The conditionally essential amino acid arginine is involved in a wide variety of biological functions. It’s needed for proper immune function, tissue–building, and for the production of a wide array of biological substances. Arginine can be found in almost every protein–containing food, and is plentiful in most modern diets.
But research has indicated that high (multi–gram) doses of supplemental arginine may be harmful if taken over extended periods of time.
How could this valuable, seemingly harmless nutrient (or even, seemingly beneficial nutrient, if you listen to the supplement industry) cause harm?
The answer lies within the wise words of Paracelsus, in which we find a fundamental tenet of nutrition itself:
“...only the dose permits something not to be poisonous."
First, A Little Background…
During the mid 20th Century, as the nutritional shortcomings of the increasingly industrialized American food supply became more widely recognized, nutritional supplements and the concept of “health food” were born.
At this time, the goal of “health foods” and vitamin supplements was generally to “fill the gaps” and replace nutrients which had become lacking in our uniquely–modern diet.
But, as nutritional science advanced during the latter part of the previous century, nutritional supplements began to shed their original role as mere “nutritional insurance,” and took on the role of sometimes significant therapeutic agents.
The effects of high–doses of isolated nutrients began to be investigated more closely, and before long, some physicians and researchers were claiming remarkable successes, not merely in correcting nutrient deficiencies, but in rectifying some full–blown disease states. Many of these pioneering researchers began advocating supraphysiologically high dosages of isolated nutrients and nutrient mixtures as alternatives to drug treatment for medical disorders such as schizophrenia, heart disease, and cancer.
These “megadoses” of nutrients became the hallmark of what is known as orthomolecular therapy, a practice whose advocates famously included chemist, and two–time Nobel Laureate, Linus Pauling.
Around this time is when the line first began to blur between the “nutrients–as–nutrients” paradigm, and the “nutrients–as–drugs” paradigm we increasingly see today. Where the orthomolecularists were often ridiculed in their early days, today, even mainstream medicine has at least begun to respect the possibility that some nutrients can, indeed, be effective pharmacological agents.
Dose is Everything
But while the orthomolecularists were medical professionals who used high–doses of nutrients to treat disease, the logical progression of their ideas gave way to the concept of life–extension nutrition. By the early 1980’s the idea of manipulating ones’ diet via unprecedented types of supplementation was being advocated as a way to prevent (or dramatically slow) the aging process itself. As a result, millions of Americans, armed with little to no biochemical knowledge, began to delve in the emerging field of anti-aging supplementation which continues today.
Of course, large numbers of people taking a pro–active stance towards their health is, generally, a very good thing. But it’s important to state the following fact explicitly: Although a case could be made that high doses of nutrients represent a relative degree of safety when compared to some pharmaceutical drugs, it’s important to realize that high–doses of isolated nutrients, more often than not, are imparting drug–like, not nutritive, effects. As such, the fact that a substance is a nutrient, or that it’s “found in food” does not, in and of itself, give us reason to believe that a substance is safe when consumed in high amounts in isolated form.
Enter Arginine
One of the hallmarks of these early life–extension–oriented nutritional programs was the supplementation of high doses of the amino acid, arginine. Based upon what we now know was a shockingly narrow view of the complexities of arginine metabolism, multi–gram doses of arginine were recommended in order to stimulate the release of the youth-associated growth hormone from the pituitary gland.
And several years later, in the early 1990’s, a groundbreaking book on sports nutrition written by an eminent PhD and sports nutrition expert also advised athletes to consume multi–gram doses of arginine in order to, similarly, increase growth hormone levels.
Generally speaking, growth hormone had (and often still has) an almost mystical allure among the anti–aging and athletic crowd as some sort of endogenously–produced fountain of youth, destined to improve performance and reverse the hands of time.
But, despite the initial enthusiasm, stimulating growth hormone release via arginine (or any other nutritional substance, for that matter) simply doesn’t seem to offer the anti–aging or performance–enhancing results which were once promised.
Although arginine may very well increase growth hormone, some studies show that arginine supplementation dramatically reduces athletic performance. The following study, for example, found that arginine supplementation was associated with average marathon times 23 minutes longer than predicted:
Quote from the above study:
Finish times were longer than predicted (23+/–21 min[utes]… for the [Arginine] group.
Arginine and Nitric Oxide
By the mid 1990’s, the arginine–for–growth–hormone fad had pretty much run its course, only to have arginine revived a decade later, this time as a “nitric oxide booster.”
But, in several editions of the Integrated Supplements Newsletter, we explained the big picture behind nitric oxide, and showed many reasons why people may want to think twice before consuming large amounts of nitric oxide precursors like arginine.
Nitric Oxide The Big Picture – Part 1
Nitric Oxide The Big Picture – Part 2
Nitric Oxide The Big Picture – Part 3
Arginine – Reason for Concern
Knowing that one of the functions of nitric oxide is to dilate blood vessels, it wasn’t all that long ago that some within the medical community had high hopes for the nitric oxide precursor, arginine, as a treatment for heart disease - but the fact that arginine repeatedly caused harm in many of the studies in which it was tested has given researchers reason for concern.
It turns out that, in controlled studies, patients taking arginine often fared notably worse than those not taking the amino acid. One important trial in heart–disease patients even had to be stopped prematurely because of an increase in death in the group taking arginine supplements:
Quote from the above study:
6 participants (8.6%) in the L–arginine group died during the 6–month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment. . . L–Arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L–Arginine should not be recommended following acute myocardial infarction.
Quote form the above study:
Although absolute claudication distance improved in both L–arginine– and placebo–treated patients, the improvement in the L–arginine–treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024). . . As opposed to its short–term administration, long–term administration of L–arginine is not useful in patients with intermittent claudication and PAD.
Study Link - Adverse Effects of Supplemental L–Arginine in Atherosclerosis
Contrary to what was first assumed, there are several mechanisms by which arginine supplementation can cause harm – the most likely being that supplemental arginine is very likely to convert largely to the potent cellular toxins, superoxide and peroxynitrite (we discussed this effect extensively in the above–linked newsletters on nitric oxide).
But recent research sheds light on a related mechanism responsible for the toxicity of high–dose arginine – its ability to interfere with creatine kinase activity. Creatine kinase is the cellular enzyme responsible for allowing creatine to rapidly regenerate the energy molecule, ATP. Interfering with this enzyme system is known to produce varied toxic effects (in our previous blog post, we saw how the chemical (and, unfortunately, dietary supplement ingredient), guanidinopropionic acid, exerts its cardiovascular toxicity by a similar mechanism).
The following study showed arginine to interfere with creatine kinase activity in the cerebellum of rats:
Study Link – Arginine administration reduces creatine kinase activity in rat cerebellum.
Quote from the above study:
The data indicate that the reduction of CK [creatine kinase] activity in cerebellum of rats caused by arginine was probably mediated by NO and/or its derivatives ONOO(–) [superoxide] and other free radicals. Considering the importance of CK for the maintenance of energy homeostasis in the brain, if this enzyme inhibition also occurs in hyperargininemic patients, it is possible that CK inhibition may be one of the mechanisms by which arginine is neurotoxic in hyperargininemia.
The fact that arginine has caused many negative effects when administered in multi–gram doses has surprised even some very intelligent medical researchers. But although the research clearly gives any rational person reason to think twice before engaging in arginine supplementation, arginine–containing products continue to be sold with almost no mention whatsoever of their potential risks.
So, as the line continually blurs between nutrients and drugs, and as inadvertent “self–medication” becomes more and more common, the take–home lesson is clear:
Any person looking to enhance his or her health through supplementation should take heed of the relevant research – and should not simply assume that a nutrient is safe at high doses merely because the same nutrient happens to be “found in food.”
This sort of false sense of security is often perpetuated by the supplement industry, itself, but may sometimes be putting our health in serious danger.
We’ll have more research coming your way soon – stay tuned.








