Who Should Not Take Glutamine

L-glutamine is the most abundant amino acid in the blood and is often marketed as a recovery and immune supplement for people who train hard. For most healthy adults, sensible amounts carry little risk. There are, however, specific medical situations in which extra glutamine is unnecessary, unwise or potentially harmful. This article sets them out clearly.

Why glutamine is usually considered safe

Glutamine is classed as a conditionally essential amino acid. The body makes plenty of it, mostly in skeletal muscle, and an ordinary diet provides several more grams each day from meat, fish, dairy, beans and grains.

Safety reviews, including work by Garlick and a risk assessment by Shao and Hathcock, concluded that healthy adults tolerate supplemental intakes of up to about 14 g per day without evidence of harm. Higher amounts have been used in clinical settings under supervision.

For athletes, the evidence of benefit is modest. A review by Michael Gleeson concluded that glutamine supplementation does not reliably improve performance or immune markers in well-fed athletes, which is worth bearing in mind when weighing even small risks.

Because glutamine is converted in the body to glutamate and ammonia, the groups who should be cautious are mainly those whose ability to process these products is impaired, or whose disease biology may be influenced by extra glutamine.

Liver disease and raised ammonia

The liver normally converts ammonia into urea, which the kidneys excrete. In advanced liver disease, particularly cirrhosis, this capacity is reduced and ammonia can accumulate in the blood.

High ammonia contributes to hepatic encephalopathy, a condition ranging from subtle confusion and sleep disturbance to coma. Glutamine is metabolised in the gut and kidneys to release ammonia, so extra glutamine could theoretically worsen the problem.

Oral glutamine challenge tests have, in fact, been used in research to provoke a rise in ammonia and unmask early encephalopathy in people with cirrhosis. That alone illustrates why such patients should not take glutamine supplements on their own initiative.

Anyone with known liver disease, including fatty liver disease with fibrosis, should discuss any amino acid supplement with their hepatology team or GP.

Kidney disease and critical illness

The kidneys play a central role in glutamine metabolism, using it to generate ammonia for acid-base balance. In chronic kidney disease, clearance of nitrogen waste is impaired, and a high protein or amino acid load may need to be managed carefully.

People with moderate to advanced chronic kidney disease often receive individual dietary advice on protein from a renal dietitian. Adding concentrated amino acid supplements without that guidance can work against their treatment plan.

Critical illness provides the strongest warning. The REDOXS trial, published in the New England Journal of Medicine in 2013, gave high-dose glutamine to critically ill patients with multi-organ failure. Rather than helping, glutamine was associated with increased mortality, particularly in those with kidney dysfunction.

Hospital use of glutamine is now guided by specialist nutrition protocols. That context is very different from a tub of powder bought for the gym, but the message is the same: in serious illness, more is not automatically better.

Cancer, neurological conditions and other cautions

Many tumours rely heavily on glutamine for energy and building blocks, a phenomenon sometimes called glutamine addiction. Altman, Stine and Dang described how this has made glutamine metabolism a target for experimental cancer drugs.

Whether dietary glutamine supplements actually fuel tumour growth in people is not established. Glutamine has even been studied to reduce side effects of chemotherapy, such as mucositis. Nonetheless, people with active cancer should not self-supplement and should seek advice from their oncology team.

Glutamate, which is made from glutamine, is the main excitatory neurotransmitter. There are theoretical concerns for people with epilepsy and, from isolated reports, for people with bipolar disorder, in whom high doses have been anecdotally linked to manic symptoms. Evidence is limited, but caution is sensible.

• People with seizure disorders or on anti-epileptic drugs should ask their neurologist first.
• People with bipolar disorder should discuss supplements with their psychiatric team.
• Those who react to monosodium glutamate sometimes report similar symptoms, though this is not well documented.
• Reye's syndrome and rare inherited disorders of urea metabolism are absolute reasons to avoid amino acid loading.

Pregnancy, children and medicine interactions

There are few controlled data on glutamine supplements in pregnancy or breastfeeding. Because a normal diet already supplies glutamine and there is no proven benefit, the cautious approach is to avoid supplements during these periods unless a doctor recommends them.

Children and teenagers who play sport have no established need for glutamine supplements. A balanced diet with adequate protein covers their requirements. The prescription use of glutamine in sickle cell disease, approved in the US following a phase 3 trial by Niihara and colleagues, is a specialist treatment and should not be confused with sports supplementation.

Interactions with medicines are not well characterised. Theoretical concerns exist with lactulose and other treatments for hepatic encephalopathy, with anti-epileptic drugs and with some chemotherapy agents. If you take regular prescription medicines, check with a pharmacist.

In the UK, glutamine is sold as a food supplement under food law. That means it has not been through the safety assessment that a medicine undergoes for specific patient groups.

Conclusions of the editorial team

For healthy adults, glutamine at typical supplement amounts is unlikely to cause harm, though the evidence that it helps performance is weak.

The main groups who should avoid it, or use it only on medical advice, are people with liver or kidney disease, the critically ill, people with active cancer, and pregnant or breastfeeding women.

When the potential benefit is small, even modest risks deserve attention.

You might also like our articles on glutamine and the immune system in athletes, on amino acid supplements and kidney health, and on what a normal diet already supplies in protein.

References

1. Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise and sport training. J Nutr. 2008;138(10):2045S–2049S.
2. Garlick PJ. Assessment of the safety of glutamine and other amino acids. J Nutr. 2001;131(9 Suppl):2556S–2561S.
3. Shao A, Hathcock JN. Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Regul Toxicol Pharmacol. 2008;50(3):376–399.
4. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368(16):1489–1497.
5. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619–634.
6. Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226–235.