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Influence of energy drink ingredients on mood and cognitive performance Emma Childs Sales of energy products have grown enormously in recent years. Manufacturers claim that the products, in the form of drinks, shots, supplements, and gels, enhance physical and cognitive performance, while users believe the products promote concentration, alertness, and fun. Most of these products contain caffeine, a mild psychostimulant, as their foremost active ingredient. However, they also contain additional ingredients, e.g., carbohydrates, amino acids, herbal extracts, vitamins, and minerals, often in unspecified amounts and labeled as an “energy blend.” It is not clear whether these additional ingredients provide any physical or cognitive enhancement beyond that provided by caffeine alone. This article reviews the available empirical data on the interactive effects of these ingredients and caffeine on sleep and cognitive performance and suggests objectives for future study. © 2014 International Life Sciences Institute

INTRODUCTION Energy drinks marketed as dietary supplements (e.g., 5-hour Energy, NOS, Spike Shooter) or beverages (e.g., Red Bull, Full Throttle, Monster) usually contain caffeine as their active ingredient, often in amounts higher than those recommended by the US Food and Drug Administration (FDA) for caffeine-containing cola-type beverages (approximately 6 mg per fluid ounce). Soda drinks (e.g., Coca-Cola, Pepsi, Mountain Dew) typically contain 2.5– 5 mg of caffeine per fluid ounce and caffeine-containing energy drinks around 80 mg per fluid ounce, while dietary supplements may contain 100 mg or more per fluid ounce. The effects of these caffeine-containing energy products on mental and cognitive energy are undisputed: several studies have shown that energy drinks increase subjective alertness and improve performance on attention and memory tasks as well as on tests of executive function.1–7 These effects are consistent with the known effects of caffeine on mood and performance,8 but energy drinks contain a multitude of other ingredients that are often implied, though not explicitly stated, to also produce beneficial effects on mood and cognition. The most common ingredients added to energy drinks

and products include carbohydrates (e.g., glucose), amino acids (e.g., taurine, tyrosine, L-tryptophan, L-arginine, L-theanine), herbal extracts (e.g., guarana, yerba maté, green tea, Gingko biloba, ginseng, St. John’s wort), vitamins (e.g., A, B, C, E) and minerals (e.g., iron, calcium), and various other nutrients (e.g., carnitine, citicoline, creatine, 1,3-dimethylamylamine, malic acid, vinpocetine, yohimbine). Many of these ingredients are considered generally recognized as safe (GRAS) by the FDA and have no recommended daily limit; moreover, manufacturers are not obliged to list the exact amounts of these ingredients present in their products. Thus, the independent contribution of caffeine and other ingredients to the overall effect of an energy product is largely unknown. This deserves further study, especially since toxic exposures to energy drinks that contain caffeine as well as other ingredients are more serious and significantly more likely to result in referral to a healthcare center than toxic exposures to drinks containing caffeine alone.9 In this article, the empirical evidence for mood and cognitive effects of common energy drink ingredients, as well as for the contribution of any beneficial effects of the energy product besides that produced by caffeine, are considered. Specific objectives of future research are also

Affiliations: E Childs is with the The University of Chicago, Department of Psychiatry and Behavioral Neuroscience, Chicago, Illinois, USA. Correspondence: E Childs, The University of Chicago, 5841 S Maryland Ave MC3077, Chicago, IL 60637, USA. E-mail: [email protected]. Phone: +1-773-702-5833. Fax: +1-773-834-7698. Key words: attention, cognition, energy drink, memory, mood 48

doi:10.1111/nure.12148 Nutrition Reviews® Vol. 72(S1):48–59

highlighted. First, the mood and performance effects of ingredients examined in combination with caffeine are discussed. Studies were only considered if the independent contribution of the ingredient to the effects of an ingredient/caffeine combination could be determined. That is, only studies in which the effects of the ingredient, of caffeine, and of a combination of the ingredient and caffeine were assessed. Studies were not considered if they did not include the appropriate controls or if the independent contribution of ingredients and caffeine could not be determined. Second, the mood and performance effects of select ingredients studied alone but not in combination with caffeine are addressed. Finally, other common ingredients for which there is little information are identified. Interaction studies Only a limited number of energy drink ingredients have been studied in combination with caffeine. These include glucose, taurine, L-theanine, and ginseng (Table 1).4,10–21 Throughout this section, “interactive effects” of ingredients in combination with caffeine refers to effects that are quantitatively or qualitatively different than the effects of the substances administered alone. Glucose. Both caffeinated and noncaffeinated energy drinks contain high concentrations of sugars, the effects of which have been well researched.22,23 Six studies4,10–14 were identified that administered glucose and caffeine alone and in combination, allowing clear dissociation of the separate and interactive effects of the substances on mood and cognitive performance.With regard to mood, 2 studies reported mixed interactive effects of glucose and caffeine,11,14 3 did not report any interactive effects,4,10,12 and 1 did not assess mood.13 In 1 study,14 30 g of glucose counteracted caffeine (80 mg)-induced increases in hostility across cognitive testing, while in the other study,11 50 g of glucose and 200 mg of caffeine administered together increased tension.11 With respect to subjective energy, only Young and Benton14 reported that 39 g of glucose counteracted short-term (30 min) increases in subjective energy as well as long-term (90–150 min) increases in tiredness after 80 mg of caffeine, while Giles et al.11 found no evidence of interactive effects on fatigue. Interactive effects of glucose and caffeine on measures of attention were found in 3 of the 6 studies,4,10,14 but not in the others.11–13 Two studies reported that a combination of glucose (37.5 mg and 75 mg) and caffeine (75 mg) produced greater decreases in reaction time than either substance administered alone,4,10 but another reported that 30 g of glucose attenuated caffeine (80 mg)induced decreases in choice reaction times at 90 min and 150 min.14 The discrepancy between studies is likely due Nutrition Reviews® Vol. 72(S1):48–59

to the tasks used: interactive effects were observed in attention tasks with a higher level of demand4,10 than simpler tasks.14 In the study by Serra-Grabulosa et al.,13 glucose and caffeine produced no interactive effects on attention performance, although the combination produced synergistic effects on brain activation during the attention task. Task-induced activation in areas associated with attention and memory was significantly lower after 75 g of glucose plus 75 mg of caffeine in comparison with placebo, which the authors interpreted as an increase in the efficiency of these processes. Finally, the interactive effects of glucose and caffeine on memory tasks have been more consistent. Of 4 studies that assessed memory performance, 3 reported that the glucose caffeine combination improved performance (working memory accuracy,11 explicit memory,4,10 and memory speed and quality4) but 1 reported that the combination did not enhance working memory speed14 in contrast to caffeine alone, which improved reaction times. Thus, there is some evidence that interactions between glucose and caffeine have an effect on high-load attention tasks and memory performance. The basis for these interactions may lie in altered pharmacokinetic profiles of the substances when administered together. Acute administration of caffeine by itself impairs glucose tolerance24 and reduces insulin sensitivity,25 causing an increase in blood glucose concentration. Therefore, caffeine likely alters the postingestion glycemic profile of glucose-containing drinks. Indeed, caffeine increased interstitial glucose levels when administered alone or together with glucose in 1 controlled study14: 80 mg of caffeine in combination with a drink containing 30 g of glucose potentiated increases in interstitial glucose levels, delayed the peak level by 10 min, and prolonged elevations above baseline (to 90 min) in comparison with glucose alone. Conversely, glucose appeared to alter caffeine absorption in 2 studies10,13: salivary caffeine concentrations were lower in the glucose/caffeine (75 g/75 mg) condition than after caffeine alone at 30 min postdosing, although these were not directly compared by the authors. Taurine. Taurine is a nonessential sulfur-containing amino acid thought to play a role in metabolic processes. As the building blocks of proteins and the precursors of neurotransmitters, amino acids are commonly added to energy drinks and supplements, the rationale being that an increased availability of amino acids will enhance protein synthesis and neurotransmitter reserve, thus influencing mood and performance. However, the exact amounts of amino acids present in energy drinks are largely unknown because amino acids are usually listed as part of the manufacturer’s proprietary blend. Taurine is 49

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No interaction

200 mg caffeine 50 g glucose 200 mg caffeine 50 g glucose

No interaction

150 mg caffeine 2 g taurine

250 mg caffeine 200 mg L-theanine 150 mg caffeine 250 mg L-theanine

Aggarwal et al. (2011)16 L-Theanine Rogers et al. (2008)17 Haskell et al. (2008)18

No interaction

Not assessed

Not assessed

Abbreviations: ANT, attention network task; BOLD, blood oxygen level dependent.

9 mg caffeine (as guarana) 75 mg ginseng

50 mg caffeine 100 mg L-theanine 50 mg caffeine 100 mg L-theanine

No interactive effect on sleepiness in sleep-deprived subjects

80 mg caffeine 1 g taurine

Peacock et al. (2013)15

Increased alertness, decreased tiredness and headache

Attenuated short-term caffeine-induced stimulation, produced long-term increase in fatigue Attenuated caffeine-induced increase in alertness

Kelly et al. (2008)19 Foxe et al. (2012)20 Ginseng Kennedy et al. (2004)21

Decreased reaction time in 1 of 4 tasks compared with placebo

No interactive effect on speed or accuracy

No interactive effect on attention bias to threat Decreased simple reaction time, no interactive effect on selective or sustained attention No interactive effect on reaction time task or Stroop task No interactive effect on sustained attention

Attenuated caffeine-induced reaction time decrease in 1 of 2 selective attention tasks No effect on reaction time or Stroop task

No interactive effect on attention network task or reaction time

No interactive effect on ANT or reaction time task No interaction No interactive effect on sustained attention. Glucose counteracted caffeine-induced increase in hits and accuracy 75 mg caffeine Not assessed Decreased BOLD activation during task 75 g glucose but had no interactive effect on sustained attention 80 mg caffeine Counteracted short-term (30 min) No interactive effect on reaction time or 3.6 g, glucose 39 g decrease and long-term (90–150 min) selective and sustained attention glucose increase in tiredness

No interaction

75 mg caffeine 75 g glucose

200 mg caffeine 2 g taurine

Young & Benton (2013)14 Taurine Giles et al. (2012)11

Serra-Grabulosa et al. (2010)13

Adan & Serra-Grabulosa (2010)10 Giles et al. (2012)11 Maridakis et al. (2009)12

Table 1 Interactive effects of energy drink ingredients and caffeine on mood, attention and memory. Reference per energy Dose Mood effect Attention effect drink ingredient Glucose 75 mg caffeine No interaction Improved speed of attention, no Scholey & 37.5 glucose interactive effect on accuracy Kennedy (2004)4

Decreased errors in 1 of 3 working memory tasks, no interactive effect on speed or secondary memory

Not assessed

Not assessed

Decreased reaction times in 1 of 3 working memory tasks and recall

Not assessed

Not assessed

Not assessed

No interactive effect on working memory

No interactive effect on immediate or delayed recall or on working memory

Not assessed

Increased hit rate in 1 of 3 working memory tasks Not assessed

Improved immediate and delayed recall. No interactive effect on memory quality and speed, or working memory Improved immediate and delayed recall

Memory effect

one of the most common ingredients in energy drinks, dietary supplements, and noncaffeinated energy drinks. In products that list the amount of taurine contained, it is usually present in amounts of 1–2 g per serving. Despite the widespread inclusion of taurine in different products, few placebo-controlled clinical studies have examined the effects of taurine on mood and cognition, and only 2 studies administered taurine alone, caffeine alone, and a taurine/caffeine combination so that the independent contribution of the ingredients could be determined.11,15 In both studies, taurine attenuated the stimulatory mood effects of caffeine, and in 1 study, the combination of taurine and caffeine increased feelings of fatigue. One study reported no interactive effect of the substances on attention and memory performance,11 while the other reported that taurine attenuated caffeineinduced decreases in selective attention reaction time.15 Finally, a third study administered caffeine alone and a caffeine/taurine combination to sleep-deprived subjects, although there was no taurine-alone condition with which to compare the effects of the mixture.16 Taurine (2 g) in combination with caffeine (150 mg) did not provide any additional reduction in subjective sleepiness beyond that provided by caffeine alone. The combination also did not influence sleep-deprivation-induced impairments in movement efficiency or accuracy on a fine motor task, but it should be noted that caffeine alone also did not improve performance on the motor task.16 Thus, the available evidence suggests that taurine appears to counteract the beneficial alerting effects of caffeine. Nevertheless, it is premature to draw definitive conclusions on the basis of only 2 controlled studies. -theanine. L-theanine is an amino acid that is structurally related to glutamate yet is purported to produce relaxant effects. In addition to being a common ingredient in energy drinks, L-theanine occurs naturally in tea. Thus, comparatively more controlled studies have assessed the mood and cognitive effects of L-theanine than the effects of some other energy drink ingredients.17–20,26–30 The interactive effects of L-theanine and caffeine on mood and cognitive performance have been investigated in 4 studies with interesting findings. First, a combination of 250 mg of L-theanine and 150 mg of caffeine increased subjective alertness and decreased headache18 in comparison with the substances alone or with placebo. Second, when assessed together, L-theanine and caffeine improved attention performance,18,19 working memory,18 and information processing18 compared with each substance alone or with placebo, although Foxe et al.20 found no interactive effects upon sustained attention. Finally, 200 mg of L-theanine was reported to attenuate increases in heart rate and blood pressure induced by 250 mg of caffeine.17 These findings suggest beneficial interactive effects of L-theanine L

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and caffeine on mood and cognitive performance but require verification in further controlled studies. Ginseng. Ginseng (Panax ginseng) is a botanical ingredient that has been used for centuries in Chinese medicine. The mood and cognitive effects of acute ginseng administration have been investigated in several studies.21,31–38 A recent review39 concluded that ginseng had the most consistent effects on declarative memory, with less reliable effects on working memory and attention. With regard to mood effects, the largest effect sizes were seen for maintaining energy during cognitively demanding tasks. There has been only 1 study of ginseng in combination with caffeine administered in the form of guarana. Kennedy et al.21 administered 200 mg of ginseng with and without guarana (containing 9 mg of caffeine). In general, there were no interactions between the substances on measures of mood, attention, or memory, although the combination did produce a prolonged decrease in errors on 1 of 2 working memory tasks. However, despite the overall lack of interactions between the 2 substances, this does not rule out the possibility of interactive effects, since the caffeine content of the guaraná extract was very low. Thus, future studies must investigate interactions between ginseng and doses of caffeine comparable to those present in energy drinks. Ingredients with mood and performance effects A number of energy drink ingredients have been studied (in isolation) for mood and performance effects. Although these ingredients have not been studied in combination with caffeine, some of them show promising effects alone and deserve further study in combination with caffeine. Guarana. Guarana is a plant native to South America, where it has a long history of use for its supposed stimulatory properties.40 Guarana contains 4–8% caffeine by weight, along with other active components (e.g., saponins, tannins) that may prolong the half-life of caffeine.41 Several excellent recent reviews of the effects of guarana on mood and performance have been published.23,42,43 Acute doses of guarana (37.5–300 mg) have been reported to increase subjective alertness44 and improve energy maintenance during cognitive testing.45 Guarana was also shown to improve attention speed,21 sustained attention performance,45 and working and explicit memory.21,44 Longer treatment periods did not produce any significant mood effects in healthy individuals (e.g., 360 mg administered 3 times daily for 3 days46) or in individuals undergoing radiation therapy (75 mg daily for 28 days47). However, 1 study reported that 50 mg of guarana administered twice daily for 21 days improved 51

ratings of fatigue and tiredness without influencing anxiety or depression in individuals undergoing systemic chemotherapy.48 There have been no direct studies of the interactive effects of guarana and caffeine, although 2 studies directly compared the cognitive effects of 1,000 mg of guarana (containing 21 mg of caffeine) with 25 mg of caffeine or placebo administered twice daily for 3 days. The first study reported no effects of any treatments on mood, attention, memory, or other psychomotor tasks in healthy young adults.49 The second study, conducted in individuals over 60 years of age, reported that guarana – but not caffeine – produced a significant improvement in performance on 1 test (mosaic test).50 Thus, despite a long history of use, few controlled studies have investigated the acute stimulant-like properties of guarana and, as yet, none have investigated the possible interactive effects between guarana and exogenous caffeine. While it may be presumed that the effects of guarana in combination with caffeine might be similar to the effects of an equivalent dose of caffeine, some researchers have suggested that other chemicals present in guarana are responsible for its observed behavioral effects; this is because the caffeine levels of the guarana doses studied were too low to produce the reported effects. A recent review42 concluded that the cognitive effects of caffeine-containing herbal extracts such as guarana often differ from those of caffeine, suggesting an involvement of other plant chemicals. Thus, studies of the other active components of guarana in combination with caffeine are warranted. Tyrosine/N-acetyl-L-tyrosine/Phenylalanine. Tyrosine is a precursor of catecholamine hormones and neurotransmitters, including adrenaline, noradrenaline, and dopamine, which are integrally involved in regulating mood and behavior. Phenylalanine is a tyrosine precursor. The majority of research studies with tyrosine have focused on its beneficial effects under stressful conditions. Reactions to acute stress involve activation of the peripheral and central nervous systems and the release of catecholamines, which depletes catecholamine stores, causing mood and cognitive impairments. Acute tyrosine administration (50 mg–2 g) has been shown to counteract impairments in attention, memory, and mood caused by stress, sleep restriction, and fatigue.51–61 However, to date, no studies have evaluated the interactive effects of tyrosine and caffeine on mood and cognitive performance. This is surprising, given the evidence that tyrosine improves mood and cognition in fatigued and acutely stressed individuals, the target consumers of energy products. Gingko biloba. Gingko biloba is used in traditional medical systems. Most research into the effects of Gingko 52

biloba extract on mood and cognition has focused on its long-term use and potential protective effect against cognitive decline. The results of these clinical studies have been mixed, with some positive findings62–66 and some negative findings67–69 reported. Similarly, reviews and meta-analyses have drawn different conclusions, with some supporting70,71 and others opposing72–74 the efficacy of gingko in counteracting age- and disease-related cognitive decline. Discrepancies between studies reporting positive and negative findings for gingko may be explained by differences in treatment duration and subject populations: studies reporting null effects were conducted over shorter periods (maximum 6 years follow-up) in subjects who, in some cases, were already cognitively impaired. Most recently, Amieva et al.62 reported 20 years of follow-up data for individuals who were aged 65 years and over and not cognitively impaired at enrollment. They found that those who reported use of gingko showed reduced global cognitive decline compared with those who used no treatments. However, the results should be interpreted with caution, since the study employed a retrospective cohort design and other confounding variables could have influenced the findings. The acute and short-term effects of gingko on mood and cognitive performance in young healthy subjects have been investigated in several controlled studies. As for its effects on mood, gingko was reported to improve well-being75 but not subjective alertness.75,76 Its effects on attention and memory have been inconsistent, with improvements as well as impairments reported. For example, Kennedy et al.77 reported dose-dependent improvements in attention speed with 240 mg and 360 mg of gingko up to 6 h postadministration, and improved memory with 120 mg up to 4 h postadministration. Later, they reported that gingko improved attention speed for 2 h but decreased attention accuracy and slowed memory speed at 4–6 h.75 Finally, to increase statistical power, the researchers combined data from 3 studies that used 120 mg of gingko and reported improved memory accuracy up to 4 h postadministration but decreased attention speed at 1 h postadministration.78 Gingko has also been shown to produce effects on brain electrical activity that are consistent with good cognitive and memory performance.79,80 In 2 studies of short-term gingko administration, 120 mg for 2 weeks reduced physical and psychological symptoms of premenstrual syndrome in 1 study81 but not in the other.82 Longer administrations in otherwise healthy subjects (>4 months) produced improvements in subjective ratings of anxiety, depression, motor incoordination, energy, and alertness.82–84 Daily administration of 80 mg of gingko for 2 weeks did not influence working memory performance, despite increased brain activity during task performance, which the authors Nutrition Reviews® Vol. 72(S1):48–59

interpreted as improved processing efficiency.85 Longer administration (80 mg gingko/day for 1 month), however, did produce improvements in working memory performance.86 In summary, the long-term use of gingko has failed to show clear effects on cognitive decline, and the acute and short-term effects of gingko administration on mood and performance have been inconsistent. A recent review87 of all placebo-controlled studies of gingko in both healthy and cognitively impaired individuals concluded that the most prominent effects of gingko were observed during complex tasks rather than simple ones, with the greatest effects observed during tests of fluid intelligence and attention. At present, the mood and cognitive effects of gingko/caffeine combinations have not been evaluated in controlled studies, although Zadoyan et al.88 found no metabolic interaction between the two substances. Theobromine, theophylline, and flavanols. Herbal extracts contain other phytochemicals, including other methylxanthines (e.g., theobromine, theophylline), saponins, tannins, and polyphenols, which may have psychoactive properties. In placebo-controlled studies,89,90 theobromine produced few effects on mood and attention aside from increases in feeling the effects of drugs.89 There has been 1 study of theobromine in combination with caffeine. Combinations of theobromine (100 mg, 200 mg) and caffeine (8 mg, 20 mg) were reported to improve simple reaction times and sustained attention performance in comparison with placebo, but this study did not include control doses of theobromine and caffeine alone for comparison of effects.91 In addition, these doses are likely not relevant to those present in energy drinks. Theophylline, another methylxanthine present in herbal extracts, has been reported to improve memory speed, information processing, and attention in healthy adults92,93 and to improve attention in elderly subjects.94 Finally, most research on the psychoactive effects of flavanols has been performed with soy isoflavones, although a few studies with cocoa95 or flavanoid extracts (e.g., from Ginkgo biloba, pine bark) have been conducted.96 In a review of placebo-controlled human challenge studies, Macready et al.96 concluded that flavanol consumption was associated with positive effects on executive function, working memory, and Mini-Mental State scores. These effects, however, were reported with doses of 100 mg/day, which is most likely greater than the amounts contained in energy drinks. Vitamins and minerals. Energy drinks often contain vitamins (e.g., A, B, C, and E) in very high amounts, along with other micronutrients (e.g., iron, calcium). These vitamins and minerals are essential for effective functionNutrition Reviews® Vol. 72(S1):48–59

ing of the nervous system, and deficiencies have been linked to cognitive deficits and mood disorders.97,98 Vitamin and mineral supplements administered over prolonged periods (3 months to 1 year) have been shown to improve attention and memory in schoolchildren,99,100 and dietary levels of B vitamins have been related to memory function in healthy adults.101 Short-term (5–12 weeks) supplementation with B vitamins has improved memory function in aged individuals102 and improved selective attention, processing, working memory, and subjective energy during testing in young adults.45,103,104 However, others have reported no consistent effects of B vitamins on cognitive function.105 Shortterm administration of vitamin C supplements has also been associated with improved mood in hospitalized patients.106 The acute effects of high doses of vitamins have not been assessed in healthy young adults but may reduce cognitive deficits induced by oxidative stress.107 The effects of vitamins in combination with caffeine have also not yet been assessed and warrant study. It is thought that vitamin and mineral supplements are most likely to benefit individuals who are deficient in a given micronutrient at the outset, and thus studies of vitamin and mineral supplements and their influence on mood and cognition must consider the baseline nutritional status of subjects. Creatine. When converted to phosphocreatine, creatine acts as a high-energy source during intense physical or mental exercise, and a limited number of studies have reported beneficial effects of acute or short-term creatine administration on cognitive performance. Two studies reported that creatine improved mood, attention, and complex working memory after short periods of sleep deprivation,108,109 and others reported significant improvements in attention and memory performance in well-rested participants.110–112 Citicoline. Citicoline is an intermediate component in the synthesis of phosphatidylcholine, the major phospholipid of cell membranes. It also activates the central cholinergic system, thereby inducing hormone release (adrenocorticotrophic hormone, growth hormone, luteinizing hormone), and has been reported to increase brain levels of noradrenaline, dopamine, serotonin, and acetylcholine.113,114 Citicoline has been shown to improve memory in aged individuals115–117 and may protect against age-related cognitive decline,118 but its behavioral effects in healthy young adults have not been well researched. Studies have reported effects on brain activity and energy use that are consistent with increased mental alertness, but no effects on behavioral measures have been reported.119,120 Its effects in combination with caffeine have not been assessed. 53

-arginine. L-arginine is involved in 2 important metabolic pathways: nitric oxide production and ammonia detoxification. It also potently induces the secretion of insulin, growth hormone, and prolactin and the release of catecholamines.121,122 There is some evidence that L-arginine supplementation increases physical performance in untrained individuals, but little evidence supports enhanced performance in trained athletes.123 Animal studies have reported improved learning and memory performance with L-arginine administration,124,125 but human studies have focused on effects in older adults with dementia who showed cognitive improvements following L-arginine treatment.126 L-arginine has also been proposed as a potential treatment for Alzheimer’s disease,127 yet no studies to date have investigated the influence of L-arginine on mood and cognitive performance in healthy individuals. L

Green tea. Tea (Camellia sinensis) is a plant native to China, where it has a long history of consumption for medicinal purposes. The leaves of the plant may be processed in a variety of ways, producing, for example, black, green, or white tea. Green tea extract contains theanine, catechins, and flavonols in addition to caffeine. Tea has been found to benefit cardiovascular health,128 but its effects on mood and cognition have been less studied. One study129 reported that a combination of green tea extract and L-theanine improved selective attention, memory performance, and brain correlates of alertness in individuals with mild cognitive impairment. A later review130 concluded that green tea consumption was associated with improved cognitive function in aged individuals but could not establish a definitive link. The mood and cognitive effects of green tea extract in healthy individuals have not been assessed. Carnitine. Carnitine is an essential dietary nutrient that plays a vital role in energy production. It has been shown to improve mood and cognitive function in individuals with cognitive impairment131–133 and to improve symptoms of depression,134 but its effects on mood and cognition have not been evaluated in healthy individuals. L-tryptophan/5-hydroxytryptophan. L-tryptophan (L-Trp) and 5-hydroxytryptophan (5-HTP) are precursors of serotonin (5-HT), a neurotransmitter that plays a central role in behavioral and emotional control. L-Trp is the least abundant amino acid and must compete with other, more common large amino acids for transport across the blood-brain barrier. In comparison, 5-HTP more readily penetrates the brain,135–137 where it is converted to serotonin, and thus dietary 5-HTP supplements may feasibly enhance brain serotonin levels.138 In 1989, the FDA recalled all dietary supplements containing 100 mg of

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L-Trp because of the association between L-Trp and an epidemic of eosinophilia-myalgia syndrome. The outbreak was thought to be due to a contaminant in a particular product, and L-Trp was subsequently reapproved in 2005, but there is some evidence of genetic sensitivity to eosinophilia-myalgia syndrome associated with 139 L-Trp. 5-HTP has been investigated as a treatment or adjunct for depression, which has been associated with low levels of serotonin. A majority of double-blind placebocontrolled studies have shown an enhanced antidepressant effect of 5-HTP in comparison with placebo,140 but in studies with healthy subjects, acute administration of 5-HTP (100–200 mg) has not influenced mood.141,142 One study reported increased subjective fatigue and attention reaction times after ingestion of 30 mg/kg L-Trp,143 another reported impaired decision-making under conditions of ambiguity with 100 mg of 5-HTP,141 and another found decreased planning ability after ingestion of 150 mg of 5-HTP.144 With regard to the interactive effects of L-Trp or 5-HTP with caffeine, 1 study reported no interactive effects on physiological parameters at rest or during exercise.145 No studies, however, have examined the effects of L-Trp/5-HTP and caffeine, both separately and combined, on mood or performance, so the independent contributions of these substances to the mood and cognitive effects of energy drinks are unknown.

St. John’s wort. Hypericum perforatum, or St. John’s wort, is a flowering shrub used in traditional medicine. Its antidepressant activity has been examined in a number of controlled clinical studies. Results from most studies suggest it is more effective than placebo for the treatment of mild depression,146,147 it is as effective as some other antidepressants, including amitriptyline, imipramine, sertraline, and fluoxetine,148–151 and has a more favorable side effect profile than other antidepressant medications,152 though there are both case reports and in vitro data suggesting it interacts with a number of medications.153 Its main constituents are hypericin, hyperforin, flavonoids, and xanthones, which have been shown to inhibit the uptake of serotonin, noradrenaline, dopamine, γ-aminobutyric acid (GABA), and glutamate; to inhibit monoamine oxidases A and B; and to bind to adenosine, GABAA, GABAB, and glutamine receptors.154–158 Its acute effects have been less investigated, although 2 studies showed that doses of 900 mg and 1,800 mg impaired visual-motor coordination, working memory, and memory recall without influencing mood, attention, or information processing.159,160 One study reported the absence of a pharmacokinetic interaction between 240 mg of St. John’s wort and 100 mg of caffeine,161 but there have been no studies on the interactive effects of St. John’s wort and caffeine on mood and cognition. Nutrition Reviews® Vol. 72(S1):48–59

Yohimbine. Yohimbine is an α2-adrenoreceptor antagonist that is sometimes added to energy drinks. Doses of 15–30 mg have been shown to improve subjective arousal and some aspects of cognition, including information processing, but also to increase anxiety and panic.162–164 It has also been associated with serious adverse effects, including tachycardia and hypertension.165 The effects of yohimbine in combination with caffeine have not been assessed. Other ingredients There are a number of other energy drink ingredients for which very little information is available. These substances deserve particular attention, given their widespread consumption by energy drink users. Yerba maté tea is derived from the leaves of the Ilex paraguariensis shrub. It contains methylxanthines (caffeine and theobromine), flavonoids, (quercetin and kaempferol), saponins, tannins, and vitamins A, B complex, C, and E. It has been reported to possess antioxidant, vasodilatory, antiglycation, and antiobesity properties,166 although its acute or short-term effects on mood and cognitive performance have not been studied. Malic acid is an intermediate component of the Krebs cycle, the biochemical process by which food is converted to energy. It is added to energy drinks to increase the bioavailability of nitric oxide donors (e.g., arginine), but there is no firm evidence for its efficacy. Vinpocetine is a phosphodiesterase inhibitor that has vasodilatory properties and increases cerebral blood flow.167 It has been shown to improve cognitive outcomes after stroke,168 but its short-term effects have not been assessed in healthy subjects. Finally, 1,3dimethylamylamine is an ingredient that has been widely used in the exercise industry and is also added to energy drinks, but its effects on mood and cognition have not been assessed in acute challenge studies. Following safety concerns,169,170 the FDA issued a warning in July 2013 to consumers to avoid supplements containing this ingredient and declared that dietary supplements containing 1,3-dimethylamylamine are illegal.171 Most manufacturers have removed supplements containing 1,3-dimethylamylamine- from the market.

CONCLUSION Overall, there is a lack of empirical evidence for beneficial interactions between caffeine and other energy drink ingredients. This is not surprising, given the wide variety of different ingredients and the general lack of information about the exact amounts contained in energy products. There have been promising findings for select ingredients that deserve further investigation and verifiNutrition Reviews® Vol. 72(S1):48–59

cation. Glucose combined with caffeine has shown the most promising effects on working and explicit memory, which could be due to the altered absorption and pharmacokinetic profiles of these substances when administered together. Administration of L-theanine and caffeine together appears to produce superior effects on mental alertness, attention, and memory. However, taurine in combination with caffeine appears to counteract the stimulating effects of caffeine on mood and attention. Thus, of the multitude of energy drink ingredients, there is some evidence of added mood and performance benefits only for glucose and L-theanine, but these results require replication. Other substances, such as ginseng, guarana, tyrosine, gingko, theophylline, flavanols, and creatine, appear to produce positive mood and performance effects by themselves in healthy individuals and should be investigated for interactive effects with caffeine. However, for others (e.g., L-tryptophan, St. John’s wort, yohimbine), the available evidence appears to indicate detrimental mood and performance effects. Some substances, including green tea, citicoline, carnitine, and L-arginine, have only been studied in older subjects or those with some degree of impairment, low mood, or nutritional deficiency and require controlled study in healthy young adults. Finally, for all other ingredients, the behavioral effects of the substances themselves have not been well characterized. Future studies in this important area should focus on mood and cognitive effects of the energy drink ingredients in the main consumers of energy products, i.e., adolescents and young adults. Caffeine-containing energy drinks and products are also targeted at fatigued individuals in whom the effects may be more prominent. There have been several reviews of valid and sensitive measures of mental energy172–174 that researchers can consult in the design of their studies to reduce the incidence of negative and discrepant results. However, without more detailed information from the energy drink manufacturers about the amounts of the different in gredients contained in their products, it will be difficult to design accurate studies to answer some of these questions. The general dearth of information about the effects of ingredients alone and in combination with caffeine is cause for concern, given that toxic exposure to these mixtures of chemicals has more serious consequences than toxic exposure to caffeine alone.9 In addition, caffeine produces physiological dependence at doses as low as 100 mg/day,175 which may underlie the recent addition of caffeine to many different foods. Thus, one area recommended for future research is how energy drink ingredients affect the positively reinforcing and dependenceproducing properties of caffeine. If energy drink ingredients alter the positive or negative behavioral 55

effects of caffeine, they will also likely influence its reinforcing potential. This deserves particular attention, especially given recent findings that energy drink consumption is associated with an increased risk of alcohol dependence176 and predicts nonmedical use of prescription drugs.177 Acknowledgments The author thanks Samuel P. King for assistance with retrieving references and preparing tables. Declaration of interest. The author has no relevant interests to declare. REFERENCES 1. Alford C, Cox H, Wescott R. The effects of Red Bull energy drink on human performance and mood. Amino Acids. 2001;21:139–150. 2. Geiß KR, Jester I, Falke W, et al. The effect of a taurine-containing drink on performance in 10 endurance-athletes. Amino Acids. 1994;7:45–56. 3. Kennedy DO, Scholey AB. A glucose-caffeine “energy drink”ameliorates subjective and performance deficits during prolonged cognitive demand. Appetite. 2004;42:331–333. 4. Scholey AB, Kennedy DO. Cognitive and physiological effects of an “energy drink”: an evaluation of the whole drink and of glucose, caffeine and herbal flavouring fractions. Psychopharmacology. 2004;176:320–330. 5. Seidl R, Peyrl A, Nicham R, et al. A taurine and caffeine-containing drink stimulates cognitive performance and well-being. Amino Acids. 2000;19:635–642. 6. Smit HJ, Cotton JR, Hughes SC, et al. Mood and cognitive performance effects of “energy” drink constituents: caffeine, glucose and carbonation. Nutr Neurosci. 2004;7:127–139. 7. Warburton DM, Bersellini E, Sweeney E. An evaluation of a caffeinated taurine drink on mood, memory and information processing in healthy volunteers without caffeine abstinence. Psychopharmacology. 2001;158:322–328. 8. Smith A. Effects of caffeine on human behavior. Food Chem Toxicol. 2002;40:1243–1255. 9. Seifert SM, Seifert SA, Schaechter JL, et al. An analysis of energy-drink toxicity in the National Poison Data System. Clin Toxicol (Phila). 2013;51:566–574. 10. Adan A, Serra-Grabulosa JM. Effects of caffeine and glucose, alone and combined, on cognitive performance. Hum Psychopharmacol. 2010;25:310– 317. 11. Giles GE, Mahoney CR, Brunye TT, et al. Differential cognitive effects of energy drink ingredients: caffeine, taurine, and glucose. Pharmacol Biochem Behav. 2012;102:569–577. 12. Maridakis V, O’Connor PJ, Tomporowski PD. Sensitivity to change in cognitive performance and mood measures of energy and fatigue in response to morning caffeine alone or in combination with carbohydrate. Int J Neurosci. 2009;119:1239–1258. 13. Serra-Grabulosa JM, Adan A, Falcon C, et al. Glucose and caffeine effects on sustained attention: an exploratory fMRI study. Hum Psychopharmacol. 2010;25:543–552. 14. Young HA, Benton D. Caffeine can decrease subjective energy depending on the vehicle with which it is consumed and when it is measured. Psychopharmacology. 2013;228:243–254. 15. Peacock A, Martin FH, Carr A. Energy drink ingredients. Contribution of caffeine and taurine to performance outcomes. Appetite. 2013;64:1–4. 16. Aggarwal R, Mishra A, Crochet P, et al. Effect of caffeine and taurine on simulated laparoscopy performed following sleep deprivation. Br J Surg. 2011;98:1666–1672. 17. Rogers PJ, Smith JE, Heatherley SV, et al. Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology. 2008;195:569–577. 18. Haskell CF, Kennedy DO, Milne AL, et al. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol. 2008;77:113–122. 19. Kelly SP, Gomez-Ramirez M, Montesi JL, et al. L-theanine and caffeine in combination affect human cognition as evidenced by oscillatory alpha-band activity and attention task performance. J Nutr. 2008;138:1572S–1577S. 20. Foxe JJ, Morie KP, Laud PJ, et al. Assessing the effects of caffeine and theanine on the maintenance of vigilance during a sustained attention task. Neuropharmacology. 2012;62:2320–2327.

56

21. Kennedy DO, Haskell CF, Wesnes KA, et al. Improved cognitive performance in human volunteers following administration of guarana (Paullinia cupana) extract: comparison and interaction with Panax ginseng. Pharmacol Biochem Behav. 2004;79:401–411. 22. Benton D. Carbohydrate ingestion, blood glucose and mood. Neurosci Biobehav Rev. 2002;26:293–308. 23. Gorby HE, Brownawell AM, Falk MC. Do specific dietary constituents and supplements affect mental energy? Review of the evidence. Nutr Rev. 2010;68:697–718. 24. Pizziol A, Tikhonoff V, Paleari CD, et al. Effects of caffeine on glucose tolerance: a placebo-controlled study. Eur J Clin Nutr. 1998;52:846–849. 25. Graham TE, Sathasivam P, Rowland M, et al. Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test. Can J Physiol Pharmacol. 2001;79:559–565. 26. Gomez-Ramirez M, Higgins BA, Rycroft JA, et al. The deployment of intersensory selective attention: a high-density electrical mapping study of the effects of theanine. Clin Neuropharmacol. 2007;30:25–38. 27. Gomez-Ramirez M, Kelly SP, Montesi JL, et al. The effects of L-theanine on alpha-band oscillatory brain activity during a visuo-spatial attention task. Brain Topogr. 2009;22:44–51. 28. Kimura K, Ozeki M, Juneja LR, et al. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007;74:39–45. 29. Lu K, Gray MA, Oliver C, et al. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol. 2004;19:457–465. 30. Nobre AC, Rao A, Owen GN. L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr. 2008;17(Suppl 1):167–168. 31. D’Angelo L, Grimaldi R, Caravaggi M, et al. A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol. 1986;16:15–22. 32. Kennedy DO, Scholey AB, Wesnes KA. Dose dependent changes in cognitive performance and mood following acute administration of Ginseng to healthy young volunteers. Nutr Neurosci. 2001;4:295–310. 33. Kennedy DO, Scholey AB, Wesnes KA. Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ ginseng combination to healthy young adults. Physiol Behav. 2002;75:739– 751. 34. Reay JL, Kennedy DO, Scholey AB. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol. 2005;19:357–365. 35. Reay JL, Kennedy DO, Scholey AB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained “mentally demanding” tasks. J Psychopharmacol. 2006;20:771–781. 36. Reay JL, Scholey AB, Kennedy DO. Panax ginseng (G115) improves aspects of working memory performance and subjective ratings of calmness in healthy young adults. Hum Psychopharmacol. 2010;25:462–471. 37. Scholey AB, Kennedy DO. Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: differential interactions with cognitive demand. Hum Psychopharmacol. 2002;17:35–44. 38. Sorensen H, Sonne J. A double-masked study of the effects of ginseng on cognitive functions. Curr Ther Res. 1996;57:959–968. 39. Neale C, Camfield D, Reay J, et al. Cognitive effects of two nutraceuticals Ginseng and Bacopa benchmarked against modafinil: a review and comparison of effect sizes. Br J Clin Pharmacol. 2013;75:728–737. 40. Henman AR. Guarana (Paullinia cupana var. sorbilis): ecological and social perspectives on an economic plant of the central Amazon basin. J Ethnopharmacol. 1982;6:311–338. 41. Seifert SM, Schaechter JL, Hershorin ER, et al. Health effects of energy drinks on children, adolescents, and young adults. Pediatrics. 2011;127:511–528. 42. Haskell CF, Dodd FL, Wightman EL, et al. Behavioural effects of compounds co-consumed in dietary forms of caffeinated plants. Nutr Res Rev. 2013;26:49– 70. 43. McLellan TM, Lieberman HR. Do energy drinks contain active components other than caffeine? Nutr Rev. 2012;70:730–744. 44. Haskell CF, Kennedy DO, Wesnes KA, et al. A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guaraná in humans. J Psychopharmacol. 2007;21:65–70. 45. Kennedy DO, Haskell CF, Wesnes KA, et al. Improved cognitive performance and mental fatigue following a multi-vitamin and mineral supplement with added guaraná (Paullinia cupana). Appetite. 2008;50:506–513. 46. Silvestrini GI, Marino F, Cosentino M. Effects of a commercial product containing guarana on psychological well-being, anxiety and mood: a single-blind, placebo-controlled study in healthy subjects. J Negat Results Biomed. 2013;12:9. 47. da Costa Miranda V, Trufelli DC, Santos J, et al. Effectiveness of guaraná (Paullinia cupana) for postradiation fatigue and depression: results of a pilot double-blind randomized study. J Altern Complement Med. 2009;15:431– 433.

Nutrition Reviews® Vol. 72(S1):48–59

48. de Oliveira Campos MP, Riechelmann R, Martins LC, et al. Guaraná (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. J Altern Complement Med. 2011;17:505–512. 49. Galduróz JC, Carlini EA. Acute effects of the Paulinia cupana, “Guaraná” on the cognition of normal volunteers. Sao Paulo Med J. 1994;112:607–611. 50. Galduróz JC, Carlini EA. The effects of long-term administration of guarana on the cognition of normal, elderly volunteers. Sao Paulo Med J. 1996;114:1073– 1078. 51. Banderet LE, Lieberman HR. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull. 1989;22:759– 762. 52. Deijen JB, Orlebeke JF. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull. 1994;33:319–323. 53. Deijen JB, Wientjes CJ, Vullinghs HF, et al. Tyrosine improves cognitive performance and reduces blood pressure in cadets after one week of a combat training course. Brain Res Bull. 1999;48:203–209. 54. Dollins AB, Krock LP, Storm WF, et al. L-tyrosine ameliorates some effects of lower body negative pressure stress. Physiol Behav. 1995;57:223–230. 55. Magill RA, Waters WF, Bray GA, et al. Effects of tyrosine, phentermine, caffeine D-amphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation. Nutr Neurosci. 2003;6:237–246. 56. Mahoney CR, Castellani J, Kramer FM, et al. Tyrosine supplementation mitigates working memory decrements during cold exposure. Physiol Behav. 2007;92:575–582. 57. Neri DF, Wiegmann D, Stanny RR, et al. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med. 1995;66:313–319. 58. O’Brien C, Mahoney C, Tharion WJ, et al. Dietary tyrosine benefits cognitive and psychomotor performance during body cooling. Physiol Behav. 2007;90:301– 307. 59. Shukitt-Hale B, Stillman MJ, Lieberman HR. Tyrosine administration prevents hypoxia-induced decrements in learning and memory. Physiol Behav. 1996;59:867–871. 60. Shurtleff D, Thomas JR, Schrot J, et al. Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacol Biochem Behav. 1994;47:935–941. 61. Thomas JR, Lockwood PA, Singh A, et al. Tyrosine improves working memory in a multitasking environment. Pharmacol Biochem Behav. 1999;64:495–500. 62. Amieva H, Meillon C, Helmer C, et al. Ginkgo biloba extract and long-term cognitive decline: a 20-year follow-up population-based study. PLoS ONE. 2013;8:e52755. 63. Andrieu S, Gilette S, Amouyal K, et al. Association of Alzheimer’s disease onset with Ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study. J Gerontol A Biol Sci Med Sci. 2003;58:372–377. 64. Herrschaft H, Nacu A, Likhachev S, et al. Ginkgo biloba extract EGb 761(R) in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012;46:716–723. 65. Ihl R, Tribanek M, Bachinskaya N. Baseline neuropsychiatric symptoms are effect modifiers in Ginkgo biloba extract (EGb 761[R]) treatment of dementia with neuropsychiatric features. Retrospective data analyses of a randomized controlled trial. J Neurol Sci. 2010;299:184–187. 66. Schneider LS, DeKosky ST, Farlow MR, et al. A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer’s type. Curr Alzheimer Res. 2005;2:541–551. 67. DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300:2253–2262. 68. Dodge HH, Zitzelberger T, Oken BS, et al. A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Neurology. 2008;70(19 Pt 2):1809–1817. 69. Vellas B, Coley N, Ousset PJ, et al. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012;11:851–859. 70. Janssen IM, Sturtz S, Skipka G, et al. Ginkgo biloba in Alzheimer’s disease: a systematic review. Wien Med Wochenschr. 2010;160:539–546. 71. Weinmann S, Roll S, Schwarzbach C, et al. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010;10:14. doi:10.1186/ 1471-2318-10-14. 72. Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2007;(2):CD003120. doi:10.1002/ 14651858. 73. Canter PH, Ernst E. Ginkgo biloba is not a smart drug: an updated systematic review of randomised clinical trials testing the nootropic effects of G. biloba extracts in healthy people. Hum Psychopharmacol. 2007;22:265–278. 74. Roland PD, Nergard CS. Ginkgo biloba – effect, adverse events and drug interaction. Tidsskr Nor Laegeforen. 2012;132:956–959. 75. Kennedy DO, Haskell CF, Mauri PL, et al. Acute cognitive effects of standardised Ginkgo biloba extract complexed with phosphatidylserine. Hum Psychopharmacol. 2007;22:199–210.

Nutrition Reviews® Vol. 72(S1):48–59

76. Rigney U, Kimber S, Hindmarch I. The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers. Phytother Res. 1999;13:408–415. 77. Kennedy DO, Scholey AB, Wesnes KA. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology. 2000;151:416–423. 78. Kennedy DO, Jackson PA, Haskell CF, et al. Modulation of cognitive performance following single doses of 120 mg Ginkgo biloba extract administered to healthy young volunteers. Hum Psychopharmacol. 2007;22:559–566. 79. Itil TM, Eralp E, Tsampis E, et al. Central nervous system effects of Ginkgo biloba, a plant extract. Am J Ther. 1996;3:63–73. 80. Kennedy DO, Scholey AB, Drewery L, et al. Electroencephalograph effects of single doses of Ginkgo biloba and Panax ginseng in healthy young volunteers. Pharmacol Biochem Behav. 2003;75:701–709. 81. Ozgoli G, Selselei EA, Mojab F, et al. A randomized, placebo-controlled trial of Ginkgo biloba L. in treatment of premenstrual syndrome. J Altern Complement Med. 2009;15:845–851. 82. Hartley DE, Heinze L, Elsabagh S, et al. Effects on cognition and mood in postmenopausal women of 1-week treatment with Ginkgo biloba. Pharmacol Biochem Behav. 2003;75:711–720. 83. Cockle SM, Kimber S, Hindmarch I. The effects of Ginkgo biloba extract (LI 1370) supplementation on activities of daily living in free living older volunteers: a questionnaire survey. Hum Psychopharmacol. 2000;15:227–235. 84. Soholm B. Clinical improvement of memory and other cognitive functions by Ginkgo biloba: review of relevant literature. Adv Ther. 1998;15:54–65. 85. Silberstein RB, Pipingas A, Song J, et al. Examining brain-cognition effects of Ginkgo biloba extract: brain activation in the left temporal and left prefrontal cortex in an object working memory task. Evid Based Complement Alternat Med. 2011;2011:164139. doi:10.1155/2011/164139. 86. Stough C, Clarke J, Lloyd J, et al. Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol. 2001;4:131–134. 87. Kaschel R. Ginkgo biloba: specificity of neuropsychological improvement – a selective review in search of differential effects. Hum Psychopharmacol. 2009;24:345–370. 88. Zadoyan G, Rokitta D, Klement S, et al. Effect of Ginkgo biloba special extract EGb 761(R) on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers. Eur J Clin Pharmacol. 2012;68:553–560. 89. Baggott MJ, Childs E, Hart AB, et al. Psychopharmacology of theobromine in healthy volunteers. Psychopharmacology. 2013;228:109–118. 90. Mumford GK, Evans SM, Kaminski BJ, et al. Discriminative stimulus and subjective effects of theobromine and caffeine in humans. Psychopharmacology. 1994;115:1–8. 91. Smit HJ, Gaffan EA, Rogers PJ. Methylxanthines are the psychopharmacologically active constituents of chocolate. Psychopharmacology. 2004;176:412–419. 92. Bartel P, Delport R, Lotz B, et al. Effects of single and repeated doses of theophylline on aspects of performance, electrophysiology and subjective assessments in healthy human subjects. Psychopharmacology. 1992;106:90–96. 93. Tiplady B, Fagan D, Lamont M, et al. A comparison of the CNS effects of enprofylline and theophylline in healthy subjects assessed by performance testing and subjective measures. Br J Clin Pharmacol. 1990;30:55–61. 94. Yu G, Maskray V, Jackson SH, et al. A comparison of the central nervous system effects of caffeine and theophylline in elderly subjects. Br J Clin Pharmacol. 1991;32:341–345. 95. Nehlig A. The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. Br J Clin Pharmacol. 2013;75:716–727. 96. Macready AL, Kennedy OB, Ellis JA, et al. Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies. Genes Nutr. 2009;4:227–242. 97. Young SN. Folate and depression – a neglected problem. J Psychiatry Neurosci. 2007;32:80–82. 98. Young SN, Ghadirian AM. Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13:841–863. 99. Falkingham M, Abdelhamid A, Curtis P, et al. The effects of oral iron supplementation on cognition in older children and adults: a systematic review and meta-analysis. Nutr J. 2010;9:4. doi:10.1186/1475-2891-9-4. 100. Vinod Kumar M, Rajagopalan S. Trial using multiple micronutrient food supplement and its effect on cognition. Indian J Pediatr. 2008;75:671–678. 101. Bryan J, Calvaresi E. Associations between dietary intake of folate and vitamins B-12 and B-6 and self-reported cognitive function and psychological wellbeing in Australian men and women in midlife. J Nutr Health Aging. 2004;8:226–232. 102. Deijen JB, van der Beek EJ, Orlebeke JF, et al. Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Psychopharmacology. 1992;109:489–496. 103. Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr. 2002;132:1345–1356.

57

104. Haskell CF, Robertson B, Jones F, et al. Effects of a multi-vitamin/mineral supplement on cognitive function and fatigue during extended multi-tasking. Hum Psychopharmacol. 2010;25:448–461. 105. Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev. 2008;(4):CD004514. doi: 10.1002/14651858.CD004514 .pub2. 106. Zhang M, Robitaille L, Eintracht S, et al. Vitamin C provision improves mood in acutely hospitalized patients. Nutrition. 2011;27:530–533. 107. Chui MH, Greenwood CE. Antioxidant vitamins reduce acute meal-induced memory deficits in adults with type 2 diabetes. Nutr Res. 2008;28:423–429. 108. McMorris T, Harris RC, Howard AN, et al. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol Behav. 2007;90:21–28. 109. McMorris T, Harris RC, Swain J, et al. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology. 2006;185:93–103. 110. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr. 2011;105:1100– 1105. 111. Ling J, Kritikos M, Tiplady B. Cognitive effects of creatine ethyl ester supplementation. Behav Pharmacol. 2009;20:673–679. 112. Rae C, Digney AL, McEwan SR, et al. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, crossover trial. Proc Biol Sci. 2003;270:2147–2150. 113. Dixon CE, Ma X, Marion DW. Effects of CDP-choline treatment on neurobehavioral deficits after TBI and on hippocampal and neocortical acetylcholine release. J Neurotrauma. 1997;14:161–169. 114. Petkov VD, Stancheva SL, Tocuschieva L, et al. Changes in brain biogenic monoamines induced by the nootropic drugs adafenoxate and meclofenoxate and by citicholine (experiments on rats). Gen Pharmacol. 1990;21:71–75. 115. Alvarez XA, Laredo M, Corzo D, et al. Citicoline improves memory performance in elderly subjects. Methods Find Exp Clin Pharmacol. 1997;19:201–210. 116. Di Trapani G, Fioravanti M. Citicoline in the treatment of cognitive and behavioral disorders in pathologic senile decline. Clin Ter. 1991;137:403–413. 117. Spiers PA, Myers D, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol. 1996;53:441–448. 118. Fioravanti M, Buckley AE. Citicoline (Cognizin) in the treatment of cognitive impairment. Clin Interv Aging. 2006;1:247–251. 119. Bruce SE. Improvements in quantitative EEG following consumption of a natural citicoline-enhanced beverage. Int J Food Sci Nutr. 2012;63: 421–425. 120. Silveri MM, Dikan J, Ross AJ, et al. Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy. NMR Biomed. 2008;21:1066–1075. 121. Cynober L. Pharmacokinetics of arginine and related amino acids. J Nutr. 2007;137(6 Suppl 2):1646S–1649S. 122. McConell GK. Effects of L-arginine supplementation on exercise metabolism. Curr Opin Clin Nutr Metab Care. 2007;10:46–51. 123. Bescos R, Sureda A, Tur JA, et al. The effect of nitric-oxide-related supplements on human performance. Sports Med. 2012;42:99–117. 124. Paul V, Reddy L, Ekambaram P. Prevention of picrotoxin convulsions-induced learning and memory impairment by nitric oxide increasing dose of L-arginine in rats. Pharmacol Biochem Behav. 2003;75:329–334. 125. Paul V, Reddy L, Ekambaram P. A reversal by L-arginine and sodium nitroprusside of ageing-induced memory impairment in rats by increasing nitric oxide concentration in the hippocampus. Indian J Physiol Pharmacol. 2005;49:179–186. 126. Ohtsuka Y, Nakaya J. Effect of oral administration of L-arginine on senile dementia. Am J Med. 2000;108:439. http://dx.doi.org/10.1016/S0002-9343(99)00 396-4. 127. Yi J, Horky LL, Friedlich AL, et al. L-arginine and Alzheimer’s disease. Int J Clin Exp Pathol. 2009;2:211–238. 128. Khan N, Mukhtar H. Tea and health: studies in humans. Curr Pharm Des. 2013;19:6141–6147. 129. Park SK, Jung IC, Lee WK, et al. A combination of green tea extract and L-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food. 2011;14:334–343. 130. Song J, Xu H, Liu F, et al. Tea and cognitive health in late life: current evidence and future directions. J Nutr Health Aging. 2012;16:31–34. 131. Malaguarnera M. Carnitine derivatives: clinical usefulness. Curr Opin Gastroenterol. 2012;28:166–176. 132. Malaguarnera M. Acetyl-L-carnitine in hepatic encephalopathy. Metab Brain Dis. 2013;28:193–199. 133. Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol. 2003;18:61–71.

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134. Tempesta E, Casella L, Pirrongelli C, et al. L-acetylcarnitine in depressed elderly subjects. A cross-over study versus placebo. Drugs Exp Clin Res. 1987;13:417– 423. 135. Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998;3:271–280. 136. Meyers S. Use of neurotransmitter precursors for treatment of depression. Altern Med Rev. 2000;5:64–71. 137. Zmilacher K, Battegay R, Gastpar M. L-5-hydroxytryptophan alone and in combination with a peripheral decarboxylase inhibitor in the treatment of depression. Neuropsychobiology. 1988;20:28–35. 138. Lynn-Bullock CP, Welshhans K, Pallas SL, et al. The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats. J Chem Neuroanat. 2004;27:129–138. 139. Okada S, Kamb ML, Pandey JP, et al. Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms. Arthritis Rheum. 2009;61:1305–1311. 140. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006;109:325– 338. 141. Gendle MH, Golding AC. Oral administration of 5-hydroxytryptophan (5-HTP) impairs decision making under ambiguity but not under risk: evidence from the Iowa Gambling Task. Hum Psychopharmacol. 2010;25:491–499. 142. Gijsman HJ, van Gerven JM, de Kam ML, et al. Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers. J Clin Psychopharmacol. 2002;22:183–189. 143. Cunliffe A, Obeid OA, Powell-Tuck J. A placebo-controlled investigation of the effects of tryptophan or placebo on subjective and objective measures of fatigue. Eur J Clin Nutr. 1998;52:425–430. 144. Gendle MH, Young EL, Romano AC. Effects of oral 5-hydroxytryptophan on a standardized planning task: insight into possible dopamine/serotonin interactions in the forebrain. Hum Psychopharmacol. 2013;28:270–273. 145. Alves MN, Ferrari-Auarek WM, Pinto KM, et al. Effects of caffeine and tryptophan on rectal temperature, metabolism, total exercise time, rate of perceived exertion and heart rate. Braz J Med Biol Res. 1995;28:705–709. 146. Kasper S, Gastpar M, Muller WE, et al. Efficacy of St. John’s wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Eur Arch Psychiatry Clin Neurosci. 2008;258:59–63. 147. Linde K, Ramirez G, Mulrow CD, et al. St John’s wort for depression – an overview and meta-analysis of randomised clinical trials. BMJ. 1996;313: 253–258. 148. Brenner R, Azbel V, Madhusoodanan S, et al. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a doubleblind, randomized pilot study. Clin Ther. 2000;22:411–419. 149. Schrader E. Equivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15:61–68. 150. Wheatley D. LI 160, an extract of St. John’s wort, versus amitriptyline in mildly to moderately depressed outpatients – a controlled 6-week clinical trial. Pharmacopsychiatry. 1997;30(Suppl 2):77–80. 151. Woelk H. Comparison of St John’s wort and imipramine for treating depression: randomised controlled trial. BMJ. 2000;321:536–539. 152. Ernst E. Second thoughts about safety of St John’s wort. Lancet. 1999;354: 2014–2016. 153. Russo E, Scicchitano F, Whalley BJ, et al. Hypericum perforatum: Pharmacokinetic, Mechanism of Action, Tolerability, and Clinical Drug-Drug Interactions. Phytother Res. 2014;28:643–655. 154. Butterweck V. Mechanism of action of St John’s wort in depression: what is known? CNS Drugs. 2003;17:539–562. 155. Chatterjee SS, Bhattacharya SK, Wonnemann M, et al. Hyperforin as a possible antidepressant component of Hypericum extracts. Life Sci. 1998;63:499–510. 156. Chatterjee SS, Noldner M, Koch E, et al. Antidepressant activity of Hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry. 1998;31(Suppl 1):7–15. 157. Muller WE, Rolli M, Schafer C, et al. Effects of Hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry. 1997;30(Suppl 2):102–107. 158. Wonnemann M, Singer A, Muller WE. Inhibition of synaptosomal uptake of 3H-L-glutamate and 3H-GABA by hyperforin, a major constituent of St. John’s Wort: the role of amiloride sensitive sodium conductive pathways. Neuropsychopharmacology. 2000;23:188–197. 159. Ellis KA, Stough C, Vivetta L, et al. An investigation into the acute nootropic effects of Hypericum perforatum L. (St. John’s Wort) in healthy human volunteers. Behav Pharmacol. 2001;12:173–182. 160. Timoshanko A, Stough C, Vivetta L, et al. A preliminary investigation on the acute pharmacodynamic effects of hypericum on cognitive and psychomotor performance. Behav Pharmacol. 2001;12:635–640. 161. Arold G, Donath F, Maurer A, et al. No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extract. Planta Med. 2005;71:331–337.

Nutrition Reviews® Vol. 72(S1):48–59

162. Charney DS, Heninger GR. Noradrenergic function and the mechanism of action of antianxiety treatment. I. The effect of long-term alprazolam treatment. Arch Gen Psychiatry. 1985;42:458–467. 163. Halliday R, Naylor H, Brandeis D, et al. The effect of D-amphetamine, clonidine, and yohimbine on human information processing. Psychophysiology. 1994;31:331–337. 164. Mizuki Y, Suetsugi M, Ushijima I, et al. Differential effects of noradrenergic drugs on anxiety and arousal in healthy volunteers with high and low anxiety. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20:1353–1367. 165. Kearney T, Tu N, Haller C. Adverse drug events associated with yohimbinecontaining products: a retrospective review of the California Poison Control System reported cases. Ann Pharmacother. 2010;44:1022–1029. 166. Heck CI, de Mejia EG. Yerba Mate tea (Ilex paraguariensis): a comprehensive review on chemistry, health implications, and technological considerations. J Food Sci. 2007;72:R138–R151. 167. Bonoczk P, Panczel G, Nagy Z. Vinpocetine increases cerebral blood flow and oxygenation in stroke patients: a near infrared spectroscopy and transcranial Doppler study. Eur J Ultrasound. 2002;15:85–91. 168. Patyar S, Prakesh A, Modi M, et al. Role of vinpocetine in cerebrovascular diseases. Pharmacological Reports. 2011;63:618–628. 169. Brown JA, Buckley NA. Toxicity from bodybuilding supplements and recreational use of products containing 1,3-dimethylamylamine. Med J Aust. 2013;198:414–415.

Nutrition Reviews® Vol. 72(S1):48–59

170. Eliason MJ, Eichner A, Cancio A, et al. Case reports: death of active duty soldiers following ingestion of dietary supplements containing 1,3-dimethylamylamine (DMAA). Mil Med. 2012;177:1455–1459. 171. U.S. Food and Drug Administration. DMAA in Dietary Supplements. 2013. Available at: http://www.fda.gov/Food/DietarySupplements/QADietarySupple ments/ucm346576.htm#FAQs. Accessed: January 2014. 172. Lieberman HR. Mental energy: assessing the cognition dimension. Nutr Rev. 2006;64(Suppl S3):S10–S13. 173. O’Connor PJ. Mental energy: assessing the mood dimension. Nutr Rev. 2006;64(Suppl S3):S7–S9. 174. O’Connor PJ. Mental energy: developing a model for examining nutritionrelated claims. Nutr Rev. 2006;64(Suppl S3):S2–S6. 175. Evans SM, Griffiths RR. Caffeine withdrawal: a parametric analysis of caffeine dosing conditions. J Pharmacol Exp Ther. 1999;289:285–294. 176. Arria AM, Caldeira KM, Kasperski SJ, et al. Energy drink consumption and increased risk for alcohol dependence. Alcohol Clin Exp Res. 2011;35:365– 375. 177. Arria AM, Caldeira KM, Kasperski SJ, et al. Increased alcohol consumption, nonmedical prescription drug use, and illicit drug use are associated with energy drink consumption among college students. J Addict Med. 2010;4: 74–80.

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