L-glutamine is the most abundant free amino acid in the body and also the most abundant amino acid the bloodstream. Originally considered to be nonessential because it can be readily synthesized by the enzyme glutamine synthetase, it has been established that glutamine can become essential under states of severe illness or injury, in which glutamine stores can become depleted [7, 12]. Glutamine is a precursor to glucose and many peptides, proteins, and nucleotides, and functions as an energy substrate for most cells [1, 8, 12]. Some areas where glutamine plays particularly important roles are the brain, immune system, skeletal muscle, and GI tract. In the immune system, glutamine is used as a metabolic fuel by fibroblasts, lymphocytes, and macrophages, and is also used for nucleotide synthesis. Skeletal muscle is the primary storage site for glutamine, and also the primary source of glutamine for other tissues. The GI tract uses glutamine as a fuel source, and uses more glutamine than any other area of the body.

The primary focus of research on the utility of supplemental L-glutamine has focused on situations of severe metabolic stress [1]. Glutamine has been researched in a wide variety of illnesses, including cancer, heart disease, and AIDS [3, 6]. Multiple meta-analyses have found that glutamine has many beneficial effects in critically ill patients, and glutamine may reduce mortality rates in long-term Intensive Care Unit patients by as much as 20% [1, 2]. Glutamine functions through multiple mechanisms of action, such as improving gastrointestinal tract health and immune health, acting as a precursor to glutathione, and decreasing ammonia buildup in the liver [1]. Along with HMB and arginine, glutamine helps decrease lean tissue wasting in cancer and AIDS patients, and glutamine prevents muscle protein breakdown from dexamethasone, a synthetic glucocortcoid [6, 11]. It is because of these benefits in catabolic states that it is postulated that glutamine supplementation would be beneficial for those engaged in intense exercise, an issue which is quite controversial.

It has been found in many studies that prolonged, exhaustive exercise causes a decrease in plasma glutamine levels. However, even after running a marathon, glutamine levels are only low for a period of 6-9 hours [9]. One study examined the glutamine levels in various types of athletes and found that some athletes, such as powerlifters, had particularly low plasma glutamine [9]. Overtraining has also been associated with a larger decrease in glutamine levels [9, 16]. In turn, it has been proposed that this decline can have a variety of negative effects that may be corrected with supplemental glutamine. Some of the proposed benefits of glutamine supplementation for athletes include increased immune function, increased protein synthesis, and increased rate of glycogen synthesis.

A central issue in the debate over whether glutamine supplements are beneficial is whether or not they actually increase levels of glutamine in the bloodstream. Most of the studies in states of critical illness utilize IV glutamine, and are therefore inapplicable. When glutamine is orally administered, a significant portion of it is taken up by the gut, where it is primarily oxidized, but also used to form glucose and for other purposes [22]. After ingestion of L-glutamine, about 50-75% of it is used by the gut depending on circumstances [9, 13, 14]. The amount that is extracted by the gut appears to be inversely correlated with dose – as more glutamine is administered, relatively less is taken up by the gut [14]. Despite the amount that doesn't make it to the bloodstream, many studies have found that orally administered L-glutamine still significantly raises plasma glutamine levels. For example, one study found that 5 g of orally administered glutamine doubled plasma glutamine within 30 minutes in healthy humans [16]. On the other hand, protein-bound glutamine (such as glutamine from casein or carob protein) has failed to significantly increase plasma glutamine in both human and animal studies where free L-glutamine was effective [11, 20]. When this information is put together, it would seem a high dose (at least 5-10 g) of free-form L-glutamine is the most effective way to increase levels of glutamine in the bloodstream.

Although L-glutamine supplements can significantly increase plasma glutamine, this does not necessarily equate to an increase in exercise performance or recovery ability. Multiple studies have been done, and none have yet shown that glutamine significantly improves exercise performance. In one study, 31 subjects were administered ~45 g of glutamine or placebo (maltodextrin) daily for six weeks along with resistance training. Compared to the placebo group, the glutamine group had slight improvements in their one rep maximum for squat and bench press and knee extension peak torque, as well as increased lean tissue mass and decreased markers of protein breakdown, but none of the differences were statistically significant [18]. Another study found that acute ingestion of glutamine did not improve weightlifting performance [21], but only six subjects were used, and given that the proposed mechanisms of action for glutamine are recovery-related, one would not expect a difference after acute ingestion in the first place. It seems that if glutamine does make a difference in exercise performance, it is a small one, especially at practical doses.

Beyond the studies that directly assess performance, there are also a number of studies on the effects glutamine has on other variables. Some researchers argue that the fall in glutamine levels after exhausting exercise may be related to suppression of the immune system. One investigation of 14 studies found that the self-reported incidence of illness in marathon runners was 32% lower in subjects who had consumed glutamine [9]. However, the mechanism for this is unknown, as most studies have found that glutamine fails to effect exercise-related changes in immune parameters [7, 9, 15]. Two studies have found that glutamine slightly blunts the postexercise increase in circulating neutrophils, but it is unknown whether this is clinically significant [9, 15]. One study also found that among certain marathon runners, glutamine speeded the restoration of circulating lymphocytes [9]. The differences in findings is probably related to differences in study design. It could be that glutamine does not significantly alter the magnitude of postexercise immune changes, but does speed the rate of recovery, especially in the case of extremely taxing exercise such as marathon running.

Another area in which glutamine has been explored is glycogen resynthesis. In one study, glutamine increased postexercise muscle glycogen concentration compared to alanine plus glycine providing an equal amount of calories. It has been argued that glutamine increases the activity of hepatic glycogen synthase, based on in vitro studies [5]. However, it could also be that glutamine is more readily converted to glucose than other amino acids. Either way, carbohydrates are still about three times as effective at promoting glycogen synthesis [19], and when glutamine was added to a glucose polymer drink it did not further promote muscle glycogen storage, although it appeared to increase liver glycogen storage [5]. Another study found glutamine alone did not effect glycogen resynthesis after glycogen depleting exercise [18], so the effect of glutamine in this area is once again controversial.

A final contention made by glutamine advocates is that it increases protein synthesis. This is based primarily on in vitro experiments, which have found that glutamine stimulates protein synthesis and inhibits protein breakdown [14]. However, in vivo, it appears that supplemental L-glutamine does not affect protein synthesis or increase glutamine levels in muscle tissue in healthy humans, even after IV administration [14, 17]. Increased glutamine availability does increase glutamine flux in muscle tissue (i.e., both uptake and outflow are increased but tissue levels are not changed), but this may limit transport mechanisms for other amino acids [17]. These studies do not rule out the potential for a small effect on protein synthesis of supplemental L-glutamine combined with an exercise program, but do indicate that it is not likely to make a significant difference.

Finally, there are a number of facts that can make glutamine supplementation less appealing. To maintain continually elevated levels of glutamine, one would have to supplement at least every two hours [16]. Glutamine administration also inhibits de novo synthesis of the amino acid in humans, which may make long-term supplementation less effective [20]. In healthy individuals, supplemental glutamine may decrease glutathione levels in some tissues by causing negative feedback [10]. Also, glutamine decreases vascular nitric oxide (NO) production [4]. There is also some concern that the metabolic by-products of glutamine may be toxic in large amounts [18]. However, there have been few reports of adverse events in clinical trials, even with large amounts of glutamine [1, 18].

In conclusion, few studies have demonstrated any sort of conclusive benefit from L-glutamine supplementation in athletes, although the existing evidence does support a small benefit. The most promising effect is a reduced incidence of infection after exhausting exercise, and in this case 5-10 g preworkout and/or postworkout may be effective. It may be especially useful during times of overtraining or high stress, such as on a diet, but this is only in theory. There is little evidence for a direct anabolic or performance enhancing effect of glutamine.

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