Health effects of caffeine
||It has been suggested that this article be merged into Caffeine. (Discuss) Proposed since October 2011.|
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. 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. Caffeine competitively inhibits different adenosine receptors and their associated G protein to make a person feel alert. A mild stimulant of the central nervous system, caffeine also stimulates cardiac muscle, relaxes smooth muscle, increases gastric secretions, and produces diuresis.
- High long-term consumption is associated with a lower risk of cardiovascular disease and diabetes.
- Research is beginning to suggest that caffeine minimizes the cognitive decline associated with aging,  including reducing risk of Alzheimer's disease.
- Caffeine increases levels of neurotransmitters such as norepinephrine, acetylcholine, dopamine, serotonin, epinephrine and glutamate.
- Acetylcholine is associated with attention, concentration, learning, and memory but there is no conclusive evidence yet that caffeine has any effect on memory and cognitive function.
- Low doses of caffeine show increased alertness and decreased fatigue.
- Caffeine has been shown to increase the metabolic rate.
- Caffeine may reduce the risk of developing cancer and produce a delay in the average onset of cancer.
- Caffeine is associated with a reduced risk of Parkinson's disease, and use of caffeine is studied as a treatment for the Parkinson’s disease motor symptoms.
- Caffeine may lower the risk of developing type 2 diabetes.
- Caffeine may reduce certain kind of hepatic cancers.
- Caffeine may be a source of healthful antioxidant activity against some free radicals inside the body.
In these studies, the greatest benefits were observed in those who drank coffee for a long period in their lifetime.
- Caffeine can increase blood pressure in non-habitual consumers. High blood pressure is associated with an increase in strokes, and cerebral vascular disease, which in turn increase the risk of multi-infarct dementia.
- Caffeine may reduce control of fine motor movements (e.g., producing shaky hands)
- Caffeine can stimulate urination.
- Caffeine can increase cortisol secretion, some tolerance is developed.
- Caffeine can contribute to increased insomnia and sleep latency.
- Caffeine is addictive. Caffeine withdrawal can produce headache, fatigue and decreased alertness.
- High doses of caffeine (300 mg or higher) can cause anxiety.
- High caffeine consumption has been linked to an increase in the likelihood of experiencing auditory hallucinations.
- High caffeine consumption accelerates bone loss at the spine in elderly postmenopausal women.
Caffeine is a methylxanthine and methylxanthines are known to have anti-inflammatory properties. 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. With the initial absorption of caffeine occurring within 15 minutes the peak time of caffeine absorption is estimated at 45 minutes. Although varying in many studies the half-life of caffeine has been found to be around 5.2-6.8 hours for adults. However, the metabolic rate of caffeine absorption differs between each species.
Toxicity and intoxication
|Poisoning by caffeine|
|Classification and external resources|
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. 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, or colloquially the "caffeine jitters". The median lethal dose (LD50) given orally, is 192 milligrams per kilogram in rats. 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.
Effects on different functions
Relationship between caffeine and adenosine
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.
How caffeine wards off drowsiness
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. Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below:
- Increased calcium uptake activating metabolic pathways and neural activity
- Activation of wake-promoting neurons
- Release of neurotransmitters producing excitation
- Release of glutamate producing anxiety
- Increased blood flow to smooth muscles and vasoconstriction
- Inhibition of dopamine reuptake
- Inhibition of gamma-aminobutyric acid (GABA) and excitation of the CNS
- Inhibition of sleep promoting neurons
- Increased ATP production through cyclic adenosine monophosphate (cAMP) accumulation
- Increased motor activity
Caffeine increases cardiac arrhythmia (improper heart rate) by increasing stress hormone (e.g.adrenaline) secretions. It has been shown there is an increase in brachial diastolic blood pressure, but not in brachial systolic blood pressure. 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. The results of increasing blood pressure mostly contributes to blockage of Adenosine A1 and A2 receptors. Since caffeine blocks adenosine A2 receptors which has vasodilatory function, blood vessels become less dilated.(i.e. vasoconstriction) However, it is controversial whether caffeine consumption increases heart rate. Some research shows that caffeine has no influence on heart rate. 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.
Moreover, the additional epinephrine increases the secretion of the main gastric hormone gastrin, which will speed up gastric peristalsis and hypersecretion of gastric juice. Additional gastric acid will lead to acidic chyme going into the small intestine and cause intestinal injury. 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. It has been suggested[by whom?] that inhibition of phosphodiesterases in the proximal tubule may contribute to the diuretic and natriuretic effects of methylxanthines. It has been noted[by whom?] that mice lacking the A1 receptor do not exhibit the diuresis and natriuresis typically elicited by the application of the methylxanthines caffeine or theophylline.
Caffeine injections before exercise show no evidence of adverse effects such as dehydration or ion imbalance, and have no effect on short term exercise. 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 affects individuals who do not drink caffeine on a regular basis. 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. As a side note, the International Olympic Committee since the summer of 2000, no longer treats caffeine as a banned substance.
The US National Institutes of Health states "too much caffeine can make you restless, anxious, and irritable. It may also keep you from sleeping well and cause headaches, abnormal heart rhythms, or other problems. If you stop using caffeine, you could get withdrawal symptoms. Some people are more sensitive to the effects of caffeine than others. They should limit their use of caffeine. So should pregnant and nursing women."
Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA) including: caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety disorder, and caffeine-related disorder not otherwise specified (NOS). The DSM-IV defines caffeine-induced sleep disorder, as an individual who regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. As of 2010 the effect of caffeine on people with ADHD is not known. Some studies have however found a modest protective against Alzheimer disease, but the evidence is inconclusive.
Caffeine can have both positive and negative effects on anxiety disorders.
1985, "It appears that anxiety disorder patients have increased caffeine sensitivity" 1988, "panic patients have increased sensitivity to caffeine" 1989, of 24 cases of GAD or Panic Disorder, 5 ceased caffeine intake and 1 significantly reduced caffeine intake; all 6 (25% of the sample group) saw much reduced symptoms many months later, and 5 took no further medication. In addition, 3 of the 6 took caffeine on one subsequent occasion and all 3 immediately saw anxiety symptoms occur. 1992, "patients with GAD are abnormally sensitive to caffeine" 1996, "there is clinical and experimental evidence that acute caffeine can exacerbate the effects of an anxiety-inducing situation, or worsen an existing anxiety disorder, especially panic disorder." 2007, "Our data suggest that there is an association between panic attacks, no matter if associated with PD or MDP, and hyperreactivity to an oral caffeine challenge test." 2010: 'Caffeine is anxiogenic [anxiety causing].' 2011, Literature review, "The 8 studies all showed a positive association between caffeine and anxiogenic [anxiety causing] effects and/or panic disorder."
At moderate and low doses the effect may depend on individual caffeine sensitivity. Caffeine can cause anxiety symptoms in normal individuals, especially in vulnerable patients, like those with pre-existing anxiety disorders. At high doses, typically greater than 300 mg, it can both cause and worsen anxiety and rarely trigger mania and psychosis.
Lower risk of type II diabetes
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. 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. 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.
Negative effects on diabetics
Although coffee 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 the caffeine in regular coffee 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. Diabetes patients have trouble controlling their sugar level in their blood due to lack of insulin resistance hormone. Alloxan is a chemical that damages insulin-producing cells and creates conditions for diabetes. Once in the human body, caffeine produces alloxan and either produces diabetes' conditions or worsens the existing diabetes.
Decrease in Parkinson's disease
Parkinson's disease (PD) is the degeneration of dopamine producing neurons. Dopamine producing neurons stimulate the motor cortex effecting motor control. Loss of dopamine produces loss of motor control skills, cognitive function, and autonomic nervous system. Epidemiological studies have shown that the risk of developing PD decreases with increasing levels of caffeine intake. 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.
Research has shown there is a strong negative correlation to coffee consumption and liver cirrhosis. However, there is a lack of evidence for other beverages that contain caffeine. 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. Since TNF-α is secreted by macrophages in response of lipopolysaccharide (LPS), and it functions as an apoptoic factors, 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). However, the specific mechanism is not clear.
Breast and ovarian cancer
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. 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. Theoretically speaking, lower estrogen levels helps protect against ovarian cancer, but more research needs to be done on this topic. 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.
Research has shown that there is no significant association between caffeine consumption and cancers of the mouth, pharynx, esophagus, stomach, liver, or pancreas. In addition, caffeine also decreases the risk of rectal and colon cancers. A possible explanation is that caffeine interferes with bile secretion, reducing bile acid, and thus leaving neutral sterol concentration in the bowel. Another possible explanation is that caffeine may inhibit some chemical carcinogens such as 4-nitroquinoline-1-oxide; however, this is hard to evaluate because other research shows that caffeine can have promotive effects on carcinogenesis.
|Classification and external resources|
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, physical pains and intense desire for caffeine containing beverages are also reported. The symptoms reflect consumers’ expectancy effects on caffeine to some degree.
Withdrawal symptoms – including headache, irritability, inability to concentrate, drowsiness, insomnia, and pain in the stomach, upper body, and joints – may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9 days. Peer knowledge, support and interaction may aid withdrawal.
Studies with placebo conditions have been done to demonstrate that the effects of caffeine depend greatly on the consumer’s expectations. 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.
Effect of genetics on withdrawal symptoms
Gene polymorphism could be associated with caffeine withdrawal symptoms and beta 1and beta-2 play roles in caffeine withdrawal. 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. It has been suspected that beta2- adrenoceptors are the main cause to this increase in mental fatigue symptom. Beta 2- adrenoceptors are receptors that regulate glycogenolysis, secret insulin and intramuscularly transport glucose that are used for cerebral and muscle activity. Another example is given by the genes ADRbeta1 Gly16 Arg and CYP1A2-163A>C polymorphisms. They are associated with the consumers’ mood swing and increased depression level. 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. Adrenergic receptors, again, play a key role in this symptom, as altered norepinephrine neurotransmission, an adrenoceptor agonist, contribute to the etiology of depression. 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.
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.
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.
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.
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:
|Age range||Maximum recommended daily caffeine intake|
Relatedly, one study found that caffeine can be used to treat hyperkinetic children. 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.
Effect of alcohol on caffeine
According to DSST, alcohol provides a reduction in performance and caffeine has a significant improvement in performance. When alcohol and caffeine are consumed jointly, the effects produced by caffeine are affected, but the alcohol effects remain the same. For example, when additional caffeine is added, the drug effect produced by alcohol is not reduced. However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed. 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.
Alcohol is a GABA agonist and binds into the GABA receptors and decreases serotonin and acetylcholine activity, whereas caffeine increases acetylcholine and serotonin neurotransmission and decreases GABA.
Effect of orally administered birth control on caffeine
Consumption of caffeine while orally administering birth control can extend the half-life of caffeine; therefore, greater attention should be taken during caffeine consumption.
- Shapiro, RE (2008). "Caffeine and headaches". Current Pain and Headache Reports 12 (4): 311–5. doi:10.1007/s11916-008-0052-z. PMID 18625110.
- Ross, GW, Abbott, RD, Petrovitch, H, Morens, DM, Grandinetti, A, Tung, KH, Tanner, CM, Masaki, KH et al. (2000). "Association of Coffee and Caffeine Intake with the Risk of Parkinson Disease". JAMA 283 (20): 2674–9. doi:10.1001/jama.283.20.2674. PMID 10819950.
- Thompson, Rebecca; Keene, Karen (December 2004). "The pros and cons of caffeine". The Psychologist (The British Psychological Society) 17 (12): 698–701.
- Sugiyama, K, Noda, Y, He, P (2001). "Suppressive effect of caffeine on hepatitis and apoptosis induced by tumor necrosis factor-alpha, but not by the anti-Fas antibody, in mice". Bioscience, biotechnology, and biochemistry 65 (3): 674–7. doi:10.1271/bbb.65.674. PMID 11330688.
- Brain, Marshall; Bryant, Charles W. (1 April 2000). "How Caffeine Works". HowStuffWorks. Discovery Communications Inc. Retrieved 2010-11-13.
- Milon, H.; Guidoux, R.; Antonioli, J. A. (1988). "Physiological Effects of Coffee and its Components". In Clarke, R. J.; Macrae, R. Coffee: Physiology. Berlin: Springer. pp. 81–122. ISBN 1-85166-186-7.
- Johnson-Kozlow, M, Kritz-Silverstein, D, Barrett-Connor, E, Morton, D (2002). "Coffee consumption and cognitive function among older adults". American journal of epidemiology 156 (9): 842–50. doi:10.1093/aje/kwf119. PMID 12397002.
- Cao, C, Loewenstein, DA, Lin, X, Zhang, C, Wang, L, Duara, R, Wu, Y, Giannini, A et al. (2012). "High Blood caffeine levels in MCI linked to lack of progression to dementia". Journal of Alzheimer's disease 30 (3): 559–72. doi:10.3233/JAD-2012-111781. PMID 22430531.
- Gilbert, Joanna (17 April 2004). "Synapses". BiologyMad. Retrieved 2010-11-13.
- Maelicke, A, Albuquerque, EX (2000). "Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease". European journal of pharmacology 393 (1–3): 165–70. doi:10.1016/S0014-2999(00)00093-5. PMID 10771010.
- Smith, A (2002). "Effects of caffeine on human behavior". Food and Chemical Toxicology 40 (9): 1243–55. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
- Acheson, KJ, Zahorska-Markiewicz, B, Pittet, P, Anantharaman, K, Jéquier, E (1980). "Caffeine and coffee: Their influence on metabolic rate and substrate utilization in normal weight and obese individuals". The American Journal of Clinical Nutrition 33 (5): 989–97. PMID 7369170.
- Dulloo, AG, Geissler, CA, Horton, T, Collins, A, Miller, DS (1989). "Normal caffeine consumption: Influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers". The American Journal of Clinical Nutrition 49 (1): 44–50. PMID 2912010.
- Koot, P, Deurenberg, P (1995). "Comparison of changes in energy expenditure and body temperatures after caffeine consumption". Annals of nutrition & metabolism 39 (3): 135–42. doi:10.1159/000177854. PMID 7486839.
- http://www.world-science.net/othernews/100622_cancer.htm[full citation needed][unreliable medical source?]
- G. Webster Ross, et. al., May 24/31, "Association of Coffee and Caffeine Intake With the Risk of Parkinson Disease", JAMA. 2000; 283 (20):2674-2679. doi:10.1001/jama.283.20.2674 (accessed May 14 2013)
- R. D. Prediger, "Effects of caffeine in Parkinson's disease: from neuroprotection to the management of motor and non-motor symptoms", J. Alzheimers Dis. 2010; 20 Suppl 1: S205-20. doi: 10.3233/JAD-2010-091459 (accessed May 14 2013).
- Cathy Whitlock, Caffeine as a Potential Treatment for Parkinson’s Disease, the National Parkinson Foundation, 8/2/2012 (accessed May 14 2013)
- León-Carmona, JR, Galano, A (2011). "Is caffeine a good scavenger of oxygenated free radicals?". The journal of physical chemistry. B 115 (15): 4538–46. doi:10.1021/jp201383y. PMID 21438616.
- Cornelis, MC, El-Sohemy, A (2007). "Coffee, caffeine, and coronary heart disease". Current Opinion in Clinical Nutrition and Metabolic Care 10 (6): 745–51. doi:10.1097/MCO.0b013e3282f05d81. PMID 18089957.
- Lovallo, WR, Whitsett, TL, Al'Absi, M, Sung, BH, Vincent, AS, Wilson, MF (2005). "Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels". Psychosomatic medicine 67 (5): 734–9. doi:10.1097/01.psy.0000181270.20036.06. PMC 2257922. PMID 16204431.
- Crowe, SF, Barot, J, Caldow, S, d’Aspromonte, J, Dell’Orso, J, Di Clemente, A, Hanson, K, Kellett, M et al. (2011). "The effect of caffeine and stress on auditory hallucinations in a non-clinical sample". Personality and Individual Differences 50 (5): 626–30. doi:10.1016/j.paid.2010.12.007.
- Rapuri, PB, Gallagher, JC, Kinyamu, HK, Ryschon, KL (2001). "Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes". The American journal of clinical nutrition 74 (5): 694–700. PMID 11684540.
- US 2994640, Hugo Zellner, "Anti-inflammatory Therapy with Purine Molecular Compounds", issued 1961-08-01, assigned to Byk-Gulden Lomberg Chemische Fabrik G.m.b.H.
- Snyder, SH (1981). "Adenosine receptors and the actions of methylxanthines". Trends in Neurosciences 4: 242–4. doi:10.1016/0166-2236(81)90076-X.
- "Background on Caffeine". Coffee Science Information Centre. Retrieved 2010-11-08.
- Csajka, C, Haller, CA, Benowitz, NL, Verotta, D (2005). "Mechanistic pharmacokinetic modelling of ephedrine, norephedrine and caffeine in healthy subjects". British journal of clinical pharmacology 59 (3): 335–45. doi:10.1111/j.1365-2125.2005.02254.x. PMC 1884794. PMID 15752380.
- Peters, JM, Boyd, EM (1967). "The influence of a cachexigenic diet on caffeine toxicity". Toxicology and applied pharmacology 11 (1): 121–7. doi:10.1016/0041-008X(67)90033-6. PMID 6056149.
- "305.90 Caffeine Intoxication". DSM-IV.
- Benowitz, NL (1990). "Clinical pharmacology of caffeine". Annual review of medicine 41: 277–88. doi:10.1146/annurev.me.41.020190.001425. PMID 2184730.
- Karau, M, Kihunyu, J, Kathenya, N, Wangai, L, Kariuki, D, Kibet, R (2010). "Determination of Caffeine Content in Non-Alcoholic Beverages and Energy Drinks Using Hplc-Uv Method". African Journal of Drug and Alcohol Studies (Centre for Research and Information on Substance Abuse) 9 (1): 15–21. doi:10.4314/ajdas.v9i1.61754.
- Huang, ZL, Qu, WM, Eguchi, N, Chen, JF, Schwarzschild, MA, Fredholm, BB, Urade, Y, Hayaishi, O (2005). "Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine". Nature neuroscience 8 (7): 858–9. doi:10.1038/nn1491. PMID 15965471.
- D. Bracco, Ferrarra, JM, Arnaud, MJ, Jéquier, E, Schutz, Y (1995). "Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women". American Journal of Physiology 269 (4): E671–8. PMID 7485480.
- Mahmud, A, Feely, J (2001). "Acute effect of caffeine on arterial stiffness and aortic pressure waveform". Hypertension 38 (2): 227–31. doi:10.1161/01.HYP.38.2.227. PMID 11509481.
- Biaggioni, I, Paul, S, Puckett, A, Arzubiaga, C (1991). "Caffeine and theophylline as adenosine receptor antagonists in humans". The Journal of pharmacology and experimental therapeutics 258 (2): 588–93. PMID 1865359.
- Daniels, JW, Molé, PA, Shaffrath, JD, Stebbins, CL (1998). "Effects of caffeine on blood pressure, heart rate, and forearm blood flow during dynamic leg exercise". Journal of applied physiology 85 (1): 154–9. PMID 9655769.
- Boekema, PJ, Samsom, M, Van Berge Henegouwen, GP, Smout, AJ (1999). "Coffee and gastrointestinal function: Facts and fiction. A review". Scandinavian journal of gastroenterology 230 (230): 35–9. doi:10.1080/003655299750025525. PMID 10499460.
- Cohen, S, Booth, GH (1975). "Gastric acid secretion and lower-esophageal-sphincter pressure in response to coffee and caffeine". The New England journal of medicine 293 (18): 897–9. doi:10.1056/NEJM197510302931803. PMID 1177987.
- Sherwood, Lauralee; Kell, Robert (2009). Human Physiology: From Cells to Systems (1st Canadian ed.). Nelsen. pp. 613–9. ISBN 0-17-644107-7.
- Rieg, T, Steigele, H, Schnermann, J, Richter, K, Osswald, H, Vallon, V (2005). "Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine". The Journal of pharmacology and experimental therapeutics 313 (1): 403–9. doi:10.1124/jpet.104.080432. PMID 15590766.
- Graham, TE (2001). "Caffeine and exercise: Metabolism, endurance and performance". Sports medicine 31 (11): 785–807. doi:10.2165/00007256-200131110-00002. PMID 11583104.
- "Caffeine". MedlinePlus. Retrieved 2012-10-22.
- Lara, DR (2010). "Caffeine, mental health, and psychiatric disorders". Journal of Alzheimer's disease 20 (1): S239–48. doi:10.3233/JAD-2010-1378. PMID 20164571.
- Santos, C, Costa, J, Santos, J, Vaz-Carneiro, A, Lunet, N (2010). "Caffeine intake and dementia: Systematic review and meta-analysis". Journal of Alzheimer's disease 20 (1): S187–204. doi:10.3233/JAD-2010-091387. PMID 20182026.
- Marques, S, Batalha, VL, Lopes, LV, Outeiro, TF (2011). "Modulating Alzheimer's disease through caffeine: A putative link to epigenetics". Journal of Alzheimer's disease 24 (2): 161–71. doi:10.3233/JAD-2011-110032. PMID 21427489.
- Arendash, GW, Cao, C (2010). "Caffeine and coffee as therapeutics against Alzheimer's disease". Journal of Alzheimer's disease 20 (1): S117–26. doi:10.3233/JAD-2010-091249. PMID 20182037.
- Winston, AP (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment 11 (6): 432–9. doi:10.1192/apt.11.6.432.
- Lee, MA, Cameron, OG, Greden, JF (1985). "Anxiety and caffeine consumption in people with anxiety disorders". Psychiatry research 15 (3): 211–7. PMID 3862156.
- Lee, MA, Flegel, P, Greden, JF, Cameron, OG (1988). "Anxiogenic effects of caffeine on panic and depressed patients". The American journal of psychiatry 145 (5): 632–5. PMID 3358468.
- Bruce, MS, Lader, M (1989). "Caffeine abstention in the management of anxiety disorders". Psychological medicine 19 (1): 211–4. doi:10.1017/S003329170001117X. PMID 2727208.
- Bruce, M, Scott, N, Shine, P, Lader, M (1992). "Anxiogenic effects of caffeine in patients with anxiety disorders". Archives of general psychiatry 49 (11): 867–9. doi:10.1001/archpsyc.1992.01820110031004. PMID 1444724.
- http://www.psychology.org.nz/cms_show_download.php?id=766[full citation needed]
- Nardi, AE, Lopes, FL, Valença, AM, Freire, RC, Veras, AB, De-Melo-Neto, VL, Nascimento, I, King, AL et al. (2007). "Caffeine challenge test in panic disorder and depression with panic attacks". Comprehensive psychiatry 48 (3): 257–63. doi:10.1016/j.comppsych.2006.12.001. PMID 17445520.
- Rogers, PJ, Hohoff, C, Heatherley, SV, Mullings, EL, Maxfield, PJ, Evershed, RP, Deckert, J, Nutt, DJ (2010). "Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption". Neuropsychopharmacology 35 (9): 1973–83. doi:10.1038/npp.2010.71. PMC 3055635. PMID 20520601.
- Vilarim, MM, Rocha Araujo, DM, Nardi, AE (2011). "Caffeine challenge test and panic disorder: A systematic literature review". Expert review of neurotherapeutics 11 (8): 1185–95. doi:10.1586/ern.11.83. PMID 21797659.
- Lee, MA, Cameron, OG, Greden, JF (1985). "Anxiety and caffeine consumption in people with anxiety disorders". Psychiatry research 15 (3): 211–7. doi:10.1016/0165-1781(85)90078-2. PMID 3862156.
- Broderick, P, Benjamin, AB (2004). "Caffeine and psychiatric symptoms: A review". The Journal of the Oklahoma State Medical Association 97 (12): 538–42. PMID 15732884.
- "Information about caffeine dependence". Caffeinedependence.org. Retrieved 2012-10-22.[unreliable medical source?]
- Smith, A (2002). "Effects of caffeine on human behavior". Food and chemical toxicology 40 (9): 1243–55. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
- "What are the symptoms of caffeine withdrawal? | Coffee and Caffeine FAQ". Coffeefaq.com. Retrieved 2012-10-22.[unreliable medical source?]
- Nehlig, A (2010). "Is caffeine a cognitive enhancer?". Journal of Alzheimer's disease 20 (1): S85–94. doi:10.3233/JAD-2010-091315. PMID 20182035.
- Iso, H, Date, C, Wakai, K, Fukui, M, Tamakoshi, A, Jacc Study, Group (2006). "The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults". Annals of internal medicine 144 (8): 554–62. PMID 16618952.
- DeNoon, Daniel J. (January 28, 2008). "Caffeine Bad for Diabetes". WebMD. Retrieved 2010-11-13.
- Jiang-Fan Chen, Xu, K, Petzer, JP, Staal, R, Xu, YH, Beilstein, M, Sonsalla, PK, Castagnoli, K et al. (2001-05-15). "Neuroprotection by Caffeine and A2A Adenosine Receptor Inactivation in a Model of Parkinson's Disease". The Journal of Neuroscience 21 (10): RC143. PMID 11319241.
- Klatsky, AL, Morton, C, Udaltsova, N, Friedman, GD (2006). "Coffee, cirrhosis, and transaminase enzymes". Archives of internal medicine 166 (11): 1190–5. doi:10.1001/archinte.166.11.1190. PMID 16772246. Lay summary – The Guardian (13 June 2006).
- Corrao, G, Zambon, A, Bagnardi, V, d'Amicis, A, Klatsky, A, Collaborative Sidecir, Group (2001). "Coffee, caffeine, and the risk of liver cirrhosis". Annals of epidemiology 11 (7): 458–65. doi:10.1016/S1047-2797(01)00223-X. PMID 11557177.
- Locksley, RM, Killeen, N, Lenardo, MJ (2001). "The TNF and TNF receptor superfamilies: Integrating mammalian biology". Cell 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407.
- Kotsopoulos, J, Eliassen, AH, Missmer, SA, Hankinson, SE, Tworoger, SS (2009). "Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women". Cancer 115 (12): 2765–74. doi:10.1002/cncr.24328. PMC 2764240. PMID 19384973.
- "Hormones may tie caffeine to cancer risk". New York: Reuters. July 7, 2009. Retrieved 2010-11-13.
- La Vecchia, C, Ferraroni, M, Negri, E, d'Avanzo, B, Decarli, A, Levi, F, Franceschi, S (1989-02-15). "Coffee Consumption and Digestive Tract Cancers". Cancer Research 49 (4): 1049–51. PMID 2912550.
- Nomura, T (1976). "Diminution of tumorigenesis initiated by 4-nitroquinoline-l-oxide by post-treatment with caffeine in mice". Nature 260 (5551): 547–9. Bibcode:1976Natur.260..547N. doi:10.1038/260547a0. PMID 817208.
- Welsch, CW, Scieszka, KM, Senn, ER, Dehoog, JV (1983). "Caffeine (1,3,7-trimethylxanthine), a temperate promoter of DMBA-induced rat mammary gland carcinogenesis". International journal of cancer 32 (4): 479–84. doi:10.1002/ijc.2910320415. PMID 6413433.
- Juliano, LM, Griffiths, RR (2004). "A critical review of caffeine withdrawal: Empirical validation of symptoms and signs, incidence, severity, and associated features". Psychopharmacology 176 (1): 1–29. doi:10.1007/s00213-004-2000-x. PMID 15448977.
- http://coffeefaq.com/site/node/11[full citation needed][unreliable medical source?]
- http://www.healthcentral.com/anxiety/c/8146/5936/coffee-anxiety[full citation needed][unreliable medical source?]
- http://www.anxietyzap.com/9-caffeine-anxiety.htm[full citation needed][unreliable medical source?]
- Day-Tasevski, Erica (6 April 2010). Genetic Determinants of the Acute Effects and Withdrawal Symptoms of Caffeine (MSc Thesis). University of Toronto. hdl:1807/24245.[page needed]
- "It's Your Health — Caffeine". Health Canada. March 2010. Retrieved 2010-11-08.
- "(untitled)". Waverly Health Center. Retrieved 2010-12-01.
- Schnackenberg, RC (1973). "Caffeine as a substitute for Schedule II stimulants in hyperkinetic children". The American journal of psychiatry 130 (7): 796–8. PMID 4712736.
- Reissig, CJ, Strain, EC, Griffiths, RR (2009). "Caffeinated energy drinks--a growing problem". Drug and alcohol dependence 99 (1–3): 1–10. doi:10.1016/j.drugalcdep.2008.08.001. PMC 2735818. PMID 18809264. Lay summary – ScienceDaily (September 25, 2008).
- MacKay, M, Tiplady, B, Scholey, AB (2002). "Interactions between alcohol and caffeine in relation to psychomotor speed and accuracy". Human psychopharmacology 17 (3): 151–6. doi:10.1002/hup.371. PMID 12404692.
- Liguori, A, Robinson, JH (2001). "Caffeine antagonism of alcohol-induced driving impairment". Drug and alcohol dependence 63 (2): 123–9. PMID 11376916.
- Marczinski, CA, Fillmore, MT (2003). "Dissociative antagonistic effects of caffeine on alcohol-induced impairment of behavioral control". Experimental and clinical psychopharmacology 11 (3): 228–36. PMID 12940502.