‘Would you like a shot of L-glutamine in your smoothie?’ asked the sales assistant with a wide smile. Would I indeed? According to the sales assistant, L-glutamine has “soooo many benefits.”
Perhaps this is the case. But I don’t know for sure.
The smoothie was already pretty expensive and adding L-glutamine would just add to that cost. A quick look at Instagram tells me that there are over 167,000 posts on L-glutamine and these posts come with images of v-shaped men with 8-packs. Hmmm, not exactly the look I am going for.
Just to be clear, I do not use Instagram as a scientific reference. On the other hand, it is a very good way to know what popular culture has to say about anything. Both the smoothie sales assistant (and Instagram) were promoting L-glutamine supplementation for bodybuilding and to aid fast recovery from exercise.
I politely decline the up-sell and resolve to read up on L-glutamine myself.
What Is L-Glutamine?
Glutamine is an amino acid which means that it is one of the building blocks in the body. In fact, it is the most abundant amino acid in the body.
Glutamine has the molecular structure of C5H10N2O3 and goes by the shorthand symbols of Q AND GLN.
Glutamine comes in two forms: R and L. This is based on the fact that glutamine can be found as two mirror images:
R meaning dextro or right and L meaning levo or left.
L-glutamine is of greater relevance to human physiology and this article will focus on L-glutamine.
L-glutamine is classified as both a non-essential and conditional amino acid. It just depends on the circumstances. Non-essential means that the body can make L-glutamine and does not need external sources of glutamine.
This is true most of the time. The body maintains fairly stable levels of L-glutamine. However, during times of stress and high cell turnover eg critical illness or major surgery, the body does need external sources of L-glutamine to meet the higher metabolic demands.
Glutamine is found in a number of food sources and can be consumed either in free form or in proteins. Good food sources of glutamine include beef, poultry, milk, yogurt, ricotta cheese, raw spinach, and parsley.
Hence everything depends on the conditions and as such glutamine is termed as both non-essential and conditional amino acid.
What does L-glutamine do in the body?
- It is a building block for making proteins and especially in rapidly dividing cells such as erythrocytes, lymphocytes, fibroblasts, and cancer cells.
- It has two nitrogen side chains and functions as a nitrogen shuttle.
- It is part of the glutamate amino acid family as such is converted to glutamate in the body.
Glutamine versus Glutamate
Glutamate is structurally related to glutamine but is considered to be a different non-essential amino acid. Glutamine is metabolized via an enzyme called glutaminase to glutamate. Glutamate is a precursor of gamma-aminobutyric which is an important neurotransmitter in the brain.
The sodium salt of glutamate is monosodium glutamate (MSG) which is sometimes used as a flavor enhancer in the food industry. MSG is the problem ingredient in some Chinese food and is widely believed to cause the Chinese Restaurant Syndrome, which was first described in 1968 (1).
What is TAG?
Glutamine has a low bioavailability which means that only a low percentage is absorbed from the gut (2). TAG is a synthetic peptide which is a fusion in alanyl and glutamine which can increase the absorption of glutamine from the gut (3).
Marketers would have you believe that TAG is “sooooo much better” (and need I say more expensive) than regular glutamine. Well, in the first place we need to establish if glutamine is good for us before we buy into the theory that even more glutamine is even better for you.
Glutamine is FDA approved for the management of sickle cell disease in adults and children over the age of 5 (4). Sickle cell disease is a genetic disorder that causes abnormalities in the shape of red blood cells and increases their risk of getting stuck in small blood vessels which cause painful ‘sickling crisis’.
There are 514 glutamine products for sale on Amazon and the average cost of a 500mg capsule is $0.10. TAG costs a whopping $2.14 per 400mg.
Is There Any Research?
There are over 40,000 publications relating to L- glutamine which includes 1000 clinical trials. To put this into context, there are almost 1,500,000 publications on amino acids and almost 30,000 clinical trials.
Does L-Glutamine Improve Gastrointestinal Health in Cancer Patients?
People undergoing radiation therapy may develop damage to the cells of their intestine as an inadvertent side effect of the treatment. Animal studies show that glutamine can help protect the upper and lower gastrointestinal tract mucosa from the effects of chemotherapy and radiotherapy (5).
The question arises as to whether glutamine can help protect the human gastrointestinal tract from radiation or chemotherapy related damage?
A study done in Turkish patients compared glutamine 15 gm three times per day to placebo in patients with radiation-induced diarrhea (6). While there was no overall difference in the rates of diarrhea between the two groups, the glutamine arm of the study had less severe diarrhea as compared to the placebo arm.
Another 2018 study reviewed 60 clinical trials looking at treatments for the prevention of chemotherapy or radiotherapy-induced mucositis (inflammation of the gut which often presents as diarrhea) (7). The researchers found that glutamine reduced chemotherapy-induced diarrhea but not radiation-related diarrhea.
There is limited data to suggest that L-glutamine may help with some of the side effects of cancer treatments but the exact nature and magnitude of this effect still need to be worked out.
Does L-Glutamine Help Ulcers?
Way back in 1957, investigators from Texas published a paper entitled ‘Glutamine in the treatment of peptic ulcer: preliminary report’ (8). Unfortunately, the actual paper is not available online. Neither is there an abstract to look at.
I am guessing that the gist of the paper was that glutamine helped. Back in 1957, it would have been very odd to write a random preliminary report suggesting no benefit.
Japanese investigators found that glutamine protected against helicobacter pylori-related peptic ulcer disease in Mongolian gerbils (9).
Researchers in Beijing used glutamine supplementation in patients with burns covering over 30% of their total body surface area ( 10). These patients would normally be expected to develop gastric stress ulcers but none of the 12 glutamine supplemented patients developed stress ulceration.
Ulcers refer to a break in the skin or mucous membrane. Now we will move from peptic ulcers in the stomach to pressure ulcers in the skin. Investigators from Singapore evaluated a specialized amino acid mixture containing (beta)-hydroxy (beta)-methylbutyrate (HMB), arginine and glutamine (11).
In this study, 23 patients were randomized to either standard of care or the glutamine containing mixture for two weeks. They analyzed the study results but concluded that the glutamine containing specialized amino acid did not appear to reduce wound size but may have a beneficial effect on tissue viability after 2 weeks.
Very sketchy data suggest that glutamine supplementation may help with peptic ulcers but not skin ulcers.
Does L-Glutamine Improve Leaky Gut, IBS and/or Diarrhea?
Leaky gut is not really a well-accepted term in medical research. There are only 300 papers and 8 clinical trials published on the topic. There are no clinical studies looking at L-glutamine in leaky gut.
An editorial style paper in 2010 suggests that L-glutamine may have a theoretical role in leaky gut (12). Where does that leave us? What do we have?
Glutamine supplementation was shown to have no benefits in persistent diarrhea in a cohort of children in the national referral hospital in Uganda (13).
US-based researchers from Galveston and Louisiana compared glutamine to placebo in 106 study subjects with post-infectious irritable bowel (14). This is a very common presentation in infectious disease clinics. These patients are commonly seen in infectious disease clinics especially after return from faraway places.
At an infectious disease clinic, we usually test for ova and parasites. If these tests are negative, then we, as infectious disease physicians, have little to offer these patients.
The study showed that glutamine statistically significantly reduced daily bowel frequency, improved bowel form, and reduced bowel permeability.
There were statistically significant improvements in symptoms and improvements in intestinal hyper-permeability’ (elevated urinary lactulose/mannitol ratios) in the glutamine arm of the study.
The glutamine was well tolerated. In fact, the researchers called the effects ‘dramatic’. That being said, they did not recommend the immediate widespread use of glutamine in this patient population.
Quite sensibly, they recommended larger randomized controlled trials to validate the findings and explore the possible mechanisms of action of glutamine.
A group of British and Australian investigators published a letter in the British Medical Journal raising concerns about some of the methodologies in the US research (15).
Concerns included the baseline selection of patients and the use of telephone calls as a means of follow up. After all, even the original US researchers advised that further research was needed and I guess that is the take-home message here.
There is some limited evidence to suggest that glutamine supplementation may help with post-infectious IBS but more research is needed.
Does L-Glutamine Help Reduce Symptoms of Arthritis?
There is one clinical trial of relevance here (16). It does not directly speak to the role of L-glutamine in arthritis per se (meaning joint swelling). It does address the issue of wasting which can accompany arthritis.
In this study, 40 people with rheumatoid arthritis were given either beta-hydroxy-beta-methylbutyrate, glutamine, and arginine or a placebo mixture of alanine, glutamic acid, glycine, and serine for 12 weeks.
The study subjects were randomized to the two treatment arms of the study. The study evaluated changes in body mass or total body protein. No benefit of the glutamine arm of the study was noted.
No, glutamine does not reduce symptoms of arthritis.
Does L-Glutamine Promote Muscle Growth and Decrease Muscle Wasting?
There is significant research interest in solutions to muscle wastage, (see, for example, growing interest in SARMs) and many claim L-Glutamine holds promise here.
A widely quoted study on this subject was sponsored by the pharmaceutical industry and has not been included here (17).
Iranian investigators looked at glutamine supplementation on athletic performance and body composition and immune function (19). Published this year, the review found 47 relevant publications.
Overall glutamine was found to have a significant positive effect on weight loss but it had no effect on the athletes’ immune function, aerobic performance or body composition.
There is a related study which is worth mentioning here. US-based investigators studied L-alanyl-L-glutamine in 10 physically fit volunteers (maybe the smoothie sales assistant has a side job as a research volunteer) (20).
The volunteers were deliberately dehydrated and then exercised (definitely not a good idea and not something you should try at home). The study found that there was an increase in time to exhaustion during mild dehydration stress.
The researchers felt that the positive effects noted had nothing to do with muscles or muscle metabolism. They believed that the beneficial effects were related to improved fluid uptake.
I hate to argue with Instagram but there is no evidence that glutamine helps with 8-packs. Photoshop beware, science will get you.
Does L-Glutamine Help Improve Diabetes?
Glutamine is known to release a glucagon-like peptide which can increase insulin release after food (21). Theoretically, this means that it may help with diabetes. There are some studies on this sub-topic (22).
- A total of 8 healthy adults were studied on 4 separate occasions and drank either:
- low nutrient beef soup
- low nutrient beef soup plus 30 gm glutamine
- high nutrient 75 gm dextrose or
- high nutrient 75 gm dextrose plus 30gm glutamine(23).
Patients were studied via ultrasound assessment of the speed of gastric emptying and blood glucose levels. The study found that glutamine slowed gastric emptying and lowered blood glucose after a nutrient-dense meal.
Thirteen adolescents with type 1 diabetes exercised on a treadmill on two separate occasions (24). They were randomized to receive glutamine or placebo in a double-blind, crossover design. The study showed reduced glucose levels after exercise but no effects on insulin sensitivity.
This can be seen as a study with mixed results. The whole reason for the study design is the fact that adolescents tend to have reduced sensitivity to insulin which represents a particular therapeutic challenge.
The researchers wondered if glutamine could enhance insulin sensitivity in this patient population. The answer was no. On the other hand, the blood glucose levels were reduced post-exercise. It seems that the glutamine story in adolescent diabetics needs a lot more work.
A multi-center study across three continents looked at the association between blood levels of amino acids, vascular disease, and death in individuals with type 2 diabetes (25).
The study was carried out on blood samples in almost 4000 people with type 2 diabetes. Glutamine levels were not found to be very relevant in these patients.
Just to add to the confusion, Iranian investigators looked at the effects of glutamine on cardiovascular complications in diabetes (26). This study involved randomizing 66 people with type 2 diabetes to either glutamine or placebo for 6 weeks.
A statistically significant reduction in body fat, waist circumference but not body weight and body mass index was noted. Significant differences were also noted in fasting blood glucose and HbA1C (which is a measure of glucose control over time).
No statistically significant difference in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride or blood pressure was noted.
The effects of glutamine in the diabetic population has yet to be worked out at this time.
Does Glutamine Help With ICU Patients?
Italian investigators looked at what we know about glutamine supplementation in the ICU population (27). The review considered data from 30 trials and almost 4000 patients.
Data from ICU tends to be of high quality as by definition patients are being monitored very closely. Taken together these studies do not show any significant clinical benefit or effect for glutamine.
Glutamine has not been conclusively shown to benefit ICU patients.
Other Glutamine Benefits
I spent ten years living in Africa and can’t help but mention two topics of interest to global health. I know that many people living outside of the developed world find it very frustrating when all we talk about are first-world issues.
Firstly, let’s look at malaria which kills children on a daily basis. A study published from the National Institutes for Health published this year found that a glutamine blocker could reverse brain changes in mice with malaria. Cerebral malaria is a particularly devastating and potentially life-threatening complication of malaria (28).
Now let’s look at sickle cell disease (29). Sickle cell disease occurs when there is a genetic mutation in the hemoglobin gene which puts people at risk of a sickle cell crisis. This means that the abnormally-shaped sickle cells can block small blood vessels and cause severe pain.
To date, there are no effective strategies for the management of sickle cell disease apart from the avoidance of known triggers such as infection. In this study, 239 children and adults with sickle cell disease were randomized to either L-glutamine or placebo for a period of 48 weeks.
During the period of observation, all patients (in both arms of the study) received hydroxyurea which is the currently best available treatment for sickle cell disease. The study found significantly less sickle cell crises and hospitalizations in the glutamine arm.
At first glance, this result offers hope to sickle cell patients. However, higher rates of nausea, chest pain, fatigue, and muscle pain were noted in the glutamine arm.
A really interesting and topical study on glutamine was published just last week (30). In fact, this study had not been published when I did my first literature review on this topic earlier last month, but I have to mention it.
This study looked at 11 men and women who either ingested a glutamine supplement or a placebo before and after simulated wildland firefighting in an environmental chamber (38°C, 35% relative humidity).
Such a topical and practical research study. The study found that gastrointestinal damage, feelings of fatigue and scores of perceived exertion were lower after glutamine supplementation compared to placebo.
I am willing to bet that the survivalist crew will pick up on this study and that glutamine will be added to lots of bug out bags.
One Very Very Last Thing
In 1957, a paper was published which suggested that glutamine could reduce alcohol cravings (31). More recently, alcohol cravings were found to be related to a dysregulation of glutamine functioning in the brain (32).
This certainly raises the question of whether glutamine may help people with alcohol addiction, but of course, further studies are needed.
Let’s just say that I have a few friends who could do with a little correction of ‘glutamine brain dysregulation’ most weekends.
Is L-Glutamine Safe?
Brazilian investigators evaluated the safety of L-glutamine in middle-aged and elderly long term care residents (33). Blood tests were monitored when the residents ingested L- glutamine or calcium caseinate for 14 days. This was followed by a 5-day washout. The residents then switched to the other treatment for 14 days.
No clinically significant change in blood testing was noted. This requires some clarification. There was a statistically significant decrease in renal function but this was not clinically significant. This mumbo jumbo means that care should be taken in people with renal disease who want to take glutamine.
One paper on the safety of glutamine has recommended that behavioral assessments should be done in people taking glutamine in order to ensure its safety in view of the fact that glutamine can be metabolized to a neurotransmitter (34). I agree with this.
Long term glutamine supplementation could possibly be problematic (35). As mentioned before, cancer cells can use glutamine for growth which raised the theoretical possibility of stimulating cancer cell growth.
Another problem relates to the sudden withdrawal of long term glutamine supplementation which could precipitate health issues due to a relative glutamine deficiency.
A US-based researcher published an umbrella review of meta-analyses on glutamine. An umbrella review provides a summary of existing published data, or a birds-eye view of a bird’s eye view (36).
As an aside, I notice a growing number of umbrella reviews in the published literature and in many ways Healthy But Smart also provides umbrella reviews.
Looking at the critically ill or surgical population, glutamine reduced the rate of hospital-acquired infections and shortened the length of hospital stay. Glutamine supplementation resulted in a non-statistically significant reduction in mortality. Very interestingly, 4 out of 22 meta-analyses reviewed were deemed to have significant publication bias.
Worse still, some of the meta-analyses never even carried out assessments for publication bias. I think this is really interesting. I usually think of meta-analyses as being like the UN. I assumed that the very point of a meta-analyses was to eliminate bias. Apparently, this is not the case.
The fatal flaw with these 4 meta-analyses was what is known as ‘the file drawer problem’. This means that small studies with null results (not what you expected to see) are filed away and are often not published. The term ‘file drawer problem’ is an actual thing and was coined by Rosenthal back in 1979.
I think that it is fair to say that neither Instagram nor the smoothie sales assistant portrayed L-glutamine accurately nor gave a full 360-degree review.
On balance, I will continue to decline the expensive L-glutamine up-sells in my smoothie, though I might grab a handful in the event of a zombie apocalypse.