L-glutamina

L-Glutamine: A Comprehensive Encyclopedic Reference

1. Identity, Chemical Nature, and Natural Sources

Chemical Identity

L-glutamine is designated chemically as (S)-2-aminoglutaramic acid, L-glutamic acid 5-amide, or (S)-2,5-diamino-5-oxopentanoic acid. With the chemical formula C₅H₁₀N₂O₃, glutamine is one of 20 naturally occurring amino acids found in protein foods. Glutamine exists in two enantiomeric forms: L-glutamine, the biologically active isomer in humans, and D-glutamine, which has minimal biological activity. In terms of chemical behavior, glutamine is classified as a neutral, polar amino acid.

Glutamine is the most abundant naturally occurring, nonessential amino acid in the human body, and one of the few amino acids that can directly cross the blood–brain barrier. L-glutamine and L-arginine are classified as semi-essential or conditionally essential amino acids, which means that the human body can synthesize them under some health conditions but not others.

It contains one atom of nitrogen as an amide and another atom of nitrogen as an amine; it also transports and delivers nitrogen to cells in quantities that are not as toxic as free ammonium.

Endogenous Synthesis

Glutamine synthesis from glutamate and ammonia is catalyzed by the enzyme glutamine synthetase. The majority of glutamine production occurs in muscle tissue, accounting for about 90% of all glutamine synthesized. Glutamine is also released, in small amounts, by the lungs and brain. Although the liver is capable of glutamine synthesis, its role in glutamine metabolism is more regulatory than productive, as the liver takes up glutamine derived from the gut via the hepatic portal system.

Dietary Sources

Found in both animal and plant proteins, including in high levels in both casein and whey protein, glutamine can also be found in animal proteins such as meats and dairy, along with plant-based protein sources such as beans, raw spinach, parsley, and red cabbage.

Industrial and Supplemental Production

Glutamine is produced industrially using mutants of Brevibacterium flavum, which gives approximately 40 g/L in 2 days using glucose as a carbon source. The industrial production of amino acids historically started with the availability of monosodium glutamate (MSG) in 1909; MSG was discovered in 1908 by Dr. Kikunae Ikeda as a basic taste substance of kelp that is a traditional seasoning in Japan. In the late 1950s, fermentation technology was established and used for the commercial production of MSG — this was the beginning of modern amino acid production.

Common Forms and Preparations

L-glutamine and glutamine are essentially the same amino acid, but the term "L-glutamine" is commonly used to refer to the pure and bioavailable form of the amino acid. L-glutamine is the natural form found in the body and is a key amino acid for various biological functions. The distinction lies in their chemical structure: L-glutamine is the isomer naturally occurring in the body and is the form that is easiest for the body to use and absorb, and is the most common form found in supplements. Commercially, L-glutamine is available as free-form oral powder, capsules, tablets, and as dipeptide forms. Some proprietary media and formulations are supplemented with L-glutamine in dipeptide forms, such as alanyl-L-glutamine and glycyl-L-glutamine. L-glutamine is tasteless, odorless and colorless, and readily dissolves in water.

2. Traditional and Historical Use

L-glutamine does not have a documented history of use as an isolated compound in classical herbal or traditional medicine systems such as Ayurveda, Traditional Chinese Medicine, or European herbalism, because it was only chemically identified as a distinct amino acid in the twentieth century. Historically, the industrial production of amino acids started with the availability of monosodium glutamate (MSG) in 1909; MSG was discovered in 1908 by Dr. Kikunae Ikeda as a basic taste substance of kelp that is a traditional seasoning in Japan. Glutamine was first isolated from beet juice by the German chemist Ernst Schulze in 1883. However, its biochemical significance in human physiology and medicine was not appreciated until the mid-to-late twentieth century.

First used in powder form by people in the fitness industry, including bodybuilders, who were looking to preserve muscle tissue, L-glutamine is an amino acid that is a building block of protein and needed by the body in large amounts. The most common original uses of glutamine powder were to meet goals of weight loss, fat burning, and muscle building. Its clinical use began to expand significantly in the 1980s and 1990s, when researchers began investigating the role of glutamine depletion in critically ill, surgical, and trauma patients. Given the multiple biological roles of L-glutamine, the use of this amino acid as a therapeutic agent, both in intravenous and enteral feeding, and as a dietary supplement ingredient, has been widely explored.

3. Key Constituents, Biochemistry, and Mechanisms of Action

Central Biochemical Roles

Glutamine is the most abundant and versatile amino acid in the body, and is of fundamental importance to intermediary metabolism, interorgan nitrogen exchange via ammonia (NH₃) transport between tissues, and pH homeostasis. Cells require the nitrogen atoms in glutamine to build molecules such as nucleotides, amino acids, amino-sugars, and vitamins. Glutamine is a precursor of glutamate, a key amino acid used for the transamination of alpha-keto acids to form other alpha amino acids.

Glutamine supports the growth of cells that have high energy demands and synthesize large amounts of proteins and nucleic acids, and is also an alternative energy source for rapidly dividing cells and cells that use glucose inefficiently. The highest consumption of glutamine occurs in the cells of the intestines, kidney cells (where it is used for acid-base balance), activated immune cells, and many cancer cells.

Key Enzymes

The most important enzymes related to glutamine metabolism are glutamine synthetase and glutaminase. Glutamine synthetase catalyzes the conversion of glutamate to glutamine using ammonia as nitrogen source (glutamate + NH₄⁺ + ATP → glutamine + ADP + Pi). Glutaminase is an enzyme that catalyzes the hydrolysis of glutamine to glutamate and an ammonium ion. In a transamination reaction, glutamate can donate its amino group for new amino acid synthesis and be deaminated to 2-oxoglutarate.

Nitrogen Transport and Inter-Organ Metabolism

Glutamine is key for the intermediary metabolism and inter-organ nitrogen exchange via ammonia (NH₃) transport between tissues. During the post-absorptive state, approximately 50% of the glutamine synthesis in the skeletal muscle takes place through glutamate uptake from the bloodstream, a fact that characterizes part of the glutamine-glutamate cycle.

Immune Function

Endogenous glutamine synthesis does not meet the human body's demands in catabolic conditions, such as in cancer, sepsis, infections, surgeries, traumas, as well as during intense and prolonged physical exercise. Glutamine assumes the role of a conditionally essential amino acid in such deficiency conditions by promoting a concomitant increase in glutaminase expression and inhibiting the glutamine synthetase action.

The modulation of glutamine on relevant signaling pathways such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and heat shock protein, and the influence of this amino acid on cell migration and adhesion molecules, have been highlighted.

Antioxidant Activity

The use of L-glutamine in sickle cell disease is based on its antioxidant activity. It increases NAD redox potential in sickle red blood cells through increasing the availability of reduced glutathione, which may lessen oxidative damage in sickle red blood cells. L-glutamine is essential for the synthesis of the pyridines for nucleotides, including nicotinamide adenine dinucleotide (NAD) and glutathione, especially during oxidative stress exposure. Sickle red blood cells have a lower NADH:[NAD⁺ + NADH] (redox) ratio than in normal RBCs, which is related to oxidative stress, so the availability of L-glutamine is important in sickle cell disease.

Intestinal Barrier Function

Glutamine supports the growth and repair of intestinal cells and serves as an energy source for rapidly dividing cells, making it essential during infections, injuries, or metabolic stress. Its role in maintaining tight junction proteins and epithelial integrity has been investigated in both animal and human models.

Dipeptide Transport

An alternative way to bypass the high glutamine consumption of enterocytes is oral supplementation with glutamine dipeptides. Bonded amino acids (e.g., di- and tripeptides) have a differentiated membrane transport in the luminal membrane through the glycopeptide transport protein-1. This system allows a higher proportion of di- and tripeptides to escape hydrolysis and metabolization by the enterocytes, and hence are more efficiently transported into the bloodstream and other tissues such as the liver, immune system, kidneys, and skeletal muscles.

4. Scientific Evidence by Area of Use

4.1 Critical Illness and Surgical Stress

Glutamine, traditionally considered to be a nonessential amino acid, is now considered "conditionally essential" following critical illness and injury. States of critical illness lead to significant decreases in plasma levels of glutamine, and when this decrease is severe it has been correlated with increased mortality.

Plasma glutamine levels are reduced in patients with critical illness or following major surgery, suggesting that glutamine may be a conditionally essential amino acid in situations of extreme stress. In the past decade, several clinical trials examining the effects of glutamine supplementation in patients with critical illness or receiving surgery have been done, and systematic review of this clinical evidence has suggested that glutamine supplementation may reduce infection and mortality rates in patients with critical illness. However, two recent large-scale randomized clinical trials did not find any beneficial effects of glutamine supplementation in patients with critical illness.

It appears that dose and route of administration clearly influence the benefit observed from glutamine administration, with high-dose parenteral glutamine demonstrating an advantage over low-dose enteral glutamine. High-dose or parenteral (greater than 0.25 to 0.30 g/kg/day IV or ≥30 g/day enterally) glutamine appears to demonstrate the greatest potential for benefit in hospitalized patients.

The therapeutic effect may be dependent on glutamine dose given, with optimal benefit traditionally observed between 0.3 and 0.5 g/kg/day. Parenteral glutamine supplementation as a component of nutrition support was considered as an approach to improve outcomes of critical illness in selected patients, and available data suggest it is safe when administered following resolution of shock and multi-organ failure, and with daily doses less than 0.5 g/kg/day.

In recent guidelines on nutrition support, parenteral supplementation with glutamine was supported in critically ill patients, while enteral glutamine supplementation in surgical or critically ill patients was not recommended because of lack of evidence.

Evidence strength: Moderate for parenteral supplementation in select critically ill patients; evidence is inconsistent and guidelines do not uniformly recommend enteral supplementation. Two large-scale RCTs found no benefit. The field requires further well-designed trials.

4.2 Gastrointestinal Health and Intestinal Permeability

Overall, glutamine supplementation did not significantly affect intestinal permeability across all included studies (WMD: −0.00, 95% CI −0.04, 0.03). Subgroup analysis showed a significant reduction in intestinal permeability with doses over 30 g/day (WMD: −0.01, 95% CI −0.10, −0.08). This finding was derived from 12 randomised placebo-controlled trials measuring gut permeability post-glutamine supplementation, published between 1998 and 2014, with 352 participants.

Short-term (less than 2 weeks) glutamine supplementation in higher dosages (greater than 30 g/day) had a significant reductive effect on gut permeability.

Evidence strength: Preliminary to moderate. Overall pooled analyses are not statistically significant; benefits appear in subgroup analyses at higher doses and shorter durations. The total number of participants across trials remains limited.

4.3 Irritable Bowel Syndrome (IBS)

A randomized, double-blind, placebo-controlled, clinical trial evaluated the superiority of adding glutamine supplement to a low FODMAP diet in patients with irritable bowel syndrome (IBS). Eligible adults were randomized to receive a low FODMAP diet either with glutamine (15 g/day) or a placebo for 6 weeks. The glutamine group had significant changes in total IBS-severity score, dissatisfaction of bowel habit, and interference with community function (58% reduction, 57% reduction, and 51% reduction, respectively). Improvement in IBS-severity score of more than 45% was observed in 88% of participants in the glutamine group, while it was only 60% in the control group. No serious adverse events were observed.

When glutamine is added to a low FODMAP diet, improvements in symptoms in individuals diagnosed with IBS may occur, but this needs to be confirmed in additional studies and should not be inferred to healthy individuals.

Evidence strength: Preliminary. Individual RCTs show promising results, particularly at 15 g/day combined with dietary intervention, but studies involve small sample sizes. Larger confirmatory trials are needed.

4.4 Sickle Cell Disease (FDA-Approved Indication)

In 2017, the Food and Drug Administration approved two medications for sickle cell anemia: hydroxyurea for children and L-glutamine for children and adults. The approval was for L-glutamine indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older.

The clinical trial evaluated the efficacy and safety of Endari in 230 patients (5 to 58 years of age) with sickle cell anemia or sickle β0-thalassemia who had 2 or more painful crises within 12 months prior to enrollment. Data indicate that L-glutamine therapy was associated with a statistically significant reduction, compared with placebo, in the median number of sickle cell crises: 3 (minimum, maximum: 0, 15) vs. 4 (0, 15), P = .006. Similarly, there were reductions in median number of hospitalizations for painful events (2 vs. 3) and cumulative days in hospital (6.5 vs. 11), as well as increased median time to first crisis (84 vs. 54 days).

There were 2 deaths in the L-glutamine group that were deemed by the investigators not to be related to study drug. Interpretation of the trial's results is complicated by high dropout rates (36% L-glutamine arm; 24% placebo arm). Nevertheless, the FDA decided that L-glutamine had a favorable risk-benefit profile and approved it for use in sickle cell anemia.

Long-term L-glutamine treatment (up to 120 weeks) significantly decreased SCD-related acute complications like vaso-occlusive crisis in patients with SCD.

Evidence strength: Moderate; supported by a pivotal Phase III RCT that was sufficient for FDA approval, though the trial had methodological limitations including high dropout rates and some questions remain about the magnitude of clinical benefit.

4.5 Short Bowel Syndrome (FDA-Approved Indication)

L-glutamine has a second FDA-approved indication. It was approved as a product called NutreStore in 2004 for use in treating short bowel syndrome. Glutamine is used together with human growth hormone and a specialized diet to treat short bowel syndrome. Safety and efficacy of glutamine to treat short bowel syndrome in children has not been established.

Evidence strength: Sufficient for regulatory approval in adults as part of a combination regimen; evidence base for glutamine alone in this condition is more limited.

4.6 Athletic Performance, Exercise Recovery, and Muscle Damage

Plasma glutamine levels can decline after prolonged exercise due to increased bodily demand and greater glutamine uptake by tissues than normal. Plasma glutamine levels can decline due to reduced production or decrease in the release of glutamine by muscles. Despite existing claims about the effects of glutamine on enhancing athletic performance and improving the immune system, the results of studies remain conflicting.

A total of 47 studies were included in a systematic review, and 25 trials matched inclusion criteria for meta-analysis. Data related to body mass, lean body mass, body fat percentage, VO₂ max, lymphocytes, leukocytes, and neutrophil counts were extracted to determine the effects of glutamine on performance outcomes. According to this meta-analysis, generally, glutamine supplementation has no effect on athletes' immune system, aerobic performance, and body composition. However, the current study showed that glutamine resulted in greater weight reduction.

In a crossover study, participants (n = 12) were supplemented with 6 g/day of glutamine or placebo for 40 days (20 days with glutamine + 20 days with placebo and vice versa). Blood samples were obtained at the beginning and at the end of each period. The glutamine supplemented group displayed significantly lower values of aspartate transaminase, creatine kinase, and myoglobin in blood, suggesting less muscle damage compared to the placebo.

In a randomized single-blind placebo-controlled design, 15 physically active males performed 100 drop jumps from 0.6 m followed by ingestion of 0.3 g/kg body mass of maltodextrin (control) or with an additional 0.3 g/kg L-glutamine (glutamine group) at 0, 24, 48, and 72 hours post-exercise.

The available evidence at present is not strong enough to support the use of glutamine supplementation in athletes for immunomodulation and/or anabolic processes. Furthermore, there is even less evidence regarding the role of glutamine in preventing exercise-induced muscle damage.

Despite the widespread use of glutamine among athletes, scientific evidence supporting its efficacy is still limited. Both preclinical and clinical studies report potential benefits on intestinal integrity, oxidative stress, muscle damage biomarkers, immune function, and inflammation, yet findings are inconsistent.

Evidence strength: Weak to preliminary for exercise-related claims. Meta-analyses do not support general benefits for aerobic performance, body composition, or immune function in athletes. There are small, positive studies on muscle damage biomarkers, but these have not been confirmed in larger trials.

5. Body Systems and Health Areas

• Gastrointestinal system: L-glutamine is involved in intestinal structure and function, immune function, nitrogen metabolism and transport, and glucose regulation. It serves as the primary fuel source for enterocytes (intestinal lining cells) and is investigated in IBS, short bowel syndrome, and intestinal permeability.
• Immune system: Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented.
• Musculoskeletal system: The majority of glutamine production occurs in muscle tissue, accounting for about 90% of all glutamine synthesized. Skeletal muscle is both the primary site of glutamine synthesis and a major reservoir consumed during catabolic stress.
• Hematological system: L-glutamine has an FDA-approved role in reducing vaso-occlusive crises in sickle cell disease through antioxidant mechanisms.
• Renal system: Within the kidney, L-glutamine has an important role in the generation of ammonia and bicarbonate. Kidney cells are among the highest consumers of glutamine in the body.
• Nervous system: Glutamine is one of the few amino acids that can directly cross the blood–brain barrier. It serves as a precursor to the neurotransmitters glutamate and GABA.
• Cell signaling: L-glutamine has multiple regulatory functions through its participation in cell signaling pathways and in gene expression.

6. Dosage Forms and Dosages Reported in Studies

L-glutamine is available in several forms, including free-form oral powder, capsules, tablets, and as stabilized dipeptides (e.g., alanyl-L-glutamine). The following dosages are reported from specific studies and regulatory contexts:

• Sickle cell disease (FDA-approved, Endari): The recommended dose of L-glutamine powder is 5 to 15 grams twice daily based on body weight. Specifically, the Phase III trial used weight-based dosing: 5 g twice daily (17–33.3 kg), 10 g twice daily (33.4–66.6 kg), and 15 g twice daily (>66.7 kg).
• Critical illness — parenteral supplementation: High-dose parenteral glutamine at greater than 0.25 to 0.30 g/kg/day IV or ≥30 g/day enterally appears to demonstrate the greatest potential for benefit in hospitalized patients.
• Critical illness — optimal parenteral dose: The therapeutic effect may be dependent on glutamine dose given, with optimal benefit traditionally observed between 0.3 and 0.5 g/kg/day.
• Gut permeability (meta-analysis subgroup): Significant reduction in intestinal permeability was found with doses over 30 g/day for less than 2 weeks.
• IBS clinical trials: Adults received 15 g/day for 6 weeks in the context of a low FODMAP diet.
• Eccentric exercise recovery: Participants received 0.3 g/kg body mass at 0, 24, 48, and 72 hours post-exercise.
• Muscle damage in basketball players: Participants were supplemented with 6 g/day of glutamine for 40 days in a crossover study design.
• Athletic supplementation — dose associated with neutrophil effects: Neutrophil numbers were reduced following glutamine intake at doses greater than 200 mg/kg body weight.
• Short-term supplementation in healthy athletes: Both short-term (20–30 g within a few hours) and long-term (0.1 g/kg four times daily for 2 weeks) glutamine supplementation in healthy athletes were associated with no significant adverse effects.

7. Safety Considerations and Interactions

General Safety Profile

There are no known contraindications to the use of L-glutamine oral powder; however, certain populations have yet to be studied. L-glutamine was not mutagenic in a bacterial mutagenicity (Ames) assay, nor clastogenic in a chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells.

Common Adverse Events

Most common adverse reactions (incidence >10%) are constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain. It can cause common non-serious adverse events like nausea, vomiting, stomach pain, gases, swelling in hands or feet, muscle or joint pain, back pain, headache, dizziness, tired feeling, mild skin rash or itching, dry mouth, runny nose, or increased sweating.

A 2020 clinical trial in 14 healthy males (aged 20–30 years) looked at gastrointestinal tolerance of oral L-glutamine supplementation (0.3 to 0.9 g/kg/fat free mass) and found that GI symptoms were greater on high versus low dose consumption. Symptoms were generally mild (discomfort, nausea, belching, upper GI pain) within the first two hours after eating.

Renal and Hepatic Considerations

The safety of Endari has not been established in patients with renal or hepatic impairment. A clinical case report identified a case of acute kidney injury as a result of tubular damage in a patient using 18 grams of L-glutamine daily. Possible mechanisms include increased single nephron ammonia production and toxicity. Cautious use of L-glutamine supplements in elderly patients with an already compromised kidney function is advised. Glutamine supplementation can cause glomerulosclerosis and serum creatinine level elevation in the setting of diabetic nephropathy.

Special Populations

The safety and effectiveness of this treatment have not been established in pregnant or lactating women, or in patients younger than 5 years of age or older than 65 years of age. Although limited trial data and clinical experience have not identified differences in responses between elderly and younger patients, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapies.

Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine. It is also not known whether L-glutamine can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity.

Drug Interactions

No drug interaction studies have been conducted for L-glutamine (Endari) per the FDA prescribing information, meaning that formal pharmacokinetic interaction data are not available.

High-Dose Considerations in Critical Care

Supplemental parenteral glutamine is safe when administered following resolution of shock and multi-organ failure, and with daily doses less than 0.5 g/kg/day. High-dose supplementation in patients with active multi-organ failure has been associated with harm in some large trials, which is reflected in the evolution of clinical guidelines away from universal recommendation in the critically ill.

References

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