Insomnia

INSOMNIA

Synopsis:
Background
Causes/Risk Factors
Non-Pharmaceutical & Nutritional Approaches 
Suggested Supplementation
References

Insomnia is 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 realize that insomnia and short sleep duration correlate with various health problems including cardiovascular disease, anxiety, and potentially cancer (Terauchi 2012; Ohayon 1998; Kakizaki 2008; Verkasalo 2005; Philips 2007). Insomnia also increases mortality in adults (Chien 2010; Hublin 2011).

Conventional treatment remain far from ideal. In fact, in 2012, a well-controlled study revealed an association between popular hypnotic sleep drugs, such as zolpidem (Ambien®), eszopiclone (Lunesta®), and temazepam (Restoril®), and a more than three-fold increased risk of death (Kripke 2012).

These alarming findings highlight the need for safe and effective strategies to improve sleep quality. We should note that those using hypnotic sleep aid drugs often have poor overall sleep quality, which could be causing the sharply increased risk of death. Hypnotic sleep aids drugs 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

(a) 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 traveling through time zones causes a temporary disruption of the body's circadian rhythm (NHLBI 1995).

(b) Acute Insomnia

• May last for several weeks. Common triggers include emotional stress or conflict, environmental changes, or anxiety associated with going to bed.

(c) Chronic Insomnia

• May last for months or years.

 

Insomnia Increases Disease Risk and Exacerbates Existing Conditions

Insomnia can lead to elevated levels of cortisol, epinephrine and other "stress" hormones (Bonnet 2010; Zhang 2011). Elevated levels of cortisol can cause weight gain, weaken the immune system, and increase risk of developing diabetes and osteoporosis (Chiodini 2008; Butcher 2005; Duong 2012).

In addition, insomnia triggers the release of chemicals (e.g., interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF–α]) that promote inflammation, which is associated with arthritis, inflammatory bowel disease, heart disease, and other conditions (Irwin 2006).

Insomnia can exacerbate chronic pain conditions by causing heightened sensitivity to pain and interfering with the body's ability to modulate central pain signals (Smith 2009). As a result, poor sleep can increase the amount of pain perceived by people with chronic pain disorders (e.g., osteoarthritis and fibromyalgia). Therefore, treating insomnia may help reduce pain in individuals with chronic pain disorders.

 A study reported that among healthy individuals, average sleep duration of six hours or less per night was associated with a four-fold increased risk of stroke compared to sleep duration of 7 – 8 hours (UAB News 2012).

 

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

(a) Mental Health Issues

Insomnia is a symptom of many mental health problems, including anxiety, depression 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.  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.

(b) 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).

(c) 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).

(d) Medications

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).

(e) Stimulants

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 (Roehrs 2008). As a result, caffeine consumption can impair sleep for many hours.

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).

(f) Lifestyle

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).

(g) Obstructive Sleep Apnea – A Hidden Epidemic with Deadly Consequences

Obstructive sleep apnea is a common and potentially lethal sleep disorder. It results from the upper airway collapsing during sleep, reducing oxygen flow. The resulting low oxygen in the bloodstream arouses the individual, resulting in disrupted sleep. 2 – 7% of adults have obstructive sleep apnea, causing poor sleep quality, snoring, and intractable fatigue (Punjabi 2008; Drager 2011).

This often overlooked sleep disorder represents a major risk factor for cardiovascular disease. Data indicate obstructive sleep apnea is associated with a 68% increase in coronary heart disease in men (Gottlieb 2010). Obstructive sleep apnea may also be associated with increased cholesterol, hypertension (Drager 2011; Pedrosa 2011), type 2 diabetes (Aronsohn 2010), cancer mortality (Nieto 2012), stroke and death (Yaggi 2005).

(a) Improving Sleep Hygiene

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.

(b) 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. 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).

(c) Cognitive-behavioral therapy

Cognitive-behavioral therapy (CBT) for treatment of chronic insomnia helps people develop behaviors that are more conducive to sleep.

(d) 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.

 

Targeted Natural Interventions

(a) Amino Acids and Hormones

Melatonin

Melatonin, a hormone made in the pineal gland, is highly correlated with the body's sleep-wake cycle. In humans, elevated melatonin levels coincide with the body's normal time for sleeping. 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 to age-matched normal controls (Cardinali 2012).

Several studies have found that melatonin supplementation is able to improve sleep. One study found melatonin helped reduce the amount of time needed to fall asleep (Geijlswijk 2010). Other studies have found it improves sleep quality and alertness after sleep (Lemoine 2012), as well as reduces the number of times subjects wake up during the night (Garfinkel 2011). Despite these successful studies, melatonin is not always an effective solution for those with severe chronic insomnia.

 

L-Tryptophan

L-tryptophan is an amino acid that serves as a precursor for serotonin and melatonin (Richard 2009; Peuhkuri 2012). L-tryptophan supplements may increase the amount of melatonin made by the pineal gland, thus facilitating sleep (Paredes 2009a). Early studies found 1 gram of L-tryptophan could reduce the amount of time needed to fall asleep (Hartmann 1974). Like melatonin, L-tryptophan levels decrease with age (Paredes 2009a). Therefore, L-tryptophan supplementation may aid in the treatment of elderly insomnia.

Animal studies have found that tryptophan supplementation reduced activity at night and lead to other biological changes that are conducive to sleep, such as a lower core body temperature and reduced levels of interleukin-6 (an inflammatory cytokine) (Paredes 2009b). 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 during the day or night (Hajak 1991). In addition, L-tryptophan may help alleviate some forms of depression, which can exacerbate insomnia (Silber 2010).

 

(b) Minerals

Magnesium

Magnesium is a mineral that plays a role in cellular communication and regulation of circadian rhythms (Durlach 2002). As sleep restriction increases, intracellular magnesium concentrations decline (Omiya 2009). Magnesium supplementation combined with melatonin and zinc has been shown to improve sleep in the elderly (Rondanelli 2011). Another trial found that magnesium supplementation helped relieve insomnia related to restless legs in subjects mean age 57 years (Hornyak 1998). A form of magnesium known as magnesium threonate may be beneficial for sleep since it has been shown to penetrate the blood-brain barrier more efficiently than other forms of magnesium (Abumaria 2011; Slutsky 2010).

Zinc

Zinc may also play a role in facilitating sleep (Rondanelli 2011). Research found that women with the highest levels of zinc in their bodies slept for longer periods of time than women with the lowest levels (Song 2012). As mentioned above, when combined with melatonin and magnesium, zinc also supported quality of sleep in the elderly (Rondanelli 2011). Among children with attention-deficit/hyperactivity disorder, zinc (in combination with magnesium and omega-3 & omega-6 fatty acids) helped relieve problems falling asleep (Huss 2010).

 

(c) Herbal Support

Valerian

Valerian is a sedative herb that has been used since the 18th century for the treatment of insomnia (Fernandez-San-Martin 2010). The putative mechanism of valerian root is interaction with the GABA system in the brain, thus helping reduce brain activity and allowing users to fall asleep more easily. Valerian affects the transport and liberation of GABA, modulating GABAergic signaling. Valerian also improves quality of sleep; one study demonstrated that valerian increases the percentage of time participants spend in slow-wave sleep. This is significant because slow-wave sleep is considered the most refreshing sleep (Alt Med Review 2004). One study compared the effects of 600 mg of valerian to the commonly prescribed tranquilizer oxazepam. During 6 weeks of treatment, valerian showed comparable efficacy to 10 mg of oxazepam (Ziegler 2002). Evidence also suggests that the side effect profile of valerian is superior to commonly prescribed sleep aids. In one small study, subjects taking valerian reported none of the mood-altering or negative cognitive effects demonstrated by diazepam (Gutierrez 2004). The typical dose of valerian is about 300 to 600 mg, 30 to 120 minutes before going to bed sleep (Fernandez-San-Martin 2010). It may take up to two weeks of daily usage for the full sedative effect of valerian to manifest (Anderson 2010).

Chamomile

Chamomile is a popular herb often used as a tea to promote sleep and relaxation (Sanchez-Ortuno 2009; Zick 2011). It was noted in a study on rats that chamomile had a mild hypnotic effect (much like benzodiazepines) and improved sleep onset latency (Shinomiya 2005), though it is not clear how it has this effect. One clinical trial found that chamomile improved daytime functioning of humans with sleep problems (Zick 2011). More research needs to be done to determine the benefits and drawbacks of using chamomile for sleep.

Passionflower (Passiflora incarnata)

Passiflora incarnate (P. incarnata), a member of the passiflower genus Passiflora, is best known for its sedative and anxiety-reducing effects (Dhawan 2004). The active compounds in P. incarnata appear to interact with the GABA and opioid systems (Nassiri-Asl 2007; Dhawan 2002; Appel 2011). In an animal model, P. incarnata was shown to reduce anxious behavior (Dhawan 2002). Additionally, another animal model found that passionflower-derived compounds were able to prevent diazepam dependence in mice when given along with the drug over a three week period (Dhawan 2003). More human studies are needed to evaluate the effectiveness and safety of passiflora products.

Ashwagandha

Withania somnifera, also known as Ashwagandha, is an Indian herb that may be beneficial for treating insomnia. This herb has been best characterized for its effects on stress, as several animal studies have found that it is able to improve the ability to handle stress and can significantly reduce anxiety (Archana 1999; Bhattacharya 2000; Kumar 2007). Because emotional stress can be a significant contributor to insomnia, using ashwagandha to reduce stress may help improve sleep. This herb has also been found to directly improve sleep in animal models; it appears to do so by increasing GABAergic activity (Kumar 2008).

Lemon Balm

Lemon balm is an herb traditionally used for its calming and anxiety-reducing effects (Raines 2009; Weeks 2009). One double-blind, placebo-controlled, randomized study showed that 600 mg of lemon balm improved mood and significantly increased self-ratings of calmness (Kennedy 2004). Lemon Balm has also been investigated in the treatment of sleep problems. A study found that a combination of valerian and lemon balm was able to treat sleeping disorders in children. About 81% of them experienced improvement of their symptoms after taking the study preparation (Muller 2006).

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. Studies have found that lavender oil improves sleep quality (Chien 2012; Lewith 2005) and reduces feelings of drowsiness after awakening (Hirokawa 2012).

 

(d) Others 

Bioactive milk peptides

Select peptides, made by breaking down milk proteins with enzymes, may relieve stress related sleep disorders (Kim 2007). These bioactive peptides were able to increase the amount of time spent sleeping and reduce the amount of sleep needed after just two weeks of treatment (Saint-Hilaire 2009). Lactium, one of the trade names for this uniquely formulated product, is sometimes combined with melatonin to improve sleep by taking advantage of the sleep promoting effects of both bioactive milk peptides and melatonin.

Amino Acids and Hormones

• Melatonin: 0.3 – 5 mg before bed (sometimes up to 10 mg)
• L-Tryptophan: 500 – 1500 mg daily or as recommended by a healthcare practitioner

Vitamins and Minerals

• Magnesium: 140 mg daily as magnesium-L-threonate; 320 mg daily as magnesium citrate
• Zinc: 30 – 90 mg daily

Herbal Support

• Valerian: 300 – 600 mg, 30 – 120 minutes before bed
• Ashwagandha Extract: 200 mg daily
• Lemon Balm: 300 – 600 mg daily
• Chamomile tea : Per label instructions
• Passiflora (Passion Flower): Per label instructions
• Lavender Oil (as aromatherapy): Per label instructions

Other Natural Therapies

• Bioactive Milk Peptides: 150 mg daily

[No authors listed]. Monograph. Valeriana officinalis. Altern Med Rev. 2004 Dec;9(4):438-41.

Abumaria N, Yin B, Zhang L, et al. Effects of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala. J Neurosci. 2011 Oct 19;31(42):14871-81.

Al-Shamma HA, Anderson C et al. Nelotanserin, a Novel Selective 5-Hydroxytryptamine2A Inverse Antagonist for the Treatment of Insomnia. The Journal of Pharmacology and Experimental Therapeutics, 2010; 332(1): 281-90.

American Academy of Sleep Medicine. The International Classification of Sleep Disorders, Revised. 2001.

Ancoli-Israel S, Krystal AD et al. A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Effect of Eszopiclone 2 mg on Sleep/Wake Function in Older Adults with Primary and Comorbid Insomnia. Sleep, 2010; 33(2): 225-234.

Ancoli-Israel S, Walsh JK et al. Zaleplon, A Novel Nonbenzodiazpeine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. Primary Care Companion, 1999; 1(4): 114-120.

Anderson GD, Elmer GW et al. Pharmacokinetics of Valerenic Acid After Single and Multiple Doses of Valerian in Older Women. Phytotherapy Research, 2010; 24: 1142-6.

Appel K, Rose T, Fiebich B, et al. Modulation of the γ-aminobutyric acid (GABA) system by Passifloraincarnata L. Phytother Res. 2011 Jun;25(6):838-43. doi: 10.1002/ptr.3352.

Archana R and Namasivayam A. Antistressor Effect of Withania somnifera. Journal of Ethnopharmacology, 1999; 64; 91-93.

Aronsohn RS, Whitmore H et al. Impact of Untreated Obstructive Sleep Apnea on Glucose control in Type 2 Diabetes. American Journal of Respiratory Critical Care, 2010; 181; 507-513.

Aurón Zaltzman D. [Amitriptyline hydrochloride in the treatment of anxiety and insomnia and as a tranquilizer]. NeurolNeurocirPsiquiatr. 1976;17(3):165-9.

Baroni A, Hernandez M, Grant MC, Faedda GL. Sleep Disturbances in Pediatric Bipolar Disorder: A Comparison between Bipolar I and BipolarNOS. Front Psychiatry. 2012;3:22. Epub 2012 Mar 20.

Barrett-Connor E, Dam TT, Stone K, et al. The association of testosterone levels with overall sleep quality, sleep architecture, and sleep-disordered breathing. J ClinEndocrinolMetab. 2008 Jul;93(7):2602-9.

Bastien CH, St-Jean G, et al. Chronic Psychophysiological Insomnia: Hyperarousal and/or Inhibition Deficits? An ERPs Investigation. Sleep, 2008; 31(6): 887-98.

Bercovitch RS and Tsai SC. Respiratory Medications and Sleep. Current Respiratory Care Report, 2012: 123-30.

Bhattacharya SK, Bhattacharya A et al. Anxiolytic/Antidepressant Activity of WithaniaSomniferaGlycowithanolides: an Experimental Study. Phytomedicine, 2000; 7(6): 463-9.

Bonnet MH and Arand DL. Hyperarousal and Insomnia: State of the Science. Sleep Medicine Reviews, 2010;14:9-15.

Borja NL and Daniel KL. Ramelteon for the Treatment of Insomnia. Clinical Therapeutics, 2006; 28(10): 1540-55.

Brower KJ, Myra Kim H, Strobbe S, et al. A randomized double-blind pilot trial of gabapentin versus placebo to treat alcohol dependence and comorbid insomnia. oholClinExp Res. 2008 Aug;32(8):1429-38.

Buscemi N, Vandermeer B et al. The Efficacy and Safety of Drug Treatments for Chronic Insomnia in Adults: A Meta-Analysis of RCTS. Journal of General Internal Medicine, 2007; 22: 1335-50.

Butcher SK, Killampalli V, Lascelles D, et al. Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity. Aging Cell. 2005 Dec;4(6):319-24.

Buysse DJ, Germain A et al. Diagnosis, Epidemiology and Consequences of Insomnia. Primary Psychiatry, 2005; 12(8): 37-44.

Canguven O, Salepci B, Albayrak S, et al. Is there a correlation between testosterone levels and the severity of the disease in male patients with obstructive sleep apnea? Arch ItalUrolAndrol. 2010 Dec;82(4):143-7.

Cardinali DP, Srinivasan V et al. Melatonin and its Analogs in Insomnia and Depression. Journal of Pineal Research, 2012; 52: 365-75.

Chien KL, Chen PC, Hsu HC, et al. Habitual sleep duration and insomnia and the risk of cardiovascular events and all-cause death: report from a community-based cohort. Sleep. 2010 Feb;33(2):177-84.

Chien LW, Cheng SL et al. The Effect of Lavendar Aromatherapy on Autonomic Nervous System in Midlife Women with Insomnia. Evidence Based Complementary and Alternative Medicine, 2012: 1-8.

Chiodini I, Scillitani A. [Role of cortisol hypersecretion in the pathogenesis of osteoporosis]. RecentiProg Med. 2008 Jun;99(6):309-13.

Cluydts R. A Breakthrough in the Pharmacological Management of Insomnia: Overview of the Clinical Profile of Zaleplon. Primary Care Companion, 2002; 4: 46-8.

Dhawan K, Dhawan S et al. Passiflora: A Review Update. Journal of Ethnopharmacology, 2004; 94: 1-23.

Dhawan K, Kumar S et al. Comparative Anxiolytic Activity Profile of Various Preparations of Passiflora incarnate Linneaus: A Comment on Medicinal Plants' Standardization. The Journal of Complementary and Alternative Medicine, 2002; 8(3): 283-91.

Dhawan K, Dhawan S, and Chhabra S. Attenuation of benzodiazepine dependence in mice by a tri-substituted benzoflavone moiety of PassifloraincarnataLinneaus: a non-habit forming anxiolytic. J Pharm Pharm Sci. 2003 May-Aug;6(2):215-22.

Drager LF, PolotskyVY et al. Obstructive Sleep Apnea: An Emerging Risk Factor for Atherosclerosis. Chest, 2011; 140: 534-42.

Duong M, Cohen JI, and Convit A. h cortisol levels are associated with low quality food choice in type 2 diabetes. Endocrine. 2012 Feb;41(1):76-81.

Durlach J, Pagès N, Bac P, et al. Biorhythms and possible central regulation of magnesium status, phototherapy, darkness therapy and chronopathological forms of magnesium depletion. Magnes Res. 2002 Mar;15(1-2):49-66.

Ellis JG, Gehrman P, Espie CA, et al. Acute insomnia: current conceptualizations and future directions. Sleep Med Rev. 2012 Feb;16(1):5-14.

Erman M, Seiden D et al. An Efficacy, Safety and Dose-Response Study of Ramelteon in Patients with Chronic Primary Insomnia. Sleep Medicine, 2006; 7: 17-24.

Espie CA. Insomnia: Conceptual Issues in the Development, Persistence and Treatment of Sleep Disorder in Adults. Annual Reviews in Psychology, 2002; 53: 215-43.

Fernandez-San-Martin MI, Masa-Font R et al. Effectiveness of Valerian on Insomnia: A Meta-Analysis of Randomized Control Trials. Sleep Medicine, 2010; 11: 505-11.

Galecki P, ski A, Talarowska M. et al. [Efficacy of trazodone in the treatment of insomnia]. Pol MerkurLekarski. 2010 Jun;28(168):509-12.

Garfinkel D, Zorin M et al. Efficacy and Safety of Prolonged-Release Melatonin in Insomnia Patients with Diabetes: A Randomized, Double-Blind, Crossover Study. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 2011; 4: 307-13.

Geijlswijk IM, Heijden KB et al. Dose Finding of Melatonin for Chronic Idiopathic Childhood Onset Insomnia: a RCT. Psychopharmacology, 2010; 212: 379-91.

George CF. Perspectives on the management of insomnia in patients with chronic respiratory disorders. Sleep. 2000 Feb 1;23 Suppl1:S31-5; discussion S36-8.

Geyer JD, Ruiter ME et al. Management of Insomnia in Patients with Chronic Obstructive Pulmonary Disease. Sleep Medicine Clinics, 2008: 379-87.

Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart healthy study. Circulation. 2010;122(4):352-60.

Gutierrez S, Ang-Lee MK, Walker DJ, et al. Assessing subjective and psychomotor effects of the herbal medication valerian in healthy volunteers. PharmacolBiochemBehav. 2004 May;78(1):57-64.

Hajak G, Huether G, Blanke J, et al. The influence of intravenous L-tryptophan on plasma melatonin and sleep in men. Pharmacopsychiatry. 1991 Jan;24(1):17-20.

Hammoud AO, Walker JM et al. Sleep Apnea, Reproductive Hormones and Quality of Sexual Life in Severely Obese Men. Obesity, 2011; 19(6): 1118-1123.

Hartmann E, Cravens J et al. Hypnotic Effects of L-Tryptophan. Archives of General Psychiatry, 1974; 31: 394-7.

Hendler RA, Ramchandani VA, Gilman J, et al. Stimulant and Sedative Effects of Alcohol. Curr Top BehavNeurosci. 2013; 13: 489-509. doi: 10.1007/7854_2011_135.

Hindmarch I, Legangeneux E et al. A Double-Blind, Placebo-Controlled Investigation of the Residual Psychomotor and Cognitive Effects of Zolpidem-MR in Healthy Elderly Volunteers. British Journal of Pharmacology, 2006; 62(5): 538-45.

Hirokawa K, Nishimoto T et al. Effects of Lavender Aroma on Sleep Quality in Healthy Japanese Students. Perceptual and Motor Skills, 2012; 114(1): 111-122.

Hoch CC, Reynolds CF et al. Protecting Sleep Quality in Later Life: A Pilot Study of Bed Restriction and Sleep Hygiene. Journal of Gerontology, 2001; 56 (1): P52-9.

Holbrook AM, Crowther R et al. Meta-analysis of Benzodiazepine Use in the Treatment of Insomnia. Canadian Medical Association Journal, 2000; 162(2): 225-33.

Hoque R and Chesson AL. Zolpidem-Induced Sleepwalking, Sleep Related Eating Disorder and Sleep-Driving. Fluorine-18 Positron Emission Tomography Analysis, and a Literature Review of Other Unexpected Clinical Effects of Zolpidem. Journal of Clinical Sleep Medicine, 2009; 5(5): 471-6.

Hornyak M, Voderholzer U, Hohagen F, et al. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep. 1998 Aug 1;21(5):501-5.

Hublin C, Partinen M, Koskenvuo M, et al. Heritability and mortality risk of insomnia-related symptoms: a genetic epidemiologic study in a population-based twin cohort. Sleep. 2011 Jul 1;34(7):957-64.

Huss M, Volp A, and Stauss-Grabo M. upplementation of polyunsaturated fatty acids, magnesium and zinc in children seeking medical advice for attention-deficit/hyperactivity problems - an observational cohort study. Lipids Health Dis. 2010 Sep 24;9:105.

Irwin MR, Wang M et al. Sleep Deprivation and Activation of Morning Levels of Cellular and Genomic Markers of Inflammation. Archives of Internal Medicine, 2006; 166: 1756-1762.

Jaehne A, Loessl B et al. Effects of Nicotine on Sleep During Consumption, Withdrawal, and Replacement Therapy. Sleep Medicine Reviews, 2009; 13: 363-77.

Kakizaki M, Inoue K, Kuriyama S, et al. Sleep duration and the risk of prostate cancer: the Ohsaki Cohort Study. Br J Cancer. 2008 Jul 8;99(1):176-8. Epub 2008 Jun 10.

Kato K, Hirai K et al. Neurochemical Properties of Ramelteon (TAK-375), a Selective MT1/Mt2 Receptor Agonist. Neuropharmacology, 2005; 48: 301-10.

Katz DA and McHorney CA. Clinical Correlates of Insomnia in Patients with Chronic Illness. Archives of Internal Medicine, 1998; 158: 1099-107.

Kennedy DO, Little W, Scholey AB. Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm). Psychosom Med, 2004; 66(4): 607-13.

Kessler RC, Berglund PA et al. Insomnia and the Performance of US Workers: Results from the American Insomnia Survey. Sleep, 2011; 34(9): 1161-1171.

Kim JH, Desor D et al. Efficacy of as1-casein hydrolysate on stress-related symptoms in women. European Journal of Clinical Nutrition, 2007; 61: 536-541.

Kolla BP and Auger RR. Jet Lag and Shift Work Sleep Disorders: How to Help Reset the Internal Clock. Cleveland Clinic Journal of Medicine, 2011; 78(10): 675-84.

Kripke DF, Langer RD, and Kline LE. Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open. 2012 Feb 27;2(1):e000850. Print 2012.

Kripke DF. Greater incidence of depression with hypnotic use than with placebo. BMC Psychiatry. 2007 Aug 21;7:42.

Krystal AD, Durrence HH et al. Efficacy and Safety of Doxepin 1 mg and 3 mg in a 12-week Sleep Laboratory and Outpatient Trial of Elderly Subjects with Primary Insomnia. Sleep, 2010: 33(11): 1553-61.

Krystal AD, Erman M et al. Long-Term Efficacy and Safety of Zolpidem Extended-Release 12.5 mg. Administered 3 to 7 Nights Per Week for 24 Weeks, in Patients with Chronic Primary Insomnia: A 6-month, Randomized, Double-Blind, Placbo-Controlled, Parallel-Group Multi-Center Study. Sleep, 2008; 31(1): 79-90.

Kumar A and Kalonia H. Protective effect of WithaniasomniferaDunal on the behavioral and biochemical alterations in sleep-disturbed mice (Grid over water suspended method). Indian J Exp Biol. 2007 Jun;45(6):524-8.

Kumar a, Kalonia H. Effect of Withania somnifera on Sleep-Wake Cycle in Sleep-Disturbed Rats: Possible GABAergic Mechanism. Indian J Pharm Sci. 2008;70(6):806-10.

Lande RG and Gragnani C. Nonpharmacological Approaches for the Treatment of Insomnia. The Journal of the American Osteopathic Association, 2010; 110(12): 695-701.

Landolt HP and Wehrle R. Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood? Eur J Neurosci. 2009 May;29(9):1795-809.

Lemoine P, Wage AG et al. Efficacy and safety of prolonged-release melatonin for insomnia in middle-aged and elderly patients with hypertension: a combined analysis of controlled clinical trials. Integrated Blood Pressure Control, 2012; 5: 9-17.

Lewith GT, Godfrey AD et al. A Single-Blinded, Randomized Pilot Study Evaluating the Aroma of Lavandulaaugustifolia as a Treatment for Mild Insomnia. The Journal of Alternative and Complementary Medicine, 2005; 11(4): 631-7.

Lieberman JA. Update on the Safety Considerations in the Management of Insomnia with Hypnotics: Incorporating Modified-Release Formulations Into Primary Care. Primary Care Companion, 2007; 9(1): 25-31.

Mastin DF, Bryson J, Corwyn R. Assessment of sleep hygiene using the Sleep Hygiene Index. J Behav Med. 2006;29(3):223-7.

McCurry SM, Logsdon RG, Teri L, et al. Sleep disturbances in caregivers of persons with dementia: contributing factors and treatment implications. Sleep Med Rev. 2007;11(2):143-53.

Mendelson WB. A Review of the Evidence for the Efficacy and Safety of Trazodone in Insomnia. Journal of Clinical Psychiatry, 2005; 66: 469-76.

Mills EJ, Wu P et al. Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals. Tobacco Induced Diseases, 2010; 8(8): 8.

Miyamoto M. [A novel therapeutic drug: ramelteon]. Nihon Rinsho. 2009 Aug;67(8):1595-600.

Moghadam-Kia S and WerthVp et al. Prevention and Treatment of Systemic Glucocorticoid Side Effects. International Journal of Dermatology, 2010; 49: 239-48.

Morin CM, LeBlanc M et al. Epidemiology of Insomnia: Prevalence, Self-Help Treatments, Consultations and Determinants of Self-Help Seeking Behaviors. Sleep Medicine, 2006: 123-30.

Muller SF and Klement S. A Combination of Valerian and Lemon Balm is Effective in the Treatment of Restlessness and Dyssomnia in Children. Phytomedicine, 2006; 13: 383-7.

Nassiri-Asl M, Shariati-Rad S et al. Anticonvulsant Effects of Arial Parts of Passifloraincarnata Extract in Mice: Involvement of Benzodiazepine and Opioid Receptors. BMC Complementary and Alternative Medicine, 2007; 8(7): 26.

National Heart, Lung, and Blood Institute (NHLBI), a division of the National Institutes of Health (NIH). Facts About Insomnia. October 1995. Available at: http://www.nhlbi.nih.gov/health/public/sleep/insomnia.txt. Accessed 6/14/2012.

Neikrug AB and Ancoli-Israel S. Sleep Disorders in the Older Adult-A Mini Review. Gerontology, 2010; 56: 181-9.

Nerbass FB, Pedrosa RP et al. Calcium Channel Blockers are Independently Associated With Short Sleep Duration in Hypertensive Patients with Obstructive Sleep Apnea. Journal of Hypertension, 2011; 29(6): 1236-41.

Nieto FJ, Peppard PE, Young T, et al. Sleep disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J RespirCrit Care Med. 2012 May 20. [Epub ahead of print]

Nonogaki K. Serotonin conflict in sleep-feeding. VitamHorm. 2012;89:223-39.

Ochoa-Sanchez R, Comai S et al. Promotion of Non-Rapid-Eye-Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT2 Melatonin Receptor Ligand. Journal of Neuroscience, 2011; 31(50): 18439-18452.

Ohayon MM, Caulet M, Lemoine P. Comorbidity of mental and insomnia disorders in the general population. Compr Psychiatry. 1998 Jul-Aug;39(4):185-97.

Omiya K, Akashi YJ, Yoneyama K, et al. Heart-rate response to sympathetic nervous stimulation, exercise, and magnesium concentration in various sleep conditions. Int J Sport NutrExercMetab. 2009 Apr;19(2):127-35.

Paredes SD, Barriga CM et al. Assessment of the Potential Role of Tryptophan as the Precursor of Serotonin and Melatonin for the Aged Sleep-Wake Cycle and Immune Function: Streptopeliarisioria as a Model. International Journal of Tryptophan Research, 2009a; 2: 23-36.

Paredes SD, Marchena AM et al. Rhythm, Core and Peripheral Temperatures and Interleukin Levels in the Ringdove: Changes with Age. Journal of Gerontology, 2009b; 64A(3): 340-50.

Pedrosa RP, Drager LF, Gonzaga CC, et al. Obstructive Sleep Apnea: The Most Common Secondary Cause of Hypertension Associated with Resistant Hypertension. Hypertension, 2011; 58:811-817.

Peuhkuri K, Sihvola N, and Korpela R. Diet promotes sleep duration and quality. Nutr Res. 2012 May;32(5):309-19.

Philips B, Mannino DM. Do insomnia complaints cause hypertension or cardiovascular disease? J Clin Sleep Med. 2007 Aug 15;3(5):489-94.

Punjabi NM. The Epidemiology of Adult Obstructive Sleep Apnea. Proc Am ThoracSoc, 2008; 5(2):136-43.

Raines T, Jones P et al. Investigation of the Anxiolytic Effects of Luteolin, A Lemon Balm Flavonoid in the Male Sprague-Dawley Rat. AANA Journal, 2009; 77(1): 33-36.

Randall S, Roehrs TA et al. Over-the-Counter Sleep Aid Medications and Insomnia. Primary Psychiatry, 2008; 15(5): 52-58.

Richard DM, Dawes MA et al. L-Tryptophan: Basic Metabolic Functions, Behavioral research and Therapeutic Indications. International Journal of Tryptophan Research, 2009; 2: 45-60.

Roehrs T and Roth T. Caffeine: Sleep and Daytime Sleepiness. Sleep Medicine Reviews, 2008; 12: 153-62.

Rondanelli M, Opizzi A et al. The Effect of Melatonin, Magnesium and Zinc on Primary Insomnia in Long-Term Care Facility Residents in Italy: A Double-Blind, Placebo-Controlled Clinical Trial. Journal of the American Geriatric Society, 2011; 59: 82-90.

Roth T and Roehrs T. Insomnia: epidemiology, characteristics, and consequences. Clin Cornerstone. 2003;5(3):5-15.

Roth T, Rogowski R et al. Efficacy and Safety of Doxepin 1 mg, 3 mg and 6 mg in Adults With Primary Insomnia. Sleep, 2007; 30(11): 1557-64.

Roth T, Walsh JK et al. An Evaluation of the Safety and Efficacy of Eszopiclone over 12 Months in Patients with Chronic Primary Insomnia. Sleep Medicine, 2005; 6(6): 487-95.

Saint-Hilaire Z, Messaoudi M et al. Effects of a Bovine Alpha S1-Casein TrypticHydrosylate (CTH) on Sleep Disorder in Japanese General Population. The Open Sleep Journal, 2009; 2: 26-32.

Saletu-Zyhlarz G, Anderer P et al. Insomnia related to postmenopausal syndrome and hormone replacement therapy: sleep laboratory studies on baseline differences between patients and controls and double-blind, placebo-controlled investigations on the effects of a novel estrogen–progestogen combination (Climodien_, Lafamme_) versus estrogen alone. Journal of Sleep Research, 2003; 12: 239-54.

Sanchez-Ortuno MM, Bélanger L, Ivers H, et al. The use of natural products for sleep: A common practice? Sleep Med. 2009 Oct;10(9):982-7.

Sateia MJ, Kirby-Long P, Taylor JL. Efficacy and clinical safety of ramelteon: an evidence-based review. Sleep Med Rev. 2008;12(4):319-32.

Sato M, Yamadera W et al. Clinical Efficacy of Individual Cognitive Behavior Therapy for Psychophysiological Insomnia in 20 Outpatients. Psychiatry and Clinical Neurosciences, 2010; 64: 187-195.

Schewitzer PK, Curry Dt et al. Pharmacological treatment of Insomnia. Clinical Handbook of Insomnia, 2010: 297-316.

Shatzmiller RA and Benbadis SR. Insomnia. Available at: http://emedicine.medscape.com/article/1187829-overview Revised 2/12/2012; Accessed 4/19/2012.

Shinomiya K, Inoue T et al. Hypnotic Effects of Chamomile and Passiflora Extracts in Sleep-Disturbed Rats. Biological Pharmacology Bulletin, 2005; 28(5): 808-10.

Silber BY and Schmitt JA. Effects of Tryptophan Loading on Human Cognition, Mood and Sleep. NeurosciBiobehav Rev, 2010; 34: 387-407.

Silva BH, Martinez D et al. A Randomized, Controlled Pilot Trial of Hormone Therapy for Menopausal Insomnia. Archives of Women's Mental Health, 2011; 14: 505-8.

Singareddy R, Vgontzas AN et al. Risk Factors for Incident Chronic Insomnia: A General Population Prospective Study. Sleep Medicine, 2012: 346-53.

Sivertsen B, Krokstad S et al. The Epidemiology of Insomnia: Associations with Physical and Mental Health. Journal of Psychosomatic Research, 2009: 109-116.

Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77.

Smith MT, Quartana PJ et al. Mechanisms By Which Sleep Disturbance Contributes to Osteoarthritic Pain: A Conceptual Model. Current Pain and Headache Reports, 2009; 13: 447-54.

Song CH, Kim YH et al. Associations of Zinc and Copper Levels in Serum and Hair with Sleep Duration in Young Women. Biological Trace Element Research, 2012.

Spadoni G, Bedini A et al. Melatonin Receptor Agonists: New Options for Insomnia and Depression Treatment. CNS Neuroscience and Therapeutics, 2011; 17: 733-41.

Taylor DJ, Mallory LJ et al. Comorbidity of Chronic Insomnia with Medical Problems. Sleep, 2007; 30(2): 213-8.

Terauchi M, Hiramitsu S, Akiyoshi M, et al. Associations between anxiety, depression and insomnia in peri- and post-menopausal women. Maturitas. 2012 May;72(1):61-5.

Turek FT and Gilette MU. Melatonin, Sleep and Circadian Rhythms: Rationale for Development of Specific Melatonin Agonists. Sleep Medicine, 2004; 5: 523-32.

UAB News. [Lollar J.] Sleep debt hikes risk of stroke symptoms despite healthy BMI. 6/11/2012 Available at: http://www.uab.edu/news/latest/item/2483-sleep-debt-hikes-risk-of-stroke-symptoms-despite-healthy-bmi?tmpl=component&print=1 Accessed 6/21/2012.

Verkasalo PK, Lillberg K, Stevens RG, et al. Sleep duration and breast cancer: a prospective cohort study. Cancer Res. 2005 Oct 15;65(20):9595-600.

Walsh JK, Erman M et al. Subjective Hypnotic Efficacy of Trazodone and Zolpidem in DSMRIII-R Primary Insomnia. Human Psychopharmacology, 1998; 13: 191-198.

Weber J, Siddiqui MA, WagstaffAJ, et al. Low-dose doxepin: in the treatment of insomnia. CNS Drugs. 2010 Aug;24(8):713-20.

Weeks BS. Formulations of Dietary Supplements and Herbal Extracts for Relaxation and Anxiolytic Action: Relarian. Medical Science Monitor, 2009; 15(11): 256-62.

Woods NF and Mitchell ES. Symptoms During the Perimenopause: Prevalence, Severity Trajectory, and Significance in Women's Lives. The American Journal of Medicine, 2005; 118: 14-24.

Xiong Y, Ullman B et al. Synthesis and in Vivo Evaluation of Phenethylpiperazine Amides: Selective 5-HydroxyTryptamine2A Receptor Antagonists for the Treatment of Insomnia. Journal of Medicinal Chemistry, 2010; 53: 5696-706.

Xu J, Jiang X et al. Propofol-Induced Sleep: Efficacy and Safety in Patients with Refractory Chronic Insomnia. Cell BiochemBiophys, 2011 Jul;60(3): 161-6.

Yaggi HK, Concato J. Obstructive Sleep Apnea as a Risk Factor for Stroke and Death. The New England Journal of Medicine, 2005; 353(19): 2034-41.

Yang CM and Lin SC. Maladaptive Sleep Hygiene Practices in Good Sleepers and Patients with Insomnia. Journal of Health Psychology, 2010; 15(1): 147-55.

Youngberg MR, Karpov IO et al. Clinical and Physiological Correlates of Caffeine and Caffeine Metabolites in Primary Insomnia. J Clin Sleep Med. 2011;7(2):196-203.

Zammit G, Erman M et al. Evaluation of the Efficacy and Safety of Ramelteon in Subjects with Chronic Insomnia. Journal of Clinical Sleep Medicine, 2007; 3(5): 495-504.

Zhang J, Ma RC et al. Relationship of Sleep Quantity and Quality with 24-Hour Urinary Catecholamines and Salivary Awakening Cortisol in Healthy Middle-Aged Adults. Sleep, 2011; 34(2): 225-233.

Zick SM, Wright BD et al. Preliminary Examination of the Efficacy of Safety of a Standardized Chamomile Extract for Chronic Primary Insomnia: A Randomized Placebo-Controlled Pilot Study. BMC Complementary and Alternative Medicine, 2011; 11: 78.

Ziegler G, Ploch M, Miettinen-Baumann A, et al. Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non-organic insomnia--a randomized, double-blind, comparative clinical study. Eur J Med Res. 2002 Nov 25;7(11):480-6.​​