Disappointing Results in 28-Day Creatine + β-Alanine Study: No Performance Benefits, No Muscle Gain, No Fat Loss, No Increase in Phosphocreatine & Carnosine in 32 Women

Let's take a closer look at the study and find how it was possible that two proven ergogenics "failed".

Creatine and beta-alanine belong to the few "proven ergogenics", but according to the latest study from the University of Pittsburg, the Texas Christian University, the University of Wisconsin – La Crosse and the Texas A&M University they are not as effective as some of us may think. Specifically the effects of beta-alanine which was tested in what you may call its "comfort zone", i.e. a graded exercise test on the cycle ergometer for VO2peak with lactate threshold determination, and multiple Wingate anaerobic capacity tests. And still, the overall results of the study is that there a "no consistent additive benefits of BA [beta alanine] and CRE [creatine] supplementation in recreationally active women.

If you are using creatine already try adding bicarbonate as extra-cellular pH-buffer

The Hazards of Acidosis

Build Bigger Legs W/ Bicarbonate

HIIT it Hard W/ NaCHO3

Creatine + BA = Perfect Match

Bicarb Buffers Creatine

Beta Alanine Fails to HIIT Back

In today's SuppVersity article, we are going to have a closer look at the study design, its outcomes and potential explanations for the absence of the highly desirable performance enhancing effects of these two (alleged) ergogenic powerhouses.

As you may know I am not a fan of beta alanine, anyway. Yet despite my alleged bias, I have to admit that the wingate tests the scientists used to determine the effects of the supplementation protocol may have been too short for BA to work. In the most comprehensive meta-analysis of the research to-date, Hobson et al. (2012) found that there are no ergogenic effects to beta alanine on exercises lasting less than 60s or more than 240s; and in the "ergogenic" 60-240s zone, the performance benefit is only 2.85%.

Figure 1: In view of the short study duration it's no wonder that there were no significant effects on body fat and lean mass, but the fact that the beta alanine only group actually gained fat after an initial high loss of body fat is still awkward - still, statistically significant was only the time effect, which tells you that exercise works (Kresta. 2014).

And as far as the absence of benefits of creatine are concerned. The results of the study are in line with previous experimental evidence like that presented by Green et al. who report in their 2001 article in the The Journal of Strength & Conditioning Research that...

"[...] short-term Cr supplementation does not enhance MP and PP during repeated upper-and lower-body Wingate tests when not accompanied by an increase in body weight." (Kresta. 2001)

Similarly, Hoffman et al. (2008) could not find perfomance benefits of short-duration beta alanine supplementation in college football players, what the scientists from the College of New Jersey did find, though was an increases training volume and reduces subjective feelings of fatigue in their highly trained subjects in response to the ingestion of 4.5g/day of beta alanine (Hoffman. 2008).

All in all, the results are thus less surprising than they appear to be...

... at least for those of you who don't believe in the unsustainable promises of the supplement industry, but rely on experimental evidence, only. For creatine, the scientists tested the wrong type of exercise. For beta alanine the exercise duration (60s) on the wingate tests was not long enough to show significant performance increases.

Figure 2: Non-significant (!) changes in carnosine (should increase with BA supplementation) and phosphocreatine (should increase with creatine supplementation) in the BA, BAC, CRE and placebo group (Kresta. 2014).

What the previous brief review of selected experimental evidence does not explain, though, are (a) neither the beta alanine, nor the creatine or combined supplementation lead to statistically significant increases in carnosine (via beta alanine) or phosphocreatine (via creatine), (b) the levels of phosphocreatine the high energy resource, that is believed to be responsible for most of the beneficial effects of creatine actually dropped after 2 weeks on maintenance dose of 0.1g/kg creatine, when it was administered after a 0.3g/kg creatine pre-load. These results stand in contrast to previous studies, like...

• Harris and colleagues (2001) who reported that β-ALA supplementation (3.2 g/day) resulted in a 42% increase in muscle carnosine levels after four weeks of supplementation not due to the fact that the carnosine levels didn't increase, but rather due to the fact that the scientists did not find statistically significant interactions among groups in muscle carnosine levels.
  
  As Kresta et al. (2014) point out, "the lack of statistical significance was apparently due to the large variability in muscle carnosine levels observed in response to β-ALA supplementation, assay variability, and/or inadequate sample size", so that "[m]ore research is needed to determine the effects of β-ALA supplementation on muscle carnosine levels in recreationally-active women" (Kresta. 2014).
• Greenhaff et al. (1994) or Harris et al. (1992) who found significant increases in phosphocreatine with similar preloading + maintenance creatine supplementation schemes as the one used in the study at hand, but yielded significantly higher and above all consistent increases in creatine of up to 40% . Results from the present study found non-significant increases in muscle PCr of up to 40%
  
  Again, Kresta et al. suspect that "the lack of significance may have simply been a result of the small sample size", but add that "it is also known that there is individual variability in response to creatine supplementation" (Kresta. 2014) - a fact that is imho unlikely to be a likely cause of the lack of effect in all subjects, though.

Overall it is thus difficult to determine the lack of consistence improvements in carnosine and phosphocreatine levels in the study at hand, it may yet, as Kresta et al. suggest also be possible...

A study by Everaert, et al. indicates that women have naturally lower carnosine levels (Evaerart. 2011 | see figure abvove). Previous studies, e.g. Tallon (2006), however, found no such difference which is interpreted by Harris et al. in their 2012 review as evidence that "that the apparent gender difference reported by Everaert et al. (2011) may have been simply due to a higher type I:II ratio in females in the voxel sampled." (Harris. 2012)

"[...]that sex may have played a role in response to creatine and/or β-ALA supplementation. In this regard, most studies on creatine and β-ALA supplementation have been conducted on males and there is some evidence that females may respond differently to creatine and/or β-ALA supplementation. For example, Fosberg and colleagues (Forsberg. 1991) reported that females had greater total creatine amounts relative to tissue weight; however, other studies show there is no difference between males and females (Forsberg. 1991; Stegen. 2014).

There are also some data suggesting that men may have greater muscle carnosine levels than women (Derave. 2002; Harris. 2012); however, a recent study showed sex did not have an effect on increasing carnosine levels with supplementation (Stegen. 2014). Additionally, Bex and coworkers (2014) reported that carnosine loading is more pronounced in trained versus untrained individuals" (Kresta. 2014).

It is thus possible, but imho again not very likely that the fact that the subjects in the study at hand were women and or their individual training status may have had and impact on the hardly existing response to creatine and/or β-ALA supplementation.

Creatine + bicarbonate appears to offer a superior synergism | learn why

In the end, it's yet not the increase in carnosine or phosphocreatine that's important for us. What we are looking for are performance increases, which were probably absent due to the selected tests, on which previous studies have already shown that creatine and beta alanine have failed before to produce significant performance increases (see previous elaborations on the non-existent effects of BA on 60s and >240s exercise and the issue with creatine and wingate tests), plus changes in body composition for which the four-week study period may simply have been too short.

Against that background I would like to point out that the study at hand does not indicate that either beta alanine or creatine are useful. What it does, thought, is to remind us of the fact that (a) you won't see results over night and (b) even beta alanine and creatine are exercise-specific ergogenics and won't boost your performance an each and every type of exercise to the same extent. Or what do you think are the implications? Comment on Facebook!

References:

• Bex, Tine, et al. "Muscle carnosine loading by beta-alanine supplementation is more pronounced in trained vs. untrained muscles." Journal of Applied Physiology 116.2 (2014): 204-209.
• Derave, Wim, et al. "Muscle carnosine metabolism and β-alanine supplementation in relation to exercise and training." Sports medicine 40.3 (2010): 247-263.
• Everaert, Inge, et al. "Vegetarianism, female gender and increasing age, but not CNDP1 genotype, are associated with reduced muscle carnosine levels in humans." Amino acids 40.4 (2011): 1221-1229.
• Green, J. Matt, et al. "The effects of creatine supplementation on repeated upper-and lower-body Wingate performance." The Journal of Strength & Conditioning Research 15.1 (2001): 36-41.
• Harris, Roger C., et al. "The absorption of orally supplied β-alanine and its effect on muscle carnosine synthesis in human vastus lateralis." Amino acids 30.3 (2006): 279-289. 
• Harris, R. C., et al. "Determinants of muscle carnosine content." Amino acids 43.1 (2012): 5-12.
• Hobson, Ruth M., et al. "Effects of β-alanine supplementation on exercise performance: a meta-analysis." Amino acids 43.1 (2012): 25-37.
• Hoffman, Jay R., et al. "Short-duration< i> β</i>-alanine supplementation increases training volume and reduces subjective feelings of fatigue in college football players." Nutrition Research 28.1 (2008): 31-35. 
• Kresta, Julie Y., et al. "Effects of 28 days of beta-alanine and creatine monohydrate supplementation on muscle carnosine, body composition and exercise performance in recreationally active females." Journal of the International Society of Sports Nutrition 9.Suppl 1 (2012): P17.
• Stegen, Sanne, et al. "The Beta-Alanine Dose for Maintaining Moderately Elevated Muscle Carnosine Levels." Medicine and science in sports and exercise (2014).
• Tallon, Mark J., et al. "Carnosine, taurine and enzyme activities of human skeletal muscle fibres from elderly subjects with osteoarthritis and young moderately active subjects." Biogerontology 8.2 (2007): 129-137.

Amino Acids for Super Humans, Part IV - Purported Ergogenics (1/3): Beta Alanine, The New Creatine?

Image 1: Despite its presence in meat,
fish and dairy, it is near impossible to
achieve supra-physiological and thus
ergogenic carnosine levels without
supplemental beta alanine.

Beta alanine, unlike l-alanine is one of the "beta-amino acids", indicating that it is neither essential nor proteinogenic, i.e. it is not built into proteins or used in the synthesis of major enzymes. Nevertheless, beta alanine plays a major role with regard to health in general and brain health and muscular performance, particular.

Taken orally, as a supplement, beta alanine (BA) has a slight sweet taste to it (the artificial sweetener suosan is derived from BA). It is highly water soluble and the funny tingles, which can be avoided by either taking it with food or by taking smaller servings (e.g. 5x 800mg for a total of 4g, which would be a reasonable amount for carnosine "loading") multiple times a day, aside, it is virtually side effects free (some people also develop benign allergic skin or mucosal reactions and/or diarrhea). 

According to Jeffrey R. Stout from the University of Oklahoma, who is one of the scientists behind many of the the commonly cited studies on beta-alanine and exercise performance, humans, in contrast to other mammals, cannot synthesize beta alanine (PerfNut. June, 2006). Humans get their beta-alanine directly from BA-containing dipeptides in our food:

• Carnosine (beta-Alanyl-L-histidine), 
• Anserine (beta-Alanyl-N(pi)-methyl-L-histidine) and 
• Balenine (beta-alanyl-N tau-methyl histidine)

are dietary sources of beta alanine. All three are particularly high in meat, eggs, dairy, which is why vegetarians tend to have significantly lower beta alanine intakes. With beta alanine being a non-essential amino acid, low intakes of beta alanine would not be a problem, if it were not the rate limiting substrate in muscular (and cerebral) carnosine synthesis.

Note: This is the detailed transcript of my show notes to "Amino Acids for Super Humans Part IV"
click here to download the podcast if you want to listen before / during / after you read the rest of the notes

Beta alanine, the rate-limiting substrate in carnosine synthesis

Carnosine, i.e. beta-Alanyl-L-histidine (C9H14N4O3), is a dipeptide which was first isolated by Gulewitsch and Amiradzhibi at the dawn of the 20th century. Yet, science begins only recently to grasp all the remarkable health and performance benefits, its presence in muscle, nerve and other tissues may provide. In the following I will summarize the most relevant facts and findings:

• carnosine levels are particularly high in brain tissue and fast-twitch muscle fibers (Harris. 1998)
• mean concentrations are 17.5 ± 4.8 mmol kg−1 dm in females and 21.3 ± 4.2 mmol kg−1 dm in males (Mannion. 1992),
• interestingly muscle carnosine levels of sprinters and other sports with short bursts of high intensity work are elevated compared to non-athletes and athletes from endurance-oriented sports such as marathon runners
  
  carnosine & the brain
  
• carnosinemia (a rare condition of low carnosine levels) effects almost exclusively the brain, which indicates that it is of utmost importance to brain health
• carnosine levels (in all tissues) decline with age; scientists speculate about the role of low carnosine levels in dementia and other age-related neurological diseases
• carnosine's antiglycation effect makes it a promising therapeutic agent in the treatment of AGE-related (AGE = advanced-glycation-end-products) pathologies such as Alzheimer's (Reddy. 2006)
  
  carnosine & athletic performance



Figure 1: In one of the most recent studies
beta alanine supplementation @ 4g/day
significantly improved performance and
body composition in trained football
players and wrestlers (Jun 13, 2011)



• carnosine appears to have general anti-oxidant capacity and could thus protect athletes from exercise induced oxidative stress
• carnosine has a PH of 6.9-7.0, which is identical with the normal intracellular PH level of 7.0 (cf. blood PH is higher: 7.4); similar to bicarbonate (PH ~8.0) which is an excellent extra-cellular buffer, carnosine can act as a buffer on the cellular level
• by buffering H+ ions which are produced in the course of strenuous exercise sessions, it reduces the buildup of lactic acid, which other than its base, lactate cannot be readily "recycled" as fuel (Catham. 2002), but contributes to exercise induced and acidosis and consecutive performance decrements (Böning. 2008)

Increasing carnosine levels by beta alanine supplementation

I has been shown, that oral beta alanine supplementation can elevate carnosine levels (in muscle) by up to 80% (Derawe. 2010). The beneficial effects of the practice of what I would like to call carnosine loading (via BA supplementation) have been confirmed by numerous studies in the course of the last decade. In a 2010 review of the literature Sale et al. conclude:

β-Alanine supplementation has consistently been shown to augment muscle carnosine concentrations in man [...] There is now a growing body of evidence to show that β-alanine supplementation of 4 weeks or longer evokes significant improvements to exercise capacity, especially when that performance is likely to be limited by the accumulation of H+ ions in the skeletal muscle (i.e. in high-intensity exercise tests lasting between 1.5 and 4 min)

In that, it is important to note that the immediate effects, many fitness enthusiasts report on the health and body building boards on the Internet, are probably placebo and/or psychological effects related to the tingling sensation, most people get from beta alanine intakes in the range of 1g+.

Muscle carnosine levels rise gradually, a sensible supplementation regimen would thus span 4-6 weeks with a daily intake of 3-5g of beta alanine per day - preferably in divided doses to avoid the tingling and ensure proper absorption.

Studies show that after a certain time-frame, which varies according to interpersonal differences and training modalities, carnosine levels saturate. Whether or to which extent continuous supplementation makes sense in these circumstances has not yet been elucidated and would certainly depend on the individual athletic demands.

Tingles, flushing and myocardial suffocation

Regardless of whether they enjoy or hate the tingling sensation that comes with higher doses of beta alanine, neither the "lovers" nor the "haters" can provide a 100% scientifically proven explanation for their occurrence. A common theory relates to the process of carnosine synthesis, of which you have already learned that it involves two amino acids: beta alanine and l-histidine. The latter is abundant in muscle tissue and the generally accepted hypothesis is that it is released in the presence of beta alanine in order to form carnosine. If a sudden spike in serum beta alanine levels occurs, the amount of histidine that is released from the muscle tissue could either surpass the amount of beta alanine that is actually there to recombine to carnosine, which would subsequently be stored within the muscle (or other tissue), or there is simply not enough carnosine synthetase (the enzyme which catalyzes the reaction of beta alanine + l-histidine to carnosine) available. In both instances there would be a net increase in "free floating" l-histidine in the blood stream, which in turn could undergo decarboxylase by the respective enzyme, L-histidine decarboxylase. The histamine produced in this reaction could then activate histamine receptors at the tissue level and provoke an "allergic" reaction that feels like a tingling sensation. Both, the non-occurrence of the tingling as well as the few reported instances, where the latter are accompanied by a rash on the tingling body parts, would support the histamine-hypothesis.

In Joe Antonio's Performance Nutrition Podcast, back in 2006, however, Jeffrey R. Stout suggested another possible mechanism (PerfNut. June, 2006). According to Stout, a direct interaction of the beta-alanine molecules with neurons in the respective tissue would be responsible for the (un-?)comfortable sensation. 

And, to make things even more complicated, I would like to suggest a third hypothesis: Those of you who have had thequestionable experience of (over-)consuming GABA orally, may have noticed that, the shortness of breath aside, the activation of peripheral GABA receptors can provoke a feeling which is not all too different from the BA-tingles. With beta alanine being a GABA-A & GABA-C agonist, this would be another, yet possibly the least likely, explanation.

Beta Alanine & Taurine - archenemies or synergists?

Figure 3: The structural difference in their
molecular structure is the outward sign of
the very different biological functions of
alanine (left) and beta-alanine (right);
one part of the energy supply chain,
the other a potent H+ buffer

Whatever the reasons for the tingles are, they are just as benign as oral beta alanine supplementation in general. In this respect, any possible concerns, my report on the hypoxic consequences of beta alanine induced taurine depletion in isolated cardiomyocytes might have brought up, would be inappropriate. Other than cells in a petri dish, your heart, or rather your whole body can very well take counter-measures against overtly high beta alanine levels and consequent cellular taurine depletion. The latter could at worst become an issue, if you decided do lace all your foods, drinking water and whatever else you consume with tons of beta alanine for weeks to deliberately deplete your taurine stores.

In the aforementioned study the scientists found that "buffering" (remember these experiments were done in a petri dish) the beta alanine with equal amounts of taurine, i.e. one taurine molecule for each beta-alanine molecule. If you wanted to mimic this equilibrium state in your supplemental regimen, the higher molecular weight of taurine (125.15 g mol−1), as opposed to beta alanine (89.09 g mol−1), would dictate a ratio of about 3:5. A reasonable way of achieving this could be 1.5g of beta alanine upon waking, 1.5g before workout, 2.5g taurine post-workout and another 2.5g before bed. 

Personally, I do not think that supplementary taurine intake would be necessary (assuming you keep your beta alanine intake in the suggested range of 3-6g per day), but since both amino acids appear to have ergogenic potential (and taurine is also involved in many other metabolic processes) it may make sense to supplement both, anyway. Whether would be necessary or even beneficial to take them one at a time in order to avoid competitive absorption is yet questionable. Under the assumption that the ratio is not totally off - like 15g of bet alanine and 500mg of taurine - I assume that you will absorb reasonable amounts of both, even when you take them together.

Beta alanine, does it have endocrine effects as well?

Aside from the neurological effects of beta alanine (Tiedje. 2010) there is yet another hitherto hardly recognized effect of 3-Aminopropanoic acid (BA) in mammals: Beta alanine appears to modulate estrogen metabolism. A 2010 study by Yang et al. (Yang. 2010) found that beta alanine significantly (-18%) decreased estradiol levels in adult rats. This is an interesting observation, especially if one takes into account the results of Walter et al. (Walter. 2010) who recorded a significant weight gain in 44 women supplemented with 1.5g of beta alanine for 8 weeks. In contrast to other studies on male subjects, the weight gain was not due to superior increases in lean mass (measured, unfortunately, by air displacement instead of DEXA), as the latter increased similarly in the control group.

Note: The study by Yang et al. does not conflict with existing human data from Hoffman 2006 and Hoffman. 2008, who found no increase in testosterone, growth hormone or cortisol response to exercise in football players and experienced resistance trainers after 10, respectively 4 weeks of beta alanine supplementation. Those endocrine parameters remained unchanged in the Yang study, as well.

It is common knowledge that the reduced estrogen production at the onset of menopause is partly responsible for the weight gain women experience at that age. That the opposite, i.e. weight loss, and more specifically, fat loss, is a consequence of lower estradiol levels in men is yet less well known. And despite the fact that this hypothesis warrants experimental verification, it may be possible that small, yet statistically significant endocrine modulations due to beta alanine supplementation may in part explain both, the weight gain the women in the Walter study experienced (Walter. 2010), as well as the improvements in fat loss and retention of lean mass in dieting wrestlers in the recently published study by Kern et al. (Kern. 2011).

Bottom line: Although beta alanine is the next "big thing" since protein and creatine supplements, it probably is a way smaller "big thing". If you got to chose and are no athlete competing in weight classes, creatine will probably provide greater benefits in view of performance increases and body recomposition or muscle building. If you can afford taking both, however, do not hesitate! Studies like Hoffman 2006 make it quite clear that the combination of creatine and beta alanine, which work via distinct mechanisms of action, is the way to go for the non-drug taking athlete who is looking for the slight edge which so often decides on victory or defeat.

Is Beta Alanine a Dangerous Neurotoxin? Or is the Latest Research Fearmongering Anti-Supplement Propaganda?

Could beta alanine "tingle down" your neuronal circuits? (img health.yahoo.com)

You wouldn't be taking a dietary supplement that does not have any studies about potential side effects, would you? ... I guess, most of you will answer this question with "No, never", or "no, I wouldn't" and will thus be pretty surprised to hear that their periworkout nutrition contains an "untested", brain-active compound with a highly familiar name: Beta-Alanine! Maybe some of you may be remembering an earlier post of mine about the hypothetical side effects the popular ergogenic could on your heart (see "Beta Alanine Suffocates Cardiomyocytes"; read more), but since I - or rather no scientists - has followed up on the notion that this widely used dietary supplement could turn out to be a wolf in sheep's clothing, even those of you who have read the respective post will probably have forgotten about it by now.

Even researchers still doubt the safety of creatine, why don't they care about beta alanine?

The absence of adequate data on its safety was also the main reason for Tanise Gemelli and her colleagues from the Universidade Federal do Rio Grande do Sul in Brazil to test whether the beta amino acid, of which the scientists emphasize that "studies about side-effects, especially brain effects in humans were not been performed" (Gemelli. 2013), is even save for human consumption.

Beta alanine, taurine and the liver - Or why the notion that chronic high dose beta alanine supplemenation may have side effects is not totally new: Taurine depletion in the liver (and other tissue) and subsequently increased susceptibility to oxidative damage by natural and exogenous pro-oxidant assaults are by no means a novel finding. In 1993, for example, Waterfield et al. were able to show that the depletion of the hepatic taurine stores due to the inhibitory effects of beta alanine on taurine uptake, increases the susceptibility of the liver to carbon tetrachloride toxicity (Waterfield. 1999; learn more about taurine).

As common practice dictates, studies into the potential side effects of drugs, supplements, herbs etc. always start with a rodent model. That may sound pathetic in the case of a substance that's being used by 100,000s of people on a daily basis, but would it would still be unethical to test a given substance, in this case beta alanine, on human subjects, if you assume that it may - in sufficiently high doses - induce similar neurological dysfunction as they've been observed in  patients with b-alaninemia, an inborn error of metabolism, in which high concentration of beta alanine accumulate, inhibit GABA uptake by competing for transporters GAT-3 and GAT-4 and cause clinical pathologies such as neurological abnormalities, even in the absence of an exogenous supply of the scarce amino acid (Gibson. 2001; Tiedje. 2010).

To elucidate whether similar neurological side effects would occur upon high dose supplementation in rodents, the Brazilian scientists administered three subsequent intraperitoneal injections (simulates oral ingestion; the injections are used solely to avoid that the animals regurgitate the substance) of 0.3 mg /g of body weight beta alanine on two different groups of Wistar rats in order to determin the oxidative stress parameters and kinase activities in their brains 60min after the amino acid made it into through their digestive tract (the use of two sets of rats was necessary, because "the buffer for brain  homogenization used for the determination of the oxidative stress parameters is different from that used for the determination of kinases activities"; Gemelli. 2013).

Figure 1: Markers of oxidative stress (DCF, sulfylhydryls, CAT, SOD; left) and levels of kinase activity (PK, AK, Cy-CK, Mi-CK; right) expressed relative to untreated control (Gemelli. 2013)

Despite the fact that a brief glimpse at the data in figure 1 will reveal that this loading protocol, which would be roughly equivalent to the ingestion of 3x3-4g of beta alanine in an average human being, will suffice to see that the increases in the serum and brain levels of the beta amino acid did yield the expected changes of all tested parameters the interpretations of these changes are not totally straight forward.

So what to the results tell us?

Creatine kinase (CK), pyruvate kinase (PK), and adenylate kinase (AK) are all thiol-containing enzymes that are involved in the phosphoryltransfer network, which is critical for an optimally functioning energy metabolism in almost all mammalian tissues. PK, in particular, is of paramount importance for optimal glucose metabolism and thus the provision of energy to the brain. It's under- and overexpression in the cerebral cortex, which plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness and the cerebellum, which is likewise involved in cognitive functions, regulates fear and pleasure responses and controls movement-related functions, respectively, could thus have significant negative effects on your physical and psychological health and behavior.

Does beta alanine hamper instead of improve your sprinting performance? The results are conflicting, but in a study from March 2013, the coingestion of BA and baking soda thwarted the ergogenic benefits of the latter (learn more)

"We observed that b-alanine administration inhibited the PK activity in cerebral cortex homogenates from rats. This same effect was observed in other amino acids administration, such as phenylalanine, where chronically induced hyperphenylalaninemia reduces PK activity in brain cortex of treated rats (Feksa. 2002). Pyruvate is an antioxidant (Das. 2005) and provides substrate for ATP synthesis in mitochondria (Yapicioglu. 2004). The diminution of PK activity is possibly caused by alteration of the crucial sulfhydryl groups of the enzyme, but it cannot be ruled out that may be caused by down-regulation of expression or damage to existing proteins." (Gemelli. 2013)

With the opposing effect in the cerebellum, the latter, i.e. the potential brain damage, remains yet just that - a potential consequence. In a similar vein, the dysregulation of CK and AK, which are likewise crucially involved in the brain energy metabolism and should actually act antagonistically, with the elevation of one of the two leading to a decrement in the other, does not necessary signal protein damage, but is an unquestionable sign that the administration of relatively high, but by no mean unrealistic dosages of beta alanine is able to disturb the normal enzymatic regulatory cycle of the brain - at least in rodents, I should add. It is nevertheless hard to debate that the..

"[i]mpairment of energy homeostasis and reduction of antioxidant defenses could [my empahsis] provoke oxidative stress with consequent apoptosis and brain cells death (Burlacu . 2001; Park. 2005). Considering that PK is also inhibited by b-alanine administration, the diminished activity of PK and AK, and possibly of other thiol-containing enzymes, might suggest a decreased ATP content with abnormal phosphoryltransfer network." (Gemelli. 2013) 

Moreover, the concomittant increase in Cy-CK activity corroborates the notion that the skewed energy supply leads to an increase in reactive oxygen species (ROS) in the cerebellum, with the differential reaction in the different parts of the brain being a result of the heterogeneous "sensitivity of [different brain] regions in response to exposures associated with oxidative stress" (Gemelli. 2013).

---

On a side note: It is of paramount importance to distinguish between beta alanine and the histidine + beta alanine peptide carnosine. Higher concentrations of the latter have been shown to have protective effects against oxidative stress in the brain. The problem is thus "beta alanine specific" and could probably be reduced / maybe even be totally negligible if you stick to lower amounts of slow-release beta alanine which would avoid spikes of the potentially neuro-toxic amino acid and allow sufficient time for it to be bonded with histidine to form carnosine.

Bottom line: Despite the fact that the results are only preliminary and the differential accumulation of the potentially toxic chemicals and/or metabolite(s) in various regions of the brain that was accompaied by a modulation of metabolic and detoxification enzymes in the brains of the lab animals must not necessarily be accompanied by cellular damage. It could, as the scientists point out, impair the phosphoryltransfer network and reduce creatine and pyruvate content. This in turn could establish a vicious circle, in which "the diminution of antioxidant defenses increases kinases inhibition which decreases pyruvate and creatine content, and so on" (Gemelli. 2013) Needless to say that this would be hardly worth the highly exercise specific +2.85% increase in performance, Hobson et al. report in response to the chronic administration of beta alanine in a comprehensive meta analysis from 2012 that's too willingly hushed up by the majority of the supplement producer and the magazines that live off their advertisment money (Hobson. 2012).

Despite the fact that I never hid the fact that I am not a fan of beta alanine (also because I never noticed anything but tingles from using is), I would be hesitant to say that it would be wise to refrain from using respective supplements in the future altogether. What you may yet want to reconsider (at least until the whole issue is further investigated) is the use of large boluses of beta alanine on an empty stomach - according to previously conducted studies, that's nonsensical, anyway (Hobson. 2012; Stegens. 2013).


References:

• Feksa LR, Cornelio AR, Rech VC, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM. Alanine prevents the reduction of pyruvate kinase activity in brain cortex of rats subjected to chemically induced hyperphenylalaninemia. Neurochem Res. 2002 Sep;27(9):947-52.
• Burlacu A, Jinga V, Gafencu AV, Simionescu M. Severity of oxidative stress generates different mechanisms of endothelial cell death. Cell Tissue Res. 2001 Dec;306(3):409-16. 
• Das UN. Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. Med Sci Monit. 2006 May;12(5):RA79-84.
• Gemelli T, de Andrade RB, Rojas DB, Bonorino NF, Mazzola PN, Tortorelli LS, Funchal C, Filho CS, Wannmacher CM. Effects of β-alanine administration on selected parameters of oxidative stress and phosphoryltransfer network in cerebral cortex and cerebellum of rats. Mol Cell Biochem. 2013 Apr 26.
• Gibson MK, Jakobs C. Disorders of b-and c-animo acids in free and peptide-linked forms. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The metabolic and molecular bases of inher-ited disease, 8th edn. McGraw Hill, New York,2001; pp 2079–2105.
• Hobson RM, Saunders B, Ball G, Harris RC, Sale C. Effects of β-alanine supplementation on exercise performance: a meta-analysis. Amino Acids. 2012 Jul;43(1):25-37. 
• Stegen S, Blancquaert L, Everaert I, Bex T, Taes Y, Calders P, Achten E, Derave W. Meal and Beta-Alanine Coingestion Enhances Muscle Carnosine Loading. Med Sci Sports Exerc. 2013 Mar 5.
• Tiedje KE, Stevens K, Barnes S, Weaver DF. b-Alanine as a small molecule neurotransmitter. Neurochem Intern. 2010; 57:177–188.
• Waterfield CJ, Turton JA, Scales MD, Timbrell JA. Reduction of liver taurine in rats by beta-alanine treatment increases carbon tetrachloride toxicity. Toxicology. 1993 Jan 29;77(1-2):7-20.

Anserine + Carnosine Supplementation: A Capped Fountain of Cognitive Youth? Plus: Beta-Alanine + Creatine Could Be A Similarly Brainy Supplement Stack for Young & Old

Carnosine + anserine supps could help her keep up with her grand daughter - physically and mentally!

As a SuppVersity reader you know that  carnosine is the stuff you actually want to increase, when you are taking beta alanine supplements - you want the beta alanine to bind to L-histidine and from β-alanyl-L-histidine aka carnosine. If you are a student who reads and memorizes all article and not just a diligent reader, you will also remember that carnosine acts as a cellular "stress" buffer and that this buffer, as important as it may be during intermittent high intensity exercise, is actually even more important for your neuronal health, or put simply, your brain!

So, even if you haven't heard about anserine before, at least the idea that taking carnosine supplements, or maybe I should say, increasing brain carnosine levels could be a good thing for your cognitive abilities should sound vaguely familiar... and if it does not, this would be another reason to read this article ;-)

You can learn more about brain health at the SuppVersity

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You should not be concerned, though, if it doesn't sound familiar, when I tell you that Budzen et al. report in their paper in the Archives of Gerontology and Geriatrics that the provision of both, carnosine and its "bird analogue" anserine, which is the major "buffering" dipeptide in bird muscle, will have astonishingly significant beneficial effects on the cognitive functioning and physical capacity of elderly individuals.

No wonder, considering the fact that carnosine, anserine and related compounds are reported to play an important physiological role in the body.

Carnosine can be transported across the blood-brain-barrier. Beta alanine, too, but as Sale et al. (2013) point out, we don't know if it will "form carnosine or act as a neuromodulator / neuro- transmitter itself, once it's in the brain" (illustration + quote from Sale. 2013). If it does the latter it will, similar to taurine interact with the GABA receptor (Horikoshi. 1988)

• They have antioxidant properties, cytosolic buffering capabilities and maintain an acid-base balance in excitable tissues of animals and humans. 
• Carnosine is an antiglycating agent. That means it protects your cells from the sugary glue that plasters their exhaust pipes until they start malfunctioning (What? No, that's not an accurate analogy, but I guess, you get what it means ;-)
• They have metal ion-chelating properties and can thus prevent toxic damage from "bad" and not so "bad" metals. Eventually even things like zinc and copper, iron, and calcium, metals your body needs for proper function, will harm you, when they cannot be handled by the body appropriately - as amino acid chelates (you don't have to take them in this form, you just have to have the building blocks your body needs to produce them!)
• Carnosine has also been shown to extend the life of cells in cell culture conditions and to regulate the activity of calcium channels in skeletal muscles.

Due to their overall ability to blunt the negative effects of oxidative and carbonyl stress, both agents have long been touted as potential "pharmacological" (in the widest sense) agents.

Studies conducted on rats and mice show that carnosine has a neuroprotective potential against cerebral ischemia, and indirectly reduces the mortality of the animal (Stvolinsky. 2000; Dobrota. 2005; Rajanikant. 2007). Human studies in patients with chronic discirculatory encephalopathy stress, a specific form of what you could call "brainflammation" (=chronic inflammation of the brain) show that carnosine enhances the efficacy of basal therapy of these patients.

Aging ➯ carnosine ↓, physical & cognitive performance ↓ - probably not a coincidence!

Suggested Read: Hydrated or Dumb: Dehydration Affects Brain, Muscle and Other Vital Organs - Plus: 15+ Causes of Dehydration  | read more

Against that background the chronic decline in whole body carnosine levels with age is something scientists have been eyeballing with concerns for quite some time. Studies have shown that the exogenous provision of beta-alanine can bring the carnosine levels in the musculature back up. In view of the fact that "brain biopsies" are not exactly on the list of favorite experimental procedures the average human study participant wants to undergo, it is yet not 100% sure whether similarly significant increases in carnosine, as they have been observed by Favero et al. in skeletal muscle, will occur in the brain and cells of the peripheral nervous system, as well.

So, if we don't know if beta alanine converts, why don't we administer carnosine, directly? That's a good question, but also one that tells me that you are no true "muscle head". Otherwise the information that carnosine is immediately metabolized and won't even make it to your muscle or brain would already have been hardwired into your brain by the marketing machinery of the fitness industry.

If carnosine is metabolized so quickly, isn't the whole study protocol bullocks, then? Yeah...ah I mean, no. It isn't. In fact it's actually quite clever! By administering carnosine in form of a chicken extract ant thus alongside its natural co-factors, of which anserine is probably only one, the scientists made use of the results of a 2011 study by Peters et al. who were able to show that anserine inhibits the previously mentioned degradation of carnosine and could thus solve the "zero bioavailability problem" (Peters. 2011).

Now, I would be curious what other co-factors in the 2g of chicken-protein hydrolysate may have had an impact on the study outcome, as well. Unfortunately, the only thing we know about the supplement that was administered daily for 13 weeks, is that it was standardized for 1g of anserine and carnosine at a 2:1 ratio (i.e. 667mg of  anserine and 333mg of carnosine).

Figure 1: Beneficial effects of the chicken protein extract anserine + carnosine supplement (Budzeń. 2014)

Practically speaking, this means that the effects I have summarized graphically in Figure 1, were brought about by ca. 667mg anserine and ca. 333mg carnosine the fifty-six 65y+ agers consumed on top of a macronutrient-wise astonishingly "anabolic" diet (1.5g/kg body weight protein,  2.5g/kg carbohydrates and 1g/kg fat).

Let's see what else happened in response to this "minimal" intervention

If you take a look at the other differences between the active treatment group, who received 2.5g of the chicken extract that contained 1g of anserine + carnosine at a 2:1 ratio, and the placebo group, you will see that next to the changes, I illustrated in Figure 1,

• 

  If the influx of beta alanine into the brain was not controlled it could have toxic effects | learn more

  the dangerous diastolic blood pressure of the elderly subjects in the placebo arm kept kreeping up, while the one of the anserine + carnosine treated subjects did not budge,
• the resting heart rate of the placebo group measured at the before and after session increased, while it remained unchanged in the active arm of the study, and
• the body mass index of the subjects in the placebo arm of the study remained steady, while the subjects who received the anserine + carnosine supplements lost a significant, but certainly not earth-shattering 0.51kg/m².

It should yet be obvious that the the changes which are shown in Figure 1, namely significant improvements in the "foot up and go", the "back scratch" and the borg scale, a measure of perceived physical exertion during exercise / physical activity, as well as the improvements in the Mini Mental State Examination, a brief 30-point questionnaire test that is used to screen for cognitive impairment, and the Short Test of Mental Status, which is a classic test that's used with dementia patients, are the more important inter-group differences the researchers from the University School of Physical Education in Wroclaw listed in their hitherto only accepted paper for the Archives of Gerontology and Geriatrics.

With exercise and EGCG (green tea), beta alanine has already been shown to increase neuro- genesis - at least in mice: The corresponding paper by Jessica Ossyra from the University of Illinois has not been published yet, but tis wouldn't be the SuppVersity if I didn't tell you that a combination of the green tea extract ingredient EGCG, beta alanine and exercise has obviously recently been shown be a major promotor of neuro- genesis in mice (Ossyra. 2014).

Now, personally, I see no reason why the provision of beta alanine in an endurance training context (medium intensity is still the best brain builder | learn more), alone, i.e. even in the absence of EGCG, would not produce similar effects in human beings. I still have to curb your enthusiasm and add: "This assumption warrants experimental verification."

Bottom line: In conjunction with significant improvements in abstraction, construction and Copying, as well as memory recall the aforementioned changes and improvements in cognitive and physical performance were all supplementation specific and support the notion that the provision of carnosine, when it is administered at a 2:1 ratio with anserine is not in vain.

What you are now probably asking yourselves, though, is whether a similar if not even more pronounced effect couldn't have been achieved by a much cheaper dietary supplement: Beta alanine. The universal carnosine precursor that's no longer "all the rage", but still "the rage" in the fitness industry? Well, why don't we take a look at the archives? ... I don't see anything, sorry. As of now there is no peer-reviewed study we could be used as a comparison, but if you asked me, it seems unlikely that it sustained release beta alanine formulas increase the physical performance of elderly subjects (del Favero. 2012) without having at least minor beneficial effects on the brain -- and if you take a look at the box to the right, you will see: In rodents it does already work :-)

What? If the 3x800mg you would take for 6 weeks to maximize your muscle carnosine levels suffice? Well, I can't tell you that, but that's certainly a good point to start from. And you know what? If you add 1.5g of creatine to each of these servings, this would be a brain-saver stack for both yourself and your grandma. Why? Well, creatine has been shown to compensate for experimentally (following sleep deprivation) or naturally (due to aging) compromised cognitive function, as well (Rawson. 2011).

References:,

• Budzeń, S., et al. "Anserine and carnosine supplementation in the elderly: effects on cognitive functioning and physical capacity." Archives of Gerontology and Geriatrics (2014).
• del Favero, Serena, et al. "Beta-alanine (Carnosyn™) supplementation in elderly subjects (60–80 years): effects on muscle carnosine content and physical capacity." Amino acids 43.1 (2012): 49-56.
• Dobrota, Dusan, et al. "Carnosine protects the brain of rats and Mongolian gerbils against ischemic injury: after-stroke-effect." Neurochemical research 30.10 (2005): 1283-1288. 
• Guiotto, Andrea, et al. "Carnosine and carnosine-related antioxidants: a review." Current medicinal chemistry 12.20 (2005): 2293-2315. 
• Horikoshi, Tetsuro, et al. "Taurine and β-alanine act on both GABA and glycine receptors in Xenopus oocyte injected with mouse brain messenger RNA." Molecular Brain Research 4.2 (1988): 97-105.
• McMorris, Terry, et al. "Creatine supplementation and cognitive performance in elderly individuals." Aging, Neuropsychology, and Cognition 14.5 (2007): 517-528.
• Ossyra, Jessica, et al. "The influence of nutritional supplementation with epigallocatechin gallate and β-alanine in combination with physical exercise on adult hippocampal neurogenesis and contextual fear conditioning in young adult BALB/cJ mice (629.4)." The FASEB Journal 28.1 Supplement (2014): 629-4.
• Peters, Verena, et al. "Anserine inhibits carnosine degradation but in human serum carnosinase (CN1) is not correlated with histidine dipeptide concentration." Clinica Chimica Acta 412.3 (2011): 263-267.
• Rajanikant, G. K., et al. "Carnosine is neuroprotective against permanent focal cerebral ischemia in mice." Stroke 38.11 (2007): 3023-3031.
• Rawson, Eric S., and Andrew C. Venezia. "Use of creatine in the elderly and evidence for effects on cognitive function in young and old." Amino Acids 40.5 (2011): 1349-1362. 
• Sale, Craig, et al. "Carnosine: from exercise performance to health." Amino acids 44.6 (2013): 1477-1491.
• Stvolinsky, Sergey, et al. "Carnosine protects rats under global ischemia." Brain research bulletin 53.4 (2000): 445-448.

Histidine As a Fat Loss Adjuvant? 6% Fat Loss Without Dietary or Exercise Intervention & More Than Half a Dozen Other Reasons Not To Ignore This Essential Amino Acid

Histidine as a fat loss adjuvant? Laughable? Not for the obese! For lean folks like her? We'll see...

If I had to guesstimate the number of fitness enthusiasts who have ever heard of histidine at all, I would say that 50% probably don't even know what it is, while the majority of the lightened ones will re-iterate what the supplement business has been preaching them "You get more than enough histidine, anyway. So don't worry our superior beta-alanine supplement will work even if you don't take additional histidine."

Short term studies confirm this notion. It looks as if we usually have more than enough histidine to have it recombine with beta alanine and form carnosine, but long-term studies are missing and let's be honest: How likely is it that an essential amino acid is nothing but a servant to a non-essential amino acid from the 2nd row?

Early results: Histidine modulates feed efficiency

Actually we could have known that histidine could have some merit as a standalone supplement for more than 50 years now, so I am not sure if the recent publications of two studies by Feng et al. in Diabetolgy and Kumi Kimura et al. in Diabetes, the journal of the American Diabetes Association are going to change that over night. What is certain, though, is that they clearly support findings that date way back into early mid 20th century, when Ellison & King found that the provision of a low histidine diet to rodents increased the feed efficiency (=weight gain per energy unit) by 75%, while the addition of 0.75% histidine (per kg chow) to an already histidine sufficient diet  (Ellison. 1968) led to a 30% decrease in food efficiency.

About 45 years later, the previously mentioned studies on the effects of histidine on hepatic gluconeogenesis (Kimura. 2013) and insulin resistance (Feng. 2013) in rodents and human volunteers, respectively, could bring the hitherto often depreciated histamine precursor back to the center of scientific attention.

4g/day histidine improve insulin restiance, reduce fat mass and suppress inflammation

In that, the study by Feng et al., which investigated the effect of 4g/day supplemental histidine on the degree of insulin resistance, inflammation, oxidative stress and metabolic disorders in 100 obese women with the metabolic syndrome (aged 33–51 years; BMI≥28 kg/m²), is probably of greater significance for the average physical culturist that the nevertheless enlightening rodent trial by Kimura et al. we are going to address later.

Figure 1: Changes in amino acid levels, glucose & lipid metabolism, body composition and markers of inflammation after 12 weeks on placebo or 4g/histidine per day (Feng. 2013)

The effects the 4g/day of histidine had especially on the markers of inflammation are quire impressive for an amino acid of which you probably thought as either the "abundant" essential amino acid that's only an adjutant to 100% non-essential and on it's own just about as useless carnosine precursor beta alanine or - even worse - as the nasty precursor to the "allergy inducing", "inflammatory" organic nitrogen compound histamine.

"Hold on, but histidine is an allergy causing nasty bitch, isn't it?"

While the former perspective on histidine is laughable anyway, the fact that there were no increases in histamine levels and none of the participants experienced side effects such as headaches, which have been observed in previous trials with whopping amounts of 64g(!) of histidine per day (Geliebter. 1994) as they have been used, when scientists still believed that the main mechanism of histidine on body weight modulation was mediated by appetite reduction, are probably relevant. After all, histamine does play a role in the inflammatory response system of your body that the latter is not negatively, but positively affected by the consumption of pretty high amounts of histidine, is thus an important and in a way counterintuitive observation. On the other hand,

First the glucose repartitioning effects of isoleucine (learn more), now the benefits of histidine - what other secrets are still out there in the world of amino acids?

[h]istidine is a free radical scavenger and can chelate divalent metal ions (Babizhayev. 1994; Lee. 1999). Its effects against oxidative stress have been well investigated in animals and cells. Histidine has beneficial effects on liver and lung injury in rats and has been reported to protect against diabetic complications in a mouse model of diabetes through its actions against oxidative stress (Lee. 2005; Cuzzocrea. 2007; Yan. 2009). It can restrict accumulation of free radicals and delay activation of extracellular signal-regulated kinase and c-jun N terminal kinase in neuronal cells (Kulebyakin. 2012).

Against that background it is actually not surprising that the levels of TNF-α, IL-6 and c-reactive protein (CRP) dropped by 33%, 35% and 33% in the course of the 12 week study period.

Health and weight loss, two independent pairs of shoes?

If histidine is a metal chelator, do I have to be afraid of losing zinc? That's easy to answer and the answer is no and not just because I believe that the importance of zinc is way overrated (cf. "15mg of Zinc are plenty"). Schechter & Prakesh have shown in 1979, already that the ingestion of 4g of histidine on a daily basis influences the excretion of zinc only in the very short run. After 2 weeks the body achieves a new steady state and the zinc excretion returns to normal. What? No you did not pee out all the zinc before. In fact histidine increases the absorption of dietary zinc as well (cf. Freeman. 1977).

Moreover the changes in serum histidine were correlated with the changes in HOMA-IR, NEFA, TNF-α, SOD, GSH-Px, WC, FM and BMI even after further adjustment for age and serum histidine, protein intake, physical activity, alcohol use, current smoking and menopause at baseline.

"Thus, improved insulin sensitivity and alleviation of inflammation and oxidative stress could be due to the increased serum histidine." (Feng. 2013)

What's questionable, though, is how interrelated the modest, but statistically significant weight, or rather fat loss (-6% total fat mass) and the improvements in inflammation are. If we take a peek at the aformentioned rodent study by Kimura et al. who observed that the effects of histidine are mediated mainly centrally via histamine action on the H1 receptors in the brain, which will - independently of insulin (!) - downregulate the hepatic glucose production, it becomes more and more evident that non-obese / insulin-resistant individuals for whom an abundant hepatic glucose production hardly ever is a problem are less likely to benefit than the patients with type 2 diabetes, Kimura et al. implicate as the group that would be most likely to benefit from high histidine diets.

What else do we know about l-histidine?

In the end, we are thus back to square one. But maybe we can find other arguments in favor or against keeping an eye on adequate histidine intake that would be significant for the non-diabetic majority(!?) of the SuppVersity readers, as well. Let's see, what about

• Ok, put up or shut up - where is the relation between histidine, histamine and obesity? As so often I have to say in advance that the intricacies of the role the histamine receptors in the brain play in the regulation of food intake and metabolism are not yet fully understood. What we do know is that histidine is the dietary precursor for histamine and that the latter can interact with the same receptors (H1-H3) which participate in the regulation of dopamine, serotonin, and norepinephrine release and exert direct modulatory effects on food intake, meal frequency, adiposity and thermogenesis (Masaki. 2003; Masaki. 2004; Yoshimoto. 2006; Yoshimatsu. 2008).
  improved absorption of vitamin B12 and increased liver folate levels (Williams. 1976) 
• low histidine intake increases carnosine breakdown, so that the ant-inflammatory intra-cellular buffer carnosine you are trying to increase by taking BA would decrease to be used as a histidine source if you actually got too little histidine in your diet (Tamaki. 1984)
• increased absorption and excretion of zinc, with a primer on the former, when intakes are low, so that the overall result is an improved management of zinc (Sandström. 1985; Van Wouwe. 1989) 
• potential anti-Alzheimer's effects; if we simply assume that an increased amount of dietary histidine could ameliorate the histidine and histamine reductions in the brains of Alzheimer patients (Mazurkiewicz-Kwilecki. 1989), it would be logical to assume that the presence of this metal-chelator could prevent the accumulation of toxic levels of copper in the brain
• significant increases in UCP-1 activity (+57%) in brown adipose tissue and thus higher energy expenditure, reduced appetite, significantly lower feed efficiency (-30%), reduced insulin levels (-48%) and significantly lowered visceral fat pad weights; allegedly in rodents w/ additional 5% histidine in the diet (Kasaoka. 2004) 

Now you could certainly argue that the studies which support the weight loss effects Feng et al. observed in their obese subjects were almost exclusively conducted on rodents... what am I supposed to say? You're right and you know that I am very skeptical that UCP-1 and brown adipose tissue activity play a significant role in human weight / body fat control. Still, the high correlations between the histidine / total protein ratio Okubo et al. observed in a cohort of non-obese 18y-old female Japanese students does clearly suggest that at least part of the effects are not species specific (Okubo. 2005).

Additional health effects 
 

Milk thistle is unquestionably the more prominent liver protectant (learn more)

Furthermore, histidine also prevented colitis by reducing gastric inflammation (Andou. 2009) and exerted  ameliorative effects on

• LDL oxidation and glycation (Lee. 2005), 
• alcohol induced liver failure (Liu. 2008), 
• acetaminophen induced liver injury (Yan. 2009), 
• diet induced hepatic steatosis (Mong. 2011)

when it was co-administered with carnosine. Unfortunately, none of the studies tested, whether the same results would have been observed if only one of the compounds had been used in the respective rodent trials.

So, no strings attached? Well, not exactly...

As usually the dose-response curve is yet non-linear and an exuberantly high intake of histidine (8% of the diet in rodents → far more than 70g per day for humans) can lead to copper depletion and corresponding lipid disturbances in cholesterol metabolism (Harvey. 1981). Needless to say that for people with a messed up histamine metabolism far lower doses could potentially exert negative effects. It should be mentioned though that the equation"more histidine = more histamine" does not necessary hold - just take a look at the data from the Feng study: More histamine? Yes! Beneficial effects? Yes! Increased circulating histamine? No!

---

Bottom line: Wile it appears likely that the provision of supplemental histidine in amounts of up to 4g/day could provide a highly beneficial adjunct to exercise and diet intervention in obese and/or diabetic individuals, it remains to be seen, whether or not lean, healthy and insulin sensitive fitness enthusiasts benefit to a similar degree.

Histidine content of various foods; w/ a focus on high histidine food items

While I would exclude that the profound anti-inflammatory effects Feng et al. observed could hamper your performance / gains, I would not exclude that the non-vegetarian majority of the SuppVersity readers is not exactly at risk of running out of histidine anytime soon (see table on the right for good dietary sources). Against that background, you may have to revise your perspective on this rarely talked about amino acid. What you probably don't have to do, though, is to go and buy a pouch of l-histidine to up your histidine intake to exorbitantly high levels... well, at least not until research on human beings confirms the beneficial effects on UCP-1, insulin and the body fat levels Ksaoka et al. observed in non-obese rodents.

References:

• Andou A, Hisamatsu T, Okamoto S, Chinen H, Kamada N, Kobayashi T, Hashimoto M, Okutsu T, Shimbo K, Takeda T, Matsumoto H, Sato A, Ohtsu H, Suzuki M, Hibi T. Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology. 2009 Feb;136(2):564-74.e2.
• Babizhayev MA, Seguin MC, Gueyne J, Evstigneeva RP, Ageyeva EA, Zheltukhina GA. L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities. Biochem J. 1994; 304(Pt 2):509–516.
• Cuzzocrea S, Genovese T, Failla M et al. Protective effect of orally administered carnosine on bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2007; 292:L1095–L1104
• Ellison JS, King KW. Mechanism of appetite control in rats consuming imbalanced amino acid mixtures. J Nutr. 1968 Apr;94(4):543-54.
• Feng RN, Niu YC, Sun XW, Li Q, Zhao C, Wang C, Guo FC, Sun CH, Li Y. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. Diabetologia. 2013 Jan 30. 
• Freeman RM, Taylor PR. Influence of histidine administration on zinc metabolism in the rat. Am J Clin Nutr. 1977 Apr;30(4):523-7.
• Geliebter AA, Hashim SA, Van Itallie TB Oral L-histidine fails to reduce taste and smell acuity but induces anorexia and urinary zinc excretion. Am J Clin Nutr. 1981; 34:119–120.
• Harvey PW, Hunsaker HA, Allen KG. Dietary L-histidine-induced hypercholesterolemia and hypocupremia in the rat. J Nutr. 1981 Apr;111(4):639-47.
• Kimura K, Nakamura Y, Inaba Y, Matsumoto M, Kido Y, Asahara SI, Matsuda T, Watanabe H, Maeda A, Inagaki F, Mukai C, Takeda K, Akira S, Ota T, Nakabayashi H, Kaneko S, Kasuga M, Inoue H. Histidine augments the suppression of hepatic glucose production by central insulin action. Diabetes. 2013 Mar 8.
• Kulebyakin K, Karpova L, Lakonsteva E, Krasavin M, Boldyrev A. Carnosine protects  neurons against oxidative stress and modulates the time profile of MAPK cascade signaling. Amino
  acids. 2012; 43:91–96
• Lee JW, Miyawaki H, Bobst EV, Hester JD, Ashraf M, Bobst AM. Improved functional recovery of ischemic rat hearts due to singlet oxygen scavengers histidine and carnosine. J Mol Cell Cardiol. 1999; 31:113–121.
• Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J
  Pharmacol. 2005. 513:145–150.
• Liu WH, Liu TC, Yin MC. Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury. Food Chem Toxicol. 2008 May;46(5):1503-9. doi: 10.1016/j.fct.2007.12.013.
• Mong MC, Chao CY, Yin MC. Histidine and carnosine alleviated hepatic steatosis in mice consumed high saturated fat diet. Eur J Pharmacol. 2011 Feb 25;653(1-3):82-8. doi: 10.1016/j.ejphar.2010.12.001.
• Okubo H, Sasaki S. Histidine intake may negatively correlate with energy intake in human: a cross-sectional study in Japanese female students aged 18 years. J Nutr Sci Vitaminol (Tokyo). 2005 Oct;51(5):329-34.
• Sandström B, Davidsson L, Cederblad A, Lönnerdal B. Oral iron, dietary ligands and zinc absorption. J Nutr. 1985 Mar;115(3):411-4.
• Schechter PJ, Prakash NJ. Failure of oral L-histidine to influence appetite or affect zinc metabolism in man: a double-blind study. Am J Clin Nutr. 1979 May;32(5):1011-4.
• Tamaki N, Funatsuka A, Fujimoto S, Hama T. The utilization of carnosine in rats fed on a histidine-free diet and its effect on the levels of tissue histidine and carnosine. J Nutr Sci Vitaminol (Tokyo). 1984 Dec;30(6):541-51.
• Van Wouwe JP, Hoogenkamp S, Van den Hamer CJ. Histidine supplement and Zn status in Swiss random mice. Biol Trace Elem Res. 1989 Oct;22(1):35-43.
• Williams DL, Spray GH. The effects of dietary histidine, methionine and homocystine on vitamin B12 and folate levels in rat liver. Br J Nutr. 1976 May;35(3):299-307
• Yan SL, Wu ST, Yin MC, Chen HT, Chen HC. Protective effects from carnosine and histidine on acetaminophen-induced liver injury. J Food Sci. 2009: 74:H259–H265.