Glycine is one the simplest amino acid yet has some remarkable and unexpected functions within the body. Glycine is found in most protein-based foods, and is also synthesised in the body, yet, mounting evidence indicates that almost everybody would benefit from supplementing with this readily available and cheap nutrient.
◀ STRUCTURE OF GLYCINE
All amino acids have the same basic molecular structure only differing in the pattern of atoms found in their side chain (R). Glycine is the simplest amino acid, having just a single hydrogen atom in this position.
As a building-block glycine is needed for synthesising a range of important proteins, including serine, sarcosine, purine, creatine, haemoglobin, glutathione, and collagen — the most abundant protein in the human body [Adeva-Andany, 2018], BUT it has dozens of other functions and properties, acting across many bio-chemical systems and operates on many levels, often synergistically.
In this article we will look at the growing evidence that makes a strong case for supplementing with 10g of glycine per day. Here are the ten reasons in brief (clicking on a heading takes you to that section in the main article)…
- Everyone is glycine deficient due to an evolutionary bottleneck that limits the quantity we can synthesise
- Supplementing glycine at 10g per day improves collagen synthesis by 200%
- Glycine has a range of anti-inflammatory effects
- Glycine has stabilising effects on the central nervous system and improves sleep
- Glycine has a range of anti-obesity and anti-diabetic effects
- Glycine protects cells from damage due to injury, trauma, hypoxia, cold etc
- Glycine protects the stomach and intestines, reducing inflammation and ulceration
- Glycine increases the body’s antioxidant capacity and enhances detoxification by multiple pathways
- Glycine has a range of benefits for the cardiovascular system, improving clotting, heart function and improving blood lipids
- Glycine has longevity, anti-glycation and anti-cancer properties
In supplemental form, glycine is a white crystalline solid, which looks surprisingly like sugar and is readily soluble in warm water. Indeed glycine is one of the sweetest amino-acids, being ⅓ as sweet as table sugar.
One of the easiest ways to increase your daily glycine intake is to use it as a sugar substitute in deserts and hot drinks. Unlike sugar, glycine does not induce tooth decay. Taken with food it actually reduces blood-sugar rise compared to the same meal without glycine. It’s final trick as a sugar substitute is that it reduces hunger through stimulation of gut hormones. Glycine can also be added to soups and sauces were its mild-sweetness complements savoury flavours.
That’s the basic low-down. If you want the details, and I think you do, read on!
10 Reasons to supplement with Glycine
Everyone is glycine deficient
Because the body can synthesise glycine from other proteins it had originally been classed as a non-essential nutrient. However, it turns out that due to an evolutionary bottleneck all fish, birds and mammals (including humans), are unable to manufacture sufficient quantities of glycine for optimal collagen synthesis. [Alves, 2019]
This evolutionary limitation explains why osteoarthritis is one of the few chronic diseases that has been observed in wild animals, including elephants, rhinos and primates, as well as being evident in the fossil record of otherwise healthy humans. Without sufficient collagen to replace ageing cartilage osteoarthritis can ensue.
Although the body can synthesise glycine, a number of competitive metabolic processes limit the amount that can be produced. The vast majority of glycine synthesised in the human body comes from serine, with theoretical calculations indicating that humans can only synthesise about 2.5 g of glycine each day.
The remainder of the glycine in the body comes from diet, being found primarily in high protein foods such as fish, meat, eggs and legumes. Hence, dietary intake varies from about 1.5 to 3 g/day, depending on the amount of protein in the diet . Glycine intake among vegetarians and vegans is typically much lower than that of omnivores, although their blood levels of glycine are often similar. This paradox may be explained by the fact that meat is also high in the amino acid methionine, and methionine ‘uses up’ glycine during its metabolism. [Alves, 2019]
Studies of glycine-dependent metabolic processes has shown that many are limited by glycine availability, often in a dose-dependnent manner; and in many cases these are running at well below their maximum efficiency. Observations such as these add weight to the hypothesis that humans are chronically deficient in glycine. This deficiency is insufficient to affect health before reproduction so has undergone little selective pressure over evolutionary time. Instead, glycine deficiency appears to manifest primarily in later life through processes associated with ageing. Consequently, many researchers have reclassified glycine as conditionally essential, or essential. Further evidence has come from multiple studies which have demonstrated health benefits from supplementing at doses between 5g and 40g per day.
How big is the glycine deficit?
A detailed study of the body’s glycine requirements compared to the amount available from glycine synthesis and diet suggests that the adult body runs a deficit of about 10g per day. [Meléndez-Hevia et al, 2009]
…glycine must be considered an essential amino acid because the capacity of its synthesis is much lower than its actual need. We also showed that this deficiency is not covered with a regular diet so glycine should be added to it as a nutritional supplement in high amounts, about 10 g/day.Paz-Lugo et al, 2018
Benefits of glycine supplementation
This deficit means that in many glycine-dependent health-pathways are significantly increased when glycine is supplemented. A short list of such benefits include:
- Preventing tissue injury
- Enhancing anti-oxidative capacity
- Promoting protein synthesis and wound healing
- Improving immunity; and
- Treating metabolic disorders such as obesity and diabetes, cardiovascular disease, ischemia-reperfusion injuries, cancers, and various inflammatory diseases.
These multiple beneficial effects of glycine, coupled with its insufficient de novo synthesis, support the notion that it is a conditionally essential and also a functional amino acid for mammals (including humans).Wang et al, 2013
Glycine and Collagen Synthesis
Collagen makes up one-third of the protein in the body. Every third amino-acid in collagen is glycine making it the most abundant amino acid in collagen [Li & Wu, 2017].
Two other important amino acids for collagen synthesis are proline and lysine — the latter being required for the scaffolding. Studies indicate that whilst normal blood levels of lysine and proline are optimal for collagen synthesis, glycine levels are well below their optimal concentrations. Supplementing with 10g of glycine per day would therefore be expected to increase collagen synthesis by 200%. [Paz Lugo et al, 2018]
As we age the collagen in our body deteriorates and becomes harder to replace. This is especially important in conditions such as osteoarthritis (which affects up to 40% of over 65’s) where regeneration of damaged cartilage requires considerable collagen synthesis. Recent studies have shown that such synthesis is primarily limited by glycine availability, and that normal levels of dietary glycine are simply inadequate to replace collagen. Supplementary glycine is therefore necessary to rebuild collagen.
[Paz-Lugo et al, 2018]
Tendons are primarily composed of collagen but due to a poor blood supply can be slow to heal following injury or inflammation. An animal study found that glycine was able to reduce inflammation and increase cartilage remodelling of the Achilles tendon. “The glycine diet stimulated the synthesis of hydroxyproline, glycosaminoglycans, non‐collagenous proteins and appeared to maintain or improve the organization of collagen molecules. The biomechanical results indicated that the tendon was more resistant to mechanical loading upon treatment with a glycine diet. Glycine also induced a rapid remodeling of tissue when compared with the groups without treatment.”
The data from this study suggest that dietary glycine supplementation may be a useful therapeutic adjunct for individuals with inflammatory injuries of tendons, such as Achilles tendon injuries, and perhaps other types of connective tissue injuries and inflammatory events.Pedrozo Vieira et al, 2014
A more recent study has shown that tenocytes (the primary cells in tendons, responsible for tissue repair) respond favourably to glycine, improving the remodelling process. [Vieera et al, 2018]
Glycine vs Collagen / Gelatine Supplements
Some of the most visible signs of ageing are due to the limitations of collagen remodelling as we get older. From the age of 25 collagen breakdown exceeds collagen replacement, leading to wrinkles, sagging and lack of tone in the skin, as well as an increased risk of osteoarthritis and other joint problems. Less visible is the increased risk of osteoporosis as collagen-loss affects bone strength. Little direct information is available on how glycine supplementation might affect these processes, but research using collagen or gelatine may be informative.
Currently, the bulk of the anti-aging research has revolved around the internal and external applications of collagen peptides and/or gelatine hydrosolates. Both of these materials, being derived from collagen-rich connective tissue, contain substantial amounts of glycine. Although these supplements might be expected to provide all of the materials necessary to form new collagen, there is evidence that (a) only a small fraction of the amino-acids can be successfully recovered from these products; (b) humans are generally replete in the required amino acids proline and lysine, but deficient in glycine, and (c) the amount of glycine available from hydrolysed collagen or gelatine is likely too small to meet the requirements of collagen synthesis. [de Paz-Lugo et al, 2018] So, it may well be that many of the positive results seen in collagen/gelatine studies may largely be due to the glycine content in these products, and that supplementing with 10g of glycine per day would achieve many of the reported benefits of collagen or gelatine, but more effectively and cheaper.
By way of example, in a recent human trial pilot study researchers used a collagen peptide which they emphasised was “high in glycine” and were able to demonstrate improved symptoms and tendon vascularisation in patients with chronic Achilles tendinopathy in combination with structured exercise. [Praet et al, 2019]
Increasing glycine in the diet may well be a strategy for helping cartilage regeneration by enhancing collagen synthesis, which could contribute to the treatment and prevention of osteoarthritis.
Anti-inflammatory effects of Glycine
Glycine reduces the activation of inflammatory cells, including macrophages and neutrophils.
A randomised pilot trial of glycine supplementation in young Cystic Fibrosis patients demonstrated improvements in symptoms (sputum), multiple inflammatory markers and breathing capacity in just 8 weeks, compared to controls. Cystic Fibrosis patients lose approximately 2% Forced Expiration Volume capacity every year. In this study the glycine group improved their FEV by 10% in just 8 weeks. The researchers noted that glycine was ‘remarkably well tolerated’, and did not show any negative side effects: a notable contrast to the typical pharmaceuticals used to control this condition. [Vargas et al, 2017]
Gums and Mouth
There is some evidence that glycine may be effective in gingivitis [Schaumann et al, 2013; Lu et al, 2018] Water jets containing glycine are currently under investigation for use during dental work. A rodent trial of glycine in mucositis — a painful oral inflammation experienced by cancer patients from the toxic side-effects of chemotherapy — demonstrated marked healing of the oral mucosa
It should be noted that glycine supplementation is simple to perform, has a low cost, and does not require an invasive method of treatment.Sá et al, 2018
Neurological effects of glycine
Glycine is found in the spinal cord and brainstem where it acts as an inhibitory neurotransmitter via its own system of receptors. Glycine receptors are ubiquitous throughout the nervous system and play important roles during brain development. [Ito, 2016] Glycine also interacts with the glutaminergic neurotransmission system via NMDA receptors, where both glycine and glutamate are required, again, chiefly exerting inhibitory effects.
Have you ever wondered why you don’t physically act out your dreams while you sleep? You have glycine to thank for that! 30 years ago it was discovered that glycine mediates the suppression of muscle movement during REM sleep. [Soja, 2008]
Glycine supplementation has been shown to improve and deepen sleep without altering the circadian clock or interfering with major sleep-wake hormones. A reduction in core temperature and reduction in REM sleep appears significant.
Glycine ingestion before bedtime has been shown to improve both subjective and objective sleep quality in people who have difficulty sleeping. Furthermore, partially-sleep-deprived subjects who were given glycine before bed had improved daytime performance over those who did not receive glycine. [Bannai, 2012]
There has been no reports of glycine causing drowsiness when taken during the day.
There is a single case study of a 17 year old who suffered from Obsessive Compulsive Disorder (OCD) which was not controlled by conventional drugs. At age 22 he was placed on high dose glycine and remained on it for 5 years. During this time there was a robust reduction in symptoms, except for periods when treatment lapsed. [Louis Cleveland et al, 2010]
The role of glycine in neurological disorders is relatively new field of study. In the last few years it has been found that first-episode psychosis patients show abnormal concentrations of glycine and glutamate in the brain [Kim et al, 2018], and that in Alcohol Use Disorder, brain glycine levels are are inversely correlated to the number of heavy drinking days.
Several studies involving schizophrenia patients have found reduction in symptoms using high-dose glycine supplementation (approx. 48g/day), where a mean reduction in negative symptoms of 23% was observed. The action appears to be via glycine’s role as a coagonist of the NMDA receptor. [Heresco-Levy et al, 1999 & 2004, Strzelecki & Rabe-Jabłońska, 2011,]
Ischemic stroke damages the brain through neurological-excitation (excitotoxicity) of the glutamate NMDA-receptors and oxidative stress. Glycine’s neuroprotective and antioxidant properties makes it a valuable treatment immediately after stroke.
Several Russian trials established that administering 1-2g of glycine per day, under the tongue, beginning within 6 hours of stroke onset for 5 days, reduced oxidative stress, stabilised neurotransmitters and reduced mortality in the subsequent 30 days. [Gusev et al, 1999, 2000];
A more recent study indicates that glycine can also protect neurones from death following hemorrhagic stroke. [Zhao et al. 2018]
Glycine’s metabolic and anti-obesity effects
Glycine has been shown to act on multiple pathways that are involved in the development of metabolic syndrome indicating its possible use in preventing and treating metabolic disorders such as obesity and diabetes.
Blood glycine levels are routinely found to be depressed in patients with obesity and diabetes. Adding glycine to the diet has been shown to exert a range of anti-diabetic effects as well as stimulating insulin secretion. There is some evidence that it also directly binds to glucose, reducing the amount of free glucose in the blood. [Chilukuri, Feb 2018]
Glycine acts via multiple pathways that benefit metabolic diseases
Glycine acts to inhibit (red) oxidative stress, hepatic glucose production and food intake. It also positively influences (green) hormonal and immune responses, enhances methylation (MTHFR), improves detoxification and supports mitochondrial function.
In obese mice, dietary glycine supplementation has been shown to improve both glucose tolerance and raised triglycerides, preventing body weight gain, accumulation of liver fat and associated inflammation. Similar effects were seen in rats fed a high-fat and sucrose diet where glycine supplementation protected them from liver damage.
Glycine has the ability to lower blood glucose, normalise lipid metabolism and reduce inflammation.
A trial including 60 adults with metabolic syndrome found that a dose of 15 g/day of glycine led to a marked decrease in markers of oxidative stress, along with a significant reduction in systolic blood pressure. [Diaz-Flores, 2013] Supplementing at this level can easily lead to a seven-fold increase in circulating blood glycine levels. [McCarty & DiNicolantonio, 2019]
it is interesting to speculate what benefits might be seen if all fizzy drink manufacturers replaced the sugar with glycine.
Fatty Liver (NAFLD)
Glycine has been shown to protect the liver from non-alcoholic fatty liver disease (NAFLD). In a rat study, those fed glycine had reduced harm from a high-sugar diet with better liver markers, lower oxidative stress and less liver fat accumulation than those without glycine. [Alves et al, 2019]
Supplementing with 5 g of glycine per day has been shown to improve insulin response and glucose tolerance. In a study of healthy subjects, when taken with food, glycine reduced the blood glucose rise (area under curve) by more than 50% without altering insulin response [Gannon et al, 2002]
In an animal study, diabetic rats treated with glycine for six months showed significant lower concentrations of glucose, total cholesterol, triacylglycerol, and glycated hemoglobin than diabetic control rats. [Alvarado-Vásquez et al, 2003]
In a 3 month trial patients with type 2 diabetes given 5g per day of glycine had a significant decrease in HbA1C and in proinflammatory cytokines, and also an important increase of IFN-gamma.
Treatment with glycine is likely to have a beneficial effect on innate and adaptive immune responses and may help prevent tissue damage caused by chronic inflammation in patients with Type 2 diabetes.Cruz et al 2008
Recent rodent studies have demonstrated that high glycine supplementation mitigated the effects of a high sucrose diet, improved mitochondrial function in the liver and corrected “an elevation of blood pressure, normalised the serum triglycerides and insulin, prevented an increase in abdominal fat mass and, in the vasculature, boosted glutathione, decreased oxidative stress and normalised endothelium-dependent vasodilation,” which so impressed the authors that they titled their paper The cardiometabolic benefits of glycine: Is glycine an ‘antidote’ to dietary fructose? [McCarty &DiNicolantonio, BMJ, 2014]
Table summarising metabolic studies of glycine
|Population||Health Status||Dose and Duration||Health Impacts of Glycine Supplementation||Reference|
Age: 21 to 52 y
|Healthy patients||Single oral morning dose of 5 g glycine +/− 25 g glucose vs. water +/− 25 g glucose||Improves insulin response and glucose tolerance in response to glucose ingestion||[Pubmed]|
Age: 23.7 ± 4.1 y
|Healthy lean patients with first degree relatives of T2DM||Single oral morning dose of 5 g glycine vs. magnesium oxide (placebo)||Improves insulin response, measured during an euglycemic-hyperinsulinemic clamp; No significant alteration in insulin action||[Pubmed]|
Age: 35 to 65 y
|Patients with MetS (NCEP/ATP III criteria)||15 g glycine/day (3 times 5 g/d) dissolved in water vs. starch (placebo) for 3 months||Improves systolic blood pressure in men; Protects against oxidative damages determined from antioxidant enzymes activity in erythrocytes and leukocytes, and thiobarbituric acid reactive substances (TBARS) in plasma||[Pubmed]|
Age: 56.1 ± 1.0 y
|Patients with HIV||1.33 mmol glycine/kg/day with 0.81 mmol/kg/day N-acetylcysteine for 14 days||Improves insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp before and after supplementation||[Pubmed]|
|Male Sprague Dawley rats: n = 48||High fat/high sucrose feeding vs. standard chow for 24 weeks||3.5 g glycine/kg/day in water vs. water (placebo) for 24 weeks||Improves hepatic steatosis assessed histologically||[Pubmed]|
|Male KK-Ay mice: n= 5/group|
Age: 7 weeks
|Animal model of obesity and T2DM||Semisynthetic diet containing 5% glycine vs. casein (placebo) for 4 weeks||Improves hepatic steatosis assessed histologically Improves glucose tolerance measured during a glucose tolerance test||[Pubmed]|
Glycine protects cells
Glycine protects against shock caused by hemorrhage, endotoxin and sepsis, prevents ischemia/reperfusion and cold storage/reperfusion injury to a variety of tissues and organs including liver, kidney, heart, intestine and skeletal muscle, and diminishes liver and renal injury caused by hepatic and renal toxicants and drugs.L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent., Zhong et al, 2003
Glycine’s ability to protect cells and prevent cell injury and death, has been robustly and repeatedly demonstrated over the last 28 years. The main mechanism appears to be glycine’s ability to “to stabilize porous defects that develop in the plasma membranes of ischemic cells, leading to leakage of macromolecules and subsequent cell death.” [Van den Eynden et al, 2009]
Glycine also exerts separate, but complimentary positive effects on inflammatory cell signalling that can combine to protect and prevent tissue damage in a variety of disease states. [Weinberg et al. 2016]
Glycine has the ability to protect cells from ischaemia–reperfusion injury, including neurons, intestinal, skeletal, heart, kidney and liver cells [Pan et al, 2009] which give it a role in organ transplant.
- Protection from hypoxia (lack of oxygen)
- Protection from iron-induced injury
- Protection from re-warming after cold preservation of both kidneys and livers awaiting transplantation
- Protection from bacterial and fungal toxins that target cell permeability barriers
- Protection from ATP (i.e. cellular energy) depletion
Glycine Therapy to Prevent Organ Transplantation Failure
“These days’ non-heart-beating donors are gaining more importance as good source of transplantable organs due to severe shortage of donor organs for clinical use. The grafts from non-heart-beating donors are treated with 25 mg/kg of glycine during normothermic recirculation to decrease reperfusion injury to endothelial cells and parenchymal cells after organ transplantation . After human liver transplantation glycine is intravenously infused to minimize the reperfusion injury. Before implantation, recipients are given 250 ml of 300 mM glycine for one hour and after transplantation 25 ml of glycine is given daily.” [Abdul Razak, 2017]
In contrast to the above, there have been calls to abandon the use of glycine irrigation during TURP (trans urethral resection of the prostate) as it appears to lead to worse outcomes when compared with alternative irrigation solutions. [Hahn, 2013]
Glycine protects the stomach and gut
Glycine receptors are expressed on the lining of the intestines. When glycine is present in the intestines these receptors stimulate the release of the hormone glucagon-like peptide-1 (GLP-1), which has a range of effects including boosting fatty acid oxidation (i.e. using fat for energy production) in the liver, and satiety signalling (reducing appetite).
Glycine receptors have also been shown to improve the mucosal barrier, protect the gut from inflammation, oxidative stress and a variety of toxins, by a variety of mechanisms, including increased production of glutathione, our most potent antioxidant. In an animal study glycine protected rat intestines from damage in a chemical model of colitis. [McCole, 2010]
Glycine may be important to the proper development of the intestines. A study in piglets demonstrated that dietary supplementation was necessary to ensure optimal intestinal development in piglets. They also noted that reduced concentrations of glycine in the lumen of the small intestine were associated with gut dysfunction in low-birth-weight piglets. [Li et al, 2016]
Glycine can protect the stomach from overproduction of acid such as occurs in gastric ulcers, in a dose dependent manner. Pretreatment with glycine has been shown to protect the stomachs from ulceration by injury and alcohol. These results have led researchers to state that “glycine possesses significant anti-ulcer and cytoprotective activity.” [Tariq & Moutaery, 1997]
Glycine protects the liver from alcohol toxicity, reduces blood alcohol levels, and reduces the accumulation of free-fatty acid levels in the brain and liver caused by alcohol intoxication. Glycine supplementation also reduced the lipid levels associated with alcoholic dislipidemia [Abdul Razak, 2017]
Leaky gut and endotoxins
Glycine is able to reduce leaky gut, thereby reducing bacterial gut toxins (endotoxins), such as lipopolysaccharides, passing into the blood. Glycine is further, able to bind such proteins and reduce the inflammatory response associated with them. [Xin Zhou et al, 2016]
The ability of glycine to reduce gut permeability may have benefits in autoimmune conditions, but there has been no research to date.
Anti-oxidant and detoxification effects
When considering antioxidants, many people think about vitamin A, C, E and selenium. However, more important than these dietary antioxidants is your body’s own natural antioxidant system, which produces a range of biochemical of which glutathione is arguably the most important and is found in every part of the body.
Glutathione production is limited by a number of factors which can seriously compromise an individuals detoxification potential and anti-oxidant response.
Glutathione is synthesised from the amino acids glutamate, cysteine, and glycine, but studies have shown that the rate of synthesis is primarily determined by levels of glycine in the tissue. If there is insufficient glycine available the glutathione precursor molecules are excreted in the urine. Vegetarians excrete 80% more of these precursors than their omnivore counterparts indicating a more limited ability to complete the synthesis process. [McCarthy et al, 2018]
Supplementing with glycine has been shown to increase the rate of glutathione synthesis while reducing markers of oxidative stress and protecting associated tissue from damage [Gould & Pazdro, May 2019]
However, there are other ways that glycine improves antioxidant response, for example by increasing the liver’s production of pyruvate which is an effective free-radical scavenger.
The body’s built-in antioxidant system is dynamic, being cranked up under certain circumstances (such as during an infection) and down regulated under others. A key regulatory pathway is controlled by Nrf2 signalling. In many glycine supplementation studies, Nrf2 has been shown to be up-regulated by glycine supplementation. [Wang, 2019]
Glycine has been shown to reduce the toxic effects of heavy metals such as lead and cadmium on the liver and kidneys. In one study it was shown that glycine supplementation significantly reduced lead accumulation in bone and completely restored the structural liver damage associated with lead poisoning . [Alcaraz-Contreras, 2011; Shaikh and Tang, 1999]
In a cadmium toxicity study glycine was able to counteract many of the effects significantly reducing the inflammatory response of macrophages.
[Our] findings support the immense antioxidant role of glycineOkoto & Awhin, Food and Chemical Toxicology, 2010
Glycine’s role in detoxification
So we have seen that glycine can support detoxification indirectly via up-regulating Nrf2 signalling and stimulating glutathione production, however, recent evidence has shown that glycine has a direct detoxification pathway of its own.
Glycine is able to bind a number of toxins and toxic metabolites (e.g., benzoate, derivatives of branched chain amino acids (BCAA), β-oxidation intermediates and metabolites of polyphenols). In doing so it makes these compounds less toxic and more soluble, enabling them to be excreted in the urine. [Irwin et al, 2016, Alves at al, Nutrients, 2019]
Glycine and taurine are two of the amino acids involved in the formation of bile acids. Bile is made in the liver and stored in the gall bladder, ready for appropriate deployment when dietary fat is detected. Of the two, glycine is the more important and the formation of the glycine conjugated bile acids has been shown to be limited by the availability of glycine. The bile acid cycle is one of the body’s main detoxification pathways. [Alves at al, Nutrients, 2019]
Glycine’s heart health benefits
There is growing evidence of a protective effect of glycine on coronary heart disease.[Wittemans et al, 2019]
Studies comparing individual amino acid intake to incidence of cardiovascular outcomes identify certain amino-acids as “protective”. High intakes of the potentially cardioprotective amino acids (arginine, cysteine, glutamic acid, glycine, histidine, leucine and tyrosine) correlated with a 74% decreased incidence of CVD events, whereas high intake of glutamic acid and proline correlated with a 30% increased risk. [Mirmiran et al, 2017]
Furthermore, blood glycine levels negatively correlate with acute myocardial infarction risk and are associated with a favourable lipid and inflammatory blood profile.
A key mechanism of glycine is its ability to activate glycine-gated chloride channels which are found on many cells including on Kupffer cells (liver cells), macrophages, lymphocytes, platelets, cardiomyocytes (heart cells) and endothelial cells (including in artery walls). Supplemenal glycine has been found to exert “anti-inflammatory, immunomodulatory, cytoprotective, platelet-stabilising and anti-angiogenic effects in rodent studies” [McCarty & DiNicolantonio, BMJ, 2014]
Glycine supplementation shows many of the “blood thinning” benefits of aspirin, but without the side-effects:
- Reduced platelet aggregation
- Increased bleed time
- Improved microcirculation
- Reduced inflammation
Hence in relation to conditions such as cardiovascular disease, stroke and sudden death researchers are saying:
…dietary supplementation with glycine should be of immense benefit in preventing diseases where increased platelet aggregation and thrombosis are involved.Schemmer et al, 2012
Young at heart
Aging is associated with a deterioration in heart function, including arterial stiffening and diastolic dysfunction. Furthermore, the mitochondria of old hearts can no longer metabolise fatty acids effectively so glucose becomes their primary energy source. Remarkably, glycine supplementation may help restore some of the heart’s youthful qualities.
In a study of old mice, a supplement of glycine and N-acetyl cysteine was found to improve many aspects of heart function (diastolic function, increasing peak early filling velocity, and reducing relaxation time, left atrial volume, and left ventricle end diastolic pressure), as well as stimulating youthful gene expression and function in heart mitochondria. The heart cells of supplemented mice regained the ability to burn fatty acids. Interestingly, N-acetyl cysteine alone failed to produce a majority of these observations [Cieslik et al, 2018]
Higher glycine levels are associated with better blood lipid and inflammatory markers (higher HDL-cholesterol and apolipoprotein A1, lower triglycerides, apolipoprotein B and C-reactive protein) [Rom et al, 2019]
The typical pattern of dyslipidemia associated with metabolic syndrome, involves the liver overproducing triglyceride-rich LDL. In a 2012 paper a study demonstrated that glycine can normalise liver production of triglycerides, potentially via glycine’s effects on the central nervous system, normalising liver signalling. [Yue et al, 2012]
In a more recent study, rats with metabolic syndrome fed a 1% glycine diet had reduced body weight, body fat, blood pressure, triglycerides, leptin, insulin and total fatty acids. [López et al, 2016]
Ageing and Longevity
It has been observed that diets high in glycine lead to a 5% increased lifespan in rodents. Intriguingly, this effect is similar to the lifespan extension that can be induced through a diet low in methionine. [Miller 2019]
In the body, the metabolism of methionine and glycine are closely intertwined, with glycine providing the final step in the breakdown of methionine. Glycine is thus consumed in the process of detoxifying methionine.
This probably explains why meat eaters, despite consuming more glycine, have similar blood levels as vegetarians: The higher level of methionine in a meat-based diet leads to more glycine being ‘used up’.
Glycine counteracts the effects of AGE/RAGE
Part of the ageing process is attributable to the damage done when glucose reacts with proteins in the body to form advanced glycation end products (AGEs). Such glycation damages proteins and produces toxic byproducts. Glycation is responsible for the gradual deterioration of collagen as we get older, leading to a loss of elasticity.
Glycation affects many other parts of the body, especially with long-lived tissue where AGEs can accumulate over time, such as the lens and cornea of the eye, cartilage in joints and blood vessels. AGE formation in the body is increased by raised blood glucose such as happens following a high carb meal and especially in diabetes where blood glucose is poorly regulated. Compounds formed by such glycation (AGEs) trigger a cycle of inflammation and oxidative stress. AGEs are key factors in complications associated with Alzheimer’s disease, cataracts, atherosclerosis and kidney aliments among others. [Chilukuri, 2018]
Glycine supplementation has been shown to markedly reduce glycation in diabetic rats, reducing the inflammation and oxidative stress associated with it. Protective effects were also observed in the aorta and heart function of rats fed glycine. [Wang et al Mar 2019]
Glycine has been shown to counteract the formation of cataracts by preventing the glycation of lens proteins. [Bahmani, 2012] In another study, glycine supplementation at 20g per day was able to improve the hearing of diabetic patients. [Muñoz-Carlin Mde et al, 2010]
Glycine’s Anti-Cancer Properties
Cancer cell proliferation makes use of one-carbon metabolism which is highly dependent on serine/glycine. Because serine and glycine can be interconverted it may be expected that either could fuel cancer proliferation. However, it appears that while dietary serine increases cancer cell proliferation, glycine does not. Diets that restrict the amino acid serine have been shown to have anti-cancer benefits, but not those that restrict glycine. [Labuschagne, 2014]
In fact glycine has been shown to have a number of anti-cancer effects. Its primary role appears to be by reducing the growth of blood vessel on which tumours depend (i.e. supressing angiogenesis) as well as reducing epithelial cell proliferation.
Evidence from studies
A mouse study of melanoma found a 65% reduction in tumour mass, and 70% fewer blood vessel in the tumor among mice fed a 5% glycine diet. [Rose et al, 1999]
The same team also conducted a rat study which showed that dietary glycine had the ability to significantly suppress liver tumour development. [Rose et al, 1999] Although other researchers have pointed out that this study is unlikely to be directly relevant to humans because of the way the tumours were induced [Corton, 2018]
A 2016 paper in Amino Acids reported that glycine completely neutralised angiogenesis (growth of new blood vessels) in colorectal cancer cell lines in a dish. They also demonstrated that glycine supplementation reduced tumour size by 35% and blood vessels by 55% in colorectal cancer in rats [Bruns et al, 2016]
Dietary glycine has been shown to decrease tumour volume and vascularisation in a model of colorectal cancer with liver metastasis, without decreasing the action of chemotherapy. [Maneikyte, 2019]
Dosing & Contraindications
- Measurable benefits have been observed from as little as 1-2 g of supplemental glycine per day.
- For improved sleep 3-5 g before bed has been shown to be effective.
- Limitations on collagen production increase from age 25. For older adults a total of 10g/day appears to be a sensible target dose. This could be spread across the day e.g. 2-3g with each meal, 3g before bed.
- Larger doses for specific conditions are probably best taken under the supervision of a practitioner.
Dosing in studies
|1-2g per day under tongue (5 days)||Reduced stroke mortality||well tolerated|
|5 g per day (3 months)||Improved blood glucose, reduced inflammation||well tolerated|
|5 g per meal (4 weeks)||Improved insulin sensitivity [ref]||well tolerated|
|5 g per meal (3 months)||Improved Metabolic Syndrome [ref]|
|3 – 9 g before bedtime (3 days)||Improved sleep [ref]||Minor digestive symptoms at upper dose|
|20 g/day||Improved auditory response in diabetics||none reported|
|60 g/day (5 years)||Psychosis treatment (case report)|
Well tolerated [ref]
|well tolerated but only one case study|
Glycine absorption and blood levels
Glycine is rapidly absorbed in the intestines. It leads to spike in blood levels after about 30 minutes when taken on an empty stomach, a little longer if eaten with food. Glycine blood levels then remain raised for a further 3 hours.
The graph above shows how 1 g oral glycine leads to a peak 60% rise in blood glycine levels after 30 minutes. Taking larger quantities will lead to a greater increase: for example, 5g leads to a 300% increase. Taking glycine with a meal, especially carbohydrates, has been shown to suppress the rise by about 10% and increase the time taken to return to baseline. [Gannon et al, 2002]
Glycine for exercise recovery
As blood glycine levels peak soon after ingestion, glycine can be considered a “fast protein” for exercise recovery. Hence, for post-exercise tendon, ligament and joint repair/remodelling glycine should be taken immediately after exercise, to maximise collagen synthesis.
For most people who are supplementing glycine for general health benefits, including improved blood sugar, cell protection, and anti-aging effects, taking a small dose several times per day is probably sufficient. Many supplement manufacturers recommend 1 g three times per day. From the studies considered above 2-3 g with each meal and 3 g before bed might be suitable protocol.
Pregnancy and Infants
There are no studies considering glycine supplementation during pregnancy or for infants. A trial to determine glycine needs in pregnancy is currently registered with Clinicaltrials.gov, but has yet to report.
Clozapine (Clozaril) is used to help treat schizophrenia. Taking glycine along with clozapine (Clozaril) might decrease the effectiveness of clozapine (Clozaril). It is not clear why this interaction occurs yet. Do not take glycine if you are taking clozapine (Clozaril). (WebMd)
A maximum tolerable daily intake for some adults is as low as 15 g of glycine per day, or 9 g in a single dose, where minor digestive disturbances were reported by some (soft stools and mild digestive discomfort). Others have been able to tolerate 60g per day as two 30g doses without discomfort. No toxicity has been reported for doses up to 60g (adult). One case study showed no toxic effects at this daily dose for five years. [Cleveland et al, 2010] These limits are likely to vary from person to person.
A study in rats found no deaths nor evidence of toxicity when feeding at the maximum protocol for toxicology studies of 2 g/kg body weight per day for 4 weeks. The LD50 dose for rats is quoted as being close to 8g/kg/day [Shibui et al, 2013] Taking into account the fact that large animals have slower metabolisms and therefore lower tolerance than small animals, and to include a safety margin, Anroop & Jacob recommend calculating a human equivalent by dividing rat doses by 6.2. This suggests the following reasonable upper safe dose and reasonable lower toxic dose.
|Daily intake||by body weight per day||for a 65kg adult per day|
|Reasonable upper safe limit*||0.3 g/kg||21 g|
|Reasonable lower toxic limit*||1.3 g/kg||84 g|
*These are not official values, but simply ones I calculated from data and assumptions given in the preceding paragraph.
The only documented cases of glycine toxicity and death in humans have been those associated with complications during surgery, where a solution of glycine used to irrigate the site of the operation entered systemic circulation in significant volume (often amounting to litres of fluid!) Not very relevant to normal oral supplementation, but I include it here for completeness.
Glycine solution is widely used for irrigation during endoscopic (keyhole) surgery. A complication of such procedures occurs when large volumes of the 1.5% glycine solution become inadvertently absorbed into circulation. This can lead to toxic levels of glycine in the blood which may cause serious complications including transient blindness or even death, although such effects are partly due to dilution of electrolytes, not just the glycine concentration. [Olsson & Hahn, 1998] Such results can be repeated in animals via intravenous infusion of 1.5% glycine solution.
Normal plasma glycine levels are 0.2–0.3 mmol/L. In non-fatal cases of irrigation fluid absorption (which may, nonetheless involve serious side effects such as transient blindness), blood levels of glycine rise to 5–8 mmol/L [Dwivedi, 2018]. Compare this to the blood levels induced by oral supplements where 1 g on an empty stomach typically increase blood levels of glycine by 0.1 – 0.2 mmol/L. In one study an approximately 5 g single, oral dose, raised blood glycine levels to 0.9 mmol/L [Gannon et al, 2002] with no reported adverse effects. Even at the extreme upper end of supplementation, the literature documents one case study where a patient took two 30g doses per day, plasma levels rose to approximately 3 mmol/L which was well tolerated, despite being close to the toxic threshold [Cleveland et al, 2010]
I highly recommend the following podcast with Chris Masterjohn: Why You Need Glycine: A Panel Discussion
I am sure you are as keen to use this very safe, very sensible amino acid as a supplement to your diet. As such I will be stocking it from now on in my clinic and utilising it in my work with patients. Over time I hope to be able to come back with some results to share.