Glutamine has had its 15 min of fame, but it will not go away. In a 2012 survey of fitness and bodybuilding Internet sites, glutamine was one of the six most commonly touted supplements (13). These Internet sites tout glutamine as “essential for serious athletes” to “increase growth hormone” and “enhance muscle metabolism.” They claim glutamine is vital for optimal immune function. They claim you cannot get enough glutamine from food or make enough when you are training hard. Your best bet is to buy it from them.
The drumbeat for glutamine that began 15 to 20 years ago was based on intriguing hypotheses. Glutamine is the most abundant free amino acid in muscle and plasma. Skeletal muscle is a major site for glutamine synthesis, and it releases glutamine into plasma at a high rate. Glutamine in muscle may buffer acids and help build glycogen and protein. Glutamine also fuels lymphocytes and macrophages. So glutamine is seen as possibly anabolic and immunity boosting. Plasma glutamine levels tend to be decreased for a few hours after prolonged exercise. A popular early hypothesis was that this decrease contributes to an “open window” of impaired immunity after marathons (7,10).
So the myth was born: Glutamine supplements are vital for strong muscles and immunity. As I will explain, research undercuts this myth. But glutamine sellers, never to be fazed by science, forge ahead: The myth endures. Maybe a new study of glutamine in the intensive care unit (ICU) can help usher glutamine offstage in sports medicine. I will start with it.
Glutamine Supplements in the ICU
In ICU observational studies, low plasma glutamine levels, compared to moderate levels, have been tied to a higher mortality rate (14,17). The hypothesis was that loss of muscle led to glutamine deficiency that weakened immune and other host defenses. But observational studies are tricky; one pitfall was that those few with the very highest glutamine levels (most had acute liver failure) also had a higher mortality rate (17). Epidemiologist John Ioannidis says that up to 80% of nonrandomized studies turn out to be wrong or exaggerated. In his provocative analysis of 49 of the most highly cited original clinical research studies, including many randomized controlled trials, about 40% of those retested were shown to be wrong or exaggerated (11). This of course is ideally how science works: If wrong at first, it self-corrects in time. Science typically advances not in giant strides but in baby steps, and for each two steps forward, there is one step back.
Self-correction is now occurring in glutamine research. The ICU observational studies that tied lower glutamine to higher mortality led to clinical trials of glutamine supplementation in critically ill ICU patients. Some trials suggested improved survival on glutamine, but the two largest ICU trials found no clear benefit from glutamine (1,20).
Now comes the blockbuster study, a randomized controlled trial in a leading journal. More than 1,200 critically ill adults in 40 ICUs were randomized to receive glutamine, antioxidants, both, or placebo for up to 28 d. Glutamine had no effect on infections and did not improve clinical outcome. In fact, glutamine was tied to a slight increase in risk of death, statistically significant at 6 months. The authors concluded that glutamine “was harmful” (9), and an editorialist said this study allows one to reject with confidence the hypothesis that glutamine supplementation in very ill patients in the ICU improves outcome (18). It seems glutamine has no role in the ICU.
Glutamine, Athletes, and Immunity
Glutamine has no role in sports, either, because the early hypotheses have not held up. Early studies found that plasma glutamine typically fell transiently after prolonged exercise, such as cycling nearly 4 h or running a marathon (5,7,10). One study suggested that two small doses of glutamine (vs placebo) after a marathon could reduce “infections,” self-reported on questionnaires, over the next week (6). But such questionnaires are validated for classical viral upper respiratory infection (URI) and are less reliable for diagnosing URI in the face of allergies or stress reactions from the marathon (2,16). In other words, the pitfall is that not all “infections” after marathons are true infections (16).
Other studies refute the hypothesis that low plasma glutamine after exercise increases the risk of infection. In a 4-wk study of intensified training of swimmers, glutamine levels tended to increase, not fall, and no difference in glutamine levels was seen in swimmers who reported URI versus those who did not (12). In laboratory studies of athletes, glutamine supplements during exercise did not prevent the typical postexercise “immunodepression.” In other words, even though plasma glutamine stayed normal, these exercisers still developed transient decrements in lymphocyte counts and functions, in activity of natural killer cells, and in salivary immunoglobulin A levels (10). Experts now see no causal link between low plasma glutamine, impaired immune function, and increased risk of URI in athletes (7,10). Scientists and sports medicine physicians have known for a decade that plasma glutamine is not linked to any putative “exercise-induced immunodepression” (10), but glutamine sellers remain willfully ignorant on their way to the bank.
Glutamine, Muscle Function, and Athletic Performance
The claim that glutamine can spur release of growth hormone seems to be based on one study of nine middle-aged volunteers. The mean value of plasma growth hormone, 90 min after a 2-g oral dose of glutamine, was 4-fold higher than the control (placebo) value, but sharp rises in growth hormone level after glutamine occurred in only 4 subjects, and the results were not statistically significant (19). It should be noted that 1 h of strenuous exercise could increase plasma growth hormone level 20-fold, so no reason exists for athletes in training to take glutamine to spur growth hormone release (7).
Nor is there evidence that extra glutamine is anabolic. After glycogen-depleting exercise, glutamine cannot improve on glucose alone at restoring muscle glycogen (3). Adding glutamine to essential amino acids and carbohydrate does not enhance muscle glycogen or protein synthesis after glycogen-depleting endurance exercise (21).
Finally, there is no good evidence that glutamine supplements improve athletic performance. When 10 trained men performed five maximal cycling bouts, acute ingestion of glutamine did not enhance performance (8). And in a randomized, double-blind study of daily glutamine (vs placebo) during 6 wk of strength training in 31 young adults, the glutamine added nothing: Gains in lean muscle mass and strength were the same on placebo as on glutamine (4).
The bottom line: No reason exists for athletes to buy or use glutamine supplements. Dr. George Phillips, writing in this journal 6 years ago (15), was right to conclude that the glutamine fad is another sad example of how marketing can trump science.
1. Andrews PJD, Avenell A, Noble DW, et al. Randomized trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ
. 2011; 342: d1542.
2. Barrett B, Brown R, Mundt M, et al. The Wisconsin Upper Respiratory Symptom Survey is responsive, reliable, and valid. J. Clin. Epidemiol.
2005; 58: 609–17.
3. Bowtell JL, Gelly K, Jackman ML, et al. Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. J. Appl. Physiol.
1999; 86: 1770–7.
4. Candow DG, Chilibeck PD, Burke DG, et al. Effect of glutamine supplementation combined with resistance training in young adults. Eur. J. Appl. Physiol.
2001; 86: 142–9.
5. Castell LM, Poortsman JR, Leclercq R, et al. Some aspects of the acute phase response after a marathon race, and the effects of glutamine supplementation. Eur. J. Appl. Physiol.
1997; 75: 47–53.
6. Castell LM, Poortsman JR, Newsholme EA. Does glutamine have a role in reducing infections in athletes? Eur. J. Appl. Physiol.
1996; 73: 488–90.
7. Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise and sport training. J. Nutr.
2008; 138: 2045S–9.
8. Haub MD, Potteiger JA, Nau KL, et al. Acute L-glutamine ingestion does not improve maximal effort exercise. J. Sports Med. Phys. Fitness.
1998; 38: 240–4.
9. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. New Engl. J. Med.
2013; 368: 1489–97.
10. Hiscock N, Pedersen BK. Exercise-induced immunodepression — plasma glutamine is not the link. J. Appl. Physiol.
2002; 93: 813–22.
11. Ioannidis JPA. Contradicted and initially stronger effects in highly cited clinical research. JAMA
. 2005; 294: 218–28.
12. Mackinnon LT, Hooper SL. Plasma glutamine and upper respiratory tract infection during intensified training in swimmers. Med. Sci. Sports Exerc.
1996; 28: 285–90.
13. Mason BC, Lavallee ME. Emerging supplements in sports. Sports Health
2012; 4: 142–6.
14. Oudemans-van Straaten HM, Bosman RJ, Treskes M, et al. Plasma glutamine depletion and patient outcome in acute ICU admissions. Intensive Care Med.
2001; 27: 84–90.
15. Phillips GC. Glutamine: the nonessential amino acid for performance enhancement. Curr. Sports Med. Rep.
2007; 6: 265–8.
16. Robson-Ansley P, Howatson G, Tallent J, et al. Prevalence of allergy and upper respiratory tract symptoms in runners of the London Marathon. Med. Sci. Sports Exerc.
2012; 44: 999–1004.
17. Rodas PC, Rooyackers O, Hebert C, et al. Glutamine and glutathione at ICU admission in relation to outcome. Clin. Sci.
2012; 122: 591–7.
18. Van den Berghe G. Low glutamine levels during critical illness — adaptive or maladaptive? New Engl. J. Med.
2013; 368: 1549–50.
19. Welbourne TC. Increased plasma bicarbonate and growth hormone after an oral glutamine load. Am. J. Clin. Nutr.
1995; 61: 1058–61.
20. Wernerman J, Kirketeig T, Andersson B, et al. Scandinavian glutamine trial: a pragmatic multi-centre randomized clinical trial of intensive care unit patients. Acta Anaesthesiol. Scand.
2011; 55: 812–8.
21. Wilkinson SB, Kim PL, Armstrong D, Phillips SM. Addition of glutamine to essential amino acids and carbohydrate does not enhance anabolism in young human males following exercise. Appl. Physiol. Nutr. Metab.
2006; 31: 518–29.