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Common Name

L-Glutamine, GLN

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Clinical Summary

The most abundant amino acid in the body, glutamine is synthesized by most body tissues and absorbed from food sources. Patients take glutamine supplements to treat cancer and HIV/AIDS related cachexia or recovery from catabolic states such as surgery, sepsis, and intense exercise. Glutamine is the major fuel source of enterocytes, lymphocytes, and macrophages, and is thought to act by enhancing gut integrity, immune function, and protein synthesis (1) (2). Several clinical trials show that parenteral or enteral free glutamine or glutamine-containing dipeptides improve nitrogen balance, preserve intestinal integrity, maintain intracellular glutamine levels, and reduce hospital stay in post-surgical or critically ill patients (7) (8) (9).

Pilot studies suggest benefit in treating HIV- and cancer-related cachexia when used in combination with beta-hydroxy-beta-methylbutyrate (HMB) and arginine (3) (4) (5). Oral glutamine was shown effective in preventing oxaliplatin-induced neuropathy in colorectal cancer patients (6) and glutamine gargles may ameliorate chemotherapy-induced stomatitis (12). Intravenous glutamine significantly reduced chemotherapy-induced nausea, vomiting, and diarrhea in patients with gastric or colorectal cancer (10). But conflicting data indicate that perioperative glutamine did not have an influence on post-surgical complications or infection in gastrointestinal cancer patients (11). Furthermore, recent findings suggest a role for glutamine in tumor cell growth and maintenance (17 More research is needed to resolve the ambiguity.

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Food Sources

Wheat, corn, barley, peanuts, soybean, egg white, milk
(14)

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Purported Uses
  • Alcoholism
  • Cancer-related cachexia
  • Chemotherapy-induced gastrointestinal toxicity
  • Enhancing tissue integrity
  • HIV- and AIDS-associated wasting
  • Immunostimulation
  • Peptic ulcers
  • Recovery from surgery
  • Strength and stamina
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Mechanism of Action
Glutamine is the most abundant amino acid in the body; it is synthesized in most body tissues and absorbed from food sources. It is the major fuel source of enterocytes and colonocytes and is therefore essential for the maintenance of intestinal mucosal integrity and function (1). It also maintains immune function by serving as the principle metabolic fuel for lymphocytes and macrophages. It acts as a precursor for protein synthesis and, with cysteine and glycine, is involved in glutathione (GSH) synthesis. Intravenous glutamine preserves liver and intestinal glutathione stores in animal models of oxidant damage. Glutamine is also involved in nitrogen exchange, as it neutralizes and eliminates excess ammonia formed during protein catabolism. As a nitrogen donor, it contributes to the synthesis of other non-essential amino acids, including the purines and pyrimidines, and is therefore essential for the proliferation of most cells (15). Glutamine plays a supportive role during biochemical stress and sepsis. Although the mechanism in treatment of cachexia is unclear, it is thought that glutamine, a modulator of protein turnover, enhances net protein synthesis (3). Clinical evidence suggests that total parenteral nutrition supplemented with glutamine improves nitrogen balance, maintains the intracellular glutamine pool, enhances protein synthesis, and prevents deterioration of gut permeability in post-surgery patients (4).

Glutamine may potentiate the tumoricidal effect of methotrexate (MTX), since polyglutamation of MTX impairs its efflux from tumor cells and may reduce its accumulation in the gut. Rats fed a glutamine-enriched diet while receiving MTX chemotherapy exhibit less enterocolitis, improved hematologic parameters, decreased sepsis, and improved survival (16). Supplemental intravenous glutamine leads to increases of GSH in the gut, but not in tumors, in a sarcoma-bearing rat model.
However, recent findings show that glutamine transporters are upregulated in tumor cells and that glutamine acts as a mitochondrial substrate and promotes protein translation. This indicates tumor cell dependence on glutamine for its growth and maintenance (17). More studies are needed.

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Pharmacokinetics

Absorption
Glutamine is taken up by enterocytes from both the gut lumen and the bloodstream. The gut lumen extracts approximately 50-80% of free glutamine when administered enterally. After ingestion of 0.1 g/kg glutamine solution, plasma levels increase by at least 50% and peak at 30 min before returning to fasting levels after about 2 h (7). De novo synthesis occurs in almost all tissues via the enzyme glutamine synthetase, which catalyzes ATP-dependent synthesis from glutamate and ammonia. Glutamine synthetase exists at high concentrations in skeletal muscle, lung, liver, brain, and stomach tissue, and is regulated by glutamine levels (15).
Distribution
Skeletal muscle exhibits the greatest intracellular concentration of glutamine; it contains approximately 60 percent of total body stores (4) (15).
Excretion
The pathways of glutamine excretion have not been fully elucidated, but probably follow that of other non-essential amino acids.

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Adverse Reactions

No significant reactions have been reported. Though concern exists that elevated blood glutamic acid concentration might occur with glutamine supplementation, clinical studies find no increase in circulating glutamic acid levels.
(8)

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Herb-Drug Interactions

Methotrexate: Glutamine may preferentially increase tumor retention of MTX, thereby increasing its therapeutic efficacy.
(16)

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Literature Summary and Critique

Giannotti L, et al. Perioperative intravenous glutamine supplementation in major abdominal surgery for cancer. Ann Surg. 2009 Nov;250:684-90.
This randomized, multicentre trial enrolled 428 subjects who were candidates for elective major gastrointestinal surgery. Patients received either an intravenous infusion of L-alanine-L-glutamine dipeptide .40g/kg/day (equal to 0.25 g of free glutamine [n=212]) or no supplementation (n=216). Glutamine infusion started on the day of surgery and continued postoperatively for at least 5 days. The overall postoperative complications rate was 34.9% in the group that received alanine-glutamine, versus 32.9% in the control group (p=0.65). Infectious morbidity was 19.3% in the alanine-glutamine group and 17.1% in the control group (p=0.55). The rate of major complications was 7.5% in the alanine-glutamine group and 7.9% in the control group (p=0.90). The authors concluded that perioperative glutamine does not affect outcome in well-nourished GI cancer patients.

Li Y, Ping X, Yu B, et al. Clinical trial: prophylactic intravenous alanyl-glutamine reduces the severity of gastrointestinal toxicity induced by chemotherapy—a randomized crossover study. Aliment Pharmacol Ther. 2009 Sep 1;30(5):452-8.
This randomized, double-blind, crossover study investigated whether intravenous alanyl-glutamine dipeptide could eliminate chemotherapy-induced gastrointestinal toxicity. This study enrolled 44 patients with gastric or colorectal cancer who had a side-effect grade of 2 or higher, according to the WHO side effect grading system. These patients were randomized to the control group (n=22) or glutamine group (n=22). During their next cycle of chemotherapy, patients were then crossed over to the other treatment group. Patients in the glutamine group received 20 g (.3 g/kg/day) of intavenous alanyl-glutamine dipeptide for 5 days concomitantly with chemotherapy. The investigators found that compared with the control group, patients receiving glutamine had a significantly higher plasma glutamine level (p<0.05) and a significantly lower plasma endotoxin level (p<0.05). Scores for nausea/vomiting and diarrhea also decreased significantly in the glutamine group. Patients receiving glutamine reported a mean score of 1.18 + 0.31 for nausea and vomiting, compared to 2.63 + 0.21 for patients who did not receive glutamine (p<0.05). Mean scores for diarrhea were 1.31 + 0.25 for patients who received glutamine and 2.82 + 0.34 for patients who did not (p<0.05). The authors concluded that prophylactic intravenous alanyl-glutamine was effective in preventing chemotherapy-induced intestinal permeability disruption and gastrointestinal toxicity.

May PE, et al. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg 2002;183:471-9.
A randomized, double-blind, nitrogen-controlled, multicenter evaluation of an amino acid nutrient mixture’s effect on weight in stage IV cancer patients with solid tumors and weight loss greater than 5%. Chemotherapy and radiotherapy were acceptable during treatment, but other forms of weight maintenance treatments were disallowed. The treatment group (n=24) received Juven® powder (3 g b-hydroxy-b-methylbutyrate (HMB), 14 g L-arginine, and 14 g L-glutamine) daily while controls (n=25) received an isonitrogenous and isocaloric mixture of nonessential amino acids. Body weight and composition were measured at baseline and weeks 4, 8, 12, 16, 20, and 24. Only nine patients (7 HMB/Arg/Gln, 2 control) finished the study: 17 withdrew before 4 weeks and 23 withdrew before 24 weeks. At the 4-week evaluation, HMB/Arg/Gln patients gained 0.95 ± 0.66 kg (1.12 ± 0.68 kg of fat-free mass), while controls lost 0.26 ± 0.78 kg (1.34 ± 0.78 kg in fat free mass). An intent-to-treat analysis showed higher weight gain in HMB/Arg/Gln patients at 24 weeks than controls (2.27 ± 1.17 kg versus 0.27 ± 1.39 kg, respectively). No changes in quality of life measures were found. Larger trials are necessary.

Clark RH, et al. Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy-beta-methylbutyrate, glutamine, and arginine: a randomized, double-blind, placebo-controlled study. J Parenteral Enteral Nutr 2000;24:133-9.
A prospective, randomized, double-blind evaluation of the effect of HMB, glutamine, and arginine supplementation on weight in patients with HIV exhibiting greater than 5% weight loss over previous 3 months. Patients were randomized to receive one packet Juven® powder (1.5 grams HMB, 7 grams glutamine, and 7 grams arginine) (n=34) or placebo (n=34) twice daily for 8 weeks. Primary outcomes measured were body weight, lean weight, body fat and muscle content, viral load, and T-cell count. Blood samples were taken to monitor patient compliance. Twenty-two patients withdrew from the study for unknown reasons and three individuals were deemed non-compliant. Final numbers of patients receiving HMB and placebo were 21 and 22, respectively. HMB supplementation significantly improved cumulative and lean weight gain as compared to placebo. Although changes in viral load and T-cell subsets were statistically significant, they were not clinically meaningful. HMB appears effective in managing weight loss associated with HIV/AIDS, but long-term studies are required.

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References
  1. Wilmore DW. Metabolic support of the gastrointestinal tract: potential gut protection during intensive cytotoxic therapy. Cancer 1997;79:1794-803.
  2. Van der Hulst RR, et al. Glutamine and the preservation of gut integrity. Lancet 1993;344:1363-5.
  3. May PE, et al. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg 2002;183:471-9.
  4. Jones C, Palmer TE, Griffiths RD. Randomized clinical outcome study of critically ill patients given glutamine supplemented enteral nutrition. Nutrition 1999;15:108-15.
  5. Griffiths RD, et al. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997;13:295-302.
  6. Wang W, Lin J, Lin T, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist 2007;12:312-319.
  7. Castell LM, Newsholme EA. The effects of oral glutamine supplementation on athletes after prolonged, exhaustive exercise. Nutrition 1997;13:738-42.
  8. Morlion BJ, et al. Total parenteral nutrition with glutamine dipeptide after major abdominal surgery. A randomized, double-blind, controlled study. Ann Surg 1998;227:302-8.
  9. Melis GC, ter Wengel N, Boelens PG, van Leeuwen PA. Glutamine: recent developments in research on the clinical significance of glutamine. Curr Opin Clin Nutr Metab Care. 2004 Jan;7(1):59-70. Review.
  10. Li Y, Ping X, Yu B, et al. Clinical trial: prophylactic intravenous alanyl- glutamine reduces the severity of gastrointestinal toxicity induced by chemotherapy—a randomized crossover study. Aliment Pharmacol Ther. 2009 Sep 1;30(5):452-8.
  11. Giannotti L, Braga R, Biffi R, Bozzetti F, Mariani L. Perioperative intravenous glutamine supplementation in major abdominal surgery for cancer. Ann Surg. 2009 Nov; 250:684-90.
  12. Skubitz KM, Andersen PM. Oral glutamine to prevent chemotherapy induced stomatitis: a pilot study. J Lab Clin Med 1996;127:223-8.
  13. Crowther M, Avenell A, Culligan DJ. Systematic review and meta-analysis of studies of glutamine supplementation in hematopoietic stem cell transplantation. Bone Marrow Transplantation. 2009;44:413-25.
  14. Brody T. Nutritional Biochemistry. San Diego(CA):Academic Press; 1999.
  15. Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev 1999;4:239-48.
  16. Rubio IT, et al. Effect of glutamine on methotrexate efficacy and toxicity. Ann Surg 1998;227:772-80.
  17. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010 Aug;35(8):427-33.
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How It Works

Bottom Line: A few clinical trials show that glutamine combined with other nutrients can prevent muscle wasting and weight loss in patients with advanced cancer and HIV, but more research is needed.

Glutamine is the most abundant amino acid in the human body. It is synthesized by most body tissues and is also found in foods such as wheat, corn, barley, peanuts, soybeans, and milk. Glutamine is essential for several bodily processes, and when patients are suffering from states in which the body is malnourished or breaking down its own muscle protein (a state called cachexia), taking extra glutamine can help replenish depleted body levels and prevent adverse health effects. For example, glutamine is the major fuel source of the cells that line the intestinal tract, and is therefore important in maintaining GI function. It is also the major fuel source for lymphocytes and macrophages, which are a vital part of the body’s immune defense. It acts both as a precursor for protein synthesis and a means by which excess toxic ammonia can be eliminated from the body. Finally, glutamine is important in the synthesis of glutathione, a molecule that helps detoxify foreign substances in the liver.

Although researchers are not exactly sure how glutamine helps treat cachexia (muscle wasting) in patients with advanced cancer and AIDS, they think that glutamine promotes the synthesis of muscle and other important bodily proteins.

Glutamine may interact with the anti-cancer drug methotrexate in a positive way: glutamine modifies the methotrexate molecule in such a way that it cannot be pumped out of tumor cells, and therefore remains inside the cells and is more effective. However, this effect has not been strongly established in humans.

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Purported Uses
  • To prevent nutritional problems in alcoholism
    No scientific evidence supports this use.
  • To prevent cachexia (muscle wasting) in advanced cancer and AIDS
    Preliminary results from clinical trials show that a combination of glutamine, arginine, and beta-hydroxy-beta-methylbutyrate (Juven®) can promote weight gain in these patients, but the long-term effectiveness is not known.
  • To reduce chemotherapy-induced gastrointestinal toxicity
    One study showed that glutamine given intravenously to patients receiving chemotherapy for gastric or colorectal cancer significantly reduced nausea, vomiting, and diarrhea.
  • To improve tissue integrity
    Clinical research supports the use of intravenous glutamine to enhance the integrity of the intestine in critically ill patients. No research has been done with oral glutamine.
  • To stimulate the immune system
    Although glutamine is a necessary fuel source for lymphocytes (a type of immune cell), there is no solid evidence that glutamine supplements can stimulate the immune system in healthy people. Intravenous glutamine has been shown to help improve the immune status, prevent infection, and help prevent depletion of intestinal immune cells in critically ill patients and patients recovering from surgery.
  • To treat peptic ulcers
    No scientific evidence supports this use.
  • Intravenously, to improve recovery from surgery
    Several clinical trials support this use.
  • To improve recovery from intense exercise
    Blood glutamine levels have been found to fall after intense exercise, but several studies have concluded that supplementation with glutamine does not improve recovery from exercise or prevent exercise-related immune suppression or infection.
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Research Evidence

Cachexia from advanced cancer and AIDS:
A combinination of glutamine, beta-hydroxy-beta-methylbutyrate, and arginine (Juven®) has been used to treat cachexia.

  • In one study, patients with stage IV solid tumors were randomly given two packets of Juven® powder or an inactive placebo powder every day. A large number of patients withdrew from this study before it could be finished, but analysis of those who stayed showed that, on average, patients taking Juven® were able to gain a small amount of weight, while those taking the placebo powder lost a small amount of weight. This effect needs to be repeated in a larger clinical trial before Juven® can be considered a helpful treatment for cachexia.
  • In a similar study, patients with HIV were randomly assigned to take two packets of Juven® or a placebo powder every day for eight weeks. Although many patients dropped out of the study, results showed that, on average, patients taking Juven® were able to gain a significant amount of weight compared to those taking the placebo. These results are positive, but it is still not known whether Juven® is safe or effective to take in the long term.

Prevention of methotrexate toxicity:
The ability of glutamine to reduce methotrexate toxicity in patients with inflammatory breast cancer was studied in a small phase I clinical trial. Nine patients started taking glutamine four weeks before starting chemotherapy, then continued to take glutamine daily while receiving a range of doses of methotrexate for three weeks. Toxicity to the liver, kidneys, or immune system due to methotrexate was greatly reduced in these patients. This study did not monitor whether glutamine increased the effectiveness of methotrexate, which is a topic that should be addressed in future clinical trials.

In total parenteral nutrition (TPN):
Several clinical trials have looked at the addition of glutamine to total parenteral nutrition (TPN), which is a fluid that critically ill patients (who cannot take food by mouth) receive intravenously. TPN contains all of the nutrients necessary for bodily functions, but these studies have asked the question whether glutamine can help improve the recovery or status of critically ill patients.

  • Twenty-eight patients who had undergone surgery to remove cancer of the colon or rectum were randomly assigned to receive five days of normal TPN or TPN supplemented with glutamine. Patients receiving glutamine showed better nitrogen balance, a higher number of immune cells, and had a shorter average hospital stay than patients who received normal TPN.
  • Of 84 critically ill patients in a hospital intensive care unit, half were randomly assigned to have glutamine added to their TPN, while half received normal TPN. After six months, patients who had received glutamine had significantly higher survival rates (24/42 versus 14/42) and lower hospital costs. However, because the patients involved in this study had very different illnesses, it is not clear for which conditions glutamine is most effective.
  • In a second study by the same researchers, 50 critically ill patients were randomly assigned to receive normal enteral nutrition (through a feeding tube to the stomach) or glutamine-enriched enteral nutrition. Again, patients that received glutamine had a shorter average hospital stay, lower average hospital costs, and fewer infections than patients who received normal enteral nutrition.
  • Twenty patients suffering from inflammatory bowel disease, cancer, or other conditions requiring the use of TPN were randomly assigned receive normal TPN or TPN supplemented with glutamine for up to two weeks. In patients taking normal TPN, intestinal health decreased, while such worsening was prevented in patients taking glutamine.
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Patient Warnings
  • This product is regulated by the FDA as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.
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Side Effects

None known

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Dosage (Inside MSKCC Only)
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Aliases
GLN
L-Glutamine
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Last updated: May 10, 2011