Sunday, May 26, 2013

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

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

  • 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.