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Posted by Dr. Kate Placzek on Friday, 10 August 2018

Glycine – A Small Molecule with a Big Impact on Sleep

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Glycine has a calming effect on the brain it helps you wind down and prepare for sleep – its role as an inhibitory neurotransmitter has been unfolding over many years of ongoing research efforts.

Easily one of the most versatile amino acids, glycine serves as a building block to proteins (collagen, the most abundant protein in our body, is one-third glycine), and is heavily utilized for the production of heme, DNA and RNA synthesis, glutathione formation, and for enriching the body’s capacity for methylation reactions [1] [2].

Sleep Problems

People need sleep. It is our basic human need. Too many of us experience sleep problems. Laying there restless, counting sheep, watching the hostile glow of the green numbers, fearing the absence of sleep – this dreaded scenario of sleep-deprived desperation is all too familiar. Needless to say, sleep issues have become a pervasive health problem, and research shows that lack of sleep affects everything from mental competence to increased risk of chronic diseases and cancer.

Glycine Promotes Sleep Without Altering Sleep Architecture

When human volunteers who have continuously experienced unsatisfactory sleep were given 3 g glycine before bedtime, their sleep improved [3]. Using polysomnography, a type of diagnostic tool in sleep studies, glycine was shown to shorten the amount of time to fall asleep and stabilize sleep state, with no alterations in sleep architecture, unlike with traditional hypnotic drugs. Glycine promoted normal nocturnal sleep cycles, from deeper to shallower with very few interruptions.

Glycine Lowers Core Body Temperature

So what is it about this tiny amino acid that could be so powerful in contributing to regulating such a complex process as sleep? First of all, glycine taken orally has easy access to the brain – it readily crosses the blood brain barrier via glycine transporters [4]. Once in the brain, glycine targets glutamate NMDA receptors in the suprachiasmatic nucleus (SCN) – the 24-hour biological clock in the central nervous system that controls when we want to be asleep and awake.

By modulating NMDA receptors in the SCN, glycine induces vasodilation throughout the body to promote lowering of core body temperature [5]. Sleep and body temperature are intertwined – in its circadian oscillation, body temperature decreases before the onset of sleep and continues to decrease throughout the night, reaching its nadir about 2 hours after sleep onset, and gradually rising as a person wakes [6]. Temperature is just one of many 24-hour rhythms our bodies experience throughout the day and as nighttime approaches – the drop is important for initiating sleep. Glycine’s effect on thermoregulation is similar to that of common prescription sleep medications that also work by reducing core body temperature to promote sleep [7] [8].

Unlike many sleep aids out there, nutraceutical or pharmaceutical, that promote sleep and leave you groggy the next day, glycine actually corrects feelings of fatigue and sleepiness during the day.

Additional mechanisms that glycine may rely on to promote sleep include inhibiting orexin neurons – the “wakefulness” neurons (the absence of which is implied in narcolepsy) [9]. However, more research is needed to fully elucidate this process.

Glycine Improves Daytime Performance

Here’s the exciting part – unlike many sleep aids out there, nutraceutical or pharmaceutical, that promote sleep and leave you groggy the next day, glycine actually corrects feelings of fatigue and sleepiness during the day [10]. Sleep-restricted volunteers receiving glycine, after waking, showed improved reaction times in in the psychomotor vigilance test compared to the placebo group and reported feeling refreshed.

Glycine Regulates Daytime Wakefulness

Glycine was found to contribute to yet another circadian process – stimulating the expression of arginine vasopressin – a neuropeptide produced in the SCN. Animal studies show that the expression levels of arginine vasopressin were increased during the day in the glycine treatment group [10].

Arginine vasopressin serves as an output signal of the hypothalamic biological clock, an important modulator of circadian processes involving the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes and the autonomic nervous system [11]. Specifically to the HPA axis, arginine vasopressin synergizes signaling with corticotropin releasing hormone (CRH) to facilitate the release of adrenocorticotropic hormone (ACTH) to ultimately trigger the production of cortisol from the adrenal glands, thus contributing to the state of wakefulness [12].

Sleep isn’t just a time to rest. It’s an active process of cleaning out toxins and repairing brain cells damaged by free radicals [13]. Think about sleep as a form of neural sanitization – during sleep, waste products of brain metabolic processes are removed from the tiny spaces between brain cells where they can accumulate [14]. Sleep, therefore, is a kind of a power cleanse that restores and rejuvenates our brain for optimal function [15]. Considering glycine's prominent role in detoxifications processes, as future research studies unfold, it would be exciting to see what additional processes glycine helps regulate to support a healthy brain.

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References 

[1] M.A. Razak, P.S. Begum, B. Viswanath, S. Rajagopal, Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review, Oxid Med Cell Longev 2017 (2017) 1716701.

[2] M.F. McCarty, J.H. O'Keefe, J.J. DiNicolantonio, Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection, Ochsner J 18(1) (2018) 81-87.

[3] W.I. Yamadera, K.; Chiba, S.; Bannai, M.; Takahashi, M., Nakayama, K., Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes, Sleep and Biological Rhythms 5 (2007).

[4] A. Kurolap, A. Armbruster, T. Hershkovitz, K. Hauf, A. Mory, T. Paperna, E. Hannappel, G. Tal, Y. Nijem, E. Sella, M. Mahajnah, A. Ilivitzki, D. Hershkovitz, N. Ekhilevitch, H. Mandel, V. Eulenburg, H.N. Baris, Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine, Am J Hum Genet 99(5) (2016) 1172-1180.

[5] N. Kawai, N. Sakai, M. Okuro, S. Karakawa, Y. Tsuneyoshi, N. Kawasaki, T. Takeda, M. Bannai, S. Nishino, The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus, Neuropsychopharmacology 40(6) (2015) 1405-16.

[6] M. Bannai, N. Kawai, New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep, J Pharmacol Sci 118(2) (2012) 145-8.

[7] R.R. Markwald, T.L. Lee-Chiong, T.M. Burke, J.A. Snider, K.P. Wright, Jr., Effects of the melatonin MT-1/MT-2 agonist ramelteon on daytime body temperature and sleep, Sleep 33(6) (2010) 825-31.

[8] E.E. Elliot, J.M. White, The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry, Neuropharmacology 40(5) (2001) 717-21.

[9] M. Hondo, N. Furutani, M. Yamasaki, M. Watanabe, T. Sakurai, Orexin neurons receive glycinergic innervations, PLoS One 6(9) (2011) e25076.

[10] M. Bannai, N. Kawai, K. Ono, K. Nakahara, N. Murakami, The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers, Front Neurol 3 (2012) 61.

[11] A. Kalsbeek, E. Fliers, M.A. Hofman, D.F. Swaab, R.M. Buijs, Vasopressin and the output of the hypothalamic biological clock, J Neuroendocrinol 22(5) (2010) 362-72.

[12] H.K. Caldwell, E.A. Aulino, K.M. Rodriguez, S.K. Witchey, A.M. Yaw, Social Context, Stress, Neuropsychiatric Disorders, and the Vasopressin 1b Receptor, Front Neurosci 11 (2017) 567.

[13] A.R. Eugene, J. Masiak, The Neuroprotective Aspects of Sleep, MEDtube Sci 3(1) (2015) 35-40.

[14] L. Xie, H. Kang, Q. Xu, M.J. Chen, Y. Liao, M. Thiyagarajan, J. O'Donnell, D.J. Christensen, C. Nicholson, J.J. Iliff, T. Takano, R. Deane, M. Nedergaard, Sleep Drives Metabolite Clearance from the Adult Brain, Science 342(6156) (10/18/2013) 373-377.

[15] A.R. Mendelsohn, J.W. Larrick, Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases, Rejuvenation Res 16(6) (2013) 518-23.

Tagged in: Sleep brain health Neurotransmitters Mental Health