Chronic High Dose BCAA Supplementation Reduces Endurance Performance by 43% Plus: How Ammonia, Glutamine, Arginine & Low Carb Could be Involved

Tired, exhausted, had to cut your workout short today? Is it the flu, or just too much BCAAs?

When some is good and more is better, even more is not necessarily going to be 'betterer' - and that's not simply due to the fact that there is no comparative to an adjective that's already in the comparative. Therefore it is actually not surprising that a team of researchers from the Department of Food and Experimental Nutrition at the Faculty of Pharmaceutical Sciences, the Department of Nutrition at the School of Public Health and the Department of Physiology and Biophysics at the Institute of Biomedical Sciences of the University of Sã o Paulo in Brazil has just published the results of a study (Falavigna. 2012) which demonstrates that there is an upper limit to the benefits of BCAA supplementation. What I guess will be surprising at least for some not so regular SuppVersity visitors, is that there is more than just a saturation effect: Too much BCAAs can actually have ergolytic (= anti-ergogenic) effects - at least under certain circumstances.

Another chapter in the book of good things that turn against you, when taken in excess

In their latest paper that has just been published in nutrients, Gina Falavigna and her colleagues analyzed effects of chronic BCAA supplementation on exercise performance in male Wistar rats. Based on previous animal and human data and the still widely supported, though actually experimentally non-validated (cf. Meeusen. 2007) theory that BCAAs would work their non-hypertrophy specific, endurance enhancing magic via the blockade of exercise induced 5-HT (serotonin) accumulation in the brain, the researchers speculated that ...

"[...] chronic BCAA supplementation (through the diet, using different BCAA  concentrations) would increase performance in rats subjected to a swimming exhaustion  test." (Falavigna. 2012)

To verify this hypothesis, Flavigna et al. randomized their rats to three different groups receiving either the standard AIN-93M diet for the maintenance of adult rodents (control group) or the same diet with additional additional 3.57% (group S1) and 4.76% (group S2) BCAAs at a ~2:1:1 ratio of lecine : valine : isoleucine (the BCAAs were manufactured by the Brazilian branch of Ajinomoto). The rodents in the S1 and S2 groups did thus receive 50% and 100% more branched-chain amino acids than the rodents in the control group which had to contend themselves with the BCAAs in the casein fraction of their diets (see figure 1, right). In order to assure that the diets would be isocaloric, an amount of starch equivalent to the amoung of BCCAs that had been added to the chow was removed from the supplemented diets.

Overall, the study lasted for six weeks. During this time the rodents were subjected to a 1h/day weight bearing swimming protocol five times a week. In the first two weeks, the rats were ...

"[...] adapted to the water medium and exercised with increasing overloads attached to the tail until an overload corresponding to 5% of total body weight was reached. This final overload was used until the end of the training protocol [...] The overloads were corrected weekly according to the variations in animal weight.  The efficiency of the training protocol was assessed on the basis of maximum activity of the enzyme citrate synthase in the soleus muscle, with a group of sedentary animals being used as the control for this parameter." (Falavigna. 2012)

Neither the overall amount of food nor the body weight gain of the rodents in the control, and the two exercise groups showed any statistically significant difference. The latter cannot be said about the exercise performance, as well as the accumulation of ammonia, though (see figure 1):

Figure 1: Exercise duration and plasma ammonia levels during / after swmming test (left) and macronutrient composition of the experimental diets (right; based on Falavigna.. 2012)

While the rodents in the +50% BCAA group (S1) do show the expected increase in endurance (+37%) their peers in the high dose (+100%) BCAA group (S2) experienced an even more pronounced drop in endurance performance (-43% vs. control), which went hand in hand with a profound increase in blood ammonia (+34%).

"Ammonia is a ubiquitous metabolic product producing multiple effects on physiological and biochemical systems. Its concentration in several body compartments is elevated during exercise, predominantly by the increased activity of the purine nucleotide cycle in skeletal muscle. Depending on the intensity and duration of exercise, muscle ammonia may be elevated to the extent that it leaks (diffuses) from muscle to blood, and thereby can be carried to other organs. The direction of movement of ammonia or the ammonium ion is dependent on concentration and pH gradients between tissues. As such, ammonia can also cross the blood-brain barrier, although the rate of diffusion of ammonia from blood to brain during exercise is unknown. It seems reasonable to assume that exhaustive exercise may induce a state of acute ammonia toxicity which, although transient and reversible relative to disease states, may be severe enough in critical regions of the central nervous system (CNS) to affect continuing coordinated activity. Regional differences in brain ammonia content, detoxification capacity, and specific sensitivity may account for the variability of precipitating factors and latency of response in CNS-mediated dysfunction arising from an exercise" stimulus, e.g., motor incoordination, ataxia and stupor. There have been numerous suggestions that elevated ammonia is associated with, or perhaps is responsible for, exercise fatigue, although evidence for this relies extensively on temporal relationships." (Falvigna. 2012; my emphasis)

Mark the last words of the previously cited paragraph: "[E]vidence for [the role of ammonia] in exercise fatigue relies extensively on temporal relationships". It is thus - as for now - a solely corollary, not yet a causative association, of which I do however feel that it would be very likely to turn into a causal one if someone actually measured the influx of ammonia into the brain during a workout.

Wait, ammonia? But ain't it more likely that the BCAAs block the uptake of tryptophan?

What's for sure is that another hypothesis, which relates to the blockade of tryptophan uptake can be ruled out as an underlying reason of the differences. After all the scientists who argue that ...

"[t]he increased synthesis of serotonin during exercise may be related to the development of central fatigue, because this neurotransmitter has several physiological functions, since it operates by  mood, lethargy, individual behavior, regulation of sleep, body temperature and blood  pressure, appetite suppression and changes in perceived exertion." (Falavigna. 2012)

...actually measured the 5-HT levels and observed no differences between the dietary groups. Overall, the study results to thus clearly indicate that both, medium nor high dose "chronic BCAA supplementation was not effective in improving the main parameters indicative of central fatigue" (Falavigna. 2012) - well, at least as long as we still stick to the hypothesis that the latter is induced by the accumulation of 5-HT in the brain.

Forget about tryptophan and serotonin, focus on ammonia

The fact that neither the high, nor medium dose of BCAAs did exert any effects on the serotonin levels in the brain does yet not explain why the medium dose supplementation regimen produced ergogenic, while the high dose regimen induced ergolytic effects.

The occurrence of direct toxic effects due to (too) high amounts of branched-chain amino acids can be ruled out based on previous studies in which the administration of more than 10g/kg body weight of BCAAs (the human equivalent would be 130g+ per day), as well as dosages of 2.5g/kg body weight chronically did not entail any toxic side effects (Shimomura.  2004). The same is true for other confounding variables, such as the citrate synthase activity, a measure of the general efficiency of the training protocol, bood glucose, insulin,free fatty acids, and lactate levels, as well as liver and muscle glycogen content, which were virtually identical in both groups. This leaves us with the increase in plasma ammonia as our 'last resort' to explain the -58% shorter swimming time in the high (S2) vs. medium (S1) dose BCAA group (-43% lower vs. non-supplemented control).

Figure 2: The reduced performance of the high BCAA group could well be related to peripheral and/or central ammonia build-up as a results of increased BCAA oxidation, camparably low glutamine intakes and the rate-limited enzymantic conversion and recycling of gluatmine (illustration originally from Earrante. 2003). Studies by Snow (2000) and Carvalho-Peixoto (2007) suggest: Both carbohydrate & glutamine supplements could help.

Based on what we know about the mammalian body, the increased build-up of ammonia in the high BCAA group could be a result of the unfortunate combination of temporary energy shortage and learned wastefulness' in a situation, where the otherwise sparse BCAAs are available in abundance. Furthermore, with a glutamine content of only 9-13% in the casein fraction of their diets (Swails. 1992), the rodents in the high BCAA group did ingest more than 2.6-3.8 times more BCAAs than glutamine; a fact which may have contributed to a temporary glutamine deficiency as a result of its increased use in the detoxification of the ammonia that's generated when the BCAAs are oxidized. The resulting peripheral and possibly central ammonia build-up (see figure 2) could then have begun to intoxicate liver and brains of the rodents and thus hampered gluconeogensis (normal levels stimulate, high levels of ammonia hamper gluconeogensis; cf. Fritz. 1988) and induced central fatigue (Wagenmakers. 1990; Nybo. 2004) -- and that not despite, but rather due to the chronic "high dose" BCAA supplementation (HED ~50g/day).

So do I have to drop my BCAAs now or what? Whether these results are relevant for you will probably depend on a whole host of parameters, which include

• the type, intensity and duration of exercise you do, 
• the ratio of BCAAs to glutamine in your diet,
• the amount of arginine, which acts as a substrate for the urea cycle and is therefore necessary to for the excretion of ammonia by the kindeys (Schaefer. 2002),
• the amount of carbohydrates in your diet (with more = less amino acid oxidation = lower ammonia and very low carb = you are in trouble; e.g. Czarnowski. 1995; Snow. 2000; Carvalho-Peixoto. 2007), 

... and those factors I will probably have forgotten to mention now. Unless you don't forget that you can neither lifve from BCCAs and protein alone, but accept the neflglected truth that too much protein is about as bad a too little protein, you can file this post under "show your stupid friends" and get back out, when they complain about feeling sick, bloated and fat "despite" eating a BCAA supplemented high protein, low carb (and often even low fat) diets.

References:

• Carvalho-Peixoto J, Alves RC, Cameron LC. Glutamine and carbohydrate supplements reduce ammonemia increase during endurance field exercise. Appl Physiol Nutr Metab. 2007 Dec;32(6):1186-90.
• Errante LD, Petroff OA. Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations. Seizure. 2003 Jul;12(5):300-6.
• Falavigna G, de Araú jo Junior JA, Rogero MM, de Oliveira Pires IS, rio Graç a Pedrosa R, Martins Junior E, Alves de Castro I, Tirapegui J. Effects of Diets Supplemented with Branched-Chain Amino Acids on the Performance and Fatigue Mechanisms of Rats Submitted to Prolonged Physical Exercise. Nutrients 2012. 4; 1767-1780.
• Fritz S, Bohnensack R. Stimulation of alanine metabolism in rat liver by ammonia. Biomed Biochim Acta. 1988;47(12):923-32.
• Meeusen R, Watson P. Amino acids and the brain: do they play a role in "central fatigue"? Int J Sport Nutr Exerc Metab. 2007 Aug;17 Suppl:S37-46.
• Nybo L, Dalsgaard MK, Steensberg A, Møller K, Secher NH. Cerebral ammonia uptake and accumulation during prolonged exercise in humans. J Physiol. 2005 Feb 15;563(Pt 1):285-90. Epub 2004 Dec 20. 
• Schaefer A, Piquard F, Geny B, Doutreleau S, Lampert E, Mettauer B, Lonsdorfer J. L-arginine reduces exercise-induced increase in plasma lactate and ammonia. Int J Sports Med. 2002 Aug;23(6):403-7.
• Shimomura, Y.; Murakami, T.; Nakai, N.; Nagasaki, M.; Harris, R.A. Exercise promotes BCAA catabolism:  Effects  of BCAA supplementation on skeletal muscle during exercise.  J. Nutr.  2004, 134, 1583S–1587S.
• Snow RJ, Carey MF, Stathis CG, Febbraio MA, Hargreaves M. Effect of carbohydrate ingestion on ammonia metabolism during exercise in humans. J Appl Physiol. 2000 May;88(5):1576-80.
• Swails WS, Bell SJ, Borlase BC, Forse RA, Blackburn GL. Glutamine content of whole proteins: implications for enteral formulas. Nutr Clin Pract. 1992 Apr;7(2):77-80.
• Wagenmakers AJ, Coakley JH, Edwards RH. Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle's disease. Int J Sports Med. 1990 May;11 Suppl 2:S101-13.

Tune Your Brain With Creatinyl Amino Acids: "Neuro-Ergogenic" New Wonder-Creatines Readily Pass the Blood Blain Barrier and Are Potential Candidates for Treatment and Prevention of Stroke.

Image 1: Photograph of acute MCA stroke.
Image taken at autopsy on 10-24-2006
[MODIFIED BACKGROUND]; photographer
Marvin 101 @ Wikipedia.org

Alpha-methylguanidino acetic acid, is an amino acid, everyone of you will be familiar with: creatine. And though this may not be the first time you will have heard of its beneficial effect on brain health, the synthesis of new forms of creatine, so called creatinyl amino acids by guanidinylation of sarcosyl peptides or creatine p-toluenesulfonate [both reactive processes in the course of which the new creatinyl amino acid is formed] appears to offer exciting new possibilities for creatine derivates in the prevention and treatment of stroke and other neurological pathologies.

In a paper, recently published in the official Journal of the European Peptide Society, Peptide Science, Burov et al. (Burov. 2011) describe the synthesis and possible use of advanced hydrophobic creatine hybrids, specifically designed to increase their ability to pass the blood brain barrier (BBB), the major obstacle for "normal" creatines to enter the brain and perform their magic, where doctors and scientists would have them do so.

Figure 1: Lifespan [in % of control] of rats in experimental model of hypoxia after intraperitoneal injection of one out of four creatinyl amino acids (calculated from data of Burov. 2011) 

In their study, the Russian scientists were able to prove the antihypoxic  (cf. figure 1) and neuroprotective activity of intraperitoneally injected creatine derivates (100–500 mg/kg) in outbred mice and male Wistar rats, respectively:

It was shown that efficacy of antihypoxic action depends on the structure of amino acid moiety. Thus, Cr-Phe-NH₂ and Cr-GABA-OEt possessed moderate activity, while Cr-Tyr-NH₂ and Cr-Gly-OEt increase life span of experimental animals about two times.

Although a final conclusion on the efficacy and usability of these new "SuperCreatines" in human beings would be premature at this point, existing human data about the beneficial effects the supplementation of plain creatine monohydrate has on cognition, mental focus and other external indicators of brain health and performance (e.g. Rae. 2003; McMorris. 2006; Sullivan. 2000)  suggest that the new creatinyl amino acids may serve as useful tools beyond the treatment of pathologies and may eventually be (ab?-)used as as "neuro-ergogenics". So, if somewhen in the near or more distant future you or kids survive a stroke or pass a test due to one of those new creatinyl amino acids, I hope you still remember that you read about them at the SuppVersity, first!

Mono-Sodium Glutamate (MSG), NAFLD, Leptin Resistance, Trans-Fats, HFCS, Gluttony, Leaky Gut & Brain, the Vagus Nerve and the Chinese Restaurant Syndrome - Bon Appetit!

Image 1 (msg-exposed.com): Is obesity the inevitable, unnatural metabolic long-term equivalent of the dreaded "Chinese Restaurant Syndrome"?

Earlier today, I posted a blurb from a recently published epidemiological study on the effects of mono-sodium glutamate, aka MSG, an umami = all taste receptor activator that is commonly found in all sorts of ready made foods that would otherwise taste as lame as their individual fake ingredients, on the SuppVersity facebook wall (Insawang . 2012). The scientists had evaluated the data from 324 families (349 adult subjects, age 35–55 years) from a rural area of Thailand and found that the prevalence of metabolic syndrome was not just significantly higher in the tertile with the highest MSG intake, but that the "odds ratio", i.e. the chance that a certain parameter, in this case "obese, yes/no" would be found to be true, increased with every 1 g increase in total MSG intake irrespective of  the total energy intake and the level of physical activity.It took roughly 2 minutes for the first sharp-witted "SuppVersity student", in this case that was Wyatt Brown, to spot that post and ask what I believed could explain this observation.

Honestly, I had not really thought about that before, but simply assumed that the effects were probably mediated via not yet fully elucidated effects of dietary glutamate on the balance of excitatory and inhibitory neurotransmitters... after thinking about that for a moment I realized that in the absence of hyperphagia (i.e. extreme hunger and subsequently higher caloric intake), which was obviously not the case for the obese Thais with high MSG intakes, this explanation was not really satisfactory.

Does it all come back to food quality once again?

My next thought was that this could yet again be an issue of food quality vs. food quantity. After all, junk food and all sorts of foodstuff that's made with tons of food-additives to disguise their inferior, nutrient-poor and thus "tasteless" ingredients are the most likely candidates with respect to the MSG exposure in the Western and Eastern "developed" *rofl* world are concerned. In view of the fact that "diet quality" was (as so often) not among the variables Insawang et al. had assessed, their study did not allow for any conclusions in this respect, so that I had to dig deeper and came up with a couple of interesting findings,  I did not want to hold back from me (sorry, Stephen, for postponing the "HIIT Manual"-post, once again, but think about it like that, what's the use of working out if your MSG intake would quash your results anyway ;-)

• * See figure 2 for exact data on the average daily human intake of MSG - with 91mg MSG /kg body weight, an amount that would translate to a daily intake of ~500+mg MSG in humans, the mice in the Collison were representative of the average American, yet not the Thai, Japanese and Korean MSG intake; against that background it is  important to note that MSG ingestion alone did not result in microscopic fat deposits in the liver. These effects were exclusively observed upon co-ingestion of the MSG with a diet with ~9% TFA content!
  "MSG intake at doses similar to human average daily intake[*] caused hepatic microsteatosis and the expression of beta-oxidative genes." - in a 2009 study, Collison confirmed the negative effects of even moderate MSG intake on liver health in a rodent model; only the common combination of trans-fatty acids (TFA) + MSG that is one of the main characteristics of modern "convenience" foods, did yet induce statistically significant increases in liver weight and hepatic triglyceride content; the increases in total, but also HDL cholesterol due to MSG + TFA were accompanied by profound increases in circulating leptin levels, probably in response to developing leptin resistance and increased storage of lipids in the white adipose tissue stores of the nine-week old C57BL/6J mice (Collison. 2009); in a follow up study Collison et al. confirmed that the double-whammy of trans-fatty acids + MSG becomes even more toxic if a third villain is added to the mixture, high fructose corn syrup (Collison. 2011) - and I don't have to tell you where in the human food chain you will find this unholy trinity, do I?
• "MSG ingestion reduces weight gain, body fat mass, and plasma leptin levels" - in a 2008 trial Kondoh and Torii observed a very different and in fact surprisingly pronounced beneficial effect of the ingestion of a 1% solution (in biology this means 1g per 100ml) MSG resulted in decreases in weight gain, body fat mass and plasma leptin levels in male Sprague-Dawley rats irrespective of the energy content of their diets (!) and without effecting total energy intake or food intake, but in the presence of a profound decrease in 24h-water intake (2g vs. 9g); these effects were observed in both adult and young animals, in the latter without any negative side effects on the normal development of body length

  

  Figure 1: Leptin levels (ng/ml) on diets with different energy density and macronturient composition with or without MSG added to the water (data based on Kondoh. 2008)

  this leaves more than enough room to speculate about centrally mediated increases in energy expenditure in response to the ~20mg total MSG (equivalent to 33mg/kg for a rodent and a human equivalent dose of ~5.5mg/kg) intake of which Kondoh and Torii speculate that they may be "mediated via gut [glutamate] receptors functionally linked to the afferent branches of the vagus." (Kondoh. 2008); subsequent studies into the effects of MSG on the "gut brain axis" appear to support this hypothesis (cf. Kondoh. 2009a,b; Otsubo. 2011)
• " MSG, in spite of mild hypophagia [reduced food intake], caused severe increase in fat body weight ratio, via leptin resistance" - in 2011 Afifi and Abbas, two researchers from the Department of Biochemistry at the Zagazig University in Egypt, report that feeding high amounts of MSG to pregnant rat dams had similar negative effects on body composition and leptin sensitivity as a hypercaloric diet and that despite an overall reduction in total food intake; moreover, despite similar gains in body fat, the negative effects on the offspring of those pregnant rats was more pronounced than in the rats on the "normal" hypercaloric diet (Afifi. 2011)
• If you suffer from "Chinese Restaurant Syndrome", you should check whether increased gastrointestinal permeability could be the root cause of your problems and avoid all foods with any of the following "ingredients": E620 Glutamic acid, E621 Mono-sodium glutamate, E622 Mono-potassium glutamate, E623 Calcium diglutamate, E624 Mono-ammonium glutamate, E625 Magnesium diglutamate!
  "Findings from the literature indicate that there is no consistent evidence to suggest that individuals may be uniquely sensitive to MSG" - in one of the few reviews evaluating exclusively human studies, Freeman did not find any placebo controlled research that would confirm the universal existence of side-effects (e.g. headaches, chest pain, flushing, numbness or burning in or around the mouth, sense of facial pressure or swelling and sweating) as a direct consequence of the consumption of food-borne mono-sodium glutamate; e.g.
  

  "The present study led to the conclusion that 'Chinese Restaurant Syndrome' is an anecdote applied to a variety of postprandial illnesses; rigorous and realistic scientific evidence linking the syndrome to MSG could not be found." (Tarasov. 1993)

  instead, the author suggests that "unique sensitivities" could explain the documented case reports (Freeman. 2008 // see also Walker. 2000; Geha. 2000); given the emerging evidence of the existence of something you could call a "leaky brain" (in analogy to "leaky gut"), it appears likely that an unnaturally increased permeability of the blood-brain-barrier and subsequent penetration of large amounts of glutamate into the brain even at lower serum concentrations could well explain those differences (although not directly related to MSG, I would still like to point you to the results of a recently released study, which found a profound decrease in the permeability of the BBB in response to an oral 1mg/kg (HED ~0.16mg/kg) Lycium barbarum extract in an experimental stroke model; Yang. 2012)
• "dietary antioxidants have protective potential against oxidative stress induced by MSG" - in 2006 Faromby and Onyema observed that previously described oxidative damage to the liver and subsequent steatosis (lipid accumulation) in response to the intra-peritoneal administration of ridiculously high amounts of MSG (4g/kg body weight) could be ameliorated by vitamin C + vitamin E + quercitin; these results suggest that exorbitantly high doses of MSG (human equivalent ~51g/day) are probably a result of an increase in reactive oxygen species
• "after intragastric administration of MSG, the MSG is preferentially metabolized through gluconeogenesis in B6 mice, whereas thermogenesis is the predominant process for 129 mice" - in previous studies scientists had observed profound differences in terms of the effects of MSG on food intake and preference; in 2009 Bachmanov et al. traced those differences back to genetic polymorphisms and respective differences in the metabolic response to / utilization of MSG - if we assume that similar differences exist in human beings, those would provide another explanation for the different incarnations of the "Chinese Restaurant Syndrome" with the classic headaches, high blood pressure and sweating in people who would be long to the human equivalent of the 129 mice and the highly rewarding and appetite stimulating gluconeogenic (hepatic production of glucose from the glutamate) effects in those humans with a similar genetic programming as the B6 mice

I could certainly go on for hours, citing study after study with "evidence" and "counter-evidence", or rather what the respective authors consider as such, but I believe that you have read enough to see a couple of basic patterns emerge, here.

So what about those differences? Genes, dosages, or what?

One of these patterns is also brought up by Kondoha and Torii in the discussion of the results of their study (remember: decrease in body fat and increase in energy expenditure; purported mechanism = activation of glutamate receptors that are linked to the vagus nerve), in which the researchers state that they believe that the diametrically opposed results of their, compared to other studies (most of which report an increase not a decrease in body fat that is accompanied by increases in circulating leptin and decreases in leptin sensitivity and not vice versa as in the Kondoh study), may well be explained by

[previous] studies [being] designed specifically to produce toxic effects in the brain (where GLU is an excitatory neurotransmitter), through the administration of extremely high doses (2000 mg/kg or more, administered repeatedly) to infant animals, either by single, direct injection or intubation (Kondoh. 2008).

Those high dosages could in fact have lead to blood glutamate concentrations that would allow the flux of the excitatory amino acid even across intact blood-brain-barriers. The more realistic, orally administered dosages  Kondoh and Torii used in their experiment, on the other hand, did not induce any (not even statistically non-significant) elevations of serum glutamate levels.

Hence, the effects seen in the present study, as discussed above, are probably linked via a physiologic mechanism, to a local action of GLU in the gut, rather than via a pharmacologic/toxicologic mechanism to a distant action of exogenous GLU forced on the brain (Kondoh. 2008).

If you review the brief rundown of the literature I've provided in the previous paragraphs you will have to acknowledge the validity of this remark (remember: the steatosis in the Collison study required co-administration of trans-fatty acids /TFA/ and even then the increase solely due to MSG was marginal compared to that of the TFAs, alone).

Without a leaky gut, you would probably have to eat pure MSG all day to do harm

If you also take into account, that in healthy individuals only <5% of the dietary glutamate are actually absorbed into systemic circulation, while the rest is used as an oxidative substrate by the intestinal mucosa (Smriga. 2007), the difference between thhe orally consumed 33mg/kg MSG that helped the rodents in the study by Kondoh and Torii to lean out and the intraperitoneally injected 4,000mg/kg that were necessary to induce the touted hepatic side effects in the study by Faromby and Onyema are way above the average intake even the worst offenders among the MSG abusers are exposed to (cf. figure 2):

Figure 1: Average per capita daily MSG intake in different countries (adapted from Löliger. 2000)

Even if we discard the oxidative loss within the intestine, those 4,000mg/kg for a rodent (in previous studies Onyema et al. had even used 6,000mg/kg to elicit the hepatic damage; Onyema. 2006) would translate to ~650mg/kg in humans and would mean that you would have to shovel down anywhere between 32g and 64g of pure MSG (depending on whether you weigh 50 or 100kg), i.e. 20-40x more than the average daily intake of a Korean (note: The "rodent model of MSG induced obesity" is induced by injection of 10,000mg/kg body weight; cf. Bunyan. 1976) and the whopping MSG equivalent of 400-800ml of soy sauce (avg. MSG content 80mg/ml), which is probably the worst offender in the E-number-laden ingredient arsenal of the Asian cuisine.

Figure 3: Protein-bound and free glutamate content of "high" glutamate foods (left) and total glutamate content of selected plant proteins (right; data adapted from Loliger. 2000)

Your best bet to ingest similar amounts of free glutamate from real foods is, as the data from a review by Loliger suggests (cf. figure 3), would be parmesan cheeese, but in all honesty, in view of the fact that you would have to consume 2.6kg of the Italian delicacy, it is pretty unlikely that the glutamate and not the sheer amount of pure energy in the cheese would be the underlying reason for subsequent weight gain. Against that background it should not be surprising that negative side-effects as they occur as a result of high to unrealistically high MSG intakes and or in especially susceptible individuals, are not exactly common in people who don't eat out and/or consume pre-packaged convenient foods on a regular, if not daily basis.

Too much of a vitally important thing at the wrong time and as part of the wrong foods...

The mere presence of non-negligible amounts of glutamate in all sorts of "real" foods, should yet remind you that glutamate is not a toxin, or a "foreign substance" we are not evolutionary adapted to, but an amino acid that is of utmost importance for the health of your central nervous system (Platt. 2005). So that at the end of this analysis we may not be back at square one, but still have to concede that it brought us back to a set of very common motifs here at the SuppVersity:

• When consumed in excess, substances that are good, healthy, beneficial and even "vitally" (=vitamin ;-) important can easily turn against you
• When substances do not have to pass the gut, the dose-response relationship can differ so substantially that results that are acquired using route A (e.g. intraperitoneal injection) cannot simply be transfered to scenarios employing different administration routes (e.g. oral ingestion)
• Inter-individual/-species differences and differences between healthy and unhealthy individuals / animals, warrant utmost caution, when it comes to interpreting data - the "Chinese Restaurant Syndrome", for example, could be a result of increased gut and blood-brain-barrier permeability that would lead to an increased absorption of glutamate from the intestine into the blood and from there across the blood-brain-barrier right into the brain.
• Oftentimes, differences due to the aforementioned factors are not of simple quantitative, but of qualitative nature, in the case of MSG this would be the difference between the metabolic activation in response to the local activation of glutamate receptors in the gut that are connected to the vagus nerve, on the one hand, and the systemic / central obesogenic (fattening) effects of glutamate that leaks from the gut into the blood and from there into the brain.

And lastly, to eventually come full circle and remind you of the results of Collison et al., we cannot ignore that MSG is one of those substances that is usually found in foods with a whole host of other nutrient-poor ingredients, anti-nutrients and proven obesogenic, pro-inflammatory and otherwise unhealthy substances and food additives. They are wrapped in plastics have an extended shelf life due to tons of preservatives and highly adorned with stickers and labels saying "low this", "extra that", "only X amounts of calories", etc. - as long as you avoid those foods on 360+ days of the year, prepare your meals from whole foods, don't dine at cheap restaurants, fast-food outlets and snack bars too often or try to find the "optimal amount of supplemental MSG to stimulate your vagus nerve and help you shed fat" *lol*, you can calmly watch the ever-recurring MSG scares on the Internet and other mass media ;-)

References:

1. Afifi MM, Abbas AM. Monosodium glutamate versus diet induced obesity in pregnant rats and their offspring. Acta Physiol Hung. 2011 Jun;98(2):177-88.
2. Bachmanov AA, Inoue M, Ji H, Murata Y, Tordoff MG, Beauchamp GK. Glutamate taste and appetite in laboratory mice: physiologic and genetic analyses. Am J Clin Nutr. 2009 Sep;90(3):756S-763S. Epub 2009 Jul 1.
3. Bachmanov AA, Inoue M, Ji H, Murata Y, Tordoff MG, Beauchamp GK. Glutamate taste and appetite in laboratory mice: physiologic and genetic analyses. Am J Clin Nutr. 2009 Sep;90(3):756S-763S. Epub 2009 Jul 1.  
4. Bunyan J, Murrell EA, Shah PP. The induction of obesity in rodents by means of monosodium glutamate. Br J Nutr. 1976 Jan;35(1):25-39.
5. Collison KS, Maqbool Z, Saleh SM, Inglis A, Makhoul NJ, Bakheet R, Al-Johi M, Al-Rabiah R, Zaidi MZ, Al-Mohanna FA. Effect of dietary monosodium glutamate on trans fat-induced nonalcoholic fatty liver disease. J Lipid Res. 2009 Aug;50(8):1521-37. Epub 2008 Nov 11.  
6. Collison KS, Zaidi MZ, Saleh SM, Makhoul NJ, Inglis A, Burrows J, Araujo JA, Al-Mohanna FA. Nutrigenomics of hepatic steatosis in a feline model: effect of monosodium glutamate, fructose, and Trans-fat feeding. Genes Nutr. 2012 Apr;7(2):265-80. Epub 2011 Dec 6. 
7. Farombi EO, Onyema OO. Monosodium glutamate-induced oxidative damage and genotoxicity in the rat: modulatory role of vitamin C, vitamin E and quercetin. Hum Exp Toxicol. 2006 May;25(5):251-9.
8. Freeman M. Reconsidering the effects of monosodium glutamate: a literature review. J Am Acad Nurse Pract. 2006 Oct;18(10):482-6.nonalcoholic fatty liver disease. J Lipid Res. 2009 Aug;50(8):1521-37. Epub 2008 Nov 11.
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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 ;-)

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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.