Caffeinated Beverages, Behavior, and Brain Structure

CAFFEINATED BEVERAGES, BEHAVIOR, AND BRAIN STRUCTURE

5

O.J. Onaolapo⁎, A.Y. Onaolapo† ⁎

Faculty of Basic Medical Sciences, Department of Pharmacology, Ladoke Akintola University of Technology, Osogbo, Nigeria †Faculty of Basic Medical Sciences, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Nigeria

5.1 Introduction Caffeine (Fig. 5.1) is the most widely used central nervous system stimulant worldwide (Porciúncula et al., 2013; Ferré, 2016), and probably mankind's most popular drug. It is a natural constituent of no fewer than 60 plant species; and a part of the human diet, by reason of its presence in drinks made from plant extracts. Caffeine is found in significant quantities in plants like; kola nut (Cola nitida), coffee bean (Coffea arabica), tea leaf (Camellia sinensis); and in little less concentration in cocoa bean (Theobroma cacao). In its pure form, caffeine is a bitter, white, crystalline, purine alkaloid belonging to the class of molecules called xanthines and has been described as an ancient wonder drug (McCarthy et al., 2008), largely for its ability to enhance mood and cognition, reverse fatigue, increase alertness, and promote wakefulness (Lieberman et al., 2002; Haskell et al., 2005) in consumers. Caffeine-containing beverages like coffee, tea, cocoa, chocolate, soft drink beverages (Coca-Cola, Pepsi-Cola, and Dr. Pepper), and energy drinks (Rostagno et  al., 2011) enjoy widespread popularity because of the stimulant effects of caffeine; making caffeine one of the most widely consumed legal and unregulated psychoactive substances worldwide. In addition to the traditional sources of consumed caffeine; it is now added to bottled water, food products like potato chips, baked goods, puddings, dairy desserts, candy, a variety of overthe-counter pharmaceuticals (such as cold medications and analgesics), and other nonfood products (like shampoo and soap); thus,

Caffeinated and cocoa based beverages. https://doi.org/10.1016/B978-0-12-815864-7.00005-2 © 2019 Elsevier Inc. All rights reserved.

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Fig. 5.1  Chemical structure of caffeine.

confirming the ever-increasing popularity of caffeine (Temple, 2009). In 1962, a Japanese company called Taisho introduced Lipovitan D, an energy drink; and by the 1980s, energy drinks that were vitamin fortified, and containing higher concentrations of caffeine were being consumed by Japanese executives and salaried workers to help them put in longer hours at work (Engber, 2013). However, by 1987, the energy drink Red Bull was introduced into the market, with the target population being adolescents, young adults, sportsmen, and women; since then, the energy-drink market has also grown extensively, with different brands containing varying concentrations of caffeine now available (Reissig et al., 2009). Caffeinated alcoholic beverages have also been added to the market (O'Brien, 2009). Widespread caffeine use is of interest; in that it reflects the propensity of people to use stimulant drugs (with the increased risk of addiction), and it may contribute to human disease, since caffeine use in excess can result in serious health hazards (Temple, 2009) and, death from caffeine overdose (Fox, 2017). In this chapter, we discuss caffeinated beverages by tracing back the history of human association with caffeine and caffeine-containing plants. We also examine how caffeinated beverage consumption affects health and well-being, with specific references to behavior, brain chemistry, and brain morphology.

5.1.1 History of Caffeine and Caffeinated Beverages Humans are believed to have been consuming caffeine or c­ affeine-containing plants since the Stone Age (Escohotado and Ken, 1999). There are reports that far back in history, people grew accustomed to chewing the seeds, bark, or leaves of certain plants because these plants had been associated with mood elevation, stimulation of awareness, and reduction of fatigue; and as time progressed, they realized that soaking these plants in hot water increased the stimulant effect. Many cultures have legends that surround the use of these plants. Worldwide, caffeine use has become steeped in culture; however, the historical origins of caffeine or caffeine-­containing plants/food like coffee, tea, kola nut, cocoa, and chocolate are hidden in myth.

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Caffeine was discovered in 1819 by Friedlieb Runge, a German chemist who was asked by Johann Wolfgang von Goethe (a German writer and statesman) to analyze a box of Arabian mocha beans; from which he isolated the world's first sample of relatively pure caffeine (Weinberg and Bealer, 2001). Since then, caffeine has been found in 63 species of plants. The word “caffeine” is believed to have originated from kaffee a German word, Dutch word “Koffe,” and café a French word, both translating directly to mean “coffee” in English. The first coffee house in Europe opened in France (Paris) in the 1800s with Armenian merchants playing a very important role in the spread of coffee. Caffeine’s influences on expanding economies (by directly or indirectly promoting health and well-being) have also been profound. The beginning of the industrial revolution in Europe has been reported to coincide with the introduction of coffee and tea; with suggestions that the widespread use of caffeinated beverages replaced the consumption of beer, thus facilitating the great transformation of human economic endeavor from the farm to the factory (Reid, 2005). Also, in the crowded work settlements of the industrial revolution factories, the health benefits of boiling water to make coffee or tea, or the increased alertness derived from the caffeine content of these beverages, make caffeinated beverages the “drug” that made the modern world possible (Reid, 2005). Cups of hot coffee, tea, and chocolate have become mainstays of the diet, and a significant day starter in most developed and developing countries the world over. In Britain, France, and America, it is dispensed in outlets in almost every street and enjoyed in the home or during breaks at work (Hope, 2015).

5.1.1.1 Coffee There have been suggestions that the English word “Coffee” is derived from the Dutch word “Koffe” in 1582, as an indirect translation from its original Arabic “qahwah,” through the Turkish translation “kahveh,” which was used to describe not the plant but the beverage derived from its infusion (Ukers, 2009). The undocumented origin and/or history of coffee have been reported to date as far back as the 10th century. Although its beginnings are shrouded in folklore and mystery; Ethiopia is considered as the native origin of undomesticated coffee. Legendary accounts claim that the ancestors of the Oromo people of Kaffa in Ethiopia were the first to recognize the revitalizing effects of the coffee plant (Weinberg and Bealer, 2001); although there are no direct evidences demonstrating exactly when, where, or whom among the native populations of Africa may have used coffee as a stimulant, or even known about it, earlier than the 17th century (Weinberg and Bealer, 2001). A popular folklore is the story of Kaldi, a 9th-century Ethiopian goatherd, who discovered coffee when he ­noticed how

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excited his goats became after eating the beans from a coffee plant; however, this narrative did not appear in writing until 1671, and is therefore, probably apocryphal (Weinberg and Bealer, 2001). In another account, the discovery of coffee has been attributed to Sheikh Omar who while on exile (from Mocha in Yemen to a desert cave near Ousab, now modern day Wusab) and in need of nourishment, happened upon some berries which after repeated attempts realized that on boiling, it produced a fragrant brown fluid which revitalized him and sustained him for days (Sweetser, 2012). Stories of this “miracle drug” reached Mocha, and Omar was asked to return and made a saint (Ukers, 1935). The earliest accounts demonstrating knowledge of the coffee tree, or evidence of people drinking coffee appears in the mid-15th century accounts of Ahmed al-Ghaffar in Yemen (Weinberg and Bealer, 2001). It was here that coffee seeds were first roasted and brewed, in ways similar to how it is prepared today. Coffee consumption was also linked to the 15th-century monasteries of the Sufis in Yemen, among whom coffee was used to keep awake during religious rituals (Houtsma et al., 2016). Prior to its appearance in Yemen, the accounts of the origin of coffee or coffee seeds differ; with one account crediting Muhammad bin Said for bringing the beverage to Aden from the African coast (Hattox, 1985), while an earlier account credits Ali bin Omar of the Shadhili Sufi order as the first to introduce coffee to Arabia (Burton, 1856). By the 16th century, coffee had reached the rest of the Middle East, Turkey, Persia, and northern Africa. There are accounts (both written and pictorial) of a Sufi Baba Budan smuggling the first viable coffee seeds (seven) out of the Middle East (Yemen) to India in 1670. Prior to this, all exported coffee was boiled or otherwise sterilized. The first plants grown from these seeds were planted in Mysore (Meyers, 2005). Coffee then spread to Italy, the rest of Europe, Indonesia, and then introduced to North America by the 17th century (Meyers, 2005; Ukers, 2009). A Frenchman, Gabriel de Clieu is also credited with taking a coffee plant to the French territory of Martinique in the Caribbean Islands, from which much of the world's cultivated Coffea arabica coffee is believed to be descended (Pendergrast, 2010).

5.1.1.2 Tea The history of tea involves multiple cultures spanning thousands of years. Historical documentations suggest that tea likely originated from southwest China as a medicinal drink during the Shang dynasty spanning 1500–1046 BC (Heiss and Heiss, 2011); with written evidence acquired from a medical text by Hua Tuo dated to the 3rd century AD. The Yunnan Province has also been designated as the birthplace of tea, since it was discovered that this region was the first place where people first recognized that consuming tea could be pleasurable, and

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not just as medicinal (Fuller, 2008), it is also home to the world's oldest cultivated tea tree. There are also stories that date the first cup of tea ever brewed to 2737 BC, when dried leaves of tea fell into a boiling cup of water served to the Chinese Emperor Shennong (Saberi, 2010). In the 16th century, Portuguese priests and merchants were also introduced to tea in China (Weinberg and Bealer, 2001); while in the 17th century, the consumption of tea became popular in Europe. Tea was introduced into the United States by Peter Stuyvesant (1650). In 1904, iced tea was invented at the St. Louis World's Fair and teabags made their appearance commercially. More recently in 2016, physical evidence from the mausoleum of Emperor Jing of Han in Xi'an, demonstrated that tea was drunk as far back as the Han Dynasty emperors of the 2nd century BC (Lu et al., 2016).

5.1.1.3 Cocoa The word “cocoa” comes from the Spanish word cacao, which was derived from the Nahuatl word cacahuatl (Bingham and Roberts, 2010), which is also a derivation of the Proto Mije-Sokean word *kakaw~*kakawa (Kaufman and Justeson, 2006). The word cacahuatl also referred to chocolate (a bitter and spicy drink), which was consumed in the New World (Chocolate Facts, 2005). The cacao tree from which the cocoa beans arise is native to the Americas (Central America and Mexico). There are reports that it had been used in spiritual ceremonies among cultures as far back as the Olmeca civilization, the Yucatán, and the Mayans. Prior to the Spanish colonization of the Americas, the cocoa bean was a common currency throughout Mesoamerica (Wood and Lass, 2001). Analysis of an archaeological site pottery residue excavated in Honduras, suggested that cocoa products were first consumed there sometime between 1500 and 1400 BC; while the analysis of another archaeological site finding (a residue found in an ancient Mayan pot) revealed that the earliest mentions of cocoa use may be dated to 600 BC (Trivedi, 2002). It is believed that the Mayan civilization worshiped the cocoa tree, giving it the Latin name Cocoa, meaning “Food of the Gods.” There is undisputed evidence that reveal that long before chocolate, cocoa was used in making a fermented beverage in the United States (Henderson et al., 2007). Following the Spanish conquest, the Spaniards discovered cocoa beans and began to trade in them, eventually monopolizing the chocolate market in Europe. As the love for the cocoa bean and chocolate grew, at about the 1700s, a Frenchman opened the very first hot chocolate shop in London; and by the 18th century, most countries in Europe were producing confections from the cocoa bean (World Cocoa Foundation, 2017). Worldwide today, more than 4.5 million tons of cocoa beans is consumed each year (World Cocoa Foundation, 2017).

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5.1.1.4  Kola Nut The kola nut, from which the term “cola” derives, is the fruit of species of kola tree, native to the tropical rainforests of Africa. The caffeine-containing fruits of these trees are employed as a flavoring ingredient in a number of beverages. The origins of the kola nut, like other caffeine-containing plants, are also ancient; with evidence of it being chewed in many West African cultures, either by individuals, in social settings or significant life events like weddings, naming ceremonies, and funerals. Its use in these parts is steeped in the strong belief that it restores vitality. It had also found importance in the traditional spiritual practices of a number of West African cultures and religions, particularly in parts of Niger, Nigeria, and Liberia (Adewale-Somadhi, 2004). Among the Hausas, the variant commonly consumed is called “goro” (Robinson, 1913); and a song titled “Goro City,” by Manu Dibang (released in 1987) was used to depict the importance of kola nut in Niamey (Niger). Kola nuts are also used by the Igbos of Nigeria in sacred offerings, during prayers, ancestor veneration and traditional worship (Epega, 2003). Kola nuts were used as a form of currency in Mali and Senegal; and in some present day communities, kola nuts are still used in negotiation of bride prices or to seal a business arrangement (Epega, 2003). In the 1800s, John Pemberton, a pharmacist in Georgia mixed kola and coca extracts with sugar and carbonated water to invent the first cola soft drink known as “Coca-Cola.” However, inclusion of cocaine in soft drinks was prohibited in the United States after 1904 (Benjamin et al., 1991; Meyers, 2011).

5.2  Caffeinated Beverages: Sources, Plant Biology, Pharmacology, and Health Benefits 5.2.1  Caffeine-Containing Plants: Biology and Morphology 5.2.1.1  Coffee Plant The coffee bean from which coffee is brewed is the world’s major source of caffeine. However, the caffeine content in coffee depends on the type of coffee bean and the method of preparation. Coffee is a very important commodity worldwide, and it is used up in massive quantities; with an estimated 2.25 billion cups consumed each day (Ponte, 2002). Tens of millions of small producers from farming societies in the developing countries earn their living by growing coffee. The coffee plant is a member of the known genus Coffea, which belong to the large family Rubiaceae. It is an evergreen shrub or tree that may

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grow up to 5 m tall when left unpruned. The leaves are dark-green and glossy, usually 10–15 cm long, 6 cm wide, simple, and opposite. The petioles of opposite leaves fuse at base to form interpetiolar stipules, which are characteristic of Rubiaceae. The flowers are axillary, and clusters of fragrant white flowers are known to bloom simultaneously. It has a gynoecium which consists of an inferior ovary, which is also characteristic of Rubiaceae. The flowers give way to oval berries that are about 1.5 cm in size (Duke, 1983). The immature beans are green, turning yellow when they ripen, then crimson, before turning black on drying. Each berry usually contains two seeds, but 5%–10% of the berries have only one; these are called pea berries (Hamon et al., 1995). Several species of the genus Coffea produce the berries from which coffee is extracted. Two main species which are cultivated commercially are Coffea canephora (Robusta) and Coffea arabica (Atkinson et  al., 2009; Botanical Aspects, 2009). The Coffea arabica accounts for over 70%–80% of the world’s coffee production, while Coffea canephora accounts for about 20%. Coffea arabica is native to the southwestern highlands of Ethiopia, the Boma Plateau in south-eastern Sudan and Mount Marsabit in northern Kenya (Clifford and Wilson, 1985). Coffea canephora is native to western and central Africa, from Guinea to Uganda and southern Sudan (Clifford and Wilson, 1985). Other species include Coffea stenophylla, Coffea liberica, Casearia mauritiana, and Caulerpa racemosa. When grown in tropical regions, coffee is a vigorous bush or small tree that usually grows to a height of 3–3.5 m. The Coffea arabica tree fruits after 3–5  years, and will continue to produce fruits for up to 50–60 years (Adriana, 2007). The white flowers are highly scented. The Arabica berries ripen in 6–8 months, while robusta takes 9–11 months (Pradeepkumar, 2008). The arabica coffee from Coffea arabica is more highly esteemed than robusta coffee which is from Coffea canephora; this is because the robusta blend is bitter and has less flavor compared to the Arabica blend. However, the robusta blend contains about 40%–50% more caffeine than Arabica (Belachew, 2003). Documentation by Rhazes (850–922 AD), a Persian medical doctor and the writings of Avicenna (980–1037 AD) both attest to the possible health benefits of coffee, and its possible use as a medicine in the treatment of a variety of ailments, including kidney stones, gout, smallpox, measles, and coughs. Presently, there are conflicting reports on the possible health benefits or potential harmful effects of coffee consumption (Kummer, 2003); with a number of the studies being complicated by differences in serving size, health status, age, and gender. Recent studies have however reported that habitual coffee consumption improves on glucose tolerance in nondiabetics (Marjo and Miia, 2010); while moderate consumption of coffee has been associated with a reduced mortality risk from cardiovascular disease (Andersen et al., 2006). The presence

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of phenolic compounds with antioxidant properties in coffee has been suggested to alter the process of atherosclerosis; by the inhibition of platelet aggregation and thrombogenesis, and reduction of lowdensity lipoprotein cholesterol levels (Bidel and Hu, 2006). However, the overall consensus remains that moderate regular coffee consumption in healthy adults is safe (van Dam, 2012), and not associated with stunting in children (Levounis and Herron, 2014).

5.2.1.2  Tea Plant The tea plant whose leaves and buds are used to brew tea is called Camellia sinensis (L.) Kuntze. Camellia sinensis is a member of the genus Camellia and flowering plant of the family Theaceae. They are evergreen shrubs or small trees that attains a height of about 10–15 m when undomesticated and about 0.6–1.5 m when cultivated (Mahmood et  al., 2010). The young leaves are generally light-green, alternate, short-stalked with serrate margin, pubescent, varying in length from 5 to 30 cm, and about 4 cm wide; while mature leaves are bright-green colored, smooth, and leathery. The flowers are white, fragrant, and occurring solitary or in cluster (Mahmood et al., 2010). Flowers bear numerous brownish red capsules (Ross, 2005). The fruit is a smooth, flattened, trigonous three-celled capsule with solitary seeds in each, the size of a small nut (Biswas, 2006). Two major varieties of the tea plant are usually cultivated: Camellia sinensis var. sinensis which is used to make Chinese teas, and the Camellia sinensis var. assamica for Indian Assam teas (ITIS, 2011). The different variants of the tea leaves (white tea, green tea, red tea, yellow tea, oolong tea, and black tea) are all harvested from one or the other, and differ only in the postharvest processing that they undergo to attain varying levels of oxidation. The green tea is the unfermented form, while the oolong tea is partially fermented and the black/red teas are fermented. The fermentation of black tea is carried out by an oxidation process catalyzed by polyphenol oxidase, while the red tea is attained by fermentation using microorganisms (Cabrera et al., 2006). The twig or Kukicha tea is also harvested from Camellia sinensis, but is made from twigs and stems of the plant and not the leaves. Tea contains a number of bioactive compounds including flavonoids (Sumpio et  al., 2006), which are called tea catechins [(−)-catechin] and constitute up to 20%–30% of the dry weight of green tea; while quercetin, kaempferol, and myricetin constitute 2%–3% of water-­ soluble extracts in tea (Mahmood et  al., 2010). Tea leaf was used in traditional Chinese medicine for the treatment of different ailments; and more recently, studies have continued to demonstrate the efficacy of tea in combating aging, cancers, Parkinson’s disease, type 2 diabetes, psychiatric, and neurodegenerative disorders (Khan and Mukhtar, 2013; Lardner, 2014; Wang et al., 2014; Caruana and Vassallo, 2015).

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5.2.1.3  Cocoa Tree The cocoa or cacao tree whose seeds (cocoa beans) are used in the production of cocoa powder, chocolate, ganache, or cocoa drink is called T. cacao. It is a small, evergreen tree belonging to the family Malvaceae (Alverson et  al., 1999) and native to the deep tropical regions of Central and South America. The three main varieties of T. cacao available commercially are: Forastero, Criollo, and Trinitario. The Forastero tree is the most commonly grown variety comprising 80%–90% of the cocoa production worldwide. The Criollo variety is rare, having lower yields compared to the Forastero variety and is also less resistant to several diseases invading the cocoa plant. Trinitario is a hybrid between Criollo and Forastero varieties; it is considered to be of much higher quality than the Forastero variety, has higher yields, and is also more resistant to disease than Criollo. T. cacao can grow as tall as 12–15 m in the wild, and about 4–8 m when cultivated. The leaves are alternate, unlobed, about 10–40 cm long and 5–20 cm broad. The tree blooms and fruits all year round; the cocoa tree flowers are small, 1–2 cm (0.39–0.79 in) diameter, with pink calyx (Ronse De Craene, 2010), cauliflory occurring in clusters directly on the trunk and older branches and are pollinated by tiny flies, Forcipomyia midges of the subfamily Forcipomyiinae (Forbes and Northfield, 2016). The fruit or cocoa pod is ovoid in shape, weighing about 500 g when ripe, and measuring about 15–30 cm long and 8–10 cm wide; ripening changes its color from yellow to orange. The pod contains 20–60 seeds, usually called “beans,” embedded in a white pulp. The seeds are the main ingredient of chocolate, while the pulp is used in some countries to prepare juice, jelly, and smoothies. Each seed contains a significant amount of fat (40%–50%) as cocoa butter. The cocoa tree begins to bear at between 4 and 5  years of age; with a mature tree producing over 6000 flowers in a year, although only about 20 cocoa pods. The high concentrations of antioxidant, procyanidins, and flavonoids in the cocoa bean have been suggested to impart antiaging properties (Gressner, 2012), cardiovascular health benefits (Schroeter et al., 2006; Ding et al., 2006; Taubert et al., 2007) following habitual or prolonged use of the raw cocoa and to a lesser extent, dark chocolate, since the flavonoids content degrades and reduces with cooking and alkalization. Short-term benefits in the reduction of LDL cholesterol levels from dark chocolate consumption have also been reported (Corti et al., 2009).

5.2.1.4  Kola Nut The kola nut is the seed of evergreen trees of the genus Cola, primarily of the species Cola acuminata and Cola nitida (Burdock et al., 2009). Cola acuminata, is an evergreen tree of the family Malvaceae,

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native to tropical Africa; while Cola nitida belongs to the family Sterculiaceae. They are native to the rainforests of tropical West Africa and common names are kola nut (both) or bitter kola (Cola nitida). The trees grow to about 20–25 m tall, with long, ovoid, leatherytextured leaves, pointed at both ends. The flowers are yellow with purple spots, giving rise to star-shaped fruits. About a dozen round or square seeds develop in a white seed-shell inside the fruit pod. The nut has a sweet and rose-like aroma; and when eaten, the first taste is bitter, but it sweetens with chewing. The seeds contain caffeine and are chewed as a stimulant and or can be boiled to extract the cola used in the manufacture of soft drinks.

5.2.2  Caffeine Content, Caffeinated Beverage Consumption, and Health The common sources of caffeine intake in humans include are coffee, tea, some soft drinks, and chocolate. The amount of caffeine in food products is known to vary depending on the serving size (of the beverage, drink, or food), the type of product (naturally occurring or added caffeine), and methods of processing or preparation. With plant-derived caffeine sources like teas, coffee, cocoa, kola nut, and mate, the plant variety also affects caffeine content. The caffeine content of beverages is known to vary from 70 to 220 mg/15 cl for coffee, 30 to 70 mg/33 cl for cola, 32 to 42 mg/15 cl for tea, 4 mg/15 cl for cocoa (Debry, 1994), and 32 mg/100 mL in energy drinks. Caffeinated beverages are consumed worldwide; although consumption levels vary significantly from one region to another. In the United States, about 80%–90% of the adult populations consume caffeine-containing beverages (Reissig et al., 2009; Temple, 2009; Fulgoni et al., 2015) with mean consumption levels reaching about 210–238 mg/day. In the United Kingdom, mean caffeine consumption is estimated at 359 mg/day (Winston, 2005); while it is 400 mg/day/person in Sweden and Finland, with almost the entire caffeine intake coming from coffee (Barone and Roberts, 1996; Viani, 1996). Studies have also shown that approximately 89% of women aged between 18 and 34  years in the United States consume an average of 166 mg caffeine/day (McCusker et  al., 2003; Frary et  al., 2005; Branum et  al., 2014; Ahluwalia et  al., 2014, Ahluwalia and Herrick, 2015). There have been concerns about the health implications of increasing levels of caffeine consumption in the general population, and among at-risk groups (children, adolescents, pregnant, or lactating women); despite reports (following extensive researches) by health authorities of its safety and the absence of any potential health risk to the general population of healthy adults, following caffeine consumption up to 400 mg/day (Nawrot et al., 2003; Health Canada, 2010;

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European Food Safety Authority, 2015). Caffeine consumption in atrisk groups like children, adolescents, pregnant, and lactating mothers have been specified; in children between 10- and12-year old, caffeine consumption should be limited to not more than 85 mg caffeine/day, not more than 125–175 mg in adolescents (13–18  years old), and in pregnant women, maximum daily intake levels of caffeine were set at approximately 200 mg/day (Health Canada, 2010; Zucconi et al., 2013; European Food Safety Authority, 2015). In recent times, the introduction of new caffeinated foods and beverages has triggered interest in health issues that might follow the inadvertent consumption of caffeine from multiple sources (like chewing gum, sweets, potato chips, water, and medicines) in addition to the more traditional caffeine sources like coffee, tea, colas, and chocolate (Verster and Koenig, 2018). In the United States, a number of conclusions have been drawn by researchers from two large national representative surveys that monitor caffeine intake from food and beverages (The Kantar World panel (KWP) and the National Health and Nutrition Examination Survey (NHANES)). Mitchell et  al. (2014) examining the KWP data concluded that coffee, carbonated soft drinks, tea, and energy drinks comprised approximately 98% of daily caffeine intake (Mitchell et al., 2014), with 63% consuming carbonated soft drinks, 55% coffee, 53% tea, and 4% energy drinks. There was also an age-related increase in caffeine consumption with about 43% in 2–5 year olds, to almost 100% in participants 65  years of age and older. They also observed an overall increase in caffeine consumption from 120 mg/day in 1999 to 165 mg/day in 2010; with an increase in caffeine contribution derived from an increase in the consumption of coffee (53%–64%), a decrease for carbonated soft drinks (29%–17%), with the contribution from tea remaining stable. Somogyi (2010) examining caffeine intake data taken from the national representative NHANES collected yearly from 1999 to 2006 as well as the NPD Group's Food Consumption surveys, conducted in 2008 concluded that caffeine consumption increased with age, with sex differences in consumption observed (men consumed more caffeine (mg/day) compared to women); with the highest caffeine intake (295.6 mg/day) observed in men within the 50–59  years age group (Somogyi, 2010). Similar conclusions were reached by researchers examining national surveys in Europe (Fitt et al., 2013; Lachenmeier et al., 2013; Rudolph et al., 2014), Australia (Beckford et  al., 2015; Food Standards Australia and New Zealand (FSANZ), 2015), and Canada (Health Canada, 2010); although the EFSA reported that tea as the main source of caffeine in the United Kingdom and Irish adult population compared to coffee in all other investigated EU countries (European Food Safety Authority, 2015). In South Korea, Lim et  al. (2015), using data from the Korean National Health and Nutrition Examination Survey (KNHNES),

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c­ onducted between 2010 and 2012 deduced that mean daily caffeine intake among Korean population was 67.75 mg/day with men consuming more caffeine than women. Among adolescents (15–18 years old), caffeine intake was 30.04 mg/day, while for children, it ranged from 1.38 mg/day in 1–3  year olds to 10.05 mg/day in children 12–14  year olds. Main sources of caffeine intake among the Korean population included coffee (89%), which was followed closely by tea, and carbonated soft drinks; although among young adults (15–19 year olds), carbonated soft drinks were the main source of caffeine (30%). Verster and Koenig (2018) reviewing national survey data from a number of countries over a 10–15 year period concluded that (1) the mean total daily caffeine intake in children, adolescents, and adults was below caffeine intake recommendations of regulatory bodies like the EFSA (3 mg/kg body weight/day for children and adolescents, and 400 mg/day for adults) or Health Canada (2.5 mg/kg body weight/day for children and adolescents, and 400 mg/day for adults), (2) total caffeine intake had remained stable in the last 10–15 years, with coffee, tea, and soft drinks being the key contributors to daily caffeine intake. They also deduced that contributions by energy drinks did not significantly increase caffeine intake; however, this opinion is not shared by all, as there have been reported a vast increase in the consumption of energy drink among young adults aged 18–24 years (Côté, 2009). In 2006, Thailand was reported to have had the highest energy drink consumption per person, although the United States reported the highest sales of energy drinks (Reissig et al., 2009). The consumption of alcoholic beverages combined with energy drinks or caffeinated alcoholic drinks has increased in last few years; the potential harmful effects of such combinations are downplayed by reports that have suggested that the caffeine content of energy drinks could decrease the intensity of ethanol-induced brain depressant effect (Ferreira et  al., 2004; FDA, 2009). The hospitalization in the fall of 2010 of college students who had consumed several cans of a caffeinated alcoholic beverage (Goodnough, 2010a) led to the banning of alcoholic beverages in some American states (Goodnough, 2010b) with warning letters issued to the producers of some of these beverages (FDA, 2010).

5.2.3  Bioactive Compounds in Caffeinated Beverages Caffeine (an alkaloid) is a bioactive compound common to all caffeinated beverages, and it has been associated with the main stimulant effects that follow their consumption. Apart from caffeine, the different plants and plant parts from which these beverages are derived contain a number of other bioactive compounds that have

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been found useful in the health promoting effects associated with the consumption of these beverages. Coffee is rich in other bioactive substances, like nicotinic acid, quinolinic acid, trigonelline, pyrogallic acid, and tannic acid (Minamisawa et  al., 2004). Coffee is also rich in polyphenolic antioxidants, with a high content of phenolic acids like caffeic, ferulic chlorogenic, sinapic, and coumaric acids (Manach et al., 2004). In human diet, coffee provides a major source of chlorogenic acids (Daglia et al., 2000); with suggestions that chlorogenic acids and their isomers (caffeoylquinic, dicaffeoylquinic, and feruloylquinic) are important in the formation of pigments, aroma, and taste of coffee beverages (Olthof et al., 2001; Yen et al., 2005), and also possessing an in vitro antioxidant activity (Moreira et al., 2001). Coffee also contains dietary minerals like chromium and magnesium. The chemical component of tea leaves includes alkaloids (caffeine, theobromine, theophylline), polyphenols (catechins and flavonoids), amino acids, polysaccharides, lipids, vitamins (like vitamin C), volatile oils, and inorganic elements (aluminum, fluorine, and manganese). However, the polyphenols, especially flavonoids have been associated with the numerous health benefits of tea. The polyphenols content of green tea and black tea varies from 30% to 40% and 3% to 10%. Flavonoids found in large quantities in green or black tea has antioxidant, antiinflammatory, anti-allergic, and antimicrobial effects; green tea also contains catechins like gallocatechin, epigallocatechin, epicatechin, gallate, and epigallocatechin gallate (EGCG) (Bhutia Pemba et al., 2015). The cocoa bean contains proteins or nitrogenous elements like theobromine which constitutes about 1.0%–2.5% of its weight and caffeine (0.06%–0.4%). It is also very rich in fat (50%), starches and sugars (together form 20%–25%) of the weight of the bean. The cocoa bean contains antioxidants and flavonoids with flavan-3-ols (epicatechin and catechin) present in high concentrations (Whiting, 2001; Gu et al., 2004). However, the concentrations of antioxidants can be altered by genetic variability, which can generate up to a one- to fourfold difference in the antioxidant content of fresh cocoa beans (Rusconi and Conti, 2010), or biological processes like roasting, fermentation, and ditching which are necessary during production of cocoa powder or chocolate preparation (Clapperton, 1994). Cocoa also contains biogenic amines like serotonin, phenylethylamine, tryptophan, tyrosine, tyramine, and tryptamine, which are present in negligible concentrations.

5.2.4  Caffeinated Beverages and the Brain Coffee and tea are the most frequently consumed beverages worldwide, and they contain high levels of caffeine and polyphenols (phenolic acids or flavonoids). Caffeine is a well-known central nervous system stimulant, while polyphenols have antioxidant potential.

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5.2.4.1  Coffee and the Brain Effects of coffee consumption have been studied extensively, with research demonstrating that caffeine (a major constituent of coffee, and also tea, chocolate, cocoa, and cola) induces a number of cellular and pharmacological responses in the brain, including stimulation of motor activity (Fredholm et al., 1999), improvement in memory and cognition (Arendash et  al., 2006; Cunha and Agostinho, 2010), increased anxiety and sleep deprivation (Nardi et  al., 2009), and antioxidant activity (Noschang et al., 2009). However, coffee also contains a number of other substances like phenolic acids, chlorogenic acids, lipids, and terpenes that also have biologically effects; like the maintenance of antioxidant status (Cho et  al., 2009) and neuroprotective effects (Herraiz and Chaparro, 2006; Hwang and Jeong, 2008). There has been evidence linking chronic consumption of coffee to improved cognitive performance in humans (Ritchie et  al., 2007; Santos et  al., 2010). Studies have also demonstrated that the consumption of coffee can decrease lipid peroxidation in the brain, increase concentration of endogenous antioxidants like glutathione, and increase activity of antioxidant enzymes such as glutathione reductase and superoxide dismutase (Abreu et al., 2011). These antioxidant properties have been attributed partly to the effects of caffeine at adenosine receptors (Inkielewicz-Stepniak and Czarnowski, 2010; Prasanthi et  al., 2010); which are also involved in the regulation of reactive oxygen species (ROSs) production, and the maintenance of oxidant antioxidant balance in neurons, and others biological systems (Thakur et al., 2010). Coffee also contains large quantities of phenolic acids like, caffeic acid and chlorogenic acid which have also been reported to have significant antioxidant potential and have demonstrated beneficial effects in the attenuation of oxidative stress in different studies (Cho et  al., 2009). The presence of diterpenes, like kahweol and cafestol, which also have antioxidant properties, has also been linked to the antioxidant potential of coffee (Lee and Jeong, 2007).

5.2.4.2  Tea and the Brain Tea (green and black tea) contains a large number of bioactive compounds with numerous health benefits (Chacko et  al., 2010; Johnson et al., 2012), although its effects on the brain have generally been attributed to its caffeine, theanine (Bryan, 2008), and catechins content (Lee et al., 2009). In a number of studies, the antioxidant, antiinflammatory, and neuroprotective effects of green tea and its constituents like catechins and theanine have been demonstrated (Lee et al., 2009, 2013; Biasibetti et al., 2013). Tea catechins have also been associated with improvement in cognitive function in rodent models of dementia (Lee et  al., 2013), while theanine has been reported to

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mitigate amyloid protein-induced memory impairment (Kim et  al., 2009). It has also been suggested that theanine may affect cognition through its effects on the availability of tyrosine and tryptophan which are precursors of brain neurotransmitter levels. Theanine also binds to receptors and transporters involved in glutamate and γ-aminobutyric acid neurotransmission (Kakuda et  al., 2002, 2008); neurotransmitters that are also involved in the modulation of attention (Levin et al., 2011). In a number of human studies, a relationship between tea consumption and cognitive function (Kuriyama et  al., 2006; Nurk et  al., 2009; Feng et  al., 2010) have been demonstrated; with these studies reporting that the consumption of green tea is associated with a decline in age-related cognitive impairment (Kuriyama et al., 2006). A few interventional studies have also verified these assertions (Kakuda, 2011; Park et al., 2011; Feng et al., 2012). Theanine is an amino acid that is found exclusively in tea, where it exists with caffeine; it has a high bioavailability, reaches its maximum concentration in plasma at approximately 45 min following the consumption of tea (Van der Pijl et al., 2010). Its chemical structure is similar to glutamic acid (Nathan et al., 2006). It is metabolized into glutamic acid and ethylamine, with a little fraction excreted in urine (Van der Pijl et al., 2010; Scheid et al., 2012). Research into the possible effects of l-theanine in humans is limited, compared to caffeine; however, a few studies have demonstrated the anxiolytic effects of theanine (Kimura et al., 2007; Rogers et al., 2008). The anxiolytic effects of theanine have also been buttressed by results of electroencephalographic studies that revealed increases in resting alpha activity which has been associated with relaxation (Nobre et al., 2008). During an attention task performance, theanine increased resting α activity and decreased tonic alpha activity (Gomez-Ramirez et  al., 2009), which has been related to better performance (Klimesch et al., 1998). Theanine has also been reported to cause a dose-dependent increase in dopamine concentrations in rodent brain (Yokogoshi et al., 1998), and also protect against human neuronal cell death in vitro (Cho et al., 2008). The psychoactive properties of theanine appear to be more complex than caffeine, although there have been suggestions that theanine may lack biologic effects in the absence of caffeine. Studies evaluating the possible cognitive effect of l-theanine reported that in isolation, it results in a decrease in cognitive performance (Gomez-Ramirez et al., 2007; Haskell et al., 2008); or in other studies, no effects (GomezRamirez et al., 2009; Haskell et al., 2008; Kelly et al., 2008; Owen et al., 2008). However, when administered with caffeine, l-theanine modulates or potentiates the effects of caffeine on cognition. l-Theanine has also been reported to antagonize the physiological effects of caffeine on blood pressure control (Rogers et al., 2008).

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The consumers of tea, caffeine, and theanine are taken together, and not in isolation. A few studies that have evaluated the effects of this combination have reported an improvement in accuracy on a cued attention test (Kelly et  al., 2008), speed and accuracy in a battery of cognitive tests (Haskell et al., 2008), accuracy on an attentionswitching task (Owen et  al., 2008; Einöther et  al., 2010; Giesbrecht et  al., 2010), and accuracy on a sustained attention test (Foxe et  al., 2012). These studies provide evidence in support of the cognitive benefits of tea consumption (Hindmarch et al., 1998) especially as it relates to attentiveness. The consumption of tea (either black or green) has been associated with mood altering effects like the feelings of satisfaction (Desmet and Schifferstein, 2008), relaxation, and refreshment (Graham, 1992; Shimbo et al., 2005); benefits that may have been attributed to the interaction of elements such as the temperature at which tea is consumed (hot), sensory properties like color and aroma, and the presence of active constituents which exert their effects either during and/or following the consumption of tea. Scientifically, a few studies have demonstrated tea’s beneficial mood-altering effects, using a number of validated self-reporting scales (Profile of Mood States, University of Wales Institute of Technology Mood Adjective Checklist); and physiologic measures, like skin conductance tests and blood pressure (Steptoe et al., 2007; Mauss and Robinson, 2008; Hozawa et al., 2009).

5.2.4.3  Chocolate and the Brain Cocoa powder and chocolate have been recognized as rich sources of flavonoids, mainly flavanols, which have potent antioxidant and anti-inflammatory effects, established benefits for cardiovascular ­ health, and more recently, beneficial effects on cognition and brain function (Field et  al., 2011; Nehlig, 2013; Sokolov et  al., 2013; Socci et al., 2017). The flavonoids when absorbed penetrate and accumulate in regions of the brain like the hippocampus that modulate in learning and memory. Flavanols, present mostly in the form of epicatechin are believed to act via direct interactions with cellular cascades that control the expression of neuromodulatory and neuroprotective proteins that promote neuronal function, brain connectivity, and neurogenesis (Williams and Spencer, 2012); they also act by increasing cerebral blood flow and angiogenesis (Fisher et al., 2006; Schroeter et al., 2006; Sorond et al., 2008; Nehlig, 2013). A number of studies have reported that long-term consumption of cocoa flavanols result in the enhancement of neurocognition with age- and disease-related improvement in cognitive decline (Desideri et al., 2012; Mastroiacovo et al., 2015). The flavonoids are believed to influence cognitive function by modulating signaling pathways involved in normal memory processing, although the precise mechanisms of action are still being studied; a few

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studies are of the opinion that cocoa flavanols stimulate angiogenesis, improve endothelial function, and upregulate the genes controlling learning in the mouse hippocampus (van Praag et al., 2007). It is commonly accepted that eating chocolate improves mood, and makes individuals feel good about themselves; and chocolate is often associated with emotional comfort. This effect is believed to be related to the ability of carbohydrates, chocolate inclusive to promote similar positive feelings via the release of multiple peptides in the gut and brain (Parker et al., 2002). Eating chocolates has been associated with increased brain levels of endorphins (which lessen pain and decrease stress) (Benton and Donohoe, 1999), stimulation of the release of serotonin (an antidepressant neurotransmitter) and stimulation of dopamine release via the dopamine precursor tyrosine (which is also present in chocolate) or by the lipid anandamide (which is an endogenous ligand for the cannabinoid receptor present in cocoa in low quantities). Hence, chocolate may also interact with neurotransmitter systems to modulate appetite, reward, and mood regulation (Nehlig, 2013; Hamburg et al., 2014).

5.3 Caffeine Methylxanthines like caffeine, theobromine, and theophylline are the most common purine alkaloids found in beverages made from coffee, tea, cocoa, and mate; while synthetic caffeine is added to soft drinks. Caffeinated beverages have gained widespread societal use primarily due to the mild central stimulant properties of caffeine (and to a lesser extent, of the other methylxanthines) which tends to increase vigilance and help defer sleep. This property has engendered extensive interest in the mechanisms underlying the in vivo effects of caffeine and how this impacts health or disease.

5.3.1  Caffeine Biosynthesis and Metabolism Caffeine (1, 3, 7-trimethylxanthine) is a member of the alkaloid family, a group of compounds obtained from plants, whose molecules consist of nitrogen-containing purine rings (Fig.  5.1). Caffeine was first isolated in a relatively pure form in 1819, while in 1827, Oudry isolated “theine” from tea; which was later discovered to be similar to caffeine (Weinberg and Bealer, 2001). The structure of caffeine was described by Hermann Emil Fischer toward the end of the 19th century, one of the achievements that led to the award of the Nobel Prize in 1902 (Weinberg and Bealer, 2001). In its pure form, caffeine is an odorless white powder, with solid or long silky-crystals, and a distinctive bitter taste. It is slightly soluble in water and alcohol, although it dissolves easily in chloroform. Aqueous solutions of caffeine

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are usually neutral (pH = 6.9) (Benowitz, 1990). Caffeine is rapidly absorbed from the gastrointestinal tract following consumption of caffeinated beverages (Newton et  al., 1981; Liguori et  al., 1997). It is detected in the blood stream approximately 5 min after ingestion, reaching peak levels at about 20–30 min (Leah et al., 2012). Caffeine has a negligible pre-systemic metabolism (Arnaud, 1993) and once caffeine is absorbed, it readily crosses the blood-placenta, bloodtestis, and blood-brain barrier. It reaches the brain quickly after absorption, accounting for the relatively rapid onset of psychological effects following the consumption of coffee. It is distributed into all body fluids (Lachance et al., 1983). Pharmacokinetics after oral or intravenous administration of caffeine in humans and animals are comparable (Arnaud, 1993). Caffeine metabolism is extensive; the hepatic microsomal enzyme system mediates 95% of caffeine metabolism, mainly through the cytochrome P450 1A2 (CYP1A2) enzyme (Cappelletti et al., 2015). The remainder of ingested caffeine is metabolized by xanthine oxidase and N-acetyltransferase 2 (NAT2) (Fenster et al., 1998), with only about 0.5%–2% of ingested caffeine excreted unchanged in the urine (Arnaud, 1993). Caffeine is metabolized into three dimethylxanthines including paraxanthine (84%), theobromine (12%), and theophylline (4%), three monomethyl xanthines, trimethyl, dimethyl or monomethyl uric acid, and three uracil derivatives (Mandel, 2002; Leah et  al., 2012). The dimethylxanthines are pharmacologically active and may contribute to the effects of caffeine in humans (Arnaud, 2011). There is significant interindividual variability in absorption and metabolism of caffeine; also, high levels of intake delay caffeine clearance and result in accumulation of its metabolites (paraxanthine and other xanthines), prolonging its duration of action. Ratios of different metabolites in the urine may be used to assess an individual's genetically determined acetylation rate, or to assess the influences of environmental exposures (such as to polycyclic aromatic hydrocarbons) on cytochrome P450-mediated metabolism. The concentrations of caffeine and theobromine in saliva can also be used as a biomarker of consumption (Ptolemy et al., 2010). The rate of metabolism caffeine is variable, with half-lives ranging from 2 to 12 h in healthy adults (Benowitz, 1990; Daly, 1993); with an average of 4–6 h. Consistent with the average half-life of 4–6 h, blood levels of caffeine increase over time in people who drink coffee throughout the day, reaching a plateau in the afternoon or early evening. Caffeine is susceptible to a number of pharmacokinetic drug interactions: its metabolism is inhibited by alcohol and drugs (like cimetidine, mexiletine, disulfiram, estrogen-containing oral contraceptives, and norfloxacin). In most people, caffeine is eliminated from the body overnight, but some of the major metabolites have longer half-lives and are present in the blood longer than caffeine (Benowitz, 1990).

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5.3.2  Caffeine: Mechanism of Action The biologic activities of caffeine, like other methylxanthines, can be explained by (1) its activity at adenosine receptors, particularly in the CNS, (2) the mobilization of intracellular calcium storage, and (3) inhibition of phosphodiesterases (Cappelletti et  al., 2015). Caffeine has been reported to induce calcium release and inhibit its reuptake (Endo, 1977; Supinski et al., 1984) in endothelial tissue; this results in the activation of nitric oxide synthase (eNOS), and increased nitric oxide levels. Caffeine has also been suggested to act as a competitive nonselective inhibitor of phosphodiesterase (Umemura et al., 2006), while also activating protein kinase A; resulting in the phosphorylation of several enzymes linked to glucose and lipid metabolism (Graham, 2001). Researchers are of the opinion that the biochemical mechanisms underlying caffeine’s biologic activity at doses reached by normal human consumption must be activated at concentrations within minimum effective dose and toxic doses. This theory automatically rules out caffeine’s effect on intracellular calcium which tends to occur only at millimolar concentrations; while its actions on cyclic nucleotide phosphodiesterases require very high doses of caffeine, above doses available following normal human consumption. Caffeine’s main mechanism of action is its ability to competitively antagonize adenosine receptors, mainly A1 and A2A subtypes (Ribeiro and Sebastião, 2010) resulting in increased release of dopamine, glutamate, and noradrenalin (Ferré et  al., 1997). In blood vessels, caffeine’s antagonism at adenosine receptors limits adenosine-mediated vasodilation resulting in the reduction of cerebral (Cameron et  al., 1990) and myocardial blood flow (Namdar et  al., 2009). Adenosine A1 receptors can be found in almost all brain areas, with significant concentrations found in the cerebral cortex, hippocampus, cerebellar cortex, thalamic nuclei (Fastbom et al., 1987), nucleus accumbens, and corpus striatum. There is evidence suggesting that antagonistic interactions exists between specific subtypes of adenosine and dopamine receptors; adenosine A2A have been localized to brain regions with high density of dopamine D2 receptors (Ferré et  al., 1997), like the basal ganglia and nucleus accumbens. In the tuberculum olfactorium, adenosine A2 receptors, and dopamine D2 are co-localized. The blockade of A2A receptors in the basal ganglia has been linked to the stimulatory effects of caffeine (Svenningsson et al., 1999). In the brain, activation of adenosine receptors slows down neural activity; however, with caffeine antagonism at these receptors, a general increase in neurotransmission occurs (Fisone et al., 2004; Smith, 2005). The resultant increase in neurotransmitters levels account for the effects of caffeine on arousal, and higher-order attentional processes

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(Ferré et al., 1997; Fan et al., 2005). The ability of caffeine to block adenosine receptors has been observed also at low doses, such as those obtained from ingesting a single cup of coffee.

5.3.3  Caffeine Use in Children and Adolescents In humans, studies have continued to shed light on the possible behavioral effects of caffeine (Smith, 2002; Rogers et  al., 2005), usually in adults; however, in recent times, there has been a noticeable increase in caffeine consumption among children and adolescents (Castellanos and Rapoport, 2002; Knight et  al., 2006; Temple et  al., 2009, 2010). While a few studies have examined the safety of caffeine use in the young, and the effects of consumer-dependent influences of caffeine use on the general body physiology in children (Castellanos and Rapoport, 2002; Knight et al., 2006; Temple et al., 2009, 2010); a lot more needs to be done for us to fully understand the possible health benefits or adverse effects on children and adolescents, considering most of caffeine research in humans had been conducted in adult populations (Temple, 2009). The main sources of caffeine in children and adolescents were usually soda and tea (Frary et  al., 2005); however, more recently, there has been an increase in the consumption of energy drinks, caffeine-containing alcoholic beverages and food (candy bars, chewing gum, sweets, and potato chips) products (Temple, 2009; Heckman et al., 2010). The concentration of caffeine in energy drinks range from 50 mg (equivalent to a can of soda) to 500 mg (equivalent to five cups of coffee) (Temple, 2009); however, there are no strict regulations for the quantity of caffeine in energy drinks, because they are regulated and marketed as dietary supplements. Consumption of high concentrations of caffeine in children and adolescents has been associated with an increase in reported cases of headaches (Hering-Hanit and Gadoth, 2003), sleep difficulties, sleep disturbances, and morning tiredness (Pollak and Bright, 2003; Orbeta et  al., 2006). Studies have also demonstrated that regular caffeine consumption in young subjects is associated with delayed bedtime, shorter time in bed, reduced slow wave, and alpha activity (Aepli et al., 2015). Temple et al. (2017) also reported that acute and chronic caffeine consumption influenced decision-making and risk-taking behaviors dose-dependently in children and adolescents. Case reports of caffeine toxicity and deaths among adolescents reflect the potential dangers of excess caffeine, which may stem from inadvertently consuming too many ­caffeine-containing products or energy drinks (Seifert et  al., 2011; Meier, 2012; Fox, 2017). Caffeinated beverage consumption has been alluded to as a coping strategy among university students, especially during stressful academic periods (Lazarus, 1993; Thoits, 1995). In a study, Rios et al. (2013)

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surveying Puerto Rican students observed that about 49% students reported caffeinated products to be useful in coping with stress. Although caffeine use has been associated with the development of substance use disorders in the general population, a few studies have suggested that this relationship may not be causal (Kendler et al., 2006). Caffeine use in children and adolescents has also been reported to be positively associated with conduct disorders and self-reported violent behavior (Kristjánsson et al., 2013). There have been suggestions that children appear to be less sensitive to the measured effects of caffeine than adults; however, a few studies have reported that adolescent rats are more sensitive to caffeine, as evidenced by the exhibition of higher locomotor activation compared with adults (Marin et al., 2011). Chronic caffeine consumption has been associated with increased tolerance to caffeine, to a greater extent in adolescents than was observed in adults, which would suggest that in adolescent animals, greater neurobiological alterations may be associated with chronic caffeine consumption (Rhoads et al., 2011). Behavioral cross-sensitization with methylphenidate, when tested in adulthood and in the absence of caffeine was also reported to accompany chronic caffeine exposure in adolescence period (Boeck et al., 2009). O'Neill et al. (2015) also reported that adolescence caffeine consumption resulted in increased expression of the dopamine D2 receptor, dopamine transporter, and adenosine A1 receptor, with a decrease in the expression of adenosine A2A receptor in the nucleus accumbens (NAc); protein expressions that were not consistent with adult consumers of caffeine. The authors also concluded that these neurobiological changes within the NAc may contribute to increases in cocaine-mediated behaviors observed (O'Neill et al., 2015). A few studies have evaluated the possible sex-differential effects of caffeine use in adolescent humans (Elkins et al., 1981; Adan et al., 2008; Temple et al., 2009; Richards and Smith, 2015) or rodents (Onaolapo et al., 2015, 2016; Franklin et al., 2017), with mixed results. While examining effects of caffeine in prepubertal boys, Elkins et al. (1981) observed a dose-related impairment of memory which was attributed to an increase in vigilance, but decreased reaction time. Temple et al. (2009), while examining the sex differences in the reinforcing effect of caffeine use in adolescents, reported that males found the caffeinatedsoda significantly more reinforcing than did females, after the exposure period; suggesting that males more than females may be more susceptible to the reinforcing effects of caffeine. Adan et  al. (2008) also reported that caffeine consumption resulted in greater arousal in young males compared with females. In a study investigating the associations between caffeine consumption and single-item measures of stress, depression, and anxiety among students from a secondary in the South West of England,

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Richards and Smith (2015) reported significant interactions between total weekly caffeine intake and sex, in relation to each of the outcome variables. While females did not show any association between caffeine and anxiety; in males, higher instances of anxiety were associated with increasing doses of caffeine. With regard to depression, caffeine consumption correlated with a risk of depression in both sexes; in males, increased risk was observed with caffeine only when compared to non-caffeine consumers, while in females, increasing doses of caffeine was significantly associated with higher reporting of depression. Fisher and Guillet (1997) also reported sex differences in caffeine effect on memory retention in neonatal rats. The deductions from these studies would suggest that in the outcomes of tasks involving caffeine administration, the influences of sex are probably task specific. In a recent study from our laboratory (Onaolapo et  al., 2016), we set out to examine the possible interactions among three factors (caffeine dose, sex, and sleep deprivation) as they relate to novelty-induced behaviors, biochemical markers of stress, and antioxidant status in prepubertal mice. Our results revealed strong associations among these factors in the open-field response and weak associations with respect to plasma corticosterone levels and brain antioxidant activity. The conclusions reached were that caffeine and sleep-deprivation influenced open-field behaviors, stress response, and brain antioxidant status in prepubertal mice; resulting in a pattern of response that is modulated by sex (Onaolapo et al., 2016).

5.3.4  Caffeine, Behavior, and Brain Function In both animals and humans, caffeine acts as a stimulant of the central and peripheral nervous system; increasing arousal, which is associated with increased cholinergic activity in the mammalian cerebral cortex and hippocampus. In a number of studies, caffeine’s effects on behaviors like drug self-administration (Lopez-Cruz et al., 2013), delayed matching-to-sample (Hudzik and Wenger, 1993), repeated acquisition (Buffalo et al., 1993), and schedule-controlled behavior (Howell and Landrum, 1997) have been reported. In rodents, caffeine’s effect on locomotor activity is biphasic; showing increased locomotion at low doses which gives way to decreased locomotion at high doses (Svenningsson et al., 1997; El Yacoubi et al., 2000; Onaolapo and Onaolapo, 2011). This biphasic pattern that stems from differential blockade of A1 and A2 receptors is seen irrespective of sleep status before caffeine administration, and it is exhibited in both sleep-deprived or non-sleep-deprived (Onaolapo and Onaolapo, 2011; Onaolapo et  al., 2015) animals. Caffeine can also induce rotational behavior in rats following unilateral lesions of the nigrostriatal dopaminergic neurons (Fenu and Morelli, 1998), and it potentiates

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the effects of ­dopamine on rotational behavior in rats with the same lesion. Caffeine’s effects on memory have also been reported in humans (Loke, 1988; Borota et  al., 2014) and nonhumans. In rodents, caffeine has been reported to improve spatial and nonspatial memory retention in rodents (Onaolapo et al., 2015; Onaolapo and Onaolapo, 2015). In rats, there was an improvement in memory retention following caffeine administration, effects that were possibly due to enhanced memory consolidation, since post-training administration of caffeine was more effective than pretraining administration at improving memory (Angelucci et al., 2002). Behavioral effects of caffeine in humans have also been well-­ documented. Short-term caffeine consumption has been associated with enhanced mood, increased alertness (Ferré, 2008; Kaplan et al., 1997), enhancement of cognitive performance, auditory vigilance, and reaction time (Temple, 2009); it also increases mental alertness, increases ability to remain awake, reverses lethargic state (Smit and Rogers, 2002), increases blood pressure (Riksen et al., 2009), heightens awareness and attention (Cysneiros et al., 2007), and improves exercise tolerance (Doherty and Smith, 2004). In higher doses, caffeine has been reported to produce insomnia, anxiety, tremors, and seizures. Caffeine may interfere with sleep by increasing sleep latency and decreasing total sleep time, but these effects are seen primarily in light caffeine users.

5.3.4.1  Caffeine, Mood, and Anxiety A number of studies have reported that caffeine consumption in moderate doses (200–300 mg) elevates mood (Lieberman et al., 1987; Swift and Tiplady, 1988), with effects lasting up to 3 h; however, at higher doses (600 mg) an increase in self-ratings of tension or anxiety have been observed (Roache and Griffiths, 1987). Anecdotal evidence has associated the consumption of an excessive amount of caffeine with anxiety (Smith, 2002). However, it is generally accepted that increases in anxiety following caffeine are often associated with the consumption of amounts that would rarely be ingested by the majority of people (Smith, 2002). It is generally accepted that caffeine when consumed moderately, is relatively safe (Nawrot et al., 2003; Higdon and Frei, 2006; Mandel, 2002); however, studies have linked caffeine consumption to the development of anxiety disorders now termed caffeine-induced anxiety disorder. Caffeine administration was linked to the precipitation of anxiety or panic disorders in adults diagnosed with panic disorder, generalized social anxiety disorder, and performance social anxiety disorder (Nardi et  al., 2009). Single nucleotide polymorphisms in the adenosine A2A receptor (a primary target antagonized by caffeine) has been linked to the development of panic disorder and agoraphobia; (Lam et al., 2005). A number of animal studies

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have also reported evidence of caffeine-induced anxiety in adult rats using behavioral paradigms like the open field (Noschang et al., 2009), elevated plus maze and/or light dark box (El Yacoubi et  al., 2000; Onaolapo and Onaolapo, 2011), following acute or chronic caffeine administration. There has also been reported increased anxiety following caffeine withdrawal (Bhattacharya et al., 1997). Caffeine-induced anxiety disorder is a subclass of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of substance/medication-induced anxiety disorder (APA, 2013); which is categorized under anxiety disorders. According to DSM-5, diagnosis is made when a subject presents with symptoms of either panic attacks or anxiety, with evidence that the panic attacks are a direct consequence of caffeine use in this case (APA, 2013). Treatment is usually by withdrawing caffeine source or reducing use to its barest minimum.

5.3.4.2  Caffeine Effects on Learning and Memory Caffeine’s effects on learning and memory have been studied extensively in humans. In studies assessing the effects of caffeine consumption on learning tasks, effects of caffeine have been task specific. In paired-associate learning, caffeine did not affect performance, when recall was assessed immediately or after a delay (Smith et  al., 1991). In studies that used serial or intentional learning, moderate or high consumption of caffeine was not associated with fluent word learning (Landrum et al., 1988; Loke, 1988, 1992; Loke et al., 1985; Rees et  al., 1999); however, high-to-moderate consumers recalled more words than low consumers (Loke, 1988; Loke and Goh, 1992). In another study using the incidental learning paradigm, caffeine was reported to facilitate acquisition and recall in highly impulsive subjects after rhyming acquisition, but hindered it after semantic acquisition (Verdejo-Garcia et  al., 2010); caffeine did not however influence recall in subjects with low-impulsivity (Gupta, 1991). The conclusions that could be drawn from these studies were that caffeine’s effects on learning were task specific; since it facilitated learning in tasks in which information is presented passively, while in intentional learning tasks, caffeine had no effect (Nehlig, 2010). Caffeine’s effects on short- and long-term memory have been examined in humans (Loke, 1988; Loke et  al., 1985; Ryan et  al., 2002; Capek and Guenther, 2009; Borota et al., 2014) and rodents (Angelucci et al., 1999; Onaolapo et al., 2015, 2016). In a number of human studies examining the effects of caffeine consumption on short-term memory tasks, caffeine was associated with (1) no effects on (Loke, 1988, 1992; Loke et  al., 1985; Rees et  al., 1999), (2) improvement in short-term memory (Arnold et  al., 1987; Rogers and Dernoncourt, 1998; Ryan et  al., 2002), or (3) impairment of short-term memory

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(Loke, 1992; Terry and Phifer, 1986; Erikson et al., 1985). Sex-related differences in caffeine’s effect in memory were also reported (Erikson et al., 1985). The differences in the results of these studies have been attributed to the sex and/or age of subjects, differences in memory tasks, or memory assessment method (recall or recognition) used in the different studies, or the time frame (immediate versus delayed) before memory recall. Caffeine is believed to impair working ­memory-dependent tasks, and facilitate tasks that are not completely working memory-­dependent (Nehlig, 2010). Studies on caffeine’s effect on long-term memory have also given mixed results; in a few studies, caffeine consumption was associated with improvement in memory (Capek and Guenther, 2009; Borota et  al., 2014), impaired memory (Nicholson et al., 1984), or no effect (Rogers et al., 1989). In some studies, a time-related enhancement of memory has been reported (Ryan et al., 2002; Sherman et al., 2016); with caffeine counteracting the decline in performance from morning to afternoon, which suggests that this time-of-day effects may be mediated by nonspecific changes in arousal (Ryan et al., 2002). In humans also, caffeine has been associated with the reversal of age-related cognitive decline (Riedel and Jolles, 1996), scopolamine-induced amnesia (Onaolapo et  al., 2015; Onaolapo and Onaolapo, 2015), and electroconvulsive therapy-­induced amnesia (Pollina and Calev, 1997). In rodents, there have also been studies evaluating the effects of caffeine on spatial and nonspatial memory, using different memory paradigms (Angelucci et al., 1999, 2002; Soellner et al., 2009; Onaolapo et al., 2015; Onaolapo and Onaolapo, 2015; Alexander et al., 2013). In a 2015 study from our laboratory examining the memory (spatial and nonspatial) effects of caffeine administration with or without sleep deprivation; in the nonspatial memory task using the novel object recognition test, we observed that pretraining caffeine administration impaired memory acquisition in non-sleep-deprived female mice, while improving it in males (Onaolapo and Onaolapo, 2015). Pretest caffeine administration also improved memory retention in females at lower doses, while in males a biphasic response was observed; in females, caffeine administration improved novel object recognition, while in males, recognition memory was impaired. There was dose-dependent improvement in object discrimination in females following pretest caffeine administration. The spatial memory test (using Y-maze spontaneous alternation test) revealed that pretest caffeine administration improved memory in males, while impairing memory in females (Onaolapo and Onaolapo, 2015). These results suggest that caffeine improves spatial memory in male mice, and nonspatial memory in females. In an earlier study by Angelucci et al. (2002) using the Morris water maze, post-training administration of caffeine improved memory retention at lower doses (0.3–10 mg/kg), but not at the higher dose

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(30 mg/kg). Pretest caffeine administration was associated with an increase in memory retrieval. However, pretraining caffeine administration did not have any effect on memory performance, suggesting that caffeine improves memory retention but not memory acquisition. Mechanisms underlying caffeine-induced changes in memory are still being studied; however, the enhancement of cholinergic transmission has been suggested as a prime candidate. Observations from previous studies point to the fact that caffeine’s ability to enhance memory is more obvious against a background of central cholinergic deficit as occurs with aging or scopolamine administration (Onaolapo and Onaolapo, 2015). Arendash et al. (2006) also suggested that the ability of caffeine to reduce amyloid beta production and restore brain adenosine levels could be involved in the cognitive protection provided by caffeine.

5.3.4.3  Caffeine and Sleep In adult humans, the function that is most sensitive to modification by caffeine is that of going to sleep. Effects on mitigating unwanted sleepiness (either when a person is working at night, or when they are sleep deprived) have been the focus of much research on caffeine and sleep. The ability of caffeine to combat sleepiness also implies that it can interfere with normal sleep. Earlier studies have shown that caffeine increases sleep latency, and reduces sleep duration; while the vast majority of controlled laboratory studies (using EEG, actigraphy, and EEG field study as measures of sleep) concluded that caffeine impacts humans sleep by increasing sleep latency and wake time after sleep onset; while it reduces sleep duration (Landolt et al., 2004; Carrier et  al., 2009; Drake et  al., 2013). However, at least one actigraphy study (Ho and Chung, 2013) and one polysomnography study (Muehlbach and Walsh, 1995) had reported no effect of caffeine on any sleep variable. The effects of caffeine at mitigating unwanted sleepiness and improving mood and alertness in shift workers are undisputed; however questions have continued to be raised as to the effects of caffeine on these parameters when examined a background of sleep deprivation (SD). A number of studies investigating the effects of caffeine following SD on a number of behaviors in humans or rodents have been published. A study by Penetar et al. (1993) assessing the effect of large doses of caffeine in mitigating changes in alertness and mood produced by prolonged sleep deprivation (48 h), reported that caffeine reversed SD-induced changes in fatigue, vigor, and confusion, producing values close to fully rested conditions. Another study by LaJambe et  al. (2005) investigated the effects of caffeine on sleep recovery in habitual caffeine users following 27 h of total SD (subjects were administered different doses of caffeine three times during the duration of SD, via chewing gum) observed that caffeine exerted a

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mild dose-response effects in preventing recovery sleep following total SD, and this observation occurred primarily early in the sleep period. Drake et al. (2013) reported that caffeine taken at least 6 h before bedtime resulted in disruption of sleep; and presently, caffeine-induced sleep disorder is a relatively new psychiatric disorder resulting from excessive caffeine consumption (APA, 2013). In rodent a study by Wurts and Edgar (2000), the effects of caffeine and SD on the expression of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep was evaluated, with reports that caffeine reduced sleep attempts during SD, but did not alter compensatory slow-wave activity (a marker of sleep pressure) during recovery sleep. Caffeine also blocked compensatory REM sleep but reduced NREM sleep duration and continuity. A 2015 study from our laboratory (Onaolapo et al., 2015) examining the effects of caffeine administration on memory performance following 6 h of total SD in mice, concluded that caffeine/SD interactions produced complex memory effects; this was attributed to the presence of competing factors, like the effect of caffeine on central cholinergic transmission, which has been considered the main mechanism behind caffeine’s ability to improve memory in non-sleep-deprived animals (Onaolapo et al., 2015). On the other hand, SD is associated with memory impairment via its effects on glutamatergic neurotransmission, resulting in a scenario in which caffeine administration could not fully compensate for SDinduced memory deficits. In another study (Onaolapo et  al., 2016) using prepubertal mice, we investigated the effect of daily caffeine administration on open-field behaviors, serum corticosterone, and brain antioxidant levels following 6 hours of total SD and concluded that repeated caffeine administration and acute sleep-deprivation led to significant changes in the pattern of open-field behavior and stress/ antioxidant response in mice (Onaolapo et al., 2016).

5.3.4.4  Caffeine Dependence Substance or drug dependence has been defined as a pattern of behavior focused on the repetitive and compulsive seeking and taking of a psychoactive drug or substance. Caffeine is arguably the most consumed psychoactive drug in the world, and it shows all the pharmacological properties (arousal, motor activation, and reinforcing effects) of classical psychostimulants like cocaine and amphetamine (Ferré, 2013), although these effects are milder with caffeine, The possibility of dependence on caffeine has been considered by several groups (Hughes et  al., 1988; Strain et  al., 1994; Oberstar et  al., 2002; Striley et al., 2011), with suggestions that caffeine has a potential for abuse; however, a consensus is lacking. The overwhelming consumption of caffeine worldwide basically demonstrates its reinforcing effects (Ferré, 2013). A number of epidemiological studies have observed

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that regular caffeine intake creates dependence, with associated withdrawal symptoms. More recently however, caffeine-withdrawal has been included alongside cannabis withdrawal as a diagnosis in the DSM-5 classification (APA, 2013). The reinforcing properties of caffeine use have been demonstrated in humans (Griffiths et  al., 2003; Tinley et  al., 2003; Juliano et  al., 2009) and animals (Tuazon et  al., 1992; Shoaib et al., 1992; Gasior et al., 2002; Green and Schenk., 2002). These properties include the ability to maintain self-administration (Hughes et al., 1998; Shoaib et al., 1992), choice behavior, and place preference (Tuazon et al., 1992; Gasior et al., 2002; Green and Schenk., 2002; Juliano et  al., 2009); with the alleviation of withdrawal symptoms increasing both caffeine reinforcement and conditioned taste preference (Garrett and Griffiths, 1998; Tinley et  al., 2003; Juliano et al., 2009). Classical psychostimulants cause dependence by a direct potentiation of central dopaminergic, noradrenergic, and serotoninergic neurotransmission, via their activities on catecholamine and serotonin transporters (Ferre, 2010, 2013). However, caffeine acts by indirectly activating these and other neurotransmitter systems like the cholinergic and histaminergic via its activity at endogenous adenosine A1 receptor which results in the removal of an inhibitory presynaptic adenosinergic tone (Ferre, 2010).

5.3.4.5  Caffeine Withdrawal The acute cessation of a daily consumption of caffeine has been associated with the development of a withdrawal syndrome which manifests as actual symptoms. These symptoms include anxiety, dysphoria, delirium, excessive fatigue/work difficulty, irritability, difficulty concentrating, decreased alertness or sleepiness, depression, headaches, loss of energy, muscle pain, increased muscle tension, and occasional tremors (Dews et al., 2002; Juliano and Griffiths, 2004). Headaches are the most commonly reported symptom of caffeine withdrawal, followed by decreased alertness and increased fatigue (Juliano and Griffiths, 2004). Caffeine withdrawal symptoms were also been reported in newborns whose mothers were heavy coffee drinkers during pregnancy, with infants displaying irritability and vomiting (Nehlig, 1999). There have also been reports demonstrating caffeine withdrawal signs in animals; the manifestations include a decrease in locomotor activity, operant behavior, and reinforcement threshold for electrical brain stimulation, changes in the time spent in various phases of slow wave sleep and avoidance of a preferred flavor when the latter was paired with caffeine abstinence (Nehlig, 1999). Regardless of the individual variability in the onset of symptoms, withdrawal symptoms have been reported to generally begin following overnight abstinence from caffeine consumption, peaking after

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20–51 h (Juliano and Griffiths 2004). However, in some individuals, these symptoms can appear within only 3 days (Evans and Griffiths, 1999). There have been suggestions that a number of these symptoms like headaches (Muhonen et al., 1995) are related to the effects of caffeine on the cerebral arteries, a rebound dilatation of cerebral vasculature, which may occur as a result of increased sensitivity to the circulating adenosine following caffeine abstinence (Mathew and Wilson, 1985; Couturier et al., 1997; Field et al., 2003). Boulenger and Marangos (1989) reported that caffeine withdrawal resulted in the alteration of cerebellar adenosine but not benzodiazepine receptors. This study also showed that compared with controls (fed regular diet), groups fed caffeine-enriched diet showed a sustained (up to 15 days after withdrawal) increase in the number of brain adenosine receptors in the cerebellum and a transient increase (<15 days) in the forebrain. The development of depression following caffeine withdrawal has been associated with alterations in serotonergic transmission that occur with chronic administration of caffeine (Haleem et  al., 1995; Khaliq et al., 2012).

5.3.4.6  Caffeine Tolerance Tolerance to a drug refers to an acquired change in a subject’s responsiveness to a drug or substance following repeated exposure. The development of tolerance may be associated with the requirement of increasing doses before the desired euphoric or reinforcing effects is reached; while in some instances a subject may develop tolerance to the aversive effects of high doses of the substance. Daily caffeine use has been reported to result in a diminution of the resultant stimulant effects of an acute caffeine dose; which in rodents was observed as an alteration in the locomotor stimulant effects of caffeine following chronic administration (Chou et al., 1985; Finn and Holtzman, 1986) or tolerance to the usual anxiety or jitteriness that occur when subjects are maintained on very high doses of caffeine (Evans and Griffiths, 1992). In animals, caffeine tolerance has been associated with tolerance to caffeine-induced locomotor stimulation, cerebral electrical activity, reinforcement thresholds for electrical brain stimulation and thresholds for caffeine or NMDA-induced seizures. The development of tolerance to caffeine in animals is usually rapid and insurmountable (Fredholm, 1982), with the development of cross-tolerance to other methylxanthines (Nehlig, 1999). Although the exact mechanism underlying the development of tolerance to caffeine remains unclear, there have been suggestions linking upregulation of adenosine receptors that follow chronic or sustained caffeine exposure to the development of tolerance (Johansson et al., 1997; Varani et al., 1999); although sensitization and other changes have been identified as well (Green and Stiles, 1986; Powell et al., 2001). In animals, tolerance has not been

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associated with the adaptative changes that occur in adenosine receptors, with suggestions that the mechanism involved may be related to compensatory changes in the dopaminergic system as a result of chronic adenosine receptor blockade (Nehlig, 1999).

5.4 Conclusion Documentations confirm humans’ long-standing relationship with caffeine through consumption of caffeine-containing beverages; also, aspects of the behavioral effects of caffeine-containing beverages had been recognized and harnessed even before the chemical isolation and characterization of caffeine. While modern science has broadened our horizon regarding caffeine’s effects on the brain; there are still a lot of details left to be understood. Over the next few years, a deeper and more precise understanding of caffeine’s brain effects, via further research into caffeine’s interactions with brain neurochemistry may witness its emergence as a “prescription drug,” which might find application in the management of brain disorders, especially those associated with deterioration of memory and reduction in alertness. Presently, it is safe to say our voyage into the understanding of caffeine’s influences on the brain is not over yet; in fact, we might just be about to open a new chapter in the journey.

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Further Reading Calev, A., 1994. Neuropsychology and ECT: past and future research trends. Psychopharmacol. Bull. 30, 461–469. Griffiths, R.R., Woodson, P.P., 1988. Reinforcing effects of caffeine in humans. J. Pharmacol. Exp. Ther. 246, 21–29.