Do you have insomnia? Perhaps you just have occasional difficulty getting to sleep or staying asleep. Either way, lack of sleep is a relatively common problem and is frequently treated with medications or alcohol. A consensus from population-based studies1 and other research2 indicate that approximately 30 percent of adult samples drawn from different countries report one or more of the symptoms of insomnia. A U.S. regional survey3 reported that about 20 percent or more of older American adults use some form of sleep aid, including prescription or over-the-counter drugs or alcohol.

MEDICATIONS AND ALCOHOL USE FOR SLEEP
The U.S. National Library of Medicine's PubMed Health4 website indicates that while over-the-counter sleep medicines to treat insomnia can sometimes be useful, there can be side effects such as daytime sleepiness, dry mouth, and blurred vision. These effects may be worse in the elderly. Furthermore, stopping these medications suddenly can cause rebound insomnia and withdrawal. Likewise, the Mayo Clinic5 indicates that taking prescription sleeping pills, such as zolpidem (Ambien), eszopiclone (Lunesta), zaleplon (Sonata) or ramelteon (Rozerem) may also help induce sleep. Side effects, which are often more pronounced in older people, may include excessive drowsiness, impaired thinking, night wandering, agitation, and balance problems. Prescription sleeping pills are generally not recommended for more than a few weeks, but several newer medications are approved for indefinite use. Nevertheless, some of these medications are habit-forming. Finally, alcohol is a sedative that may help induce sleep, but it also prevents deeper stages of sleep and often causes an awakening in the middle of the night.6

NATURAL ALTERNATIVES FOR SLEEP
So, what are the natural alternatives? Certainly, a variety of dietary supplements are commonly self-prescribed for treating sleep problems. Some of the most well known—of which include melatonin and valerian root—"old school" remedies which, nevertheless, do have adequate research to support their use for this purpose. However, it should be noted that melatonin and valerian are not always without side effects. Although generally well tolerated, the most common side effects of melatonin include daytime drowsiness, headache, and dizziness—although these don't seem to occur any more frequently than with placebo.7 Likewise, although generally well tolerated, valerian side effects reported in clinical studies include headaches, gastrointestinal upset, mental dullness, excitability, uneasiness, and cardiac disturbances.8,9 Luckily, there are some other natural remedies, which have shown promising results for promoting healthy sleep, but without these side effects. These remedies include GABA, Apocynum venetum, ashwagandha, and lutein/zeaxanthin.

GABA AND Apocynum venetum
GABA (gamma amino butyric acid) is the primary neurotransmitter in the central nervous system for exerting sedative and anti-anxiety effects.10 Apocynum venetum is an herbal remedy with a long history of use in traditional Chinese medicine for soothing the nerves, insomnia, and for other purposes.11 These two nutraceuticals have been used together and individually in human clinical research for their stress reducing, mood enhancing, and sleep-promoting effects. The stress-reducing effects are also important for sleep since stress can make it difficult to get to sleep and sustain sleep.

GABA AND Apocynum venetum STUDY 1
A double-blind, placebo-controlled crossover study12 was conducted to examine the stress-reducing effect of ingesting 25 mg/day GABA, and 25 mg/day Apocynum venetum leaf extract (Venetron®), a combination of both, or a placebo. Following intake, subjects were exposed to a stress-inducing mental task and then tested for the stress marker known as salivary chromogranin A (CgA), and scored on a mental questionnaire. Results showed that the combination significantly reduced salivary CgA secretion compared to placebo. Individually, GABA and Apocynum venetum leaf extract also reduced CgA secretion, but they did not reach statistical significance over placebo. In conclusion, the combination of GABA and Apocynum venetum leaf extract was able to reduce markers of cognitive-induced mental stress.

GABA AND Apocynum venetum STUDY 2
In another study, the effects of 100 mg/day GABA and 25 mg/ day Apocynum venetum leaf extract (Venetron), were investigated on sleep improvement in a single-blind, placebo-controlled study.13 The electroencephalogram (EEG) test revealed that both nutraceuticals had beneficial effects on sleep. GABA shortened the time it took to fall asleep and increased non-rapid eye movement (REM) sleep time. Simultaneous intake of GABA and Apocynum venetum leaf extract shortened the time it took to fall asleep and increased non-REM sleep time. The result of questionnaires showed that GABA and Apocynum venetum leaf extract enabled subjects to realize the effects on sleep. These results mean that GABA can help people to fall asleep quickly, Apocynum venetum leaf extract induces deep sleep, and they function complementarily with a simultaneous intake. The researchers concluded that this combination can be regarded as safe and appropriate for daily intake in order to improve the quality of sleep.

Apocynum venetum LEAF EXTRACT STUDY 1
In a double-blind, randomized trial14, individuals with mild depression and symptoms of anxiety, were treated with 50 mg/ day Apocynum venetum leaf extract (Venetron) or placebo at different times over eight weeks. Global scores of depression and blood samples for serotonin levels were measured at baseline and after eight weeks. The changes were assessed using a 17-item Hamilton Depression (HAM-D) rating scale that evaluates depressed mood, vegetative and cognitive symptoms of depression, and anxiety symptoms. Global scores of depression and blood samples for serotonin levels were measured at baseline and after eight weeks. The results were that after eight weeks of treatment, 40 percent of the subjects in Apocynum venetum leaf extract group showed a greater-than-10-point decrease in HAM-D scores. Likewise, 50 percent had a decrease of 50 percent or greater in the symptoms of depression as compared with the placebo group. There were also significant improvements of decreased anxiety and reductions of insomnia in the middle of the night and later in the sleep cycle. In the Apocynum venetum leaf extract group, 50 percent of subjects had increased serotonin concentrations, demonstrating biochemical evidence of improvement (since maintaining healthy serotonin levels are necessary for healthy mood and sleep). HAM-D scores decreased by 50 percent or greater in the Apocynum venetum leaf extract group. Also, 60 percent of the Venetron group had a HAM-D score of eight or less by week eight. Other symptoms that showed significant improvements within the Apocynum venetum leaf extract group included middle- and late-night insomnia, work, activities, and anxiety. In conclusion Apocynum venetum leaf extract significantly improved anxiety and reduced insomnia in the middle of the night and later in the sleep cycle.

Apocynum venetum LEAF EXTRACT STUDY 2
In this human clinical intervention trial15, the symptoms of depression were assessed in subjects having widely varying severity using the Sheehan Disability Scale (SDS). This scale used to measure depression was developed to assess functional impairment using three interrelated areas: work/school, social, and family life. The patient is able to rate the extent that work/ school, social life, and home life or family responsibilities are impaired by symptoms of depression as a composite of three self-rated items designed to measure the extent to which these three major life sectors are impaired by panic, anxiety, phobic, or depressive symptoms. Patients took 50 mg/day Apocynum venetum leaf extract for 14 days. Results were that the SDS scores of subjects improved in symptoms of depression ranging from minimal to mild depression and moderate to severe depression. The mean measurement significantly declined to the normal range after 14 days of ingestion. In conclusion, Apocynum venetum leaf extract improved depression in patients with varying degrees of symptom severity.

VENETRON STUDY 3
A human clinical intervention trial16 consisting of case studies was conducted. Subjects included one 29-year-old woman with PMS, a 39-year-old woman with PMS, a 55-year-old woman, a man, 36 years old, and two older men, one 66 and the other 75 years of age. All subjects received 50 mg/day Apocynum venetum leaf extract. The results were as follows: In the 29-year-old woman with PMS, Apocynum venetum leaf extract for one month reduced melancholy and overeating. In the 39-year-old woman with PMS, Apocynum venetum leaf extract for two weeks before menses and over a 3-month period, improved emotional symptoms such as irritability and depression. In the 36-year-old man, Apocynum venetum leaf extract for six months resulted in improvements in concentration and his feeling more optimistic. The 55-year-old woman, using Apocynum venetum leaf extract decreased fatigue and grief. In the 66- and the 75-year-old men, Apocynum venetum leaf extract for two weeks resulted in decreases in the frequency of waking up throughout the night and promoted deeper sleep. In conclusion, case studies have shown very good results in patients with depressive PMS disorders, and in younger and older depressed patients. The types of symptoms that improved include melancholy, overeating, emotional symptoms such as irritability, difficulty in concentrating, optimistic outlook, fatigue, and grief, and improvements in sleep.

GABA STUDY 1
Two studies17 investigated the effect of GABA on relaxation and stress in humans. The first study evaluated the effect of GABA intake on their brain waves. Electroencephalograms (EEG) were obtained after three tests on each volunteer as follows: intake only water, 100 mg GABA, or 200 mg L-theanine. After 60 minutes of administration, GABA significantly increases alpha waves (i.e. relaxing brain waves) and decreases beta waves compared to water or L-theanine. These findings denote that GABA not only induces relaxation but also reduces anxiety. The second study was conducted to see the role of relaxant and anxiolytic effects of 100 mg GABA intake on immunity in stressed volunteers. Eight acrophobic subjects were divided into two groups (placebo and GABA). All subjects were crossing a suspended bridge as a stressful stimulus. Immunoglobulin A (IgA) levels in their saliva were monitored during bridge crossing. The placebo group showed a marked decrease of their IgA levels, while GABA group showed significantly higher levels. In conclusion, GABA could work effectively as a natural relaxant and its effects could be seen within one hour of its administration to induce relaxation and diminish anxiety. Moreover, GABA administration could enhance immunity under stress conditions.

GABA STUDY 2
Researchers studied18 the psychological stress reducing effect of chocolate enriched with 28 mg/day GABA, on stress induced by an arithmetic task using changes of heart rate variability (HRV) and salivary chromogranin A (CgA). Fifteen minutes after eating GABA-enriched chocolate, subjects were assigned an arithmetic task for 15 minutes. After that, an electrocardiogram was recorded and saliva samples were collected. HRV was determined from the electrocardiogram, and the activity of the autonomic nervous system was estimated through HRV. The CgA concentration of all saliva samples, an index for acute psychological stress, was measured. From HRV, those taking GABA chocolate made a quick recovery to the normal state from the stressful state. The CgA value after the task in those taking GABA chocolate did not increase in comparison with that before ingestion. From these results, GABA chocolate was considered to have a psychological stress reducing effect.

ASHWAGANDHA STUDY
Withania somnifera, also known as ashwagandha, has historically been used in Asia for treating stress-related health conditions. In this study,19 researchers investigated the effects of standardized ashwagandha root and leaf extract (Sensoril®) in chronically stressed humans in a clinical trial. Participants were randomly assigned to receive different doses of ashwagandha root and leaf extract, or placebo. Stress levels were assessed at Days 0, 30, and 60 using a modified Hamilton anxiety (mHAM-A) scale. Between Days 0 and 60, those receiving 125 mg/day ashwagandha root and leaf extract experienced a significantly greater decrease than placebo for the average mHAM-A score, serum cortisol, serum C-reactive protein, pulse rate, and blood pressure. In addition, those receiving 125 mg/day ashwagandha root and leaf extract had an improvement in the sleeplessness score from 3.1 on day 0, to 1.9 on day 30, to 0.9 on day 60—a percentage change of about 71 percent. Therefore, this study provides evidence that the consumption of ashwagandha root and leaf extract significantly reduced experiential and biochemical indicators of stress without adverse effects.

Reduction in gross stress condition in 30 and 60-day periods

LUTEIN/ZEAXANTHIN
To understand why lutein/zeaxanthin is beneficial for sleep, you must first understand a little bit about blue light, a powerful and potentially damaging component of visible light from the sun, digital devices (computers, tablets, smartphones, etc.) and artificial light.20,21,22,23,24,25 As it passes through the lens of the human eye, the visible wavelengths of light, including ultraviolet and blue light, focus upon the macular area of the retina. In particular, the blue wavelengths penetrate deeply into the eye, and have the greatest potential to damage retinal tissue by inducing free radicals, etc.26,27,28,29 In fact, ongoing exposure to blue light (regardless of the source) is a major risk factor for various retinal damage.30,31,32,33

SYMPTOMS OF CHRONIC BLUE LIGHT EXPOSURE
Research indicates that chronic exposure to blue light can cause a variety of symptoms. These include headaches, eye fatigue and other indications of eye strain are associated with the daily use of video display terminals on computers and other electronic devices and are common with three or more hours/day of exposure. In addition, blue light has been shown to delay or suppress the release of melatonin, your body's sleep hormone.34,35,36 Unfortunately, 30 percent of adults spend more than half their waking hours (more than nine hours) using a digital device, 50 percent of Americans use digital devices more than five hours a day, and 70 percent use two or more digital devices at the same time.37 Consequently, it's not surprising that so many people have problems with eye fatigue, eye strain and sleep.

PROTECTION WITH LUTEIN AND ZEAXANTHIN ISOMERS
The good news is that lutein and zeaxanthin isomers (rr- and rs-(meso)-zeaxanthin), macular carotenoids well known for the role they play in supporting eye health, can help mitigate the effects that blue light has on common retinal damage. The way it works is that lutein/zeaxanthin have a yellow coloration. Because yellow pigments absorb blue light, lutein effectively protects the retina from the region of the light spectrum that can cause tissue damage, and also limits the ability of light to generate free radicals. Basically, lutein/zeaxanthin act as a sort of internal pair of sunglasses, protecting the macular region of the retina from blue light damage. In addition, various studies have shown that supplementation with 10 mg/2 mg–20 mg/4 mg lutein/zeaxanthin (Lutemax®2020 Marigold flower extract) can help make users of computers and other digital devices more comfortable throughout the day, reducing eye strain and relieving tired eyes. Supplementation also protects eyes against harmful blue light and against oxidative stress and harmful free radicals.38,39,40

LUTEIN AND ZEAXANTHIN ISOMERS, AND SLEEP
More specific to the subject of this article, there is a direct connection between blue light, lutein/zeaxanthin, and sleep. It has to do with melatonin, a hormone, secreted by the pineal gland,41 whose primary role is regulation of the body's circadian rhythm, and sleep patterns.42,43 Specifically, light, including blue light, inhibits melatonin secretion and darkness stimulates secretion.44,45 Consequently, too much light exposure, particularly at night, can inhibit melatonin secretion and interfere with sleep. Interestingly, research has shown that, at night, even blue light from smartphones can negatively impact sleep.46 That's where blue-light filtering lutein and zeaxanthin isomers can help.

To determine if increasing macular levels of lutein/zeaxanthin, by supplementing lutein/zeaxanthin isomers, would affect sleep quality, a two-part study47 was conducted. The first part was a 3-month, double-blind, placebo-controlled trial. Subjects in the active supplement group ingested lutein/zeaxanthin isomers daily (LutemaxR2020 Marigold flower extract). Sleep quality was evaluated with the Pittsburgh Sleep Quality Index (PSQI). Critical flicker fusion frequency1 (CFF) and contrast sensitivity (CS) were also measured. Outdoor and indoor exposure to light (UV) and electronic devices before and after supplementation were recorded. The results showed that the lutein/zeaxanthin group exhibited significant improvement in overall sleep quality and levels of macular pigments, as well as CS and CFF, at three months. There were no changes in the placebo group. This trial found that increasing macular pigments via lutein/zeaxanthin isomers supplementation, might serve to absorb more blue light from sources (such as computer screens, tablets, or smartphones) that can be used during nighttime hours, and would otherwise provide a circadian signal to stay awake.

(1. CFF is a diagnostic tool used for several purposes, including the degree of light or dark adaptation, i.e., the duration and intensity of previous exposure to background light, which affects both the intensity sensitivity and the time resolution of vision.)

The second part was also a 6-month, double-blind, placebo-controlled trial in which 34 healthy individuals participated. The same supplementation regimen and assessment methods were used as with the 3-month study. Results were that at six months macular pigments, CFF, CS, sleep quality improved with lutein/ zeaxanthin supplementation, with no changes in the placebo group.

CONCLUSIONS
Lack of sleep is a relatively common problem and is frequently treated with medications or alcohol— both of which are associated with undesirable side effects. Even melatonin and valerian root may have side effects for some individuals. Alternatively, include GABA, Apocynum venetum, ashwagandha, and lutein/zeaxanthin are other natural remedies, which have shown promising results for promoting healthy sleep, but without these side effects. Since these natural remedies work by different mechanisms, they can all be used at the same time without redundancy. They can also be used individually.

Endnotes

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  9. National Toxicology Program, US Department of Health and Human Services. Chemical Information Review Document for Valerian (Valeriana officinalis L.) [CAS No. 8057-49-6] and Oils [CAS No. 8008-88-6]. Supporting Nomination for Toxicological Evaluation by the National Toxicology Program. November 2009.
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  12. Yoto A, Ishihara S, Li-Yang J, Butterweck V, Yokogoshi H. The Stress Reducing Effect of γ-Aminobutyric Acid and Apocynum venetum Leaf Extract on Changes in Concentration of Salivary Chromogranin A. Japanese Journal of Physiological Anthropology. 2009 14(3): 55.59.
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  14. Venetron® brochure, Tokiwa. Summarized in Maypro document "Venetron Clinical Evidence." Topic: What was the effect of a daily dose of 50 mg of Venetron® in individuals with mild depression over 8 weeks?
  15. Venetron® brochure, Tokiwa. Summarized in Maypro document "Venetron Clinical Evidence." Topic: What effect does Venetron® have on patients with various degrees of depression?
  16. Venetron® brochure, Tokiwa. Summarized in Maypro document "Venetron Clinical Evidence." Topic: What have been the results of Venetron® in case studies of patients having depression, PMS, anxiety, and/or insomnia?
  17. Abdou AM, Higashiguchi S, Horie K, Kim M, Hatta H, Yokogoshi H. Relaxation and immunity enhancement effects of gammaaminobutyric acid (GABA) administration in humans. Biofactors. 2006;26(3):201-8.
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  19. Auddy B, Hazra J, Mitra A, Abedon B, Ghosal S. A Standardized Withania Somnifera Extract Significantly Reduces Stress-Related Parameters in Chronically Stressed Humans: A Double-Blind, Randomized, Placebo-Controlled Study. JANA. 2008;11(1):2008:50.56.
  20. Nakashima Y, Ohta S1, Wolf AM2. Blue light-induced oxidative stress in live skin. Free Radic Biol Med. 2017 Mar 15. pii: S0891. 5849(17)30134-X.
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  22. The Vision Council. Eyes Overexposed: The Digital Device Dilemma. 2016 Digital Eye Strain Report. Thevisioncouncil.org.
  23. The Vision Council. Hindsight is 20/20/20: Protect your eyes from digital devices. 2015 Digital Eye Strain Report. Thevisioncouncil.org.
  24. Smick K, et al. Blue Light Hazard: New Knowledge, New Approaches to Maintaining Ocular Health. Report of a Roundtable: March 16, 2013, New York City, NY, USA. Essilor of America.
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  26. Tosini, Ibid.
  27. Wu J, Seregard S, Algvere PV. Photochemical damage of the retina. Surv Ophthalmol. 2006 Sep-Oct;51(5):461–81.
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  29. Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). 2012. Health Effects of Artificial Light. Accessed from http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_035.pdf.
  30. Cruickshanks KJ, Klein R, Klein BEK. Sunlight and age-related macular degeneration—the Beaver Dam Eye Study. Arch Ophthalmol. 1993;111:514–8.
  31. Klein R, Klein BEK, Jensen SC, Cruickshanks KJ. The relationship of ocular factors to the incidence and progression of agerelated maculopathy. Arch Ophthalmol. 1998;116:506–13.
  32. Algvere, Ibid.
  33. Taylor HR, Muñoz B, West S, Bressler NM, Bressler SB, Rosenthal FS. Visible light and risk of age-related macular degeneration. Trans Am Ophthalmol Soc. 1990;88:163–73.
  34. Figueiro MG. Individually tailored light intervention through closed eyelids to promote circadian alignment and sleep health. Sleep Health. 2015 Mar 1;1(1):75–82.
  35. Daneault V, Dumont M, Massé É, Vandewalle G, Carrier J. Light-sensitive brain pathways and aging. J Physiol Anthropol. 2016; Mar 15;35:9.
  36. Lockley SW, Evans EE, Scheer FA, Brainard GC, Czeisler CA, Aeschbach D. Short-wavelength sensitivity for the direct effects of light on alertness, vigilance, and the waking electroencephalogram in humans. Sleep. 2006 Feb;29(2):161–8.
  37. Richer S. Lutein and zeaxanthin protect against "bad blue" light. Eye Health Insider. December 2016: 4.
  38. Stringham J. Effects of three levels of lutein supplementation on macular pigment optical density, psychological stress levels, and overall health. Nutritional Neuroscience Laboratory, University of Georgia. Unpublished. 2016:17 pgs.
  39. Lutein/Zeaxanthin Isomers Supplementation Impact on Vision Health. Unpublished. 2016:8 pgs.
  40. Blue Light Study Eye Stress. Unpublished. 2016: 2 pgs.
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  42. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95.
  43. Lissoni P, Barni S, Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 1995;71:854-6.
  44. Brzezinski, Ibid.
  45. Daneault, Ibid.
  46. Yoshimura M, Kitazawa M, Maeda Y, Mimura M, Tsubota K, Kishimoto T. Smartphone viewing distance and sleep: an experimental study utilizing motion capture technology. Nat Sci Sleep. 2017 Mar 8;9:59-65.
  47. Stringham JM et al. Short-term macular carotenois supplementation improves overall sleep quality. ARVO 2016 Annual Meeting Abstracts

Gene Bruno, MS, MHS

Gene Bruno is the Dean of Academics and Professor of Dietary Supplement Science for Huntington College of Health Sciences (a nationally accredited distance learning college offering diplomas and degrees in nutrition and other health science related subjects. Gene has two undergraduate Diplomas in Nutrition, a Bachelor’s in Nutrition, a Master’s in Nutrition, a Graduate Diploma in Herbal Medicine, and a Master’s in Herbal Medicine. As a 32 year veteran of the Dietary Supplement industry, Gene has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines, and peer-reviewed publications. Gene's latest book, A Guide to Complimentary Treatments for Diabetes, is available on Amazon.com, and other fine retailers.

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