INTRODUCTION:

Caffeine has been used for thousands of years and is one of the most widely consumed active food ingredient throughout the world. It is found in common beverages including coffee, tea and soft drinks, as well as products containing cocoa or chocolate, and a variety of medications and dietary supplements[1,2].Caffeine is metabolized in the liver, but the amount that is metabolized varies in different people[3]. After metabolism, this substance is converted into the following three compounds :

1- Paraxanthine - causes lipolysis, as well as increases glycerol and free fatty acid in blood plasma.

2- Theobromine- causes dilatation of blood vessels and increases the volume of urine.

3- Theophlyine- relaxes the smooth muscles in bronchial. [3]

Received on 15.06.2015 Modified on 24.06.2015

Research J. Pharm. and Tech. 8(9): Sept., 2015; Page 1312-1319

DOI: 10.5958/0974-360X.2015.00237.1

Each of the substances, created by the metabolism of caffeine, can be used in the therapeutic field with considering their effects [3]. The primary mechanism of action of caffeine is competitive antagonism at A₁ and A_2A adenosine receptors [4]. After oral ingestion, caffeine is rapidly and completely absorbed, with peak blood levels generally reached in 30–45 min [5]. The elimination half-life of caffeine ranges between 3 to 7 hours and can be influenced by many factors, including sex, age, use of oral contraceptives, pregnancy and smoking. Caffeine’s half-life has been reported to be 20–30% shorter in females than in males. The half-life in newborns ranges from 50 to 100 hours, but it gradually approaches that of an adult by 6 months of age [6]. Caffeine has global effects on the central nervous system (CNS) and on hormonal, metabolic, muscular, cardiovascular, pulmonary, and renal functions during rest and exercise. It stimulates bronchodilator of alveoli, vasodilatation of blood vessels, neural activation of muscle contraction, blood filtration in the kidneys, catecholamine secretion, and lypolysis. These metabolic, physiologic, and hormonal effects of caffeine lower the respiratory exchange ratio, peripheral fatigue, rating of perceived exertion (RPE), and the threshold for exercise-induced cortisol and B-endorphin release; they also increase oxygen uptake, cardiac output, ventilation, circulating levels of epinephrine, metabolic rate, and fat oxidation during endurance exercise in trained and untrained individuals [7].

Sources of Caffeine:

Caffeine (1,3,7-trimethylxanthine)[Figure 1] is an alkaloid of the xanthine group widely known worldwide due to its occurrence in extensively consumed beverages, drinks and food. Natural sources of caffeine include different varieties of coffee beans (Coffea canephora, Coffea arabica), tea leaves (Camellia sinensis), guarana seeds (Paullinia cupana), mate leaves (Ilexparaguariensis), kola nut seeds (Cola nitida, Cola acuminata) and cocoa beans (Theobroma cacao). Despite the fact that tea is globally consumed more widely than coffee, coffee is the main source of caffeine in daily consumption given its generally higher caffeine content. Other dietary factors that contribute to daily overall caffeine consumption include foods like certain soft and energy drinks, chocolate, candies and sweets, as well as that contained in some medications, such as stimulants, diet aids, painkillers and cold remedies [8]. Table 1 outlines a variety of caffeinated beverages and sweets that are available in the market and their ranges in caffeine content [9].

Table 1:Concentration of caffeine in selected beverages and sweets.

*Size listed in fluid ounces (oz.) and milliliters (ml).

*Caffeine is listed are in milligrams (mg).

Item

Size

Caffeine

Type of coffee-

Brewed

Brewed, decaffeinated

Espresso, restaurant-style

Espresso, restaurant-style, decaffeinated Instant

Instant, decaffeinated

Type of tea – (Brewed tea)

Black tea

Black tea, decaffeinated

Green tea

(Iced tea)

Instant, prepared with water

Type of soft drink-

Coca-Cola

Diet Coke

Diet Pepsi

Pepsi

Type of energy drink-

Red Bull, regular or sugar-free

Sweets-

Chocolate chips, semisweet

Dark chocolate-coated coffee beans

8 oz. (237 ml)

1 oz. (30 ml)

8 oz. (237 ml)

12 oz. (355 ml)

8.4 oz. (248ml)

1 cup (168 g)

28 pieces

95-200 mg

2-12 mg

47-75 mg

0-15 mg

27-173 mg

2-12 mg

14-70 mg

0-12 mg

24-45 mg

11-47 mg

23-35 mg

23-47 mg

27-37 mg

32-39 mg

75-80 mg

104 mg

336 mg

(Mayoclinic,2014)[9]

Figure 1:Chemical structure of caffeine

Caffeine Consumption:

The per capita consumption level of caffeine for all consumers (of all ages) is approximately 120 mg per day, or a mean intake of 1.73 mg/kg body weight/day. Children consume significantly less caffeine than adults. As of 2004, the average daily intake of caffeine by young children ages 1-5 and 6-9 years from all caffeinated beverages was 14 and 22mg/day, or 0.82 and 0.85mg/kg body weight/day, respectively [10].

Health Canada issued recommendations in 2006 regarding levels of safe use to be ≤400 mg/day, and again in 2009 with specific recommendations for children (45–85 mg per day for 6–12 years;2.5 mg/kg/day for ≥12 years) and pregnant women (<300 mg/day) [11].Evidence from both scientific reviews and specific studies on consumption of caffeine generally concludes that daily consumption of 300 mg/day, or about three cups of coffee, is safe,even for more sensitive segments of the population, such as young children and pregnant women. [6].

The FDA released a letter in August 2012 stating that for healthy adults, caffeine intake up to 400 mg/day is not associated with adverse health effects [12]. Table 2 presents the average daily caffeine intake from coffee, tea, mate, and cocoa among adults in various countries [4].

Table 2: Average daily caffeine consumption.

Country	Adults(mg/d)
Australia	232
Brazil	40
Canada	210
China	16
Denmark	390
Finland	329
India	27
Japan	169
Kenya	50
South Africa	40
Switzerland	288
United Kingdom	202
United States	168

( Fredholm and others,1999) [4].

Caffeine Addiction (i.e. Caffeine dependence):

In recent years, the term “addiction” has been used colloquially to refer to certain foods of enjoyment, prompting speculation as to whether it is possible to be truly “addicted” to the foods and beverages we consume. [13]. The habitual daily use of caffeine >500–600mg (four to seven cups of coffee or seven to nine cups of tea) represents a significant health risk and may therefore be regarded as ‘abuse’ [14].

Based on the studies, N. Ogawa and H. Ueki [15] suggested that caffeine can produce a clinical dependence syndrome similar to those produced by other psychoactive substances and has a potential for abuse. One such study in 36 adolescent daily caffeine consumers found that 22.2% of the sample could be classified as caffeine dependent based on their criteria [16]. However, the average daily caffeine consumption in this sample was 244 mg, which is well above the typical consumption for adolescents (and even for adults). Similarly, Hughes and colleagues performed telephone surveys in 162 self-described caffeine users and found that 30% reported three or more symptoms consistent with caffeine dependence [17].The most common withdrawal symptoms include increases in headache, drowsiness, and work difficulty (including impaired concentration) and decreases in feelings of contentment and sociability [18].

In 2004, Juliano and Griffiths [19] summarized forty-two double-blind trials. In these trials, subjects typically underwent placebo replacement for caffeine for various periods of time. The researchers then compare withdrawal symptoms in those who received a placebo versus those who continued to receive caffeine. The bulk of the studies showed that caffeine abstention resulted in the placebo group reporting higher rates of lethargy, fuzziness, and headache. Sometimes doses as low as 100 mg/d can provoke these symptoms. The symptoms begin twelve to twenty-four hours after sudden cessation of continuous use, reach a peak at twenty to forty-eight hours, and resolve after ingesting caffeine.[20] The American Psychiatric Association’s (APA) “Diagnostic and Statistical Manual of Mental Disorders (DSM-V,2013) cites evidence for caffeine withdrawal [21].

Benefits of Caffeine:

Prevention of Type 2 Diabetes Mellitus:

Type 2 diabetes is one of the most serious global health concerns and its incidence is increasing .The total number of people with diabetes worldwide is projected to rise from 366 million in 2011 to 552 million by 2030 [22]. Recent evidence suggests that coffee consumption is associated with a decreased risk of type 2 diabetes. A dutch cohort study reported that participants drinking at least 7 cups of coffee per day were half as likely to develop type 2 diabetes compared with those who did not consume coffee [23].

In a 2005 review of nine cohort studies (193,000 men and women), the authors found a 35% lower risk of type 2 diabetes in people who consumed at least six cups of coffee per day and a 28% lower risk for those drinking between four and six cups per day, compared with people who drink fewer than two cups per day [24]. Both caffeinated and decaffeinated coffee have also been shown to reduce insulin sensitivity(a potential precursor to diabetes) [25].In another long-term study of the relationship between caffeinated beverage consumption and incidence of type 2 diabetes, the authors followed more than 41,000 participants over ten years, assessing coffee consumption every two to four years. The results suggest that caffeine intake from coffee and other sources is associated with a significantly lower risk for type 2 diabetes [26].

Prevention of Parkinson’s Disease:

Coffee, tea, and other caffeinated beverages appear to lower the risk of Parkinson’s Disease (Parkinson’s). The mechanism responsible for this reduced risk is thought to be protection of the dopaminergic (DA) cells (neurons in the brain) against neurotoxicity. In an article on risk factors of Parkinson’s, studies showed coffee drinkers had a 30% lower risk of Parkinson’s than non-coffee drinkers.[27]

In the Cancer Prevention Study (CPS) II cohort of more than 500,000 men and women in the US, coffee consumption was inversely associated with Parkinson’s disease mortality in men but not women [28].The failure of prospective studies to find an inverse relationship between coffee consumption and Parkinson’s disease in women may be due to the modifying effect of estrogen replacement therapy [29]. Further analysis of the Nurses’ Health Study cohort revealed that coffee consumption was inversely associated with Parkinson’s disease risk in women who had never used postmenopausal estrogen, but a significant increase in Parkinson’s disease risk was observed in postmenopausal estrogen users who drank at least 6 cups of coffee daily [30]. In the CPS II cohort, a significant inverse association between coffee consumption and Parkinson’s disease mortality was also observed in women who had never used postmenopausal estrogen,but not in those who used postmenopausal estrogen [28].

Prevention of Alzheimer’s Disease:

The majority of human epidemiological studies suggest that regular coffee/caffeine consumption over a lifetime reduces the risk of developing Alzheimer ’s disease (AD), particularly in the elderly. A 2012 case control study considered the evidence from human and animal models suggesting a role for caffeine in protecting against Alzheimer ’s disease. The result suggested that coffee/caffeine intake is associated with reduced risk, or delayed onset of dementia particularly in those with mild cognitive impairment [31]. Among the most prominent studies, a case control study, including 54 patients and 54 controls matched for age and sex, showed that caffeine intake was inversely associated with AD (risk ratio 0.40),independently of other confounding variables [32]. In a Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study found that moderate coffee (3–5 cups/day) consumption at midlife was associated with a decreased risk of dementia and Alzheimer ’s disease by about 65% in late-life. Tea consumption, however, showed no association with dementia or Alzheimer ’s disease in the CAIDE-study population [33].

Prevention of Gall Bladder Disease:

Coffee consumption was recently found to be protective for symptomatic gallbladder disease in men [32]. A publication from the Health Professionals Follow-up Study on 46,008 men diagnosed 1,081 new cases of ultrasound documented gallbladder disease and found that men who drank 4 or more cups of coffee per day were 45% less likely to develop the disease [32]. Similarly, a publication from the Nurses Health Study on 80,898 women identified 7,811 cholecystectomies and found that women who drank 4 or more cups of caffeinated coffee per day were 28% less likely to have their gallbladder removed [33]. A decreased risk of gallstones associated with coffee drinking was reported in a prospective study based on gallbladder ultrasonography in Italy [34], and intake of regular coffee, but not of decaffeinated coffee, was associated with a decreased risk of symptomatic gallstones in a prospective study of health professionals in the United States [32]. The latter study also showed a protective association between caffeine intake and symptomatic gallstones [32].

Prevention of Liver Disease:

Coffee intake may have beneficial effects on the liver. Increasing coffee consumption has been inversely associated with liver enzyme concentrations, including alanine aminotransferase (ALT), aspartate aminotransferase(AST), and gamma-glutamyltransferase [37-42].

Two population-based studies (The National Health and Nutrition Examination Survey I and III) have reported that higher caffeine consumption (2 cups/day) was associated with a lower risk of elevated alanine aminotransferase(ALT) levels and a lower risk of chronic liver disease [41,43]. Other case control studies have demonstrated that coffee consumption reduces the risk of cirrhosis, with four cups per day having the greatest effect [44,45].

Additionally, a large cohort study of 330 patients with alcoholic and nonalcoholic cirrhosis showed a strong inverse relationship between coffee drinking (4 cups/day) and elevated serum enzymes, especially in those who drank large quantities of alcohol [42]. In an analysis of four continuous cycles (2001–2008) of the National Health and Nutrition Examination Survey (NHANES), a dietary intake questionnaire collected by the National Center for Health Statistics of the Centers for Disease Control and Prevention revealed that caffeine intake was independently associated with a decreased risk of development of Non alcoholic fatty liver disease (NAFLD) (OR 0.931, CI 0.900–0.964). [46] Several other studies also support the hypothesis that coffee consumption leads to decreased risk of liver cancer [47].

Prevention of Colorectal Cancer:

Colorectal cancer is one of the most common cancers worldwide [48,49]. Coffee is considered to be a protective factor against colorectal cancer through activity of its anti carcinogenic constituents, cafestol and kahweol [50].It may also decrease the risk of colorectal cancer by reducing the excretion of bile acids and neutral sterols into the colon [51].

In 1990, a Working Group of the International Agency for Research on Cancer reviewed the data on coffee consumption and colorectal cancer risk and concluded that in man ‘there is some evidence of an inverse relation between coffee drinking and cancer of the large bowel’ [52]. In a meta-analysis of coffee consumption and colorectal cancer risk, the combined results of 12 case control studies revealed a significant 28 percent reduction in colorectal cancer risk for high coffee consumption versus low consumption [53].

Moreover, the newest meta-analysis of case–control studies by Galeone et al. found a significantly positive effect when comparing the highest with non/low coffee intake [54].In a review, Tavani and La Vecchia showed that not only was there no risk of colon or colorectal cancer with caffeinated beverages, but there may even be a protective effect[55].

Health Risk of Caffeine:

Anxiety and Insomnia:

The consumption of caffeine by adults has been associated with an increase in anxiety in several studies. In patients with generalized anxiety disorder, the administration of caffeine increased their already high anxiety level in a dose related manner [56]. Increased anxiety was also reported following caffeine by Loke et al. where the doses were high (either 3 or 6 mg/kg) [57].Similarly, Sicard et al. found increased anxiety following 600 mg of caffeine [58]. Green and Suls also found that caffeine increased anxiety, and again the volunteers were consuming very high amounts (125 mg caffeine per cup of coffee over the day) [59].The stimulation of anxiety in response to caffeine may be due to increased levels of lactate in the brain . The role of adenosine in mediating caffeine-induced anxiety is supported by the finding that there is an association between different anxiety levels after caffeine administration and polymorphisms on the A2A receptor gene [60]. It is well-known that caffeine produces insomnia.

It reduces slow-wave sleep in the early part of the sleep cycle and can reduce rapid eye movement (REM) sleep later in the cycle. Caffeine increases episodes of wakefulness, and high doses in the late evening can increase the time taken to fall asleep. In elderly people, the use of medication containing caffeine is associated with an increased risk of difficulty in falling asleep [60].

A recent review noted that the main effects of caffeine on sleep are decreased sleep latency, shortened total sleep time, decrease in power in the delta range, sleep fragmentation, and possibly a decreased accumulation of sleep propensity during waking. They also pointed out that the great variability in the sensitivity for caffeine among individuals may be atleast in part explained by genetic variations in genes related to adenosine metabolism [61].

Osteoporosis and Hip Fracture:

Dietary caffeine acutely increases urinary calcium loss [62], and these losses are not entirely compensated for in the 24 h after caffeine consumption [63]. In an overview on the literature of osteoporosis, a high consumption of caffeine was suggested as a risk factor for loss of bone mass and fragility fractures [64].The interaction of caffeine intake with calcium on bone loss was reported by Harris and Dawson-Hughes [65].These investigators found that bone loss from the spine and total-body bone mineral density occurred only in postmenopausal women who had both low calcium intakes (440–744 mg/d) and high caffeine intakes (450–1120 mg/d). Similarly, Rapuri et al. demonstrated that if the intakes of caffeine in amounts more than 300 mg/d (approximately 514 g, or 18 oz, brewed coffee) accelerated bone loss at the spine in elderly postmenopausal women [66].

Four prospective studies evaluated caffeine as one of several risk factors for incident fracture (Kiel et al.,1990; Hernandez-Avila et al.,1991; Cummings et al.,1995; Meyer et al.,1997) [67-70]. All four reported a significant association. In the largest of these studies, utilizing the Framingham cohort, the increase in hip fracture risk was nearly three-fold. However, the highest age in the cohort was 65, and there were few fractures overall [67]. In the Norwegian study (Meyer et al.,1997) fracture risk was increased only for individuals consuming nine or more cups of coffee per day, with no dose–response relationship at lower coffee intakes [70]. Lloyd et al. were unable to find any association of caffeine with bone loss in a 2-y prospective study of 112 postmenopausal women [71]. Similarly, Hannan et al. did not find that caffeine (or calcium intake) was associated with bone loss in the Framingham study population [72]. The impact of coffee or caffeine consumption on the risk of osteoporosis is not clear. However, currently available evidence suggests that ensuring adequate calcium and vitamin D intake and limiting coffee consumption to 3 cups/d (300 mg/d of caffeine) may help reduce the risk of osteoporosis and osteoporotic fractures, particularly in older adults [73].

Cardiovascular Health:

The majority of prospective cohort studies looking at coffee/caffeine consumption did not find any adverse effect of coffee/caffeine consumption on cardiovascular function. There was no association between caffeine consumption and arrhythmias[74], atrial fibrillation[75] and cardiac variability[76] showing that there is no need to abstain from caffeine in those populations. Although scientific review author James suggested there is strong experimental evidence that blood pressure remains reactive to caffeine in the diet, and that overall epidemiological evidence implicates caffeine as a risk factor for hypertension, more recent studies on women have not supported this [77]. According to the American Heart Association (AHA)’s policy on caffeine, “Whether high caffeine intake increases the risk of coronary heart disease is still under study”[78]. Nawrot et al. concluded that moderate caffeine consumption (400 mg or less, or four or fewer cups of coffee per day) does not adversely affect cardiovascular health. Insufficient data exist to be able to draw conclusions about the risk of coronary heart disease (CHD) or mortality associated with consumption of much higher amounts [6]. The observed effects of coffee consumption on cardiovascular disease and its risk factors are unlikely to be explained by caffeine alone.

Caffeine and Hydration:

It is a common held belief that drinking caffeinated coffee can lead to dehydration. The Institute of Medicine (IOM), in its Dietary Reference Values for Water, Potassium, Sodium, Chloride and Sulfate states that “caffeinated beverages appear to contribute to total daily water intake, similar to non-caffeinated beverages.”[79]. Similarly, other recent studies and literature reviews on the effects of caffeine during normal life activities conclude that moderate caffeine consumption does not lead to dehydration [80]. In athletes, there is no evidence to suggest that moderate caffeine intake (up to 450 mg) induces chronic dehydration or negatively affects exercise performance, temperature regulation, and circulatory strain in a hot environment. Caffeinated fluids contribute to the daily human water requirement in a manner that is similar to pure water [80,81].

Caffeine and Children:

Caffeine may have a negative effect on a child's nutrition if caffeinated drinks replace healthy drinks, such as milk. A child who consumes caffeine may also eat less, because caffeine reduces the appetite [82]. A recent scientific review concluded that for children aged between 4-12 years caffeine intake should be limited to 2.5 mg/kg bodyweight (equivalent to 45 – 85 mg of caffeine from all sources for children weighing 18 – 34 kg). It is unclear whether caffeine plays a significant role in behavioral disturbance in children [83].

Caffeine and Pregnancy:

Fertility:

The vast majority of scientific research indicates that moderate caffeine consumption does not affect fertility. A 2003 comprehensive epidemiological review by Nawrot et al concluded that caffeine intake of 300 mg/day or less does not reduce fertility in otherwise fertile women [6].

In 2006, Higdon and Frei suggested that women experiencing difficulty conceiving limit caffeine consumption to less than 300 mg/day, in addition to eliminating tobacco and alcohol use [84]. Another study conducted by Sata et al in Japan found that only women having a particular genetic background (homozygous CYP1A21F alleles) are at increased risk of reduced fertility due to caffeine consumption [85].

Miscarriage:

In 2010, a Chinese case-control study [86] and a small US prospective cohort study [87]did not find any association between caffeine consumption and the risk of miscarriage. A study by Wen et al. likely provides the best evidence for the pregnancy signal phenomenon to date. In this study, increased risk of miscarriage was only observed for caffeine consumed after nausea onset, but not for caffeine consumed before nausea onset, or among those without nausea [88].

The 2010 Committee Opinion of the American College of Obstetricians and Gynecologists stated that “Moderate caffeine consumption (less than 200 mg per day) does not appear to be a major contributing factor in miscarriage; … a final conclusion cannot be made as to whether there is a correlation between high caffeine intake and miscarriage.”[89].

Birth defects (teratology):

At present, there is no convincing evidence from epidemiological studies that moderate caffeine consumption by pregnant women ranging from 300–1,000 mg per day throughout the entire pregnancy increases the risk of birth defects [6]. However, in light of other women’s health issues, such as fertility and miscarriage, pregnant women are advised to keep caffeine consumption at or below 300 mg/day (or approximately three cups of coffee).

A 2011 study, evaluating data from the National Birth Defects Prevention Study, examined the association between maternal caffeine consumption (from coffee, tea, soda and chocolate) and the risk of selected birth defects. The cohort of 3,346 cases was matched with 6,642 controls. No convincing evidence of an association between maternal caffeine intake and the birth defects was discovered in this study [90]. A further study, also evaluating data from the National Birth Defects Prevention Study, assessed associations between maternal dietary caffeine intake and congenital limb deficiencies. In this study, 844 cases and 8069 controls, high soda consumption was associated with an elevated risk for longitudinal limb deficiencies. Coffee and tea consumption was not associated with any limb deficiency subtype [91].

Breastfeeding:

The American Academy of Pediatrics (AAP)Committee on Drugs Policy Statement states that caffeine consumption (equivalent to 2-3 cups of caffeinated beverages per day) is usually compatible with breastfeeding. Although caffeine is passed from the mother to the infant through breast milk, the amount is small and, if maternal caffeine consumption is not excessive, should not have an effect on the baby. Large amounts of caffeine, however, may cause some nursing infants to become irritable or may affect sleeping patterns, so practicing moderation is key [92].

CONCLUSION:

As clearly discussed in the above review, there is evident that caffeine consumption at varying levels may help reduce the risk of several chronic diseases. However, sensitive sub-populations, including pregnant women, children and older individuals, should limit the consumption to three cups of coffee per day, or no more than 300 mg/ day, to avoid adverse effects.

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