Safety profile of amino acids Part 2

In last week’s post, I wrote that traditional toxicology does not describe the safety of ingested amino acids in any reliable manner. I also came to the conclusion that we did not know much about the tolerability of high amino acid doses, despite their wide use in medical foods and sport supplements. This is also due to the use of experimental animals to answer toxicological questions that are primarily rooted in human physiology and metabolism.

ICAAS members have stepped up and devoted effort to testing the safety of key amino acids DIRECTLY in humans. This original research effort focused on leucine, the amino acid frequently added to sport supplements, and proteins. Indeed, research studies conducted in the last 15 years have confirmed that leucine has functions that go beyond being an essential nutrient. In respect to skeletal muscle, the key leucine function is the ability to promote protein synthesis via activation of the mammalian target of rapamycin (mTOR) pathway (for those interested in the newest efficacy studies:

In the ICAAS-sponsored clinical study of leucine safety, the scientists aimed to determine the upper “metabolic limit” to oxidize excess dietary leucine fed to adult volunteers They measured excretion of carbon-labeled leucine in response to gradually increasing loads of orally ingested leucine. The key experimental hypothesis was that the labeled leucine will be excreted in parallel to the increasing leucine intake, because the body will be effectively dealing with the dietary excess. If an increment in leucine ingestion does not lead to an increase in excreted leucine (breakpoint), one could assume that the body has lost the metabolic capacity to deal with the dietary excess. Indeed, such a breakpoint was found at a dose of 555 mg of leucine per kg body weight (approx. 44 g of leucine in an 80 kg human). This led the authors and others ( to propose 55 mg leucine/kg/day as the true upper limit. Note that the proposed limit is substantially higher than the average leucine intake from food (approx. 6 g per day) and shows a huge safety margin for leucine used in supplements, as we predicted earlier.

The same approach is being applied to elderly people (due to the high importance of leucine in preserving muscle mass in the elderly, which will be our topic next week). Preliminary data presented during this spring’s “Experimental Biology” meeting indicated that age had no substantial impact on our ability to process amino acids, and thus, on the safety factors.

Similar to the above conclusion about leucine, a clinical study conducted in Japan in healthy women found that another essential amino acid, tryptophan (a popular sleep aid), can be ingested safely up to 5.0 g per day ( This is very relevant considering that typical doses of tryptophan for sleep quality improvement or in stress reduction are 0.5 - 1.0 g per person.

ICAAS is soon expecting data on arginine and methionine safety. Scientists at Texas A&M University who conducted pre-testing of arginine safety in pigs ( concluded in their peer-reviewed article that, “…results indicate that dietary supplementation with arginine (up to 630 mg/kg body weight/day) is safe in pigs for at least 91 days. Our findings help guide clinical studies to determine the safety of long-term oral administration of arginine to humans”. This dose would correspond to almost 50 g of arginine eaten by an 80 kg human daily for three months, which is again a very high margin considering that you are probably consuming only 4 – 5 g of arginine from your daily diet. By this October, we will have this margin confirmed (or not) from a clinical study.

Taken together: (a) even if safety studies are not the “hottest” medical research area, ICAAS is proactively devoting resources in order to establish a framework for the evaluation of amino acid safety; (b) presently available data document a huge safety margin for most amino acids that would be practically impossible to breach via normal dietary means. Amino acids are effective substances, and it seems that we can use them SAFELY to supplement our diet in specific situations.

So, why worry about upper limits for amino acids? Indeed, ICAAS recommends to those involved in regulating, researching, and using amino acids to concentrate much more on the quality and specifications of amino acids than on their dose-limits. This aspect can be discussed again in the near future.