Nutraceuticals for Improving Sleep Quality

Nutraceuticals for Improving Sleep Quality: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Nenad Naumovski.

Functional beverages can be a valuable component of the human diet with the ability to not only provide essential hydration but to deliver important bioactive compounds that can contribute to chronic disease treatment and prevention. One area of the functional beverage market that has seen an increase in demand in recent years are beverages that promote relaxation and sleep. Sleep is an essential biological process, with optimal sleep being defined as one of adequate duration, quality and timing. It is regulated by a number of neurotransmitters which are, in turn, regulated by dietary intake of essential bioactive compounds.

sleep
nutraceuticals
theanine
chamomile extract
tryptophan
cysteine
functional beverages

1. Introduction

Beverages play an important role in human health and nutrition, not only from the perspective of hydration, but also as mediators of social and cultural connectedness. They can also serve as a source of essential nutrients, particularly for people who may not consume a balanced diet ^[1]. Beverages are also becoming increasingly popular carriers for the development of functional food products. The last few decades have seen increasing awareness and emphasis on the importance of nutrition for overall health ^[2]. In addition, busy lifestyles, an aging population and rising healthcare costs in most developed countries have fueled demand for functional food products, particularly beverages [3,4]^[3][4]. These products may contain naturally derived bioactive compounds that can be used to potentially treat and prevent a range of chronic illnesses in addition to optimizing general health [4,5,6]^[4][5][6].

A substantial body of evidence exists on the health-protective benefits of specific dietary patterns rich in antioxidants and polyphenols, most notably the Mediterranean diet [7,8]^[7][8]. In addition, traditional medicine is now widely accepted in modern medicine as consumers seek more ‘natural remedies’ to treat and prevent illness ^[9]. In Indian Ayurvedic medicine, for example, Ashwagandha root, is used to treat a range of brain disorders including, anxiety, depression, Alzheimer’s disease, Parkinson’s disease, Schizophrenia and bipolar disorder ^[10]; Malkangani oil or Jyothishmati oil, obtained from Celastrus paniculatus, provides neuromodulatory, anti-oxidant, anti-inflammatory and sedative properties, among others ^[11]; Nardostachys jatamansi provides numerous beneficial properties by acting as an anticonvulsant, neuro-protective, hepatoprotective, neuroprotective and hypotensive ^[12]; and Terminalia arjuna which is used for angina, hypertension, congestive heart failure and dyslipidemia ^[13].

These dietary patterns and the integration of traditional medicine have led to the research and development of bioactive compounds originating from plant, fungi and animal sources, representing an innovative and fast-emerging area of the food industry [14,15]^[14][15]. Advancement in extraction technologies and refinement of isolation and purification techniques has given rise to specifically formulated products with relatively high purity of selective ingredients of near pharmaceutical standards, providing the amalgamation of nutritional and pharmaceutical products jointly identified as nutraceuticals [15,16,17]^[15][16][17]. Whilst consumption of a number of supplements in the form of tablets, powders and extracts to improve health is widely accepted, the benefit of a functional beverage is the ability to deliver one or several nutraceutical compounds in one product ^[18]. Additional benefits include their convenience, storage capabilities, size and flavor variabilities, acceptability and relatively low cost ^[19]. Some successful commercial examples of the functional beverage concept include sports drinks, ready to drink teas, energy drinks and vitamin-enriched water ^[20]. These beverages are often designed to improve hydration, concentration and endurance; and delivery of essential vitamins, minerals and polyphenols [4,18]^[4][18]. One area of the commercial health and wellness market which has seen an increase in demand are functional beverages to improve sleep quality ^[21].

Sleep is essential for wide ranging physiological processes including growth, cognition, immune function, metabolism and cardiovascular health [22,23]^[22][23]. Optimal sleep comprises adequate duration, quality and timing that is regulated by several neurotransmitters including glutamate, acetylcholine, dopamine, serotonin, norepinephrine, histamine, orexin, gamma-aminobutyric acid (GABA), adenosine, melatonin and melanin-concentrating hormone, among others ^[24]. Some of these compounds are also important in mood, cognition, appetite, behavior and stress ^[25]. A bidirectional relationship exists between sleep disruption and physiological state, that is influenced by a number of different modalities (Figure 1), and an alteration in neurotransmitter levels can result in sleep disruption, fatigue, impaired performance and impaired memory [26,27,28]^[26][27][28]. Furthermore, chronic sleep disruption is associated with an increased risk of cognitive decline and memory impairment [27^[27][29],29], metabolic syndrome (MetS) ^[30], anxiety and depression ^[31], type 2 diabetes mellitus (T2DM) ^[32], cardiovascular disease (CVD) ^[33], inflammation and infection ^[34].

Figure 1.

Factors Affecting Sleep Quality.

In support of the bidirectional relationship between diet and sleep, macronutrients have also been found to influence sleep quality. A review by St. Onge et al. (2016) reported that a high carbohydrate diet can negatively affect sleep quality by reducing slow-wave sleep and increasing rapid eye movement sleep (REM) ^[35]. Whereas, a high protein diet can positively effect sleep quality by reducing sleep onset latency and the number of wake episodes during the night ^[35]. Analysis of data from the National Health and Nutrition Survey (NHANES) conducted in the USA (n = 26,211) has also found that micronutrient deficiencies are inversely associated with sleep duration ^[36]. Furthermore, adherence to diets that are rich in fish, fruits, vegetables and nuts, such as the Mediterranean diet, have been found to be associated with better sleep quality, including better sleep efficiency and reduced sleep disturbances [37,38]^[37][38]. These diets are rich sources of important compounds involved in the sleep-wake cycle such as L-tryptophan, melatonin, magnesium and vitamin B6, among others, which have been the subject of numerous intervention studies to improve sleep quality [37,38,39]^[37][38][39]. These compounds are now being included in commercially available functional relaxation or sleep beverages.

2. Active Compounds

The summary of active compounds included in this review iere is presented in Table 1. The range of compounds is comprised of amino acid, hormone, vitamin and mineral compounds that influence the neurological pathways involved in sleep with potential for development into a functional beverage.

Table 1.

Selected nutraceuticals used in the promotion and improvement of quality of sleep and their outcomes in different population groups.

Compound		Reference/Country		Participants				Study Design			Outcome		Measures			Effects on Sleep
	Markus et al. (2005) ^[40]	Netherlands		Adults without sleep complaints	( n = 14)	Age (22 ± 3 years)		Adults with mild sleep complaint		( n = 14)		Age (22 ± 2 years)			20 g L-TRP-enriched		A-LAC protein		(4.8 g L-TRP/100 g amino acids w/w )		1 night			Double-blind		Placebo-controlled			Subjective Sleep Quality Measures:		Stanford Sleepiness Scale			Improved morning alertness		( p = 0.013) and increased attention (p = 0.002) in both groups.		Improved performance in participants with sleep complaints only ( p = 0.05).
L-Tryptophan		Ong et al. (2017) ^[41]	Australia		Healthy males without sleep complaint	( n = 10)		Age (26.9 ± 5.3 years)			20 g L-TRP-enriched		A-LAC protein		(4.8 g L-TRP/100 g amino acids w/w ) of A-LAC protein		2 nights			Double-blind		Placebo-controlled		Randomized		Crossover			Objective Sleep Quality Measures (Actigraphy):		Total sleep time		Sleep onset latency		Sleep efficiency (%)		Wake time after sleep onset		Subjective Sleep Measures (Sleep Log):		Bedtime		Time taken to fall asleep		Frequency of awakenings		Time taken to return to sleep		Waking time		Rising time	Total sleep time		Increased objective and subjective total sleep time by 12.8% (p = 0.037) and 10.8%	( p = 0.013), respectively; increased objective sleep efficiency by 7.0%	( p = 0.028).
	Cubero et al. (2007) ^[42]	Spain		Pre-weaning infants	( n = 30)	Age (4–20 weeks)			Diet A: Standard formula Diet B: Standard formula during the day and night formula (3.4 g L-TRP/100 g protein)		Diet C: Day formula during the day (1.5 g L-TRP/100 g protein) + night formula (3.4 g L-TRP/100 g protein) in the evening		1 week per formula			Double-blind		Randomized			Objective Sleep Quality Measures (Actigraphy):		Time of nocturnal sleep		Minutes of immobility		Sleep latency		Nocturnal awakenings		Sleep efficiency (%)		Sleep Diary:		Sleep over 24 h		Number of bottle feeds		Observations or incidences that would influence the infants rest			Diet C improved objective total sleep time (p < 0.05) and subjective (parent) sleep improvement; Diet B and Diet C reduced objective sleep onset latency; Diet B improved objective sleep efficiency.		(All p’s < 0.05)
	Bravo et al. (2013) ^[43]	Spain		Older adults with sleep difficulties	( n = 35)	Age (55–75 years)			L-TRP (60 mg) enriched cereal for breakfast and dinner		1 week			Blind assay			Objective Sleep Quality Measures (Actigraphy):		Time in bed		Assumed sleep		Actual sleep time		Sleep onset latency		Sleep efficiency (%)		Number of awakenings		Immobile time		Total activity		Fragmentation index (indicator of quality of rest)			Improvements in objective sleep measures including increase in actual sleep time (p < 0.01); increase in sleep efficiency (p < 0.001); increase in immobile time (p < 0.01); reduction in sleep latency (p < 0.01); wake bouts		( p < 0.05); total activity (p < 0.01); fragmentation index (p < 0.001).
5-HTP		Bruni et al. (2004) ^[44]	Italy		Children with sleep terrors	( n = 45)		Age (3.2–10.6 years)			2 mg/kg		(Daily)		20 days			Randomized, controlled			Frequency of sleep terrors			After 1-month:		Sleep terrors reduced > 50% from		baseline in 93.5% of children treated with 5-HTP ( p < 0.00001).		After 6 months:		51.6% were sleep-terror free		( p < 0.001).
Melatonin		Scheer et al. (2012) ^[45]	USA		Hypertensive adults on beta blockers	( n = 16)		Age (45–64 years)			2.5 mg		(nightly, 1 h before bedtime)		3 weeks			Randomized,		Double-blind		Placebo-controlled		Parallel-group design			Objective Sleep Quality Measures		(Polysomnography):		Sleep stages		Total sleep time		Time in bed		Sleep efficiency (%)		Objective Sleep Quality Measures (Actigraphy):		Sleep onset latency		Total sleep time		Sleep efficiency (%)			Increased total sleep time by 32 min		( p = 0.046); increased sleep efficiency by 7.6% (p = 0.046). Decreased sleep onset latency to stage 2 NREM sleep by 14 min (p = 0.001) and increased the duration of stage 2 NREM sleep by 42 min (p = 0.037).
	Grima et al. (2018) ^[46]	Australia		Adults with sleep disturbance post onset of traumatic brain injury	( n = 33)	Age (37 ± 11 years)			2 mg		(nightly 2 h before bedtime)		4 weeks			Randomized,		Double-blind		Placebo-controlled		Two-period		Two-treatment		Crossover study			Objective Sleep Quality Measures (Actigraphy)		Sleep onset latency		Total sleep time		Sleep duration		Sleep efficiency (%)		Sleep Diary:		Sleep onset/offset		Sleep duration		Subjective Sleep Quality Measures:		PSQI		ESS		FSS		Improved subjective sleep quality	( p < 0.0001) and objective sleep efficiency (p < 0.04).
	Xu et al. (2020) ^[47]	China		Adults with primary insomnia (n = 97)	Age (45–60 years)		3 mg		(nightly 1 h before bedtime)		4 weeks			Randomized,		Double-blind		Placebo-controlled		Parallel study			Objective Sleep Quality Measures		(Polysomnography):		Sleep stages		Total sleep time		Sleep onset latency		Wake after sleep onset		Sleep efficiency (%)		Subjective Sleep Quality Measures:		PSQI		ESS		ISI			Decreased objective sleep measures including early morning wake (p = 0.001) and decreased percentage of Stage 2 NREM sleep (p = 0.031).
L-Cysteine		Sadasivam et al. (2011) ^[48]	India		Adults with obstructive sleep apnea	( n = 20)		Age (53.1 ± 2.3 years)			600 mg (Mucinac,		Cipla), three times per day		30 days			Randomized,		Placebo-controlled			Objective Sleep Quality Measures		(Polysomnography):		Sleep stages		Total sleep time		Sleep onset latency		Wake after sleep onset		Sleep efficiency (%)		Sleep apnea		Snoring		Subjective Sleep Quality Measures:		ESS			Improvements in objective slow wave sleep as sleep percent time (p < 0.001) and sleep efficiency.		( p < 0.05).		Reduction in subjective Epworth Sleepiness Score ( p < 0.001).
	Rao et al. (2019) ^[49]	Japan		Healthy adult males	( n = 22)	Age (27.5 ± 0.9 years)			4 × 50 mg		(nightly, 1 h before bedtime)		6 days			Randomized,		Double-blind		Placebo-controlled		Crossover trial			Objective Sleep Quality Measures (Actigraphy):		Time in bed		Wake after sleep onset		Sleep onset latency		Sleep length		Sleep efficiency (%)		Subjective Sleep Quality Measures:		Obstructive Sleep Apnea		Inventory questionnaire			Improvements in objective sleep measures including an increase in objective sleep efficiency (p < 0.047) and reduction in intermittent		wakening ( p < 0.044).		Improvements in subjective sleep measures including feeling of recovery from exhaustion or fatigue scores ( p < 0.042) and improvement in refreshed upon awakening scores		( p < 0.014).
L-Theanine		Lyon et al. (2011) ^[50]	Canada		Boys with ADHD	( n = 98)		Age (8–12 years)			2 × 100 mg		(twice per day,		morning and evening)		6 weeks			Randomized,		Double-blind		Placebo-controlled		Parallel trial			Objective Sleep Quality Measures (Actigraphy):		Wake after sleep onset		Sleep onset latency		Sleep length		Nocturnal activity		Sleep efficiency (%)		Subjective Sleep Quality Measures:		Pediatric Sleep Questionnaire			Improved objective measures including sleep efficiency (p < 0.05), and reduced nocturnal activity (p < 0.05).
	Sarris et al. (2019) ^[51]	Australia		Adults with GAD	( n = 46)	Age (40.7 ± 15 years in TG; 32.2 ± 9.29 years in PG)			225 mg (twice daily); increased to 450 mg (twice daily) if anxiety score did not reduce by ≥35% after 4 weeks		8 weeks			Randomized,		Double-blind		Placebo-controlled		Multi-center pilot study			Subjective Sleep Quality Measures:		ISI			Improved subjective sleep		satisfaction		( p < 0.015); improvements in ISI scores for “difficulty in falling asleep”		( p < 0.049); “Problems waking up too early” ( p < 0.017); and “interference with daily functioning” (p = 0.030) in control.
	Hidese et al. (2019) ^[52]	Japan		Healthy Adults	( n = 30)	Age (48.3 ± 11.9 years)			200 mg tablet daily before sleep		4 weeks			Randomized,		Double-blind		Placebo-controlled		Crossover trial			Subjective Sleep Quality Measures:		PSQI			Improved subjective sleep quality (p < 0.013), reduced sleep onset latency, sleep disturbance and use of sleep medication (All p’s < 0.05).
Vitamin B12		Mayer et al. (1996) ^[53]		Healthy Adults	( n = 20)	Age (CB12 = 36.6 ± 5.2 years.		MB12 = 36.2 ± 5.2 years)			3 mg		(cyano-(CB12) or methylcobalamin (MB12))		14 days			Randomized		Single-blind		Between subject’s design			Objective Sleep Quality Measures (Actigraphy):		Wake after sleep onset		Sleep onset latency		Sleep length		Nocturnal activity		Sleep efficiency (%)		Subjective Sleep Quality Measures:		Morning and Evening VAS			Reduction in objective sleep time		( p = 0.036) in MB12 group improvements in sleep quality and daytime alertness (All p’s < 0.05).
	Luboshitzky et al. (2002) ^[54]	Israel		Healthy Adult Males	( n = 12)	Age (22–26 years)			100 mg		(5.00 PM)		Once			Randomized		Placebo-controlled		Parallel trial			Objective Sleep Quality Measures (EEG):		Sleep stages (%)		Total recording time		Sleep latency		Actual sleep time		Sleep efficiency (%)		REM latency			No effect.
Vitamin B6		Ebben et al. (2002) ^[55]	USA		Healthy Adults	( n = 12)		Age (18–28 years)			100 mg		250 mg		Placebo		(All nightly before bed)		5 days per treatment			Placebo-controlled		Double-blind		Crossover trial			Subjective Sleep Quality Measures:		Sleep questionnaire		Dream Salience Scale			Increase in dream salient scores in		250 mg B6 treatment compared to placebo ( p = 0.05).
	Aspy et al. (2018) ^[56]	Australia		Healthy Adults	( n = 100)	Age (mean = 27.5)			120 mg		(pyridoxine hydrochloride)		Vitamin B Complex		(120 mg pyridoxine hydrochloride + other B vitamins)		Placebo		(All nightly before bed)		5 days			Randomized		Double-blind		Placebo-controlled trial			Subjective Sleep Quality Measures:		Sleep log			Increased the amount of dream content recalled (p = 0.032) and decrease in sleep quality (p = 0.014) in B complex group.
Vitamin D		Ghaderi et al. (2017) ^[57]	Iran		Adults undergoing Methadone Treatment.	( n = 68)		Age (25–70 years)			50,000 IU		(once per fortnight)		12 weeks			Randomized		Double-blind		Placebo-controlled trial			Subjective Sleep Quality Measures:		PSQI			Improvement in subjective sleep score		( p = 0.02).
	Mason et al. (2016) ^[58]	USA		Overweight menopausal females with low VitD	( n = 218)	Age (50–75 years)			2000 IU vitamin D3		(daily)		12 months			Randomized		Double-blind		Placebo-controlled trial			Subjective Sleep Quality Measures:		PSQI			Increase in PSQI score (p = 0.01) and increase in need to take sleep medication (p < 0.01).
Vitamin C		Dadashpour et al. (2018) ^[59]	Iran		Adults on hemodialysis with sleep disorder	( n = 90)		Age (18–70 years)			500 mg /5 cc intravenously–3 times per week		8 weeks			Randomized		Double-blind		Trial			Subjective Sleep Quality Measures:		PSQI		VAS			Reductions in subjective sleep quality, sleep latency, daytime dysfunction		(All p’s = 0.001).
	Yeom et al. (2007) ^[60]	Korea		Adults with Stage IV cancer	( n = 39)	Age (53.5 ± 10.5 years)			10 g vitamin C intravenously twice with 3-day interval, then		4 g oral supplement daily		1 week			Prospective study			Subjective Sleep Quality Measures:		European Organization for		Research and Treatment of Cancer Core Quality-of-Life questionnaire (EORTC QLQ-C30)-Korean Version			Lower subjective scores for sleep disturbance and fatigue (p < 0.005).
	Murck et al. (2000) ^[61]	Germany		Older adults without sleep disturbances (n = 12)	Age (60–80 years)		10 mmol for 3 days, then		20 mmol for 3 days, then		30 mmol daily for 14 days			Randomized		Placebo-controlled		Crossover design			Objective Sleep Quality Measures (EEG):		Sleep stages (%)		Total recording time		Sleep latency		Actual sleep time		Sleep efficiency (%)		REM latency			Increase in slow wave sleep (p < 0.05), delta and sigma waves (p < 0.05 for both).
Magnesium		Abbasi et al. (2012) ^[62]	Iran		Older adults	( n = 43)		Age (65 ± 4.6 years)			414 mg magnesium oxide (250 mg Mg)		Twice per day		8 weeks			Double-blind		Placebo-controlled trial			Subjective Sleep Quality Measures:		ISI		Sleep Log			Increase in subjective sleep time		( p = 0.002) and subjective sleep efficiency (p = 0.03); decrease in subjective sleep onset latency (p = 0.04), and insomnia severity index (p = 0.006).
	Hornyak et al. (2004) ^[63]	Germany		Alcohol dependent adults in subacute withdrawal with sleep disturbance	( n = 11)		30 mmol Magnesium		L-aspartate hydrochloride (10 mmol morning and 20 mmol evening) daily		4 weeks			Open Pilot Study			Objective Sleep Quality Measures (Polysomnography):		Sleep stages		Total sleep time		Sleep onset latency		Wake after sleep onset		Sleep efficiency (%)		Periodic leg movements in sleep (PLMS)		Subjective Sleep Quality Measures:		PSQI			Decrease in objective sleep latency		( p = 0.03), improvement in subjective sleep quality (p = 0.05).
Zinc		Saito et al. (2017) ^[64]	Japan		Healthy Adults	( n = 94)		Age (20–84 years)			Group A: Placebo		Group B: 15 mg		Group C: 15 mg + Astx		Group D: Placebo + 16 mg + Astx		12 weeks			Randomized		Double-blind		Placebo-controlled		Parallel group trial			Objective Sleep Quality Measures (Actigraphy):		Wake after sleep onset		Sleep onset latency		Sleep length		Frequency		Nocturnal activity		Sleep efficiency (%)		Subjective Sleep Quality Measures:		PSQI			Improvements in objective sleep efficiency in group B (p = 0.025); objective sleep onset latency in Group B and D (p < 0.032) and (p = 0.004), respectively.
	Gholipour et al. (2018) ^[65]	Iran		ICU nurses	( n = 54)	Age (31.2 ± 5.42 years)			1 × 220 mg		(every 72 h)		1 month			Multi-center		Randomized		Two parallel group		Placebo-controlled trial			Subjective Sleep Quality Measures:		PSQI			Improvements in subjective total sleep quality (p < 0.002); sleep onset latency		( p < 0.003), sleep duration (p < 0.02) and total sleep quality score (p < 0.008).

Note: L-TRP-L-Tryptophan; A-LAC–alpha-lactalbumin; EEG–Electroencephalography; 5-HTP–5-hydroxytryptophan; SWS–Slow Wave Sleep; REM–Rapid Eye Movement; NREM–Non-Rapid Eye Movement; ADHD–Attention Deficit Hyperactivity Disorder; GAD–Generalized Anxiety Dissorder; TG–Treatment Group; PG–Placebo Group; PSQI–Pittsburgh Sleep Quality Index; ICU–Intensive Care Unit; ESS–Epworth Sleepiness Scale; FSS–Fatigue Severity Scale; ISI–Insomnia Severity Index; VAS–Visual Analogue Scale; Astx-Astaxanthin.

3. DNutraceutiscussiocals as Potential Targets for the Development of a Functional Beverage for Improving Sleep Quality

WThe researchers have indicated that L-TRP and melatonin may effectively improve sleep quality, as expected, due to their central roles in the sleep-wake cycle and the extensive studies conducted on these compounds. While the evidence is still relatively limited, micronutrients and 5-HTP may also be effective as functional ingredients due to their important roles in modulating the neurotransmitters of the sleep-wake cycle, particularly serotonin and melatonin. Another finding of this review search is the association between inflammation and oxidative stress on sleep quality. Oxidative stress leads to overexcitation of glutamate, decreasing L-CYS uptake. This also activates the kynurenine pathway, redirecting L-TRP and reducing sleep quality [177]^[66]. The use of compounds with antioxidant properties, such as L-THE, NAC and vitamins C and D may also be effective in improving sleep quality by reducing oxidative stress. In addition, wthe researchers have presented the supporting evidence on the effectiveness of traditional sleep promoting beverages, however these findings require further investigation in well-designed clinical trials. In many cases, particularly for the herbal varieties, an extract in the form of a capsule was used to evaluate its effectiveness, and thus the same effect may not be achieved through usual daily consumption of the beverage.

Given the common physiological pathways of the compounds presented in this reviewere, preliminary data suggests nutraceutical combinations could be effective in improving sleep quality through either a synergistic or enhancing effect. This was evident from the studies looking at the effect of a melatonin/magnesium/B vitamin complex combination, and a melatonin/magnesium/zinc combination.

The future directions for development of functional beverages to improve sleep quality must consider several factors to ensure its claims of functionality are substantiated. The bioavailability and functionality of the nutraceutical compound within the beverage may be affected by dose, solubility, pH, possible interactions with the beverage matrix and other nutraceutical compounds, digestion and gut microbiota following consumption [178,179]^[67][68]. Melatonin, for example, has a bioavailability of approximately 15% following consumption of 2 mg and 4 mg [180]^[69]. Whereas L-THE is reported to have a bioavailability of approximately 45%–54% following digestion [181]^[70]. The mechanism of action of the nutraceutical and its interaction with other drugs is also important to consider as it may interfere with the action of the drug. For example, magnesium supplementation and the absorption of calcium channel blockers. It may enhance the effect of a drug resulting in an adverse reaction, such as L-TRP supplementation potentially increasing peripheral serotonin in conjunction with SSRI’s. Furthermore, herbal extracts, which can contain over 100 bioactive constituents, may reduce the effectiveness of other nutraceuticals due to chemical interactions. Processing and preserving the beverage and the stability of the nutraceutical compounds within the beverage during storage may also affect their bioavailability [179]^[68]. These compounds may need microencapsulation, whereby a compound is encapsulated in a food-grade, biodegradable shell to protect its bioavailability and shelf life [182]^[71]. Vitamin C is susceptible to degradation during food preservation [183]^[72], whereas L-THE is stable in acidic environments, can withstand high temperatures and has been found to have a long shelf-life [98]^[73]. Additionally, a sensory profile of the beverage is essential to ensure its likeability. NAC is reported to have a pungent taste and smell due to its sulfur groups and would therefore require additional flavors and delivery to make it more palatable [184]^[74]. The volume of the beverage must also be considered as an increased propensity to urinate after consuming the drink may disrupt normal sleep. Furthermore, when assessing the effectiveness of the beverage, the use of objective sleep assessments such as actigraphy, used in combination with subjective sleep diaries and questionnaires, and a food diary will offer a more comprehensive assessment of efficacy.

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