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).

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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.

The Pro-Diabetic Effects of Shark Liver Oil - Plus: Can it Be Coincidence that the Omega-6-Laden Nigella Sativa Oil has Just the Opposite Effects on Blood Glucose & Triglycerides

Image 1: Even if you kill him, he will take revenge and increase your blood glucose and triglyceride levels. And if you don't die from the negative side effects of the oil from his liver the neurotoxins from his fins will take care of the rest (cf. Science Daily)

"Healthy fats"... not to long ago even the combination of these two words was an oxymoron (an intrinsic contradiction). "How on earth can fats be healthy?" Was what the blank stares were telling you, when you set out to explain how and why people should not buy the latest and greatest "no fat" products from their local grocery stores. As of late the tides have changed and even mainstream media is jumping on the "healthy fats"-bandwagon - unfortunately, in a similarly single-sided way as before, with the "healthy polyunsaturated fats" on the one side of the divide and the "unhealthy saturated fats" on the other. Now, we all know that this distinction is flawed, but are really all fats made equal? Probably not, after all the overall message in the blogosphere has been changing from "limit omega-6s and get as much fish oil as you can" over "avoid omega-6s alltogether and make sure you get enough fish oil" to "avoid all PUFAs, but make sure that you get a decently low omega-6 to omega-3 ratio from the PUFAs you cannot avoid".

Sharks vs. blackseed - round 1: Fight!

A recently published study from the Faculty of Medical Sciences at the University of Science and Technology in the Republic of Yemen does yet provide further evidence that even this may not be the answer to everything. After all, the (formerly ;-) healthy 18 subjects (age: 23-31 years) in Doa’a A. Ibraheem study did not react particularly favorable to 2 weeks on 500mg of omega-3 fatty acids from an American shark liver oil product (Vitex  Pharmaceuticals).

Figure 1: Changes in glucose and lipid metabolism in 18 healthy volunteers in response to 2-weeks on either 500mg of omega-3 rich shark liver oil or 1,200mg of omega-6 rich nigella sativa oil (data calculated based on Ibrahiim. 2011)

As you can see in figure 1, the GMP certified "healthy" fish oil variety from shark livers did exactly what people who pop tons of cod-liver or regular fish oil want to avoid: It increased the fasting blood sugar and triglyceride levels - and if Mr. Ibraheem had had the financial resources to measure their insulin levels, I would bet any money that those were elevated as well.

The "bad" Nigella Sativa Oil of which the "poor" subject ingested even 1,200mg per day for another 2 weeks (in fact this trial was done 4 weeks before the SLO trial with an appropriate wash-out period in-between), with its 13% saturated fat, 25.5% MUFA and 58.5% of the dreaded omega-6s (it has only 1% omega 3) did not only induce a significant drop in fasting blood glucose, it also left the lipid parameters untouched.

And what about fish oil?

Now, despite the fact that shark liver oil is not identical to either fish, or cod liver oil, and that some if not all the health benefits of nigella sativa could be induced by other (micro-)nutrients than , I would hope that results like this will make more people question the "revised" perspective on "healthy fats", according to which all omega-6 acids are like vampires, that must be parried with garlic... ah, pardon omega-3 ;-)

Alarmingly High Levels of Lead in Calcium Supplements: Pb Content per Serving Up to 18x Over "Acceptable Levels".

Image 1: You better pick the right source of calcium: healthy milk / dairy vs. lead poisoned pills from your local pharmacy or supermarket - you still have the choice.

This, I can assure you, is a "SuppVersity News", i.e. something you will not read on the major news portals, simply because there is too much money at stake in the 3billion $ market for calcium supplements (figure according to January 2008 edition of "Heartwire") - money a huge part of which is spent by Novartis & Co to advertise their products to consumers from all age groups, regardless of the individuals' dietary calcium intake; and that despite accumulating evidence for an association of supplemental calcium intake and heart disease (for one of the latest reviews cf. Bolland. 2011)! A very recent study published in the Journal of Biological Trace Element Research (Rehman. 2011) does yet cast another, even darker shadow onto the "healthy" white chalk tabs...

What? "Pb" is not the symbol for Calcium in the Periodic Table?

Lead, that stuff nuclear physicists value, because it effectively absorbs radioactive radiation, is one of the most toxic "heavy metals" we are exposed to. And this is by no way a recent discovery. Even in ancient times, people knew about the toxic effect vessels made of this metal had on the water they contained. Back in 1990 E.K. Silberberg summarized the contemporary knowledge about the dangers of environmental lead exposure in a paper for the Environmental Defense Fund as follows (Silberberg. 1990):

[...] epidemiological studies have suggested that central nervous system (CNS) effects in children are observed at the lowest increments of lead exposure [...] Similarly, clinical studies indicate that early exposure to lead produces functionally irreversible damage to the CNS; experimental research demonstrates that this irreversibility may involve failure to remove lead from brain, permanent effects on synaptogenesis; and chelant-induced redistribution of lead from the periphery to the CNS. [...] New data on release of bone stores of lead during physiological conditions of demineralization indicate that mobilization of bone lead adds to in utero exposure of the fetus. Furthermore, postmenopausal demineralization of bone can increase blood lead levels in women by 25%; this raises concern about the potential effects of lead in an aging population and the difficulties in comprehensive exposure assessment.

As you may have guessed, time has not affected the dangers or the irreversibility of lead toxicity, so that you would assume that the results of an investigation into the lead content of 27 "commonly used" commercially available calcium supplements should be alarming enough to receive at least some public recognition. After all, it would suffice to read the abstract to be alarmed by the fact that of the calcium supplements Sohaila Rehman and her colleagues from the Pakistan Institute of Nuclear Science Technology analyzed only one out of ten "met the criteria of acceptable Pb levels (1.5µg/daily dose) in supplements / consumer products set by the United States" (Rehman. 2011).

Figure 1: Lead levels in µg in daily dose of respective calcium supplement; solid red line = acceptable Pb level for calcium supplements, dashed red line = tolerable total daily Pb intake for children <7y, dotted red line = tolerable daily Pb intake for women in childbearing age (data adapted from Rehman. 2011).

"One out of ten", well that does not sound so bad, does it? I guess you will change your mind, when you take a closer look at figure 1 - the red line at the bottom of the graph is the "acceptable Pb level" and as you can see it is met by exactly 1 out of 13 calcium chelate products (CAC 1000 by Novartis), and none of the 3 calcium chelates the researchers tested for their lead content.

Figure 2: Lead levels in µg in daily dose of respective calcium supplement; solid red line = acceptable Pb level for calcium supplements, dashed red line = tolerable total daily Pb intake for children <7y (data adapted from Rehman. 2011).

And while the lead levels of the calcium + vitamin C and calcium + vitamin D levels in figure 2 look somewhat better, there are still several outliers with Cal-C Plus from Himont Pharma, for example, providing more than 2x the tolerable daily lead intake for a child under the age 7 y (and remember these are only the official FDA figures - and you know what that means ;-) on a per serving base.

Note: The results of the study at hand may well explain a) the different outcomes of (controlled) trials and epidemiological studies on the effects of calcium supplements on cardiovascular health and b) the beneficial effects of milk and dairy intake on heart health (Soedamah-Mutuh. 2011). After all, a very recent study that was published in the Journal of Neurotoxicology and Teratology in October 2011, shows that there is a "potential for autonomic dysregulation" that manifests in "significantly greater vascular resistance and reduced stroke volume and cardiac output" in 9-11 year old children even "at levels of Pb typical for many US children" (the exact levels were 1.01µg/dL, cf. Gump. 2011).

And as if all that was not enough, the US Food and Drug Administration (FDA) and the glorious Center for Disease Control and Prevention (CDC) would have been aware of the potential of serious chronic lead intoxication from calcium supplements, if they spent more time reading scientific journals than counting the cashflow from the BigPharma companies that finance their bureaucracy. After all, Bourgoin et al. conducted a very similar study back in the 1990s, the results of which the scientists summarize in their abstract as follows (Bourgoin. 1993):

Daily lead ingestion rates revealed that about 25% of the products exceeded the US Food and Drug Administration's "provisional" total tolerable daily intake of lead for children aged 6 years and under.

In the Rehmann study it were 16 out of 27 tested calcium supplements (59%) which exceeded this limit. So  maybe the "feds" just did not act, because 1 out of 4 is not bad enough? Well, if you look at the individual results in figure 3 (usually I redo graphs, but in this case the original looks just too damn impressive), it is immediately obvious that the averages the scientist report in their abstract, do not reflect the actual potential of lead toxicity from the 70 supplemental sources Bourgoin et al. tested.

Figure 3: Results of a 1993 large-scale analysis of the lead content of 70! commercially available calcium supplements and milk (my emphasis), the safe exception (from Bourgoin. 1993)

Obviously, some of the bone based and a whole host of the "natural sources" ("natural source of calcium carbonate" according to label claim; note that coral calcium would fall into this category, as well!) are about as toxic as the worst offenders in the Rehman study. What I find do yet find particularly interesting, is that the lead content in one serving of commercial milk, which would provide the same amount of (even more bioavailable) calcium as the supplements in the study did, would provide no more than 0.71µg/day and is thusly the one and only "natural source" of dietary calcium that does not set you up for lead toxicity!

"Pah, lead!? What doesn't  kill you just makes you stronger"

Image 2: So, calcium supplement with lead are a safe source of dietary calcium, but raw milk is not? (img CounterThink)

In view of the "longstanding" history of ignorance on behalf of the governmental agencies, it sounds almost sarcastic, when Bourgoin et al. conclude their article by citing the Center for Disease Control's (CDC) statement on lead poisoning, which according to these reputable protectors of the health of the American society *cough* is "one of the most common and preventable pediatric health problems today". Notwithstanding this early insight (this is from a 1991 document from the CDC) the officials obviously have neither taken Bourgoin et al.'s advice to control calcium supplements "more rigidly" in order to "prevent unnecessary exposure in all segments of the population, particularly young children" (Bourgoin. 1993), nor have they followed the recommendation of a more recent study by Kim et al., which  estimates the mean lead intake from calcium supplements to about 5µg/day and recommends that "measures to prevent potentials of Pb toxicity from overtaking some Ca supplements should be considered" (Kim. 2010).

And while the CDC and the FDA could incidentally have missed those papers. They should actually be aware of Proposition 65, which is the common name for California's Safe Drinking Water and Toxic Enforcement Act of 1986 (Dietary Supplement Standard 173, Metal Contaminant Acceptance Levels. NSF International. August 19, 2003). In this paper, of which W.W. Kilgore writes in retrospective that (Kilgore. 1990)

[i]t creates a list of chemicals (including a number of agricultural chemicals) known to cause cancer or reproductive toxicity; [i]t limits discharges of listed chemicals to drinking water sources; [i]t requires prior warning before exposure to listed chemicals by anyone in the course of doing business; [i]t creates a list of chemicals requiring testing for carcinogenicity or reproductive toxicity; and [i]t requires the Governor to consult with qualified experts (a 12-member "Scientific Advisory Panel" was appointed) as necessary to carry out his duties.

the proposed Acceptable Intake Level (AIL) for inorganic lead (as extrapolated from animal studies) is 0.5µg/day and thusly 1/3 of the current Californian standards and 1/50 of the FDA allowance of 25µg/day! But hey, who cares? As long as the American citizens are protected from the dangers of raw milk, everything is all right, isn't it?

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!