Insomnia

Insomnia

1 Introduction

Summary and Quick Facts

  • Most people should target getting seven to nine hours of sleep per night. It’s estimated however that a third of American adults don’t get the recommended amount of sleep. Unfortunately, conventional treatment options are far from ideal.
  • In this protocol you will learn about the risks associated with pharmaceutical sleep aids. You will also discover simple lifestyle strategies, emerging therapies and several natural compounds for improving sleep.
  • Combining the natural interventions discussed in this protocol with appropriate treatments under physician guidance may help you achieve a good night’s sleep.
  • Low melatonin levels have been linked to insomnia. Supplementation with melatonin has been shown in several studies to be associated with improvements in several factors related to sleep.

Insomnia—the inability to fall asleep or stay asleep—is a problem of epidemic proportions in the United States. According to data from the National Sleep Foundation, 30% of Americans experience sleep disruptions, and another 10% struggle with insomnia.1 The Centers for Disease Control and Prevention (CDC) estimates that more than a third of American adults do not get the recommended seven hours of sleep per night.2 Older people and those with chronic health conditions are especially prone to insomnia.

The typical adult should get about seven to eight hours of sleep per night for optimal health.3 Sleep is essential for learning and memory formation, emotional wellbeing, physical growth and development, immune function, and cardiovascular health. Sleep is also integral to cellular repair processes and helps regulate insulin and other hormones that control appetite. Sleep deficiency can dramatically diminish a person’s quality of life. Insufficient sleep also increases risk of a variety of health problems, including cardiovascular disease, depression, and obesity.4-10

Insomnia can lead to a variety of symptoms such as not feeling well-rested after waking, daytime fatigue, irritability, depression or anxiety, excessive uneasiness about sleep, difficulty performing school or work tasks, and increased risk of accidents, especially involving an automobile.11

Despite the major toll insomnia takes, conventional treatment options remain far from ideal. For instance, popular hypnotic sleep aids, such as zolpidem (Ambien), eszopiclone (Lunesta), and temazepam (Restoril), have been consistently associated with significantly increased risk of death and other serious adverse effects.12-14 However, people who use hypnotic sleep aids often have poor overall sleep quality, which could explain some of these associations.

These alarming findings highlight the need for safe and effective strategies to improve sleep quality, especially as up to 10% of U.S. adults use hypnotic sleep aids.14 Hypnotic sleep aids are by no means a cure for chronic insomnia.

In this protocol, you will learn about the causes of sleep problems and simple lifestyle changes that can improve your sleep quality.15,16 You will also discover emerging therapies that have achieved prolonged improvements in sleep quality, with potentially fewer side effects than some popular sleep drugs.17 In addition, you will read about several natural compounds that modulate sleep biology which may be safer than some pharmaceutical treatment options.

2 Types of Insomnia

Generally speaking, there are two types of insomnia:

  • Onset insomnia ‒ difficulty falling asleep
  • Maintenance insomnia ‒ difficulty staying asleep

Both onset and maintenance insomnia may be acute or chronic.

  • Acute insomnia is generally associated with a disruptive or stressful life event and typically resolves within a few weeks without treatment. About 30‒50% of people in industrialized nations experience periodic acute insomnia.18,19 Some cases lasting only a few days may be described as transient insomnia.20
  • Chronic insomnia is long-term sleep difficulty occurring at least three nights per week for at least three months. Chronic insomnia is the type associated with long-term health problems and affects about 5‒10% of the population.18

Finally, insomnia may be described as primary or secondary.

  • Primary insomnia arises without any clear underlying cause.
  • Secondary insomnia, which may be described as comorbid insomnia, arises as a consequence of another condition or disease. For instance, people with chronic back pain may be unable to sleep well due to unrelenting discomfort.

3 Diagnosing Insomnia

In order to diagnose insomnia, a physician will perform a physical exam to determine any underlying medical cause for sleep problems, including a blood test to rule out a thyroid condition. In addition, a detailed sleep questionnaire or sleep diary may clarify a patient's sleep-wake pattern and level of day and night sleepiness. In the case of other signs of a sleep disorder, such as sleep apnea, a patient may need to undergo a sleep study, where tests that monitor and record body activities (including brain waves, breathing, heartbeat, and eye and body movements) during sleep are performed.11

4 Risk Factors

Risk factors for insomnia include female gender, having a previously diagnosed mental or physical health condition, being over age 60, stress, using certain medications such as stimulants, and having an irregular sleep schedule.11

Gender and Hormones

Women are more likely to struggle with insomnia than men due to hormonal changes during menstruation, pregnancy, and menopause. Sex hormones (eg, estrogen, progesterone, and testosterone) may significantly impact sleep, particularly in women. As many as 61% of postmenopausal women report symptoms of insomnia.21 Research suggests hormone replacement therapy in menopausal women can significantly improve sleep.22

Sleep disorders have been linked to lower testosterone levels in both men and women. In a cohort study of over 1,300 men aged 65 and older, subjects with lower testosterone levels had lower sleep efficiency (the percentage of time spent asleep while in bed) and increased night waking, although this association was largely explained by being overweight.23 Obesity and abdominal fat is associated with lower testosterone levels in men, and in turn, low testosterone levels may promote obesity.24 Low testosterone levels may also worsen overall sleep quality, which may improve with moderate levels of testosterone replacement therapy.25

Lower serum testosterone levels correlate with increased obstructive sleep apnea severity.26,27 Obstructive sleep apnea is most common in middle aged men, especially those who are overweight. People with obstructive sleep apnea have increased night waking, fragmented sleep, reduced sleep efficiency, and less rapid eye movement (REM) sleep, which in turn may lower testosterone levels.24 More research is required to understand causal relationships between sleep quality and testosterone levels, especially in older or obese individuals and those with chronic health conditions.

Obstructive Sleep Apnea—A Hidden Epidemic with Deadly Consequences

Obstructive sleep apnea is a common yet often overlooked sleep disorder that causes breathing to stop and start during sleep. It occurs when the throat muscles relax and block the airway, reducing oxygen flow. The resulting low oxygen levels in the bloodstream arouse the individual, resulting in disrupted sleep (even if they do not fully remember awakening). This pattern may be repeated five to 30 times an hour throughout the night.28 More than 18 million Americans have obstructive sleep apnea, causing poor sleep quality, snoring, mood changes, and intractable fatigue.29-31

Sleep apnea represents a major risk factor for cardiovascular disease, the leading cause of death in American adults, and is also linked to obesity.32 Obstructive sleep apnea has been associated with a 68% increase in coronary heart disease in men33 and may also be associated with increased cholesterol levels, hypertension,31,34 type 2 diabetes,35 cancer mortality,36 stroke, and death.28,37

For more information, refer to Life Extension’s Sleep Apnea protocol.

Psychological Health

Comorbid insomnia may be a symptom of and contributor to many mental health problems, including anxiety, depression, schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder.38-40 Patients with untreated insomnia are two to 10 times more likely to experience new or recurrent episodes of depression. A longitudinal study of people aged 65 and older in Japan found a statistically significant bi-directional relationship between insomnia and the development of depression.41

Studies indicate insomnia is a risk factor for the development of anxiety disorders and substance abuse as well.42 In one longitudinal study in adolescents, insomnia symptoms were associated with the use of alcohol, cannabis, illegal drugs, and suicidal ideation and attempts.43 Insomnia is also linked to certain personality traits, such as social introversion and the repression of feelings.44

One randomized controlled study found people who were sleep deprived showed more emotional reactivity to unpleasant images than those who were not sleep deprived, which suggests that sleep plays a role in emotional reactivity.45 In another controlled study of 14 people with chronic, primary insomnia, participants underwent an MRI scan during an emotional regulation task in which they were shown either negative or neutral imagery. They were asked to either view the images or use cognitive reappraisal techniques (in which you work to interpret the image as less negative in order to feel better about what you view) to decrease their emotional responses. Insomniacs showed higher levels of activity in the emotional processing area of the brain, suggesting they had neural circuity dysfunctions that impacted their ability to regulate emotions.46

Psychophysiological insomnia is a common type of chronic insomnia that can be very difficult to treat. It appears to be linked to hyper cortical arousal when going to bed. Psychophysiological insomnia is associated with excessive worrying at bedtime, specifically focused on not being able to sleep.47 Afflicted individuals have a hard time relaxing when they go to sleep, resulting in racing thoughts. They often focus on their difficulty falling asleep, which results in more anxiety that further disturbs sleep.

Over time, poor sleep and worries about sleeping can become associated with going to bed, resulting in a pattern of chronically poor sleep that affects daytime activities. Some believe that in addition to heightened arousal, individuals with psychophysiological insomnia may have some dysfunctional neurological inhibitory mechanisms that would normally help the mind "disengage" from daytime thought patterns.48

Treatment of psychophysiological insomnia includes good sleep hygiene practices, no daytime napping, limiting caffeine intake, cognitive behavioral therapy, and approaches that acknowledge worries (such as journaling or making a worry list). A recent longitudinal case series study with 60 subjects found that psychiatric comorbidities were strongly linked to negative treatment outcomes for people with psychophysiological insomnia, and people with strong social support and cognitive coping skills were most successful in treatment.49

Medical Conditions

Certain medical conditions can disrupt sleep, increasing the risk of insomnia. These include chronic pain conditions, asthma, heart failure, stroke, gastrointestinal issues, and an overactive thyroid.50

Age

Most adults aged 65 and over require approximately seven to nine hours of sleep per night. However, people in this age group often struggle with insomnia.51 A poll by the National Sleep Foundation found that one in five adults aged 55‒84 years experienced difficulty falling asleep, and a quarter of this population reported waking early a few days per week in the past year. Sleep efficiency is known to decrease after age 60.52

Insomnia is associated with epigenetic aging, which reflects a person’s biological age based on DNA methylation. One review of data from the Women’s Health Initiative determined that insomnia symptoms were associated with advanced epigenetic age of blood tissues and higher amounts of late differentiated T cells (immune cells that trigger inflammatory responses). These results implicate sleep duration in accelerated aging.53

Medications and Stimulants

A wide variety of prescription medications can affect sleep patterns, and sleepiness is one of the most common reported side effects of medication use.54,55 Medication-induced insomnia can be caused by a wide variety of drugs, including decongestants, diuretics, antihistamines, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), corticosteroids, chemotherapeutic agents, calcium channel blockers, beta-agonists, and theophylline.56-59

While some medications can cause insomnia, others disrupt sleep patterns or cause daytime drowsiness.55 In addition, over-the-counter medications, such as pain, allergy, or cold medicines and weight-loss products, may contain stimulants that contribute to insomnia.11 If you think a medication may be disrupting your sleep, speak with your physician. They may switch you to a different medication or modify the dosage of your current medication.55

Caffeine. Caffeine is one of the most widely consumed stimulants in the world. Found most commonly in coffee and other drinks, caffeine is used to combat sleepiness and enhance performance. Stimulants make it harder for the brain to achieve the state of relaxation needed for sleep.

The half-life (ie, the amount of time it takes the body to break down 50% of a dose) of caffeine is between three and seven hours; larger amounts and/or repeated doses of caffeine lead to slowed caffeine clearance, causing the effects to last even longer.60 As a result, caffeine consumption can impair sleep for many hours. In a national survey that evaluated caffeine consumption and difficulty falling and staying asleep, amount of non-restorative sleep, daytime sleepiness, and typical duration of sleep attained per night, caffeine consumption was associated with insomnia symptoms, especially daytime sleepiness.61

Another review of randomized controlled trials and epidemiological studies found caffeine prolongs sleep latency (the amount of time it takes to transition from a wakeful state to sleep), reduces total sleep time and sleep efficiency, and worsens perceived sleep quality.62 Older adults may be more sensitive to the effects of caffeine. Most research suggests mild caffeine consumption in the morning does not impair sleep.63

Nicotine and smoking. The use of nicotine and nicotine replacement therapy as well as nicotine withdrawal can contribute to insomnia.64 One study analyzed 29 years of data from the Children and Adults in the Community Study to assess the prevalence of insomnia among heavy/continuous smokers, late-start smokers, occasional smokers, quitters/decreasers, and nonsmokers. The study found chronic smokers were more likely to develop insomnia symptoms later in life.65 Another review of data from over 83,000 people in the Behavioral Risk Factor Surveillance System indicates current smokers or smokeless tobacco users are twice as likely to have insufficient sleep as non-smokers and non-smokeless tobacco users, independent of age, sex, race, alcohol use, and body mass index (BMI). Secondhand smoke exposure was also associated with insufficient sleep among people who never smoked or who quit.66

Alcohol. While most people think of alcohol as a sedative, it increases dopamine release within the brain, which has a stimulating effect.67 Chronic alcohol use is associated with insomnia, as is alcohol withdrawal.68 A review of over 60 studies indicated 2‒3 drinks before bed may promote sleep, but this effect diminishes after three continuous days.69 Sleep disturbances are common among those who abuse alcohol, and are often associated with relapse.70 A study examining the prevalence of insomnia in 302 alcohol-dependent patients in a treatment program in Poland found that over 60% had symptoms of insomnia, with delayed sleep being the most common symptom. A history of childhood abuse, poor health, and severity of alcoholism were predictors of insomnia in this group.71

A longitudinal outcomes study including 267 subjects with alcohol-dependence issues found that at baseline, 47% of subjects were classified as having insomnia. Abstaining from or reducing alcohol intake reduced reported sleep disturbances, although insomnia persisted in 60% of cases, particularly in those with severe insomnia. Alcohol treatment programs should include insomnia evaluation during the treatment period to help focus care and prevent relapse.72

More information is available in Life Extension’s Alcohol: Reducing the Risks protocol.

Stress

People under stress often struggle with insomnia.73 Worries about finances, work, school, and family issues may cause a state of hyperarousal, making it difficult to relax into a restful sleep state. One study demonstrated that those who are vulnerable to cognitive and emotional hyperarousal may be more likely to experience stress-related insomnia.74 Stress can also decrease sleep quality.11 Major life events, such as job loss, moving, the birth of a child, death of a loved one, or divorce may also trigger a bout of insomnia.

Shift Work

Not all U.S. employees have a traditional 9 a.m. to 5 p.m. job. Nearly 10% of those with a non-standard work schedule (such as rotating shifts, on-call work, or permanent night shifts) have shift-work disorder, which is a disconnect between the body's circadian rhythm and the earth’s natural day-night cycle.75 An additional 30% of shift workers experience symptoms such as excessive sleepiness when they need to be awake and alert, insomnia, problems focusing, a lack of energy, and depression. Even shift workers who get enough sleep during the day may experience some of these symptoms, as their internal clock sends signals to indicate it is time to sleep during nighttime hours.76 Shift work may also be associated with increased risk of certain diseases, including cancer and heart disease.

5 Complications of Insomnia

Sleep is important to maintaining overall health and wellbeing, and chronic insomnia can have serious mental and physical health consequences. People with insomnia not only report a lower quality of life, but may also struggle with poor job and school performance, higher risk of automobile accidents, and physical diseases including heart disease, some cancers, and immunological conditions.11

Insomnia is associated with many medical conditions, which can directly or indirectly contribute to difficulty sleeping. Some health conditions frequently associated with insomnia include arthritis, asthma, urinary and gastrointestinal issues, sinus problems, endocrine abnormalities, and neurological conditions.51

Insomnia can also be a symptom of another underlying problem, such as sleep apnea or restless leg syndrome. Restless leg syndrome is a condition in which a person feels discomfort in the legs and a strong urge to move them. These urges can be strongest when trying to fall and stay asleep.51

A recent prospective study that followed nearly 5,000 people for 11 years concluded that insomnia was associated with a greater risk of cardiovascular disease.77 Another prospective study following nearly 55,000 people for 13 years found that insomnia was associated with an increased risk of heart failure. In this study, people with multiple insomnia-related symptoms had a higher risk of heart failure.78 A recent controlled study of nearly 4,000 subjects found a very short sleep duration (ie, less than six hours of sleep per night) was associated with an increase in subclinical atherosclerosis compared with those who slept six to seven, seven to eight, or more than eight hours per night. Those with more fragmented or interrupted sleep had more areas of atherosclerotic plaque.79

Sleep is also influenced by and has an influence on the immune system. A lack of sleep can weaken immunity, leaving one more susceptible to viral, bacterial, and parasitic infections.80 Research indicates sleep deficiency is associated with decreased immune function and increased levels of inflammatory markers, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which promote inflammation.

Insomnia affects the endocrine system.81 Steroid hormones may influence sleep, and the immune and endocrine systems may have a bidirectional relationship with sleep.80 Insomnia can lead to elevated levels of cortisol, epinephrine, and other stress hormones.82,83 Elevated levels of cortisol can cause weight gain, weaken the immune system, and increase the risk of developing diabetes and osteoporosis.84-86 Data from epidemiological studies indicate an association between sleep deprivation and serious metabolic and endocrine disorders, including diabetes and hormonal changes in the hypothalamus, pituitary, and adrenal axis.81

Insomnia has been associated with chronic pain and musculoskeletal issues. A controlled study of 34 people, half with insomnia and half without, found those with insomnia experienced pain twice as often as those without. The insomnia group had more frequent and intense pain, more sensitivity to heat and pressure, and a dysfunctional pain inhibition system.87 Researchers concluded that sleep quality is associated with the regulation of pain processing and ability to modulate pain. In a crossover study involving 14 healthy subjects who underwent a night of total sleep deprivation and a night of habitual sleep, researchers found that a night of sleep deprivation resulted in increased levels of sleepiness, anxiety, and sensitivity to heat and pressure.88

6 Treating Insomnia: Non-pharmacological Therapies

Non-pharmacological interventions have been shown to improve sleep quality in patients with insomnia. These treatment options include cognitive behavioral therapy, sleep restriction, sleep hygiene, and relaxation therapy.89

Improving Sleep Hygiene and General Lifestyle Considerations

One of the most widely effective behavioral therapies for insomnia is improving sleep hygiene.90 Sleep hygiene refers generally to habits surrounding sleep, such as consistent bedtime, limiting blue light exposure before bed, limiting time in bed to sleep only, etc. Good sleep habits may help prevent insomnia.15,16,90

A prospective cross-sectional analysis of 548 college students examined the relationship between sleep hygiene and insomnia severity. Students complained of inconsistent sleep-wake cycles and frequently worrying in bed. Improper sleep scheduling, uncomfortable sleep environments, and engaging in behaviors that create hyperarousal before bed were associated with insomnia severity. After controlling for other risk factors, sleep scheduling was most strongly associated with insomnia severity.91 Another analysis of 130 patients admitted to a hospital burn unit found that a nurse-driven sleep hygiene protocol was successful in helping patients fall asleep more quickly and experience fewer sleep disruptions.92

Consider the following sleep hygiene and general lifestyle measures:

  • Keep your bedroom cool, dark, and quiet.
  • Keep sleep and wake times consistent throughout the week.
  • Avoid eating large meals two to three hours before bed, as indigestion can make falling asleep difficult.
  • Limit stimulant intake (eg, caffeine, nicotine, and alcohol) during the day, especially close to bedtime.
  • Limit daytime sleep.
  • Spend time outdoors in natural light each day.
  • Engage in daily physical activity, but avoid vigorous exercise during the two hours prior to sleep.
  • Create bedtime rituals (eg, taking a warm bath and listening to soft music) to improve relaxation. Resolving stress may help improve sleep quality. People with insomnia should also review the Stress Management protocol.
  • Avoid activities not related to sleep (eg, watching TV, reading, or listening to the radio) in the bedroom. Use the bedroom for sexual activity and sleep only (stimulus control).11
  • If worrying about the time keeps you awake, cover the alarm clock.

Sleep Restriction to Reset Circadian Rhythms

Sleep restriction therapy limits time in bed (including naps) to increase the biological need for sleep at night. This process usually begins by restricting time in bed to the estimated amount of time one should spend sleeping. For example, a person who stays in bed for nine hours but only sleeps six will initially restrict time in bed to six hours. This causes mild sleep deprivation in the beginning, but the sleepiness it creates trains the body to fall asleep more quickly. As the body adjusts, people can extend time spent in bed by 15 to 20 minutes, until they are able to get a full night sleep without spending extra time in bed.93

A study comparing sleep hygiene therapy plus sleep restriction to sleep hygiene therapy alone found sleep restriction improved sleep efficiency.93,94 A review of evidence for sleep restriction as a standalone treatment for insomnia found it improved sleep efficiency and total sleep time, and researchers concluded it was an effective means of treating chronic insomnia.95

Cognitive Behavioral Therapy

In 2016, the American College of Physicians recommended that cognitive-behavioral therapy be the initial treatment protocol for patients with chronic insomnia.18 Cognitive behavioral therapy helps people develop behaviors more conducive to sleep. It involves regular visits to a clinician who will assess sleep patterns and work to change how the patient gets to sleep. Cognitive behavioral therapy works by teaching the subject to change their beliefs about sleep, develop good sleep habits, and improve their sleep environment.96

Cognitive behavioral therapy may involve sleep restriction and education on sleep hygiene. It also may involve biofeedback, which provides information via electrical sensors about certain biological functions, such as respiration, heart rate, and muscle contraction. This information allows a person to make subtle changes (such as in breathing rate or muscle relaxation) to try to control bodily functions to better manage conditions such as anxiety, pain, and insomnia. Stimulus control therapy focuses on removing factors that encourage people to resist sleep, such as an inconsistent bedtime or using the bedroom for activities other than sleep.96

Cognitive behavioral therapy has been shown to be an effective treatment for both primary and secondary insomnia.97-100 A recent randomized controlled trial that followed 36 people for six months suggests cognitive behavioral therapy improved insomnia severity scores, sleep measures, and dysfunctional sleep beliefs.101 A recent review concluded cognitive behavioral therapy may be more effective than benzodiazepine and non-benzodiazepine drugs for long-term treatment of insomnia.102 Other research suggests cognitive behavioral therapy decreases depression, improves mental health, and is more effective in treating insomnia than hypnotic sleep aids.103,104

Relaxation Therapy

Some patients with insomnia have high levels of cognitive and physiological arousal, as evidenced by increased cerebral metabolism of glucose. Relaxation therapies (including meditation, visualization techniques, breathing exercises, and progressive muscle relaxation) aim to achieve a more relaxed state prior to bedtime. Most of these techniques can be self-administered after some initial guidance from a medical professional.89

Social support, stress reduction techniques (including meditation and yoga), and improving coping mechanisms for dealing with stress may be useful ways to combat insomnia in some people.105 Research involving 30 adults with insomnia found that mindfulness-based stress reduction, including meditation training, resulted in significant improvements in sleep quality, including time to sleep and total sleep time.106 Another study of 44 postmenopausal women aged 50‒65 who were not undergoing hormone replacement therapy found practicing yoga for four months lowered insomnia and stress severity scores and increased quality of life.107

7 Treating Insomnia: Pharmacologic Treatment

There are many pharmacological treatment options for insomnia, including over-the-counter medications, benzodiazepines, non-benzodiazepines, and antidepressants.108 These medications are generally intended for occasional, intermittent use.

Over-the-Counter Medications

Over-the-counter (OTC) medications can be safely and effectively used to occasionally promote a good night’s sleep.109 One of the most common types of OTC sleep medications is antihistamines, such as doxylamine (Unisom) and diphenhydramine (Benadryl). Antihistamines block receptors that respond to histamine; this reduces congestion, sneezing, coughing, and allergy symptoms. Blockade of histamine receptors in the central nervous system causes sedation, and thus, antihistamines can be used as sleep aids. Side effects include daytime drowsiness, dry mouth, and constipation.

There are few rigorously designed trials to definitively determine the efficacy of OTC sleep aids.110 Diphenhydramine can remain in the body for long periods of time, resulting in sedation the following day. Note some people may develop a tolerance or dependence to these medications, and they may cause dangerous side effects when used with other medications. In addition, if taken for a long time and then stopped, they may worsen sleep problems.111

Special caution should be used when elderly people use OTC sleep aids. One review found 50‒65% of older adults misused OTC sleep medications. Drug-drug interactions and drug-age interactions were most common.112 In 2015, the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommended individuals over age 65 not use products containing the ingredients diphenhydramine and doxylamine.113

Speak with a physician prior to using a sleep aid to ensure it does not interact with any medications you currently take or conditions you have. Avoid alcohol; do not engage in activities that require being alert after taking the medication, such as driving a vehicle; and do not use any sleep medications for more than two weeks.109

Benzodiazepines

Benzodiazepines (eg, alprazolam [Xanax], clonazepam [Klonopin], and diazepam [Valium]) were the cornerstone for treatment of insomnia until the 1990s. These medications enhance effects of the neurotransmitter gamma-aminobutyric acid (GABA)—one of the main inhibitory neurotransmitters in the brain—by binding to multiple brain receptor sites.114 Studies found benzodiazepines enhance sleep onset, reduce the number of nighttime waking, and improve total sleep time and sleep quality with short-term use.108

Benzodiazepines can be classified based on their duration of action. Short-acting benzodiazepines are more likely to cause withdrawal symptoms, whereas long-acting ones are more likely to leave users feeling groggy.114 A recent longitudinal cohort study of over 200 nursing home residents in Belgium found long-term use of benzodiazepines actually decreased sleep quality over the course of one year, as compared to people who did not use these medications. This suggests chronic use of these drugs does not maintain a high sleep quality.115

Non-Benzodiazepines

Non-benzodiazepines, also called benzodiazepine-like drugs, such as zaleplon (Sonata), zolpidem, and eszopiclone, act on fewer brain receptors than benzodiazepines, and therefore are typically associated with fewer side effects.4 Zaleplon, one of the first non-benzodiazepines developed for the treatment of insomnia, has been proven effective in reducing the amount of time it takes to fall asleep. Its short half-life (1 hour) also reduces the risk of lasting effects the following morning, which may make it less useful for people who wake up during the night.116 Older adults should not take zaleplon because it is not as safe or effective as other medications available.108

Note while using zaleplon, some individuals experienced sleep disturbances such as getting out of bed and engaging in activities like driving cars, having sex, or consuming food while partially asleep. These people were typically unable to remember what happened the next day. Also, a person’s mental health may change unexpectedly while using this medication, including aggressiveness, hallucinations, memory problems, depression, confusion, and suicidal ideation. Zaleplon should only be taken under the direction and observation of a healthcare professional.116

Zolpidem's half-life (about 2.5 hours) may make it more effective at reducing the amount of time it takes to fall asleep and aid in staying asleep while reducing residual daytime sleepiness.108 A literature review found 10 mg of zolpidem in adults and 5 mg in those age 65 and over reduced sleep latency and increased sleep duration in people with insomnia. Residual daytime effects are not common, as long as the individual is in bed for at least eight hours before waking for the day.117 Zolpidem clears more slowly in women than men. Morning blood levels may be higher, which may affect psychomotor performance. In 2013, the Food and Drug Administration (FDA) required manufacturers to lower the recommended dosage from 10 mg to 5 mg for immediate-release preparations and from 12.5 mg to 6.5 mg for extended-release forms.108

Eszopiclone has also been shown to be effective at improving sleep.118,119 This medication lengthens total sleep time and helps people fall asleep more quickly. It takes longer to work than other non-benzodiazepines, but also lasts longer.4 The FDA recently lowered the recommended starting dosage of eszopiclone to 1 mg due to risk of next-day impairment to driving, memory, and concentration. A double-blind study involving 91 people between ages 25 and 40 demonstrated that 3 mg eszopiclone was associated with psychomotor and memory impairment 7.5‒11 hours after dosing. Dosages may be increased to 2‒3 mg under physician guidance, but 3 mg is associated with a state of altered mental awareness.120

Note recent research suggests hypnotic sleep aids may be associated with severe adverse events, including dependency/withdrawal, driving impairment, cognitive difficulties, and an increased risk of accidents or falls. There is also an association between use of hypnotic sleep aids and increased depression, infection, and mortality rates. These risks are most commonly observed in elderly individuals.121 Moreover, in 2012, a well-controlled study revealed an association between sleep aids, such as zolpidem, eszopiclone, and temazepam, and a more than three-fold increased risk of death.14 However, we should note those using hypnotic sleep aid drugs often have poor overall sleep quality, which could be the factor causing the sharply increased risk of death.

In a recent review, 43 of 46 epidemiological studies found that the use of hypnotics was associated with an excess mortality rate, and 45 of the studies found hypnotic use did not benefit patient survival.103 Results from two large cohort studies indicate benzodiazepine use is associated with an increase in all-cause mortality. Some researchers suggest the risks associated with hypnotic sleep aids outweigh any minimal benefit. In fact, in April 2019, the United States FDA announced that the agency was requiring boxed warnings on eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (e.g., Ambien). A boxed warning is the most prominent warning the agency requires. This move was based on safety monitoring studies that found these drugs are associated with increased risks of engaging in potentially dangerous behaviors while not fully awake, such as driving.122 These medications should be used under the direction and supervision of a physician only.

Antidepressants

Antidepressants may be useful in treating insomnia for some people. As many people with depression also struggle with insomnia, these medications may help relieve symptoms of both conditions. Research suggests antidepressants may reduce the amount of time it takes to fall asleep and help prevent nighttime awakenings. In addition, the sedating effects of these medications allow for the relaxation necessary to fall asleep more quickly. In general, antidepressants reduce REM sleep, but seem to have little impact on deeper sleep cycles.123

Many antidepressants, such as doxepin (Silenor) (a histamine receptor antagonist with tricyclic antidepressant properties), trazodone (Desyrel) (a serotonin antagonist and reuptake inhibitor), and amitriptyline (Elavil) (a tricyclic antidepressant), are used to treat insomnia because they have sedative properties.108 Doxepin has been found to increase sleep time without causing significant adverse effects.124,125 Research indicates at doses of 1‒3 mg, doxepin improved sleep onset, duration, and quality over a 12-week period.125,126 Higher doses (3‒6 mg) led to improvements in sleep maintenance and reduction of early morning wakings.126

Some data have shown trazodone, functioning as a mild hypnotic, may temporarily help people fall asleep.127 Trazodone, a serotonin modulator used to treat major depressive disorder, may cause daytime sedation. Few well-designed studies demonstrate its effectiveness in managing insomnia.128 In a randomized, double-blind, placebo-controlled study, 16 insomniacs were given 50 mg trazodone or placebo 30 minutes before bed. The study was designed with two groups of participants, each of which took either the drug or placebo for one week, followed by a one-week washout period, and then another week of placebo or drug—whatever the participants took the first week of the trial.

Trazodone reduced night-time waking and improved sleep quality, but also resulted in small but significant impairments in short-term memory, verbal learning, and arm muscle endurance.129 Researchers concluded that while efficacious in improving sleep, its risks may outweigh its benefits, particularly in those more susceptible to these side effects, including the elderly.108,129 In a randomized, double-blind, placebo-controlled trial involving 30 Alzheimer’s patients, individuals who took 50 mg trazodone once daily for two weeks slept 42.5 minutes more per night compared with placebo. Treatment did not affect daytime sleepiness or cognitive functioning.130

Amitriptyline, a sedating antidepressant that alters brain chemistry to stabilize mood, is sometimes used off label to treat insomnia. Note this medication has been shown to increase suicidal thoughts in individuals under age 24.131 There are no controlled trials evaluating amitriptyline for insomnia in the absence of other medical conditions.128

Mirtazapine (Remeron) is a tetracyclic antidepressant used to treat insomnia. A randomized, double-blind, placebo-controlled trial involving 19 men found 7.5 mg mirtazapine and 50 mg of the neuroleptic quetiapine (Seroquel) increased total sleep time and reduced night waking, although they also increased daytime sleepiness. More research is needed to determine the long-term effects of these medications.132

A recent review of published literature on antidepressants and sleep found the best results come from low dosages of these drugs administered early at night (prior to bedtime) as part of an intervention that also involves behavioral treatments, such as cognitive behavior therapy.133

Ask the Scientist: Insomnia and Risks Associated with Hypnotic Sleep Medications

Daniel F. Kripke, MD, is Professor Emeritus of Psychiatry at UC San Diego. He has spent decades studying sleep and the side effects of sleep medications.

  • Hi, Dr. Kripke. Thank you for taking time out of your day to share your thoughts with us. Would you start by telling us a little bit about your background and training?

I am a research psychiatrist who opened one of the country’s first sleep clinics to study the causes of depression. Insomnia and depression are often linked. They have common genetic predispositions, and depression seems to cause insomnia, and vice versa.

  • You’ve been studying the association between hypnotic sleep aids and adverse outcomes for quite a long time. Why were you drawn to this area of study?

American Cancer Society data from one million questionnaire participants showed that self-reported long sleep duration and short sleep duration predicted early death.134 Over 40 years ago, I noticed that their data showed that reported use of sleeping pills predicted early death more so than insomnia did. I have since been trying to clarify the risks of sleeping pills.

  • What are some of your most compelling findings related to the risks associated with hypnotic sleeping pills?

People who take hypnotics are at significantly greater risk of mortality than people who do not take them. Almost all of 46 studies from all over the world demonstrate this, but the amount of risk has varied greatly in the research due variations in study methodology.103 There is uncertainty surrounding how much of risk is caused by sleeping pills. Controlled clinical trials show that hypnotics can cause depression and are associated with increased risk of suicide. Also, hypnotics considerably increase the risk of infections, likely including an increased risk of potentially severe infections such as pneumonia. Finally, hypnotics impair automobile driving and may increase the risk of falls and other accidents.

  • One of the limitations with the research in this area is that much of it is correlational and not necessarily reflective of a causal link between sleeping pills and negative outcomes. Are there trials underway or planned that you think will overcome this uncertainty?

The data for depression and infection include randomized studies that establish causality. Some studies of autopsied deaths, especially those linked to opioids, list hypnotics as contributing or primary causes. Hypnotics are used to put animals to sleep (permanently) and for executing prisoners, so there is no question that, at excessive doses, these drugs can kill. The question is how often they are lethal in combination with risky behavior, health problems, and other medications. There are studies planned to clarify these uncertainties, but I cannot tell you that any definitive study has already begun.

  • You’ve expressed some frustration in some of your past published work that the FDA has not adequately responded to these concerns about hypnotics and adverse outcomes. Have you seen any evolution in the agency’s position recently? If not, what is keeping the FDA from taking action?

The FDA has been essentially unresponsive to the new research that demonstrates hypnotic risks. Moreover, the FDA has the authority to order manufacturers to do clinical trials of marketed drugs to establish the causality of newly recognized risks, but it has made no effort to do so. The FDA has its own animal testing facilities that could be used to help clarify the cancer risk associated with these drugs. In my opinion, the FDA position is an unscientific one.

  • Do you think hypnotic sleep aids actually work? What does the evidence say?

Recent studies sponsored by the government’s Agency for Healthcare Research and Quality (AHRQ) and by the NIH have found that there is weak evidence to suggest that hypnotic sleep aids make people sleep 10 or 20 minutes more per night. It is generally agreed that hypnotic sleep aids do not make people objectively more alert and productive the day after taking them at bedtime. In fact, much of the evidence suggests sleeping pills make people sleepier and reduce performance time the next day. Moreover, there is absolutely no evidence that sleeping pills improve general health.

  • Are there any newer sleep aids that you think are better options than hypnotics? If so, what are they and why would you prefer them over hypnotics?

The AHRQ report and the American College of Physicians guidelines conclude that no drug is as useful for insomnia as cognitive behavioral therapy. I think that when circadian rhythm disturbances or depression are associated with cases of insomnia, bright light treatments are superior to hypnotics. It would be nice to have more long-term studies comparing light versus hypnotics.

  • What can people who don’t want to take any form of sleeping medication do to get a better night’s sleep? Are there any particular habits that you suggest?

First of all, there are many reasons people want to sleep better, and they need different approaches. In the sleep clinic, we commonly see patients who think there is something wrong with their sleep when it really is not since their sleep pattern is normal. Part of this comes from drug-company-sponsored propaganda suggesting that everyone needs eight hours of sleep or more, which is not true in all cases. Family doctors, psychologists, and sleep specialists can advise what treatments to try first. There is useful information about cognitive behavioral therapy for the treatment of insomnia on the internet or at the library. The VA now offers its patients a free website that provides cognitive behavioral therapy, and there are several commercial websites that offer similar services for less than the cost of sleeping pills.

  • Do you find that people who suffer with insomnia typically make certain mistakes or engage in certain habits that contribute to their insomnia? If so, what are they, and how can they be avoided?

There are many causes of insomnia. One of the most common is spending more time in bed than is needed to sleep: spending less time in bed results in less insomnia. Another common problem is getting too little bright light exposure. People feel better and sleep better with at least an hour a day of outdoor daylight or its equivalent. Since exercise is also helpful, walking for thirty minutes to an hour a day in daylight is a simple and effective treatment. Avoiding too much caffeine and alcohol can promote healthy sleep patterns, as well as not using cell phones, tablets, and computer screens shortly before bedtime. The bright bluish light of modern display screens can be neutralized with software that decreases blue light or by wearing orange (blue-blocking) glasses for an hour or two before bedtime. An irregular sleep schedule may also contribute to insomnia. Staying up late on weekends may make it difficult to get to sleep early enough on Sunday night, which makes it hard to wake on time on Monday morning.

Your comments have been very interesting and insightful, Dr. Kripke. Thanks again for sharing your knowledge with us.

8 Novel and Emerging Treatments

Targeting Melatonin Receptors

Melatonin is a hormone involved in controlling the body’s sleep-wake cycle. Supplemental melatonin supports the body’s natural melatonin cycle. Melatonin activates two receptors, MT1 and MT2, in a region of the hypothalamus that controls circadian rhythms, and in some peripheral tissues. Supplemental melatonin modulates central nervous system activities via these MT1 and MT2 receptors.135 Drugs that target these receptors work similarly to melatonin, but may interact with the receptors in a slightly different fashion.

Targeting melatonin receptors may help modulate sleep rhythms. Note these therapeutics are not identical to supplemental melatonin. Rather, they are melatonin receptor agonists, meaning they mimic melatonin and bind to its receptor, activating it and inducing sleep.

Ramelteon (Rozerem) is an FDA-approved insomnia medication that binds to and activates melatonin receptors (MT1 and MT2).136 Ramelteon promotes sleep by regulating the sleep-wake cycle, not depressing the central nervous system.137 It is highly selective for the melatonin receptors MT1 and MT2, and has a half-life of just over one hour.120,138-140 Ramelteon can be used long-term, with no major safety issues noted. There is no evidence of dependence.137

In a study of adults aged 65 and older, this medication significantly reduced sleep latency over five weeks with no significant side effects.141 In another randomized, double-blind, placebo-controlled trial in adults aged 18‒64, subjects who received 8 or 16 mg of ramelteon had reductions in sleep latency and sleep onset.142

Tasimelteon (Hetlioz) is a high-affinity MT1-MT2 receptor agonist that regulates sleep and shifts circadian rhythms. It was originally developed to treat non-24-hour sleep-wake disorder, in which individuals cannot train the body clock to the 24-hour dark-light cycle. In one placebo-controlled clinical trial in healthy individuals, tasimelteon reduced sleep latency and increased sleep efficiency with no side effects.143

Animal research has demonstrated that the melatonin receptor MT2 promotes deep sleep.144,145 Drugs that specifically target the MT2 receptor are beginning to emerge, including IIK7 and UCM765. Animal research suggests these medications increase amount of deep sleep and reduce sleep latency in mice.144,145 However, further human research is needed to confirm safety, efficacy, and potency.146

Orexin Receptor Agonists

Suvorexant (Belsomra) is an FDA-approved medication that blocks the excitatory neuropeptides orexin A and orexin B, which promote wakefulness, from binding to their receptors. This helps to stabilize the sleep-wake cycle. Suvorexant suppresses waking after bedtime, improves sleep efficiency, increases total sleep time, and decreases sleep latency, although it may cause next-day drowsiness and impaired driving or cognitive funciton.137,147 Two randomized trials including 2,030 subjects demonstrated that 30‒40 mg suvorexant improved sleep maintenance, as compared with placebo.148 Another trial of 781 patients randomly assigned to receive 30 mg (elderly subjects) or 40 mg (nonelderly subjects) suvorexant or placebo indicated the drug was safe, tolerable, and helped enhance total sleep time.149 While preliminary research suggests this medication is safe and effective, long-term data are lacking.108

5-HT2 Receptor Antagonists

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter that plays a role in regulating sleep, appetite, thermoregulation, emotion, and cognition.150 It acts by binding to and activating various 5-HT receptors in the ventrolateral preoptic nucleus (VLPO), the main structure of neurons that trigger non-REM sleep.151,152 Impairments in 5-HT transmission have been linked to depression, anxiety, and sleep disorders. In one study, 5-HT deficient mice demonstrated a disrupted sleep-wake cycle with an increase in restless sleep (a period of sleep with frequent wakings).153

In animal research, sleep-promoting neurons in the VLPO can be characterized by their response to neurotransmitters such as noradrenaline and 5-HT. Those inhibited by 5-HT are known as Type 1 neurons, and those excited by 5-HT are known as Type 2. Type-2 neurons are involved in sleep initiation, and activating them activates Type-1 neurons. Type-1 are thought to be responsible for sleep maintenance, and their activation inhibits the brain’s arousal system.150

5-HT receptors 5-HT2A and 5-HT2C are of particular interest with regard to sleep. Activation of these receptors interferes with deep sleep.152 Therefore, some therapeutics attempted to reduce signaling through these receptors to facilitate high-quality sleep.154,155

While both animal and human data suggest blocking 5-HT2A/C signaling appears to be a promising mechanism for improving sleep quality, more research is needed.154,155

Propofol: Novel Use of an Anesthetic to Reset Sleep Rhythms

Propofol is a rapid, short-acting anesthetic often administered intravenously for the induction and maintenance of sedation during monitored anesthesia. While propofol is typically used for sedation for operations or medical procedures, some researchers have found that mild dosing regimens may help restore normal sleep rhythms.

Propofol induces a state of unconsciousness resembling non-REM sleep. Brain activity during anesthesia and sleep shares many similarities but also distinct differences.156 Interestingly, propofol sedation without surgery has been shown to alter diurnal melatonin secretion in animals, suggesting the drug can influence the body’s circadian clock system.157

In a randomized, placebo-controlled, double-blind clinical trial, subjects receiving a two-hour infusion of propofol for five consecutive nights showed improvement in sleep onset latency (ie, amount of time needed to fall asleep), quality of sleep, ease of waking up, and behavior after waking. These improvements persisted for six months, suggesting the benefits of propofol could continue after initial treatment. In addition, subjects showing no response to traditional agents, such as zopiclone (Imovane) or zolpidem, before study treatment were able to effectively use them on occasion after treatment, suggesting propofol restored the brain's response to conventional sleep aids.17 The study showed using propofol for a short period of time (at the same time each night) could help reset the body's natural circadian rhythm, providing long-term benefits for people with chronic refractory insomnia.

As of the time of this writing, no sleep centers that we are aware of are routinely offering propofol, which requires strict medical vigilance and adherence to safety protocols to avoid overdose. The novel use of propofol to reset sleep patterns, administered under carefully controlled clinical conditions, is an area of insomnia research that requires further study.

9 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.

Minerals

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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