Dietary Protocols to Promote and Improve Restful Sleep: A Narrative Review

Abstract

Humans spend approximately one third of their life asleep but, as counterintuitive as it may sound, sleep is far from being a quiet state of inactivity. Sleep provides the opportunity to perform numerous biological and physiological functions that are essential to health and wellbeing, including memory consolidation, physical recovery, immunoregulation, and emotional processing. Yet, sleep deprivation, chronic sleep restriction, and various types of sleep disorders are all too common in modern society. Failure to meet the recommended 7-9 hours of restful sleep per night is known to increase the risk of several health conditions, reason why regular and adequate sleep should be seen as a priority instead of an unnecessary commodity easily traded as required by the commitments of our busy lives. While both the quantity and the quality of sleep can be largely improved with relatively straightforward practices dictated by good sleep hygiene, emerging research suggests that dietary and supplementation protocols focused on certain foods, nutrients, and biochemical compounds with sleep-promoting properties can act as subsidiary sleep aids in complementing these behavioral changes. The scope of this narrative review is to summarize the available evidence on the potential benefits of selected nutraceuticals in the context of circadian rhythm and sleep disturbances, namely melatonin, magnesium, omega-3 fatty acids, tart cherry juice, kiwifruit, apigenin, valerian root, L-theanine, glycine, ashwagandha, myoinositol, Rhodiola rosea, and phosphatidylserine. A comprehensive recapitulation of the relevant literature is provided, alongside corresponding evidence-based nutritional protocols to promote and improve restful sleep.

INTRODUCTION

Over the past few decades, there has been an increasing appreciation of the negative impact of sleep disturbances and circadian misalignments on all aspects of human health and performance, ranging from objective alertness, learning, memory, and cognition to emotional regulation, social wellbeing and, most remarkably, physical health. The prevalence of sleep behaviors falling below the recommended 7-9 hours of sleep per night is endemic in modern society,^1,2 and the current understanding of the physio-psychological consequences of this ubiquitous practice clearly points toward the progressive deterioration of our mental and physical health.^3,4

Sleep is a complex biological process whose evolutionary purpose has remained equivocal for quite some time.⁵ More recently, however, compelling evidence has emerged, leading to recognition of the numerous metabolic and physiological functions sleep contributes to and actively supports. Epidemiological studies have revealed that sleep deprivation is associated with an increased risk of all-cause mortality,^6,7 alongside numerous chronic conditions imposing a heavy burden on our healthcare and socioeconomic systems alike,^8–10 including cardiovascular disease, stroke, obesity, type 2 diabetes, and various types of cancer and neurological disorders.^11–16

Despite these pervasive, well-documented sequelae, adequate sleep rarely sits at the top of our priority list and, for most of us, sleep curtailment is often the first line of approach when trying to meet the stressful demands of our busy lives. This lack of urgency in the adoption of healthful sleep habits, particularly in young adulthood and throughout midlife, compromises our cognitive and physical health in older age,^17,18 at which point it might be too late for clinical diagnoses and targeted interventions to reverse or shift this downward trajectory.

Notably, sleep disturbances are commonly experienced in the presence of underlying health issues affecting the central nervous system (CNS), such as traumatic brain injury (TBI), dementia syndromes, and mental illnesses.^19–24 Structural and functional changes to brainstem regions and neural pathways that regulate sleep–wake cycles are thought to alter or deplete the neurochemical environment that is necessary to establish and maintain restful sleep.^25,26 In turn, poor or insufficient sleep disrupts the normal functioning of the CNS, thus exacerbating disease symptoms and creating a vicious cycle that becomes increasingly difficult to break.¹⁵

Notwithstanding, sleep is a modifiable risk factor and/or disease manifestation that can be effectively addressed through appropriate sleep hygiene education and behavioral changes, at least to some extent.²⁷ For example, low solar angle sunlight exposure both in the early morning and in the late afternoon, coupled with limited use of electronical devices prior to bedtime, has been shown to help synchronize our circadian clock by regulating the timely release of melatonin, the primary sleep-promoting hormone.^28–31 Simple thermostatic adjustments and cooling strategies to lower brain and body temperature by as little as 1° C (2°-3° F) help reduce sleep onset latency (ie, the time it takes to fall asleep), and sleep fragmentation throughout the night.^32–34 Finally, wind-down routines, including guided meditation, breathing exercises, or other relaxing activities such as reading, alleviate some of the stress accumulated during the day, thus preparing our minds and bodies to embrace a few hours of (hopefully) uninterrupted, restorative slumber.^35–37

In addition to these practical tools, and in situations where such tools might be difficult to implement (eg, due to shift work or jet lag) or insufficient/ineffective (eg, due to mild-to-moderate insomnia or other low-severity sleep-related conditions), certain dietary protocols may provide alternative or complementary solutions. Evidence suggests that the macro- and micronutrient composition of our diets is a significant determinant of the quantity, quality, and regularity of sleep.³⁸ Accordingly, the increasing popularity of dietary and supplemental approaches to improve measures of sleep has fueled formal inquiries into the design of specific, evidence-based nutritional interventions and a number of foods, nutrients, and over-the-counter nutraceuticals, which are defined as any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of diseases,³⁹ have emerged as safe and potentially effective sleeping aids.^40–42 These foods or biochemical compounds naturally found in certain plants or commercially available in supplemental form include melatonin, magnesium, omega-3 fatty acids, tart cherry juice, kiwifruit, apigenin, valerian root, L-theanine, glycine, ashwagandha, myoinositol, Rhodiola rosea, and phosphatidylserine.

The scope of this narrative review is to summarize the available evidence on the mechanisms of action and potential benefits of the above-listed nutrients in the context of acute or chronic sleep disturbances. In this critical analysis of the current literature, emphasis is largely placed on human research, with a particular focus on a number of vulnerable populations, such as older adults and patients affected by mental disorders (eg, anxiety and depression) or neurodegenerative diseases (eg, Alzheimer, Parkinson, and Huntington disease), where patterns of disordered sleep are thought to contribute to the development or exacerbation of these conditions. Relevant findings from this extensive body of research are discussed alongside frequent methodological limitations and knowledge gaps for future enquiries to address.

While severe sleep-related conditions undoubtedly require pharmacological treatment under the supervision of medical professionals, nutritional approaches to address dietary gaps or mitigate temporary disruptions to habitual sleep patterns have the potential to move the needle in a positive direction by providing a safe and straightforward solution to help reconcile healthy, restorative sleep in an otherwise chronically sleep-deprived world.

METHODS

The following sections present an overview of the foods, micronutrients, and biological compounds that have been suggested to improve quantitative and qualitative measures of sleep to a varying degree. A systematic search of relevant research studies was conducted using the MEDLINE (PubMed) and Cochrane online databases. Key search terms, including MeSH terms, were determined using the PICO method and included all foods and nutrients of interest (eg, “melatonin,” “magnesium,” “kiwifruit”) as well as “nutraceuticals,” “supplements,” “sleep,” “sleep quality,” “sleep disorder,” and “insomnia”. The asterisk symbol (*) was used to capture the derivatives of search terms. Studies considered eligible were systematic reviews and meta-analyses as well as clinical or observational studies published in peer-reviewed journals that investigated the effects of a dietary intervention on at least one measure of sleep, either in home settings or in the controlled environment of sleep research facilities. Methodologies commonly employed to assess sleep-related variables included self-reported measures such as questionnaires and sleep diaries, and/or objective measurements obtained via polysomnography (PSG), electroencephalography (EEG), or actigraphy recordings. Sleep quantity, quality, and efficiency, as well as sleep onset latency, waking time after sleep onset, and next-day daytime sleepiness were the primary outcomes of interest, along with specific blood biomarkers to trace the serum concentration of certain compounds following supplementation. Preliminary screening was completed by reviewing titles and abstracts to assess study eligibility. Full-text articles were then reviewed to determine inclusion.

The results from this extensive literature search are discussed below, in relation to the physiological mechanisms by which the foods and nutrients under investigations are thought to exert their sleep-promoting effects. Based on these clinical findings, a summary of dietary sources, recommended supplementation protocols, optimal timings, and preferred forms of consumption is provided (Table 1).

Table 1.

Recommended Intakes, Supplementation Strategy and Dietary Sources of Key Foods, Nutrients and Biological Compounds to Improve Measures of Sleep

Food/Nutrient/Biological compound	Recommended intake and supplementation strategy	Side effects	Best dietary sources
Melatonin	2-3 mg/d, 1-2 h prior to bedtime for 4-12 wk	None	Wheat (110-140 ng/g)a Kidney beans (529  ng/g) Mushrooms (1300-13500 ng/g) Roasted coffee beans (8000-10000  ng/g) Tart cherries (12.3-14.5 ng/g) Pistachios (233 ng/g)
Magnesium (any bioavailable form)	500 mg, 1 g/d, 1-2 h prior to bedtime	Minimal gastrointestinal symptoms at high doses	Pumpkin seeds (184 mg/100g)b Chia seeds (131 mg/100g) Almonds (94 mg/100g) Spinach (78 mg/100g)
Omega-3 fatty acids (DHA and EPA)	1-2 g/d of combined DHA and EPA (preferably in a 2:1 ratio)	None	Salmon (2.15 g/100 g)b,c Herring (2 g/100 g) Sardines (1.4/100 g) Mackerel (1.2/100 g) Trout (1 g/100 g)
Tart cherry juice	100 g fresh cherries or 30 mL of tart cherry juice concentrate twice a d	None	NA
Kiwifruit	2 medium-sized kiwifruit 1 h prior to bedtime	None	NA
Apigenin	400 mg chamomile extract twice a d	Mild headaches, drowsiness, digestive problemsd	Chamomile (5320 mg/100g)e Parsley (1350 mg/100g) Fenugreek seeds (731 mg/100g)
Valerian root	200 mg/d (containing 2% total valerenic acid), 1 h prior to bedtime	Mild headaches and drowsiness	NA
L-Theanine	200-400 mg/d for 4-8 wk	None	Green tea (6.56  mg/g)f White tea (6.26 mg/g) Black tea (5.13 mg/g)
Glycine	3 g/d, 1 h prior to bedtime on 4 consecutive nights	None	Gelatin powder (19 g/100g)b Sesame flour (3.4 g/100 g) Chicken skin (3.2 g/100 g) Egg whites (3 g/100 g dry) Beef (1.5 g/100 g)
Ashwagandha	600-700 mg/d for 4-8 wk	None	NA
Myoinositol	2000 mg, 1 h prior to bedtime	None	Cinnamon (1.21 mg/g)e Lettuce (1.07 mg/g) Blueberries (0.96 mg/g) Carrots (0.80 mg/g)
Rhodiola rosea	NAg	None	NA
Phosphatidylserine	NAg	None	Soybeans (1650 mg/100 g)h Mackerel (480 mg/100 g) Herring (360 mg/100 g) Chicken (134 mg/100 g) White beans (107 mg/100 g)

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; NA, not applicable.

^aMeng et al.⁶⁴

^bUnited States Department of Agriculture: Agricultural Research Service.²¹²

^cNutritional contents are expressed in g/100g of cooked sample.

^dMild side effects were reported in some of the studies employing apigenin-containing chamomile, although no statistically significant differences could be found between treatment and control groups.

^eNutritional contents are expressed in mg/g of dry weight of sample.^133,213

^fL-Theanine content of listed tea varieties is from Boros et al.²¹⁴

^gAvailable evidence is insufficient to determine optimal intakes and supplementation protocols.

^hPhosphatidylserine content of listed foods is from Souci et al.²¹⁵

POSITIVELY ASYMMETRIC NUTRIENTS AND COMPOUNDS

Melatonin

Melatonin, a hormone produced by the pineal gland and directly involved in the regulation of circadian rhythms and sleep–wake cycles, is arguably the most researched and commonly prescribed sleep-promoting agent. From a physiological standpoint, melatonin is synthesized from the essential amino acid tryptophan via the neurotransmitter serotonin, and the endogenous production of melatonin starts at 3-4 months of age and progressively increases throughout childhood. By contrast, during puberty and after the age of 45 years, melatonin synthesis sees a dramatic decrease, likely contributing to the changes in sleep–wake patterns often observed in both adolescents and elderly individuals.^43,44 Plasma melatonin concentrations are heavily influenced by daylight exposure and naturally increase in response to darkness, thereby signaling to the brain and body that the time for sleep is approaching.⁴⁵ These chronobiotic properties further extend to thermoregulatory processes whereby peak melatonin levels (100-200 pg/mL) at nighttime are achieved when the body temperature is lowest.⁴⁶

When exogenously supplied, melatonin presents a relatively linear pharmacokinetic profile, in that it can freely pass the blood–brain barrier⁴⁷ and is therefore rapidly absorbed and metabolized, reaching the maximum plasma concentration within 40 minutes of administration.⁴⁶ Based on the dose and the specific supplemental formulation consumed, ie, immediate vs prolonged release,⁴⁸ melatonin’s half-life ranges between 45 minutes and 8-10 hours. In light of these well-established pharmacodynamics, numerous formal enquiries have investigated the potential benefits of melatonin supplementation in the context of insomnia and other sleep disturbances, including circadian misalignment or dysregulation induced by socioenvironmental factors like shift work and jet lag.

For example, Fatemeh et al⁴⁹conducted a systematic review and meta-analysis of randomized controlled trials where subjective sleep quality was assessed via Pittsburgh Sleep Quality Index (PSQI) scores. This self-rated questionnaire evaluates 7 sleep components (sleep quality, latency, duration and efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction) on a scale from 0 to 3 to produce a global score ranging from 0 to 21. Higher PSQI values indicate poor sleep quality and scores greater than 5 suggest significant sleep difficulties. Results from this analysis revealed significant improvements following melatonin supplementation in adults affected by respiratory, metabolic, or primary sleep disorders,⁴⁹ as demonstrated by a decrease in PSQI scores. Similarly, in a separate systematic review and meta-analysis Salanitro et al.⁵⁰ found evidence that melatonin administration significantly improves sleep onset latency and total sleep time in children and adolescents presenting with intellectual disabilities or neurodevelopmental disorders, as well as subjectively reported sleep onset latency and polysomnography-derived total sleep time in adults with delayed sleep phase disorder.⁵⁰

The administration of melatonin in the treatment of comorbid insomnia has also been extensively explored, with clinical evidence pointing to beneficial effects on various sleep-related measures in patients with mood or bipolar disorders,^51,52 schizophrenia,⁵³ autistic spectrum disorder,^54,55 Alzheimer’s disease,⁵⁶ Parkinson’s disease,⁵⁷ and multiple sclerosis.⁵⁸

As far as circadian rhythm disruptions are concerned, a recent randomized crossover trial in 24 older adults (mean age: 64.2  ±  6.3 years) by Duffy et al.,⁵⁹ who compared the effects of high and low doses of exogenous melatonin (5 vs 0.3 mg) on total sleep time and sleep efficiency while participants were scheduled for 4 weeks of shortened sleep–wake cycles of 20 hours (ie, 6 hours and 40 minutes of sleep and 13 hours and 20 minutes of wakeful activity). Accordingly, each night bedtimes occurred 4 hours earlier than the previous night, meaning that this phase-shifting experimental protocol allowed examination of the potential benefits of melatonin supplementation on sleep both during periods when endogenous melatonin production was high (ie, when sleep was scheduled during the biological night) and when it was low (biological day). Importantly, participants did not leave the research facility for the entire duration of the trial, thus allowing for core body temperature and plasma melatonin concentrations to be continuously monitored throughout the study, and for EEG signals to be recorded during all sleep episodes. Results indicated that high, but not low, doses of supplemental melatonin significantly increased sleep efficiency during both biological day and night, mainly by increasing the duration of stage 2 sleep (also known as non–rapid eye movement [NREM] sleep) and by shortening the duration of awakening episodes.⁵⁹ Based on these findings, short periods of high melatonin administration may be an effective strategy to address temporary circadian rhythm dysregulations, such as those that occur during travel across multiple time zones or in the context of shift work.

Notably, the efficacy of exogenously supplied melatonin on sleep parameters, particularly sleep onset latency, seems to be influenced by the timing of administration. Such variability is thought to result from the potential overlap of the exogenous melatonin with the natural rise in endogenous melatonin production regulated by both daylight exposure and chronotype-dependent physiological dynamics.⁶⁰ Interindividual differences aside, converging evidence from studies in populations of older adults and individuals with insomnia suggests that melatonin administration prior to bedtime facilitates the transition to sleep and helps reduce waking time after sleep onset (WASO).^61,62,63

Finally, although several dietary sources of melatonin have been identified,⁶⁴ the suitability of these foods for provision of serotonin in the amounts required to enhance sleep quality is doubtful.⁶⁵ As such, supplementation protocols typically constitute the preferred line of approach. Short-term and/or acute interventions do not seem to cause any adverse effects, but whether prolonged used of exogenous melatonin is equally safe is unclear.⁶⁶ In this respect, it is worth keeping in mind that melatonin affects a wide range of physiological systems and has clinically important drug interactions.⁶⁷ In the presence of certain comorbidities in particular, like liver disease and labile hypertension, melatonin would be best considered and prescribed as a medication rather than a dietary supplement,⁶⁶ which is a reason why recommended doses of supplements rarely exceed 2-3 mg.

Magnesium

Magnesium is an essential micronutrient involved in more than 300 metabolic reactions taking place in the human body, including ATP production, DNA, RNA, and protein synthesis, and muscle contraction.⁶⁸ Magnesium is also known to exert neuroprotective effects by regulating glutamatergic neurotransmissions^69,70 and by reducing excitotoxicity and oxidative stress, particularly following traumatic brain injury.⁷¹

In recent years, the popularity of magnesium supplements as possible over-the-counter remedies for sleep disorders has steadily increased and so has the number of magnesium formulations commercially available in both pharmacies and convenience stores. Several population-based cross-sectional studies have reported significant associations between magnesium deficiency scores and sleep quality in adult cohorts,^72–74 yet clinical evidence favoring the use of magnesium for the treatment of sleep disturbances is mixed.⁷⁵

A recent systematic review and meta-analysis by Rawji et al.⁷⁶ revealed significant heterogeneity among available research trials in terms of study populations, dosages (ranging from 250 to 729 mg per day) and treatment periods (between 5 days and 10 weeks), along with the different forms of supplemental magnesium used in each intervention (oxide, chloride, citrate, and L-aspartate). From their critical evaluation, the authors concluded that the majority of the trials under examination demonstrated at least modest positive results following magnesium supplementation with regard to sleep quality, as evidenced by consistent declines in PSQI scores, especially at higher doses and in individuals with low magnesium status at baseline.⁷⁶

The above results have also been replicated in a randomized cross-over trial by Breus et al.,⁷⁷ in which 31 adult participants (aged 27-55 years) received 1 g of magnesium chloride or placebo (sucrose) to consume 120 minutes or less prior to bedtime every night for 2 weeks. Following a 1-week washout period, participants engaged in the alternative condition. Data regarding subjective sleep-related measures were obtained through sleep diaries, alongside a battery of validated questionnaires, namely the PSQI, Insomnia Severity Index (ISI), Restorative Sleep Questionnaire (RSQ), Profile of Mood States Questionnaire (POMS), Flinders Fatigue Scale (FFS), Perceived Stress Scale (PSS), Pain and Sleep Questionnaire (PSQ), and Trait Anxiety Inventory (TAI). Furthermore, participants were instructed to wear an Oura ring multisensory device for the assessment of nocturnal heart rate and movement, heart rate variability, and body temperature. This intervention resulted in significant improvements in PSQI, POMS, and Oura-derived Readiness scores, particularly sleep balance and heart rate variability, thus demonstrating more regular and restorative sleep patterns upon magnesium supplementation compared to placebo.⁷⁷

Finally, the combined effects of magnesium and melatonin on sleep-related measures were recently investigated in a randomized crossover trial by Carlos et al.⁷⁸ In this study, 32 adults (aged 35-55 years) received either 200 mg of magnesium citrate and 1.9 mg of melatonin or placebo to be consumed every night, 30 minutes prior to bedtime, for 4 weeks. After a 1-week washout period, participants engaged with the alternate condition for another 4 weeks. Throughout the study period, physical activity and sleep parameters were evaluated via continuous actigraphy monitoring. Results revealed a significant decrease in total sleep time following treatment compared to placebo, along with a significant increase in sleep efficiency, shorter sleep onset latency, and fewer awakening episodes.⁷⁸ Nonetheless, the final PSQI scores still indicated poor sleep quality on average, thus suggesting that appreciable improvements in overall sleep architecture were relatively modest. Notably, these promising findings resonated with prior research studies employing similar magnesium-plus-melatonin supplementation protocols, albeit at higher melatonin doses (ie, 5-6 mg),⁷⁹ and/or in combination with additional nutrients like zinc,⁸⁰ vitamin B6 and B12, and folate.⁸¹

As far as safety is concerned, converging evidence indicates that supplemental magnesium is well tolerated, with only minimal gastrointestinal symptoms, if any, being reported in a limited number of studies.⁷⁶ To keep away from potential side effects of exogenous supplementation altogether, adequate amounts of magnesium can be easily obtained through the consumption of a plant-forward diet including green leafy vegetables, beans, legumes, nuts, and seeds.

Undoubtedly, further randomized controlled trials with larger samples and longer durations focused on readily absorbed forms of magnesium (eg, magnesium bisglycinate, taurate, threonate, and malate)^82,83 are needed to clarify the relationship between dietary magnesium and healthy sleep behaviors. In the meantime, the clinical evidence summarized above suggests that chronic supplementation up to 1 g per day may be beneficial in individuals at risk of magnesium deficiency or experiencing sleep disturbances.

Omega-3 Fatty Acids

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly referred to as omega-3s, are long-chain polyunsaturated fatty acids typically found in seafood and marine algae. In addition to their many structural and metabolic functions, omega-3s are particularly well known for supporting and improving neurocognitive development and function across the lifespan^84–86 and research suggests that these beneficial effects may extend to sleep quality and health.^87,88

For example, in a recent systematic review and meta-analysis of randomized controlled trials and longitudinal studies, the authors Dai and Liu⁸⁹ concluded that omega-3 supplementation or exposure can reduce symptoms of sleep disturbances throughout childhood, especially in the presence of clinically-diagnosed sleep problems.^90,91 Interestingly, maternal omega-3 status or intake during pregnancy was found to affect neonatal sleep–wake patterns,^92–94 although the physiological mechanisms underpinning this relationship have not been fully elucidated.

By contrast, when it comes to adult and elderly cohorts, the available evidence from clinical and observational studies is mixed. A systematic review of randomized controlled trials in postmenopausal women did not find sufficient evidence to support the efficacy of omega 3 consumption in improving sleep quality. Importantly, in all of the studies included in this analysis the sample size was relatively large (ranging from 188 to 355 participants) and the study period relatively long (12 weeks), while supplemental protocols comprised a variety of low (615 mg/d) and high dosages (1.8 g/d) of combined EPA and DHA.^95–97 Taken together, these experimental studies effectively addressed some of the most common methodological limitations typically observed in nutrition research, thus providing clear and robust evidence for the above-mentioned lack of positive effects in the postmenopausal population.

On the other hand, a cross-sectional study in patients with obstructive sleep apnea (OSA) revealed that erythrocyte levels of docosahexaenoic acid (DHA) are negatively correlated with OSA severity,⁹⁸ thus suggesting that omega-3 supplementation may be worthy of consideration in individuals suffering from this condition.⁹⁹

With respect to normal sleep, a recent randomized controlled trial in 84 healthy adults (aged 25-49 years) investigated the differential effects of EPA and DHA supplementation on several subjective and objective sleep measures.¹⁰⁰ Subjects were required to consume either 900 mg of DHA and 270 mg of EPA (DHA group), 900 mg of EPA and 360 mg of DHA (EPA group), or placebo (ie, 1 capsule containing 1 g of refined olive oil) at their usual bedtime every night for 26 weeks. Sleep diaries and actigraphy data were collected in the 7 days prior to the beginning of the study and during the last week of the protocol. Results from this study pointed to improvements in actigraphy-measured sleep efficiency and sleep onset latency upon consumption of high doses of DHA compared to placebo. Interestingly, post intervention participants allocated to EPA reported feeling more rested (P = .017) compared to their DHA counterparts, although the average total sleep time was significantly higher in the DHA compared to the EPA group (7 hours and 35 minutes vs 7 hours and 7 minutes, P = .019). Based on these findings, the authors suggested that EPA and DHA may be involved in different sleep-related mechanisms. More precisely, higher levels of DHA might help modulate the transition between wakefulness and sleep by facilitating the enzymatic conversion of serotonin to melatonin.^100,101 On the other hand, by interfering with the formation of prostaglandins, which in turn inhibit the release of serotonin,¹⁰² higher levels of EPA might help regulate healthy sleep cycles, hereby protecting against too little as well as too much sleep, which have both been shown to be detrimental to overall health.^103,104

Last, Yokoi-Shimizu, et al¹⁰⁵ randomized 66 Japanese healthy adults (mean age: 58.2 ± 5.5 years) to receive either 6 480-mg capsules of DHA/EPA-containing refined fish oil (total DHA: 576 mg, total EPA: 284 mg) or placebo (ie, corn oil) every day for 12 weeks. Post intervention, participants’ sleep efficiency scores, measured on the Sleep State Test (using Tanita SL-511-WF2 sleep monitor mats) were significantly higher in the treatment compared to the control group (96.0 ± 2.6 vs 93.7 ± 9.4, P = .018), and no adverse effects were identified. As a result, these findings provide further evidence for the safety and efficacy of chronic omega-3 supplementation in the promotion of healthy sleep, even at relatively modest doses.

Tart Cherry Juice

Montmorency tart cherries (Prunus cerasus) contain a high concentration of melatonin and multiple anti-inflammatory and antioxidant phytonutrients, including polyphenols and flavonoids. As such, dietary interventions employing tart cherry juice have recently attracted interest within the scientific community. The capacity for tart cherry juice to reduce oxidative stress and regulate healthy sleep–wake patterns has mostly been investigated in athletic populations.¹⁰⁶ Converging evidence from these studies points to tart cherry juice supplementation as a potential strategy to improve recovery and exercise performance, by reducing delayed onset muscle soreness and exercise-induced inflammation on the one hand,^107–109 and improving subjective sleep quality on the other.¹¹⁰

As clinical evidence on these beneficial effects continued to emerge, formal enquiries focused on sleep management have attempted to characterize the mechanisms by which tart cherries may promote healthy sleep, particularly in individuals suffering from insomnia symptoms. Results from the 8 prospective cohort studies or randomized controlled trials conducted so far were summarized in a systematic review and meta-analysis by Stretton et al.¹¹¹ Notably, in the large majority of these studies the sample size was relatively small (8 to 30 subjects), and the study period was relatively short (3, 7, or 14 days), with the exception of 1 3-month trial in 50 healthy adults.¹¹² Additionally, dietary interventions included varying amounts of powdered freeze-dried cherries, fresh cherries, cherry juice concentrate, or a blend of cherry and apple juice, to be consumed either prior to bedtime or twice a day. Despite such methodological heterogeneity, the ample use of objective sleep measures in this body of work must be acknowledged. Interestingly, while statistically significant improvements in actigraphy- or polysomnography-derived total sleep time and sleep efficiency were observed in the cherry cohorts compared to placebo, meta-analyses revealed no differences between treatment and control groups in any subjective sleep variable investigated.¹¹¹

Most recently, Erfe et al¹¹³ examined the effects of a commercially available sleep aid product called Sip2Sleep^®, combining extracts from Montmorency tart cherries and Apocynum venetum (a Chinese medicinal herb known for its sedative properties), in a cohort of 43 adults with moderate to severe insomnia. In this 4-week open-label study, participants were required to consume the prescribed compound 30-60 minutes prior to bedtime for 7 nights on weeks 2 and 4 of the protocol. Throughout the study period, participants completed sleep diaries and questionnaires, while data on sleep time and sleep onset latency were collected from wearable devices such as Fitbits, Apple watches, Oura rings, and Whoop. Results showed increased subjective sleep quality and daytime alertness and reduced ISI scores following treatment.¹¹³ However, caution is warranted in the generalization of these findings, given that the intervention was undeniably short and did not include any placebo or control condition. Furthermore, despite remarkable technological advancements, the accuracy of sleep measurements obtained from wearable sleep trackers remains controversial¹¹⁴ and standardized assessment methods such as EEG or PSG are preferred.

An important consideration to keep in mind is that in all available clinical studies on tart cherry juice and sleep, the treatment dose administered to participants corresponded to 200-300 g of fresh cherries per day, whose melatonin and tryptophan content is estimated at 0.27-0.40 μg and 18-27μg, respectively.¹¹⁵ By contrast, for these sleep-promoting agents to positively affect sleep duration and quality, recommended intakes are typically in the order of 0.5-5 mg (melatonin) and 1.2-2.4g (tryptophan). As a result, it is unlikely that the observed benefits of tart cherry juice on various components of sleep health result directly and exclusively from the supply of these specific compounds.¹¹¹ Further investigations into possible alternative and/or complementary mechanisms are required. In the meantime, chronic supplementation with tart cherry juice appears to be a safe and potentially effective dietary strategy to support restorative sleep.

Kiwifruit

Kiwifruit (Actinidia deliciosa) is a fruiting vine native to Eastern Asia. The numerous pharmacological properties and health benefits of kiwifruit have long been recognized¹¹⁶ and its therapeutic use in traditional Chinese medicine can be traced back to as early as 700 BC.¹¹⁷

In the past few years, a number of clinical studies have examined the effects of kiwifruit consumption on the treatment of sleep disorders, and despite the limited use of objective methodological assessments, available results point in a positive direction. The first dietary intervention to test the efficacy of kiwifruit in improving measures of sleep was conducted by Lin et al¹¹⁸ and involved 24 adults (aged 20-55 years) with self-reported sleep disturbances. Participants were asked to consume 2 medium-sized kiwifruits 1 hour before bed every night for 4 weeks. Analyses of subjective sleep measures (ie, sleep diaries and the Chinese version of the Pittsburgh Sleep Quality Index [CPSQI]), coupled with actigraphy data, revealed significant increases in total sleep time (16.9%) and sleep efficiency (2.4%), as well as significant decreases in CPSQI scores (42.4%), sleep onset latency (28.9%), and WASO (35.4%, all P-values < .05).¹¹⁸ While providing preliminary evidence in favor of kiwifruit consumption, this pioneering study did not include any placebo or control condition. As a result, a subsequent study by Nødtvedt et al.¹¹⁹ attempted to replicate these findings by randomizing 67 university students with chronic insomnia symptoms to consume ∼130 g of either kiwifruit or pear 1 hour before bedtime for 4 weeks. Results from this study showed that subjective sleep quality (Cohen’s d = 0.68, P < .05) and daytime functioning (Cohen’s d = 0.51, P < .05) were improved in the kiwifruit compared to the pear group, although such differences were not reflected in objective sleep measures.

More recently, Doherty et al.¹²⁰ examined the potential impact of kiwifruit consumption on sleep and recovery in a small cohort of elite-level athletes (24 subjects, mean age 23.2 ± 3.9 years). Athletic populations are known to be especially prone to sleep inadequacies such as insufficient or fragmented sleep due to high training frequency, volume, intensity, and performance anxiety, which is why dietary and supplementation protocols to improve both the quantity and the quality of sleep are especially popular within sport circles. Once again, the study protocol prescribed 2 kiwifruits 1 hour before bedtime for 4 weeks. This intervention was found to improve recovery stress balance (assessed via the Recovery Stress Questionnaire for Athletes, RESTQ Sport) and subjective sleep quality (ie, PSQI scores), increase total sleep time and sleep efficiency, and reduce both the number of awakenings and WASO, as indicated by participants’ sleep diaries.¹²⁰ However, it must be acknowledged that the study was conducted in the midst of the COVID-19 pandemic, meaning that lockdown restrictions prevented the use of objective sleep measurements.

Last, a randomized cross-over trial by Kanon et al.¹²¹ investigated the acute effects of fresh vs dried kiwifruit, compared to a water control, on sleep quality, mood, and urinary concentration of serotonin and melatonin metabolites in 24 young men (mean age 29 ± 1 years) classified as “good” or “poor” sleepers based on PSQI scores. Participants were studied on 3 separate occasions and were required to consume the flesh of 2 green kiwifruits (∼200 g), 32 g of freeze-dried whole green kiwifruit with 200 mL of water, or 200 mL of water immediately after a standardized evening meal, 4 hours prior to bedtime. Regardless of the sleep quality group, compared to control, consumption of dried kiwifruit was found to improve morning sleepiness, alertness upon awakening and vigor. In poor sleepers, ease of awakening also improved by 24% after dried kiwifruit consumption, while in good sleepers ratings of getting to sleep increased by 9% with fresh kiwifruit.¹²¹ As the authors suggested, these results may be related to the high polyphenolic content of kiwifruit skin extracts, alongside changes in serotonin metabolism, given that both kiwifruit interventions increased urinary concentration of the serotonin metabolite 5-HIAA compared to control (fresh: +1.56 ± 0.4 ng/g, P = .001; dried: +1.30 ± 0.4 ng/g, P = .004).

From a nutritional standpoint, the results summarized above are not entirely unexpected since kiwifruits are exceptionally rich in vitamin C (92.7 mg/100g), vitamin E (1.46 mg/100g), folate (25 mg/100 g), dietary fiber 3 g/100 g,¹²² and serotonin (580 μg/100 g).¹²³ Based on this specific micronutrient profile, several candidate mechanisms have been identified to explicate the sleep-promoting effects observed upon kiwifruit consumption.

First, evidence suggests that following chronic sleep deprivation and in the presence of sleep disorders the concentration of reactive oxygen species (ROS) in the brain is significantly increased.^124,125 Commonly referred to as free radicals, these highly reactive chemicals drive the production of inflammatory cytokines and cause oxidative stress and molecular damage, thus interfering with the detoxification and repair processes naturally occurring during sleep.^126–128 According to this view, kiwifruit’s high antioxidant capacity may help scavenge circulating free radicals and thereby enhance the quality of sleep.¹²⁹ Similarly, kiwifruit’s relatively high folate content may help alleviate certain sleep disturbances related to folate deficiency,¹³⁰ particularly restless leg syndrome.¹³¹

Finally, emerging research on the gut microbiome indicates that dietary fiber supports healthy sleep via multiple pathways along the gut–brain axis, including immune, neural, and endocrine mechanisms. By increasing the microbial diversity of the gut flora, and especially bacterial strains known to produce short-chain fatty acids, dietary fiber is involved in the synthesis, secretion and expression of various neurotransmitters that regulate (or disrupt) circadian rhythms and sleep, such as serotonin and gamma-aminobutyric acid (GABA).¹³² While further inquiries are needed to elucidate the precise contributions of these different micronutrients in the promotion of healthy sleep, at present kiwifruit consumption prior to bedtime appears to be a safe and promising strategy to improve several measures of sleep.

Apigenin (Chamomile Extract)

Apigenin is a natural flavonoid commonly found in a variety of fruits, vegetables, herbs, and beverages, including celery, onions, oranges, parsley, basil, oregano, chamomile, and tea.¹³³ The antiviral, anti-inflammatory, and antimutagenic properties of apigenin are well documented^134–136 and its therapeutic potential has been investigated in several clinical trials (see¹³⁷ for a comprehensive review). The anxiolytic effects of apigenin are thought to derive from its propensity to bind to benzodiazepine receptors, hereby increasing GABAergic activity in the brain.¹³⁸ Studies involving apigenin-containing chamomile extract have showed that apigenin alleviates anxiety and depression symptoms, relieves pain, and improves mood scores.^139–141 The consistency of these results, despite significant methodological heterogeneity in terms of dosages (ranging from 220 to 1500 mg/d), and protocol length (4, 8, or 12 weeks), strongly demonstrates the efficacy of apigenin administration in ameliorating numerous health components in the context of mental disorders.

On the other hand, formal enquiries on apigenin use in populations presenting with sleep disturbances are scant. In a pilot randomized controlled trial by Zick et al.,¹⁴² 34 patients with primary insomnia (aged 18-65 years) received 270 mg of chamomile twice a day (in the form of 3 90-mg capsules of dry extract of chamomile flowering tops, each containing 3.9 mg of apigenin) or placebo for 4 weeks. Outcome measures related to sleep quantity and quality were obtained through the completion of sleep diaries for 7 consecutive days immediately prior to the intervention, and during the last week of the study. Interestingly, no significant differences could be found between groups in any of the sleep variables under examination. A positive trend in daytime functioning was observed upon chamomile consumption, though it did not reach statistical significance.¹⁴²

By contrast, 2 methodologically identical studies in 77 elderly hospitalized individuals with a mean age of 74.3 ± 10.6 years,¹⁴³ and 110 postmenopausal women aged 50-60 years,¹⁴⁴ found that 400 mg of chamomile extract twice a day for 4 weeks significantly improved PSQI sleep scores following treatment (from 8.8 ± 4.3 to 5.0 ± 3.7, P < .001, and from 13.68 ± 1.68 to 9.07 ± 1.53, P = .001, respectively) compared to placebo. These results were further replicated in another randomized controlled trial in 60 older adults (mean age: 70 ± 5.7 years) receiving either 200 mg of chamomile extract twice a day for 4 weeks or placebo.¹⁴⁵ Once again, PSQI scores showed a progressive and statistically significant decrease over the course of the study in the treatment group, but not in the control group.

Finally, in a study by Chang and Chen¹⁴⁶ 40 postpartum women (aged 24-43 years) were randomly allocated to 1 cup of chamomile tea per day (from 2 g of dried flowers infused in 300 mL of hot water) for 2 weeks. The control group, also comprising 40 postpartum women, did not receive any treatment, but all participants completed the Postpartum Sleep Quality Scale, the Edinburgh Postnatal Depression Scale, and the Postpartum Fatigue Scale questionnaires before the beginning of the trial, as well as 2 and 4 weeks postintervention. Between-group comparisons at 2 weeks posttest indicated that chamomile tea improved physical symptoms associated with sleep inefficiency along with symptoms of depression, although these beneficial effects appeared to be relatively short lived given that they had already dissipated at the 4 weeks’ mark. However, the study reported no adverse effects upon treatment and, given the relatively safe profile of chamomile tea,¹⁴⁷ future trials testing multiple daily consumptions or larger doses may be expected to produce longer-lasting effects.

To summarize, chronic supplementation protocols involving apigenin-containing chamomile extract appear to be safe and effective in ameliorating symptoms of sleep disturbances, at least in the short term. Nonetheless, given the difference in supplementation protocols between available trials, along with the lack of objective sleep measurements, further research employing polysomnography is required to elucidate the precise mechanisms by which apigenin may positively impact sleep quality and architecture.

Valerian Root

Valerian root (Valeriana officinalis) is a flowering plant native to Europe and Asia with a long history of therapeutic and medicinal use due to its well-documented sedative and anxiolytic properties.^148,149 In fact, extracts of valerian root are one of the most commonly consumed herbal supplements in the context of sleep disturbances, although empirical evidence to support their purported benefits in the treatment of insomnia is largely controversial.^150,151

As evidenced by a comprehensive umbrella review of systematic reviews and meta-analyses by Valente et al.,¹⁵² clinical studies exploring the relationship between valerian root and sleep are numerous, but the significant methodological variability within this ample body of literature, in terms of study populations, treatment doses, methods of preparation, and protocol lengths, further compounded by the limited use of objective sleep measurements, has disappointingly yielded conflicting or inconclusive results. Another potential explanation for these inconsistent outcomes is the relatively unstable nature of some of the active constituents found in valerian root.¹⁵³ Accordingly, standardized methodological procedures to validate and safeguard the quality of these herbal extracts are required.

Furthermore, the characteristic odor of valerian root may be difficult to replicate, and failure to adequately disguise the valerian treatment in placebo-controlled trials may introduce an expectation bias on the effectiveness of the intervention.¹⁵²

Despite these limitations, encouraging results to clear some of the confusion have emerged from a recent randomized controlled trial by Chandra Shekhar et al.¹⁵⁴ In this study, 72 participants received either 200 mg of valerian extract or placebo capsules to consume 1 hour prior to bedtime every night for 8 weeks. The study protocol included 3-day visits to the research facility at baseline (days −3 to −1) and on days 1-3, 12-14, 26-28, and 54-56. On these occasions, participants completed a series of questionnaires evaluating several sleep-related measures (PSQI, Beck Anxiety Inventory, Epworth Sleepiness Scale, and Visual Analogue Scale) and were required to wear a wrist actigraphy device for continuous monitoring. Additionally, polysomnography recordings were obtained from a subset of 40 subjects on day 1 and day 56 of the protocol. Results revealed significant, progressive improvements in PSQI total scores, actigraphy and PSG-derived sleep latency, total sleep time and sleep efficiency, anxiety, daytime drowsiness, and feelings of waking up refreshed over the course of the study period in the treatment compared to the control group.¹⁵⁴

In addition to the robust experimental design and methodology employed in this study, the authors point out the use of valerian extracts containing 2% total valerenic acid, compared to the 0.5%-0.8% typically seen in prior research. Valerenic acid is thought to be the active constituent responsible for the anxiolytic and sedative effects of valerian root by means of allosteric modulation of GABA-A receptors and enhanced benzodiazepine binding.^155,156 As such, it is possible that the positive effects observed by Chandra Shekhar, Joshua, and Thomas¹⁵⁴ resulted from the higher content of valerenic acid in the herbal treatment participants received.

Last but not least, consistent findings across the available literature indicate that valerian root is well tolerated and safe to consume, with only mild side effects such as drowsiness and headaches being reported at daily doses ranging from 200 mg to 3 g.¹⁵² Given such a high safety profile and based on the evidence presented above, regular consumption of valerian root as a complementary sleep aid may be considered in individuals suffering from sleep disturbances.

L-Theanine

L-theanine is a nonproteinogenic amino acid found in green tea and certain mushrooms (Xerocomus badius)¹⁵⁷ which has been shown to positively affect brain function by relieving stress-related symptoms and improving mood and cognitive performance.¹⁵⁸ Due to its anxiolytic properties, L-theanine has also been suggested to improve sleep quality.¹⁵⁹

A series of randomized crossover trials from a Japanese research group demonstrated that 200 mg of supplemental L-theanine 1 hour prior to bedtime for 6 consecutive nights improved sleep quality and sleep efficiency, while also reducing WASO and feelings of fatigue in healthy male subjects (22 participants, mean age: 27.5 ± 0.9 years).¹⁶⁰ The same experimental protocol on menopausal women (20 participants, mean age 57.3 ± 3.9 years) was found to improve sleep and dream quality, as well as recovery from exhaustion.¹⁶¹ Furthermore, the authors reported that participants’ pulse rates were lower in the first half of sleep following treatment compared to placebo, while parasympathetic nerve activity was significantly higher throughout the night. Finally, to validate the safety of this supplementation strategy, the authors conducted a third randomized crossover study incorporating psychomotor vigilance tests to measure daytime drowsiness 1 hour post L-theanine administration either in the morning (13 participants, mean age: 36.4 ± 4.5 years) or in the afternoon (14 participants, mean age: 30.8 ± 7.1 years). Results from this study confirmed that participants were at least equally alert following treatment with L-theanine and placebo.¹⁶² Given that L-theanine achieves its maximum uptake in the brain within 30-40 minutes,¹⁶³ these findings effectively ruled out the possibility of L-theanine–related daytime drowsiness often induced by conventional sleep medicines with anxiolytic properties.

Further evidence in favor of L-theanine use as a sleep-promoting aid comes from a randomized controlled trial by Lyon et al.¹⁶⁴ in which 93 young boys (mean age: 9.6 years) with attention deficit hyperactivity disorder (ADHD) were randomized to receive 4 chewable tablets of L-theanine (two 100-mg tablets in the morning and two in the late afternoon) or placebo every day for 6 weeks. Participants were required to wear an actigraph watch on their nondominant wrist for 5 consecutive nights in the pretreatment period and at the end of the experimental protocol, while parents completed a validated pediatric sleep questionnaire to evaluate their child’s sleep problems at the beginning of theanine or placebo administration, at the halfway point, and immediately posttreatment. Results indicated that total sleep time and sleep efficiency were significantly higher in children consuming L-theanine compared to those receiving placebo, alongside a nonsignificant trend in WASO.

A separate study in 20 patients with major depressive disorders (mean age: 41.9 ± 13 years) showed a significant decrease in PSQI scores following 8 weeks of 250 mg/d of supplemental L-theanine.¹⁶⁵ Similar improvements in subjective sleep scores have been observed in a subsequent randomized crossover trial in 30 cognitively healthy adults (mean age: 48.3 ± 11.9 years) by Hidese et al.¹⁶⁶ Notably, the experimental protocol of this follow-up study included only 4 weeks of L-theanine administration and supplemental doses were also lower than those employed in prior work (ie, 200 mg/d).

The beneficial effects of L-theanine on sleep have also been investigated in combination with other nutrients or biochemical compounds. For example, a recent randomized controlled trial by Lim et al.¹⁶⁷ evaluated the impact on enhancing sleep quality of LTC-022, a commercially available dietary supplement containing Lactium (500-mg tablet, 60% Lactium) and L-theanine (700-mg tablet, 29.16% L-theanine). In this study, 40 participants experiencing sleep disturbances consumed either LTC-022 or placebo 1 hour prior to bedtime for 8 weeks. Sleep quality and insomnia symptoms were measured using PSQI and ISI questionnaires, along with sleep diaries. In the treatment group, total sleep time, sleep efficiency, and sleep onset latency were significantly improved postintervention, while WASO showed a significant decrease compared to placebo. As far as other potentially effective nutrient combinations are concerned, experimental models in rats have demonstrated that L-theanine, consumed together with either magnesium or GABA, has a positive effect on sleep quality and duration,^168,169 although no clinical studies that investigated this synergistic relationship in human cohorts are currently available.

To conclude, L-theanine seems to represent a safe and effective nutraceutical to improve measures of sleep, particularly in individuals suffering from mental health conditions.

Glycine

Glycine is a nonessential amino acid with antioxidant, anti-inflammatory, cryoprotective, and immunomodulatory properties that acts as an inhibitory neurotransmitter in peripheral and central nervous tissues and is the precursor of a variety of important metabolites, including glutathione, porphyrins, purines, heme, and creatine.¹⁷⁰

The effects of glycine supplementation on sleep quality have been examined in several clinical trials. The first study on this topic was a placebo-controlled crossover trial by Inagawa et al¹⁷¹ in which 15 women (aged 24-53 years) with sleep complaints received 3 g of glycine or a flavor-matched placebo solution 1 hour before bedtime on 4 consecutive nights. Results from this study revealed that glycine supplementation improves subjective feelings of fatigue, as measured by the Space-Aeromedicine fatigue checklist. In a follow-up study in 11 self-reported poor sleepers (aged 30-57 years) combining subjective sleep measures with PSG, 3 g of supplemental glycine was found to improve subjective sleep quality, sleep efficacy, and cognitive function, while also reducing daytime sleepiness and PSG-measured latency to both sleep onset and slow-wave sleep (ie, latency to the first appearance of stage 3). Importantly, a third study by the same research group in 12 adult individuals (aged 25-39 years) with no particular problems with their sleep reported no adverse effects with high doses of exogenous glycine up to 9 g/d.

The efficacy of glycine supplementation in improving sleep quality was also investigated in the context of acute sleep deprivation. In a small randomized cross-over trial by Bannai et al.,¹⁷² 7 healthy males (mean age: 40.6 years) were randomized to 3 g of glycine supplementation or placebo to be consumed 30 minutes before bedtime on 3 consecutive nights, while their habitual time in bed (7.3 hours on average) was restricted by 25%. On the first and last day of the experimental protocol, participants rated their feelings of fatigue and daytime sleepiness and undertook a battery of cognitive performance tasks to assess objective alertness, memory, and executive function. Results showed significant reductions in fatigue and a tendency toward reduced sleepiness, alongside significant improvements in psychomotor vigilance tests compared to placebo.¹⁷² The authors of this study suggested that improvements in sleep quality upon glycine supplementation may be induced by heat dissipation mechanisms,¹⁷³ given that experimental models in rats had previously demonstrated that exogenous glycine decreases core body temperature by increasing vasodilation.¹⁷⁴

ADDITIONAL NUTRIENTS AND COMPOUNDS WITH EMERGING CLINICAL EVIDENCE BUT REQUIRING FURTHER RESEARCH

Ashwagandha

Ashwagandha (Withania somnifera) is an evergreen branching shrub native to Western India that has been long and prominently featured in Ayurvedic medicine due to its anti-inflammatory, antioxidant, chemoprotective, immunomodulatory, and hemopoietic properties.^175,176 While the precise mechanisms underpinning ashwagandha’s extensive therapeutic potential are not fully understood, converging evidence suggests that supplementation with this adaptogenic herb helps mitigate stress and anxiety,^177–179 which, in turn, may have a positive impact on the quality of sleep.

A recent systematic review and meta-analysis of 5 randomized controlled trials by Cheah et al.¹⁸⁰ found that ashwagandha extract significantly improves subjective sleep quality, sleep onset latency, total sleep time, WASO, and sleep efficiency, particularly in adults diagnosed with insomnia, at treatment doses ≥600 mg/d, and following 8 or more weeks of chronic administration. Improvements in subjective sleep quality were also observed in a 30-day randomized controlled trial in 60 college students (mean age: 22.25 ± 4.5 years) receiving either 700 mg/d of ashwagandha root extract or placebo (ie, chlorophyll capsules), whereby restorative sleep scores were significantly higher in the treatment group.¹⁸¹ As far as safety is concerned, ashwagandha extract seems to be well tolerated, with minimal, if any, adverse effects being reported, even at very high doses of 6-10 g/day.¹⁸²

Despite the paucity of clinical evidence on the long-term efficacy of ashwagandha extract on key sleep parameters, alongside the requirement for standardized treatment formulations and dosages, preliminary results are encouraging. Further investigations in elderly individuals employing a combination of subjective and objective assessment methods are necessary to address the methodological limitations and knowledge gaps within the relevant scientific literature.

Myoinositol

Inositols are sugar-like cyclic alcohols that are naturally found in a variety of plant and animal foods and are involved in several metabolic pathways and biological processes, particularly insulin signaling mechanisms and antioxidant activities.^183,184

Within the inositol family, myoinositol is the most common stereoisomer and is thought to play a role in sleep regulation.¹⁸⁵ This purported relationship was formally investigated in a recent neuroimaging study employing proton magnetic resonance spectroscopy in adolescents suffering from depression and sleep disturbances (9 patients and 10 healthy controls, mean age: 16.0 ± 0.8 years).¹⁸⁶ Results from this study revealed that myoinositol concentrations in the dorsolateral prefrontal cortex were negatively correlated with depression severity (r = −0.561, P = .012), and positively correlated with total sleep time (r = 0.542, P = .025).¹⁸⁶ Importantly, these results emerged from objective evaluations of participants’ sleep, given that sleep duration and sleep efficiency were assessed via 2 consecutive nights of ambulatory PSG immediately prior to imaging testing.

The above-described associations suggest that myoinositol supplementation may exert sleep-promoting benefits in populations that are especially susceptible to sleep disturbances. Preliminary evidence in support of this hypothesis comes from a recent randomized controlled trial in 56 pregnant women with an average gestational age of 14 weeks (mean age: 28.6 ± 4.2 years). Participants in this study received either 2000 mg of myoinositol in powder form and 200 µg folic acid or placebo (ie, 2000 mg of white flour and 200 µg of folic acid). The solution was to be consumed every night, 1 hour prior to bedtime, for 10 weeks. Postintervention, subjective sleep quality, sleep duration, and sleep efficiency were significantly increased in the treatment compared to the control group, as indicated by improvements in PSQI scores (mean differences: −0.427, −0.670, and −0.561, respectively, all P-values ≤ .022), although no objective sleep assessment was conducted to corroborate these positive trends.

Accordingly, further inquiries employing a combination of subjective and objective assessments are required to ascertain the efficacy of myoinositol supplementation in improving measures of sleep, elucidate the potential physiological mechanisms responsible for these positive effects, and help develop evidence-based supplementation protocols.

Rhodiola Rosea

Rhodiola rosea is a flowering plant native to the wild Arctic regions of Europe, Asia, and North America. Existing records of the medicinal use of Rhodiola rosea in the treatment of anxiety, depression, and fatigue can be traced back to the ancient Tibetan pharmacopoeia, and the anti-inflammatory, antioxidant, immunoregulatory, and neuroprotective properties of Rhodiola rosea are extensively documented.¹⁸⁷

Recently, it has been suggested that such a multiplicity of beneficial effects may also extend to improvements in sleep quality, specifically in individuals presenting with insomnia symptoms. This intriguing hypothesis was put to the test in a small pilot study by Kim et al.¹⁸⁸ In this trial, 13 adults (mean age: 33.40 ± 14.27 years) with objective or subjective sleep problems were required to consume 750 mg/d of a mixture of Rhodiola rosea and Nelumbo nucifera (commonly known as sacred lotus, or simply lotus) in a 2:1 ratio every night for 2 weeks. Subjective sleep quality was assessed via PSQI and ISI scores at baseline, as well as 1 and 2 weeks thereafter, while WASO, total sleep time, and sleep efficiency were estimated based on records from sleep diaries. Results revealed a progressive decrease in PSQI and ISI scores (from an average of 10.62 down to 7.46 and from 12.69 down to 8.15, respectively), along with a significant 9-minute reduction in WASO, and concomitant increase in sleep efficiency (from 77.05% ± 16.34% to 82.6%5 ± 9.55%). Notably, the experimental protocol and the treatment formulation used in this study were informed by previous research in animal models whereby preclinical evidence suggests that Rhodiola rosea may exert its sleep-promoting effects by acting on serotonergic and GABAergic immune-related mechanisms.¹⁸⁹ Notwithstanding, to this day no other trial has investigated the potential benefits of Rhodiola rosea on sleep measures in human cohorts, meaning that targeted clinical interventions are required to corroborate these preliminary findings.

Phosphatidylserine

Phosphatidylserine is a membrane phospholipid accounting for approximately 13%-15% of the total phospholipid content in the human cerebral cortex.¹⁹⁰ Within the plasma membrane phospholipid bilayer, phosphatidylserine can be found exclusively in the cytoplasmic leaflet where it plays a major role in the regulation of several signaling pathways related to neuronal survival, neurite growth, and synaptogenesis.^191–193 Phosphatidylserine content in human gray matter is highly dependent on the concentration of DHA in the brain since DHA-containing phosphatidylcholine and phosphatidylethanolamine constitute the primary phospholipid substrates for phosphatidylserine biosynthesis.^194,195

Converging evidence from clinical studies demonstrates that supplemental doses of 200-600 mg/d of phosphatidylserine, administered over a period of 6 weeks to 6 months, significantly improve cognitive function and memory performance in elderly individuals.^196–201 Notwithstanding, given that phosphatidylserine metabolism requires partial or complete hydrolysis to facilitate absorption, it remains unclear whether these cognitive benefits are attributable to the exogenous supply of this nutraceutical per se as opposed to DHA released during digestion.²⁰²

Regardless, the synergistic effects of phosphatidylserine and DHA in preserving or increasing brain function are believed to improve overall sleep quality by regulating basal levels and circadian rhythms of salivary cortisol.^203–205 In fact, the cortisol-reducing properties of phosphatidylserine are well documented in chronically stressed populations²⁰⁶ and may be especially relevant to improve recovery and performance outcomes in athletic and military cohorts (see^207,208 for comprehensive reviews).

In conclusion, while dietary interventions to investigate the potential benefits of phosphatidylserine on sleep measures are currently not available, the findings presented above suggest that, by regulating cortisol levels in the brain and supporting cognitive function, exogenously supplied phosphatidylserine may help restore and maintain the neurochemical balance that is conducive to restful sleep.

DISCUSSION

Healthy sleep is arguably at the cornerstone of mental health, physical health, and performance. Yet, sleep deprivation and chronic sleep restrictions are commonly experienced in the general population due to a multiplicity of socio-ecological and environmental factors. Beside sleep hygiene education, evidence-based dietary and supplementation protocols involving over-the-counter sleep-promoting agents have the potential to alleviate some of the harmful consequences of sleep curtailment, while steering clear of the side effects and pharmacological dependence induced by prescription drugs. The scope of the present review was to summarize the available evidence on the benefits of selected foods, nutrients, and biochemical compounds on the quantity and quality of sleep, while also pointing out the underpinning physiological mechanisms by which they are believed to exert their positive effects.

In spite of a few conflicting or inconclusive findings, the current body of literature converges to suggest that melatonin, magnesium, omega-3 fatty acids, tart cherry juice, kiwifruit, and apigenin-containing chamomile subjectively and objectively improve several sleep-related parameters and outcomes in young, older, and clinical cohorts. By contrast, popular herbal remedies with a long-standing history of traditional medicinal use, namely valerian root extracts, lack adequate support to justify their use in individuals experiencing sleep disorders. Though less known or not as extensively investigated, L-theanine and glycine seem to present promising sleep-promoting properties, while ashwagandha, myoinositol, Rhodiola rosea, and phosphatidylserine may be considered as subsidiary sleep aids by working in synergy with other soporific nutrients or by addressing concomitant physiological mechanisms that may disrupt healthy sleep–wake patterns by indirect routes.

This critical review highlights the wealth of clinical research that has been conducted over the past couple of decades to disentangle the intricate relationship between nutrition and sleep. However, several methodological limitations compromising the accuracy and reliability of observed outcomes were identified. These shortcomings include small sample sizes, short intervention periods, significant heterogeneity in dosages, and modalities of treatment and administration, as well as great diversity of selected demographic groups. Coupled with the limited use of validated objective assessment methods, these methodological issues warrant caution when generalizing current findings to larger cohorts.

The ubiquity of self-reported sleep measurements clearly stems from the practical constraints of implementing long-term and well-controlled experimental protocols incorporating gold-standard methodologies like electroencephalography and polysomnography. As such, in randomized trials extending over a considerable period of time continuous sleep monitoring is not always possible and, in the attempt to evaluate targeted interventions in real-life settings, certain trade-offs between subjective and objective measurements may be inevitable.

Notwithstanding, when combined, these approaches provide valuable insight into sleep-related processes and allow minimization of imprecision in data collection due to deliberate omissions or recall bias while simultaneously taking into account participants’ expectations and physio-psychological reactions toward specific treatments.

The growing and widespread use of over-the-counter sleep aids raises concern about the reliability, adequacy, and purity of both herbal and synthetic formulations.²⁰⁹ Third-party testing to promote and safeguard the quality of available supplements should be strongly encouraged to avoid undesirable side effects due to the consumption of supraphysiological doses.²¹⁰ Avoidance of undesirable side effects is especially important in critical age groups, such as infants and children, and vulnerable populations presenting with severe comorbidities. Caution should be taken with exogenous melatonin in particular, given the numerous metabolic functions and multisystem mechanistic interactions involving this sleep-promoting hormone.⁶⁰ In recent years, the risk of toxicity due to extensive melatonin use in pediatric cohorts has steadily increased,²¹¹ strongly manifesting the need for health authorities to raise public awareness on the consequences of unregulated or excessive melatonin administration in developmental stages.

More generally, stricter regulations and procedural rigor should be enforced in the production, quality control, and distribution of sleep-promoting pharmacological agents, especially when access to these therapeutical formulations is not restricted by the requirement for medical prescriptions or professional supervision. Before turning to supplements, sleep-promoting dietary interventions involving minimally processed foods along with lifestyle changes focused on sleep hygiene should represent the first line of approach in the management of sleep disturbances and mild insomnia symptoms. Importantly, otherwise healthy individuals suffering from these conditions should trial and tailor the recommendations outlined in this review to determine the nutritional protocol that is best suited to their specific situation and needs. If unsuccessful, cognitive behavioral therapy should be the next logical step, while prescription medicines should be seen as the very last resort and cautiously taken for temporary relief under the expert guidance of qualified medical professionals.

CONCLUSION

In recent years, dietary and supplemental strategies to promote or reconcile healthy sleep have undeniably generated increasing interest within the general public, and practical applications of these behavioral approaches are extremely relevant in both clinical and professional settings. As compelling scientific evidence continues to emerge, concerted efforts in this rapidly evolving area of research will ultimately unravel the complex mechanisms of action by which selected nutrients and biochemical compounds can effectively address, or at least alleviate, commonly experienced sleep-related disturbances. Until then, the protocols summarized in this review will hopefully provide a safe and potentially effective tool to improve the quantity and quality of restful sleep.

Author Contributions

F.C.: Conceptualization, Methodology, Investigation, Formal analysis, and Writing.

Funding

This work received no external funding.

Conflicts of Interest

None declared.