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Caffeine Effects on the Central Nervous System and Behavioral Effects Associated with Caffeine Consumption

In addition to its potential impact on cardiac health, public health experts are concerned about the effect of high levels of caffeine exposure on the central nervous system and behavior. In the Day 1, Session 4, panel, moderated by Thomas J. Gould, Ph.D., Department of Psychology, Temple University, Philadelphia, Pennsylvania, panelists explored scientific evidence on the effects of caffeine exposure on the central nervous system. In the Day 1, Session 5, panel, moderated by Richard H. Adamson, Ph.D., TPN Associates, panelists considered the behavioral effects of caffeine consumption. This chapter summarizes the panelists’ presentations in both sessions and the discussions that followed. Because of the similarity in topics, also included in this chapter is a summary of Andrew Smith’s presentation from Day 2, Session 2. Box 6-1 describes the key points made by each speaker.

MECHANISMS OF THE CENTRAL NERVOUS SYSTEM EFFECTS OF CAFFEINE

Presented by Sergi Ferré, Ph.D., M.D., National Institute on Drug Abuse

Caffeine is a psychostimulant with the same central effects as the classical nervous system psychostimulants cocaine and amphetamine, according to Sergi Ferré. That is, it increases motor activity and has both arousal and reinforcing effects, although its reinforcing effects are not as strong as those of the classical psychostimulants. But its mechanism of



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6 Caffeine Effects on the Central Nervous System and Behavioral Effects Associated with Caffeine Consumption In addition to its potential impact on cardiac health, public health ex- perts are concerned about the effect of high levels of caffeine exposure on the central nervous system and behavior. In the Day 1, Session 4, panel, moderated by Thomas J. Gould, Ph.D., Department of Psycholo- gy, Temple University, Philadelphia, Pennsylvania, panelists explored scientific evidence on the effects of caffeine exposure on the central nervous system. In the Day 1, Session 5, panel, moderated by Richard H. Adamson, Ph.D., TPN Associates, panelists considered the behavioral effects of caffeine consumption. This chapter summarizes the panelists’ presentations in both sessions and the discussions that followed. Because of the similarity in topics, also included in this chapter is a summary of Andrew Smith’s presentation from Day 2, Session 2. Box 6-1 describes the key points made by each speaker. MECHANISMS OF THE CENTRAL NERVOUS SYSTEM EFFECTS OF CAFFEINE Presented by Sergi Ferré, Ph.D., M.D., National Institute on Drug Abuse Caffeine is a psychostimulant with the same central effects as the classical nervous system psychostimulants cocaine and amphetamine, according to Sergi Ferré. That is, it increases motor activity and has both arousal and reinforcing effects, although its reinforcing effects are not as strong as those of the classical psychostimulants. But its mechanism of 89

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90 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS action is different. Ferré provided an overview of research conducted since the early 1990s on the mechanism of action of caffeine on the cen- tral nervous system. BOX 6-1 Key Points Made by Individual Speakers • Sergi Ferré described caffeine as a psychostimulant with the same central nervous system effects as classical psychostimulants such as cocaine and amphetamine. That is, it increases motor activity, induc- es arousal, and creates reinforcing effects. Its mechanism of action is different, however. Ferré explained how caffeine exerts its psychost- imulant effects by blocking adenosine receptors. • Jennifer Temple noted that most studies on the psychopharmacologi- cal and other physiological effects of caffeine have been conducted on adults. Temple described her research group’s work on behavioral and cardiac effects in children and adolescents. Many of her findings are consistent with what has been found in adults, except for a lack of difference in response between low versus high caffeine users. Of note, boys appear to be more responsive to caffeine than girls are. • Roland Griffiths brought up the point that scientists have conducted numerous studies on the behavioral effects of caffeine exposure, in- cluding its reinforcing effects (the self-administration of caffeine), tol- erance (reduced responsiveness due to drug exposure), physical de- pendence (withdrawal), and addiction (“DSM [Diagnostic and Statisti- cal Manual] dependence syndrome”).  Both Griffiths and Charles O’Brien explained how the growing evi- dence base for caffeine withdrawal led to it being recognized as a di- agnosis in the fifth edition of the DSM (DSM-5). Griffiths expressed concern that withdrawal-sensitive youth who experience delays or disruptions in their habitual pattern of intake will likely experience ad- verse emotional, cognitive, and behavioral consequences. • Caffeine addiction, on the other hand, is not as well studied and thus not recognized as a diagnosis in DSM-5. But caffeine addiction is recommended as a diagnosis for further study. O’Brien emphasized the individual variation in the behavioral effects of caffeine exposure and suggested that caffeine addiction may have a genetic basis. • Amelia Arria said the consumption of caffeinated energy drinks was first associated with risk-taking behavior in 1996. Arria discussed evi- dence that has accumulated since then and the rising concerns among public health professionals that the possible contribution of caffeinated energy-drink consumption to risk-taking behavior may have health and safety consequences for adolescents and young adults.

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CENTRAL NERVOUS SYSTEM AND BEHAVIORAL EFFECTS 91 • Andrew Smith said that beginning in the 1990s, scientists have demonstrated beneficial effects of caffeine exposure alongside their negative effects. Indeed, in Smith’s opinion, the levels of caffeine consumed by most people have largely beneficial effects on alert- ness, attention, and other behaviors. Smith cautioned, however, that excessive consumption can cause problems in children and other sensitive individuals. Research in the Early 1990s Ferré said that it is well known that the mechanism underlying the motor and reinforcing effects of cocaine and amphetamine are caused by the drugs’ stimulation of central dopaminergic transmission, particularly in the striatum. The striatum, the input structure of the basal ganglia, is an area of the brain involved in the elicitation and learning of reward- related behaviors, and it contains the highest concentration of dopamine and dopamine receptors. Cocaine and amphetamine are able to produce psychostimulant effects by binding to what is known as a dopamine transporter and either blocking (e.g., cocaine) or reversing (e.g., amphet- amine) its effects. In both cases, the end result is a significant increase of dopamine in the extracellular space, which in turn activates the postsyn- aptic dopamine D1 and D2 receptors. In contrast to cocaine and amphetamine, in the early 1990s scientists already knew that the main mechanism underlying caffeine psychostimu- lation was adenosine receptor antagonism. It was known then that caf- feine at brain concentrations obtained after drinking coffee was enough to block the effects of the A1 and A2A receptors, with A2B being in- volved only in pathological situations and A3 having little affinity for caffeine. (There are four adenosine receptors: A1, A2A, A2B, and A3.) The question then was, How does adenosine modulate the dopaminergic system? Also in the 1990s, scientists were aware that caffeine does not pro- duce a clear or strong presynaptic dopamine-releasing effect. That is, it does not really increase dopamine in the extracellular space in the brain. Knowing that, Ferré and collaborators investigated the possibility of a postsynaptic interaction between adenosine and dopamine receptor sig- naling (Ferré et al., 1991a). They used the reserpinized mouse model to test their hypothesis. (Reserpine depletes dopamine and other catechola- mines in the brain, resulting in an animal becoming immobile, or catalep-

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92 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS tic. The only way to counteract the catatelptic effect is to administer a dopamine receptor agonist, that is, something that stimulates the postsynaptic dopaminergic receptors.) They used bromocriptine (a D2 agonist) to produce locomotor activity in reserpinized mice. They found that the locomotor effect of bromocriptine was counteracted by the aden- osine receptor agonists NECA (an A1/A2A agonist) and L-PIA (an A1 agonist) with a potency that suggested predominant involvement of A2A receptors. Ferré and collaborators (1991a) also found that caffeine (an A1/A2A agonist) and caffeine metabolites theophylline (an A1/A2A agonist) and paraxanthine, but not theobromine, had the opposite effect; that is, they potentiated locomotor activity of bromocriptine. That finding suggested the existence of an antagonistic interaction between the postsynaptic adenosine A2A and dopamine D2 receptors, through which A2A recep- tor agonists would behave as D2 receptor antagonists, and A2A receptor antagonists would behave as dopamine as D2 receptor agonists. Indeed, in a separate study, Ferré et al. (1991b) demonstrated for the first time that central administration of an A2A receptor agonist would produce catalepsy, as a dopamine D2 receptor antagonist would do. Later, when selective adenosine A2A receptor antagonists became available, others demonstrated the opposite effect: that A2A receptor antagonists elicit motor activation (Karcz-Kubicha et al., 2003). The findings reported in Ferré et al. (1991a,b) strongly suggested that caffeine produces motor activation by blocking adenosine A2A receptor–mediated inhibition of dopamine D2 receptor activation. Later, through radioligand-binding experimentation, Ferré and his team found evidence for a more direct interaction between the two receptors (Ferré et al., 1991c), with the dopamine D2 receptor antagonist being displaced by dopamine in a dose-dependent manner and with the ability of dopamine to displace the antagonist being modified by the addition of an adenosine A2A receptor agonist (CGS21680). That is, the agonist CGS21680 de- creased the affinity of dopamine D2 receptors for dopamine. That exper- iment also demonstrated that the A2A and D2 receptors should be local- ized in the same neuron. But which neuron was it? Subsequent study pointed to the efferent striatal gamma- aminobutyric acid (GABA)-ergic medium spiny neuron, also known as MSN. MSNs are efferent neurons that constitute more than 95 percent of the striatal neuronal population. They receive two main inputs: glutama- tergic inputs from the cortical-limbic-thalamic area and mesencephalic dopaminergic inputs from the substantia nigra and ventral tegmental area.

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CENTRAL NERVOUS SYSTEM AND BEHAVIORAL EFFECTS 93 There are two subtypes of MSNs, each of which gives rise to a separate efferent pathway connecting the striatum with the output structures of the basal ganglia (i.e., the medial segment of the globus pallidus and the sub- stantia nigra pars reticulate). One of the pathways is direct, the other indi- rect. Using freely moving rats, Ferré et al. (1993) inserted one probe into the striatum, where cell bodies of the indirect MSN are localized, and an- other probe into the ipsilateral global pallidus, where the nerve terminals of the indirect MSN are localized and where GABA is released. They found that perfusion of a D2 receptor agonist, pergolide, through the striatal probe resulted in a significant reduction of extracellular levels of GABA in the ipsilateral globus pallidus. The effect was significantly counteracted by the striatal coperfusion of an A2A receptor agonist, CGS21680, and signif- icantly potentiated by the xanthine theophylline. Two New Concepts Ferré described what he said were two new concepts being used in pharmacology to help explain the central mechanism of action of caf- feine and many other compounds: receptor heteromer and local module. The receptor concept was introduced in 1878; since then, receptors have been considered as single functional units. But that view is changing. A receptor heteromer is defined as a macromolecular complex composed of at least two functional receptor units with biochemical properties that are demonstrably different from those of its individual components (Ferré et al., 2009). The second concept, local module, relates to the MSN and the con- vergence of MSN’s two main inputs (i.e., the cortical-limbic-thalamic glutamatergic terminal making synaptic contact with the head of the den- dritic spine and the mesencephalic dopaminergic terminal making synap- tic contact with the neck of the dendritic spine). Together, these various elements—the dendritic spine, the glutamatergic terminal, dopaminergic terminal, and glial processes that wrap around the glutamatergic synapse—constitute a functional unit known as the striatal spine module, a type of local module. A local module is defined as the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit (Ferré et al., 2007). As described by Ferré, the concept of a local module provides a framework for understanding the functional roles of extrasynaptic trans- mission. Dopamine is released not only intrasynaptically, but also extra-

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94 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS synaptically, which allows activation of extrasynaptic receptors localized at dopamine and glutamate synapses and modulation of glutamatergic neurotransmission. The same is true of glutamate. It is not only released intrasynaptically but also spills over and stimulates extrasynaptic gluta- mate receptors localized at glutamate and dopaminergic synapses and modulates dopaminergic neurotransmission. Extrasynaptic transmission and extrasynaptic localization of receptors, in turn, provide a framework for understanding the existence and possible functional role of receptor heteromers. According to Ferré, much work has been done using artificial sys- tems and resonance energy transfer techniques (BRET and FRET), as well as mass spectrometry analysis of peptide-peptide interactions, to demonstrate the formation of A2A-D2 receptor heteromers (Canals et al., 2003; Woods and Ferré, 2005; Navarro et al., 2010). Ferré and his col- leagues have used patch-clamp experiments (i.e., with transgenic mice that express green fluorescent protein and show fluorescence in the D2 receptor–containing neuron) to gain an understanding of these interac- tions at the cellular level. Specifically, they have shown that the N- methyl-D-aspartate (NMDA) receptor induces strong activation, an effect that is completely inhibited by the D2 receptor agonist N-1- naphthylphthalamic acid (NPA) and that the A2A receptor agonist CGS21680, which by itself does not produce any effect, completely counteracts the D2 receptor–mediated inhibition (Azdad et al., 2009). Furthermore, Azdad et al. (2009) found that infusing a peptide corre- sponding to an A2A receptor epitope involved in A2A-D2 receptor het- eromerization interrupts the antagonistic interaction between the A2A and D2 receptors. Other Mechanisms of Caffeine Psychostimulant Effects In Ferré’s opinion, scientists have reached a high level of under- standing of at least one mechanism of action of caffeine: the A2A-D2 antagonistic interaction mediated by the A2A-D2 receptor heteromer localized in the indirect MSN. The mechanism explains not only the motor-depressant effects of A2A receptor agonists but also the motor- activating effects of caffeine and other A2A receptor antagonists (Orrú et al., 2011). On the basis of this knowledge, researchers have been testing the efficacy of A2A receptor antagonists in the treatment of Parkinson’s disease.

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CENTRAL NERVOUS SYSTEM AND BEHAVIORAL EFFECTS 95 Not all caffeine effects are mediated by A2A, according to Ferré. Some motor effects are mediated by the A1 receptor (Karcz-Kubicha et al., 2003). Ferré did not elaborate, but he did remark that the same meth- ods were used to identify an antagonistic A1-D1 receptor interaction in the direct MSN that also mediates the postsynaptic effects of caffeine (Ferré et al., 1996). In addition to postsynaptic mechanisms, presynaptic mechanism could also be involved in caffeine’s locomotor-activating effects. Al- though no evidence indicates that caffeine releases dopamine like co- caine and amphetamine do, Solinas et al. (2002) showed that it does re- lease dopamine in the very ventral part of the striatum, in an area called the shell of the nucleus accumbens, by acting on adenosine A1 receptors localized in glutamatergic and dopamatergic terminals. A final mechanism for the motor and probably reinforcing effects of caffeine was recently described in the literature (Ferré et al., 2013; Orrú et al., 2013). It involves paraxanthine, the main metabolite of caffeine in humans, which has a very strong psychostimulant effect in rats and is correlated with a significant dopamine release in striatal areas of the brain where caffeine is ineffective. Ferré and his team learned that par- axanthine has a unique pharmacological profile. In addition to being an A1 and A2A receptor antagonist, it is also a selective inhibitor of cGMP- preferring phosphodiesterase (PDE) and thus plays a role in potentiating nitrous oxide transmission. Most of the mechanisms that Ferré discussed were relevant to the motor and reinforcing effects of caffeine. Arousal is another central ef- fect of caffeine that, according to Ferré, seems to be related to multiple interconnected ascending arousal systems moderated by adenosine A1 receptors (Ferré, 2010). Conclusions About the Neurological Effects of Caffeine Ferré concluded with four main summary points: 1. Two new concepts, “receptor heteromer” and “local module,” facilitate the understanding of the functional role of interactions between neurotransmitters and receptor heteromers in the central nervous system and of the mechanisms of caffeine and other central-acting drugs.

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96 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS 2. The motor and rewarding effects of caffeine depend on its ability to release the pre- and post-synaptic brakes that adenosine im- poses on dopaminergic neurotransmission by acting on different adenosine A2A and A1 receptor heteromers localized in different elements of the striatal spine module. 3. The arousal effects of caffeine depend on its ability to release the A1 receptor-mediated inhibitory modulation of the highly inter- connected multiple ascending arousal systems. 4. Paraxanthine, the main metabolite of caffeine in humans, dis- plays a strong psychostimulant profile that depends on its selec- tive ability to potentiate nitric oxide neurotransmission. DEVELOPMENTAL AND PSYCHOPHARMACOLOGICAL EFFECTS OF CAFFEINE Presented by Jennifer Temple, Ph.D., University of Buffalo Caffeine has many physiological effects, both acute (e.g., cardiovas- cular, ergogenic) and chronic (e.g., tolerance and withdrawal) (Bender et al., 1997; Fredholm et al., 1999; Wesensten et al., 2002; Waring et al., 2003; Davis and Green, 2009; Juliano et al., 2012; Rogers et al., 2013). Caffeine also has many well-described psychopharmacological effects, including increased energy (Griffiths et al., 1990), increased alertness (Haskell et al., 2008), improved mood (Garrett and Griffiths, 1998), and enhanced cognitive performance (Smit and Rogers, 2000). According to Jennifer Temple, most studies on the effects of caffeine have been con- ducted in adults. Temple presented data from her research on the effects of caffeine in children and adolescents. First, however, she remarked on variation in caffeine use. Not only does the dosage of caffeine vary widely across sources, with several cof- fees and energy drinks exceeding the FDA limit for caffeine in cola, but caffeine use patterns vary across the lifespan. Average daily caffeine consumption increases and peaks in the 35- to 54-year-old age group and then tapers off (Frary et al., 2005). More important for Temple’s re- search, dietary sources of caffeine also vary across the lifespan. Accord- ing to data collected between 1994 and 1998 and reported in Frary et al. (2005), the primary source of caffeine for children under the age of 18 is soda, with very little coffee consumption, with a big shift occurring after

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CENTRAL NERVOUS SYSTEM AND BEHAVIORAL EFFECTS 97 the age of 18, when coffee becomes the primary source of caffeine. That finding does not take into account energy drinks; Temple suspected that the data would show a slightly different pattern if energy drinks were included. Three Vulnerable Populations From the perspective of caffeine use, Temple identified three vulner- able populations: (1) pregnant women, with some evidence that exces- sive caffeine may increase the risk of miscarriage but with little known about the effects of caffeine use during pregnancy on offspring later in life; (2) children, because of their exposure to high doses in terms of mil- ligrams of caffeine per kilogram of body weight and because caffeine may be a gateway to other substances; and (3) adolescents, because of escalating use during adolescence and the combining of energy drinks and alcohol. Focusing just on children and adolescents, Temple identified three main differences between those two populations and adults that explain why she considers children and adolescents to be vulnerable populations. First, sources of caffeine are different, again with children and adoles- cents drinking more soda and adults drinking more coffee. Although the caffeine content of coffee can vary on the basis of how it is brewed and where it is purchased, nonetheless caffeine is a natural component of cof- fee. Soda and energy drinks do not naturally contain caffeine. Rather, those beverages are vehicles for caffeine. A second difference is that the lifetime experience with caffeine is very different in children than in adults. Most adults consume caffeine and have had a history of caffeine use, which affords them some tolerance to the effects of caffeine. In con- trast, children, especially young children, are fairly naïve with respect to caffeine use. They tend to consume caffeine at relatively low doses and with less frequency or less regularity than adults do, which may make them particularly vulnerable to the effects of a large amount of caffeine consumed at once. A third difference is that children’s and adolescents’ brains are still developing, especially in the frontal lobe, with little known about the impact of high levels of caffeine on the brain during this critical period of brain development.

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98 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS Evidence on the Effects of Caffeine in Children and Adolescents When Temple and her colleagues first starting studying the effects of caffeine in children and adolescents, about 7 years ago, so little research had been conducted that she felt as though they were starting from scratch. Her research has focused on four main areas: reinforcing proper- ties of caffeine, cardiovascular responses to caffeine, subjective effects of caffeine, and cognitive effects of caffeine. She discussed each in turn. Reinforcing Properties of Caffeine Curious about why manufacturers would add caffeine to soda, Temple and her team first conducted studies on the reinforcing properties of caf- feine. The claim from beverage manufacturers is that caffeine is added to enhance flavor. But caffeine has an extremely bitter flavor, and at the levels of caffeine added to sodas, studies have shown that few people can taste the difference between caffeinated and noncaffeinated soda. Temple and her colleagues approached this work with the hypothesis that caf- feine is added not just to increase the liking of soda but also to increase the reinforcing properties of soda. Specifically, she and her research team designed a study aimed at testing whether caffeinated soda becomes rein- forcing over time (Temple et al., 2009). Temple described the study participants as 12 to 17 years of age, stratified by caffeine use (<25 mg/day; 25–50 mg/day; 50–75 mg/day; and >75 mg/day). The researchers set up an operant response condition in the lab, where participants pressed a mouse button and after so many mouse button presses were reinforced with a portion of soda. Participants were provided both caffeinated and noncaffeinated versions of the same soda and were evaluated for their willingness to work for each type of soda. After the test, participants were sent home with four 2-liter bottles of either caffeinated or noncaffeinated soda, with participants not know- ing which type they had, where they consumed the same amount of soda daily (32 oz) for 1 week. At the end of the first week, they were inter- viewed about how they liked the soda and their mood over the course of the week and were then provided with the opposite type of soda (either noncaffeinated or caffeinated) and asked to again consume the same amount of soda daily (32 oz) for another week. At the end of the second week, participants were again interviewed about how they liked the soda and what their mood had been like. They were also evaluated again for their willingness to work for each type of soda.

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CENTRAL NERVOUS SYSTEM AND BEHAVIORAL EFFECTS 99 400 400 Male Female Number of Button Presses Number of Button Presses 300 300 200 200 100 100 0 0 4 8 16 32 64 128 256 512 1,024 2,048 4 8 16 32 64 128 256 512 1,024 2,048 Schedule of Reinforcement Schedule of Reinforcement FIGURE 6-1 Results from operant response test for caffeinated soda. NOTES: Baseline results in the left graph and results obtained after exposure in the right graph. See text for detailed explanation. SOURCE: Temple et al., 2009. The results for willingness to work for a caffeinated soda are illus- trated in Figure 6-1, with the panel on the left reflecting baseline results and the panel on the right showing results obtained after the exposure period. The y-axis represents the number of button presses; the x-axis represents the number of times the button had to be pressed in order to receive a soda. Typically, data like these show an increase in the number of button presses (y) as the schedule of reinforcement increases (x) and then a decrease. With these data, at baseline, there was no difference be- tween males and females. But after the exposure period, the reinforce- ment value in males increased significantly, and the reinforcement value in females decreased slightly. That is, after becoming more familiar with caffeinated soda, the soda became more reinforcing for males and less reinforcing for females. Temple did not show the data, but she said that there was no change in the reinforcing value of the noncaffeinated soda in either males or females. Nor were any differences observed on the ba- sis of use (stratification). In sum, according to Temple, the study showed that adding caffeine to soda can increase the reinforcing value of soda. Next, Temple and her colleagues wanted to see whether caffeine in- creases subjective liking of soda. Again, they stratified their participants by caffeine use. They provided participants with seven novel sodas on their visit and then picked the beverage ranked fourth by each partici-

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118 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS Conclusions About Caffeine and Performance In conclusion, Smith reiterated that the levels of caffeine consumed by most people have largely beneficial effects on alertness, attention, and oth- er similar behaviors. He emphasized, however, that excessive consumption can lead to problems, especially in sensitive individuals. For Smith, here “sensitive” means a child. In a pilot study on diet, behavior, and attainment in 200 secondary school children, researchers found several associations between diet and detention (personal communication, Nicholas Milward, Pool Academy, January 2012). For example, students who consumed en- ergy drinks were 60 percent more likely to receive detention. On the basis of the results of that pilot study, Smith and colleagues conducted a longitudinal study involving 2,000 pupils. They administered two dietary surveys, one at the start and the other at the end of the school year, and collected two sets of measures of attainment and behavior. The researchers are currently analyzing cross-sectional data.3 Thus far, they have shown that those who often consumed energy drinks were more like- ly to have low attendance, receive a sanction, and receive poorer grades. These findings are true even when controlling for possible confounders, such as socioeconomic status and special educational needs. Smith acknowledged that he and his colleagues are unable to infer causality. Longitudinal data and dose–response data will provide a clear- er view, as will results of a planned intervention study aimed at measur- ing the effects of reducing energy drink intake. Until such clarity is reached, there are two plausible mechanisms. Either energy drinks are causing the problems among the school children that he and his col- leagues are observing, or energy drink consumption may itself be an out- come, with some other factor driving both energy drink consumption and poor attainment, attendance, and behavior. It is a critical distinction, Smith observed, and one that they hope to have an initial answer for soon. PANELIST DISCUSSION WITH THE AUDIENCE This section provides a synopsis of the panelist discussions that took place after the sessions summarized in this chapter. Most of the questions 3 Smith, A. P. 2012–2014. Effects of energy drinks and junk food on school children. Project funded by the Waterloo Foundation.

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CENTRAL NERVOUS SYSTEM AND BEHAVIORAL EFFECTS 119 asked of the panelists revolved around data they had presented, including how those data are being interpreted and gaps in data. Mechanism of Caffeine’s Effect on the Central Nervous System There was some discussion about conflicting results in the scientific literature on where exactly dopamine is released after exposure to caf- feine. Ferré explained that as he mentioned during his talk, caffeine is a weak “dopamine releaser” (although more research needs to be done on the clear dopamine-releasing properties of paraxanthine). Nevertheless, he and his research team found that caffeine in fact induces dopamine release in a specific part of the shell of the nucleus accumbens and that other data suggesting that it occurs not in the nucleus accumbens but in the cortex might be the result of contamination from the shell of the ac- cumbens. He referred workshop participants to a review that he and his team wrote explaining the difference (Ferré, 2008). The take-home mes- sage, according to Ferré, is that caffeine is not a very good dopamine releaser when compared to cocaine or amphetamine, because the main mechanism is postsynaptic and results from adenosine-dopamine recep- tor interactions. When asked how to reconcile the fact that the mechanism of action for caffeine (which acts on adenosine receptors) is very different from the mechanism of action for cocaine (which acts on dopamine receptors), Ferré responded that the effects are similar because they act in the same brain areas, that is, in the striatum, and that the difference is more quanti- tative than qualitative. Most of the panel discussion following Arria’s presentation revolved around the interpretation of the evidence presented and the gaps in data. Cross-Sectional Versus Prospective Studies for Evaluating Long-Term Effects of Exposure in Children There was a question about the roles of cross-sectional versus pro- spective designs in evaluating the long-term effects of caffeine exposure in children and adolescents. Temple remarked that cross-sectional data are confounded in many ways and that there is a strong need for long- term prospective studies.

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120 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS Cardiovascular Effects of Caffeine Exposure in Children and Adolescents: Sex Differences Temple was asked whether any of her research involved electrocar- diogram monitoring of children and adolescents. Temple explained that her team was not set up to do that and agreed that it would be interesting. Her team measured only heart rate and blood pressure. In this regard, John Higgins expressed intrigue at the blood pressure findings described by Temple, specifically the sex difference found after puberty and the greater responsiveness seen in postpubertal males in comparison to post- pubertal females to some of the effects of caffeine. He noted that five of the six deaths reported to be associated with caffeine-containing energy beverages were in males between the ages of 12 and 19. Temple suggest- ed that the difference might be related to circulating steroid hormones. According to Temple, it is well known that steroid hormones affect caf- feine metabolism. She and her team are trying to figure out how to test that hypothesis other than by measuring salivary hormone levels. Other data (which she did not present) have shown that blood pressure effects in females are lower when salivary estradiol levels are higher. Temple reiterated that she and her research team have found a greater respon- siveness to caffeine among postpubertal males “across the board,” that is, not just with cardiovascular effects but also with reinforcing and subjec- tive effects. Blinded Studies of Caffeine Withdrawal Griffiths identified Silverman et al. (1992) as another study on caf- feine withdrawal that did not inform participants that caffeine was being tested. Other withdrawal studies have similarly blinded participants (see Juliano and Griffiths, 2004). In Silverman et al. (1992), participants were told only that they were participating in a study on dietary substances. They were provided with misinformation about shellfish, NutraSweet, and so forth, to distract them. In addition, Juliano and Griffiths (2004) have estimated a 13 percent incidence of significant functional impair- ment, compared to Dews et al.’s (1999) 2.6 percent. Even 2.6 percent is not trivial in a population in which caffeine is consumed by 85 percent of the population, in Griffiths’s opinion.

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CENTRAL NERVOUS SYSTEM AND BEHAVIORAL EFFECTS 121 The Association Between Caffeine Use and Other Substance Use in Adolescents and Young Adults A driver for both caffeine use and the nonmedical use of prescription drugs is the availability of resources needed to acquire those substances, according to a member of the audience. The audience member asked Arria if she and her colleagues had examined the purchasing power of the study participants in the Arria et al. (2010) study and whether possi- bly the individuals with the ability to purchase caffeinated beverages were, coincidentally, the same individuals with the ability to acquire pre- scription drugs. Arria explained that she and her team have studied avail- ability and access to nonmedical use of prescription stimulants and have found that, by and large, students obtain them for free from friends, rela- tives, and acquaintances. The substances are widely accessible. Because all the study participants in Arria et al. (2010) came from the same cam- pus, she thinks it unlikely that some students would have greater access than others. Arria was also asked about the pattern of use among the students she and her colleagues followed. For example, were they consuming greater doses of energy drinks over time in order to get the same buzz? Were they later substituting analgesics or other substances for the energy drinks be- cause they were no longer getting the same buzz with the energy drinks? Were they using both simultaneously? Arria found it an interesting sugges- tion that consumption might be related to the likelihood to try something with greater potency. Arria referred workshop participants to a recent study, Woolsey et al. (2013), where the researchers found a great overlap between the substitution of energy drinks and the use of nonmedical pre- scription stimulants for studying. In addition, the researchers reported that every individual with a prescribed attention deficit hyperactivity disorder (ADHD) medication was using energy drinks, a finding that suggested to Arria that someone should probably be studying the interaction between energy drinks and medical use of prescription stimulants. Another audience member observed that many people with ADHD self-medicate with caffeine. He asked Arria whether individuals in her study might be substituting the stimulants for caffeine, not necessarily because they were seeking something with greater potency, but as a way to self-medicate. She explained that her study has collected data on the motives of energy drink consumption and has yet to analyze the data. Arria was also asked whether results were different between female and male participants. She explained that she and her research team con-

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122 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS trolled for gender in Arria et al. (2010). She noted that she has observed a difference in energy drink use, with a higher proportion of girls drinking coffee and a higher proportion of boys drinking energy drinks. She was also asked about the nature of the survey. She did not send the survey out to students. Rather, her research team conducted face-to- face interviews. She also clarified that other studies have looked at a va- riety of risk-taking behaviors but that, for the sake of time, she chose to focus her presentation of the subsequent use of an illicit drug as the be- havior of interest. When asked whether she was suggesting that energy drinks were causative of risk-taking behavior, she replied that it will take an accumulation of evidence to infer causality. Arria et al. (2010) was the first of what she hopes will be a series of prospective investigations into the contribution of energy drinks to future illicit drug use. In her opinion, at this point, rather than causality, the focus should be on safety. She said, “I think the burden of proof on whether or not regulations need to occur is really [on] a demonstration of safety rather than on a demonstra- tion of causality.” When the same audience member pressed her further about whether there has been a demonstration of causality between ener- gy drinks and risk-taking behavior, she replied that there are very com- pelling, consistent data across studies to demonstrate a contributory asso- ciation but agreed that more data are needed to demonstrate causality. When asked about what her theory was, she referred to her earlier com- ments about neural development of the adolescent brain. Withdrawal Suppression Following Smith’s presentation, Roland Griffiths commented about withdrawal suppression and the fact that some experts attribute all ob- served beneficial effects to caffeine withdrawal suppression. “That seems radical,” Griffiths said. At the same time, he did not think that the with- drawal suppression hypothesis should be so readily dismissed. The right methodology for addressing it would be a balanced design involving chronic caffeine administration compared to chronic placebo administra- tion (e.g., Sigmon et al., 2009). Smith agreed that the hypothesis should not be dismissed and that there certainly are individuals for whom with- drawal is a significant problem. At the same time, he does not think it is a ubiquitous explanation. He agreed that more research along the lines of what Griffiths suggested is necessary and observed that withdrawal is like- ly more important with mood changes than with performance changes.

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