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Diet promotes sleep duration and quality

Katri Peuhkuri⁎, Nora Sihvola, Riitta KorpelaInstitute of Biomedicine, Pharmacology, Medical Nutrition Physiology, University of Helsinki, PO Box 63, FIN-00014, Helsinki, Finland

A R T I C L E I N F O

Abbreviations: 5-HTP, 5-hydroxytryptophaenergy intake; GABA, γ-aminobutyric acid; LTDO, tryptophan 2,3-dioxygenase; TRP, trypt⁎ Corresponding author. Tel.: +358 9 191 25 36E-mail address: katri.peuhkuri@helsinki.f

0271-5317/$ – see front matter © 2012 Elsevidoi:10.1016/j.nutres.2012.03.009

A B S T R A C T

Article history:Received 4 October 2011Revised 13 March 2012Accepted 20 March 2012

Sleep, much like eating, is an essential part of life. The mechanisms of sleep are onlypartially clear and are the subject of intense research. There is increasing evidence showingthat sleep has an influence on dietary choices. Both cross-sectional and epidemiologicstudies have demonstrated that those who sleep less are more likely to consume energy-rich foods (such as fats or refined carbohydrates), to consume fewer portions of vegetables,and to have more irregular meal patterns. In this narrative review, we pose the oppositequestion: can ingested food affect sleep? The purpose of this review is to discuss theevidence linking diet and sleep and to determine whether what we eat and what kind ofnutrients we obtain from the food consumed before bedtime matter. In addition, scientificevidence behind traditional sleep-promoting foods such as milk and some herbal productsis briefly described. These are reviewed using data from clinical trials, mostly in healthysubjects. In addition, we discuss the possible mechanisms behind these observations.Lastly, we summarize our findings that emerging evidence confirms a link between diet andsleep. Overall, foods impacting the availability of tryptophan, as well as the synthesis ofserotonin and melatonin, may be the most helpful in promoting sleep. Although there areclear physiological connections behind these effects, the clinical relevance needs to bestudied further.

© 2012 Elsevier Inc. All rights reserved.

Keywords:SleepDietFoodNutrientsProteinTryptophan

1. Introduction

Sleep is a physical andmental resting state, in which a personbecomes relatively inactive and unaware of their environ-ment. The purposes and mechanisms of sleep are onlypartially clear and are the subject of intense research [1,2].

Sleep is considered adequate when there is no daytimesleepiness or dysfunction. The amount of sleep a personneeds varies individually and depends on various factors, oneof which is age. Most adults need about 7 to 8 hours of sleepper day, but infants and teenagers need more [3]. With age,sleep latency, sleep arousals, and awakenings as well as

n; AADC, aromatic L-amiNAA, large neutral aminoophan.6; fax: +358 9 191 25 364.i (K. Peuhkuri).

er Inc. All rights reserved

reductions in sleep duration increase, although decline innighttime sleep duration is paralleled by an increase innapping during the daytime [4]. Sleep is controlled by thecircadian clock, sleep-wake homeostasis, and willed behavior.Sleep duration can be measured with fairly simple methods.Subjective methods include a sleep diary and validatedquestionnaires, whereas electroencephalogram, polysomno-graphy, and actigraphymeasurements providemore objectiveresults. Other parameters to define sleep, such as thesubjective experience of sleep quality, are more complicatedbecause even the term “sleep quality” has not been rigorouslydefined [5].

no acid decarboxylase; CCK, cholecystokinin; E%, percent of totalacid; PYY, peptide tyrosine-tyrosine; REM, rapid eye movement;

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Cross-sectional and epidemiologic studies have demon-strated connections between sleep duration and diet. Sleepdeprivation can modify dietary choices, and reduced sleepduration has been associated with both metabolic disordersand the increased prevalence of obesity [3]. Adequate sleep ispositively associated with health-related behavior such asadopting a healthy diet. These associations have been shownin children [6], adolescents [7–10], and adults [11–13]. Thosewho sleep less are more likely to consume energy-rich foods,get higher proportions of calories from fats or refinedcarbohydrates, consume lower proportions of vegetables andfruits, and have more irregular meal patterns and consumesnacks more often than those sleeping more.

Sleep has an influence on meal patterns, but even thetiming of meals may influence sleep. It is well documentedthat individual eating episodes are highly interrelated; thus,the timing of the previous meal and the resulting satietylargely determine the time and size of the followingmeal [14].The incidence and prevalence of skipping breakfast aretypically higher in persons with low sleep duration than inthosewith normal sleep duration [15,16]. Low sleep duration isespecially typical in subjects with nocturnal lifestyles whoreplace meals with snacks and who consume most of theirfood in the later evening and at night. Thus, they are nothungry in the morning and replace breakfast with an earlymorning snack. As a matter of fact, a regular habit of snackingis associated with shorter sleep duration [16]. Interestingly,very long sleep duration is also associated with an unconven-tional eating rhythm [16]. Because snacking is generally foundto indicate a nutritionally poor and energy-rich diet [17], theobserved association betweenmeal patterns and sleepmay, atleast partially, be due to the quality of diet, that is, an absenceof nutrients or excessive amounts of energy-rich foods.

Despite methodological differences, almost all of thepreviously mentioned studies indicate that an unhealthydiet is associated with shorter sleep duration and irregularsleeping patterns. These studies, however, do not revealwhether compliance with a recommended diet results inbetter sleep or vice versa—whether sleep-deprived people eatmore unhealthy foods just because they are too tired tofollow recommendations.

Both epidemiologic and methodological studies indicate arelationship between sleep and health [18,19]. However, littleis known about the impact of diet and nutrients on sleep—that is, whether what we eat and what kind of nutrients weobtain from the food we consume before bed are of anyconsequence. Because there are no recent overviews on theeffects of diet on sleep [20–24] and there are interesting newpublications on the topic, this narrative review aims toprovide an overview of clinical studies, mostly on healthyhumans, to clarify whether the duration or quality of sleep isassociated with the quality of diet or the intake of energy,carbohydrates, proteins, fats, or other nutrients. However, wewill mostly concentrate on the impact of diet on sleepduration, which is fairly simple to measure reliably, and theresults are more comparable as compared with measure-ments of sleep quality, which is an even more complexphenomenon. Lastly, we will discuss the need and directionsof future research in this area. Effects of drugs, drug-likeproducts such asmelatonin supplements, or other intoxicants

such as alcohol are excluded from this overview. We used theelectronic bibliographical database PubMed until March 2012(without any methodological restrictions) to identify studiesusing the following keywords: sleep, diet, nutrient, energy,carbohydrate, protein, tryptophan (TRP), fat, vitamin, andmineral. In addition, we reviewed the references of identifiedstudies and of selected narrative review articles.

2. Diet and chronotype

The term “chronotype,” also referred to as the circadian type, isused to characterize sleep patterns. There are 3 mainchronotypes: morning, evening, and midrange [24]. Theseindividual differences are, in part, heritable, but additionalfactors such as cultural and environmental influences mod-ulate chronotype.

As reviewed previously, nutrients such as glucose, aminoacids, sodium, ethanol, and caffeine, as well as the timing ofmeals, can reset the bodily rhythmsof rodents [25]. Evidence inclinical studies of humans is scarce. Kräuchi et al [26] showedthat a single carbohydrate-richmeal may have the capacity toentrain human circadian rhythms, especially through periph-eral oscillators,measuredas changes in core body temperatureand heart rate. Unfortunately, this interesting study presentsno data on sleep patterns. The intake of certain nutrients andfoodsdifferedsignificantly by chronotype,whichwasassessedby the midpoint of sleep in more than 3000 young Japanesewomen [27]. A late midpoint, that is, the evening type, wasassociated with energy intake from alcohol, fat, confections,andmeat. By contrast, themorning chronotypewasassociatedespecially with a greater intake of calcium and vitamin B6, aswell as eating more vegetables and pulses. Fleig and Randler[28], on the other hand, found no relationship betweenchronotype and the intake of sweets, vegetables, salad, ormeat but, instead, noticed that later bedtimes and rising timeswere associated with a tendency to drink caffeinated drinks,eat fast food, and consume fewer dairy products.

To conclude, even if clinical evidence of an associationbetween thehumanchronotypeanddiet is lacking, results fromcross-sectional studies and animalmodels at least suggest thatmorning-oriented people tend to have a healthier and moreregular lifestyle compared with evening-oriented ones.

3. Traditional sleep-promoting foods

All nations around the world have traditions regarding thespecific foods that are served to promote healthy sleep. Inmany Western countries, for example, cow's milk hastraditionally been considered a tranquilizing beverage withsleep-inducing capacity. Study conducted almost 80 years agoreported adults consuming a meal of corn flakes and milk toexhibit a stronger tendency toward uninterrupted sleep [29].Forty years later, in an open study using electrophysiologicrecordings in a sleep laboratory, other researchers foundimprovements in sleep in terms of duration and a reducednumber of awakenings in 18 older people who ingested milkfortified with Horlicks powder, a malted barley and wheat, atbedtime, and reported the action of the fortified milk to be

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more effective with serial administration [30]. A modest effectof milk and Horlicks powder, observed by camera recordings,was also noticed in 4 healthy male students with no sleepingproblems [31]. More recently in elderly subjects, a daily dose of100 g or a large dose of 500 g of normal commercial milk hadno effect on sleep or alertness the following morning [32,33].On the other hand, when commercial milk was replaced withmelatonin-rich nighttime milk in a double-blinded study,morning activity, reflecting better sleep and rest during theprevious night, was significantly increased in 80 elderlysubjects [32]. Melatonin is a natural compound in cow'smilk, but its concentration increases significantly if cows aremilked in darkness at nighttime. Similarly, when Lactobacillushelveticus–fermentedmilk was used in another double-blindedstudy, sleep efficacy was improved and the number ofepisodes of awakening was reduced, which were measuredby means of actigraphy and a sleep questionnaire (n = 29) [33].Supplemented probiotics, however, had no effect on sleep in75 healthy volunteers with symptoms of stress [34].

Other examples of sleep-promoting foods include herbalproducts and certain fruits. The use of herbal products such aschamomile tea to improve sleep is common [35], even if robustscientific evidence supporting this is, in many cases, nonex-istent, as reviewed recently [36,37]. In addition, there arerecent reports indicating that certain fruits such as tartcherries or kiwifruits promote sleep. A double-blinded pilotstudy showed that fresh tart cherry juice, consumed twicedaily, produced reductions in insomnia in 15 elderly subjects,and the time required to fall asleepwas reduced by 17minutes[38]. The researchers found, however, no influence on anyother sleep parameters during the 2-week clinical trialcompared with a placebo beverage. The influence of cherrieswas also noticed in another study of 6 middle-aged and 6elderly Spanish volunteers [39]. Daily doses of different cherrycultivars increased sleep time significantly and reduced thenumber of awakenings measured by actigraphy comparedwith baseline measurements. Another recent study demon-strated that consuming 2 kiwi fruits an hour before bedtimeimproves sleep, both the total sleep time as well as sleepefficiency during a 4-week open clinical trial with 24 healthysubjects wearing an actigraphy watch [40].

Clinical evidence for the sleep-promoting effects of thepreviously mentioned products is mostly based on individualstudies and is, unfortunately, mainly done with small studypopulations. These observations remain to be confirmed, andthe mechanisms remain to be clarified.

4. Energy and macronutrients

The number of clinical trials to explain how the nutrientcontent of a single evening meal or the diet of the precedingday affects the parameters of sleep of the following night islow. Postprandial clinical trials have mainly focused onsleepiness or daytime naps shortly after breakfast or lunch.The effects of lunch and no-lunch conditions on postprandialafternoon nappingmeasured by polysomnography recordingswere compared in 2 clinical trials in young men with normalsleeping habits [41,42]. Lunchtime food (n = 12) or an alteredenergy content of a midday meal (n = 21) did not promote

the initiation of sleep, but eating ameal increased the durationof sleep episodes more than 3-fold if an afternoon nap wastaken. Furthermore, themacronutrient content of the daytimemeal does not seem to have a notable influence on postpran-dial sleepiness recorded by polysomnography in 10 to 16subjects [43,44]. Instead, only a trend toward sleepiness after ahigh-fat, low-carbohydrate morning meal compared with alow-fat, high-carbohydrate meal was noticed in 18 healthyvolunteers [45]. A low-protein, high-carbohydrate breakfastinduced more drowsiness according to sleep diaries in 21young men, which gave the researchers reason to speculatethat a high concentration of proteins may increase postpran-dial alertness [46].

In addition to the aforementioned influence of daytimeeating and drowsiness, the influence of food is amore relevantquestion for nighttime sleep because night is the principaltime of rest for most people. However, the number of studiesfocusing on this is evenmore limited. Higher-energy intake atthe evening meal extended the sleep duration by 1.4 s/kJ inhealthy toddlers (n = 594) [47]. Nevertheless, no significantdifferences in any of the subjective or objective sleepparameters recorded in sleep laboratory by polysomnographybetween a fast (no meal), a high-energy meal (11.9 MJ) and anormal, control meal (5.7 MJ) 2 hours before going to bed wereobserved in 7 adults [48].

In a cross-sectional design, teenage girls who slept less than5 hours per night were observed to get about 420 kJ more energyfrom carbohydrates than thosewho sleptmore (n = 126) [10], butin other studies, adolescents of roughly the same age (n = 240)and adults (n = 2828) sleeping more than 9 hours per nightconsumedmore energy from carbohydrates than those sleepingless [8,13]. In toddlers, the intake of carbohydrates wasaccompaniedby longer sleepduration (0.8min/g) [47].No clinicaltrials seeking tomeasure the impact on sleepduration causedbythe carbohydrate content of an evening meal were found.

However, all other sleep parameters except duration maybe influenced by the total amount of carbohydrates. In8 healthy young males, a high-carbohydrate, low-fat mealreduced deep slow-wave sleep (non–rapid eye movement[non-REM] sleep) and increased the proportion of REM sleepcompared with normal-balanced or low-carbohydrate, high-fat diets [49], which was confirmed later with 6 subjects [50],both studies using polysomnographic recordings. Also, a dietvery low in carbohydrates and rich in fat reduced the shareof REM sleep recorded by polysomnography, but alsoincreased the percentage of deep slow-wave sleep comparedwith a control diet high in carbohydrates and low in fat [51].In this study protocol with 14 subjects, however, it was notpossible to conclude whether the improvement of the qualityof sleep was due to a reduced percentage of carbohydrates(<1% vs 72% of the total energy intake [E%]) or an increasedpercentage of fat (12.5 E% vs 61 E%) or proteins (15.5 E% vs38 E%). Either way, the researchers speculated the differenceto be linked to the metabolism of dietary fat and after therelease of cholecystokinin (CCK) corresponding to previousobservation by Wells et al [45].

Dietary carbohydrates contain a large variety of sugarchains with different metabolisms. Thus, it is not surprisingthat the amount of any individual carbohydrate has noconsistent influence on sleep parameters. As shown in the

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aforementioned cross-sectional study of toddlers, the con-sumption of foodswithhighGlycemic Indexwas accompaniedby longer sleep time (1.3min/g) [47]. However, in a clinical trialof 12 healthy youngmen consuming carbohydrate meals withhigh or low glycemic loads, profiling the type of carbohydrateingested, did not affect sleep duration or any other sleepindexes according to polysomnographic recordings, except forthe onset of sleep [52]. The study noticed shortened sleep-onset latency by approximately 10 minutes after a carbohy-drate-rich eveningmeal with a high Glycemic Index comparedwith a low-index meal, suggesting a difference between thecarbohydrates. The carbohydrate content of these rice-basedmeals was more than 90% of the total energy content, and themeals were ingested 4 hours before bedtime.

Clinical trials assessing the impact of other macronutri-ents, that is, proteins and fats, on sleep duration are scarce.Clinical trials show some support that protein fragments oramino acids, when administered in pharmacologic doses,may have sleep-promoting influence. Supplemented TRP isbeing used as a sleep aid, even if the clinical evidence ischallenged, as reviewed previously [53,54]. Tryptophan is aprecursor to the neurotransmitter serotonin and the neuro-secretory hormone melatonin, both of which are linked tosleep and alertness [1,2]. In a study using polysomnographicequipment on 17 healthy volunteers, TRP depletion pro-duced by a 48-hour low-protein diet increased REM sleeplatency by 21 minutes, but no effect on sleep duration ornon-REM sleep was noticed during the following nights'sleep [55]. Regardless of the above finding, as little as 250 mgof pure pharmaceutical-grade TRP has improved sleep inpeople with sleeping problems [53,54].

As part of the diet, the metabolism of TRP is morecomplicated. Protein-sourced TRP (de-oiled butternut squashseeds) was compared with pharmaceutical-grade TRP in ahealth bar containing carbohydrates and vitamins [56]. Atrend toward an increase in the total sleep time of about 19minutes (5.5% increase)was observedwith protein-sourced TRPin a placebo-controlled study of 49 subjectsmeeting the criteriafor insomnia. α-Lactalbumin, one of the primary milk proteins,is a good source of TRP. An α-lactalbumin–rich evening meal,however, did not induce feelings of sleepiness measured byelectroencephalographic recordings in a sleep laboratory studyof 14 healthy subjects with mild sleep complaints, although allsubjects felt more alert the next morning compared with whenthey were administered the placebo meal [57].

According to cross-sectional studies, the influence ofdietary fat on sleep duration is conflicting. In small children(n = 594), teenage girls (n = 126), and in a small study of 30Greek women, a trend was observed toward longer sleepduration, with subjects consuming more energy from fat,whereas in other large studies with adolescents (n = 240) andadults (n = 459 and n = 2828), short sleep duration wascorrelated with increased fat intake [8,10–13,47,58]. Studies ofhigh-fat, low-carbohydrate diets have not observed markeddifferences but only a remote trend on sleep duration, but alsosome influence on the relation of non-REM and REM sleep asdescribed above [45,49,51]. Very long-chain fatty acids play animportant role in the pineal gland and the production ofmelatonin [59]. Despite this clear biological connection tosleep, no improvement either in subjective or objective

parameters of sleep or secretion of melatonin was noticed inmore than 100 adults with chronic insomnia after supple-mentation with polyunsaturated fatty acid capsules [60].

To conclude, regarding the influence of energy andmacronutrients on sleep, clinical interventions confirm thecross-sectional observations that there is a connectionbetween the intake of macronutrients and sleep. Althoughthe number of studies is small and definite differences indesigns and methods exist, the macronutrient content of adiet or evening meal seems to modify sleep duration at mostonly 10 minutes in healthy subjects with no sleep problems.Carbohydrates and fats, at least in large quantities, maymodulate sleep quality by influencing the ratio of REM andnon-REM sleep. Of proteins, amino acid TRP is the mostpromising candidate as a sleep-promoting nutrient at leastwith pharmacological doses.

5. B vitamins and magnesium

Deficiencies of group B vitamins and minerals may disruptsleep. Their effect seems to be based on their influence on thesecretion of melatonin. Melatonin is a hormone secretednaturally by the pineal gland, especially at night. In severalstudies, pharmacological doses of melatonin have been foundhelpful in inducing and maintaining sleep both in childrenand in adults with normal sleep patterns and those havinginsomnia [61,62]. However, the effect of melatonin is mostapparent only if a person's melatonin level is low.

The secretion of melatonin is influenced by some externalfactors such as artificial light. Vitamin B12 contributes tomelatonin secretion [63]. Treatment with varying doses ofvitamin B12 has a potentially beneficial effect on the sleep-wake rhythm and in delayed sleep-phase syndrome inhealthy subjects measured by actigraphy equipment (n = 20)[64] and sleep diary (n = 102) [65] and in patients withAlzheimer dementia using actigraphy recordings (n = 28)[66], although conflicting results exist [67]. No clear benefit,however, has been reported in sleep duration.

Some clinical evidence substantiates the influence of othergroup B vitamins on sleep. Administration of nicotinamide(niacin) to 6 people with normal sleep pattern increased REMsleep, and when given to subjects with moderate to severeinsomnia, the sleep efficacy, recorded in a sleep laboratoryusing electroencephalogram, was improved [68]. Niacin isbiosynthesized from dietary TRP via the so-called kynureninepathway. The researchers speculate that administration ofniacin results in the buildup of nicotinamide adenine dinucle-otide, which may reduce the amount of TRP converted toniacin, thus leaving TRP available to the synthesis of serotoninand melatonin.

Vitamin B6, pyridoxine, is needed in the synthesis ofserotonin from TRP. 5-Hydroxytryptophan (5-HTP), which isan intermediate in this process, is converted to serotonin byan enzyme called aromatic L-amino acid decarboxylase (AADC)[69]. Aromatic L-amino acid decarboxylase is a pyridoxal 5′-phosphate–dependent enzyme, and pyridoxine is a precursorfor pyridoxal 5′-phosphate. Despite the clear physiologicalconnection between dietary pyridoxine and melatonin secre-tion, no effect on sleep using polysomnographic recordings

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was observed after evening treatment with oral pyridoxineeither on melatonin secretion or on sleep duration in 12healthy men compared with the placebo capsule [70]. In apreliminary placebo-controlled double-blind study, however,pyridoxine was found to increase cortical arousal during REMsleep and to increase the vividness of the dreams of 12 collegestudents [71], thus demonstrating some influence on sleep.

A relationship between the concentration ofmagnesium inthe blood and sleep has been suggested [72–74]. Thisdocumentation is based mostly on experimental modelswith rodents, and clinical evidence is scarce. Nonetheless,oral magnesium supplementation has improved sleep qualityand total sleep time recorded by polysomnography in 2separate studies with about 10 subjects with low magnesiumstatus [75,76]. Rondanelli et al [77] found a preparationcontaining melatonin, magnesium, and zinc taken daily for8 weeks 1 hour before bedtime to improve sleep quality andtotal sleep time recorded bywearable armband-shaped sensorin 43 elderly subjects with primary insomnia compared with aplacebo capsule. This is believed to be based on magnesiumenhancing the secretion of melatonin from the pineal glandby stimulating serotonin N-acetyltransferase activity, thekey enzyme in melatonin synthesis [36], and it being aγ-aminobutyric acid (GABA) agonist [74,75]. γ-Aminobutyricacid is the main inhibitory neurotransmitter of the centralnervous system, and it is well established that activation ofGABA(A) receptors favors sleep. To be precise, many hypnoticdrugs and anesthetics enhance GABA-mediated neurotrans-mission. Magnesium sulfate has shown a GABA-agonisticeffect on sleep in 10 healthy men, even if no effect onmelatonin release was observed [78,79].

To conclude, nutritional deficiencies such as that ofmagnesium or group B vitamins may impair sleep. There is

Fig. 1 – Dietary factors promote sleep via circulating intestinal homelatonin, acting on GABAergic or serotonergic neurons or via o

evidence of a modest influence of group B vitamin andmagnesium supplementation on sleep and, more clearly, onsleep quality and the regulation of sleep-wake rhythm than onsleep duration. Physiologically, this is based on the mediationof neurotransmission by interacting in the synthesis ofserotonin and melatonin.

6. Possible mechanism for the relationshipbetween diet and sleep: sleep-promoting andwake-promoting substances

Sleep is an active process that requires the participation of avariety of brain regions. The daily cycle of sleep andwakefulness is regulated by various hormones produced bythe hypothalamus and external stimuli, with the amount oflight being the most obvious example [1,2]. Nerve-signalingchemicals or neurotransmitters control whetherwe are asleepor awake by acting on different groups of nerve cells in thebrain. Many sleep-promoting substances have been identified,and they can be divided into 2 basic groups: wake-promotingneurochemical factors including noradrenalin, serotonin,acetylcholine, histamine, and orexin and the sleep-promotingsystem including GABA, adenosine, and nitric oxide, asreviewed recently [1,2]. In general, sleep can be promotedeither by inhibiting wake-promoting mechanisms or byincreasing sleep-promoting factors either by dietary or byother means (Fig. 1).

6.1. The role of intestinal peptide hormones and sleep

Food intake induces the release of various gut hormonesaffecting local sites or circulating in the blood and signaling

rmones, by stimulating the synthesis of serotonin andther unidentified mechanisms.

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via vagal nerve afferents that communicate with the hypo-thalamus and the brain. Some reports have demonstratedvarious appetite-modulating substances such as CCK, ghrelin,and peptide tyrosine-tyrosine (PYY) to have a significant effecton sleep. In addition to these, there are other neuropeptidesacting both in the gut and in the brain, such as vasoactiveintestinal polypeptide, with known influence on intestinalphysiology and sleep regulation [80].

Dietary fats and proteins and, to a much smaller extent,carbohydrates stimulate the release of CCK from mucosacells in the duodenum and the jejunum. Cholecystoki-nin regulates gut motility and stimulates the delivery ofdigestive enzymes from the pancreas and the gallbladder.Cholecystokinin is also produced in the enteric nervoussystem and is abundantly distributed in the brain as well[81]. The postprandial release of CCK induced sleepinessin healthy adult volunteers 2 to 3 hours after a high-fat,low-carbohydrate meal [45]. The nutritional compositionof the served test meal was, however, far from a normalWestern diet containing 74 E% from fat and only 19 E%from carbohydrates.

Ghrelin is mostly known to stimulate appetite and plays arole in energy balance. In addition, during the last decade,various studies have been published, showing its effects onsleep-wake behavior, as reviewed recently by Steiger et al [80].It seems that ghrelin stimulates the activity of the somato-tropic and the hypothalamic-pituitary-adrenal axis affectingconcentrations of growth hormone and cortisol, which bothare involved in sleep regulation. The influence of ghrelin onsleep seems to be more obvious in men [82].

Peptide tyrosine-tyrosine is one of the major componentsof the gut-brain axis. It is released from the gastrointestinaltract postprandially in relation to the energy content of ameal. After its release, PYY can cross the blood-brain barrierand act on the central nervous system. In animal experiments,nocturnal intraperitoneal administration decreased wakeful-ness and enhanced non-REM sleep [83]. The precise mecha-nism is not clear, but the relationship between serotonin andPYY is believed to exist [84].

It is known that secretion of gastrointestinal regulatorypeptides is not affected by sleep [85], but it is not certainwhether naturally secreted gut peptides induce or modifysleep. Observations have been made mainly in rodents andby using intraperitoneal or intravenous administration ofgut peptides. Further studies are needed to verify whether thenatural release of peptide hormones by dietary modulationhas a role in sleep regulation.

6.2. Dietary TRP as a precursor for serotoninand melatonin

The commonly discussed mechanisms increasing sleepduration are the ways to promote the synthesis of serotonin.Serotonin is a neurotransmitter that relays information todifferent parts of the brain, regulating many of the vitalsystems in the body, as reviewed previously [86–88]. Inaddition, serotonin controls most brain functions such assleep cycles either indirectly or directly [1,2]. Generally,serotonin promotes consciousness and suppresses sleep, butthere are at least 15 different serotonin receptors with varied

effects after serotonin binding. Together, these serotonergicneurons innervate many brain regions that influence sleep-wake behavior. One of the most potent ways for serotonin toregulate sleep is through changes in melatonin concentrationbecause serotonin is an intermediary product in the produc-tion of melatonin, as shown in Fig. 2.

Some foods contain melatonin and serotonin as such.They have been detected in a considerable variety of plantspecies including roots, leaves, fruits, and seeds [89]. Thesefoods may also contain TRP. There is no clear evidence of theclinical importance of food-based melatonin on sleep, butsupplementedmelatonin is absorbed and can be released intocirculation, thus increasing the plasma concentrations ofmelatonin [90].

More evidence on the influence of nutrients on thesynthesis of serotonin is available (Fig. 2). Tryptophan is aprecursor of serotonin, and increased TRP levels in the braininduce the synthesis of serotonin. The traverse of dietary TRPthrough the blood-brain barrier is favored by a higher plasmaconcentration of TRP in comparison with the other competinglarge neutral amino acids (LNAAs). It is known that the plasmaTRP/LNAA ratio is affected by both dietary carbohydrates anddietary proteins [91]. Proteins rich in TRP, such as α-lactalbumin, increase the plasma TRP/LNAA ratio up to 130%and increase brain serotonin concentration [57]. However, ifthe diet contains plenty of other LNAAs, TRP transportthrough the blood-brain barrier is reduced. Thus, to increasethe availability of TRP in adequate amount, the addition ofdietary proteins containing TRP may not be the only or eventhe most effective way.

Insulin release from the pancreas is promoted, especiallyby the presence of carbohydrates in the gut lumen. Theeffect of insulin on drowsiness is not fully understood.Insulin has an influence on the transport of TRP after acarbohydrate-rich meal [56]. A high postprandial level ofinsulin after a carbohydrate load favors the transport ofTRP to the brain because being a powerful anabolic agent,insulin either inhibits peripheral amino acid release orpromotes the peripheral uptake of the other LNAAs.Thus, in response to an increasing plasma glucose concen-tration after a carbohydrate load, insulin mediates theuptake of LNAAs into muscle but not TRP, which is largelybound to plasma albumin. Consequently, the TRP/LNAAratio remains high, and the concentration of other compet-ing LNAAs is reduced [91,92]. A dose-response curve forglucose to increase the serum concentration of TRP in com-parison with other LNAAs has been discovered [93,94].Meals high in protein usually result in a less pronouncedpostprandial insulin increase compared with high-carbohy-drate meals [91].

Some vitamins may promote the availability of TRP forserotonin synthesis. Vitamin B3, or niacin, suppresses theactivity of tryptophan 2,3-dioxygenase (TDO), known also asTRP pyrrolase, which is one of the key enzymes in theconversion of TRP to niacin (nicotinic acid). If TRP is convertedto niacin, it will not be available as a precursor to serotonin inthe brain, and thus, supplementation with vitamin B3 canreduce the “loss” of TRP to nicotinic acid. Vitamin B6,pyridoxine, is needed by AADC, which, in turn, is required toconvert 5-HTP to serotonin, as described previously.

Fig. 2 – Possible mechanisms of the influence of dietary components on the synthesis of serotonin and melatonin. A, Diet as asource of TRP: TRP ismetabolized in the brain along different pathways to serotonin,melatonin, and niacin and partly used as asource of protein synthesis. B, Dietary influence on TRP transport to the brain: other dietary components such as carbohydratesand other LNAAs affect the intensity of TRP in crossing the blood-brain barrier. C, Stimulating the synthesis of serotonin andmelatonin: 5-HTP is converted to serotonin by an enzyme, AADC, which needs pyridoxine (vitamin B6), and enzymearylalkylamine-N-acetyltransferase (NAT) which needs n-3 fatty acids. D, Availability of TRP to the synthesis of serotonin andmelatonin: TDO is an enzyme that catalyzes the chemical reaction of TRP to formylkynurenine, which is rapidly converted tokynurenine and, finally, to niacin. Niacin (vitamin B3) suppresses the activity of TDO, thus leaving more TRP to be used in thesynthesis of serotonin.

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6.3. Other possible mechanisms related to dietary proteinsand nucleotides

Proteins exert a wide range of nutritional, functional, andbiological activities. Some of them have sequences posses-sing specific biological properties that make these fragmentspotential ingredients of health-promoting foods, as reviewedby Kekkonen and Peuhkuri [95]. Bioactive peptides may bereleased after enzymatic digestion either in the gastrointes-tinal tract or during industrial processes. Bioactive pep-tides may enter peripheral blood and exert systemic effects,or exert local effects in the gastrointestinal tract. In adults,intestinal mucosa acts as an efficient barrier betweenluminal contents and the systemic circulation. However,bioactive peptides have been found in the blood of adulthumans after ingestion [96]. Thus, it is possible thatrelatively large bioactive peptides can cross the adultdigestive endothelium in significant amounts.

Increasing attention is focused on milk-based bioactivepeptides including peptides with opioid and opioid antagonistactivities that may have a functional role by interacting withthe endogenous opioid system [97]. Some of them have beenassociated with a slight impact on sleep. α-s1-Casein hydro-lysate, for example, exhibits a benzodiazepine-like activity onthe GABA(A) receptor [98]. Other bioactive peptides may also

be related to GABAergic or serotonergic neurons and, thus,regulate sleep, but this remains to be studied.

The nonprotein nitrogen fraction of diet includes food-based DNA and RNA as well as nucleotides and theirfragments. Nucleotides are building blocks of nucleic acidsresponsible for storing and transmitting genetic information.It is estimated that depending on diet, the daily amount ofDNA-originated fragments may be 1 to 2 g [99]. The moreprocessed food humans consume, the fewer untouched cellscontaining nucleotides exist in the diet.

Adenosine 5′monophosphate is considered as an endoge-nous sleep factor [100] partly because of the well-knownmechanism of caffeine as an adenosine receptor antagonist.Another nucleotide, guanosine 5′monophosphate, stimulatesthe secretionof the sleep-hormonemelatoninvia thesecondarymessenger cyclic guanosine monophosphate-including nucle-otideparts.Nucleotides arenaturallypresent inbreastmilk, andimproved sleep (after orally dosednucleotides)hasbeenstudiedmainly in infants [101–103]. However, the relevance of dietarynucleotides in promoting sleep in adults can be questionedbecause the endogenous liberation of nucleotides exceedsthe amount of absorbed dietary nucleotides [99].

To conclude, there are several possible mechanisms thatmediate the influence of nutrients on sleep. The principalroute seems to be via the production of serotonin and

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melatonin. In addition, ingested food induces local secretionof many intestinal peptides such as CCK, some of which areknown to slightly mediate sleep as well. Bioactive peptides orthe nonprotein nitrogen fraction of diet may promote sleepeven if the clinical relevance of these findings requiresfurther investigation.

7. Future challenges in diet and sleep research

The amount and quality of sleep have an enormous impacton daily life. Disordered sleep affects work, concentration,and ability to interact with others. Because the need for sleepvaries individually and longer sleep duration does notnecessarily lead to alertness in the morning, sleep durationis a robust way to describe sleep, especially if it isdetermined only with subjective questionnaires and sleepdiaries. More objective and sophisticated methods to esti-mate sleep are definitely needed to demonstrate slightnutritional nuances both in sleep duration and its qualityin healthy subjects.

There are still large uncertainties regarding the associ-ation between diet, the intake of nutrients, and sleep bothin duration and in quality. The evidence presented ismostly based on small individual studies, which remainto be confirmed with large populations and subgroups suchas subjects with sleep problems. Furthermore, there is aclear need for clinical trials with objective methods tomeasure sleep, confirming the cross-sectional and epide-miologic observations.

8. Conclusions

In this review, we discussed studies to illustrate the complexinteraction between diet and sleep. Although concrete clinicalrelevance has yet to be established, emerging evidencesuggests a link between nutrients and sleep. Studies toprove the effects of both macronutrients and micronutrientson sleep parameters, however, are limited by small numbersof participants and varied designs and methods.

Whether ingested food directly affects sleep is difficult toaddress because the extent to which diet and nutrients canboost sleep remains unclear. Eating the right combination offoods before going to sleep and what foods to avoid in theevening may be beneficial in enhancing sleep. Althoughtraditional sleep-promoting foods are backed by only limitedclinical evidence, they may be useful in some cases. One suchexample is milk, which contains several nutrients withpotential sleep-promoting properties. Tryptophan is a com-pulsory ingredient for the body to produce serotonin, theneurotransmitter best known for inducing feelings of calm-ness and drowsiness. Group B vitamins are also needed in thesynthesis of serotonin. Obtaining an optimal amount of TRPrequires a combination of foods containing TRP with amplecarbohydrates. According to the reviewed studies, a balancedand varied diet that is rich in fresh fruits, vegetables, wholegrains, and low-fat protein sources (all of which containplenty of TRP, as well as group B vitamins, minerals, andunrefined carbohydrates) can improve sleep. Until further

studies are conducted, this is the best means to address theissue for the time being.

Acknowledgment

The authors declare no conflict of interest regarding thisreview. They have not received any funding or benefitsfrom industry, but K.P. and N.S. received support from TheSalWe Research Program for Mind and Body (Tekes–TheFinnish Funding Agency for Technology and InnovationGrant 1104/10).

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