Glycine - Improving Sleep Quality

Sleeping can be complicated business! Those individuals with no difficulty achieving healthy, regular sleep would think it the simplest of physiologic phenomena. Roughly 30% of the population suffers from insomnia, however,^[1] which has real and important health consequences, in addition to affecting quality of life. Even short-term sleep disruption is associated with metabolic problems, insulin insensitivity, poor bloodsugar control, increased body mass index (BMI), increased pain and inflammation levels, and even increased mortality.^[2] And pathogenic sleep disruption may be a hallmark of or contribute to both psychiatric ^[3] and neurodegenerative disorders.^[4]

If you’re among the thousands of individuals who suffer from sleep difficulties, you might be aware that modern science still has a relatively tenuous grasp on the complicated relationships between diet, hydration, emotional/spiritual health, environmental contributors, and brain chemistry related to sleep. This is an area that is receiving considerable attention in scientific study at present, and the findings are having far-reaching implications. Glycine’s role in sleep regulation is an excellent example. Glycine is a small, nonessential amino acid. It is relatively ubiquitous in our muscle tissue and skin, and it plays an important role in the regulation and support of many critical pathways. Previously considered to be biologically inert, unexpected findings in a study using glycine as a placebo to investigate the function of other amino acids on the brain led to a study on the effects of glycine on human sleep quality and patterns.^[5] Glycine undergoes passive diffusion through the blood-brain barrier and acts primarily on N-methyl-D-aspartate receptors (NMDA).^[5] Its actions on the NMDA receptor are believed responsible for inhibiting muscle activity during rapid eye movement (REM) sleep,^[6] and for lowering core body temperature to facilitate sleep.^{[7, 8]} Oral glycine administration also increases serotonin levels without increasing dopamine levels ^[5] to help normalize circadian rhythms. In addition to helping objectively normalize the physiology of sleep,^[8] oral glycine supplementation ameliorates the subjective symptoms of sleep deprivation.^[9] On testing, subjects report improved sleep satisfaction and decreased daytime sleepiness and cognitive impairment.^{[2, 9]} A pinch of glycine powder under the tongue can give immediate relief from “spinning thoughts” or over-thinking, which is a common complaint among insomniac patients and contributes to difficult sleep onset.^[9] Indeed, oral glycine powder at bedtime ameliorates all subjective symptoms of sleep deprivation, from morning fatigue to eye strain and feelings of unease and difficulty concentrating, as well as improving memory recognition.^{[10, 11]} This naturally sweet amino acid is safe for ongoing use as an oral supplement. At moderate doses, glycine supplementation can help normalize sleep architecture to restore the myriad benefits of restful, restorative sleep. 

Glycine and Mental Health

Glycine — this smallest and simplest of amino acids was first thought to be inert in its effects on physiology.^[6] But study in recent years shows this little molecule to be a powerhouse! We have already discussed the impact of glycine on normalizing sleep by acting on the NMDA receptors.^{[12, 13, 14, 15]} Through the same mechanism, oral glycine supplementation also helps normalize the brain chemistry of addiction and prevent relapse. Glycine is critically involved in regulating ethanol (alcohol) consumption.^[13] Elevating concentrations of glycine in the signalling junction between neurons has consistently been demonstrated to reduce alcohol intake,^[13] and inhibit drug-seeking for cocaine and amphetamines.^{[14, 15]} The mechanism of these effects is still poorly understood, but evidence suggests that increased glycine levels also attenuate the effects of amphetamines on the brain.^[14] To date, medicine has focused on blocking drug effects in order to treat and manage the physiology of addictions. The fact that glycine helps both attenuate the effects of drugs like alcohol, cocaine, and amphetamines, and to decrease the drive to consume these substances is very exciting. It’s so exciting, in fact, that a series of pharmaceutical drugs are currently being tested to modulate glycine uptake, in order to effectively increase the amount of glycine in the brain in therapeutic applications.^[16] Human trials have not yet reported their results for most of these medications, but we do know that simply supplementing with oral glycine will have similar effects!^[3]

We can utilize oral glycine to decrease the urge to consume drugs and alcohol (both in addicts and among moderate users),^[17] and to help block the effects when the drugs are consumed. But glycine doesn’t stop there! Supplementing with oral glycine can improve behavioural training to overcome addictions and prevent relapse (extinction training).^{[14, 18, 19]} It’s unclear whether these improvements are related to improved memory recall, such that recovering addicts are able to remember and employ their cognitive behavioural techniques.^[20] We do know, however, that changes to glycine levels in the brain correspond with improved attention, memory, impulsivity, emotional memory, and intellectual learning memory.^[21] These traits are all negatively impacted with addiction, so a treatment protocol with potential “side effects” that help normalize behaviour-related changes opens a world of possibilities. Glycine’s therapeutic uses to treat addictions go yet a step further. There is evidence that supplemental glycine helps reduce liver toxicity from chronic alcohol consumption and expedites recovery from alcohol-induced liver injury.^[22] Risks of oral glycine supplementation, even at therapeutic levels, are negligible. And so, for a vast number of reasons and applications, this little amino acid packs a big punch in addiction-recovery protocols. 

Brain Health

The growing body of evidence regarding impact of glycine levels in the brain does not end with sleep implications and addictions, though these effects alone are exciting for their therapeutic implications and potential improvement to quality of life. A good deal of study is also looking at the effects of supplementing oral glycine as part of pharmacologic management of schizophrenia to benefit patient outcomes.^[23] Since the late 1980s, there has been an understanding that glycine therapy is useful to treat negative symptoms of schizophrenia, such as depression and loss of mental fluency or flexibility.^[24] Recent double-blinded, placebo-controlled trials consistently support the conclusions that adding oral glycine to the pharmacologic protocols markedly improves negative symptoms and cognitive troubles, and may even improve psychotic symptoms in some cases.^{[25, 26, 27, 28]} Since negative symptoms of schizophrenia typically have a larger impact on real-world function and impact of the illness than do positive symptoms, such as psychosis, the finding that glycine supplementation can improve these devastating symptoms is highly significant. What’s more, these benefits to learning and memory retrieval appear to extend beyond applications to mental health and addiction recovery to healthy volunteers as well.^[3] 

As pharmaceutical companies develop drugs to mimic the impact of supplementing oral glycine, there is a renewed interest in the role of glycine on schizophrenic pathology. Current thinking is that impairment of the NMDA receptor system (stimulated by glycine) may actually be the cause and pathogenicity of schizophrenia.^{[29, 30]} This new insight into the effects of glycine on the brain spills into other psychiatric, mood, and cognitive disorders, ranging from psychosis and depression through neurodegenerative diseases such as Huntinton’s disease and Alzheimer’s disease.^[29] This line of scientific study has led to greater understanding of how oral glycine may even be of benefit in treating and managing brain injury and stroke.^{[30, 31, 32]} Examining regulation of NMDA receptors and amino-acid balance has led to potential implications with respect to ADHD and autism,^[31] and greater understanding of the neurochemistry of posttraumatic stress disorder and Parkinson’s.^[32] The implications are far-reaching and profound. While some of the study into these areas focuses on glycine supplementation directly, much is directed toward pharmacologic targets to inhibit NMDA receptors. Oral glycine supplementation may effectively accomplish the same task.^[5] However, while the safety profile of the pharmaceuticals has barely begun to be established, oral glycine supplementation has a well-established safety profile at therapeutic doses. As medical science continues to explore the therapeutic benefits of glycine supplementation, we will see a growing list of advantageous effects for adding this inexpensive amino acid to many therapeutic protocols.

Somatic Effects and Dosing

In addition to the psychiatric and neurochemical applications of glycine supplementation, recent studies are leading us to consider this powerhouse amino acid for somatic applications. We have already mentioned the hepatoprotective benefit of glycine supplementation in the context of chronic and acute alcohol abuse.^[33] We have also touched on the benefits to traumatic brain injury and stroke.^{[32, 34]} These demonstrate additional, nonpsychiatric benefits of glycine on other body tissues. Ischemia (loss of blood supply) is a major cause of death in trauma, surgery, and organ replacement. Glycine significantly reduces tissue damage and loss in these cases, though the mechanism is not fully understood. What is clear is that glycine has direct cell-protective effects.^[35] It protects against the damage of the inflammatory response, which is triggered as bloodflow returns to ischemic areas (ischemic reperfusion injury).^{[35, 36]} These cell-protective and anti-inflammatory effects are not limited to tissue trauma due to ischemia. In fact, the anti-inflammatory benefits of glycine have been applied to the prevention and treatment of other inflammatory conditions. Inflammation is the primary mechanism in arthritis. Animal studies indicate that oral glycine supplementation can mitigate this inflammatory process,^[5] and mechanistic study suggests these effects have multiple potential therapeutic applications in humans as well.^{[37, 38]} Conditions such as ulcerative colitis,^[39] inflammatory pain,^[40] muscle wasting in cancer,^[41] and even inflammatory contributors to obesity ^{[42, 43, 44]} show improvement with glycine supplementation. With the growing body of data supporting therapeutic use of supplemental glycine, it is important to note that appropriate dosing is not clearly established for most applications. Table 1 reflects established dosing.

The safety of glycine supplementation has been clearly established. Surgeons routinely utilize an irrigation solution of glycine during procedures, delivering relatively high-dose glycine without adverse effects. Clinical trials have investigated oral glycine supplementation in humans quite thoroughly, indicating that long-term oral doses of 31 g/d ^[44] and 50 g/d ^[5] yield no adverse events. Short-term studies of 200 mg/kg daily of IV glycine also yielded no adverse effects.^[5] While more study is required to fully elucidate the full breadth and potential of therapeutic glycine, the mounting body of evidence is certainly exciting.