Targeted Natural Interventions
Amino Acids and Hormones
Melatonin. Melatonin, a hormone made in the pineal gland, is highly correlated with the body's sleep-wake cycle. During the day, the pineal gland is relatively inactive, but when the sun goes down, it begins producing melatonin. In humans, the brain’s production of melatonin peaks in the late evening (usually at 9:00 p.m.), coinciding with the body's normal time for sleeping. Melatonin levels typically stay high in the blood for about 12 hours, and by daylight levels naturally fall to barely detectable levels. Note that exposure to light is a major factor in regulating human sleep patterns. Light exposure stimulates nerves that run from the eye to the brain to signal increasing body temperature and the release of stimulating hormones, such as cortisol. Darkness, by contrast, stimulates melatonin production and decreasing body temperatures.158
Low melatonin levels have been linked to insomnia, particularly in the elderly. In a clinical review, serum melatonin levels were reported to be significantly lower (and the time of peak melatonin values delayed) in elderly subjects with insomnia compared with age-matched normal controls.159
Research suggests melatonin supplementation improves sleep. A meta-analysis of 19 randomized placebo-controlled trials including 1,683 patients found that melatonin improves sleep quality, increases total sleep time, and decreases sleep latency.160,161 Other studies suggest it enhances alertness after sleep162 and reduces the number of times people wake up during the night.163
A randomized, double-blind, placebo-controlled trial involving 125 children and adolescents with autism spectrum disorder who were struggling with sleep disturbances found that 2‒5 mg of prolonged release melatonin mini-tablets for 13 weeks increased total sleep time and decreased sleep latency and sleep disturbances. Subjects in this trial unsuccessfully attempted to improve their sleep with four weeks of parent-led behavioral intervention alone prior to the trial.164
Nobiletin and the Circadian Clock
Circadian rhythms are biological processes that vary during the natural 24-hour day-night cycle. Maintaining consistent and healthy circadian rhythms promotes overall health and well-being, including healthy sleep patterns.165,166
The human body contains two regulatory elements that respond to circadian rhythms: the central clock and peripheral clocks.167 Melatonin helps modulate the central clock. Nobiletin, a flavonoid derived from citrus peels, helps modulate peripheral clocks.168,169
Preclinical research suggests nobiletin may protect against metabolic syndrome and age-related health deterioration in part by helping regulate peripheral clocks. When given to obese mice, nobiletin counteracted metabolic syndrome and increased energy expenditure.169 Another animal study demonstrated that nobiletin reduced symptoms of delirium in mice. Researchers believe the mechanism of action involves regulating the expression of the proteins that help maintain a stable circadian rhythm.170 Nobiletin may also help alleviate circadian rhythm disorders and jet lag.171
L-tryptophan. L-tryptophan is an amino acid that serves as a precursor for serotonin and melatonin.172,173 L-tryptophan supplements may increase the amount of melatonin made by the pineal gland, thus facilitating sleep.174 L-tryptophan has long been of interest in the sleep field: research dating back over 44 years found that 1 gram reduced the amount of time needed to fall asleep.175 Like melatonin, L-tryptophan levels decrease with age174; therefore, L-tryptophan supplementation may aid in the treatment of elderly insomnia.
Animal studies found tryptophan supplementation reduced activity at night and led to other biological changes conducive to sleep, such as lower core body temperature and reduced levels of IL-6 (an inflammatory cytokine).176 In one small human clinical trial, intravenous infusion of L-tryptophan caused dramatic increases in plasma melatonin levels and had a sleep-inducing effect, regardless of whether it was administered day or night.177 In addition, L-tryptophan may help alleviate some forms of depression, which can exacerbate insomnia.178
An analysis of data from the National Health and Nutrition Examination Survey (NHANES) (2001‒2002) involving over 29,000 individuals determined that tryptophan intake was positively associated with sleep duration.179 Another study examined whether consumption of cereals fortified with tryptophan improved the sleep/wake cycle in 35 individuals aged 55‒75. The study compared consumption of either the subjects’ usual diet, cereals enriched with 22.5 mg tryptophan per 30 grams of cereal (consumed at breakfast and dinner), or 60 mg tryptophan per 30 grams of cereal (consumed at breakfast and dinner). The cereal with the higher dosage of tryptophan increased sleep efficiency and total sleep time and decreased sleep fragmentation and latency.180
Another randomized study involving 33 male college students investigated the effects of tryptophan consumption at breakfast time and daytime light exposure on melatonin secretion and sleep. Subjects ingested either a tryptophan-poor meal paired with dim light, tryptophan-rich meal with dim light, tryptophan-poor meal and bright light, or tryptophan-rich meal with bright light exposure. The combination of bright light and a tryptophan-rich meal at breakfast promoted melatonin secretion in the evening and supported higher quality sleep.181
Glycine. Glycine, a non-essential amino acid that transmits chemical signals in the brain, helps support bone health, digestion, and metabolism.182 This compound is also a novel and safe way to promote healthy sleep patterns. In one randomized, single-blind, crossover trial, 11 healthy volunteers who took 3 grams glycine one hour before bedtime experienced shortened time to sleep onset and improved sleep satisfaction, without next day sleepiness.183 In a randomized, double-blind, crossover trial, 3 grams glycine before bedtime improved sleep quality and next day fatigue.184 In a randomized, single-blind, crossover trial, 10 sleep-restricted but otherwise healthy men were given 3 grams glycine or placebo before bed. The next day, participants took memory, cognition, and reaction time performance tests and a questionnaire rating their fatigue levels. Subjects given glycine had reduced fatigue and sleepiness and improved neurobehavioral performance compared with the control group.185
In an animal model, glycine administered to rats who have experienced disturbed sleep resulted in a shortened sleep latency, decreased body temperatures, and the induction of non-REM sleep.186 Oral glycine administration may also help elevate levels of serotonin, a neurotransmitter that plays a role in mood, learning, memory, appetite, and sleep.
Magnesium. Magnesium is a mineral that plays a role in cellular communication, energy production, muscle function, blood sugar maintenance, and regulation of circadian rhythms.187 The Food and Nutrition Board at the Institute of Medicine at the National Academies recommends a daily intake of 420 mg for men and 320 mg for women aged 31 and older.188
Optimal levels of magnesium are associated with normal sleep regulation.189 Magnesium deficiency is associated with shorter sleep duration,190 and may cause inflammation, which could result in conditions associated with poor sleep, including diabetes and cardiovascular disease.191 In addition, research suggests as sleep restriction increases, intracellular magnesium concentrations decline.192 Magnesium supplementation combined with melatonin and zinc has been shown to improve sleep in the elderly.193
Another trial found magnesium supplementation helped relieve insomnia related to restless legs.194 In a double-blind placebo-controlled clinical trial, 43 patients in long-term care with chronic insomnia were given 5 mg melatonin, 225 mg magnesium, and 11.25 mg zinc or placebo one hour before bedtime every night for eight weeks. The treatment group saw improved sleep quality and improved quality of life measures compared with placebo.193
A form of magnesium known as magnesium threonate may be beneficial for sleep, as it penetrates the blood-brain barrier more efficiently than other forms of magnesium.195,196
Zinc. Zinc, a trace element that is essential for many biological functions, including immune health and neurocognition, may help reduce the risk of inflammatory diseases.197 Studies indicate zinc may also play a role in facilitating sleep.193 A literature review indicates serum zinc levels vary with amount of sleep, and oral administration of zinc increases both amount and quality of sleep.198,199 In another trial, mice fed a yeast extract containing zinc had increased levels of non-REM sleep and decreased motor activity levels when sleeping.200
Another study showed women with the highest levels of zinc in their bodies slept for longer periods of time than women with the lowest levels.201 As previously mentioned, when combined with melatonin and magnesium, zinc also supported quality of sleep in the elderly.193
How zinc supports sleep patterns remains unclear, but some researchers speculate that oral administration of zinc rapidly increases blood levels, which activates a signaling pathway in the central nervous system.198 Zinc may act as a circadian regulator that induces sleep.198
Herbal Support and Other Integrative Interventions
Valerian. Valerian is a perennial flowering plant that has been used for medicinal purposes, including inducing sleep, reducing anxiety and stress, and stimulating digestion, since ancient times.202 Valerian root contains several compounds with sedative effects, including valerenic acid and valepotriates.203 Valerian root is believed to affect the transportation and liberation of GABA and stimulates GABA receptor activity.204,205
In one randomized, triple-blind, controlled trial involving 100 postmenopausal women struggling with insomnia, treatment with 530 mg valerian root for four weeks resulted in improved sleep quality.206 One preclinical model examined the effects of a mixture of hops and valerian on sleep quality. Researchers found that sleep behaviors, including total sleep time, improved via modulation of a GABA signaling pathway in the treatment group.207
One study compared the effects of 600 mg valerian to the commonly prescribed tranquilizer oxazepam. During six weeks of treatment, valerian showed comparable efficacy to 10 mg oxazepam.208 A review of relevant studies indicated valerian is an advisable treatment option for people struggling with sleep issues, and it appears to have a favorable safety profile with no known interactions with common medications.209 The typical dose of valerian is about 300‒600 mg, 30 to 120 minutes before going to sleep.210 It may take up to two weeks of daily use for the full sedative effect of valerian to manifest.211
Valerian may also be useful when applied topically. One randomized clinical trial involving 85 severely ill patients found that acupressure with valerian between the hours of 7:00 p.m. and 10:00 p.m. resulted in increased sleep time and less frequent night wakings.212
Chamomile. Chamomile is a popular herb often used as a tea to promote sleep and relaxation.213,214 The dried flower extracts of chamomile contain terpenoids and flavonoids that may help combat inflammation, insomnia, ulcers, wounds, pain, and muscle spasms. Sedative properties of this herb are believed to be due to certain flavonoids that may modulate benzodiazepine receptor signaling in the brain.215
One randomized, placebo-controlled, double-blind study involving 57 people with a history of anxiety and depression found that chamomile supplementation reduced mood and depressive symptom scores.216 In a randomized controlled trial of 80 postnatal women, drinking chamomile tea for two weeks helped alleviate symptoms of depression and improve sleep quality.217 In a randomized controlled trial, 200 mg chamomile twice daily for 28 days improved sleep quality in a group of elderly subjects.218 In another clinical trial of 77 elderly subjects, 400 mg chamomile twice daily improved reported sleep quality measures.219 One randomized placebo-controlled clinical trial found 270 mg chamomile twice daily for 28 days improved daytime functioning of 34 subjects with sleep problems.214
Passion flower. Passiflora incarnata, a member of the passiflower genus Passiflora, has long been used to treat anxiety and insomnia in Europe.220 The active compounds in P. incarnata appear to interact with the GABA and opioid systems.221-223 Extracts of this plant have shown sedative, anti-diabetic, and anti-asthmatic activities in preclinical research.220
In one randomized double-blind trial, 78 insomniacs were given either a 10 mg dosage of zolpidem or a combination of hops, valerian, and passion flower for two weeks. Both groups displayed improved sleep time, sleep latency, and night wakings.224 One randomized study compared supplementation with either passion flower or St John’s wort in 59 menopausal women experiencing sleep disturbances and depression. After six weeks, both groups demonstrated improved sleep quality.225 In one animal model, P. incarnata was shown to reduce anxious behavior.222 Additionally, another animal model found that passion flower-derived compounds prevented diazepam dependence in mice when given with the drug over a three-week period.226 While this extract has a good safety profile, more rigorous clinical data is necessary to assess its efficacy in humans.
Ashwagandha. Withania somnifera, also known as ashwagandha, is an Indian herb used for centuries as a wellness-promoting tonic. It may be beneficial for reducing anxiety, promoting calmness, and treating insomnia. This herb has been best characterized for its effects on stress. A randomized, double-blind, placebo-controlled trial in 64 individuals struggling with chronic stress found 300 mg of an ashwagandha extract twice daily for 60 days reduced reported stress and serum cortisol levels.227
A systematic literature review including five human trials concluded that ashwagandha supplementation (125–12,000 mg/day) improved self-reported stress and anxiety scores, but further research is warranted to confirm these results due to the effects of a poor study design and small sample sizes.228 Several animal studies have found that this extract improves the ability to handle stress and reduce anxiety.229-231 Cellular research suggests a component of this herb, withanone, protected neural cells from oxidative stress.232,233 Because emotional stress can be a significant contributor to insomnia, ashwagandha may help indirectly improve sleep.
This herb has also been found to directly improve sleep in animal models by increasing GABAergic activity.234 In one animal model, sleep-deprived rats given an ashwagandha extract showed improvements in behavioral tests, indicating the supplement may help abate the cognitive and memory impairments seen in insomniacs. These rats showed decreased cellular stress and apoptosis in the hippocampus.235 Another mouse model study determined that an active component of ashwagandha is triethylene glycol, which has been shown to induce non-REM sleep.236
Lemon balm. Lemon balm is an herb from the mint family traditionally used for its calming and anxiety-reducing effects.237,238 One randomized, double-blind, placebo-controlled study showed 600 mg lemon balm improved mood and significantly increased self-ratings of calmness.239 Lemon balm has also been investigated for the treatment of sleeping problems.
Research indicates rosmarinic acid, ursolic acid, and oleanolic acid are the active compounds in lemon balm, with rosmarinic acid being responsible for most of the activity associated with this herb. Lemon balm may inhibit GABA transaminase, which plays a role in anxiety and neurological disorders.240 In a randomized controlled trial of 11 healthy people supplemented with lemon balm containing 500 mg rosmarinic acid, the herb was found to be safe and tolerable.241
In an open-label prospective study, 20 stressed individuals took a standardized lemon balm extract for 15 days. Improvements in anxiety and insomnia symptoms were reported.242 In a randomized placebo-controlled trial, 100 menopausal women with sleep disorders received a combination of valerian and lemon balm. The treatment group experienced a reduction in sleep disorder symptoms.243 One study found a combination of valerian and lemon balm improved symptoms of a sleep disorder in 81% of children who took the preparation.244
Lavender (as essential oil aromatherapy). Aromatherapy is an alternative medicine practice that utilizes plant oils to treat health problems. Lavender oils have been extensively studied for the treatment of insomnia. A randomized controlled clinical trial involving 79 college students with sleeping difficulties found that inhaled lavender combined with good sleep hygiene practices was more effective than sleep hygiene alone in improving sleep quality.245 In another trial, 67 middle-aged women with insomnia were randomized to either inhale lavender oil for 20 minutes twice weekly for 12 weeks or receive sleep hygiene education. The treatment group experienced an improved quality of sleep compared with the control group.246
In a four-week study involving 28 postpartum women struggling with anxiety and depression, subjects were either randomized into a group that inhaled a blend of rose otto and lavender essential oils or instructed to avoid essential oil use during the study period. The aromatherapy group had significant improvements in depression and anxiety scores, with minimal risk of negative effects.247 Studies found lavender oil also reduces feelings of drowsiness after waking.248 In an animal model, lavender oil use for seven days reduced behaviors associated with depression and anxiety. Exposure to the oil also has been shown to decrease aggressive behaviors and improve social interactions.249
Some researchers are examining the use of oral lavender to combat sleep problems. In a multi-center, randomized, double-blind trial, silexan (an oral lavender oil capsule) was compared to lorazepam (a benzodiazepine) in patients with generalized anxiety disorder. After six weeks, silexan was effective at reducing anxiety symptoms, with no sedative side effects.250
Lavender is thought to possess antioxidant abilities and reduce inflammatory pathways. It also may alter ion channels in neurotransmitter junctions, which suggests it may be beneficial in Alzheimer’s patients. The oil may act via the limbic system and cause central nervous system depression when absorbed through the skin after topical application. While lavender oil appears safe and tolerable, and evidence supporting its use is promising, more clinical trials with long-term data are required to further clarify its role in promoting sleep and relaxation.249
Saffron. Saffron, a spice derived from the Crocus sativus flower, has been widely used as a flavoring agent and traditionally used to treat depression and asthma. It has powerful antioxidant properties, and preclinical studies indicate its major compounds safranal, crocin, and crocetin may have anti-tumor and anti-atherosclerotic properties.251 Animal and in vitro research suggest saffron may be a potential therapeutic agent for Alzheimer disease, cardiac ischemia, and age-related macular degeneration.252 In vitro and in vivo studies indicate saffron and crocin may have neuroprotective properties.253
Preliminary evidence suggests saffron may promote sleep. Animal studies on safranal indicate it supports non-REM sleep and decreases sleep latency.254 One placebo-controlled human trial examined the effect of 300 mg saffron on sleep quality in 50 diabetic patients. After one week, sleep quality improved in the treatment group.255 However, more high-quality human data is necessary to determine if and how saffron can be used to treat insomnia.
Honokiol. Honokiol is a ligand extracted from the bark, seeds, and leaves of the Magnolia tree. It has traditionally been used to treat mood disorders, including anxiety and depression,256 and is believed to have anti-tumor, anti-inflammatory, and antioxidative effects.257 It can cross the blood-brain barrier, resulting in enhanced bioavailability, and research suggests it exerts neuroprotective abilities in the central nervous system.258 Honokiol enhances GABA receptor activity in neurons in the hippocampus.256
In one animal study, mice administered honokiol experienced shortened sleep latency and increased amounts of non-REM sleep.259 Several older research studies with animal models support these finding, including one in which mice given seven daily treatments of two different traditional plant-based tinctures (Hange-koboku-to and Saiboku-to) had reduced anxiety and improved maze tests scores. These effects were mainly due to the honokiol content, as varying the chemical content of the samples still produced similar results as long as honokiol was contained in the sample. The honokiol-free preparations did not influence anxiety levels in the mice.260 Mice administered 20 mg/kg honokiol showed reduced anxiety levels in a maze test without a reduction in motor function. 261 Another animal model demonstrated that honokiol had similar anxiolytic effects as diazepam, but without possible amnesia and drug dependence.262 While these results are promising, more human clinical trials are required to understand how honokiol affects sleep.
Danshen. Danshen (Salvia miltiorrhiza) is an herb traditionally used to promote sleep and proper blood circulation, thus improving cardiovascular health.263 S. miltiorrhiza, whose main components include rosmarinic acid and salvianolic acid, is often used in combination with borneol for better pharmacological results.264 Early animal research suggests Danshen has tranquilizer-like properties.265 However, well-designed clinical data is lacking, and adequate research must be carried out to understand how Danshen alters sleep.
Bioactive milk peptides. Certain peptides derived from the enzymatic breakdown of milk proteins may relieve stress-related sleep disorders. These peptides are believed to act on GABA receptors in the brain, inducing relaxation and sleep. In one study, these bioactive peptides increased time spent sleeping and reduced the amount of sleep needed after just two weeks of treatment. Another randomized, double-blind, placebo-controlled study of 63 women suggests 150 mg daily of the milk protein alpha-s1 casein hydrolysate reduced stress-related symptoms, including sleeping difficulties.266,267
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