ 166 ]. An inverse association between coffee consumption and CVD risk factors (blood pressure and arterial stiffness) was also observed in another study, showing the beneficial effect of moderate coffee consumption [ 167 ]. A similar association was observed concerning coffee consumption and hypertension risk [ 168 ].

Therefore, despite some studies linking high coffee or caffeine consumption to CVD risk, most studies have reported that its moderate consumption has potentially beneficial and even protective effects on CVD. Table 5 summarizes the recent research on the effects of caffeine on CVD.

Overview of the latest research regarding caffeine’s impact on cardiovascular diseases.

HR, heart rate; HF-HRV, heart rate variability; mTOR, mammalian target of rapamycin; VSMCs, vascular smooth muscle cells.

4. Caffeine Impact on Sports Performance

Coffee’s best-known constituent, caffeine, is the most widely consumed psychotropic drug in the world, with an estimated daily intake of up to 4 mg/kg body weight in American adults [ 173 , 174 , 175 , 176 ]. It is a psychostimulant that can lead to physical dependence [ 177 ]. Caffeine intake is widespread among inactive individuals and high-performance athletes, especially since 2004, when it was removed from the World Anti-Doping Agency’s list of banned substances for competition [ 178 ]. It is also readily available in various forms such as capsules, powders, caffeinated beverages, and energy drinks [ 173 ].

However, while there is evidence that caffeine improves athletic performance [ 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 ], due to particular protocols and study designs, some research seems conflicting. Some studies show ergogenic effects on aerobic endurance (>90 min), high-intensity efforts (20–60 min), muscular endurance, sprint performance and maximal strength (0 to 5 min), and ultra-endurance (>240 min) and endurance races with prolonged intermittent sprints (team sports), while others report no evidence for its administration [ 180 , 181 , 182 ]. We assume that an ergogenic substance is a substance used with the aim of improving athletic performance and promoting recovery after exercise by delaying fatigue. The word is of Greek origin: ergo (work) and gen (generation). As a result, it is commonly consumed by athletes, and research suggests that 75 to 90% of athletes consume caffeine before or during athletic competition [ 181 ]. In an analysis of 20,686 urine samples from elite athletes, 73.8% of the samples contained caffeine at concentrations greater than 0.1 µg/mL, suggesting that three out of four athletes consume caffeine before or during competition [ 175 ].

It should be recalled that the consumption of caffeine is not prohibited for athletes, with the maximum allowable concentration being 12 mg/L of urine (International Olympic Committee). The fact that caffeine affects the nervous system, adipose tissue, and skeletal muscle originally led to the hypothesis that caffeine might affect athletic performance. For example, caffeine may increase skeletal muscle contractile force at submaximal contraction and increase the athlete’s pain threshold or perceived exertion, which could lead to longer training sessions [ 180 , 181 ].

However, it should be remembered that caffeine intake has several side effects. Blood pressure increases both at rest and during exercise and heart rate increases, and it may impair recovery and sleep patterns, most likely in athletes who do not regularly consume caffeine [ 180 ]. In addition, Martins et al. demonstrated that high doses of caffeine have side effects. In a recent study using a caffeine dose of 12 mg/kg, almost all participants reported side effects such as tachycardia and palpitations, anxiety or nervousness, headache, and insomnia [ 175 ].

However, according to our research, it seems important to us to better evaluate certain aspects to achieve better scientific clarification with implications for practice, such as the ideal dosage, time of intake, abstinence, training time vs. caffeine consumption, physiological factors, gender, and caffeine users or not.

4.1. Optimal Dosage

Higher-than-ideal caffeine doses, 3–6 mg/kg, before exercise do not further improve athletic performance. Additional and higher doses of caffeine may lead to side effects in athletes [ 180 ].

Low doses of caffeine (~200 mg) have also been shown to improve attention, alertness, and mood, and cognitive processes during and after strenuous exercise. Thus, the ergogenic effects of low doses of caffeine appear to be due to changes in the central nervous system [ 180 ].

The generally accepted dosage of caffeine for performance enhancement is between 3 and 6 mg/kg, 60 min before exercise [ 175 ].

Although a meta-analysis reported that caffeine intake can be ergogenic in a variety of physical activities, the “optimal” caffeine dose remains difficult to determine [ 178 ].

4.2. Timing of Intake

The early ingestion of caffeine prior to physical activity has been shown to enhance performance. For example, caffeine can improve performance during high-intensity sprints when taken 45–60 min before exercise [ 176 ].

Because caffeine has so many positive effects on exercise performance, it can—and perhaps should—be taken before or during exercises. For most sports, it is recommended that caffeine be taken about 60 min before the start of the first set of the training session if used before exercise. This period varies depending on the individual, the type of event, and the type of caffeine ingested, with caffeinated mouthwashes and chewing gums generally requiring much less time. For longer training sessions, there is evidence that ingesting caffeine later in the day, and at lower doses, may be effective [ 181 ]. Other interesting data refer to the concentration peak that occurs in the first 15 min [ 183 ].

The isolated consumption of anhydrous caffeine results in maximal plasma peaks of the substance between 30 and 90 min after the consumption of low (2–3 mg/kg), moderate (3–6 mg/kg), or high doses (6–9 mg/kg) [ 175 , 184 ].

4.3. Abstinence

It appears that, short-term, caffeine withdrawal before competitions does not enhance the ergogenic effects of caffeine in habitual users. Withdrawal is associated with numerous negative consequences, including headache, fatigue, irritability, muscle pain, sleep disturbance, and nausea. However, these acute withdrawal symptoms, shortly before important competitions, may have a negative impact on the subjective self-confidence and well-being of the athlete [ 181 ].

4.4. Training Time vs. Caffeine Consumption

Increases in physical performance as a function of training time have been demonstrated in various sports. Studies suggest that anaerobic and aerobic activities may be more powerful due to the diurnal fluctuations of the circadian cycle between 4 and 8 pm. Morning caffeine consumption had a more beneficial effect than afternoon consumption [ 175 ].

4.5. Physiological Factors

Hypothetically, the potential performance enhancement from caffeine ingestion may be greater in trained individuals than in untrained individuals because trained individuals have an enhanced neuromuscular action potential. Trained individuals have a higher concentration of adenosine A2a receptors than untrained individuals [ 175 , 185 ].

The main finding of this review is that very low doses of caffeine (>1–2 mg/kg, generally taken 60 min before exercise) improve resistance training performance in terms of muscle strength, muscle endurance, and average speed [ 174 ].

Aerobic endurance appears to be the sport in which caffeine consumption most consistently produces moderate to significant benefits, although the magnitude of the effect varies among individuals [ 185 ].

4.6. Gender

Caffeine ingestion positively affects resistance exercise performance in women, and the magnitude of these effects appears to be comparable to those observed in men [ 184 ]. Even considering the woman’s menstrual cycle, a study showed that caffeine increased peak aerobic cycling power in the early follicular, preovulatory, and mid-luteal phases. Thus, the ingestion of 3 mg of caffeine per kg of body mass might be considered an ergogenic aid for eumenorrheic women during all three phases of the menstrual cycle [ 186 ].

4.7. Caffeine Consumers or Not

For the first study using a performance test, 17 moderately trained men were recruited, 8 of whom did not routinely consume caffeine (<25 mg/day) and 9 of whom regularly consumed caffeine (>300 mg/day). It was found that there were no differences between the groups in time to exhaustion at any of the doses, suggesting that habitual caffeine consumption does not attenuate the ergogenic effects of caffeine [ 181 ]. In another study, on cycling, habitual caffeine intake was found to have no effect on athletic performance, suggesting that habituation to caffeine has no negative effect on caffeine ergogenesis [ 187 ].

5. Future Directions: Nanotechnology-Based Delivery Strategies

Caffeine is usually consumed through the ingestion of beverages, especially coffee, tea, and pharmaceuticals, which allows for rapid absorption and distribution in all tissues [ 9 ]. However, caffeine has a short half-life (3–5 h) [ 188 ]. In addition, the oral intake of high concentrations of caffeine may cause gastrointestinal problems [ 189 ] and its wide distribution may lead to undesirable side effects, such as the stimulation of the nervous system.

Nanotechnology is a multidisciplinary field that enables the manipulation of matters at the nanoscale (1 to 100 nm) and the creation of novel devices with unique properties [ 190 ]. Nanotechnology is frequently explored for drug delivery to a target tissue. Drug delivery systems (DDS) or nanocarriers offer important advantages for caffeine delivery, namely, a high loading capacity, the co-encapsulation of different drugs, controlled and sustained release, a high surface area allowing greater interaction with tissue, and a high ability to permeate through tissues [ 191 ]. In addition, other routes of administration besides oral can be used, such as intranasal [ 192 ] and dermal [ 188 ] ( Figure 2 ) .

Possible administration routes for caffein-loaded nanosystems and their main outcomes.

Nanocarriers’ compositions are tailored depending on the drug(s), route of administration, and target tissue. Therefore, different nanocarrier compositions based on lipids, polymers, or metals have been proposed for caffeine delivery, as reported in this section.

Lipidic nanocarriers have been widely explored for topical drug delivery through the skin for cosmetic and pharmaceutical applications [ 193 ]. The composition of lipid carriers is an important factor to be considered to improve skin permeation and therapeutic effects. For example, among the various phospholipids (1,2-distearoyl-snglycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt (DPPG), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)) tested for liposome preparation and the topical delivery of caffeine, DPPG was the most promising. Ex vivo studies showed that DPPG was able to enhance the permeation of encapsulated and free caffeine through hairless rat skin by disrupting the lipid barrier of the stratum corneum (SC) [ 194 ]. A similar effect was observed for lipid nanocapsules (NCs) in porcine skin. The ability of lipid NCs to increase skin permeation of free caffeine has been attributed to the combination of several factors, namely, the occlusion effect of nanoparticles on the skin surface, accumulation in hair follicles, and the effect on barrier function of SC [ 195 ]. On the other hand, the incorporation of propylene glycol into phosphatidyl liposomes has been shown to enhance the permeation of caffeine through the skin, as demonstrated ex vivo in human full-thickness skin [ 196 ]. In this sense, the researchers proposed the combination of the lipolytic activity of caffeine with the increased permeation capacity of propylene glycol liposomes as a noninvasive treatment for cellulitis [ 196 ]. Amasya et al. also proposed semisolid lipid nanoparticles as a promising treatment for cellulitis because they can penetrate the skin and reach the adipose tissue [ 197 ].

Flexible liposomes composed of phosphatidylcholine and higher surfactant content (polysorbate 80 and polysorbate 20) were also proposed for the treatment of alopecia by topical application [ 198 ]. The therapeutic potential of caffeine in alopecia is due to its ability to inhibit 5-α-reductase and phosphodiesterase and increase vasodilatation and blood supply to hair follicles [ 199 ]. The nanocarriers co-encapsulating minoxidil and caffeine resulted in an increase in hair length comparable to the aqueous solution of the drugs and the commercial alcoholic solution. Nevertheless, liposomes loaded with caffeine and minoxidil led to a significant increase in hair weight, an indicator of healthy and strong hair, demonstrating the potential of liposomes for the treatment of hair loss [ 198 ]. Other types of nanosystems, namely, nanoemulsions containing eucalyptol and oleic acid, have been shown to accumulate in hair follicles and increase caffeine retention in these structures, demonstrating the potential of these nanosystems for the treatment of alopecia [ 200 ]. Considering that hair follicles are nourished by blood vessels, targeted accumulation in these structures may enhance the permeation of caffeine. Therefore, these approaches can also be used to develop novel therapeutics for diseases of other tissues to avoid systemic or oral delivery.

In this sense, proniosomes have been proposed for the treatment of migraine by the topical application of caffeine. As expected, caffeine-loaded proniosomes, applied topically to Swiss albino mice, were able to penetrate the skin. Moreover, the treatment resulted in a significantly higher caffeine concentration in the blood and brain, as well as prolonged and sustained effects, compared with orally administered caffeine solution [ 188 ]. Recently, the co-delivery of caffeine and ergotamine to the brain by intranasal administration (olfactory route) has also been proposed. Hybrid lipid–polymer nanoparticles of lecithin, poly(lactic-co-glycolic acid) (PLGA), and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine functionalized with polyethylene glycol (PEGylated DPPC) showed a high encapsulation efficiency (87%) and controlled release over a period of 48 h. In addition, the results showed that the nanoparticles had high targeting accuracy in the brain without causing toxic effects. Furthermore, the synergistic effects of the drugs enhanced the anti-migraine effect [ 192 ].

The anti-cancer effect of caffeine has also been enhanced by the use of nanocarriers. Liu et al. prepared lipid-based nanosystems for the co-delivery of caffeine and imiquimod. Caffeine enhanced the therapeutic effect of the immunomodulator imiquimod and radiotherapy in an orthotopic breast cancer model. The authors suggested that this may be due to the modulation of the tumor microenvironment [ 201 ]. On the other hand, polymer-based nanocarriers, i.e., gelatin nanoparticles loaded with caffeine, showed the ability to decrease the viability and proliferative capacity of murine melanoma cells (B16F10) without causing significant cytotoxic effects in normal fibroblast cells (L929) [ 202 ]. Other studies have reported the combination of caffeine with metallic nanocarriers. For example, silver–caffeine complexes anchored to magnetic nanoparticles were proposed for the treatment of hepatocellular carcinoma [ 203 ]. This type of cancer is known to be resistant to radiotherapy and chemotherapy and can be caused by hepatitis-related infections. The most promising nanoparticles showed higher cytotoxicity against the cancer cells (hepatocellular carcinoma cells, HCC) than against the normal cells (normal hepatic cells, WRL-68). On the other hand, the targeted hyperthermia effect of the magnetic nanoparticles can improve the anti-tumor effect of the formulation and avoid the side effects of the commonly used therapeutics. In addition, these silver–caffeine magnetic nanoparticles also showed antibacterial activity against Escherichia coli , Staphylococcus aureus , and Bacillus cereus [ 203 ]. Other caffeine–metal nanoparticles have been developed for antibacterial applications. Khan et al. [ 204 ] demonstrated the ability of caffeine–gold nanoparticles to inhibit biofilm formation and eliminate mature biofilms. In addition, the nanoparticles showed antibacterial activity against resistant pathogenic bacteria ( Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , Listeria monocytogenes ), demonstrating their potential for treating chronic infections.

Overall, the different types of nanocarriers have shown the potential to improve the therapeutic effect of caffeine. Table 6 provides an overview of the recent research on the development of lipid-, polymer-, and metal-based nanocarriers loading caffeine for biomedical applications.

Overview of the latest research regarding nanocarriers loading caffeine for biomedical applications.

NLCs, nanostructured lipid carriers; AgNPs, silver nanoparticles; DPPG, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt; CTAB, cetyltrimethylammonium bromide; EGCG, (-)-epicatechin-3-gallate.

6. Conclusions

Coffee is the most consumed caffeinated beverage, while caffeine can also be found in tea, soft drinks, and energy beverages. Studies on the associations between coffee consumption and a range of health outcomes have been completed. Epidemiological studies reveal that, for the majority of people, coffee consumption is advantageous and adversely connected with risk for a number of diseases. Numerous researchers have recently conducted studies on the effects of caffeine on diseases such as cancer, cardiovascular, immunological, inflammatory, and neurological disorders, among others, as well as in sports, suggesting that this field of study is expanding quickly. To clarify the link between caffeine consumption and specific diseases and to examine consumption patterns in relation to health outcomes, randomized controlled studies are required because association does not imply causality. Because most studies have focused on adults, little is known about the negative consequences of children and adolescents consuming items with caffeine. On the other hand, several advancements in innovative DDS have been made in order to lessen the adverse effects and boost bioavailability for the treatment of various diseases. Thus, DDS have potential importance for clinical applications in several diseases, potentiating the effect of caffeine. However, the growing volume of articles, meta-analyses, and scientific evidence is not yet sufficient to confirm the quality and quantity of caffeine in the treatment of several disorders and in sports, being an avenue to explore in the future.

Funding Statement

This work was funded by the Programa Operacional Regional do Centro (CENTRO-04-3559-FSE-000162) within the European Social Fund (ESF), CICS-UBI (UIDP/00709/2020) financed by National Funds from Fundação para a Ciência e a Tecnologia (FCT), Community Funds (UIDB/00709/2020), by Fundação La Caixa and Fundação para a Ciência e Tecnologia (FCT) under the Programa Promove Project PD21-00023, and project PRR-C05-i03-I-000143 (RedFruit4Health). The authors are also grateful to the Foundation for Science and Technology (FCT), the Ministry of Science, Technology and Higher Education (MCTES), the European Social Fund (EFS), and the Europe Union (EU) for the PhD fellowships of Ana C. Gonçalves (2020.04947.BD).

Author Contributions

Conceptualization, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; methodology, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; software, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; validation, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; formal analysis, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; investigation, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; resources, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; data curation, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; writing—original draft preparation, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; writing—review and editing, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; visualization, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; supervision, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; project administration, S.M.S., T.A.J., A.C.G., D.G. and L.R.S.; funding acquisition, S.M.S., T.A.J., A.C.G., D.G. and L.R.S. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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Health Benefits of Guarana

Guarana ( Paullinia cupana ) is a plant native to the Amazon basin in South America. Guarana seeds have been consumed by indigenous communities in the Amazon region for centuries, both as an energy source and as a natural medicine for conditions such as headaches, period pain, and digestive disorders.

Best known for its stimulating properties, guarana has one of the highest caffeine contents of all plants. It contains approximately four times more caffeine than coffee beans.

Because of its energizing effects, guarana is a common ingredient in stimulant supplements and products, such as energy drinks and pre-workouts. While consuming guarana may benefit certain aspects of health, such as cognitive function and athletic performance, guarana is associated with several side effects and health concerns.

Design by Health / Getty Images

May Improve Energy and Alertness

Guarana has powerful stimulating effects, and products have been used for centuries to boost energy and alertness. Guarana contains several compounds that affect the central nervous system (brain and spinal cord) to help you feel more awake and energized.

Guarana seeds contain up to 8% caffeine by weight. Caffeine crosses the blood-brain barrier—a barrier between the blood vessels of the brain and the brain tissue that prevents harmful substances from reaching the brain. It blocks receptors for adenosine, a neurotransmitter that plays a critical role in the sleep cycle.

Adenosine increases the need for sleep by making you feel drowsy. Caffeine blocks adenosine’s ability to bind with adenosine receptors, which makes you feel less sleepy and more alert.

In addition to caffeine, guarana contains other stimulating compounds, such as catechins and tannins, which may have energy-boosting effects on the body. Studies show that guarana is more effective for increasing energy levels than caffeine alone.

Consuming guarana products like energy drinks and supplements could help you feel more awake. For example, one small 2023 study that included 25 participants found that those who ingested 125 milligrams per kilogram (mg/kg) of guarana experienced significant improvements in alertness scores compared to people who received a placebo treatment (e.g., a sugar pill).

Has Cognitive-Enhancing Properties 

Some study findings suggest that guarana supplements can improve cognitive performance . This may benefit those who need a boost before a mentally taxing task, such as a marathon study session or an important presentation. 

For example, a 2023 review of eight studies found guarana ingestion effective for improving response time during various cognitive tasks. It also didn't have any negative effects on accuracy. Though the improvement seen in this study was small, it suggests that consuming guarana may help boost your performance on time-related tasks.

Additionally, the 2023 study of 25 people mentioned above found that those who took guarana supplements experienced significant improvements in reaction times on cognitive tests before and after intense exercise .

Some research findings suggest that guarana supplements may also increase information processing, which may help you perform better at work or school.

May Boost Athletic Performance 

Guarana may be a useful supplement for athletes and those looking to improve their exercise performance. Study findings suggest that taking guarana before exercising may make your workout feel easier and increase your workout efficiency.

One small 2019 study of 10 high-level athletes found that consuming 300 mg of guarana before and during exercises reduced levels of perceived exertion and improved cognitive performance compared to a placebo.

Additionally, the researchers of the 2023 study of 25 participants suggested that guarana may be helpful for athletes involved in sports and activities that require quick responses, like soccer and hockey, as it helps improve reaction times.

How To Take Guarana 

Guarana is available in several forms, such as capsules, liquids, and powders. It’s often combined with other natural stimulants like caffeine and ginseng in products designed to boost energy and concentration.

Guarana is a popular ingredient in energy drinks, protein bars , and other food and beverage products designed to fight fatigue. It can be taken when you need a boost of energy or want to improve focus and concentration, such as when studying for an exam.

Pre-workouts containing guarana are commonly consumed by gym-goers before a workout to enhance their exercise performance and improve their reaction time and focus. Avoid taking it before bed because it can disrupt sleep and cause insomnia.

Guarana doses typically range from 37.5-222 mg, though higher doses have been used. Research studies have also used doses of guarana ranging from 75-100 mg per day for up to four weeks.

Always read product labels for dosing recommendations, as guarana is commonly combined with different ingredients.

Is Guarana Safe?

Guarana is generally considered safe when taken in recommended doses, but its use has been associated with several health concerns. For example, overuse of guarana-containing supplements and products containing guarana, like energy drinks, might negatively affect heart health and lead to irregular heartbeat, high blood pressure, and several other heart-related side effects. This is especially true for people with pre-existing cardiovascular conditions.

There have also been reports of seizures in healthy young adults who consumed energy drinks containing guarana and other ingredients.

Guarana contains caffeine, so avoid it if you're pregnant , breastfeeding, or sensitive to caffeine. Caffeine may worsen symptoms of some health conditions, such as anxiety and cardiac conditions like arrhythmia (irregular heartbeat).

Caffeine Toxicity

Guarana, which is already high in caffeine, is often combined with other stimulants. Therefore, caffeine toxicity is another risk. Caffeine toxicity can cause dangerous symptoms like seizures , vomiting, and hallucinations. It’s recommended that adults keep their caffeine intake to less than 400 milligrams per day. Although rare, you can consume a fatal dose of caffeine, which is estimated to be between 10-14 grams (g).

This is why it’s important to know how much caffeine is in guarana products, like supplements and energy drinks, and to avoid products that contain very high doses of this stimulant. 

Potential Drug Interactions

Guarana has the potential to interact with several commonly prescribed medications, including:

• Blood-thinners: Guarana may increase the effects of blood-thinning medications , such as warfarin, as it might decrease the body’s ability to clot blood. Though this potential effect hasn't been confirmed in humans, always check with your healthcare provider before supplementing with guarana if you take blood thinners.  
• Adenosine: Adenosine is a drug used to treat heart rhythm disorders. It's also sometimes used during a cardiovascular stress test . Guarana seems to block the absorption of adenosine, so it may interfere with how this drug works. Avoid all caffeine-containing products, including guarana, for at least 24 hours before undergoing a stress test.   
• Clozapine: Clozapine is an antipsychotic medication. Caffeine may increase its effects and worsen psychotic symptoms. 

Guarana may interact with other drugs, so always talk to your healthcare provider before trying it.

What To Look For

If you’re interested in taking a guarana supplement, it’s important to choose a safe supplement from a reputable company. Many supplement companies are certified by third-party organizations like UL, USP, and NSF International, which set strict standards for supplement safety and quality.

Read product labels carefully for other ingredients that might interact with medications or might not be safe for you.

Can You Take Too Much Guarana?

Guarana contains caffeine, which can lead to dangerous side effects if over-consumed. As mentioned above, it’s recommended to keep your caffeine intake to less than 400 mg per day to avoid side effects such as sleep disturbances, irregular heart rate, irritability, and insomnia .

Some guarana-containing products, like energy drinks, contain multiple servings per container, which can easily lead you to over-consume caffeine. Read ingredient labels and note how much caffeine the product contains so you can stay within a safe limit. 

Side Effects of Guarana 

Guarana can lead to many side effects, especially when consumed in high doses. Here are some of the most common:

• Stomach burning
• Vomiting 
• Restlessness
• Nervousness
• Rapid heartbeat 
• Increased urination

The potential for adverse side effects may increase if you’re taking a supplement or ingesting a product that contains multiple stimulants. 

If you experience any side effects, stop taking the product and consult your healthcare provider if the symptoms don’t resolve. 

A Quick Review

Known for its stimulating properties, guarana is a popular ingredient in products like pre-workouts and energy drinks. Some research suggests that supplementing with guarana may improve energy levels, alertness, athletic performance, and cognitive function. However, guarana is high in caffeine and can lead to adverse side effects when taken in large doses.

Guarana isn’t safe for everyone and has the potential to interact with common medications. It can also worsen symptoms of several health conditions. Always consult your healthcare provider before trying it.

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Gurney T, Bradley N, Izquierdo D, Ronca F. Cognitive effects of guarana supplementation with maximal intensity cycling . Br J Nutr . 130(2):253-260. doi:10.1017/S0007114522002859 

Hack B, Penna EM, Talik T, Chandrashekhar R, Millard-Stafford M. Effect of guarana (Paullinia cupana) on cognitive performance: A systematic review and meta-analysis . Nutrients . 2023;15(2):434. doi:10.3390/nu15020434 

Pomportes L, Brisswalter J, Hays A, Davranche K. Effects of carbohydrate, caffeine, and guarana on cognitive performance, perceived exertion, and shooting performance in high-level athletes . Int J Sports Physiol Perform . 2019;14(5):576-582. doi:10.1123/ijspp.2017-0865

NatMed. Guarana . In: NatMed . NatMed; 2023.

Wassef B, Kohansieh M, Makaryus AN. Effects of energy drinks on the cardiovascular system . World J Cardiol . 2017;9(11):796-806. doi:10.4330/wjc.v9.i11.796 

Costantino A, Maiese A, Lazzari J, et al. The dark side of energy drinks: A comprehensive review of their impact on the human body .  Nutrients . 2023;15(18). doi:10.3390/nu15183922

Rodak K, Kokot I, Kratz EM. Caffeine as a factor influencing the functioning of the human body—Friend or foe? Nutrients . 2021;13(9):3088. doi:10.3390/nu13093088

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