Health Care Professional Information

Common Name

L-Glutamine, GLN

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). A meta-analysis showed that glutamine supplementation benefits patients with acute pancreatitis who receive total parenteral nutrition (25). However, glutamine supplementation may not be effective in decreasing sepsis in surgical infants with gastrointestinal disease (20); a systematic review failed to find sufficient data to support use of glutamine in young infants with severe gastrointestinal disease (21).

Glutamine was shown to prevent genotoxic and clastogenic damages caused by cisplatin in mice (26).
Pilot studies suggest benefit of glutamine 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); helped reduce chemotherapy-induced mucositis and gastrointestinal toxicity (12) (18) (19); and may be effective against radiation morbidity in breast cancer patients (23). Intravenous glutamine significantly reduced chemotherapy-induced nausea, vomiting, and diarrhea in patients with gastric or colorectal cancer (10).
Conclusions from a meta analysis indicate benefits of glutamine in reducing the duration, but not severity of diarrhea (22). However, 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) (24).
More research is needed to resolve the ambiguity.

Food Sources

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

Purported Uses
  • Alcoholism
  • Cancer-related cachexia
  • Chemotherapy-induced gastrointestinal toxicity
  • AIDS-associated wasting
  • Immunostimulation
  • Peptic ulcers
  • Recovery from surgery
  • Strength and stamina
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 is therefore essential for the maintenance of intestinal mucosal integrity and function (1). Glutamine 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). And a recent study demonstrated that glutamine helps cancer cells survive acidic stress, rather than provide nutrition, through enzymatic deamidation (24).

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.

Adverse Reactions

No significant adverse reactions have been reported. Although elevated blood glutamic acid concentration may occur with glutamine supplementation, clinical studies did not show an increase in circulating glutamic acid levels.
(8)

Herb-Drug Interactions

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

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 intravenous 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.

Dosage (Inside MSKCC Only)
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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. Choi K, Lee SS, Oh SJ, et al. The effect of oral glutamine on 5-fluorouracil/leucovorin-induced mucositis/stomatitis assessed by intestinal permeability test. Clin Nutr. 2007 Feb;26(1):57-62.
  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.
  18. Aquino VM, Harvey AR, Garvin JH, et al. A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study. Bone Marrow Transplant. 2005 Oct;36(7):611-6.
  19. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut. 2001 Jan;48(1):28-33.
  20. Ong EG, Eaton S, Wade AM, et al. Randomized clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease. Br J Surg. 2012 Jul;99(7):929-38.
  21. Wagner JV, Moe-Byrne T, Grover Z, McGuire W. Glutamine supplementation for young infants with severe gastrointestinal disease. Cochrane Database Syst Rev. 2012 Jul 11;7:CD005947. Review.
  22. Sun J, Wang H, Hu H. Glutamine for chemotherapy induced diarrhea: a meta-analysis. Asia Pac J Clin Nutr. 2012;21(3):380-5.
  23. Rubio I, Suva LJ, Todorova V, et al. Oral Glutamine Reduces Radiation Morbidity in Breast Conservation Surgery. JPEN J Parenter Enteral Nutr. 2013 2013 Sep;37(5):623-30.
  24. Huang W, Choi W, Chen Y, et al.A proposed role for glutamine in cancer cell growth through acid resistance. Cell Res. 2013 May;23(5):724-7.
  25. Asrani V, Chang WK, Dong Z, et al. Glutamine supplementation in acute pancreatitis: a meta-analysis of randomized controlled trials. Pancreatology. 2013 Sep-Oct;13(5):468-74.
  26. Oliveira RJ, Sassaki ES, Monreal AC, et al. Pre-treatment with glutamine reduces genetic damage due to cancer treatment with cisplatin. Genet Mol Res. 2013 Dec 2;12(4):6040-51.

Consumer Information

How It Works

Bottom Line: 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.

Glutamine may help treat cachexia (muscle wasting) in patients with advanced cancer and AIDS.

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.
  • 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.
Research Evidence

Gastrointestinal Cancer:
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 or no supplementation. Glutamine infusion started on the day of surgery and continued after surgery 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. Infectious morbidity was 19.3% in the alanine-glutamine group and 17.1% in the control group. The rate of major complications was 7.5% in the alanine-glutamine group and 7.9% in the control group. The authors concluded that perioperative glutamine does not help well-nourished GI cancer patients.

Chemotherapy-induced toxicity:
This randomized study was conducted to find out if intravenous alanyl-glutamine dipeptide could eliminate chemotherapy-induced gastrointestinal toxicity. This study enrolled 44 patients with gastric or colorectal cancer. These patients were randomized to the control group or glutamine group. During their next cycle of chemotherapy, patients were crossed over to the other treatment group. Patients in the glutamine group received 20 g of intravenous alanyl-glutamine dipeptide for 5 days along with chemotherapy. The investigators found that compared with the control group, patients receiving glutamine had a significantly higher plasma glutamine level and a significantly lower plasma endotoxin levels. Nausea/vomiting and diarrhea also decreased significantly in the glutamine group. The authors concluded that prophylactic intravenous alanyl-glutamine was effective in preventing chemotherapy-induced gastrointestinal toxicity.

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