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Amino Acids for Super Humans, Part IV - Purported Ergogenics (3/3): Glutamine, the Anabolic Immune Booster?

Image 1: Still one of the top-
sellers in almost all supplement
shops - l-glutamine; tip: buying
bulk powder will save money

Although glutamine is one of the non-essential amino acids, even the fact that your body continuously 'sacrifices' truly essential amino acids to synthesize glutamine in your muscle tissue, should go to tell you that, after all, glutamine, the most abundant amino acid in human muscle and plasma, cannot be so non-essential as its classification would suggest.

Under normal conditions it forms 50% of the whole body amino acid pool. In cells, esp. muscles, where glutamine makes up 66% of the amino acid pool. Within the cellular space, the purported cell-volumizer can reach concentrations that are up to 33 times higher than on the outside of the cell.

In times of acute stress, severe burns or surgical trauma, on the other hand, tissue glutamine levels have been observed to decline by up to -50% - an observation, which gave and still gives rise to the hypothesis that glutamine repletion / supplementation could ameliorate or even prevent the catabolic processes which threaten all metabolically active tissues and weaken the immune system whenever the human body is exposed to severe physiological (and even psychological) stress. In that, it is important to understand that glutamine does not reduce the amount of corticosteroids which are released in those circumstances, but may reduce the negative effects of increased cortisol and catecholamine levels on the body. In a 1995 study by Hickson et al., for example, intravenous infusion of glutamine reduced muscle mass losses subjects who had previously received a glucocorticoid infusion by -70% and ameliorated the cortisol-induced decline in untra-muscular myosin heavy-chain content by -50% (Hickson. 1995).

Did you know that 90% of the nitrogen that is derived from BCAA catabolism is released as glutamine, which is formed primarily in your muscles, but also in your lungs, your liver and your brain in a process called glutamine synthase, where glutamate, which has a side-chain hydroxyl instead of the amine group of glutamine, and ammonia are synthesized to form glutamine. During its subsequent hydrolysis, i.e. the catalysis of glutamine to glutamate + ammonia in the intestine, cells of the immune system and the liver, a substantial amount of energy is released. In that, glutamine, the 2nd major interorgan nitrogen carrier, derives a major advantage over alanine, the #1 interorgan nitrogen carrier, from its protein and amino acid derived carbon skeleton, which constitutes an energetically denser substrate for gluconeogensis (esp. in the liver) than that of alanine or aspartate, the third most abundant interorgan nitrogen carrier in the human body.

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

I. Physiological role of glutamine in the human body

Stress-protection aside, glutamine performs a whole host of other important physiological functions. Glutamine...

... is required for hepatic ureagenesis and renal ammoniagenesis, is an essential contributor to detoxification processes;
... is necessary to maintain and restore an optimal ph-balance;
... is a substrate / precursor to peptides and proteins, amino sugars, purines and pyrimidines;
... is used as cellular fuel in muscle, intestine, skin and immune system, where it's availability / non-availability directly regulates protein synthesis and degradation;
... is intricately involved in the anti-oxidant defense system of the body as a precursor to glutathione (=glutamate + cysteine + glycine) production.

Glutamine and intestinal health & function

You may be surprised to see that I devote an entire chapter of this write-up to the role of glutamine in gut health; yet with the increasing public interest in and scientific awareness of pathologies beyond Crohn's, Celiac & Co, I consider the direct effects glutamine and glutamic acid exert on the health of the intestinal system of paramount importance.

Table 1: Effects of glutamine supple-
mentation on intestinal health
(Stehle & Fürst in ed. Cynober. 1955)

In their contribution to Pharmacological nutrition: immune nutrition (ed. Cynober, Fürst, Lawin. 1995) Stehle and Fürst compiled a list of immediate effects of glutamine supplementation on gut function (cf. table 1), many of which could be of great importance for athletes, who are not only particular reliant on optimal nutrient absorption, but also at an extraordinary risk of developing increased gut permeability, which has lately become commonly known and almost hysterically feared as "leaky gut" (syndrome). In this context, Carl V. Gisolfi writes in a review of the importance of optimal intestinal function for athletes (Gisolfi. 2000):

An increase in gut permeability may be an important link to gut-barrier impairment (Fig. 3). The hypothesis proposes that exercise stress produces biochemical changes that uncouple oxidative phosphorylation, reducing ATP produc ion and increasing Ca2+ efﬂux from mitochondria and endoplasmic reticulum. These events lead to increased cytosolic Ca2+ concentration, the generation of reactive oxygen species, and loss of tight junction control, producing increased intestinal permeability. [...] When the tight junctions open, their maxi-
mal channel size is too small to permit passage of endotoxin but will allow passage of luminal contents that are chemotactic for neutrophils. These agents (dietary antigens, chemotactic oligopeptides) stimulate intraepithelial lymphocytes to secrete interferon-γ. [...] Interferon-γ opens tight junctions and activates macrophages and neutrophils to release oxygen radicals and immunosuppressive peptides. Thus increasing intestinal permeability by opening tight junctions can initiate immunologic and inﬂammatory events that can alter gut structure and function.

Image 2: More than 50% of the
dietary glutamine are used by your
digestive system and do not even
reach systemic circulation.

Scientifically documented causative factors for increased gut permeability in athletes are ...

prolonged exercise (triathlon, marathon, etc.)
high intensity endurance exercise at 80% of VO2 max
(co-)ingestion of aspirin with medium intensity exercise at 60-65% of VO2 max

And desite the fact that Coeffier et al., in a recent review on the efficiacy of gutamine supplementation in patients with irritable bowel syndrome, state that previous "clinical studies with oral glutamine in CD [Crohn's disease] are until now disappointing" (Coeffier. 2010). There is substantial evidence for glutamine to exert beneficial effects on overall enterocyte health and accumulating evidence for the ability of glutamates, the carboxylate anions and salts of glutamic acid, to stabilize the gut lining and to reduce intestinal permeability (Vermeulen. 2011).

Did you know that in a 2010 study by dos Santos et al. (dos Santos. 2010), administration of glutamine at a dose of 500mg/kg/day (human equivalent ~40mg/kg or 3.2g per day for an adult weighing 80kg) to mice with experimentally induced intestinal obstruction "decreased intestinal permeability and bacterial translocation to physiologic levels in the treated animals and preserved intestinal barrier integrity".

Thus, even if the following dissertations will entail the conclusion that the ergogenic value of glutamine is largely overrated, the increase in gut permeability that has been observed after strenuous workouts (Davis. 2005) would be an argument in favor of post-workout glutamine / glutamic acid supplementation, you should remember.

II. Glutamine and the athlete

While intravenous glutamine infusions are a longstanding and well-established part of medical treatment strategies used in hospitalized and critically ill patients (Windle. 2006), the use(-fulness) of glutamine as a dietary supplement for athletes is still questioned by many of the practicing exercise and nutrition scientists. In the following I will try to tackle the two most frequent promises you ill hear and read about in the advertisements for respective products.

"Glutamine supplementation saves athletes from getting sick"

It is unquestionably true that glutamine is of paramount importance for healthy immune function (Calder. 1999).
It is also non-debatable that intense exercise, and, in that, specifically chronic endurance exercise (cf. figure 1), has been shown to decrease both serum as well as tissue glutamine levels.

Figure 1: Serum glutamine and glutamate levels in ultra-marathon runners pre- and at different time-points post exercise (data adapted from Castell. 1997)

As the data from figure 1 documents, the exercise induced decline of glutamine levels is yet far from being as dramatic as the -50% drop which has been reported for hospitalized critically ill patients. Nevertheless, the highly advertisable claims of increased incidences of upper respiratory infects due to weakened immunity secondary to exercise induced glutamine-deficiency are going on forever and I doubt that this will ever change, although the recently published position stand on dietary supplements by Walsh et al. is only the latesst in a line of reviews to conclude, based on contemporarily available evidence, that glutamine supplementation for athletes is "[n]ot recommended, [because] body stores [generally] exceed exercise-lowering effects" (Walsh. 2011).

With reference to the purported beneficial effects of supplemental glutamine on immunity in the athletic population, Newsholm et al. (Newsholm. 2011) write in Part 18 of a 2010/11 series on purported ergogenic sport supplements in the British Journal of Sports Medicine:

Glutamine supplementation after exercise reduced the self-reported incidence of illness in endurance athletes. However, when glutamine was given to athletes to combat exercise-induced depletion of circulating glutamine, no effects were observed on the immune parameters studied, apart from reduced neutrocytosis and increased circulating IL-6.

But if the existing anecdotal evidence is not merely a result of placebo effects (If you spent 50 bucks on a big pot of l-glutamine you do want that stuff to work, don't you? And if each and every "pro" tells you it does, it should work, shouldn't it?) or an increased awareness of how healthy you have "become", now that you are taking supplemental glutamine (when you have in fact been healthy all along), dosing issues, the addition of other nutrients and most importantly, training type and intensity would have been taken into consideration to explain the inconsistency of respective trials.

Did you know that moderate training, in contrast to the bodybuilding "go heavy or go home" type of training, leads to "improved glutamine availability due to a positive balance between muscle synthesis and peripheral clearance", while physical inactivity can reduce glutamine synthesis and availability!

In this context, it is noteworthy that declining glutamine levels after / in the course of periods of increased training intensity have only lately been (re-)introduced as a potentially useful indicator of overtraining by Agostini & Biolo (Agostini. 2010). They point out that "[s]trenuous physical exercise as well as exhaustive training programs [which] lead to glutamine depletion due to lowered synthesis and enhanced uptake by liver and immune cells". Lower glutamine levels, on the other hand, have been "associated" (notice we do not have enough evidence for a causal relationship here) with compromised immunity. Immediate / continuous repletion of whole body glutamine stores (serum & tissue) via adequate dietary or supplemental intake could thus very well help to maintain immunity.

Image 3: BCAAs are not only way
more ergogenic, they may in fact
also be a more versatile source of
glutamine than l-glutamine, itself.

Personally, I find it telling that much of the positive data on glutamine supplementation for immune health comes from studies on endurance athletes from the early and late 1990s. If you consider the poor nutritional advice those athletes were given at that time, many of them were hardly getting enough protein along with the shitloads of carbohydrates they were told to eat. Now, someone who lacks essential amino acids, and more specificically BCAAs, for glutamine production, is of course at higher risk of 'running out of fuel for his immune system', especially if he exhausts his already compromised tissue stores by chronic endurance exercise.

Conversely, the group of athletes who consumes the largest amounts of supplemental glutamine, i.e. bodybuilders, is probably the one who will benefit least of all from additional l-glutamine in their diet. No wonder that Candow et al. who studied the effect of a standardized strength training protocol with or without a 0.9g/kg lean tissue mass glutamine supplement on strength, body composition and protein turnover in young athletes found "that glutamine supplementation during resistance training has no significant effect on muscle performance, body composition or muscle protein degradation in young healthy adults" (Candow. 2001). While this obviously does not say anything about immunity you may safely assume that the latter was not compromised in the first place and thus evidently would not have benefited from the roughly 50-60g of l-glutamine (certainly a "sufficient" dose ;-) the subjects in the Candow study consumed.

"Glutamine increases regeneration and improves muscle and strength gains"

My preceding remarks on the useful- respectively -lessness of glutamine supplementation in marathon runners and bodybuilders have already touched on one of the recurring themes of the Amino Acids for Super Humans series: What is essential and beneficial for athlete A in situation B may be ineffective for athlete B in situation B or even athlete A in situation A. The data (table 2) from studies, which evaluated the effects of oral glutamine supplementation on exercise-related parameters in humans ("+" indicates improvement; "#" indicates no effect; "-" indicates detrimental effect), substantiates this observation.

Author(s)	Protocol	+/#/-	Main Result(s)
Castell. 1997	exhaustive exercise in middle-distance, marathon and ultra-marathon runners, and elite rowers, in training and competition 2x5g glutamine vs. maltodextrin 0, 2h post exercise	+ immunity	"[...] provision of oral glutamine after exercise appeared to have a beneficial effect on the level of subsequent infections [...] the ratio of T-helper/T-suppressor cells appeared to be increased in samples from those who received glutamine"
Bishop. 2000	review of intra-workout / -competition supplementation	#cortisol #immune	Consuming "carbohydrate [...] but not glutamine [...] during exercise attenuates rises in stress hormones, such as cortisol, and appears to limit the degree of exercise-induced immunosuppression"
Krzywkowski. 2001	bicycle exercise for 2 h at 75% of maximum O(2) 5x 3.5g glutamine vs. 3.5g maltodextrin at 0, 45, 90, 135, 170min post cycling	#immune	"no effect on lymphocyte trafficking, NK and lymphokine-activated killer cell activities, T cell proliferation, catecholamines, growth hormone, insulin, or glucose [...] Neutrocytosis was less pronounced in the glutamine-supplemented group, but it is unlikely that this finding is of any clinical significance"
Wilkinson. 2006	90 min cycling at 65% VO2_max post-exercise oral CHO 1g/kg/h + 9.25g EAA + glutamine 0.3g/kg BW vs isoenergetic CHO-EAA w/out glutamine	#anabolism, +long-term recovery	Consuming "addition of glutamine to a CHO + EAA beverage had no effect on post-exercise muscle glycogen resynthesis or muscle protein synthesis, but may suppress a rise in whole-body proteolysis during the later stages of recovery"
Carvalho-Peixoto. 2007	15 athletes, 120 min (approximately 34 km) outdoor running 3 groups CHO g/kg/d + Gln 70 mg/kg/d; only CHO or only Gln in addition normal diet	+ammonia detox	"ammonia was not different for the first 60 min, but for the second hour [ammonia] was lower than in the control"
Wilkinson. 2006	90 min cycling at 65% VO2_max post-exercise oral CHO 1g/kg/h + 9.25g EAA + glutamine 0.3g/kg BW vs isoenergetic CHO-EAA w/out glutamine	#anabolism, +long-term recovery	Consuming "addition of glutamine to a CHO + EAA beverage had no effect on post- exercise muscle glycogen resynthesis or muscle protein synthesis, but may suppress a rise in whole-body proteolysis during the later stages of recovery"
Favano. 2008	9 soccer players, cardiopulmonary exercise test + simulated soccer match, peptide glutamine (Gln) = 50 g of maltodextrin + 3.5 g of peptide glutamine or CHO alone 50 g of maltodextrin 30 min before test	+performance	"Total distance covered was 12750 [CHO] and 15571 [Gln]", i.e. +22% distance; "total duration of tolerance was 73 +/- 23 min when using CARBO and 88 +/- 24 min when using [Gln] (p<0.01)", i.e. +20% duration of tolerance"
Bassini-Cameron. 2008	prof. football players, Gln Alanine 100mg/kg, either short-term or long-term, immediately before exercise; intervals (n = 18) and continuous intensity (n = 12) exercise tests	#anabolism, +long-term recovery	"[...] results suggest that chronically supplemented Gln protects against exercise-induced hyperammonemia depending on exercise intensity and supplementation duration
Table 2: Some scientific data from human studies on oral glutamine supplementation from the last years ("+" indicates improvement; "#" indicates no effect; "-" indicates detrimental effect)

Despite the fact that the existing human data does not support the idea that athletes in general and weight trainers or fitness fanatics in particular would benefit from the tons of glutamine supplements that are sold year by year, some of the advertisment claims are in fact based on observations in petri dishes or animal models:

In the petri dish, glutamine actually is the potent "cell volumizer" the advertisments would have it and its administration to isolated hepatocytes (liver cells) does in fact stimulates anabolic processes within the cells, which involve an increased synthesis of DNA, RNA, and proteins.
It has also been found in cell studies that glutamine-induced cell swelling activates extracellular signal-regulated kinases and p38 (mitogen-activated protein kinase, MAPK), which are involved in stress response + adaptation and could thus facilitate muscle growth.
Two grams of glutamine taken on an empty stomach have furthermore been shown to evoke an immediate growth hormone response, which - and this is the major caveat - is not only so minuscule that it is physiologically irrelevant; it also reduces the amount of growth hormone that is released after the sudden burst occurred, so that the overall AUC, the area under the 24h GH curve or, in other words, the overall 24h growth hormone production remains unaltered (similar effects have been observed for acetyl-l-carnitine (more on ALCAR in Part IV (2/3) of the AA for SH Series) and combinations of l-lysine and l-ornithine).
And even the beneficial effects of parenterally administered alanyl-l-glutamine, an alanine + glutamine dipeptide, on (unfortunately) whole body insulin sensitivity are well established (Bakalar. 2006).

The reproduction or transfer of these effects from the respective model into real world results that would be relevant for the athletic practice have yet failed time and again and a mechanism which would explain the anecdotal evidence on the performance enhancing or muscle building effect of glutamine, which has repeatedly been confirmed by members of the bodybuilding and fitness world, could well be encapsulated within a fundamental physiological process that has acquired sort of a bad reputation lately: gluconeogenesis.

Did you know that in a 2010 study by van Hall et al. (Hall. 2010) a glutamine/carbohydrate mixture (0.8 g x kg(-1) body weight of glucose + 0.3 g x kg(-1) glutamine) failed to increase the rate of glycogen resynthesis in muscle over glucose alone. On the other hand, an isocaloric whey hydrosolate and even a wheat hydrosolate did (whey +20%; wheat +21%). What the study by Hall et al. confirms with respect to the regenerative effects of glutamine, is confirmed in terms of its effects on immune function, muscle protein breakdown and athletic performance by findings from Basset et al. (Basset. 2000), Hole (Hole. 2001) and Lehmkuhl et al. (Lehmkuhl. 2003), where the actual immuno-modulators, anti-catabolics and ergogenics were BCAAs and creatine, and the BCAA induced elevation of glutamine levels were corollary and not causative, and the addition of supplemental glutamine to creatine monohydrate without any effect on exercise performance.

In view of the current scare of everything carbohydrate-, god-forbid, insulin-related I hardly dare telling you that no other amino acid is so readily (ab-)used by your liver for glycogen production (=glyconeogenesis) as glutamine. This is especially true for doses that exceed the 2-5g range. They do not only provoke an accelerated glutamine clearance which is consistent with the activation of hepatic glutamine removal, but have also been shown to increase glucose formation in humans up to 7-fold (28g of glutamine infused in 4h time window; Perriello. 1997) at rest and to keep blood glucose levels up, glucose formation elevated (+24%) and glucose utilization increased (+16%) in a study, where dogs had received 12 micromol/kg/min glutamine intravenously during and after exercise (Iwashita. 2005).

Now, even if you are a carbophobic insulin-hater, this does not mean that you should flush your glutamine supply down the toilette. In view of the fact that even the marked increase in gluconeogenesis that was observed by Perriollo et al. was not accompanied by an increase in insulin or glucogon levels, glutamine may in fact turn out to be the ideal supplement for endurance athletes or dieting body builders or figure competitors who want to maintain healthy blood glucose levels on a low carb diet. For a sedentary person on a no-carb diet, or example, even 20–40g glutamine per day would probably be enough to fuel their glycogen demands.

Conclusion

Image 4: You do not always need supplements.
Oftentimes a nutritionally dense diet with a high
amount of protein will work at least just as well
as the latest and greatest amino acids supplement
you read about in your favorite fitness magazine.

The latter creative application of glutamine as a carbohydrate replacement aside, I am, based on the available data on the ergogenic effects of supplemental glutamine, inclined to subscribe to the conclusion of the authors of the BJSM Supplement Review (Newsholm. 2011) on glutamine who point out that

[...] there is no consensus or unifying concept to explain the efficacy of exogenous provision of glutamine alone on performance in athletes, although in combination with carbohydrate or other amino acids, significant improvements have been reported.

Thus, notwithstanding its importance in many performance related physiological processes, an appropriately nourished human body is well able to synthesize more than enough glutamine from essential amino acids (and BCAAs in particular) to satisfy both everyday, as well as athletic demands. Consequently, athletes who wish to take advantage of the undeniably beneficial effects of adequately filled glutamine pools should give priority to the provision of adequate amounts of essential amino acids (EAAs), in general, and BCAAs, in particular. And despite the fact that the supplement industry would have you believe otherwise, most recreational athletes can easily satisfy their EAA demands by consuming a nutritionally dense high protein diet and an optional whey protein supplement.

Amino Acids for Super Humans, Part IV - Purported Ergogenics (2/3): L-Carnitine, ALCAR, LCLT, GPLC & Co.

Image 1: Even bought in bulk,
the carnitines are not exactly
cheap, so you better read on
to gather whether ALCAR,
L-CAR, P-LCAR, L-CLT & Co
are worth spending money on.

Despite the fact that even my grandmother has heard of the miraculous energizing and fat-burning abilities of carnitine, most people - and even those who are buying those carnitine-enriched functional, or should I say disfunctional foods are not even aware that L-3-hydroxy-4-N,N,N-trimethylaminobutyric acid (l-carnitine) is a naturally occurring amino acid, all mammals (humans included) can synthesize from l-lysine or l-methionine in their livers and kidneys.

Necessary co-factors for carnitine synthesis are

ascorbic acid (vitamin C),
pyridoxine (vitamin B6),
niacin (vitamin B3) and
S-Adenosyl methionine (SAMe)

Interestingly, supplementation of the EAA substrates and co-factors failed to raise carnitine synthesis and or serum levels in respective studies. Gamma-butyrobetaine, a down-stream metabolite in carnitine synthesis from lysine, on the other hand, doubled plasma, brain, kidney and liver levels of carnitine in juvenile mice; cf. Higashi. 2001).

In view of the limited capacity for endogenous biosynthesis of carnitine, it is not very surprising that mammals obtain the heat sensitive (at 284°F ~ 140°C carnitine starts to decompose) amino acidprimarily from their diet (Vaz. 2002); and in that, it is probably no coincidence that colostrum and breast milk are particularly high in l-carnitine, as the need for this essential metabolite in the mammalian energy metabolism increases in phases of rapid growth.

Did you know? The first soy-based baby formulas were low in carnitine, so that neonates who were fed respective products had 1/3 lower carnitine levels than babies who were breast-fed or received milk-based products. Even in the absence of symptoms of overt carnitine deficiency, sub-optimal carnitine levels put these children at risk of early or late metabolic complications (Olson. 1989). Consequently, almost all soy-based infant formulas are enriched with l-cartinine, today.

Vegetarians and Vegans generally have lower plasma carnitine levels

Table 1: Amount of carnitine in food;
meat, fish and dairy are particularly
good sources of dietary l-carnitine
(data adapted from wikipedia.org)

That's unfortunate news for all vegetarians and vegans out there, because as the data in table 1 shows, meat, fish and dairy are the richest dietary sources of l-carnitine. "Omnivorous humans generally ingest 2-12 µmol of carnitine per day per kg of body weight" (Vaz. 2002), which is up to 10x the estimated amount of our endegenous production (1.2µmol /kg/day). So that 75% of the well-stocked carnitine stores of meat-eaters come from dietary, and only 25% from de novo biosynthesis. Needless to say that, with an average daily carnitine intake of <0.1µmol /kg body weight, vegetarians and vegans are usually significantly lower than those of their omnivores fellow men (Rebouche. 1992).

Symptoms of overt carnitine deficiency, such as cardiomyopathy,
hepatomegaly, myopathy, recurrent episodes of hypoketotic
hypoglycaemia, hyperammonaemia and failure to thrive have yet not been observed in the absence of CDSP (primary carnitine defiency), a pathology that has been mapped to human chromosome 5q and is characterized by excessive renal and intestinal wastage of carnitine.

Attention Atkins dieters! In a German study (Liebhaber. 2006) the long-term effects of ketogenic diets on epileptic children, carnitine deficiency was detected in 57% of the patients who did not receive supplemental l-carnitine. There was a large interpersonal variety as far as the onset of carnitine deficiency was concerned. On average subjects developed carnitine defiencey after about 32 weeks, one subject was however carnitine deficient after only two days and one subject maintain sufficient carnitine levels for 248 weeks before carnitine deficiency was diagnosed. These observations stand in line with results of Stadler et al. (Stadler. 1999) who had previously established that a high fat intake increases carnitine excretion. Taken together, this data suggests that people who follow a high fat (not the high protein low carb diet everybody is on these days) would generally benefit from carnitine supplementation.

How carnitine facilitates "fat-burning"

Illustration 1: Carnitine is like the man who
shovels the coal. It's just a small wheel in the
mitochondrial fat burning machinery. Without
lipolytic activity (= free fatty acids floating aroun) and
a sufficient number of properly functioning
mitochondria, increased carnitine levels
won't translate into fat loss (picture in the back-
ground from Ptak Science Books. 2009)

The previous remarks on potentially low carnitine levels suggest the assumption that their diet puts this group of people at risk of high triglyceride levels, obesity and all other sorts of metabolic pathologies related to suboptimal fatty acid oxidation. There is however very little evidence that plasma l-carnitine is - under normal conditions - rate limiting in mitochondrial beta-oxidation. If you think of coal-fired steam engines of the Titanic, would the ship have been faster and thus be able to take the safer route and still win theBlue Riband of the Atlantic if there had been more workers to fire up the ovens? Probably not, because the engines were already running at full throttle... the same is true for your mitochondria, just because there is an overabundance of carrier molecules that does not mean that your "ovens",... pardon me..., your mitochondria will be able to oxidize more fat.

The commonly touted "fat burning" effects of l-carnitine (and all other forms of carnitine) thusly belong to the realms of advertismental oversimplifications, or should I say frauds? Even taken poundwise carnitine by itself will neither empty, nor burn the contents of a single of your unaesthetic fat cells. On the other hand, a profoundly lowered carnitine levels as they were reported for elderly and obese patients by Noland et al. (Noland. 2009) could lead to or exasperate existing weight problems by compromising the transport of fatty acids from the cytosol, i.e. the intracellular fluid, into and back out of the mitochondria.

Figure 1: Free and bound (esterified) carnitine content in mg/kg of different meat products
(data adapted from Seline. 2007)

In and out that's the way things have to go

Image 2: Lipofuscin accumulation (fine
brown / yellow granular pigment)
in liver cells (photo by Nephron).

The latter, the transport of partly oxidized, "damaged fats", so called lipofuscins out of the mitochondria, may in fact be about as important for your overall metabolic health as the well-known transportation of esterified fatty acids into the mitochondria. Mitochondrial malfunction and failure aside, a way more visible effect of lipofuscin accumulation are the brown stains on old peoples skin. Of greater significance are yet the negative effects of lipofuscin depositions in the brain, which have been shown to be ameliorated by acetyl-carnitine supplementation (Kohjimoto. 1988). And it is likely that many of the established benefits of (acetyl-)l-carnitine supplementation stem from the clearance not the the entrance of fatty acids into the cells.

Inter-cellularly, carnitine also functions as a temporary buffer for the unused acetyl-CoA. The accumulation of respective acyl-carnitines within the mitochondrion, which goes hand in hand with a depletion of unbound l-carnitine that would faciliate the transport of fatty acids into the mitochondria, has been implicated as one of the confounding factors in the etiology of the metabolic syndrome.

Figure 2: Simplified illustration of the underlying mechanism of carnitine mediated fatty acid transport in and out of the mitochondrion (The AOCS Lipid Library)

L-Carnitine as a selective glucocorticoid receptor modulator & useful tool in hyperthyroidism

Beside its effects on mitochondrial health, l-carnitine also exhibits anti-inflammatory properties by directly interacting with glucocorticoid receptors on immune cells (Manoli. 2006). In experiments Manoli et al. conducted back in 2006, l-carnitine in a glucocorticoid-like fashion "suppressed the lipopolysaccharide-stimulated release of tumor necrosis factor α and interleukin-12 from primary human monocytes". Despite its ability to stimulate glucocorticoid receptors (GR), and to reduce binding of the cortisol analogue ³H]-dexamethasone to GRs, LCAR apparently lacks the deleterious side effects corticosteroids have on other organs/tissues in the human body.
Moreover, a study by Benvenga et al. in which women received supraphysiological doses of the synthetic thyroid hormone levothyroxin (T4) to induce symptoms of hyperthyroidism confirmed previous observations that l-carnitine even at doses as low as 2-4g/day "antagonizes hyperthyroidism-related [...] symptoms and biochemical responses of thyroid hormone target tissues". Data from cell culture experiments suggest that it is the property to inhibit T3 and T4 entry into cell nuclei, which it at the heart of the anti-(hyper-)thyroid effect of l-carnitine, since l-carnitine supplementation does not substantially affect thyroid hormone levels or radioactive iodine uptake by the thyroid.

Did you know? Both full-blown hyper- as well as hypothyroidism have been associated with muscular carnitine depletion (Sinclair. 2005), as a consequence of insufficient synthesis (hypo-) and increased usage (hyper-) of carnitine.

In that, it is interesting to note that, vice-versa, thyroid hormone also influences the rate of carnitine synthesis (Galland. 2002), which, again, brings up the idea of tightly regulated, feedback-control mechanisms intended to keep the metabolic rate (including the mitochondrial beta oxidation of fatty acids) in a narrow physiological range, so that in people with high levels of thyroid hormones (not necessarily hyperthyroidism) and increased carnitine production, or in people with low levels of thyroid hormones (not necessarily hypothyroidism) and decreased carnitine production the respective ratios of carnitine / thyroid hormone could lead to similar cellular T3 / T4 uptake in the presence of fundamentally different serum levels of these hormones.

Carnitine intake and clearance - does supplementation make sense at all?

In healthy human beings, on the other hand, the main regulatory mechanisms take place in the kidney and a basic understanding of the relation of carnitine intake to urinary loss is of fundamental importance for anyone who does not want to feed his expensive carnitine supplements to sewer rats.

Figure 2: Free and bound (esterified) carnitine content in mg/kg of different milk products
(data adapted from Seline. 2007)

In general, dietary l-carnitine has a bioavailability of 54%-84% and is thusly much better absorbed than supplemental carnitine in powdered or capped form, for which Rebouche et al. report a bioavailability of meager 14%-18% (Rebouche. 2006). Ideally, you would thus get about 1.28g of carnitine from 1kg of Kangaroo steak, which turns out to be by far the best source of dietary l-carnitine.

Note: According to the data from Rebouche et al. you wanted to get the same 1.28g of carnitine from a supplement, instead of a 3-4 dilicious steaks, you would have to consume 7-9g of supplemental carnitine in pill or capsules for the same amount of l-carnitine to hit your blood stream!

A vegan, who abstains from eating meat, fish and dairy, on the other hand, would have to eat his share of 60kg of mushrooms to get an equal amount of 1.28g of carnitine. Although the act of eating 60kg of mushrooms would already border the supernatural, the of 320kg of carrots you would have to eat, alternatively, are merely hypothetical.

Figure 3: Free and bound (esterified) carnitine content in mg/kg of different mushroom, vegetable and fruit products
(data adapted from Seline. 2007)

Unfortunately things do not turn out to be that easy as the above calculations would suggest, because, as we physicists use to say, bioavailibilty B(m, C, F) "is a function of body weight m, carnitine availability C and the form of carnitine F" and thus depends on how much you weight, how much carnitine you eat in a single sitting, how much carnitine is already floating around in your blood stream and what form of carnitine (free l-carnitine or esterified carnitines, such as acetyl-l-carnitine or (glycine-)propionyl-l-carnitine, you ingest. Add to that some interpersonal variability and plot the total ingested and absorbed amounts of l-carnitine from a previous study of Rebouche et al. (Rebouche. 1999) in a graph and you get something that looks like this:

Figure 4: Total ingested (full bars) and absorbed (blue part of the bar) amount of dietary carnitine in mg/kg body weight
(data adapted from Rebouche. 1999 & Rebouche. 2006)

It's quite obvious that - despite all interpersonal variety among the 12 test subjects - the relative amount of carnitine that actually hits the circulation decreases with increasing amounts of carnitine in the diet.

Did you know that multiple small doses of carnitine are way superior to a single large dose if your aim is to persistently increase serum carnitine levels? In contrast to Rebouche et al. (Rebouche. 2006), who achieved relatively stable carnitine levels >50% above baseline by having their subjects take their 2g of carnitine in three divided doses (at 8am, 12pm, and 6pm) trials using a single, large bolus of l-carnitine (orally and even intraveniously) did not produce sustainable elevations in plasma carnitine levels. Furthermore, the addition of carbohydrate (96g glucose in addition to 3g l-carnitine/day) and the concomitant insulin release have been found to decrease uriniry carnitine clearance, or, converesely, increase carnitine retention by ~40% (Stephens. 2007).

The decreased absorption of dietary carnitine from the gut goes hand in hand with a decreased reabsorption of carnitine in the kidneys. At low to normal serum carnitine levels the latter conserve 90-99% of the circulating carnitine. When carnitine levels increase, however, the clearance rate increases way beyond the 1-3 mL/min that would leave your body in the form of urinary losses under "normal" circumstances. Thusly, increased carnitine levels, as they are the result of an intravenous infusion of 0.5g of carnitine, return to baseline in less than 12h, with a rapid decline (-80%) in the first hour after administration. Whole body turnover, i.e. the "renewal" of creatine stores, in slow (muscle) and fast turnover (liver, kidney, and other tissues) stores is estimated to take about 38-119h (Rebouche. 2006).

On the different forms of carnitine

The absorption issue immediately reminds me of the bro-scientific mambo-jambo about the bioavailability of different forms of carnitine you can find wherever L-CAR, ALCAR, P-LCAR, LCLT & Co are sold. In most cases the the individual bioavailibility appears to depend on the venue the respective vendor will get from the different forms of carnitine. In that, supplement manufacturers cash in on the lack of scientific studies comparing the absorption kinetics of the various commercially available forms of carnitine in a single objective model. In this context it is also noteworthy that both commercially available carnitine-esters, i.e. acetyl-l-carnitine (ALCAR) and (glycine-)propionyl-l-carnitine (PLCAR, (G)PLC), are no invention of the supplement industry, but naturally occurring forms of carnitine, the pharmacokinetics of which have been studies by Cao et al. after oral administration of 2g of l-carnitine to 12 healthy volunteers (Cao. 2009).

Table 2: Pharmacokinetics of l-carnitine (L-CAR), acetyl-l-carnitine (ALCAR) and propionyl-l-carnitine (PLC) after oral administration of 2g of l-carnitine to 12 healthy volunteers (data adapted from Cao. 2009)

As it was to be expected both, the maximal, as well as the absolute plasma concentration of l-carnitine of l-carnitine are greater than that of its esters. Yet despite the sudden spike in l-carnitine levels, the clearance rate for ALCAR and PLC were greater. Conversely, the carnitine-esters have a -40% (ALCAR) and -57% shorter half-life than the free form of carnitine. In that, the high 24-h urinary excretion of ALCAR, which equals about 2x the area under the curve suggest that both long PLC esters that have previously been broken down to shorter acetyl-esters, as well as "used" and thus esterified l-carnitine are excreted as acetyl-l-carnitine.

The results of Cao et al. stand in line with findings of Eder et al. (Eder. 2005), who used a pig model ( which is pretty reliable when it comes to modeling the human digestive system) to estimate the bioavailability of various L-carnitine esters (acetyl-L-carnitine and lauroyl-L-carnitine) and salts (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate) and found that

AUC [aera under the curve] values, calculated for the time interval between 0 and 32 hours, for both free and total carnitine were similar for base of free L-carnitine and the three L-carnitine salts (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate) while those of the two esters (acetyl-L-carnitine, lauroyl-L-carnitine) were lower.

In that, it is of particular interest that l-carnitine-l-tartrate (LCLT), which is heavily promoted as the "best" carnitine supplement, did in fact "yield a higher plasma free carnitine AUC value for the time interval between 0 and 3.5 hours than [any] of the other compounds." The faster absorption of LCLT aside, the data of this (unfortunately) unique study would suggest that the fancy "L-carnitine salts have a similar bioavailability" as the way cheaper free form of carnitine (l-carnitine) and both appear to be better absorbed than any of the l-carnitine esters .

Did you know? Gram per gram the tartrate salt of carnitine (LCLT) provides only 40% carnitine. If, for example, you wanted 2g of pure carnitine, you would have to take 5g of LCLT.

Acetyl l-carnitine the one and only (?) brain booster

In the case of ALCAR, for example, it is well established that its oral bioavailability is decreased due to increased hydrolysis. Oral bioavailability, on the other hand, is only one of the attributes the addition of the acetyl ester to the free form of carnitine changes. For example, it is often cited that ALCAR would be the only form of carnitine that is able to pass the blood-brain-barrier (BBB) in mammals. This statement is simply false! While it is true that the acetylated form of carnitine passes enters the brain more easily, i.e. it takes lower concentrations outside the barrier to achieve the same levels of carnitine within the brain, the difference in K(m) values, which area a measure of the concentration of substrate required to produce 50% of the maximal uptake, is only 5% (K(m)_Alcar=31.3 vs. K(m)_Carn=33.1, cf. Kido. 2008).

Anyway, at least those of you who have some sort of cognitive / neurological problem, probably won't really care if ALCAR is actually the only, or maybe just the favorable form of carnitine to treat neurological diseases, as long as it will help mitigate your problems - and indeed, ALCAR appears to be a formidable "brain nutrient" which has been used succesfully in a variety of brain-related clinical conditions (Alternative Medicine Review. 2010):

Alzheimer's disease
Depression
Attention deficit / hyperactivity disorder (ADHD) and Fragile X Syndrome
Peripheral (diabetic, antiretroviral and chemotherapy-induced) neuropathy
Cerebral ischemia and reperfusion
and others

The underlying mechanisms of action most likely are:

Increasing neural energy production
Protecting neurons from toxins
Maintaining neuron receptors
Increasing availability of the neurotransmitter acetylcholine
Decreasing accumulation "damaged fats" (lipofuscins) in brain tissue

If administered orally, dosages usually range from 2.0-5.0g of ALCAR, mostly taken in divided doses. Reports on side effects are scarce, and generally limited to agitation, nausea and vomiting, so that ALCAR is generally considered safe, even wit long-term administration (Spagnoli. 1991).

(Glycine) propionyl l-carnitine the one and only (?) nitric oxide booster

Image 3: Molecular structure
of the bulky 3-Propanoyloxy-
4-(trimethylazaniumyl)butanoate
molecule which usually goes by
the name Propionyl-L-carnitine, or
its abbreviations PLC or PLCAR.

GPLC, i.e. glycine propionyl l-carnitine certainly is the fancier of the two readily available carnitine esters. I mean, who cares about brain health, if GPLC promises huge pumps? The target group of the colorful ads in the bodybuilding magazines probably doesn't. Yet while studies from the Department of Health and Sport Sciences at the University of Memphis (Bloomer 2007; Bloomer. 2009), the Department of Exercise Science and Health Promotion at the Florida Atlantic University (Jacobs. 2009) support the claim that the combination of glycine and propionyl l-carnitine can increase nitric oxide production, decrease lactate accumulation and increase performance in high intensity exercises such as sprinting, the exact underlying mechanism remains questionable. Especially in view of the fact that Bloomer et al. (Bloomer 2007) administered glycine (1g) and the carnitine ester PLC (3g) in an unbound form, further investigation, whether co-administration of glycine and l-carnitine would not produce similar, yet more cost effective results, are warranted.

Note: I assume, you have also heard of the paradoxical effect 4.5g of GPLC had on sprint performance in a 2010 follow-up study of Jacobs et al. (Jacobs. 2010). In contrast to what the scientists had expected based on previous results (Jacobs. 2009), long-term supplementation of a high dose (4.5g vs. 1.5g) of glycine propionyl l-carnitine did not only fail to improve sprint performance beyond what was achieved with 1/3 of the dosage, the huge pump, the athletes were complaining about, even compromised their performance. If you are an athlete, exceeding a dose 1-2g of GPLC per day would thus be more than a waste of money, it could actually cost you your victory. Remember: With most supplements taking more does not equal greater benefits!

L-carnitine l-tartrate the one an only (?) testosterone booster

Image 4: "Supported" studies make
LCLT highly marketable (Lonza, Inc)

Based on what you (should) have learned from the previous paragraphs, you should not be surprised to hear that l-carnitine l-tatrate at dises of 5g (equiv. to 2g of carnitine), just as his "brethren" l-carnitine, acetyl- and propionyl l-carnitine may be considered a scientifically proven ergogenic. Ester (ALCAR, PLC) or salt (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate), after all, its all carnitine... that being said, I do not question any of the highly marketable results Kraemer, Volek and the other scientists from the Human Performance Laboratory, Department of Kinesiology at the University of Connecticut have produced. I am just asking myself, why none of these studies compared the expensive tartrate salt, L-Carnipure® tartrate, the scientists received along with research grants from Lonza, Inc, to the much cheaper non-patented free form of carnitine. You do not have an answer, do you?

Did you ever think of the remote possibility that the "subtle yet significant" effects l-carnitine l-tartrate had on androgen receptor expression and testosterone in the heavily cited 2006 study by Kraemer et al. (Kraemer. 2006), may come from the tartrate and not the carnitine? Me neither, but the idea Owner (pseudonym) from the Mind&Muscle boards brought up, back in the days, is not totally devious. Join the smartest BB-community on the net and revive the discussion, if you will!

Conclusion

Do you remember? This write-up started out with the purported fat-burning effects of carnitine, established that carnitine is a necessary, but not sufficient co-factor in mitochondrial beta oxidation and clearance of fatty acid, elaborated on the metabolic and neurological health benefits of carnitine and concluded on the true ergogenic value of what turned out to be a whole group of quite expensive amino acids, the use of which you should take into consideration only after you got your (carnivorous) diet, your training regimen and your basic supplement protocol (protein, creatine + facultative EAA/BCAA) in check.

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

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

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

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

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

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

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

Beta alanine, the rate-limiting substrate in carnosine synthesis

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

carnosine levels are particularly high in brain tissue and fast-twitch muscle fibers (Harris. 1998)
mean concentrations are 17.5 ± 4.8 mmol kg−1 dm in females and 21.3 ± 4.2 mmol kg−1 dm in males (Mannion. 1992),
interestingly muscle carnosine levels of sprinters and other sports with short bursts of high intensity work are elevated compared to non-athletes and athletes from endurance-oriented sports such as marathon runners

carnosine & the brain
carnosinemia (a rare condition of low carnosine levels) effects almost exclusively the brain, which indicates that it is of utmost importance to brain health
carnosine levels (in all tissues) decline with age; scientists speculate about the role of low carnosine levels in dementia and other age-related neurological diseases
carnosine's antiglycation effect makes it a promising therapeutic agent in the treatment of AGE-related (AGE = advanced-glycation-end-products) pathologies such as Alzheimer's (Reddy. 2006)

carnosine & athletic performance

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

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

Increasing carnosine levels by beta alanine supplementation

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

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

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

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

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

Tingles, flushing and myocardial suffocation

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

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

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

Beta Alanine & Taurine - archenemies or synergists?

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

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

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

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

Beta alanine, does it have endocrine effects as well?

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

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

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

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