Safety profile of amino acids Part 1

Amino acids have been present in our food supply since the origin of the human species. Nine amino acids that our body cannot synthetize must be ingested daily from food to avoid negative influences on the immune system, growth or even the quality of our skin. For those nine amino acids, dietary requirements (minimum safety limits) have been established by the World Health Organization and the Food & Agriculture Organization of the UN in 2007.

www.who.int/nutrition/publications/nutrientrequirements/WHO_TRS_935/en/

The maximum safe limits for amino acids in general, however are a still disputed. We ingest substantial amounts with our daily diet (for example, based on the Dietary Reference Intakes (1994) published by National Academies Press in 2001, a person on a typical western diet daily ingests more than 5 grams of leucine and lysine each). One could therefore assume that a human body has the capacity to deal with an increased intake, even if taken for specific supplemental needs (for example, lysine to prevent recurrent herpes, leucine to enhance skeletal muscle recovery or arginine to support the cardiovascular system).

How much is “too much”, though? How much would override our innate capacity to deal with high intakes?

Traditional toxicological approaches are not helpful in respect of these questions. Those approaches had been developed to evaluate new, artificially created ingredients or medicines and relay heavily on rodent studies. In a simple way, a toxicologist would feed a growing rat for thirteen consecutive week on a diet supplemented with a given amino acid at levels ranging from 1 to 5 % (as a portion of the overall diet) and search for the maximum dose which would not yet cause any pathology (a so-called NOAEL dose). Since rats are not people, the expert then would use a “safety factor” (usually a number between 100 and 300) to divide the NOAEL dose and to establish “Acceptable Daily Intake” (ADI) for humans. So, if a substance had an ADI equal to1 gram per day, you would have to eat 100 grams of that substance every day for 13 weeks before reaching the equivalent dose that had triggered a problem in rats!

This approach has been tried with a few amino acids. Interestingly, the ADI for many of the studied essential amino acids were determined to be at levels that were comparable to minimum dietary requirements for the same amino acids! For example, the minimum dietary requirement for leucine in an adult with body weight of 70 kg is roughly 2.2 gram per day, while the ADI for leucine was indicated at 2.3 gram per day.

(https://www.ncbi.nlm.nih.gov/pubmed/15204732).

So, the “upper limit” was practically equal to what you really needed to ingest to keep your body healthy! Clearly, this approach did not work. Using traditional toxicology to study the safety of substances which have been in our body, environment and food for millennia does not seem to be effective.

In addition, Dietary Reference Intake data point to a substantial spread of amino acid intakes among the US population (the best studied population in this respect). For example, the mean daily intake of an essential amino acid tryptophan in the US adult population was 0.9 gram, but 1% of the population took as much as 2.1 grams per day – and no harm has been reported from those intakes (on the contrary, a high tryptophan intake correlated with positive mood and quality of sleep). For another essential amino acid, lysine, the mean daily intake was 5.3 grams and the highest daily intake (1% of population) was as much as 12.6 grams.

One could try to consider historic intake data from those population groups that are characterized with the highest intakes and, if no evidence of harm was reported, consider those levels as appropriate upper limits for population as a whole. But, is this truly so simple? Can infants or frail elderly take as much as a healthy teenager? On the other hand, what about those sub-groups who choose to use very high doses occasionally (let’s say more than 3 grams of tryptophan daily to improve sleep, https://www.ncbi.nlm.nih.gov/pubmed/3097693) ?

We do not really know how to fully answer those questions.

However, there is a medical area which perhaps could offer assistance, because amino acids have been used in medical elemental diets and even intravenous infusions since the late 1950s (amino acids are the building blocks of proteins and are generally more easily ingestible than complete protein). Not only have they been used, but also applied at very high doses in traumatic events, when the body was losing nitrogen and essential nutrients rapidly. Post-operative states are a typical example. So, there are historic data from the use of nine essential, as well as some non-essential (glutamine, arginine, alanine) amino acids. For example, a healthy American ingests about 4.2 grams of arginine every day from her or his diet, but a patient may receive an infusion with 25.0 grams to save her life! Another example, patients with liver cirrhosis triggered by chronic alcohol intake were requested to take 12.0 grams of supplemental branched chain amino acids for 3 years and no harm was reported (https://www.ncbi.nlm.nih.gov/pubmed/16206505). On the contrary, many patients were saved specifically because they were receiving high doses of branched-chain amino acids! So, can we take the patient data in the cases where very high doses of free amino acids were applied and extend them to healthy population en masse?

I am repeating myself, but we do not know how to fully answer even this question.

For the above reasons, ICAAS members and ICAAS scientific advisors have invested substantial efforts and money to proactively come up with safety evaluation systems that would rely on the direct testing of amino acid safety in humans and those evaluations have already confirmed that the most frequently used supplemental amino acids are very safe and well tolerated. This will be the subject of our next post.