Friday, August 9, 2013

The Neurotransmitter Depleting Effects of Branched Chain Amino Acids (BCAAs) and Their Potential Ergolytic, Anxiogenic & Depressive Downstream Effects

Oh yes, this will happen despite if not because you've taken large amounts of BCAA before the workout.
Usually you don't put the cart before the horse, but I guess you won't mind if I do so and postpone a summary of the information on magnesium from yesterday's installment of the Science Round-Up to tomorrow, when this means that we are going to take care of the "BCAA crisis" today.

Ok, maybe "crisis" is not the best word to describe the reverberations the recent publication of a study by SuJean Choi et al. should be having (=nobody buys BCAAs anymore), but I was looking for something better than the usual "the truth about..." Science, and I am not going to tire repeating that, is after all not about truth (that's what the confessional box is about), but about experimentally verifiable/verified and non-verifiable/non-verified hypothesis (Popper. 1994).

BCAAs can have ergolytic effects - A verifiable hypotheses?

Based on the observations Choi et al. made in by then decapitated lab animals (so much about the "why don't they prove this works in humans"-argument), the administration of a solution that contained either a BCAA + Arginine + Glutamine mix, or one out of two different EAA mixtures, it is safe to say that the hypothesis formulated in the subheading of this paragraph could belong to the former, i.e. the verifiable, hypothesis; and that despite the fact that the addition of glutamine and arginine to the human equivalent of 19:12:12 mg/kg body weight of leucine:isoleucine:valine (less than most BCAA products offer) would at least buffer the previously discussed performance decrements due to the accumulation of ammonia (learn more)
Table 1: Amino acid composition (mg/kg body weight) of the AA supplements tested (Choi. 2013)
In the end, the results Choi et al. present contradict both, the promises on the labels of the countless BCAA products and Newsholme's and Blomstrand's hypothesis that the inhibitory effect the BCAAs exert on the uptake of tryptophan from the blood into the brain and the way this forestalls the subsequent conversion of tryptophan to serotonin would lead to a reduction of central fatigue during exercise (Newsholme. 1996).
Figure 1: Effects of BCAA and BCAA + 100mg/kg l-tyrosine supplementation on serum and brain amino acid and neurotransmitter levels in sedentary rats; data expressed relative to vehicle (Choi. 2013)
Now, the data in figure 1 does confirm the first part of the Newsholme + Blomstrand hypothesis: The adminstration of BCAAs in an amount similar to many low dose BCAA supplements that are currently being marketed as ergogenic agents does blunt the increase in serotonin by competitively inhibiting the uptake of l-tryptophan from the bloodstream. The latter is a necessary consequence of the fact that both the BCAAs and the said 5-HTP (=serotonin) precursor are being transported by the same large amino acid transporter (think of it like a taxi that is allowed to pass the blood brain barrier) as l-tryptophan.
A note on the pro-obesity effects mentioned during the show: While some scientists invoke the increased BCAA levels in obese individuals and the subsequent blockade of serotonin (and dopamine) production in the brain to the constant insatiable cravings, anxiety and depression in these individuals (Breum. 2003; She. 2007; Coppola. 2013) a more fundemental contribution to the obesity pandemic has been proposed by Newgard et al. (2009). Their hypothesis is that a continuous presence of BCAAs in the blood will lead to a continuous overexpression of mTOR that increases the susceptibility to diet induced obesity and insulin resistance.
Now, it is also true that this will blunt the increase in 5-HTP synthesis in the brain (-48%; in the absence of exercise; see figure 1), but with the concomitant -25% decline in hypothalamic DOPA (=dopamine, the "get going neurotransmitter") in the brain after ~30min, the net ergogenic effect will, just as it was the case in the majority of pertinent rodent and human studies, be negligible, at best!
Modulatory Effects of Different Macronutrient & Stress Compositions on Serotonin (read more)
"Following oral intubation with the ‘‘BCAA’’ mixture to sedentary rats (see Table1; n=3/group), serum TRP and TYR concentrations showed non-significant reductions; the serum TRP and TYR ratios, and cortical TRP and TYR concentrations dropped markedly at 30 min. Cortical TRP and TYR concentrations remained low for the duration of the study (120 min), while the ratios began to recover at 90–120 min. DOPA and 5HTP synthesis dropped to nadir values at 60 min; DOPA synthesis remained low, while 5HTP synthesis had rebounded by 120 min (bottom panels, Fig.2).

Inasmuch as the maximal effects on DOPA and 5HTP synthesis occurred 60 min following intubation, all subsequent studies used 60 min as the experimental endpoint." (Choi. 2013)
In fact, the overall and as you've just read persistent drop in neurotransmitter levels can not only make you tired, previous research even suggests that it may be invoked in the etiology of depression / central fatigue (see previous SuppVersity post "Study Investigates Modulatory Effects of Different Macronutrient Compositions on Serotonin in the Presence and Absence of Stress" | read more).

Balancing leucine with tyrosine at a ~1:1 ratio helps

The data in figure 1 does however also tell you that you can mitigate the problem by the addition of 100mg/kg body weight of l-tyrosine to the supplement. With that being roughly equivalent to the amount of leucine in the BCAA formula (cf. table 1), this is yet far more of the dopamine precursor than your average BCAA product is going to have... after all it's a maximal leucine concentration that sells and is propagated as being "modern" and "maximal anabolic".
Figure 2: Hypthalamic DOPA and 5HTP levels after BCAA or BCAA + 100mg/kg tyrosine ingestion with / without exercise, left (Choi. 2013); effects of BCAA or l-tyrosine supplementation on time to exhaustion (Strüder. 1998)
With the addition of 100mg/kg l-tyrosine, you may yet in fact expect to see some benefits. Unfortunately, the currently available literature will put you right in a study that was conducted by Strüder et al. for example neither 21g of BCAAs nor the whopping dose of 20g of pure l-tyrosine resulted in the expected increase in the time-to-exhaustion during time trials in trained cyclists (see figure 2, right; Strüder. 1998) and Blomstrand concludes in his review for the British Journal of Sports Medicine's A-Z Supplement Review Series:
"Under certain conditions, BCAA supplementation can also improve physical performance, although the majority of studies have found no effect of BCAA on performance when supplied together with carbohydrates." (Blomstrand in Burke. 2009)
This, on the other hand, tells you that the performance enhancing effects are a mere result of the oxidation of BCAAs of which both Blomstrand, who is by the way defending his own hypothesis here, and the recently discussed by Falavigna et al. (see SuppVersity News) indicate that the ensuing increased release in ammonia production "may be detrimental to performance" (Blomstrand in Burke. 2009). If you also take into consideration that a study by van Hall et al. from 1995, i.e. before Newsholme & Blomstrand came up with the hypothesis the whole BCAA myth was built on, basically falsified the tryptophan hypothesis of fatigue, In the pertinent study the scientists were after all able to show that the provision of BCAAs as workout fuel is not superior to that of tryptophan and that despite a 8-12% reduction in brain tryptophan uptake at exhaustion with BCAAs and a 7- to 20-fold increase in response to the ingestion of a tryptophan supplement (van Hall. 1995).

Milk protein EAAs: An option, but a logical one?

If you finally take a look at the data in figure 3  you will notice that the head-to-head comparison would place an amino acid pattern as the one you can find in milk proteins, would probably be the best amino acid supplement source to resort to (don't ask me what exactly it is that makes the difference, I can't tell, but suspect it could be related to lysine which is also going to block the same small AA channel into the brain + the inclusion of non-essential amino acids in milk protein vs. pure EAAs).
Figure 3: Comparison of the the effects of BCAA, regular EAAs and an EAA amino acid mix from milk protein; composition of the mixtures see table 1 (Choi. 2013)
But let's be honest, does it really make sense to buy an additional supplement, when you already have a pouch of cheap and tasty whey and/or another fast digesting high BCAA protein such as pea protein lying around at home?

So what's the verdict then? As you've heard on the Science Round-Up, yesterday, I personally think that this does not make sense, because ...
  1. .
    Suggested Read: "Spiking Whey W/ EAA Will Provide Inferior Results" (read more)
    .. neither the total amount of amino acids that are obsorbed within 1h from free form EAAs, nor the the utilization speak in favor of EEAs - both have been shown to be +7% and +92% higher with slightly hydrolized whey vs. EAAs (Monchi. 1993),
  2. ... nor is there any anabolic benefit to the addition of EAAs or leucine to whey, in fact "25 g of whey is better suited to increase resistance exercise-induced muscle anabolism" compared to lower amount of whey that has been pimped with additional EAAs and leucine to offer the same amount of the purpoted "anabolics" as the 25g dose of plain whey protein (click on the picture to the right to learn more; Churchward-Venne. 2012)
Contrary to Carl's jovial suggestion to simply throw away your BCAA supplements, I would suggest you keep them (unless you already have problems with anxiety, etc.), cut back on the dosage and monitor your response closely. The latter is especially true, when you take them on an empty stomach. After you've run out, train a month with nothing but cheap protein and decide afterwards whether or not your past "great training experience", "superior intensity" and whatever else the ads tell you the respective products will do was more than just another instance of the brocebo effect (learn more about brocebos).

References:
  • Breum L, Rasmussen MH, Hilsted J, Fernstrom JD. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr. 2003 May;77(5):1112-8. 
  • Burke LM, Castell LM, Stear SJ, Rogers PJ, Blomstrand E, Gurr S, Mitchell N, Stephens FB, Greenhaff PL. BJSM reviews: A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance Part 4. Br J Sports Med. 2009 Dec;43(14):1088-90.
  • Choi S, Disilvio B, Fernstrom MH, Fernstrom JD. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines. Amino Acids. 2013 Aug 1. [Epub ahead of print] 
  • Coppola A, Wenner BR, Ilkayeva O, Stevens RD, Maggioni M, Slotkin TA, Levin ED, Newgard CB. Branched-chain amino acids alter neurobehavioral function in rats. Am J Physiol Endocrinol Metab. 2013 Feb 15;304(4):E405-13.
  • Churchward-Venne TA, Burd NA, Mitchell CJ, West DW, Philp A, Marcotte GR, Baker SK, Baar K, Phillips SM. Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. J Physiol. 2012 Jun 1;590(Pt 11):2751-65.
  • Monchi M, Rérat AA. Comparison of net protein utilization of milk protein mild enzymatic hydrolysates and free amino acid mixtures with a close pattern in the rat. JPEN J Parenter Enteral Nutr. 1993 Jul-Aug;17(4):355-63. 
  • Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS Jr, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009 Apr;9(4):311-26.
  • Newsholme EA, Blomstrand E. The plasma level of some amino acids and physical and mental fatigue. Experientia. 1996 May 15;52(5):413-5. Review.
  • Popper, KR. Zwei Bedeutungen von Falsifizierbarkeit [Two meanings of falsifiability]. In Seiffert, H.; Radnitzky, G. Handlexikon der Wissenschaftstheorie. München: Deutscher Taschenbuch Verlag. 1994.  
  • She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1552-63. Epub 2007 Oct 9.
  • Strüder HK, Hollmann W, Platen P, Donike M, Gotzmann A, Weber K. Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res. 1998 Apr;30(4):188-94.  
  • van Hall G, Raaymakers JS, Saris WH, Wagenmakers AJ. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol. 1995 Aug 1;486 ( Pt 3):789-94.