Nutraceuticals for Improving Sleep Quality

Nutraceuticals for Improving Sleep Quality: History

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Subjects: Nutrition & Dietetics

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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]. 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].

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]. 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]. 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]. 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]. 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]. 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]. Furthermore, chronic sleep disruption is associated with an increased risk of cognitive decline and memory impairment [27,29], 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]. 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]. 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 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	Intervention/Duration	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).

Compound

Reference/Country

Participants

Intervention/Duration

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. Discussion

We 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 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]. 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, we 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 review, 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]. Melatonin, for example, has a bioavailability of approximately 15% following consumption of 2 mg and 4 mg [180]. Whereas L-THE is reported to have a bioavailability of approximately 45%–54% following digestion [181]. 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]. These compounds may need microencapsulation, whereby a compound is encapsulated in a food-grade, biodegradable shell to protect its bioavailability and shelf life [182]. Vitamin C is susceptible to degradation during food preservation [183], whereas L-THE is stable in acidic environments, can withstand high temperatures and has been found to have a long shelf-life [98]. 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]. 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.

This entry is adapted from the peer-reviewed paper 10.3390/beverages7020033

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