The most common sleep disorder!

Affecting one in four people (Kessler 2011; Shatzmiller 2012; American Academy of Sleep Medicine 2001).

It is well-known that sleep problems can significantly diminish quality of life. However, many people may not realise that insomnia and short sleep duration correlate with various health problems including cardiovascular diseaseanxiety, and potentially cancer 

Despite the dramatic toll insomnia takes on individuals and populations, conventional treatment options remain far from ideal. In fact, in 2012, a well-controlled study revealed an association between popular hypnotic sleep aids, such as zolpidem (Ambien®), eszopiclone (Lunesta®), and temazepam (Restoril®), and a more than three-fold increased risk of death.

These alarming findings highlight the need for safe and effective strategies to improve sleep quality, especially since up to 10% of adults in the U.S. use hypnotic sleep aids (Kripke 2012). We should note, however, that those using hypnotic sleep aid drugs often have poor overall sleep quality, which could be the factor causing the sharply increased risk of death. 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 (Yang 2010; Lande 2010). You will also discover that some emerging therapies have achieved prolonged sleep quality improvements in studies, with potentially fewer side effects than some popular sleep drugs (Xu 2011). In addition, you will read about several natural compounds that can modulate the biology of sleep and may be safer than some pharmaceutical options.


Types of Insomnia

Transient Insomnia
Transient insomnia, lasting a few days to a week, can be triggered by many things (e.g., excess environmental noise, medications, and extreme temperatures). One type of transient insomnia is jet lag, in which travelling through time zones causes a temporary disruption of the body’s circadian rhythm (NHLBI 1995).

Acute Insomnia
Acute insomnia may last for several weeks. Common triggers include emotional stress or conflict, environmental changes, or anxiety associated with going to bed. Acute insomnia can also be triggered by the same things that trigger transient insomnia (American Academy of Sleep Medicine 2001; Ellis 2012).

Chronic Insomnia
Chronic insomnia, which may last for months or years, can have profound effects on health, quality of life, productivity, and safety (Roth 2003).


What Causes Insomnia?

In many cases, insomnia may be a consequence of another underlying medical problem.

Mental Health Issues

Insomnia is a symptom of many mental health problems, including anxietydepression and bipolar disorder (Morin 2006; Buysse 2005; Baroni 2012).

Not only can mental health disorders trigger insomnia, but insomnia can be a major risk factor for mental health issues. Data indicate that insomnia complaints are a major predictor for onset of depressive disorder within 1-35 years (Buysse 2005).

Insomnia is also linked to certain psychological personality traits, such as social introversion and repression of feelings (Singareddy 2012).

Psychophysiological insomnia (PPI). PPI, a type of chronic insomnia, is associated with excessive worrying specifically focused on not being able to sleep. It appears to be linked to hyper-arousal when going to bed (Sato 2010; Bonnet 1997; Bastien 2008). The hypothesis behind it is that afflicted individuals have a hard time relaxing and settling down when they go to sleep, resulting in “racing thoughts.” They then focus on their difficulty falling asleep, which results in anxiety that further disturbs sleep. Over time, poor sleep and worrying 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 PPI may have some dysfunctional neurological inhibitory mechanisms that would normally help the mind “dis-engage” from daytime thought patterns (Espie 2002), preventing them from falling asleep.

Physical Health Issues

Many conditions are associated with insomnia, including musculoskeletal problems, cardiovascular disease, gastrointestinal and urinary problems, neurological problems, respiratory problems, immunological problems, and cancer (Sivertsen 2009; Buysse 2005; Taylor 2007; Geyer 2008; Katz 1998; George 2000).

Hormonal Imbalances

Levels of sex hormones (i.e., estrogen, progesterone, and testosterone) may have a significant impact on sleep. This is especially true for women; the incidence of sleep disturbances in women rises to 40% three years after menopause (Woods 2005). Studies have found that hormone replacement therapy in menopausal women can significantly improve sleep (Silva 2011; Saletu-Zhylarz 2003).

The relationship between sleep and hormone levels occurs in men as well; lower levels of testosterone correlate with increased severity of obstructive sleep apnea (a particularly serious sleep disorder) (Hammoud 2011). People with trouble sleeping should have their hormone levels tested. It used to be thought that higher testosterone levels in men worsened sleep apnea, but more recent studies show it is low testosterone that is associated with sleep disturbance s in aging men (Barrett-Connor 2008; Canguven 2010).


Medication-induced insomnia can be caused by a wide variety of drugs, including decongestants, monoamine oxidase inhibitors (MAOIs), selective-serotonin reuptake inhibitors (SSRIs), corticosteroids, chemotherapeutic agents, calcium channel blockers, beta-agonists, and theophylline (Neikrug 2010; Moghadam-Kia 2010; Nerbass 2011; Bercovitch 2012).


Stimulants (e.g., caffeine and nicotine) contribute to insomnia by making it harder for the brain to achieve the state of relaxation needed for sleep. The half-life (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 caffeine’s effects to last even longer (Roehrs 2008). As a result, caffeine consumption can impair sleep for many hours. Although, some studies have found that mild caffeine consumption in the morning does not impair sleep (Youngberg 2011).

Nicotine use and nicotine withdrawal can contribute to insomnia (Jaehne 2009). Even those undergoing nicotine replacement therapy (to quit smoking) experience the adverse effects of nicotine on sleep (Mills 2010).

While most people think of alcohol as a sedative, it increases dopamine release within the brain, which has a stimulating effect (Hendler 2013). Chronic alcohol use is associated with insomnia, as is alcohol withdrawal (Brower 2008).


Shift work sleep disorder. Shift work sleep disorder is a type of insomnia in which non-standard work schedules (such as rotating shifts, on-call work, or permanent night shifts) trigger a disconnect between the body’s circadian rhythm and time (Kolla 2011).


Non-pharmacological Therapies

Improving Sleep Hygiene

One of the most widely used behavioral therapies is improving “sleep hygiene.” There is a correlation between good sleep hygiene and reduced daytime sleepiness (Mastin 2006; Yang 2010). Sleep hygiene encompasses a number of behaviors and environmental factors that contribute to good quality sleep (Yang 2010; Lande 2010). Consider the following sleep hygiene measures:

  • Minimize the amount of light, noise and changes in temperature in the bedroom.
  • Avoid eating large meals before bed. Indigestion can make falling asleep difficult.
  • Limit the amount of stimulants (e.g., caffeine, nicotine, and alcohol) consumed during the day, especially close to bedtime.
  • Avoid vigorous exercise during the two hours prior to sleep.
  • Avoid bedtime activities not related to sleep (e.g., watching TV, reading, or listening to the radio).
  • If worrying about falling asleep and the time, cover the alarm clock to avoid anxiety.

Sleep Restriction to Reset Circadian Rhythms

Sleep restriction therapy limits the amount of time spent in bed (including naps) to increase the biological need for sleep at night. A study comparing sleep hygiene therapy plus sleep restriction to sleep hygiene therapy alone found that sleep restriction improved “sleep efficiency,” a measure of the proportion of time spent in bed that resulted in sleep (Hoch 2001; McCurry 2007). This process usually begins by restricting the time spent in bed to the amount of time estimated 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. However, the sleepiness it creates trains the body to fall asleep more quickly. As the body adjusts, people can extend the amount of 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 (McCurry 2007).

Cognitive-behavioral therapy

Cognitive-behavioral therapy (CBT) for treatment of chronic insomnia helps people develop behaviors that are more conducive to sleep. It has been shown to be an effective treatment for both “primary insomnia” (insomnia not due to other diseases) (Edinger 2001; Smith 2003) and insomnia caused by other medical problems (Savard 2005; Smith 2005). Notably, CBT for treatment of chronic primary insomnia may be more effective than the medication zopiclone in older adults (Sivertsen 2006).

General Lifestyle Considerations

General lifestyle considerations that may benefit people with insomnia include (Lande 2010):

  • Getting regular exercise
  • Developing a sleep ritual aimed at improving relaxation and resolving emotional dilemmas before going to bed. Resolving stress may help improve sleep quality. People with insomnia should also review the Stress Management protocol.


Conventional Pharmacological Treatment

Over-the-counter medication

One of the most common types of OTC sleep medications are antihistamines, such as doxylamine (Unisom®) and diphenhydramine (Benadryl®). Antihistamines block the receptors that respond to histamine; this reduces congestion, sneezing, coughing, and allergy symptoms. Centrally, blockade of histamine receptors causes sedation; thus antihistamines can be used as sleep aids.

Despite the widespread use of these OTC drugs, there are significant concerns regarding their efficacy and safety. Although some studies have found that these OTC drugs can improve sleep, there are few well designed trials to definitively determine their efficacy (Randall 2008). Diphenhydramine can remain in the body for long periods of time, resulting in sedation the following day. In addition, the human body can build up a tolerance to the effects of antihistamines. Evidence appears to suggest that antihistamines may be useful for insomnia for short periods of time, but not efficacious in treating chronic insomnia (Randall 2008).


Benzodiazepines (e.g., alprazolam [Xanax®], clonazepam [Klonipin®], and diazepam [Valium®]) were the cornerstone for the treatment of insomnia until the 1990s. These medications enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA), which is one of the main inhibitory neurotransmitters in the brain (Lieberman 2007). Studies have found that benzodiazepines are able to reduce the amount of time users need to fall asleep (Buscemi 2007; Holbrook 2000).

Benzodiazepines can be classified based on their duration of action. Short-acting benzodiazepines are more likely to cause withdrawal symptoms, whereas long-acting are more likely to leave users feeling groggy and produce a “hangover” feeling (Lieberman 2007), as well as paradoxical rebound anxiety.


Non-benzodiazepines, also called benzodiazepine-like drugs, such as zaleplon (Sonata®), zolpidem (Ambien®), and eszopiclone (Lunesta®), are the next generation of sleep aids (Lieberman 2007). Zaleplon, one of the first non-benzodiazepines developed for the treatment of insomnia, has been proven to be effective in reducing the amount of time it takes to fall asleep (Ancoli-Israel 1999; Cluydts 2002). Its short half-life (1 hour) also reduces the risk of lasting effects the following morning. However, this may make it less useful for people who wake up during the night (Ancoli-Israel 1999). 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 stay asleep. In order to improve zolpidem’s effectiveness for maintaining sleep, “modified release” and “extended release” formulations have been designed. Studies have found that modified release forms are very effective at improving sleep, with over 92% of individuals reporting that zolpidem helped them sleep when taken three to seven nights per week; also, that it may not affect performance the next day (Hindmarch 2006; Krystal 2008). Eszopiclone has also been shown to be effective at improving sleep (Roth 2005; Ancoli-Israel 2010).

There are some significant risks associated with taking these drugs. For example, zolpidem can cause sleep-walking, sleep-driving, and eating while sleeping (Hoque 2009). In addition, sedative hypnotics increase the risk of depression, and long-term effects on the brain are not known (Kripke 2007). Moreover, in 2012, a well-controlled study revealed an association between popular hypnotic sleep aids, such as zolpidem (Ambien®), eszopiclone (Lunesta®), and temazepam (Restoril®), and more than three-fold increased risk of death (Kripke 2012). We should note, however, that those using hypnotic sleep aid drugs often have poor overall sleep quality, which could be the factor causing the sharply increased risk of death. Hypnotic sleep aids are by no means a cure for chronic insomnia, despite ads run on national TV claiming miraculous sleep improvement.


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 (Weber 2010; Aurón Zaltzman 1976; Galecki 2010). Doxepin has been found to increase sleep time without causing significant adverse effects (Roth 2007; Krystal 2010). Some data have shown that trazodone, functioning as a mild hypnotic, may temporarily help people fall asleep (Walsh 1998). However, there are few well-designed studies that demonstrate its effectiveness. Trazodone can cause significant side effects such as dizziness as well as slowed thinking and movement the next day. Therefore, its risks may outweigh its benefits, particularly in those more susceptible to these side effects (e.g., the elderly) (Mendelson 2005). Although amitriptyline is commonly prescribed by physicians as a sleep aid, data regarding its effectiveness for the treatment of primary insomnia is limited (Schweitzer 2010).

Targeting Melatonin Receptors

Ramelteon (Rozerem®) is an insomnia medication that binds to and activates receptors (MT1 and MT2) for melatonin (Miyamoto 2009). It has a higher affinity for the receptors than melatonin itself and a half-life of just over one hour (Turek 2004; Kato 2005; Sateia 2008). Studies have found that ramelteon is effective at reducing the amount of time it takes to fall asleep and increasing the amount of time people stay asleep (Sateia 2008; Erman 2006; Borja 2006; Zammit 2007). Few side effects have been demonstrated in humans. Studies also indicate a low potential for abuse (Sateia 2008).

Selective MT2 Drugs

The particular melatonin receptor MT2 has been shown in animal studies to be important for promoting deep sleep (Ochoa-Sanchez 2011; Spadoni 2011). Drugs that specifically target the MT2 receptor are beginning to emerge. Two of these novel medications, IIK7 and UCM765, have increased the amount of deep sleep in mice (Ochoa-Sanchez 2011; Spadoni 2011). However, human research needs to be done to confirm safety, efficacy, and potency.

5-HT2 Receptor Antagonists

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter with diverse roles during sleep and wakefulness. It exerts activities by binding to and activating various 5-HT receptors whose biological roles depend on tissue distribution (e.g., central vs. peripheral), structural variations, interaction with other compounds (e.g., melatonin), and the environment (e.g., light/dark cycle) (Nonogaki 2012; Landolt 2009).

With regard to sleep, two 5-HT receptors are of particular interest: 5-HT2A and 5-HT2C. Activation of these receptors interferes with deep sleep (Landolt 2009). Therefore, some emerging therapeutics attempt to reduce signaling through these receptors to facilitate high-quality sleep (Xiong 2010; Al-Shamma 2010).

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 (Al-Shamma 2010; Xiong 2010).

Novel Use of an Anesthetic to Reset Sleep Rhythms

Propofol is a rapid, short acting anesthetic that is often administered intravenously for the induction and maintenance of anesthesia.

Electroencephalography (or EEG, a technique that measures the brain’s electrical activity) confirms that there are distinct differences between sleep and sedation. Anesthetic agents (e.g., propofol) can induce activity in areas of the brain important for regulating sleep, particularly in people with insomnia (Xu 2011).

Clinical trial subjects receiving a two-hour infusion of propofol for five consecutive nights showed improvement in sleep onset latency (i.e., amount of time needed to fall asleep), quality of sleep, ease of waking up, and behavior after awakening. These improvements persisted for six months, suggesting that the benefits of propofol could continue long after the initial treatment. In addition, the subjects showing no response to traditional agents such as zopiclone or zolpidem before study treatment were able to effectively use them on occasion after treatment, suggesting that propofol restored the brain’s response to conventional sleep aids (Xu 2011). The study showed that 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.

Life Extension is funding a propofol sleep study, but there are no sleep centers currently offering propofol, which requires strict medical vigilance and adherence to safety protocols to avoid dying of a propofol overdose as Michael Jackson did. The therapeutic use of propofol, administered under carefully controlled clinical conditions, is separate and distinct from the irresponsible use of propofol by incompetent healthcare personnel without adequate cardiopulmonary monitoring.