Sick Over Arginine
The whole hemodilator theory is relatively simple. Arginine is the precursor for NO synthesis and it's been shown that high dose arginine infusion directly into the bloodstream can lead to vasodilation in healthy fasted humans (17). Unfortunately, high doses can lead to decreases in total body water and sodium (4). And even a dose as low as 10 grams has been associated with gastric upset when consumed orally (26,14).
Researchers involved in a third study demonstrating oral arginine-induced GI distress actually had to reduce the quantity originally given so the trials could be completed effectively (29). Despite the reduction to seven grams an hour for three hours (for a 200 pound man), the researchers reported: "All of our subjects reported mild intestinal cramping and diarrhea that lasted for approximately five hours."
But wait, it gets worse! This arginine dose still had no significant effect on glycogen storage following exercise (29)! Because oral arginine only has 70% bioavailability, and up to 50% of this can be broken down to ornithine, taking arginine tablets or powder is impractical for research (6, 9). This is why arginine is usually infused directly into the blood via peripheral IV for scientific studies, and even then an impractical dose of 30 grams of this amino acid is common.
In fact, one study compared infusions and oral dosing. The researchers found that six grams of arginine had no effect via either route of administration, while it took a 30 gram infusion to cause vasodilation (6). So, it takes a 30 gram IV dose to get results. If we were to get these results from an oral dose, we’d have to take 43 grams because only 70% of it is bioavailable (i.e. 30 / .7 = 43).
Now if 10 grams can cause gastric upset, then the 43 gram oral dose (with bioavailability taken into account) makes me more than a little uneasy.
Arginine: A No Go for NO
If you think that this lack of effect is an isolated incident, other studies investigating high oral doses of arginine and NO induced blood flow have shown no effect when 21 grams (7 g 3x/d) were used (1). Two additional studies where 20 grams per day were taken for 28 days also showed no effects (11,12).
At first, this complete lack of effect was a little surprising considering that arginine is the precursor for nitric oxide synthesis. But upon closer inspection, natural arginine levels are far in excess of what should activate the enzyme responsible for NO production — an effect known as the arginine paradox (21).
In yet another study, a six day, arginine free diet had no effect on nitric oxide synthesis. This indicates that arginine isn't limiting for NO production, and its regulation is far more complicated than supplement companies would have us believe (9).
Of course, the whole rested and fasted thing doesn’t apply to you, so let’s see what happened when exercise was involved. This next noteworthy study used 10 grams of arginine along with 70 grams of carbohydrates in subjects who either performed resistance training or cycling exercise (26). The results? There were no changes in blood flow or glucose uptake compared to placebo, regardless of which mode of exercise was used. This is significant because it directly contradicts the claims of the supplement manufacturers.
For those who are more skeptical, or perhaps just brainwashed by flashy advertising, you’re probably not happy with studies using pure arginine. Oh no, it has to be special arginine, like the ones used in the popular products, before you’ll believe any results. Fine, let's look into the science and crack that nut.
The Acid Test
While it’s important to understand the evidence behind normal arginine supplementation, many would argue that it doesn’t apply to the original nitric oxide-stimulating supplement, NO2. This is because the aforementioned product contains arginine alpha-ketoglutarate, not simply arginine. The theory is that alpha ketoglutarate (AKG) somehow makes this supplement "work." Okay, that’s cool, let’s see what science has to say.
This specific product had several studies performed on it, and they were presented at the International Society of Sports Nutrition conference in the summer of 2004. While the findings do not yet come from peer reviewed publications, they yield important information about the efficacy, or lack thereof, of this supplement.
The first study examined the blood levels of arginine and "time released arginine" (following a four gram supplementation with each) to determine whether the latter enhanced the duration of elevated blood arginine levels (18). The reasoning for this study is due to the claim that NO2 has time-release technology, resulting in "perpetual pumps."
Unfortunately for the company, blood arginine levels were nearly all quite similar, and at times 30% lower, in the time-release trial compared to the pure arginine trial! The reason for the lower levels of the former group remains elusive, but could be due to a decreased absorption by the gut, an increased uptake by tissues, or a half dozen other fates for arginine (see 4). Not surprisingly, there was nothing resembling a "time release" effect.
The second study of interest evaluated the effects of NO2 on body composition, muscle strength and endurance (8). For eight weeks, subjects took either 12 grams of NO2 or placebo and underwent a resistance training protocol. At the end of the time period, subjects between groups had no differences in either muscle mass or body fat percentage.
Interestingly, the NO2 group threw an average of 19 pounds onto their bench 1RM, while the placebo group added less than a six pound mean. Does it seem strange to anyone else that this supplement alone supposedly added an average of more than 13 pounds to bench press 1RM over placebo without a concomitant change in muscle mass? This would indicate that the changes are strictly neural in origin, which gets quite complicated and goes beyond the scope of this article.
I'll briefly mention that while nitric oxide itself can have a negative effect on the force of muscle contraction (25), this effect has yet to be shown in humans, and doesn’t warrant serious consideration for our purposes. More importantly, all of the scientific evidence indicates that it's not even possible for us to consume high enough levels of arginine to effectively increase nitric oxide levels! Since this unpublished study is already gracing the advertisements for this supplement, we need to examine the results in a little more detail.
If the subjects in the above study were untrained, they would all add a significant amount of strength without changes in muscle mass within the first several weeks of working out. In this case, these rapid neural adaptations would be expected in both groups, but wouldn't explain how arginine seemingly tripled the improvement in the nervous system activation.
However, since the subjects were in fact trained, the situation is even more puzzling. Unlike novice trainees, strength increases in trained individuals tend to be more a result of muscle growth, which means that there should've been some changes in lean body mass accompanying the other gains. There wasn't.
I would've been impressed, albeit skeptical, by a three or four pound gain over the placebo group on bench press 1RM, but an average of 13 pounds?! Looking at it another way, this means an average gain of two and a half pounds on bench 1RM each week, and this progress is maintained for a whole eight weeks on the same program!
If this trend continued for all exercises, which it presumably does, everyone with these results could easily become a competitive powerlifter. Although such improvements might be theoretically possible, you must remember that these fantastic results were achieved on a training program and diet that normally leads to a mere six pound addition to bench press. Furthermore, to have such incredible strength gains throughout every muscle group, without even the slightest trend for improved muscle growth, demands questioning.
Considering the other research which showed no effect on blood flow and no time release effect, the results just don’t fit. Whether it be improper group selection, outliers in the data, or measurement error, the results presented remain questionable.
With my objective experience as a strength coach, researcher and bodybuilder, I don't believe these results to be possible. Having said that, this article is merely intended to give you the facts that you won’t get anywhere else, and allow you make up your own mind.