Insomnia: Review of Nutritional Interventions
Jonathan E. Prousky, ND, MSc
Insomnia, as defined by the American Academy of Sleep Medicine,1 is unsatisfactory sleep that impacts daytime functioning. The Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) describes the essential features of insomnia disorder as a predominant complaint of insomnia lasting for at least 1 month and causing significant distress or daytime impairments in social, occupational, or other sectors of daily life.2-4 Insomnia affects more than two-thirds of all adults in any given year, and some 2% to 6% of them use medication to facilitate sleep.5 Individuals having insomnia suffer from increased morbidity and mortality due to cardiovascular disease and psychiatric disorders, making insomnia a major public health issue.6 The major risk factors for chronic insomnia include increasing age, female sex, the presence of psychiatric illness, medical comorbidities, impaired social relationships, lower socioeconomic status, separation from a spouse or partner, and unemployment.7
It is easiest to separate insomnia into either acute (ie, <30 days) or chronic (ie, ≥30 days) for diagnostic purposes (Table 1).8-10 The majority of insomnia cases are associated with other medical conditions, giving rise to a more appropriate diagnosis of comorbid insomnia. In a mere 15% to 20% of cases, insomnia is unrelated to medical conditions, denoting primary insomnia.11 The workup of chronic insomnia should include the following: (1) a thorough medical history (involves a medication inventory and sometimes an interview with a patient’s spouse, partner, or caregiver); (2) physical examination, which should involve a neurological and Mini-Mental State Examination; (3) a sleep diary, which should span 2 weeks and cover daytime symptoms and frequency of napping, if present; and (4) specialized tests, if necessary, such as polysomnography (multiple sleep latency testing), actigraphy (an activity monitor or motion detector to evaluate sleep patterns), or neuroimaging (to look for structural lesions).12
Table 1. Common Causes of Insomnia
|Causes of Acute Insomnia||Causes of Chronic Insomnia|
|Situation stress such as occupational, interpersonal, financial, academic, or medical problems||Medical disorders (eg, cancer, chronic pain, congestive heart failure, and gastroesophageal reflux disease)|
|Environmental stressors such as noise pollution||Medications (eg, antidepressants, bronchodilators, and central nervous system stimulants)|
|Death or illness of a loved one||Primary sleep disorder (eg, restless legs syndrome and sleep apnea)|
|Psychiatric illness (eg, anxiety disorders, bipolar disorder, and schizophrenia)|
|Sleep-wake schedule disorder (eg, jet lag and shift work)|
|Substance abuse (eg, alcohol, caffeine, drug withdrawal, and central nervous system stimulants)|
Adapted from Ramakrishnan and Scheid DC.12
Improving sleep habits should be the foundation of a program designed to correct insomnia, especially if it has lasted longer than 30 days. Improving sleep hygiene is uncomplicated, but it does require a consistent commitment from your patients. To achieve better sleep hygiene, a patient must be willing to do the following: (1) fix a bedtime and a waking time; (2) avoid daytime napping; (3) avoid alcohol and caffeine 4 to 6 hours before bedtime; (4) avoid heavy, spicy, or sugary foods 4 to 6 hours before bedtime; and (5) exercise regularly, but not immediately before bedtime.
In addition, the bedding and room temperature should be comfortable, the room should be well ventilated, all distracting noises need to be blocked out (if possible), and the bed should be reserved only for sleeping and sexual activity. Before bed, a light snack might help such as warm milk (assuming no dairy allergy or sensitivity) and a banana. It might be a good idea for patients to do some type of relaxation technique to facilitate sleep to reduce muscle tension and anxiety. Some patients should be encouraged to create a presleep ritual such as taking a warm bath or even reading for a few minutes before sleep. Once ready for sleep, it is important to tell patients that they should start sleeping in their most comfortable (ie, favorite) position.13
Melatonin is included here because it is a heavily used over-the-counter hormone and the best-studied natural intervention for insomnia. It is secreted by the pineal gland and regulates and establishes the circadian rhythm.14 It is effective when there are circadian rhythm disruptions, as in jet lag and shift work.12 It is also effective for primary insomnia, even when unrelated to jet lag or shift work. Although melatonin levels decline with age and although some young individuals have low melatonin levels, low production of the hormone does not predict a therapeutic response.15 Melatonin (as prolonged-release melatonin) will reduce sleep latency in elderly patients even if their endogenous production of the hormone is normal.15 Prolonged-release melatonin can be used for 6 months, is generally well tolerated, and is not associated with any rebound or withdrawal symptoms upon discontinuation among patients aged 18 to 80 years.16 Even among patients aged 20 to 80 years who took prolonged-release melatonin continuously for 12 months, discontinuation of the hormone after 12 months was not associated with adverse events, withdrawal symptoms, or even suppression of endogenous melatonin secretion.17 In a review that systematically evaluated the benefits of melatonin, the authors concluded that prolonged-release melatonin (2 mg once daily) has no safety concerns if patients are concurrently taking antihypertensive, antidiabetic, lipid-lowering, or anti-inflammatory drugs.18 While this review specifically addressed the usefulness of prolonged-release melatonin for patients 55 years or older, we have found this preparation to be useful for the treatment of insomnia among adults of all ages. Melatonin can also be useful in facilitating benzodiazepine discontinuation in approximately one-third of older adults (≥55 years) with insomnia.19 For perimenopausal patients taking mirtazapine for insomnia, prolonged-release melatonin can be used as a replacement sleep aid, while also circumventing the mirtazapine-induced weight gain.20 Melatonin is not associated with impairment of psychomotor functions, memory recall, or driving skills.21 In addition, individuals taking prolonged-release melatonin will not experience impaired postural instability (ie, body sway) should they wake up several hours after taking the hormone.22
Based on numerous clinical studies, the ideal dosage of melatonin is 2 mg about 1 hour before sleep, while the ideal preparation of melatonin is the prolonged-release melatonin formulation. Sometimes, increasing the prolonged-release melatonin to 3 mg achieves better results. Some individuals have a very good initial response, followed by a loss of response several weeks later. In such individuals, it is possible that they have developed tolerance due to slow liver metabolism of exogenous melatonin.23 To help these patients regain an effective sleep pattern, it is wise to stop melatonin for about 3 weeks and then resume it at a much lower dosage. The therapeutic effects of melatonin might be enhanced with the concurrent administration of magnesium (≥225 mg) and zinc (≥11 mg) at bedtime.24
The most common adverse effects of melatonin are vivid dreams and morning grogginess. The vivid dreams are not a concern unless they tend to be disturbing or frightening. The morning grogginess typically goes away in less than 20 minutes upon waking.
Some labels recommend against taking melatonin concurrently with sedative or hypnotic medications. Some labels also warn against the use of melatonin among individuals having autoimmune diseases. We have safely used melatonin to augment the effects of sedative or hypnotic medications. We have also given melatonin to patients with autoimmune diseases, when indicated. There do not appear to be any absolute contraindications to combining melatonin with the aforementioned classes of medications or among individuals with autoimmune diseases.
A few clinical studies have shown that glycine, a nonessential (or neutral) amino acid, is an effective sleep aid for primary insomnia. In a randomized, double-blind, crossover trial, 3 g of glycine or placebo was administered to human volunteers before bed.25 In the morning, the volunteers were evaluated to ascertain their subjective feelings and responses. Glycine administration was associated with significant improvements in subjective feelings, as per the subjects’ report of less fatigue and more “liveliness and peppiness” and clearheadedness. In a study26 using the same dosage of glycine, human volunteers who were continuously experiencing poor sleep were given glycine and then had their sleep quality evaluated, as per changes in polysomnography. The use of glycine improved subjective sleep quality and sleep efficacy and reduced polysomnography latency without altering sleep architecture. Glycine also reduced daytime sleepiness and improved tasks that involved memory recognition. The authors concluded that glycine before bed is associated with subjective and objective improvements in sleep quality by mechanisms different from those of benzodiazepine medications. Another trial evaluated whether glycine could improve sleep quality among volunteers who had their sleep partially restricted by assessing daytime sleepiness, fatigue, and various performance measurements.27 Ten volunteers (age range, 30-61 years; mean age, 41.4 years) entered into the study, but only 7 completed the randomized, single-blind, crossover trial. Their time in bed was artificially reduced by 25% for 3 consecutive nights (ie, from an average of 7.3 hours to 5.5 hours) to ascertain the therapeutic effects of 3 g of glycine ingested 30 minutes before bed. There was a significant improvement in fatigue (P = .02) the day after glycine was ingested (ie, day 1). No significant effects were noted in other parameters on day 1 compared with placebo, but there was a trend suggesting benefits in drowsiness, instability, and eyestrain. On day 3, no significant differences were noted in fatigue and the other parameters. With respect to performance tests, psychomotor vigilance (ie, reaction time) was significantly decreased from glycine ingestion on days 1 and 3 (P = .003 and P = .05, respectively). Overall, glycine can be prescribed to patients with primary insomnia and to patients who have periods when their sleep is restricted (eg, those having young children). In primary insomnia, glycine improves sleep quality, and in individuals among whom sleep has been restricted, glycine improves fatigue and offsets psychomotor deficits.
With respect to glycine’s mechanism of action, Bannai et al27 have summarized what is known from studies done on rats. Glycine passively diffuses across the blood-brain barrier and facilitates sleep, not by influencing melatonin levels or the expression of circadian-modulated genes, but by decreasing core body temperature. Core body temperature declines at the onset of sleep, further decreases during sleep, and gradually increases as a person wakes. Glycine also offsets the consequences of sleep restriction by increasing specific neuropeptides (ie, arginine vasopressin and vasoactive intestinal polypeptide) during the light period.
Glycine (3 g) is administered 30 minutes before sleep. It should be taken with a carbohydrate such as orange juice.
There are no adverse reactions associated with this dosage of glycine.
There have been anecdotal reports that cherry juice enhances sleep because it contains high amounts of melatonin and possesses anti-inflammatory properties that modulate cytokines implicated in sleep. In a randomized, double-blind, crossover design pilot study,28 a group of 15 healthy older adults went through a 2-week baseline (washout) period, then were given cherry juice or placebo, and were followed up for 2 weeks; they then underwent another 2-week washout period, followed by another 2-week intervention period. All participants were instructed to drink two 8-oz servings of their assigned intervention (ie, either cherry juice or placebo), with 1 serving in the morning between 8 and 10 am and 1 serving in the evening 1 to 2 hours before bedtime. Compared with placebo, the use of cherry juice was associated with a statistically significant improvement in insomnia severity (ie, minutes awake after sleep onset), but not in other parameters that were evaluated. The effect sizes were either moderate or negligible. While cherry juice produced some benefits, it should only be considered as an adjunct to more effective treatments like melatonin and glycine.
Drink two 8-oz servings of cherry juice daily, with 1 serving in the morning between 8 and 10 am and the second serving in the evening 1 to 2 hours before bedtime.
There are no adverse reactions associated with the consumption of cherry juice.
In a 2005 study,29 deoiled butternut squash seed meal (10 mg of tryptophan per 1 g of deoiled seed meal) was used as the protein source of tryptophan. Protein-source tryptophan facilitates sleep by increasing the synthesis of serotonin, which is also metabolized to melatonin. Protein-source tryptophan was given in combination with carbohydrate (ie, dextrose) and was compared with pharmaceutical-grade tryptophan and carbohydrate and with carbohydrate only.29 Added to all 3 of the studied treatments was 25 mg of vitamin B3 and 5 mg of vitamin B6. Fifty-seven subjects entered in this double-blind, placebo-controlled study, and 49 completed the required 3-week study period. Both the protein-source tryptophan and pharmaceutical-grade tryptophan produced statistically significant improvements in subjective and objective measurements of insomnia. The protein-source tryptophan, and not the pharmaceutical-grade tryptophan, was also effective at reducing the time awake during the middle of the night. The authors concluded that protein-source tryptophan is comparable to pharmaceutical-grade tryptophan for the treatment of insomnia.
One tablespoon of protein-source tryptophan is given 30 minutes before bed for 3 nights. It is then increased to 2 tablespoons 30 minutes before bed thereafter.
Some patients find that it works better if the protein-source tryptophan is taken for 5 to 7 nights in a row, then discontinued for 2 to 3 nights, and then resumed again for another cycle of 5 to 7 nights.30
This essential amino acid possesses hypnotic properties, making it a useful sleep aid.31 Schneider-Helmert and Spinweber32 have reported on the clinical uses and benefits of tryptophan treatment. In younger patients with longer-than-usual sleep latencies, they concluded that the use of tryptophan (1-15 g) can help reduce sleep-onset time. In more chronic patients with well-established sleep-onset insomnia, they reported that repeated lower dosages might be required in order to have good therapeutic outcomes. They also noted that stopping tryptophan treatment and then restarting it can sometimes be an effective way in which to prescribe this amino acid. Because tryptophan is not associated with impairment of visuomotor, cognitive, or memory performance and has no tolerance associated with its use, they recommended that it may be considered as an option for insomnia. Despite the apparent safety and usefulness of tryptophan, it is best reserved for cases of mild insomnia because it is only likely to benefit some 30% of individuals taking it.33
One gram or more of tryptophan at bedtime will increase sleepiness and decrease sleep latency (ie, time to sleep).34 Usual dosage ranges are 1 to 4 g,33 but sometimes very high dosages (15 g) might be needed.32
It is best to take tryptophan with a carbohydrate (eg, orange juice). This should be taken around 30 to 60 minutes before bed.
Case Study 1
An 81-year-old woman presented to the Robert Schad Naturopathic Clinic, Toronto, Ontario, Canada, in May 2012, with chief complaints of depression, insomnia, and anxiety. She told us that overall she felt “blah.” In December 2011, the patient had experienced an upsetting altercation with several family members. Following that event, she began eating excessively, worrying too much, thinking negatively, and having upsetting dreams. For the past 3 months, she reported increased anxiety and insomnia. She described having panic attacks immediately upon waking 3 to 4 times each week. She was getting only 2 hours of uninterrupted sleep each night and was waking up every 2 hours until morning. Her medical history included diagnoses of osteoarthritis, hypertension, and clinical depression. We diagnosed her with chronic insomnia and depression. At one of our initial visits with this patient, we prescribed a combination product containing gamma-aminobutyric acid, l-theanine, 5-hydroxytryptophan, melatonin, valerian root, passionflower, and lemon balm extract. We also prescribed a B-complex supplement containing a good range of all the B vitamins. A few weeks later, the patient returned for a follow-up visit, and she had not tolerated or responded to the combination product. It had not changed her sleep and had caused her to experience terrible nightmares. She did find, however, that the B-complex supplement improved her mood, resolved the blah feeling, and stopped the morning panic attacks. We told her to discontinue the combination product and replaced it with 1 teaspoon (approximately 5 g) of glycine powder mixed in water 30 minutes before bed, as well as 1 glass of cherry juice twice daily (morning and evening). Three weeks later, she returned for another follow-up visit and described a continual improvement in her mood. She was happy to report that she was now getting 5 to 6 hours of sleep every night, despite getting up once each night to urinate. She would fall asleep easily after getting up and was not concerned with this. She also noted some trouble falling asleep each night but was optimistic about these improvements. At her final appointment (3 weeks later), she reported complete resolution of all her sleep issues. She was now falling asleep easily and was getting 7 to 8 hours of uninterrupted sleep every night. Her mood remained good, and she felt that she would return only if she had to. She also told us that she would take both the glycine and cherry juice as needed going forward, instead of daily.
Case Study 2
A 90-year-old woman had been attending the Robert Schad Naturopathic Clinic for several years for a variety of medical complaints. In October 2012, she reported worsening sleep over the last 3 to 4 weeks. At night, she would feel very restless and would continually toss and turn. She described mind racing before bed, even though she was using relaxation tapes and warm milk to calm her down. Despite being in bed by 9 pm, she would not fall asleep until around 2:30 am and awoke sometime between 6:30 and 7:30 am. We diagnosed her with acute insomnia because her sleep issues had significantly worsened in fewer than 30 days. We increased her prolonged-release melatonin from 3 mg to 6 mg. We had previously prescribed the prolonged-release melatonin for the patient’s gastroesophageal reflux35,36 but felt that increasing the dosage would have a more marked effect on her insomnia. We also prescribed 1 teaspoon of glycine (approximately 5 g) mixed in water 30 minutes before bed. The patient returned 1 month later and reported a better quality and duration of sleep, even though she was still having some trouble with falling asleep. Unfortunately, the intern documenting the visit did not specify quantitatively how the patient’s sleep improved. It was clear, however, that both the increased dosage of melatonin and the addition of glycine favorably impacted this patient’s insomnia.
Patient Care Considerations
First, in addition to nutritional treatments (summarized in Table 2), patients should be encouraged to learn mind-body techniques because they are effective interventions for insomnia.37 These include yoga, relaxation, and cognitive behavior therapy.
Second, treatment-resistant depression might be due, in part, to an underlying sleep disorder. Depressed patients who are not getting better should be referred to a sleep specialist for a complete evaluation.
Third, for restless legs syndrome, only a few nutritional treatments have been shown to moderate symptoms. These include iron supplementation (ie, among patients with low-normal ferritin levels),38 magnesium,39 and folic acid.39
Fourth, for sleep apnea, nutritional supplements will do very little to resolve the underlying sleep problem. When patients self-identify as having sleep apnea, it is important to encourage them to use their continuous positive airway pressure device because it is the first-line treatment for such patients. When they refuse to use the device because they find it inconvenient or a nuisance and request alternative (ie, nutritional) treatments, it will not be possible to facilitate effective sleep unless they agree to regularly use it.
Fifth, all patients with insomnia should be encouraged to regularly exercise, no matter what limitations they have. Long-term moderate aerobic exercise (≥6 months) can significantly improve sleep quality, moods, and quality of life.40
Table 2. Summary of Nutritional Treatments for Insomnia
|Melatonin||Prolonged-release melatonin (2-3 g) at 1 h before bed|
|Glycine||Glycine (3 g) at 30 min before bed|
|Cherry juice||Drink two 8-oz servings of cherry juice|
|Protein-source tryptophan||Protein-source tryptophan (1 tablespoon) at 30 minutes before bed for 3 nights and then 2 tablespoons thereafter|
|Tryptophan||Tryptophan (1 g or more) with a carbohydrate (eg, orange juice) at 30-60 min before bed|
Acknowledgment: Dr Prousky’s article is adapted from the “Insomnia” chapter of his recently released book, Textbook of Integrative Clinical Nutrition, published by CCNM Press Inc in 2012.
Jonathan Prousky, ND, MSc, graduated from Bastyr University (Kenmore, Washington) with a doctorate in naturopathic medicine. He is the chief naturopathic medical officer at the Canadian College of Naturopathic Medicine (Toronto, Ontario) and supervises at the Robert Schad Naturopathic Clinic there. He is a passionate advocate for patients having psychiatric disorders and focuses his clinical practice on optimizing mental and neurological health with orthomolecular nutrition, botanical (plant based) medicines, and lifestyle counseling. He has lectured extensively on various health-related topics, especially mental health. Dr Prousky is the current editor of the Journal of Orthomolecular Medicine. His clinician-based research primarily involves the neuropsychiatric applications of vitamin B3.
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- Lemoine P, Garfinkel D, Laudon M, et al. Prolonged-release melatonin for insomnia: an open-label long-term study of efficacy, safety, and withdrawal. Ther Clin Risk Manag. 2011;7:301-311.
- Lemoine P, Zisapel N. Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia. Expert Opin Pharmacother. 2012;13:895-905.
- Kunz D, Bineau S, Maman K, et al. Benzodiazepine discontinuation with prolonged-release melatonin: hints from a German longitudinal prescription database. Expert Opin Pharmacother. 2012;13:9-16.
- Dolev Z. Case series of perimenopausal women with insomnia treated with mirtazapine followed by prolonged-release melatonin add-on and monotherapy. Arch Womens Ment Health. 2011;14:269-273.
- Otmani S, Demazières A, Staner C, et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008;23:693-705.
- Otmani S, Metzger D, Guichard N, et al. Effects of prolonged-release melatonin and zolpidem on postural stability in older adults. Hum Psychopharmacol. 2012;27:270-276.
- Braam W, van Geijlswijk I, Keijzer H, et al. Loss of response to melatonin treatment is associated with slow melatonin metabolism. J Intellect Disabil Res. 2010;54:547-555.
- Rondanelli M, Opizzi A, Monteferrario F, et al. The effect of melatonin, magnesium, and zinc on primary insomnia in long-term care facility residents in Italy: a double-blind, placebo-controlled clinical trial. J Am Geriatr Soc. 2011;59:82-90.
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- Pigeon WR, Carr M, Gorman C, et al. Effects of a tart cherry juice beverage on the sleep of older adults with insomnia: a pilot study. J Med Food. 2010;13:579-583.
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