Science Round-Up Seconds: 8 Nootropics to Combat Stroke, Alheimer's & Co and Boost Cognitive Performance. Plus: 7 Rarely Thought of Side Effects of High Dose Glutamine.

Effects of infusion times on phenol content of black tea (Ramalho. 2012)

If you have already listened to the podcast of yesterday's Science Round-Up on the Super Human Radio Website (click here if you haven't and wan't to know what the following is all about), I suppose you will not mind that I compiled some of the complex information about "optimal" tea brewing in the illustration to the right (based on Ramalho. 2012). The colored arrows indicate the time-points at which the given compounds in the tea achieved peak values. The exact time point is also given in minutes, so that a 9' in front of the green caffeine and on the left to the green arrow pointing at the 9 min point tells you "it took 9 minutes for the caffeine content to reach it's maximum in the British tea". The graph in the background shows the catechin concentration depending on the infusion time.

Cholinergenic nootropics - What a recent review says

I guess some of you will probably have heard about piracetam or lecithine as purported enhancers of cognitive function. According to a recent review in the Journal of Experimental Pharmacology those two are yet not the most prosing agents:

Eggs are rich in choline which is an essential nutrient and was abundant in the classic BB diets (rear more)

• Piracetam: no cerebroprotective effects in patients who have open heart surgery, but does help on non-open cardiopulmonary bypass surgery (Holinski. 2008), beneficial effects in response to cerbrovascular and cognitive disorders traumatic origin (Malykh. 2010), intravenous piracetam can prevent cognitive deficits in response to anesthesia (Fesenko. 2009)

• Lecitin: does not improve cognitive deficits in patients (Amenta. 2011; Parnetti. 2007)

More promising "nootropics" - specifically in view of what most people do actually expect, when they buy such products.

• Oxiracetam: improves cognitive performance except for patients with dementia (Malykh. 2010)

• Citocoline: general neuroprotective effects (Alvares-Sabin. 2011), improvements in cognitive performance in healthy and patients and patients with dementia (Secades. 2010), helps with cognitive dysfunction in Parkinson's (Vale. 2008), helps with cognitive function in dementia of neurodegenerative and vascular origin (Parnetti. 2007), prevents cognitive decline after a stroke (Alvarez. 2011), improves recovery after stroke (Garcia-Cobos. 2010) 

• Cerebrolysine: produces signifant cognitive improvements in vascular dementia (Guekht. 2011), effective for both cognitive function and behavioral symptoms in Alzheimer's (Alvarez. 2011), promising results in patients with Alzheimer's (Plosker. 2009)

And a couple of things you would not usually associate with nootropics:

• 

  Suggested read: Amino Acids for Super Humans on the effects and differences between the various forms of carnitine (read more).

  Acetyl-L-carnitine: improves cognitive performance in patients with encephalopathy, decreases anxiety and increases general energy and wellness, as well as fatigue and age-related cognitive deficits (Malaguernera. 2008, Liu. 2008),can reduce or block neuronal death in neurodegenerative diseases (Manusco. 2007), helps ammeliorate hyperammonemia (Cagnon. 2007)

• Saffron extract: beneficial effects in mild to modest Alzheimer's  (Akhondzadeh. 2010)

• DHA (fish oil): positive effects on verbal recognition memory in old subjects (Yurko-Mauro. 2010)

Interestingly, the most profound effects appear to be brought about by acetyl-l-carnitine. In that it's worth mentioning that the benefits could still be related to cholinergic mechanisms, since it has long been known that ALCAR can increase the expression of choline acetyltransferase activity in the central nervous system (Taglialatela. 1994). And the latter is, as the name implies, necessary to form the neurotransmitter acetylcholine .

Glutamine probably not suitable for chronic high dose supplementation

Czech scientists warn about the risks of chronic high dose glutamine supplementation. I know that many of you are still too bamboozeled by the "protein for everything and let the liver take care of any glucose demands I may have" theory, of which you could probably argue that it is the bastard child of the standard BB diet with low carb. Maybe the following recently published paper by a scientist from the Charles University in Prague can help cure this "disease" (and your cognitive problems, fatigue and brainfog).

According to Holecek, the chronic ingestion of glutamine / glutamine enriched diets in can lead to...

Figure 1: In the presence of high amounts of glutamine outside of the cell, the glutamine synthesis (GLN) and with it the ammonia detoxification from muscle tissue sucks (Holecek. 2012).

"(1) Alterations in amino acid transport-as GLN shares the transporters with other amino acids, enhanced GLN intake may impair amino acid distribution among tissues and their absorption in the gut and kidneys.

(2) Alterations in GLN metabolism-GLN supplementation may impair synthesis of endogenous GLN and enhance glutamate and ammonia production.

(3) Alterations in ammonia transport-GLN supplementation may impair ammonia detoxification and negatively affect the role of GLN as the carrier of ammonia among tissues.

(4) Abnormalities in aminoacidemia-increased plasma levels of GLN, glutamate, citrulline, ornithine, arginine, and histidine and decreased levels of valine, leucine, isoleucine, glycine, threonine, serine, and proline are reported.

(5) Alterations in immune system-as GLN has immunomodulating properties, the effect of chronic GLN consumption on the immune system needs to be assessed.

(6) Effect on tumor growth-it should be elucidated whether chronic intake of GLN increases the risk of cancer.

(7) Effect of the withdrawal of GLN supplementation-due to the adaptive response of the organism to enhanced GLN consumption, the withdrawal of GLN may enhance the risk of health problems resulting from GLN deficiency." (Holecek. 2012)

Remember the post on the ammonia induced peripheral and central fatigue with high dose chronic BCAAs supplementation?

In view of the fact that some people consumer up to 40g of glutamine regularly, Holecek demands that "long-term studies should be performed" to test the side effects and evaluate whether there is any benefit at all to justify chronic consumption of a GLN-enriched diet.

So, relying on glutamine instead of carbs, as smart as this idea appears to be in the current carbophobia, could actually make you stupid due to the disruption of the intracellular ammonia detoxification, which is not a problem in muscle only, but also in the brain.

In the end, what we are seeing here is just another instance of a disruption in the natural balance of things. Ornithine, citrulline and arginine, for example are involved in the detoxification of ammonia via the urea cycle. They are however not the only bottleneck to the system.

Obviously your liver and kidneys will have to handle the clearance. People with liver problems (or persons taking "supplements" or NSAIDs that may impair the liver function) are therefore particularly prone to hyperammonemic encephalopathy (Kanamori. 1996; Lemberg. 2009)

Bottom line: Glutamine, just like everything else, in moderation and by no means so much that your body runs on glutamine as fuel. Aside from the mentioned amino acids that help the clearance of ammonia from the blood stream, taurine appears to exert a direct protective affect in the brain (Chepkova. 2006), and lactulose (a fermentable carbohydrate) can reduce the ammonia influx from ammonia producing bacteria in the gut (Vince. 1980). So if you want to wear a helmet when you bang your head against the wall, these would be suggested "take supplement B in order to counter the side effects of supplement A" - side effects of a supplement you would not even have to take, by the way (100% bro-logic ;-)

References: 

• Amenta F, Carotenuto A, Fasanaro G, Lanari A, Rea R, Traini E. Preliminary results of Ascomalva trial on the association of donepezil and choline alphoscerate in Alzheimer’s disease with associated cere-brovascular injury. G Gerontol. 2011;59:89–9.
• Akhondzadeh S, Shaf iee Sabet M, Harirchian MH, Togha M. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativusin the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology (Berl). 2010;207:637–643.
• Alvarez XA, Cacabelos R, Sampedro C, et al. Efficacy and safety of cerebrolysin in moderate to moderately severe Alzheimer’s disease: results of a randomized, double-blind, controlled trial investigating three dosages of cerebrolysin. Eur J Neurol. 2011;18: 59–68.
• Alvarez-Sabín J, Román GC. Citicoline in vascular cognitive impair-ment and vascular dementia after stroke. Stroke. 2011;42(Suppl 1): S40–S43.
• Cagnon L, Braissant O. Hyperammonemia-induced toxicity for the devel-oping central nervous system. Brain Res Rev. 2007;56:183–197.
• Chepkova AN, Sergeeva OA, Haas HL. Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis. 2006 Sep;23(3):512-21.
• Fesenko UA. Piracetam improves children’s memory after general anaesthesia. Anestezjol Intens Ter. 2009;41:16–21. Polish
• García-Cobos R, Frank-García A, Gutiérrez-Fernández M, Díez-Tejedor E. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci. 2010;299:188–192.
• Guekht AB, Moessler H, Novak PH, Gusev EI; Cerebrolysin Investigators. Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial. J Stroke Cerebrovasc Dis. 2011;20:310–318. 
• Holecek M. Side Effects of Long-term Glutamine Supplementation. JPEN J Parenter Enteral Nutr. 2012 Sep 18.
• Holinski S, Claus B, Alaaraj N, et al. Cerebroprotective effect of piracetam in patients undergoing coronary bypass surgery. Med Sci Monit. 2008;14:153–15.
• Kanamori K, Ross BD, Chung JC, Kuo EL. Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutamine synthetase in vivo. J Neurochem. 1996 Oct;67(4):1584-94.
• Lemberg A, Fernández MA. Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress. Ann Hepatol. 2009 Apr-Jun;8(2):95-102.
• Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008;33:194–203.
• Mancuso C, Bates TE, Butterfield DA, et al. Natural antioxidants in Alzheimer’s disease. Expert Opin Investig Drugs. 2007;16:1921–1931.
• Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch Gerontol Geriatr. 2008;46:181–19
• Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci. 2008;53: 3018–3025
• Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. Drugs. 2010;70:287–31
• Pantoni L. Treatment of vascular dementia: evidence from trials with non-cholinergic drugs. J Neurol Sci. 2004;226:67–70
• Parnetti L, Mignini F, Tomassoni D, Traini E, Amenta F.  Cholinergic precursors in the treatment of cognitive impairment of vascular origin: ineffective approaches or need for re-evaluation? J Neurol Sci. 2007;257:264–269.
• Ramalho SA, Nigam N, Oliveira GB, Alves de Oliveira P, Matos Silva TO, Passos dos Santos AG, Narain N. Effect of infusion time on phenolic compounds and caffeine content in black tea  Food Research International; 13 December 2012 [ahead of print]
• Secades JJ. Citicoline: pharmacological and clinical review. Rev Neurol. 2010;52 Suppl 2:S1–S62.
• Vale S. Current management of the cognitive dysfunction in Parkinson’s disease: how far have we come? Exp Biol Med (Maywood). 2008;233:941–951.
• Vince AJ, Burridge SM. Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol. 1980 May;13(2):177-91.
• Yurko-Mauro K. Cognitive and cardiovascular benefits of docosahexaenoic acid in aging and cognitive decline. Curr Alzheimer Res. 2010;7:190–196.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Forget about tryptophan and serotonin, focus on ammonia

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

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

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

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

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

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

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

References:

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

More Endurance, Greater Strength Gains, Less Exhaustion: Alpha-Keto Acids (KIC, AKG & Co) - Overlooked Ergogenics?

This is a scenario, where the results of the study at hand would apply - if that's you, go ahead get yourself some BCKAs; if it's not read at least the bottomline before you spend your money on the "latest", but not necessarily "greatest" ergogenic

As a seasoned SuppVersity veteran, you will be aware that the number of supplements that work is pretty small. The number of supplements that will actually make a difference that's not just statistically significant can probably even be counted on the fingers of one hand and arginine-alpha-ketoglutarate, aka AAKG, the purported nitric oxide booster is certainly not one of them and that despite the fact that there are one or two studies, which showed minuscule performance improvement from large doses of this combination of arginine and the alpha-keto acid to glutamine alpha-ketoglutarate. Against that background it is however even more intriguing that a group of scientists from the Section of Sports and Rehabilitation Medicine, Department of Internal Medicine II at the University of Ulm in Germany and a colleague from China report in a soon to be published paper in the Journal of the International Society of Sport Nutrition (JISSSN)that AKG, as in "AAKG minus arginine", and even more so its cousins KIC, KIV and KMV, the alpha-keto acids to the BCAA (thus BCKAs) are pretty potent ergogenics.

From sick people to sedentary people

Based on physiological considerations, as well as previous research that has unfortunately mostly been conducted with sick participants, Liu et al. hypothesizes that the provision of spplemental keta-acids (KAS) would be able to improve exercise tolerance, training effect, and stress-recovery in healthy subjects, as well. In order to validate this hypotheses, the researchers recruited 36 untrained male volunteers and assigned them randomly to one of the three study arms. Depending on which of the arms the subjects belonged to, they had to ingest one of the following visually identical supplement mixes

• AKG - 0.2 g/kg body weight AKG in the form of Na-AKG and Ca-AKG
• BCKA - 0.2 g/kg b.w. α-ketoisocaproate, KIC, 47.4%; α-ketoisovalerate, KIV, 30.0% and α-ketomethylvalerate, KMV, 22.6% from Na-KIC, Ca-KIV and Ca-KMV
• Placebo - energy and sodium, as well as calcium equivalent with glucose, CaCO3, NaHCO3 

twice a day; either within two hours before and two hours after their 5 training session or between 4PM and 8PM on non-training days (note: the supplementation was not discontinued in the 5th recovery week either

Endurance + HIIT-like sprinting = temporary overtraining aka overreaching

Though the protocol was specifically designed to induce a state of temporary overtraining aka overreaching, I know people who are training like this for years - allegedly no beginners, although some of them look like that... and that's not 'cause they don't supplement with AKG or KIC ;-) That aside, I am still asking myself how you can possibly sprint "all out" for 3 minutes and would discourage you copy this "HIIT-esque" exercise protocol and stick to shorter (~30s) real all out sprints /w 90-120s rest in-between

The actual training intervention lasted for 4 weeks and consisted of a standardized workout program, of which Yuefei Liu and his colleagues write that it was specifically designed to "challenge energy metabolism by achieving an 'overreaching' [aka temporary overtraining] training level" (Liu. 2012). To make that possible, the 33 untrained subjects (BMI~24kg/m²; age 25-26y) who made it through the four week protocol (three dropped out) performed the two-part exercise regimen consisting of 

• 30 minute treadmill running at the anaerobic threshold run followed by,
• 3 x 3 minute sprints (all out; HR  ≥ 95% max)

five times a week under professional supervision. The training was carefully documented, training times recorded and rest-stress-questionnaire-sport (RESTQ; cf. Kellmann. 2001) questionnaires had to be filled at the end of every training week.

The diet was comparable among the different groups and did not change throughout the study period (total caloric intake: 2509 ± 115 kcal/day; 49.2% carbs, 30.3% fats; 17.1% protein and alcohol 3.4% *wtf!*) and no other supplements were allowed to make sure that the results would not be skewed by copious amounts of sodium bicarbonate ;-)

Note: Since KAS are meant to buffer ammonia build-up while sodium bicarbonate, aka baking soda will buffer blood pH (and inhibit the formation of lactic acid), they would stack well (click here to read more about baking soda and the latest study about the beneficial effects of baking soda on high volume leg days)!

Surprising results: Longer, harder, ...

Just as the researchers had assumed, the relatively small amounts supplemental α-keto acid  (KAS), of which the scientists expected that they would reduce the exercise induced hyperammonemia (=accumulation of ammonia, a breakdown product from the oxidation of amino acids in the blood) Banister and Wilkinson held (at least partly) responsible for the fatiguing effect of longer lasting high intensity exercise (Banister. 1990; Wilkinson. 2010).

Unfortunately, the scientists don't make it 100% clear what the "training time" they measured was, but I hope that you would agree that it is sensible to assume that this refers to the timespan during each workout at which the subjects actually reached the prescribed target heart rates, i.e. the anaerobic threshold for the endurance part and 95%+ of their individual HRmax for the sprints.

Figure 1: Effect of AKG and BCKA (KIC+KIV+KMV) supplementation on exercise performance (expressed relative to target time at the given HR) in the course of the 4-week overreaching phase (data based on Liu. 2012)

In order to make the data more legible and thus easier to understand I did therefore express the figures the scientists measured relative to the maximal time the participants could have been performing at the target heart rates, i.e. 5 x 30min (150min running)  and 5 x 3 x 3min (45 min sprinting) per week, in the endurance and sprint part of their five weekly sessions, respectively. Based on the plot of these calculations (figure 1), you can easily see that the provision of the keto acids of the BCAAs, i.e. KIC, KMV & KIV, the BCKAs, were more effective than the keto acid of glutamine (AKG) in buffering the cumulative performance decrements that occurred from week 1-4.

... less exhausting and more productive

Figure 2: Somatic and emotional RESTQ-sport scores (top, middle), as well as isokinetic peak force development (Liu. 2012)

These findings are corroborated by both, the results of the weekly RESTQ questionnaires, i.e.

• the general stress levels were markedly increased in the control group during the third week, but did not change in BCKA group; a significantly higher baseline stress level in the AKG group make the data difficult to interpret, but it can still be assumed that the "stress-buffer effect" was similar to the BCKA group, as the levels remained constant over the whole 4 +1 week study period
• the somatic complaints showed a slight increase in the control group, but were overall not statistically different between the groups (see figure 2, top)
• the emotional exhaustion did increase significantly in both, the control and the AKG group, but it does not appear certain that the slight disadvantage the AKG group appears to have compared to the control group is more than statistically significant; after all, thebaseline general stress levels were also higher and could be a confounding factor here (see figure 2, middle)

as well as the performance increases in the isometric maximum torque and isokinetic maximum performance tests for the quadriceps femoris of the dominant leg, which yielded statistically significant...

• increases in torque & isokinetic strength only in the AKG and BCKA groups and

The gains in endurance capacity, on the other hand, did not differ between the groups.

Remember: Ergogenics allow you to work harder - in other words, you got to do more, not less!

Overall the data does still support something people tend to overlook and supplement manufacturers and vendors like to disguise: Ergogenics don't build muscle, strength or make you run faster over night. Regardless of the exact mechanism by which those compounds work, it in the end always the increase in training intensity and/or volume (or your ability to increase the latter faster without running the risk of overtraining), which will eventually help you to make greater or faster progress - or as the subheading says: You got to work harder / more - not less!

That said, despite the fact that AKG, did perform astonishingly well (so well indeed that the occasional beneficial study result from arginine-alpha-ketoglutarate =AAKG studies could actually be a result of the AKG part of the purported NO booster), the alpha-keto acids of the three BCAAs appear to be the better supplement choice for beginners in overreaching phases... but wait! Let's be honest, is it really advisable for a beginner to employ an advanced training technique like overreaching? And wouldn't you advice him or her to strength train if strength (remember, the only exercise parameter with significant improvements, in the study at hand) was his / her goal? I would think so...

Bottom line: The study is nice, the results are impressive, but the study population (untrained individuals) and their diets (low protein, low fat variety of SAD diet + a beer every evening *hello?*) don't really allow for conclusions to be drawn as far as the effects of keto acids, i.e. the effects of both AKG, as well as the BCKAs, on trained athletes / seasoned gymrats with adequate protein intakes on reasonable training regimen is concerned. To cut a long story short, I would not go and buy any of those keto acids before we don't have at least a single independent, peer-reviewed study that would confirm their efficiacy in a group of trainees who are at least experienced recreational athletes. It would obviously be even better to see those trainees supplement with KAS on top of a protein shake, creatine and maybe BCAAs while they eat a protein rich, nutritionally balanced whole-foods diet (like you?), but let's be honest, I don't think we will see a study like that anytime soon, ... but in case we do, you know where you are going to read about the results first, right?

References

• Banister EW, Cameron BJ:  Exercise-induced hyperammonemia: peripheral and central effects. Int J Sports Med 1990, 11(Suppl 2):S129–S142. 
• Kellmann M, Kallus KW. Recovery-Stress Questionnaire for Athletes. Human Kinetics. 2001 ISBN-13: 9780736037761  
• Liu Y, Lange R, Langanky J, Hamma T, Yang B, Steinacker JM. Improved training tolerance by supplementation with alpha-Keto acids in untrained young adults: a randomized, double blind, placebo-controlled trial. J Int Soc Sports Nutr. 2012 Aug 2;9(1):37. 
• Wilkinson DJ, Smeeton NJ, Watt PW: Ammonia metabolism, the brain and fatigue;
  revisiting the link. Prog Neurobiol 2010, 91:200–219. 

Supplement Review: Lactulose - Isomerized Lactose With Prebiotic, Anti-Constipation, -Cancer, -Hyperammonia, -Salmonella, -Endotoxin & Pro-Mineral Absorption Effects

Don't worry: There is more than flatulence and diarrhea to lactulose... I mean, why do you think I'd write about it, then?

I am not sure if all of you have already heard of 4-O-β-D-galactopyranosyl-D-fructose aka lactulose, a synthetic nondigestible sugar you can buy either as a white, odorless powder or as a syrup. It tastes, contrary to what you may expect, pretty good, a bit like hilariously sweet honey, if you asked me, and sweet enough to be used as an "artificial" sweetener. A sweetener that has traditionally been sold as a medicinal drug for decades but is not appearing on an ever-increasing number of ingredient lists of so-called "functional" food products. Despite the fact that the market has grown appreciably over the last 10 years (Panesar & Kumari. 2011), lactulose is after all not yet as "popular" as inulin and the rest of its prebiotic brethren.

From drug, to supplement to food additive

The mere fact that the easiest but certainly not cheapest way to acquire lactulose is still the pharmacy obviously doesn't imply that you can use it as any other over-the-counter (it is OTC, even in Germany ;-) supplement. And that's true in spite of the fact that your doctor may actually prescribe it, if you are suffering from hepatic encephalopathy, constipation, or salmonella (Schumann. 2002).

Lactulose content (mg/l) of milk (Marconi. 2004)

There is "natural" lactulose in milk: Due to the fact that lactulose can be produced by the heat-induced isomerization of lactose (see inset in figure to the left for a reaction curve for milk that's heated at 130°C), all varieties of heat treated milk, even the low-temperature pasteurized variety will contain a certain, albeit low amount of lactulose (see figure to the left).

If that was all lactulose was good for, it would yet probably not have made it into the SuppVersity Supplement Review. The latter is rather due to its ever-increasing presence in "functional foods", where it is used as a prebiotic for its impressive beneficial effects on the composition of the colonic microflora.

If lactulose is added to the formula milk, such babies have same composition of the colonic microflora as the breast-fed babies (Knol. 2005).

I see, now you're listening... I would suggest, then, that we take a brief look at other established and suspected benefits lactulose supplements / lactulose-enriched functional foods have to offer:

• Constipation - I already mentioned it in the introduction. If you ask your doctor about lactolose supplements, he will probably raise his eye-brow and say: "Are you constipated?" While the general recommendation is to treat constipation by increasing your water intake, the amount of fibrous foods you eat, etc. lactulose has a long history as an intermediate adjunct to these changes in patients of all ages, including babies.
  
  
  Flatulence Warning: Don't ingest lactulose before your first date with the girl or guy of your dreams ;-)
  Lactulose is an osmotic laxative. This means it will draw more water into the the colon and can thus offer relief of constipation, including chronic constipation within about 24-48h. When it reaches the intestine, the lactulose molecule is still intact. Lactulose is not digested in the small intestine as the specific disaccharidase is lacking.
  
  It transits unchanged to the colon where it serves as an energy source for the carbohydrate-splitting bacteria, predominantly lactobacillus acidophilus and L-bifidus (Saarela et al., 2003; Cardelle-Cobas et al., 2011; Hernandez-Hernandez et al., 2012).

Lactulose "feeds" the good bacteria in your gut: As you can see in the figure to the left, the continous ingestion of 5g of lactulose for 42 days lead to statistically significant increase in the  16 healthy volunteers who were included in Bouhnik et al.'s controlled, randomised, double-blind, parallel group trial (Bouhnik. 2004).

• These bacteria split lactulose into its active components that will then exert the previously mentioned osmotic effect. Unfortunately, the fermentation process, will usually give rise to some gas... especially in people who are not used to the ingestion of fibrous foods this can lead to temporary gaseous social incompatibility (aka flatulence; cf. Blanc. 1992).

• 

  Table 1: Summary of treatment, comparison and results of studies on the effects of lactulose on PSE that were reviewed by Conn et al. (1977) and Heredia et al. (1987); (+) clinical improvement, (=) no significant difference, (±) treatment lead to improvement in psychometric tests

  Portal systemic encephalopathy (PSE) therapy - According to Prasad et al. (2007) lactulose exerts significant beneficial effects on the impaired neuronal function and cognitive performance of PSE patients. In the corresponding study that involved thirty-one patients received lactulose treatment for 3 months (+30 controls who did not) the lactulose group showed significant improvements in their quality of life and emotional behavior.
  
  It must be said, though that not all pertinent studies were able to detect significant beneficial effects of lactulose supplementation on PSE. In fact, more than 50% of the studies Conn et al. (1977) as well as Heredia et al. (1987) have reviewed (see Table 1) were unable to detect a significant difference between the patients in the lactulose and those in the healthy control group.
• Salmonella - While peer-reviewed studies on the effects of lactulose in patients with nontyphoid salmonella (Schumann. 2002), there is plenty of anecdotal evidence that lactulose at dosages of up to 60 g per day (diarrhea alert!) can kill the intruders by inducing a a sharp drop of the colonic pH, which makes the survival of salmonella difficult.
• Endotoxins - As a SuppVersity reader you know that endotoxins are what you could call the "toxic poop" of the bacteria that colonize your gut. In a 2003 study Koutelidakis et al. were able to show that jaundice patients who had been pretreated with lactulose showed a significantly reduced increase in endotoxins after surgery. These observations are supported by animal experiments that have shown that oral lactulose administration reduced the mortality associated with endotoxin in obstructive jaundice. 

• 

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

  Reduction of blood ammonia levels - This effect of lactulose can actually come very handy for the average protein addicted gymrat as well.
  
  You will probably remember the article about the BCAA induced performance decrements from November 2012 ("Chronic High Dose BCAA Supplementation Reduces Endurance Performance by 43% Plus: How Ammonia, Glutamine, Arginine & Low Carb Could be Involved" | read more).
  
  If said effects are actually a consequence of the ammonia accumulation it may come handy to reduce the baseline ammonia influx from the gut by reducing its production via the acidifying effects of lactulose (Wright. 2011).
• Cancer - Not directly gym-relevant, but certainly as important is the protective effect lactulose may have on colon carcinogenesis. This type of cancer usually develops in the presence of high amounts of secondary bile salts, which could partially explain the reported lower rate of cancer recurrence in colon cancer patients who were treated with lactulose. Rodent studies by Verma & Shulka also suggest that lactulose has a direct protective effect on the DNA of the colon mucosa of rats (Verma. 2013; note: on a per gram basis inulin, which was also tested in this study was a more effective DNA protector).
  
  In addition to its (more or less) direct effects, the lactulose induced increase in bifidobacteria may also have cancer protective effects - not just in the colon, but in the mammary gland and liver, as well (Reddy. 1993)
• Enhancement of mineral absorption - When you surf through the blogosphere you will be confronted with horror-stories about the inhibitory effects all sorts of food products are supposed to have on the absorption of calcium, magnesium iron and co. Against that background it's almost relieving to know that lactulose can significantly augment the absorption of calcium, magnesium, zinc, copper, iron (Seki. 2007).

  

  Figure 1: Effects of 2g and 4g lactulose added to a standardized test meal on the absorption (measured by urinary excretion) of calcium and magnesium in 24 healthy volunteers (Seki. 2007)

  Pometto al. report that the effects are sufficient enough to exert anti-osteoporotic effects in a rodent model (Pometto. 2006). Whether the same goes for human beings hasn't been established, though.

If you review the overall effects, I guess you will be able to trace most of them back to the prebiotic properties of lactulose. The latter is a good thing, but in view of the fact that lactulose is by no means the only prebiotic with promising health effects the question is.

A word of caution to everyone out there with existing intestinal problems: As you may remember from the SuppVerstiy Facebook News Whelan et al. have only recently published a paper that reviews the the evidence that some prebiotics in high doses worsen functional symptoms in IBS and Crohn's patients. (Whelan. 2013 | cf. SvFb Post).

Do we actually need lactulose? As I pointed out in the previous paragraphs, lactulose has plenty of health benefits. It is yet questionable which, if any are "exclusive" to the isomerization product of lactose which has the nasty tendency to produce socially unwanted side effects and highly impractical such as flatulence and diarrhea.

If you don't overdo it (1-2g/day is a good starting dose) you should however be able to avoid loose stools and control the gas production. In this case lactulose can more very handy as one out of many tools you can use to increase the prebiotic content of your diet. Plus: Contrary to most other prebiotics lactulose tastes actually pretty good and can be used as a tasty and healthy sweetening agent in all sorts of products. The latter is also the reason that I expect that you will see it on more and more ingredient labels of commercially available food products in 2014 and beyond.

References:

• Aït-Aissa, A. and Aïder, M. (2013), Lactulose: production and use in functional food, medical and pharmaceutical applications. Practical and critical review. International Journal of Food Science & Technology
• Blanc, P., Daures, J. P., Rouillon, J. M., Peray, P., Pierrugues, R., Larrey, D., ... & Michel, H. (1992). Lactitol or lactulose in the treatment of chronic hepatic encephalopathy: Results of a meta‐analysis. Hepatology, 15(2), 222-228. 
• Knol, J., Scholtens, P., Kafka, C., Steenbakkers, J., Gro, S., Helm, K., ... & Wells, J. (2005). Colon microflora in infants fed formula with galacto-and fructo-oligosaccharides: more like breast-fed infants. Journal of pediatric gastroenterology and nutrition, 40(1), 36-42.
• Koutelidakis, I., Papaziogas, B., Giamarellos-Bourboulis, E. J., Makris, J., Pavlidis, T., Giamarellou, H., & Papaziogas, T. (2003). Systemic endotoxaemia following obstructive jaundice: the role of lactulose. Journal of Surgical Research, 113(2), 243-247.
• Marconi, E., Messia, M. C., Amine, A., Moscone, D., Vernazza, F., Stocchi, F., & Palleschi, G. (2004). Heat-treated milk differentiation by a sensitive lactulose assay. Food Chemistry, 84(3), 447-450. 
• Reddy, B. S., & Rivenson, A. (1993). Inhibitory effect of Bifidobacterium longum on colon, mammary, and liver carcinogenesis induced by 2-amino-3-methylimidazo [4, 5-f] quinoline, a food mutagen. Cancer research, 53(17), 3914-3918. 
• Panesar, P. S., & Kumari, S. (2011). Lactulose: production, purification and potential applications. Biotechnology advances, 29(6), 940-948.
• Pometto, A., Shetty, K., Paliyath, G., & Levin, R. E. (Eds.). (2005). Food biotechnology. CRC Press.
• Seki, N., Hamano, H., Iiyama, Y., Asano, Y., Kokubo, S., Yamauchi, K., ... & Kudou, H. (2007). Effect of lactulose on calcium and magnesium absorption: a study using stable isotopes in adult men. Journal of nutritional science and vitaminology, 53(1), 5-12.
• Schumann, C. (2002). Medical, nutritional and technological properties of lactulose. An update. European Journal of Nutrition, 41(1), i17-i25.
• Van Boekel, M. A. J. S. (1998). Effect of heating on Maillard reactions in milk. Food Chemistry, 62(4), 403-414. 
• Wright, G., Chattree, A., & Jalan, R. (2011). Management of hepatic encephalopathy. International journal of hepatology, 2011.