The health effects of caffeine have been extensively studied. Short term side effects such as headache, nausea, and anxiety have been shown as symptoms of mild caffeine consumption.[1] The long term effects of moderate caffeine consumption can be a reduced risk of developing Parkinson's disease, type 2 diabetes, hepatic diseases, and cardiovascular disease.[2][3][4] Caffeine competitively inhibits different adenosine receptors and their associated G protein to make a person feel alert.[5] A mild stimulant of the central nervous system, caffeine also stimulates cardiac muscle, relaxes smooth muscle, increases gastric secretions, and produces diuresis.[6]
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In these studies, the greatest benefits were observed in those who drank coffee for a long period in their lifetime.
Caffeine is a methylxanthine and methylxanthines are known to have anti-inflammatory properties.[15] This is due to the similarity in molecular structure to the nucleotide adenosine. Methylxanthines or sometimes known as xanthines have a heterocyclic ring with nitrogen included in the ring structure; they are derived from amino acids, are basic in nature, and can generally form water soluble salts. Caffeine blocks the action of adenosine by acting as a competitive inhibitor for the A1 and A2a adenosine receptor.[16] With the initial absorption of caffeine occurring within 15 minutes the peak time of caffeine absorption is estimated at 45 minutes.[17] Although varying in many studies the half-life of caffeine has been found to be around 5.2-6.8 hours for adults.[18] However, the metabolic rate of caffeine absorption differs between each species.[17]
| Poisoning by caffeine | |
|---|---|
| Classification and external resources | |
| ICD-10 | F15, T43.6 |
| ICD-9 | 305.90, 969.71 |
| eMedicine | article/821863 |
Caffeine toxicity can present as a spectrum of clinical symptoms. Most of these originate in the central nervous and circulatory systems and can follow ingestion of 1g or more of caffeine. Insomnia, breathlessness and excitement progressing to mild delirium may be seen. Sensory disturbances, diuresis, tachycardia, extrasystoles, and elevated respirations as well as vomiting induced by potent gastric irritation can be present. Fatalities of caffeine poisoning are rare because the gastric irritation and vomiting develop before absorption of toxic amounts can occur. Normally, caffeine is rapidly and completely absorbed from the gastrointestinal tract with distribution in various tissues in approximate proportion to their water content. Convulsions result from the central stimulating effect with death caused by respiratory failure. Hyperglycemia and ketonuria associated with caffeine toxicity have been reported. These latter findings may be attributed to a stress reaction or the xanthine’s ability to mimic the metabolic effects of the cathecholamines including lipolysis, glycogenolysis and gluconeogenesis.[19] An acute overdose of caffeine usually in excess of about 300 milligrams, dependent on body weight and level of caffeine tolerance, can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90),[20] or colloquially the "caffeine jitters". The median lethal dose (LD50) given orally, is 192 milligrams per kilogram in rats.[19] The LD50 of caffeine in humans is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adult taken within a limited time frame that is dependent on half-life. For additional information see: Caffeine.
The predominate mechanism of action of caffeine is the antagonism of adenosine receptors. Adenosine is a locally released purine hormone that acts on different receptors (A1 and A2) that can increase or decrease cellular concentrations of cyclic AMP (cAMP). Adenosine inhibits adenyl cyclise via high affinity (A1) receptors and stimulates adenyl cyclise via low affinity (A2) receptors. Adenosine receptors are found throughout the body including the brain, in the cardiovascular, respiratory, renal and gastrointestinal system and in adipose tissue. Caffeine nonselectively blocks both adenosine receptors and competitively inhibits the actions of adenosine. Adenosine acts presynaptically to inhibit neuronal release of acetylcholine, norepinephrine, dopamine, gamma amino butyric acid and serotonin. Adenosine also reduces spontaneous firing of neurons in many regions of the brain which produces sedation and has anticonvulsant activity. Caffeine releases norepinephrine, dopamine and serotonin in the brain and increases circulating catecholamines consistent with reversal of the inhibitory effects of adenosine on these systems.[21]
Caffeine and other methylxanthine derivatives are also used on newborns to treat apnea and correct irregular heartbeats. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses.[22] Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below:[23]
Caffeine increases cardiac arrhythmia (improper heart rate) by increasing stress hormone (e.g.adrenaline) secretions.[24] It has been shown there is an increase in brachial diastolic blood pressure, but not in brachial systolic blood pressure.[24] However, both aortic systolic and diastolic blood pressures increase significantly during caffeine consumption. It has been noted that long term consumption leads to increasing aortic systolic pressure which leads to chronic arterial stiffness.[25] The results of increasing blood pressure mostly contributes to blockage of Adenosine A1 and A2 receptors.[26] Since caffeine blocks adenosine A2 receptors which has vasodilatory function, blood vessels become less dilated.(i.e. vasoconstriction)[27] However, it is controversial whether caffeine consumption increases heart rate. Some research shows that caffeine has no influence on heart rate.[25][27] It is hard to say how much dosage will cause increasing heart rate as no studies have shown significant data. Different people have different tolerance for caffeine based on individual metabolic activity, so there is no clear distinction between caffeine consumption and the amount heart rate increases.
Caffeine can stimulate the secretion of stress hormones (such as epinephrine and norepinephrine), which can increase blood pressure. Moreover, stress hormones activate the body's "fight or flight" reactions, causing the body to redirect blood supply from the digestive system to muscles. In this way, decreased blood flow to the gastrointestinal tract will slow down the absorption rate and lead to indigestion.[28] Moreover, the additional epinephrine increases the secretion of the main gastric hormone gastrin, which will speed up gastric peristalsis and hypersecretion of gastric juice.[29][30] Additional gastric acid will lead to acidic chyme going into the small intestine and cause intestinal injury.[28] Therefore, it is not recommended for ulcer patients to drink too much coffee.
Caffeine intake increases renal excretion of sodium and water. This is caused by both slightly increasing the glomerular filteration rate and inhibiting the tubular reabsorption of sodium and water. Although the ability for caffeine and theophylline to induce diuresis and natriuresis is well established, the mechanisms behind them are not well understood.[31] It has been suggested that inhibition of phosphodiesterases in the proximal tubule may contribute to the diuretic and natriuretic effects of methylxanthines. It has been noted that mice lacking the A1 receptor do not exhibit the diuresis and natriuresis typically elicited by the application of the methylxanthines caffeine or theophylline.[32]
Caffeine injections before exercise show no evidence of adverse effects such as dehydration or ion imbalance, and have no effect on short term exercise.[33] However, studies show that 5 mg/kg body weight of caffeine intake allows free fatty acids to mobilize faster, which in turn enhances the endurance performance during long term exercise. This only effects individuals who do not drink caffeine on regular basis.[33] This means that if a 60 kg non-regular caffeine ingesting adult consumes 300 mg of caffeine, which is equivalent to 3 cups of regular coffee, before exercising, he will be able to exercise at the same intensity for a longer period of time.[33] As a side note, the International Olympic Committee since the summer of 2000, no longer treats caffeine as a banned substance.[33]
Ingesting single doses of 300 mg of caffeine, which is many times greater than the amount contained in an average caffeine containing beverage, can increase one’s anxiety level. Anxiety or panic attacks, caused by ingesting excessive amounts of caffeine is seen more often in consumers with panic disorders. However, panic attacks are most often misdiagnosed with caffeinism, which is virtually indistinguishable from severe chronic anxiety. Caffeinism is a condition caused by ingesting a great amount of caffeine that shows a constellation of symptoms including insomnia, restlessness, excitement, dieresis, and tremors. When examining whether caffeine consumption leads to anxiety and mood changes, it is important to assess the participator’s level of anxiety. It has been claimed that people tend to drink caffeine containing beverages more frequently when they feel nervous, jittery or anxious. In 1986, Shanahan and Huges did a study on whether other stressors are capable of influencing anxiety increased by caffeine intake. Results show that in a healthy individual, consuming 400 mg or more caffeine while performing a stressful task results in increasing anxiety. Generally speaking, increasing levels of anxiousness after caffeine intake are mostly found in consumers who have consumed an amount that would not normally be consumed by majority of consumers. Lower doses of caffeine intake have little effect on consumers’ state. In fact, small amount of caffeine consumption may reduce one’s anxiety level.[10]
Higher caffeine consumption leads to tremors and impairs hand steadiness in some individuals.
Research has shown links between heavy caffeine consumption and osteoporosis, high blood pressure, heart disease, heart burn, ulcers, severe insomnia and infertility.[34]
The relationship between caffeine and diabetes mellitus has been a controversial topic among scientists.
Caffeine consumption has been associated with a lower risk of diabetes mellitus type 2. The majority of the studies on this topic were done on coffee. Test results indicate that consumers who drink at least three or more cups of either caffeinated or decaffeinated coffee every day show a decrease in the risk of type II diabetes. In Japan, a recent study was done to examine the relationship between consumption of green, black, and oolong teas and the risk of diabetes; and it was found that caffeine containing beverages were associated with a decreased risk of type II diabetes.[35] The mechanism responsible for this inverse relationship between caffeine containing beverage and the risk of diabetes includes basal energy expenditure, fat oxidation stimulation, glycogen mobilization in muscles, and stimulation of increased lipolysis from peripheral tissues.[35] Unfortunately, tolerance of caffeine can develop. Certain antioxidant substances in these beverages also play roles in decreasing risks of diabetes. For example, epigallocatechin gallate, present in green tea, helps by acting on insulin resistance and glucose metabolism.[35]
Although caffeine has been associated with a lowered risk of developing type 2 diabetes, it has also been claimed to have negative effects on diabetes patients, because caffeine is capable of reducing insulin sensitivity and makes it difficult for patients with diabetes to control their blood glucose levels. Studies have shown that caffeine consumption increases blood glucose, but diabetes medication pills decrease blood glucose levels showing that the two counter-interact.[36] Diabetes patients have trouble controlling their sugar level in their blood due to lack of insulin resistance hormone.[36] Alloxan is a chemical that damages insulin-producing cells and creates conditions for diabetes.[36] Once in the human body, caffeine produces alloxan and either produces diabetes' conditions or worsens the existing diabetes.[36]
Parkinson's disease (PD) is the degeneration of dopamine producing neurons.[37] Dopamine producing neurons stimulate the motor cortex effecting motor control.[37] Loss of dopamine produces loss of motor control skills, cognitive function, and autonomic nervous system.[37] Epidemiological studies have shown that the risk of developing PD decreases with increasing levels of caffeine intake.[37] Caffeine binds to the adenosine receptor (A2aR) and indirectly prevents MPTP (an experimental neurotoxin known to cause PD) from destroying dopamine producing neural cells thus preventing neural degeneration and loss of motor control.[37]
Research has shown there is a strong negative correlation to caffeine consumption and liver cirrhosis. However, there is a lack of evidence for other beverages that contain caffeine.[38] It has been difficult to prove the exact cause for caffeine and its interaction with reducing the risk of liver cirrhosis. In addition, there is other research that shows caffeine to have suppressive effects of Tumor necrosis factor-alpha (TNF-α) induced hepatitis but yet has no effect on Anti-Fas induced hepatitis.[4] Since TNF-α is secreted by macrophages in response of lipopolysaccharide (LPS), and it functions as a apoptoic factors,[39] there are two ways that caffeine could suppress the hepatitis (e.g. by suppressing the TNF-α production and suppress the TNF-α induced apoptosis).[4] However, the specific mechanism is not clear.
Caffeine is suspected to increase the risks in cancer, because it leads to the fluctuation of plasma sex hormones and sex hormone-binding globulin (SHBG) in women. Circulating estrogens and androgens are important factors in female cancer development.[40] Recent studies show that in premenopausal women, there’s an inverse relationship between caffeine intake and total luteal and estradiol levels in the second half of the menstrual cycle, and also has a positive association with progesterone levels.[41] Theoretically speaking, lower estrogen levels helps protect against ovarian cancer, but more research needs to be done on this topic.[41] For postmenopausal women, increased caffeine consumption is associated with a higher level of sex hormone-binding globulin (SHBG), which reduces the estradiol and testosterone activity and decreases the risk of breast cancer.[41]
Research has shown that there is no significant association between caffeine consumption and cancers of the mouth, pharynx, esophageal, stomach, liver, or pancreas.[42] In addition, caffeine also decreases the risk of rectalcolon cancers. A possible explanation is that caffeine interferes with bile secretion, reducing bile acid, and thus leaving neutral sterol concentration in the bowel.[42] Another possible explanation is that caffeine may inhibit some chemical carcinogens such as 4-nitroquinoline-1-oxide;[43] however, this is hard to evaluate because other research shows that caffeine can have promotive effects on carcinogenesis.[44]
| Caffeine withdrawal | |
|---|---|
| Classification and external resources | |
| ICD-10 | F15.1 |
| ICD-9 | 292.0 |
Caffeine addiction leads to some levels of physical dependence. The most frequently seen withdrawal symptoms are headache and fatigue. Such symptoms affect consumers’ mood, but show no evidence of influencing ones’ performance. In prolonged caffeine drinkers, symptoms such as increased depression and anxiety, nausea, vomiting and intense desire for caffeine containing beverages are also reported. Withdrawal symptoms begin after 12–24 hours and peaks at 20–48 hours after abstinence from caffeine. The symptoms reflect consumers’ expectancy effects on caffeine to some degree.[10]
One patient reported: I had symptoms such as the flue, slept day and night for several days. After that, I felt as walking in a fog, far away from life, and had difficulty doing anything. After about three months, the withdrawal symptoms had almost completely declined.[45]
Studies with placebo conditions have been done to demonstrate that the effects of caffeine depend greatly on the consumer’s expectations.[10] When heavy caffeine drinkers are led to believe that they are consuming beverages that contain caffeine, they tend to perform better regardless of the caffeine content within the sample that was given to them.
Gene polymorphism could be associated with caffeine withdrawal symptoms and beta 1and beta-2 play roles in caffeine withdrawal.[46] For example, compared to people with homozygous Gly16 allele, consumers with the heterozygote ADR beta-2 Gly16 Arg gene polymorphism have a higher chance of feeling fatigue after 48 hours of caffeine withdrawal.[46] It has been suspected that beta2- adrenoceptors are the main cause to this increase in mental fatigue symptom.[46] Beta 2- adrenoceptors are receptors that regulate glycogenolysis, secret insulin and intramuscularly transport glucose that are used for cerebral and muscle activity.[46] Another example is given by the genes ADRbeta1 Gly16 Arg and CYP1A2-163A>C polymorphisms.[46] They are associated with the consumers’ mood swing and increased depression level.[46] Among subjects homozygous for the CYP1A2 allele, ADRbeta1 Gly389 allele carriers are reported to have a higher percentage of depression level increase when compared to Arg389 homozygotes subjects.[46] Adrenergic receptors, again, play a key role in this symptom, as altered norepinephrine neurotransmission, an adrenoceptor agonist, contribute to the etiology of depression.[46] This symptom is often seen in faster caffeine metabolizers, because caffeine effects diminish quicker in these consumers and provide them less opportunity to adapt to caffeine loss.[46]
Health Canada has not developed definitive advice for adolescents 13 and older because of insufficient data. Nonetheless, Health Canada suggests that daily caffeine intake for this age group be no more than 2.5 mg/kg body weight. This is because the maximum adult caffeine dose may not be appropriate for light weight adolescents or for younger adolescents who are still growing. The daily dose of 2.5 mg/kg body weight would not cause adverse health effects in the majority of adolescent caffeine consumers. This is a conservative suggestion since older and heavier weight adolescents may be able to consume adult doses of caffeine without suffering adverse effects. For the rest of the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg.[47]
According to the US-based Waverly Health Center, three 8 oz cups of coffee (about 250 milligrams of caffeine) per day is considered an average or moderate amount of caffeine; ten 8 oz cups of coffee per day is considered an excessive intake of caffeine.[48]
Caffeine's potential impact on female fertility, and its precise impact on pregnancy, is still being studied, but caution and moderation, as with many other substances in these cases, is warranted in any case until further information is known. For women of childbearing age, Health Canada recommends a maximum daily caffeine intake of no more than 300 mg, or a little over two 8 oz (237 mL) cups of coffee.[47]
For children age 12 and under, Health Canada recommends a maximum daily caffeine intake of no more than 2.5 milligrams per kilogram of body weight. Based on average body weights of children, this translates to the following age-based intake limits:[47]
| Age range | Maximum recommended daily caffeine intake |
|---|---|
| 4-6 | 45 mg |
| 7-9 | 62.5 mg |
| 10-12 | 85 mg |
Relatedly, one study found that caffeine can be used to treat hyperkinetic children.[49] The research showed 200–300 mg of caffeine has a similar effect to methylphenidate in treating hyperkinetic impulse disorder. Moreover, the caffeine treatment did not show the side-effects caused by methylphenidate.[50]
According to DSST, alcohol provides a reduction in performance and caffeine has a significant improvement in performance.[51] When alcohol and caffeine are consumed jointly, the effects produced by caffeine are affected, but the alcohol effects remain the same.[52] For example, when additional caffeine is added, the drug effect produced by alcohol is not reduced.[52] However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed.[52] Alcohol consumption alone reduces both inhibitory and activational aspects of behavioural control. Caffeine antagonizes the activational aspect of behavioural control, but has no effect on the inhibitory behavioural control.[53]
Consumption of caffeine while orally administering birth control can extend the half-life of caffeine; therefore, greater attention should be taken during caffeine consumption.[21]
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