Coffee and tea are among the most popular beverages worldwide and contain substantial amounts of caffeine, making caffeine the most consumed psychoactive agent. A variety of plants contain caffeine in their seeds, fruits and leaves. In addition to coffee and tea, these plants include cocoa beans (an ingredient in chocolate), yerba mate leaves, and guarana berries (used in various beverages and supplements).
Caffeine can also be synthesized and is added to foods and beverages, including soft drinks, energy drinks, and tablets marketed to reduce fatigue. Additionally, caffeine is widely used as a treatment for apnea of prematurity in infants and caffeine and analgesic agents are used together in pain medications.
Coffee and tea have been consumed for hundreds of years and have become an important part of cultural traditions and social life. Additionally, people use caffeinated beverages to increase wakefulness and work productivity.
For a typical serving, caffeine content is highest in coffee, energy drinks, and caffeine tablets; intermediate in tea; and the lowest in soft drinks.
In the United States, 85% of adults consume caffeine daily, and the average caffeine consumption is 135 mg per day, which is equivalent to approximately 1.5 standard cups of coffee (with a standard cup defined as 235 ml). Coffee is the predominant source of caffeine ingested by adults, while soft drinks and tea are more important sources of caffeine ingested by adolescents.
There has long been concern that coffee and caffeine may increase the risks of cancer and cardiovascular disease, but more recently, evidence of health benefits has also emerged.
A key issue in research on caffeine and coffee is that coffee contains hundreds of other biologically active phytochemicals, including polyphenols such as chlorogenic acid and lignans, the alkaloid trigonelline, melanoidins formed during roasting, and modest amounts of magnesium. , potassium and vitamin B 3 (niacin).
These coffee compounds can reduce oxidative stress, improve the gut microbiome, and modulate glucose and fat metabolism. In contrast, the diterpene cafestol , which is present in unfiltered coffee, increases serum cholesterol levels. Therefore, research results for coffee and other dietary sources of caffeine should be interpreted with caution, as the effects may not be due to caffeine itself.
Metabolism, physiological effects and toxic effects
> Absorption and metabolism
Chemically, caffeine is a methylxanthine (1,3,7-trimethylxanthine). Caffeine absorption is almost complete within 45 minutes after ingestion, with peak blood caffeine levels occurring between 15 minutes and 2 hours after ingestion. Caffeine spreads throughout the body and crosses the blood-brain barrier.
In the liver, caffeine is metabolized by cytochrome P-450 (CYP) enzymes, particularly CYP1A2. Caffeine metabolites include paraxanthine and, in small amounts, theophylline and theobromine, which are then metabolized to uric acid and ultimately excreted in the urine.
The half-life of caffeine in adults is typically 2.5 to 4.5 hours, but is subject to large variations from person to person. Newborns have a limited ability to metabolize caffeine, and the half-life is approximately 80 hours. After 5 to 6 months of age, the capacity for caffeine metabolism per kilogram of body weight does not change much with age.
Smoking greatly accelerates the metabolism of caffeine, reducing the half-life by up to 50%, while the use of oral contraceptives doubles the half-life of caffeine. Pregnancy greatly reduces caffeine metabolism, especially in the third trimester, when the half-life of caffeine can be up to 15 hours.
The activity of caffeine-metabolizing enzymes is partly inherited. For example, a variant in the gene encoding CYP1A2 is associated with higher plasma caffeine levels and a lower paraxanthine-to-caffeine ratio (reflecting slower caffeine metabolism), as well as lower caffeine intake.
People with a slower caffeine metabolism tend to compensate with lower caffeine consumption than people without this genetic predisposition. Additionally, some classes of drugs (including various quinolones, cardiovascular drugs, bronchodilators, and antidepressants) can delay the clearance of caffeine and increase its half-life, generally because they are metabolized by the same liver enzymes. Similarly, caffeine can affect the action of several medications, and doctors should consider possible interactions between caffeine and medications when prescribing the latter.
> Beneficial effects on cognitive performance and pain
Adenosine in the brain inhibits arousal and increases drowsiness.
The molecular structure of caffeine is similar to that of adenosine , which allows caffeine to bind to adenosine receptors, block adenosine, and inhibit its effects.
In moderate doses (40 to 300 mg), caffeine can antagonize the effects of adenosine and reduce fatigue, increase alertness, and reduce reaction time. These effects of caffeine have also been observed in people who do not regularly consume caffeine and after brief periods of abstinence in regular users.
Caffeine intake may also improve alertness during long-duration tasks that provide limited stimulation, such as working on an assembly line, driving long distances, and flying airplanes. Although these mental benefits are more pronounced during sleep deprivation, caffeine cannot offset the decline in performance after long-term sleep deprivation. Caffeine may contribute to pain relief when added to commonly used pain relievers.
> Effects on sleep, anxiety and hydration and withdrawal symptoms
As expected from its effects on fatigue, caffeine consumption later in the day may increase sleep latency and reduce sleep quality.
Additionally, caffeine can induce anxiety, particularly at high doses (>200 mg per occasion or >400 mg per day) and in sensitive individuals, including those with anxiety or bipolar disorders. Interpersonal differences in the effects of caffeine on sleep and anxiety are large.
These differences may reflect variation in the rate of caffeine metabolism and variants in the adenosine receptor gene. Caffeine consumers and physicians should be aware of these possible side effects of caffeine, and people who drink caffeinated beverages should be advised to reduce caffeine intake or avoid it later in the day if these occur. effects.
High caffeine intake may stimulate urine production , but no detrimental effects on hydration status have been found with long-term intake of moderate doses of caffeine (≤400 mg per day).
Stopping caffeine after regular consumption can cause withdrawal symptoms , including headaches, fatigue, decreased alertness, and depression, as well as flu-like symptoms in some cases. These symptoms typically peak 1 to 2 days after cessation of caffeine intake, with a total duration of 2 to 9 days, and can be reduced by gradually decreasing the caffeine dose.
> Toxic effects
Side effects of caffeine at very high levels of intake include anxiety, restlessness, nervousness, dysphoria, insomnia, excitement, psychomotor agitation, and a rambling flow of thought and speech.
Toxic effects are estimated to occur with intakes of 1.2 g or more, and a dose of 10 to 14 g is thought to be fatal.
A recent review of blood caffeine levels in fatal overdose cases showed that the mean postmortem blood caffeine level was 180 mg per liter, corresponding to an estimated intake of 8.8 g of caffeine.
Caffeine poisoning from consuming traditional caffeine sources such as coffee and tea is rare because a large amount (75 to 100 standard cups of coffee) would have to be consumed in a short time for the dose to be fatal. Caffeine-related deaths have generally been due to very high doses of caffeine in tablets or supplements, primarily in athletes or patients with psychiatric disorders.
In case reports, high consumption of energy drinks and shots , especially when mixed with alcohol , has also been linked to adverse cardiovascular, psychological, and neurological events, including fatal events.
Caffeine in the form of energy drinks and shots may have more adverse effects than other caffeinated beverages for several reasons: high episodic consumption of these forms of caffeine, which does not allow the development of caffeine tolerance; popularity among children and adolescents, who may be more vulnerable to the effects of caffeine; lack of consumer awareness of caffeine content; possible synergistic effects with other components of energy drinks; and combination with alcohol consumption or vigorous exertion.
High consumption of energy drinks (approximately 1 liter, containing 320 mg of caffeine) produced short-term adverse cardiovascular effects (increased blood pressure, prolonged QTc interval, and palpitations). For this reason, people who consume energy drinks should be advised to check the caffeine content and avoid high consumption (>200 mg of caffeine per occasion) or consumption in combination with alcohol .
Coffee, caffeine and the risk of chronic diseases
> Methodological considerations
Studies on caffeine intake and health outcomes may have several potential limitations.
- First, observations of the acute effects of caffeine may not reflect long-term effects because tolerance to the effects of caffeine can develop.
- Second, epidemiological studies on caffeine intake and chronic disease risk are potentially confounded by smoking or other unfavorable lifestyle factors, and early studies that did not adequately account for this bias led to poor results. misleading.
- Third, measurement error may affect the assessment of caffeine consumption. However, self-reports of coffee drinking frequency are generally very accurate and reproducible. Variation in cup size, coffee concentration, type of coffee bean, and amounts of sugar and milk or cream added to coffee are generally not captured in epidemiological studies of coffee consumption, resulting in a exposure misclassification. However, within many populations, the variation in cup size and brewing strength is likely to be modest compared to the large variation in frequency of consumption.
- Finally, in prospective studies on caffeine intake, coffee and tea have been the predominant sources of caffeine. It is unclear whether the results seen with these caffeinated beverages also apply to other sources of caffeine.
> Blood pressure, blood lipids and cardiovascular diseases
In people who have not previously consumed caffeine, caffeine intake increases epinephrine levels and blood pressure in the short term. Tolerance to the effect develops within a week, but may be incomplete in some people. In fact, meta-analyses of longer trials indicate that ingesting caffeine alone (i.e., pure caffeine, not in the form of coffee or other beverages) produces a modest increase in systolic and diastolic blood pressure.
| However, no substantial effect on blood pressure was found in trials of caffeinated coffee, even among people with hypertension, possibly because other components of coffee, such as chlorogenic acid, counteract the effect of caffeine. Similarly, in prospective cohort studies, coffee consumption was not associated with an increased risk of hypertension. |
The concentration of the cholesterol-raising compound cafestol is high in unfiltered coffee, such as French press and boiled Turkish or Scandinavian coffee, intermediate in espresso, and negligible in drip-filtered and instant coffee.
In randomized trials, high consumption of unfiltered coffee (median, 6 cups per day) increased low-density lipoprotein cholesterol levels by 17.8 mg per deciliter (0.46 mmol per liter), compared with coffee filtered, predicting an estimated 11% increased risk of major cardiovascular events.
In contrast, filtered coffee did not increase serum cholesterol levels. Therefore, limiting consumption of unfiltered coffee and moderate consumption of espresso-based coffee may help control serum cholesterol levels.
Experimental studies in humans and cohort studies do not show an association between caffeine intake and atrial fibrillation.
Many prospective studies have examined coffee and caffeine consumption in relation to risks of coronary heart disease and stroke. The results consistently indicate that consumption of up to 6 standard cups of filtered caffeinated coffee per day, compared with no coffee consumption, is not associated with an increased risk of these cardiovascular outcomes in the general population or among people with a history of hypertension, diabetes or cardiovascular diseases.
In fact, coffee consumption was associated with a lower risk of cardiovascular disease , with lower risk in the 3 to 5 cups per day group. An inverse association has been observed between coffee consumption and coronary artery disease, stroke, and death from cardiovascular causes.
> Weight control, insulin resistance and type 2 diabetes
Metabolic studies suggest that caffeine may improve energy balance by reducing appetite and increasing basal metabolic rate and food-induced thermogenesis, possibly through stimulation of the sympathetic nervous system and uncoupling by protein 1 in tissue. brown adipose (UCP1).
Repeated caffeine intake throughout the day (6 doses of 100 mg caffeine) led to a 5% increase in 24-hour energy expenditure. Increases in caffeine intake were associated with slightly less long-term weight gain in cohort studies. Limited evidence from randomized trials also supports a modest beneficial effect of caffeine intake on body weight. However, caffeinated beverages that are high in calories, such as soda and energy drinks and coffee or tea with added sugar, can cause excessive weight gain.
Caffeine intake reduces short-term insulin sensitivity , as assessed with euglycemic clamp (e.g., a 15% reduction after a dose of 3 mg per kilogram of body weight). This may reflect an inhibitory effect of caffeine on the storage of glucose as glycogen in muscle and may be in part the result of increased release of epinephrine.
However, drinking coffee (4 to 5 cups per day) for up to 6 months does not affect insulin resistance.
Furthermore, consumption of caffeinated and decaffeinated coffee reduces hepatic insulin resistance induced by fructose overfeeding.
Additionally, regular coffee consumption has been consistently associated with a reduced risk of type 2 diabetes , with similar associations for caffeinated and decaffeinated coffee.
Taken together, these findings suggest that tolerance develops to the adverse effect of caffeine on insulin sensitivity or that the adverse effect is offset by the long-term beneficial effects of other coffee components on glucose metabolism, possibly in the liver.
> Cancer and liver diseases
The results of many prospective cohort studies provide strong evidence that coffee and caffeine consumption are not associated with a higher incidence of cancer or a higher rate of cancer death.
Coffee consumption is associated with a slightly lower risk of melanoma, non-melanoma skin cancer, breast cancer, and prostate cancer. Stronger inverse associations have been observed between coffee consumption and the risk of endometrial cancer and hepatocellular carcinoma.
For endometrial cancer, the associations are similar with caffeinated and decaffeinated coffee, while for hepatocellular carcinoma, the association appears to be stronger with caffeinated coffee.
Coffee has also been consistently associated with other aspects of liver health, including lower levels of enzymes that reflect liver damage and a lower risk of liver fibrosis and cirrhosis. Caffeine may prevent liver fibrosis through adenosine receptor antagonism because adenosine promotes tissue remodeling, including collagen production and fibrinogenesis.
In line with this observation, caffeine metabolites reduce collagen deposition in liver cells, caffeine inhibits hepatocarcinogenesis in animal models, and a randomized trial showed that consumption of caffeinated coffee reduces collagen levels in the liver in patients with hepatitis C. Additionally, coffee polyphenols may provide protection against hepatic steatosis and fibrogenesis by improving fat homeostasis and reducing oxidative stress.
> Lithiasis
Coffee consumption has been associated with a lower risk of gallstones and gallbladder cancer, with a stronger association for caffeinated coffee than for decaffeinated coffee, suggesting that caffeine may play a protective role.
Coffee consumption can prevent cholesterol gallstone formation by inhibiting the absorption of gallbladder fluid, increasing the secretion of cholecystokinin, and stimulating gallbladder contraction. In US cohorts, consumption of caffeinated and decaffeinated coffee was associated with a reduced risk of kidney stones.
> Neurological diseases
Prospective cohort studies in the United States, Europe, and Asia have demonstrated a strong inverse association between caffeine intake and risk of Parkinson’s disease. Furthermore, caffeine prevents Parkinson’s disease in animal models, possibly by inhibiting nigrostriatal dopaminergic neurotoxic effects and neurodegeneration through adenosine A 2A receptor antagonism .
Coffee and caffeine consumption have also been associated with lower risks of depression and suicide, although these findings may not hold for people with very high intakes (≥ 8 cups per day). Coffee consumption has not been associated with the risk of dementia or Alzheimer’s disease.
> Mortality from any cause
Consumption of 2 to 5 standard cups of coffee per day has been associated with reduced mortality in cohort studies worldwide and in people of European, African American, and Asian ancestry. With consumption of more than 5 cups of coffee per day, the risk of death was lower than or similar to the risk without coffee consumption in large cohort studies, after adjustment for confounding by smoking.
Coffee and decaffeinated coffee consumption were similarly associated with a lower risk of death from any cause. In line with this observation, the inverse association between coffee consumption and all-cause mortality did not differ depending on whether caffeine metabolism was fast or slow.
Effects of caffeine intake during pregnancy
In prospective studies, higher caffeine intake has been associated with lower birth weight and increased risk of pregnancy loss. Caffeine passes easily into the placenta, and slow caffeine metabolism in the mother and fetus can result in high levels of circulating caffeine.
Caffeine may induce vasoconstriction or placental hypoxia by increasing the levels of catecholamines in the blood of the mother and fetus. Associations with low birth weight have been observed for both coffee and tea (in a predominantly tea-drinking population) and showed a dose-response relationship, with no clear threshold. In contrast, the association between caffeine and pregnancy loss was not significant at lower levels of intake and may have been affected by publication bias.
Additionally, prepregnancy coffee consumption, an indicator of caffeine intake during pregnancy that is not confounded by nausea, has been associated with an increased risk of miscarriage. Although the evidence for the adverse effects of caffeine on fetal health is inconclusive, prudence suggests limiting caffeine consumption during pregnancy to a maximum of 200 mg per day.
Conclusions A large body of evidence suggests that coffee consumption, the leading source of caffeine intake in adults in the United States, does not increase the risk of cardiovascular disease and cancer. In fact, consuming 3 to 5 standard cups of coffee per day has been associated with a lower risk of several chronic diseases. However, high caffeine intake can have several adverse effects, and limits of 400 mg of caffeine per day have been recommended for adults who (except pregnant) or lactating women and 200 mg per day for pregnant and lactating women. A large majority of adults in the United States adhere to these guidelines, but due to person-to-person variation in metabolism and sensitivity to caffeine, a lower or slightly higher amount may be appropriate in individual cases. Current evidence does not guarantee caffeine or coffee intake for disease prevention, but suggests that moderate coffee or tea consumption may be part of a healthy lifestyle. |
