Sleep Benefits™: Support for Brain, Mood, and Metabolic Health*

Glossary of Neurotransmitters and Hormones Involved in Healthy Sleep Patterns 

• Cortisol, or the stress hormone, is released in higher amounts in the morning (following the circadian rhythm) to help wake up. Low levels of cortisol are important for falling and staying asleep, while chronic stress or elevated cortisol levels at night can disrupt sleep. Cortisol works in conjunction with norepinephrine (noradrenaline) and epinephrine (adrenaline) during moments of acute stress.
• Dopamine is involved in wakefulness and arousal. Higher dopamine levels during the day promote alertness, while lower levels at night allow for relaxation and sleep. Disruptions in dopamine levels can affect sleep quality, causing restlessness or insomnia.
• GABA (Gamma-Aminobutyric Acid) is the brain's main inhibitory neurotransmitter, which slows down nerve activity, promoting relaxation and sleep. It helps calm the brain and is essential for falling asleep and maintaining deep, restful sleep.
• Melatonin is the primary hormone responsible for supporting the sleep-wake cycle (circadian rhythm). It is released in response to darkness and signals to the body that it's time to sleep, helping to promote and maintain sleep.
• Serotonin is involved in regulating the sleep-wake cycle by helping produce melatonin, the sleep hormone. High levels of serotonin during the day help with wakefulness and mood, while at night, it contributes to the onset of sleep through melatonin production.

1: Getting To Sleep

Lemon balm extract, L-theanine, and GABA work together to support the relaxation response in order to set the stage for a good night’s sleep.*

Lemon balm (Melissa officinalis) has been used traditionally to support a healthy stress response and promote healthy sleep habits.* It has been used to support cognitive health and has antioxidant activity.7 German Commission E has confirmed the role of lemon balm in healthy sleep patterns.

In clinical research, lemon balm has been shown to support a calm, positive mood, memory, focus and learning.* It promotes healthy levels of GABA through supporting normal GABA transaminase inhibition, acts as a receptor agonist for muscarinic acetylcholine receptor M1, thereby exerting supportive effects on the central nervous system (CNS).* Lemon balm also supports normal cortisol levels.*  

Lemon balm reduces excitability, anxiety, stress, and sleep disturbance in human studies.7,8* It also improves mood and cognitive performance.7-9* In animals, lemon balm has reduced corticosterone levels and increased GABA levels in the hippocampus.8,9* In acute stress simulation, lemon balm increased mathematical processing, showing that it can reduce the adverse intellectual effects of stress.9*

In a pilot study, a standardized M. officinalis extract reduced anxiety, anxiety-associated concerns, and lowered sleeplessness.9* Initial, middle, and delayed insomnia were improved. Those who had moderate difficulties falling asleep and restless nights at the beginning of the study, found they had no sleep difficulties after taking the extract and experienced restorative rest. Their rate of awakening after falling asleep also decreased.9 

Suntheanine® L-Theanine is 100% pure L-theanine, the primary amino acid found in green tea leaves.10 L-theanine supports concentration, focus, deep muscle relaxation and improved quality sleep probably through its action on glutamate, serotonin, and dopamine neurotransmission.11* Theanine increases alpha brain wave activity in humans, which may explain its calm and relaxing effect.12* Theanine may counteract the everyday stress response, as it has been shown to help reduce heart rate, blood pressure, and salivary immunoglobulin A, even under acute stress.12* Children with cognitive focus challenges showed higher total sleep time, lower nocturnal motor activity, and a trend for less wakefulness after sleep onset when they were given Suntheanine.13* 

GABA is an inhibitory neurotransmitter that helps to initiate and maintain sleep by suppressing arousal signals in the brain.* Formulas that enhance GABA levels are well known to help induce sleep and are used to treat insomnia.14 People with primary insomnia have been shown to have lower levels of GABA throughout the brain. Similarly, people who wake up frequently after sleep onset, or who have poorer sleep quality, also have reduced brain levels of GABA.15 Normal GABA levels are therefore critical to a healthy sleep pattern. 

2: Supporting Quality Sleep

Melatonin is among the most powerful sleep support nutrients and is historically used to support a deep, restful and refreshing sleep cycle.* However, individuals who have difficulty with melatonin products may find Maizinol®, a unique hormone-free alternative, to have similar sleep-promoting actions.*

Melatonin is involved in the circadian rhythm. Darkness leads to a spike in melatonin which promotes the onset of sleep. Melatonin has a number of physiological activities including support of normal circadian rhythms, antioxidant, immune-promotion, and it helps to clear free radicals.¹⁶* Secretion of melatonin decreases with age, which may begin as early as 30 years of age.¹⁷ It is believed that melatonin dysregulation is caused by the suprachiasmatic nucleus, the “master clock of the circadian rhythm,” thereby causing a loss of noradrenergic control of the pineal gland.¹⁶ 

Studies have shown that melatonin increases total sleep time, helps relieve daytime fatigue, resets the sleep-wake cycle, helps with sleeplessness, initiates sleep onset, and prevents a phase shift (which means wake and sleep times are shifted earlier or later than normal).^16,18* Five randomized, placebo-controlled studies showed an improvement in nocturnal sleep in participants with cognitive challenges.¹⁶ Typically well-tolerated,¹⁹ melatonin and its analogs help to initiate, promote, and maintain sleep.^20,21* These changes bring about better quality sleep and greater mental, physical and emotional rejuvenation.* 

On the other hand, low melatonin can contribute to sleep disturbance.²⁰ Abnormal levels of melatonin have been seen in relation to certain health concerns.

Maizinol® is the star ingredient in Sleep Benefits™ Melatonin Free. It is a Zea mays corn leaf standardized extract, which contains the sleep-supporting compound 6-methyoxybenzoxazolinone at > 2,000 parts per million. Also known as 6-MBOA, this substance is naturally occurring in corn and promotes a healthy melatonin system within the body.* 6-MBOA binds melatonin receptors, it supports the body's natural production of melatonin, it frees up melatonin building blocks for biosynthesis, and relaxes muscles.*

This powerful, hormone-free ingredient has been clinically tested to increase the restorative stage of sleep and improve sleep quality by following our bodies’ natural circadian rhythm.* 

According to a double-blinded, placebo-controlled study, Maizinol® helped promote melatonin biosynthesis via 6-MBOA and improved sleep quality.²²* Maizinol® reduced salivary cortisol up to 36%; increased deep stages of sleep within two weeks of starting oral supplementation; increased total sleep time; and enhanced mood as assessed by the Profile of Mood States (POMS).* Sleep quality according to the Pittsburg Sleep Quality Index (PSQI) was increased in all subjects as early as one week and remained significant during the 4-week trial.²²

Maizinol® is a unique hormone-free alternative to melatonin products and has the following benefits:

• Increases the restorative stage of sleep*
• Naturally supports sleep without common adverse effects such as morning grogginess*
• Helps endogenous production of melatonin*
• Improves sleep quality as measured by the PSQI in human clinical studies*
• Helps support a healthy mood*
• Helps reduce cortisol levels, possibly modulating the effects of stress on the body*
• Has free radical scavenging effects*

The sleep-promoting effects of melatonin come from the activation of G protein-coupled receptors known as MT1 and MT2.* These receptors have specific roles to modulate sleep.* The MT1 receptor  promotes rapid eye movement (REM) sleep and the MT2 receptor helps increase non-REM sleep.²³*  In vitro studies (pre-publication) by the manufacturer suggest that Maizinol® has the ability to act on both receptors to help with all stages of sleep with a significant increase in deep stage sleep and total sleep time.*

Figure 1. Possible Maizinol® Mechanisms of Action. Maizinol® promotes melatonin synthesis by providing more circulating tryptophan, a building block for melatonin. It binds melatonin receptors for better sleep quality.* It relaxes and calms muscles, which can help prepare the body for sleep.*

For people with a known corn allergy, consult with an allergist before consuming this product. However, Maizinol® is not believed to present a risk. People with a corn allergy typically react to proteins found in the corn kernel, not the leaves. Corn allergy is caused by the immune system mistakenly reacting against proteins in corn (like zein, a major corn protein). Unlike the corn kernel, the leaf of the corn plant does not usually contain the same allergens in significant amounts as the kernel, so most people with a corn allergy won’t react to the leaf itself. 

3: Staying Asleep

Shoden® Ashwagandha is intimately connected to the sleep cycle, circadian rhythm and can have profound effects on the quality of sleep.*  In addition, nourishing the adrenal glands can also provide metabolic support and help balance blood glucose levels, which are very important for staying asleep.* 

Shoden® Ashwagandha  (Withania somnifera) has been used for centuries in Ayurvedic practices to enhance memory and overall cognitive performance, due to its modulation of the neuroendocrine-immune system.24* Ashwagandha extracts have been reported to influence cholinergic24 and GABA-ergic neurotransmission.25 *

Ashwagandha shows calming effects in humans and animals.26* Human studies with Ashwagandha show promising results, significantly decreasing reports of routine stress and anxiety on validated scales and even lowering blood cortisol levels in one study.26 * However, further well-designed studies are needed to confirm these findings. 

Ashwagandha has been studied for its effects on the CNS, particularly in preventing conditions of stress.24* Pharmacological studies show that it has antioxidant and neuroprotective properties.* Ashwagandha improved reaction time and helped maintain psychomotor abilities in subjects under stress.* It does not cause sedation; instead, it eases the mental stress bundle, permitting beneficial mental and psychomotor performance.24*

Animal studies show that supplementation with Ashwagandha lessens the effects of routine stress and improves stress tolerance.26*  Components of the extract can facilitate the regeneration of axons and dendrites and prevent neuronal death in animals. 27* In rats, Ashwagandha promoted healthy sleep after sleep deprivation.* Animals pretreated with Ashwagandha fell asleep more quickly, woke up less frequently and had more total sleep time and more non-rapid eye movement sleep than controls.25*

The Science of Sleep

Sleep disorders are one of the most common complaints encountered in medicine and psychiatry because of their negative effects on quality of life.⁴ Each year, between 20 and 40% of adults complain of difficulty sleeping at some point and about 17% consider it to be a serious problem.⁴ Americans report that they are getting 1.5-2 hours less sleep per night, on average²⁸ and forty-four percent of shift workers report insufficient sleep.²⁹

Sleep Deprivation

Sleep deprivation first and foremost affects cognitive functions: memory, attention, executive function, mood, and response time which can lead to hazardous situations.^1-3 Even two nights of recovery sleep does little to counteract the effects of sleep deprivation.³⁰ Several mental health issues are associated with sleep disturbances. ³¹ Sleep deprivation has been associated with a higher incidence of car accidents, comparable to driving under the influence of alcohol.³

Sleep is vital not only for neurological health, but for overall health and function as it “significantly impacts almost all aspects of human behavior.”³² Lack of sleep increases all-cause mortality² and sleep deficits have been implicated in many health conditions.⁶ Sleep deprivation can damage mitochondria in nerve cells³³ and increase inflammation.³⁴ Therefore, sleep hygiene and corrected sleep patterns (with a minimum of seven hours of sleep per night) are a fundamental component of a comprehensive health plan. 

Sleep Physiology

Sleep is critical for the brain to recover, recharge, and remove toxins.^1,2  During sleep, new synapses are formed, memories are consolidated, and neurons are regenerated.³  Melatonin, the hypothalamic-pituitary-adrenal (HPA) axis, and aminergic and cholinergic neurons in the brainstem modulate sleep and wakefulness.^28,35* Circadian rhythms in cortisol release are dictated by the HPA axis, which follows a distinct 24 hour pattern. The suprachiasmatic nuclei (SCN) of the hypothalamus is often referred to as the “master clock of the circadian rhythm” because of its central role in sleep and wake cycles.^6,36 

A normal cortisol rhythm over the course of the day indicates healthy HPA function and normal sleep-wake cycles.  The circadian rhythm of cortisol is established in early infancy.³⁷ Cortisol is responsible for the normal awakening response, arousal, and alertness. Before waking, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released in a pulsatile fashion leading to adrenocorticotrophin (ACTH) synthesis and release of cortisol by the adrenal medulla.³⁸ Cortisol follows a characteristic diurnal pattern:  a daily peak 30 minutes after rising and tapering over the course of the day until it reaches its lowest level at nighttime as a person prepares for sleep. Changes in lighting, feeding schedules, activity, and stress disrupt this diurnal pattern.³⁸    

Melatonin and GABA are also important players in the circadian rhythm.* Melatonin is a neurohormone synthesized in the pineal gland and is specifically involved in the onset of sleep.^20,21*  Melatonin release is synchronized with the typical hours of sleep and the release of melatonin each day is correlated with the most dramatic increase in nocturnal sleepiness.²¹ Melatonin levels decrease with nighttime light exposure and with increasing age.²⁰ 

GABA is an inhibitory neurotransmitter strongly implicated in the initiation and maintenance of sleep.¹⁴* GABA suppresses arousal systems and inhibits neurotransmitters that encourage wakefulness.* In addition, GABA is essential for moderating the HPA stress response.¹⁴*

The HPA Axis & Stress

The HPA axis is responsible for the circadian rhythm and the stress response, the latter of which triggers a domino effect of hormones to ensure survival in the face of danger. Under acute stress, physiologic processes that promote “fight or flight” are favored while resources are shunted away from processes involved in rest, recovery, and health maintenance. ³⁸

A stressor activates both the HPA axis and the sympathetic adrenomedullary system (SAM) in the brain. HPA axis activation with acute stress eventually leads to the release of the glucocorticoid, cortisol, from the adrenal glands into the blood to affect function and metabolism at various levels. Because of cortisol’s system-wide harmful effects, there are many feedback inhibition loops in place to limit its bioactivity. The stress pathway also triggers norepinephrine and epinephrine production by the adrenal glands.

A healthy stress response is short-lived and returns to baseline the instant the stressor is removed. Chronic stress, however, can eventually override the feedback loops and cortisol’s effects on the body can go unchecked.  A glucocorticoid response that is elevated, extended, or inadequate can impair a person’s adaptation to stress, increase or decrease HPA axis activity, interfere with sleep patterns, and is considered a health risk.^39,40

Sleep, Stress & Metabolism

Sleep and stress have a bidirectional relationship, each one influencing the other.²⁸ Chronic stress can alter HPA function and interfere with the circadian rhythm, leading to sleep disturbance and resulting in sleeplessness and mental health concerns.⁴⁰ Stress decreases rapid eye movement (REM) sleep, slow-wave (deep) sleep, and delta power ( a measure of intensity of non-rapid eye movement sleep).²⁸

On the other hand, sleep deprivation increases cortisol levels,⁴¹  disturbs HPA homeostasis and the sympathetic adrenomedullary system, and ultimately throws off the biological clock, eventually affecting arousal and metabolism. Without REM sleep, a person cannot easily adapt to, and recover from, stressors.⁴⁰ It’s easy to see how a vicious cycle can arise; with chronic stress and sleep deprivation, ultimately causing maladaptive changes to HPA function.^28,35

Poor sleep harms human metabolism and alters glucose homeostasis.²⁹ Short sleep duration is a predictor for weight gain and a risk factor for developing certain health conditions.²⁸ Shift workers have higher rates of metabolic illnesses and weight gain, pointing to a clear link between the circadian clock and metabolism.²⁹ 

Alterations to HPA function lead to downstream effects on neuroendocrine levels,²⁸ especially cortisol, norepinephrine, epinephrine, and dopamine.⁴² Excess  cortisol and cortisol metabolites can increase glucose and insulin levels and this may explain the association between obesity and sleep disturbance.²⁸ Further support of this hypothesis is that HPA hyperactivity has been documented in humans and animals with diabetes.²⁸

Promote a Good Night’s Sleep for Overall Health

Sleep is fundamental for cognition, metabolism, quality of life, and longevity. Stress can disrupt the HPA axis, hormones, and neurotransmitters that orchestrate circadian rhythms. Likewise, sleep deprivation can cause stress, maladaptive changes to the HPA axis and cortisol elevations, perpetuating sleep issues. A comprehensive sleep formula naturally supports sleep onset, sleep quality, and decreased waking after falling asleep.* By supporting the body’s natural circadian rhythms and addressing everyday stress and HPA axis dysfunction, Sleep Benefits™ and Sleep Benefits™ Melatonin Free help to ensure optimal brain health, positive mood, and metabolic balance.*

References

1. Eugene AR, Masiak J. The Neuroprotective Aspects of Sleep. MEDtube Sci. Mar 2015;3(1):35-40. 
2. Miller MA. The Role of Sleep and … in the Development, Diagnosis, and Management of Neurocognitive …. Front Neurol. 2015;6:224. doi:10.3389/fneur.2015.00224
3. Sanches I, Teixeira F, dos Santos JM, Ferreira AJ. Effects of Acute Sleep Deprivation Resulting from Night Shift Work on Young Doctors. Acta medica portuguesa. Jul-Aug 2015;28(4):457-62. 
4. Lubit RH, Ahmed I. Sleep disorders. Medscape. Updated Jan 28, 2015. Accessed Mar 30, 2016. http://emedicine.medscape.com/article/287104-overview#a5
5. Chaput JP. Is sleep deprivation a contributor to … in children? Eat Weight Disord. Mar 2016;21(1):5-11. doi:10.1007/s40519-015-0233-9
6. Costa G. Sleep deprivation due to shift work. Handbook of clinical neurology. 2015;131:437-46. doi:10.1016/B978-0-444-62627-1.00023-8
7. Sepand MR, Soodi M, Hajimehdipoor H, Soleimani M, Sahraei E. Comparison of Neuroprotective Effects of Melissa officinalis Total Extract and Its Acidic and Non-Acidic Fractions against A beta-Induced …. Iran J Pharm Res. Spring 2013;12(2):415-23. 
8. Cases J, Ibarra A, Feuillere N, Roller M, Sukkar SG. Pilot trial of Melissa officinalis L. leaf extract in the … of volunteers suffering from mild-to-moderate … and sleep disturbances. Med J Nutrition Metab. Dec 2011;4(3):211-218. doi:10.1007/s12349-010-0045-4
9. Feliu-Hemmelmann K, Monsalve F, Rivera C. Melissa officinalis and Passiflora caerulea infusion as physiological stress decreaser. Int J Clin Exp Med. 2013;6(6):444-51. 
10. Scheid L, Ellinger S, Alteheld B, et al. Kinetics of L-theanine uptake and metabolism in healthy participants are comparable after ingestion of L-theanine via capsules and green tea. J Nutr. Dec 2012;142(12):2091-6. doi:10.3945/jn.112.166371
11. Ota M, Wakabayashi C, Matsuo J, et al. Effect of L-theanine on sensorimotor gating in healthy human subjects. Psychiatry Clin Neurosci. May 2014;68(5):337-43. doi:10.1111/pcn.12134
12. Yoto A, Motoki M, Murao S, Yokogoshi H. Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses. J Physiol Anthropol. 2012;31:28. doi:10.1186/1880-6805-31-28
13. Lyon MR, Kapoor MP, Juneja LR. The effects of L-theanine (Suntheanine(R)) on objective sleep quality in boys with …: a randomized, double-blind, placebo-controlled clinical trial. Altern Med Rev. Dec 2011;16(4):348-54. 
14. Morgan PT, Pace-Schott EF, Mason GF, et al. Cortical GABA levels in primary …. Sleep. Jun 2012;35(6):807-14. doi:10.5665/sleep.1880
15. Meyerhoff DJ, Mon A, Metzler T, Neylan TC. Cortical gamma-aminobutyric acid and glutamate in … and their relationships to self-reported sleep quality. Sleep. May 2014;37(5):893-900. doi:10.5665/sleep.3654
16. Urrestarazu E, Iriarte J. Clinical management of sleep disturbances in …: current and emerging strategies. Nat Sci Sleep. 2016;8:21-33. doi:10.2147/NSS.S76706
17. Walecka-Kapica E, Klupinska G, Chojnacki J, Tomaszewska-Warda K, Blonska A, Chojnacki C. The effect of melatonin supplementation on the quality of sleep and weight status in postmenopausal women. Prz Menopauzalny. Dec 2014;13(6):334-8. doi:10.5114/pm.2014.47986
18. Costello RB, Lentino CV, Boyd CC, et al. The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature. Nutrition journal. 2014;13:106. doi:10.1186/1475-2891-13-106
19. McGrane IR, Leung JG, St Louis EK, Boeve BF. Melatonin … for REM sleep behavior …: a critical review of evidence. Sleep Med. Jan 2015;16(1):19-26. doi:10.1016/j.sleep.2014.09.011
20. Hardeland R. Neurobiology, pathophysiology, and … of melatonin deficiency and dysfunction. TheScientificWorldJournal. 2012;2012:640389. doi:10.1100/2012/640389
21. Jehan S, Masters-Isarilov A, Salifu I, et al. Sleep … in Postmenopausal Women. J Sleep Disord Ther. Aug 2015;4(5)doi:10.4172/2167-0277.1000212
22. Gobbi G, Comai S. Sleep well. Untangling the role of melatonin MT1 and MT2 receptors in sleep. J Pineal Res. Apr 2019;66(3):e12544. doi:10.1111/jpi.12544
23. Talbott SM, Talbott JA, Brownell L, Yimam M. UP165, A Standardized Corn Leaf Extract for Improving Sleep Quality and Mood State. Journal of medicinal food. Jan 2023;26(1):59-67. doi:10.1089/jmf.2021.0197
24. Pingali U, Pilli R, Fatima N. Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants. Pharmacognosy research. Jan 2014;6(1):12-8. doi:10.4103/0974-8490.122912
25. Kumar A, Kalonia H. Effect of Withania somnifera on Sleep-Wake Cycle in Sleep-Disturbed Rats: Possible GABAergic Mechanism. Indian J Pharm Sci. Nov 2008;70(6):806-10. doi:10.4103/0250-474X.49130
26. Pratte MA, Nanavati KB, Young V, Morley CP. An alternative …: a systematic review of human trial results reported for the Ayurvedic herb ashwagandha (Withania somnifera). Journal of alternative and complementary medicine. Dec 2014;20(12):901-8. doi:10.1089/acm.2014.0177
27. Dhar N, Razdan S, Rana S, Bhat WW, Vishwakarma R, Lattoo SK. A Decade of Molecular Understanding of Withanolide Biosynthesis and In vitro Studies in Withania somnifera (L.) Dunal: Prospects and Perspectives for Pathway Engineering. Frontiers in plant science. 2015;6:1031. doi:10.3389/fpls.2015.01031
28. Hirotsu C, Tufik S, Andersen ML. Interactions between sleep, stress, and metabolism: From physiological to pathological …. Sleep Sci. Nov 2015;8(3):143-52. doi:10.1016/j.slsci.2015.09.002
29. Givens ML, Malecki KC, Peppard PE, et al. Shiftwork, Sleep Habits, and Metabolic Disparities: Results from the Survey of the Health of Wisconsin. Sleep Health. Jun 2015;1(2):115-120. doi:10.1016/j.sleh.2015.04.014
30. Lo JC, Ong JL, Leong RL, Gooley JJ, Chee MW. Cognitive Performance, Sleepiness, and Mood in Partially Sleep Deprived Adolescents: The Need for Sleep Study. Sleep. 2016;39(3):687-98. doi:10.5665/sleep.5552
31. Krysta K, Krzystanek M, Bratek A, Krupka-Matuszczyk I. Sleep and … markers in different psychiatric …. J Neural Transm (Vienna). Dec 9 2015;doi:10.1007/s00702-015-1492-3
32. Cheng P, Drake C. Occupational Sleep …. Sleep medicine clinics. Mar 2016;11(1):65-79. doi:10.1016/j.jsmc.2015.10.006
33. Qiu H, Zhong R, Liu H, Zhang F, Li S, Le W. … Sleep Deprivation Exacerbates Learning-Memory … and … Pathologies in AbetaPPswe/PS1DeltaE9 Mice. J Alzheimers Dis. Jan 12 2016;50(3):669-85. doi:10.3233/JAD-150774
34. Periasamy S, Hsu DZ, Fu YH, Liu MY. Sleep deprivation-induced multi-organ …: role of oxidative stress and …. EXCLI J. 2015;14:672-83. doi:10.17179/excli2015-245
35. Han KS, Kim L, Shim I. Stress and sleep …. Exp Neurobiol. Dec 2012;21(4):141-50. doi:10.5607/en.2012.21.4.141
36. Postnova S, Fulcher R, Braun HA, Robinson PA. A minimal physiologically based model of the HPA axis under influence of the sleep-wake cycles. Pharmacopsychiatry. May 2013;46 Suppl 1:S36-43. doi:10.1055/s-0033-1333763
37. Jessop DS, Turner-Cobb JM. Measurement and meaning of salivary cortisol: a focus on health and … in children. Stress. Jan 2008;11(1):1-14. doi:10.1080/10253890701365527
38. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Journal of psychosomatic research. Oct 2002;53(4):865-71. 
39. de Kock A, Malan L, Hamer M, Cockeran M, Malan NT. Defensive coping and … - Adrenal fatigue in a cohort of Africans and Caucasians: The SABPA study. Physiology & behavior. Aug 1 2015;147:213-9. doi:10.1016/j.physbeh.2015.04.033
40. Suchecki D, Tiba PA, Machado RB. REM Sleep Rebound as an Adaptive Response to Stressful Situations. Front Neurol. 2012;3:41. doi:10.3389/fneur.2012.00041
41. Minkel J, Moreta M, Muto J, et al. Sleep deprivation potentiates HPA axis stress reactivity in healthy adults. Health psychology : official journal of the Division of Health Psychology, American Psychological Association. Nov 2014;33(11):1430-4. doi:10.1037/a0034219
42. Klumpers UM, Veltman DJ, van Tol MJ, et al. Neurophysiological effects of sleep deprivation in healthy adults, a pilot study. PLoS ONE. 2015;10(1):e0116906. doi:10.1371/journal.pone.0116906