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.

A Cup of Coffee in the Bluelight District: Synergistic Effects of Caffeine + Blue Light on Psychomotor Effects. Plus: Yerkes-Dodson and U-Shaped Dose-Response Curves

This could be your new wake-up routine: Strong coffee and a bath in blue light.

"The abuse of ADHD drugs in people from all social classes is on the rise..." I guess you will have heard or read news like these several times over the past 12 months and in an article over at Forbes.com that was published on St. Nicholas' Day, Todd Essing even claimed: "Adderall use at work by the healthy to enhance cognitive performance is back in the news." Essing cites, among others, Stephen Petrow whose article over at The Atlantic is what Essing calls "a love letter to his 2-3 times per week Adderall use" - and a scary one for Petrow who is a psychologist by trade and says of himself that he "treats lots of hard-driving career-focussed 20- and 30-somethings". (Essing. 2013)

I guess Essing, whose previous article "When ‘Study Drugs’ Kill" took a reasonably critical stance towards the use of Adderal and similar drugs by healthy individuals, will be delighted by the results C. Martyn Beaven and Johan Ekström present in their latest paper in the peer-reviewed open access journal PLOS|One (Beaven. 2013). The intention of their experiment was ...

"[....] to compare and contrast the physiological responses to blue light and caffeine, administered both separately and conjointly. Measures of cognitive function, reaction time and wakefulness were assessed and it was hypothesized that similarities would be observed with the administration of 240 mg of caffeine and a 1 h dose of ~40 lx blue light." (Beaven. 2013)

Moreover, Beaven and Ekström assumed that combining the caffeine equivalent of two small or one large, strong coffees with the 'enlightening' power of a r  ~40lx  blue light LED light source (Techlight® RGB, 3W,  λmax = 470 nm) would induce alerting and psychomotor effects greater than either intervention in isolation.

What exactly did the scientists test for? The study participants had to complete a computer-based psychomotor vigilance test protocol (PVT) that consisted of 20 trials of a visual and audio Go/No-Go test, an Eriksen Flanker test, and 5 trials of a visual reaction time task (all tasks are available online at www.cognitivefun.net, so just try them out and judge for yourself how significant they are).

In view of the fact that you will probably have read the "Sunlight à la Carte" (read more) article I published as part of my Circadian Rhythm Series, you shouldn't be surprised by either, ...

• the experimental design that involved the ingestion of a gelatine capsule containing either 240 mg of caffeine or a visually indistinguishable sugar placebo with a small glass of water (CAF), the exposure to ~40 lx of blue light from a LED light source (Techlight® RGB, 3W, λmax = 470 nm) or a white light alternative (~100 lx) for 1 h (BLU) or a combination of both, or
• the assumption that caffeine and blue light should exert additive effects on both physical and psychological measures of alertness

... the effects of both caffeine and high frequency (=low wavelength) light have after all been discussed at length, here at the SuppVersity. What struck me (and maybe you, too) as odd, initially, though, was the assumption that "eye colour would influence the degree of the psychomotor and physiological responses to blue light" (Beaven. 2013), as well.

Figure 1: Eye color determines the extent of the melatonin suppressing effects of 2h of bright light exposure during the night. The effect is significantly stronger in "dark-eyed" Asians vs. "light-eyed" Caucasians (Higuchi. 2007)

The assumption that light-eyed participants would show a more pronounced reaction to light exposure is based on observations by Higuchi et al. (2007) who observed a direct link between eye color and the decrease in melatonin secretion in response to light, when they compared the effects of 2h of nightly light exposure in "light-eyed" Caucasians "with blue, green, or light brown irises" to Asians with "dark brown irises" (Higuchi. 2007).

Contrary to what you may have expected, the suppression was increased for the Asians (see Figure 1), not the Caucasians, of whom you'd argue that their ancestors lived at a latitude, where sun is scarce in the winter time, so that you'd have to make the most of it, when it shines.

If we now turn to the results of the study at hand, we'll see that Beaven and Ekström observed a very similar trend in their study, where he increase in visual reactions in the blue light only condition was significantly more pronounced in the blue-eyed, non-shift worker, non-smoking, low to moderate caffeine and alcohol consuming study participants (13 men, 18 women) than in their darker-eyed peers.

Figure 2: Effects of placebo (Pla), blue light (BLU), caffeine (CAF) or blue light + caffeine (BCAF) on psychomotor performance in 24 (13 male, 11 female) healthy subjects with a mean age of 26 ± 4 years; as it is common in science changes that were statistically significant are marked with letters, i.e. "a", "b", "c" (Beaven. 2013)

When they took a closer look at the caffeine (CAF), blue light (BLU) and caffeine + blue light (BCAF) treatment induced performance boosting effects you can see in Figure 1, the researchers from the Mid Sweden University observed a baseline advantage in reaction times in the visual reaction time task in male vs. female study participants (255 vs 274 ms; p = 0.0172). If you scrutinize the data in Figure 2, you will also realize that Beaven & Ekström are generally correct, when they state that their experiment is the first demonstration of distinct effects of caffeine and blue light on aspects of psychomotor function - it's after all hard to deny that (a) both worked and that (b) they did not have identical effects.

Beware of the consequences of the Yerkes-Dodson law

The researchers go on to explain that "[b]oth blue light exposure and caffeine ingestion improved accuracy in the visual Go/No-Go task", but that their combination "did not result in enhancement in the number of correct responses" (see Accuracy in incongruent task in Figure 2). For caffeine alone similar effects have been observed. These observations form the basis of the"Yerkes-Dodson law", in which it is postulated that the relationship between arousal and performance follows an inverted U-shape curve (Fredholm. 1999). Consequently, Beaven & Ekström suspect that

"[...], it is possible to rationalize that the combined treatment of blue light and caffeine dose exceeded the optimal state of arousal and consequently resulted in impaired accuracy." (Beaven. 2013)

At first sight, this hypothesis appears to conflict the improved fast reaction time the researchers observed in the visual Go/No Go task, but when you come to think about it, the stimulating effect of caffeine + blue light that is an advantage, when it comes to relatively simple tasks, may well be too pronounced for an exercise that requires a higher degree of mental focus / contentration.

Learn how to use light to modulate or realign your circadian rhythm.

So what we learn from the results? Actually there are two things you can take away from the study.

• It may well be worth to add a blue light lamp to your list of birthday, not Christmas presents. You do after all you want to have it before Fall 2014.
• You would be well-advised if you remembered "Yerkes-Dodson law" and the futility of a "more helps more" approach to cognitive enhancement.

Considering the fact that it's Christmas Eve this certainly isn't too bad as far as the total amount of subject matter or its quality is concerned - right? Apropos: Merry Christmas!

References:

• Beaven, C. M., & Ekström, J. (2013). A comparison of blue light and caffeine effects on cognitive function and alertness in humans. PloS one, 8(10), e76707.
• Essing, T. (2013). Managing The Risks Of Taking Adderall To Enhance Work Performance. Forbes.com. Dec. 06 2013 < http://www.forbes.com/sites/toddessig/2013/12/06/managing-the-risks-of-taking-adderall-to-enhance-work-performance/ > retrieved on 12-24-2013.
• Fredholm, B. B., Bättig, K., Holmén, J., Nehlig, A., & Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological reviews, 51(1), 83-133.
• Higuchi, S., Motohashi, Y., Ishibashi, K., & Maeda, T. (2007). Influence of eye colors of Caucasians and Asians on suppression of melatonin secretion by light. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 292(6), R2352-R2356.
• Petrow, S. (2013). The Drugs of Work-Performance Enhancement. The Atlantic. < http://www.theatlantic.com/health/archive/2013/11/the-drugs-of-work-performance-enhancement/281055/ > retrieved on 12-24-2013.

DS Craze - An Obituary Notice From the Lab: Highly Variable Amounts of "Amphetamine-Like" Compounds in DS Craze & Gaspari's Detonate. Plus: Phenetylalamine in MP's Assault

2013's fitness craze was about Craze

Let me first get this straight: I have no intention whatsoever to comment on the reasons of the "amphetamine contamination" of Driven Sport's flagship pre-workout product Craze - I'll leave that to better informed gossipers.

I guess, I would even have let the whole issue rest forever, if Mahmoud A. ElSohly and Waseem Gul hadn't published a peer-reviewed paper earlier this week that contains much more information than the previous short lab report ElSohly sent back to his clients over at Thermolife who had commissioned his lab to test a sample of DS Craze for amphetamines and decided that it was in everyone's best interest to publicize the results immediately.

Craze is not alone, Detonate & Assault join the party - but you already knew that, right?

The paper was published under advanced access in the Journal of Analytical Toxicology on December, 15 and the main result, i.e. the fact that the researchers "found an amphetamine-like compound that's not disclosed on their labels and puts athletes at risk of being banned from competition" (USAToday.com) did even make it into the online edition of USAToday.

What is phenethylamine? Phenethylamine (PEA) is a natural monoamine alkaloid that belongs to a class of chemicals with many compounds of known psychoactive and stimulant effects (Glen. 2005). It functions as a neuromodulator or neurotransmitter (Sabelli. 1976) with similar actions as amphetamine: Norepinephrine + dopamine release (Parker. 1988; Paterson. 1993). PEA and its substituted forms NDP and ETH is rapidly metabolized when taken orally (Shulgin. 1995-2009).

I guess by now few of you will be surprised that Craze was not the only supplement, of which  ElSohly and his colleague, Waseem Gul, from the University of Mississippi found that it contains "undisclosed amounts" of "amphetamine like substances".

What's the cause of the random fluctuations in "amphetamine-like" compounds

If you take a look at the data in Table 1, it does however become obvious that the total amount of "amphetamine-like" compounds in one cap of Gaspari Nutrition's fat burner / energy supplement Detonate is significantly lower than the varying amounts of N-ethyl-a-ethylphenethylamine aka ETH and phenethylamine aka PEA (also b-phenethylamine, or phenylethylamine) in a 5.5g serving of the tested LOTs of DS Craze - in the worst (or best?) case the latter contained ~80mg of either one or a combination of both agents.

Table 1: List of the analyzed products + ETH, phenethylamine & N, N-diethylphenethylamine contents (ElSohly. 2013)

If we compare the different lots of Craze, it does also become obvious that both, the ratio of ETH : phenethylamine, as well as their total value varies. There does yet not appear to be a distinct pattern, like ever-increasing or decreasing PEA levels. It's thus unlikely that someone changed the formula purposefully. Rather than that, the following explanations come to mind:

• 

  On a side note: A big belly is a greater threat to our brains than Craze | more

  The source of "contamination" is actually a source of contamination, i.e. PEA and ETH occur randomly in some batch of raw ingredients DS got from God knows where in China.
• The assay the researchers developed is not accurate, or at least not as accurate as their (albeit sophisticated) tests would suggest, i.e. the day-to-day variability was significantly higher than the 9.8%, and 3.1% the researchers measured using a low and high dose control sample.
• Someone at DS was super smart and thought: "If the effects of these ingredients are similar, I will just randomize the exact dosage, to make sure that it looks as if it was accidentally contaminated".

I guess you could come up with more speculations, but actually those three are already more than I had intended to present. I will thus close this somewhat inglorious chapter of supplement history with a brief hint on the red circle in the utmost right column of Table 1.  The circle indicates that the two known suspects, i.e. Detonate and Craze were not the only PEA offenders; and I wonder, if MusclePharm knew that, when they suddenly reformulated their best-selling preworkout product Assault a couple of weeks...

What? Oh, yes, I start gossiping, again. Sorry! But that's just human; or, as R.I.M. Dunbar from the University of Liverpool has it, it's evolutionary preserved and an "important a component of human interaction" and displays "a mechanism for bonding social groups, tracing these origins
back to social grooming among primates." (Dunbar. 2004)

PEA Alternatives: "Theanine or Caffeine? Soda, Black or Green Tea? What's Going to Get Your Brain Going?" | more

Bottom line: As the last lines of today's SuppVersity article tell you, it's just human that there was such a craze about Craze. If we are honest with ourselves, it's "much ado about nothing", anyway.

As far as I know nobody got physically harmed and the amounts of PEA and ETH in Craze are not exactly so high that you'd have to be afraid that you could have killed a couple of brain cells with it. And unless he or she found a way to inject the PEA equivalent of ~100g of Craze right into his /her veins, it's unlikely that he or she'd die (the figure is calculated based on the LD50 in rodents, so I would not rely on its accuracy; cf. Lands. 1952 ;-) ...

Don't get me wrong, I don't intend to play the whole case down, but let's not get carried away, here.

References:

• Dunbar, R. I. (2004). Gossip in evolutionary perspective. Review of general psychology, 8(2), 100. 
• ElSohly, M. A., & Gul, W. (2013). LC–MS-MS Analysis of Dietary Supplements for N-ethyl-α-ethyl-phenethylamine (ETH), N, N-diethylphenethylamine and Phenethylamine. Journal of Analytical Toxicology, bkt097.
• Glen, R., Hanson, P.J., Venturelli, A., Fleckenstein, E. (2005) Drugs and Society.9th edition. Jones and Bartlett Publishers: Sudbury, MA. ISBN 978-0-7637-3732-0 Retrieved 2011-04-19. 
• Lands, A. M., & Grant, J. I. (1952). The vasopressor action and toxicity of cyclohexylethylamine derivatives. Journal of Pharmacology and Experimental Therapeutics, 106(3), 341-345.
• Parker, E. M., & Cubeddu, L. X. (1988). Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. Journal of Pharmacology and Experimental Therapeutics, 245(1), 199-210.
• Paterson, I. A. (1993). The potentiation of cortical neuron responses to noradrenaline by 2-phenylethylamine is independent of endogenous noradrenaline. Neurochemical research, 18(12), 1329-1336.
• Sabelli, H. C., Mosnaim, A. D., Vazquez, A. J., Giardina, W. J., Borison, R. L., & Pedemonte, W. A. (1976). Biochemical plasticity of synaptic transmission: a critical review of Dale's Principle. Biological psychiatry, 11(4), 481-524.
• Shulgin, A., Shulgin, A.Erowid Online Books: ‘PIHKAL’ - #142 PEA. Transform Press: Berkeley, CA. < http://www.erowid.org/library/books_online/pihkal/pihkal142.shtml > (20 Dec 2013, date last accessed)

Science Round-Up Seconds: Follow-Up on Gum Arabic for Fat Loss. DMAA or Schizandra, Which Caused a Stroke in a Young Soldier? Low Doses of Resveratrol Better Than High Ones? Vitamin E Keeps Diabetic Brains Intact.

When it's served like this, Gum Arabic looks more like a healthy snack than a weight loss adjuvant.

I guess everyone who has already listened to the podcast of yesterday's show or was even able to listen live, will have noticed that the audio quality - yet not my German accent - have improved significantly, now that Carl and I did eventually switch to Skype instead of the landline. I know, you have been telling me that all along... be that as it may, unless my Internet connection hangs up for whatever reasons we will continue to do the SuppVersity Science Round-Ups via Skype from now on. Apropos, there will definitely be another show next Thursday (assuming that the world did not collapse by then ;-)

Follow up on Gum Arabic: Dosing & mechanism

In addition to that, I was actually presently surprised how much ground we were able to cover. Allegedly, we have gone way over the scheduled 60min, and I guess I could have said a couple of additional words on the Gum Arabic study and the astonishing fat loss results what I did mention was that it works astonishingly well, what I did not tell you about - or I have forgotten I did (too little caffeine I guess ;-) - is the dosage and the mechanism of action. At least as far as the former is concerned there is no debating that the fat loss magic (-2.1% from ~20% body fat to ~18% in 6 weeks; cf. Babiker. 2012) happened with just 30g of the substance that's derived  from exudates of Acacia senegal or Acacia seyal trees per day. Oher than the diarrhea and bloating, I did already mention on the show, the on average 19-year old perfectly healthy young women in the active arm of the study complained about nausea (82% in the first week) and an  "unfavourable oral viscous sensation" (100% in the first week). The latter is particularly interesting, because it does actually give us a hint on the underyling mechanism which is "not yet fully elucidated, because of a small number of conducted studies" (on its weight loss effects, but could be related to the increase in plasma leptin (without resistance obviously) as well as the increased fatty acid oxidation in muscle tissue in response to viscous fiber ingestion Islam et al. have reported only recently in Obesity (Silver Spring) earlier this year (Islam. 2012). I guess that we are going to see follow up studies on this one pretty soon and you all know that the Science Round Up and of course the SuppVersity news is where you are going to read about them first ;-)

Now that we lost the working weight loss adjuvants behind us, let's get to one which doesn't have any record of helping with weight and was still in each and every fat burner on earth before it was banned: DMAA (1,3 dimethylamylamine) aka geranium oil or geranium extract.

DMAA induced stroke in young soldier!? Or is it maybe the Schizandra that's to blame?

We all know that the job of a soldier is dangerous. A recently published case-report in Military Medicine does yet show that these dangers may not always be due to standing in the line of fire, but can also arise as a consequence of having too much DMAA supplements in your stash (Young. 2012) :

Is schizandra to blame? While the data is in fact scarce and the overall understanding of it's effects would suggest that the TCM herb would rather protect than harm the brain, it is at least worth noting that (a) schizandra has been found enhance the stimulation of the dompaminergic system (Chang. 1991) and (b) that we know that the abuse of cocaine has very similar effects on neurotransmitters (Prakash. 1993) and is associated with an increased risk of hemorrhagic stroke (Kousik. 2012)

"A 26-year-old male was presented to a military treatment facility in Afghanistan shortly after taking a weight-lifting supplement called Jack3d with a severe headache and was subsequently found to have suffered a Dejerine-Roussy variant right thalamic hemorrhagic stroke. Jack3d active ingredients include geranamine, schizandrol A, caffeine, β-alanine, creatine monohydrate, and L-arginine α-ketoglutarate. A literature search revealed case reports suggesting some of the constituent ingredients may predispose to stroke and hemorrhage and also revealed a substantial paucity of data existed regarding schizandrol A, a herb used in traditional eastern medicine." (Young. 2012)

Now, you always have to take case reports like this with an appropriate amount of skepticism - specifically, when the subject has a personal interest of not disclosing all the "supplements" he may have been taking in order not to lose is job. That being said, you know my take on DMAA from the round-table discussion with Patrick Arnold, Kurtis Frank, and one of the guys from Ergo Log. Bottom line: There really isn't any reason to be pissed of by the ban. Even if it's not to prevent stroke, it will prevent the onset of chronic fatigue syndrome in many aspiring physical culturists.

A re-appreciation of vitamin E and resveratrol

"Regular" vitamin E, i.e. alpha tocopherol, has gotten somewhat of a bad rep as of late and whenever resvertatrol is found to produce any the myriad astonishing health effects scientists have identified, it's either these effects occur either in the petri dish or in a rodent model with (often injected) mega-doses you imply couldn't afford taking on a regular basis. In this regard, a recently published paper which reports profound reductions in the fatty acid synthase, and fatty acid oxidation in the livers and adipose tissue of mice in response to a 0.005% resveratrol enriched high fat chow (this would be ~36mg/day for a human) is yet more than only an exception to the rule (Cho. 2012).

Figure 1: Metabolic effects of high fat diet (HFD) or HFD with two different doses of resveratrol; data expressed relative to mice on a standard diet (Cho. 2012)

I mean, take a look at the effects this low dose had compared to the 4x higher dosing in a second group of mice who received the human equivalent of ~142mg/day (see figure 1). Is this really another instance where more does not only yield no additional benefits, but actually reduces the effect (incidentally, de la Lastra et al. have discussed the pro-antioxidant effects of high doses of resveratrol in 2007 already; cf. de la Lastra. 2007)? Or is this just because "mice are no little human beings" and the results are therefore meaningless for us?

If you believe the latter is the case, I suggest you simply scroll down to the overview of some recent facebook news instead of reading how the adminstration of vitamin E to alloxan-induced diabetic rodents (standard model for type II diabetes) did ameliorate the shrinkage of Purkinje cells and apoptosis of cells in the granular layer, the mitochondrial defects, the splitting  of the myelin sheaths and widening axonal spaces, as well as the decrease in the number of GFAP-positive astrocytes (those that still produce a protein, namely GFAP that's responsible to keep their structure intact) in the cerebellar cortex (Mohammed. 2012)

 + + + + + + + + + + + + + +

That's it for today: You know the holiday season is coming so having too many Seconds isn't a particular good idea these days. If you still need something I suggest you pick one of the easily digestible Facebook news, for example...

• GI, GL and cancer risk - While there are statistically significant associations, only the ones for the glycemic load, which adds another quality factor namely GI + carbs per 100g to the equation, appear to have real world significance, though (read more)
• Folic acid in pregnancy - It's not all gold that glitters in ads and carries the letters "RDA". Among the profound epigenetic effects that have been observed in rodent studies, some sound as if they were from a list of the most rampant current pathologies (read more)
• Adiposity will shrink your brain - Leptin resistance is associated with reduced brain volume, associations persist even when they are corrected for BMI (read more)

You know there is more and there is even more to come. So in case the world does not explode within the next hours you know where to go if you are bored waiting for the "Zombie Repopulation" to happen.
 
References:

• Babiker R, Merghani TH, Elmusharaf K, Badi RM, Lang F, Saeed AM. Effects of gum Arabic ingestion on body mass index and body fat percentage in healthy adult females: two-arm randomized, placebo controlled, double-blind trial. Nutr J. 2012 Dec 15;11(1):111. 
• Cho SJ, Jung UJ, Choi MS. Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice. Br J Nutr. 2012 Dec;108(12):2166-75.
• de la Lastra CA, Villegas I. Resveratrol as an anti-oxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans. 2007;35:1156–1160.
• Islam A, Civitarese AE, Hesslink RL, Gallaher DD:  Viscous dietary fiber reduces adiposity and plasma leptin and increases muscle expression  of fat oxidation genes in rats. Obesity (Silver Spring)2012, 20(2):349–355.
• Kousik SM, Napier TC, Carvey PM. The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation. Front Pharmacol. 2012;3:121.
• Prakash A, Das G. Cocaine and the nervous system. Int J Clin Pharmacol Ther Toxicol. 1993; 31:575–581.
• Young C, Oladipo O, Frasier S, Putko R, Chronister S, Marovich M. Hemorrhagic Stroke in Young Healthy Male Following Use of Sports Supplement Jack3d. Military Medicine. December 2012; 177(12): 1450-1454(5).
• Zhang L, Niu X. [Effects of schizandrol A on monoamine neurotransmitters in the central nervous system]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1991 Feb;13(1):13-6.

Some Things Fishy: Oxidized Fish Oil Totally Benign!?Plus: The Inflammatory Side of EPA and Peroxide & Alkenal Levels in Commercial Fish and Vegetable Oils.

Image 1: Surströmming, a Swedish delicates is essentially rancid fish and it stinks exactly like that. Now, the results of a recent study show that the rancidity does probably not compromise the health benefits of the fish... so if you like it, go for it!

You know that whenever something is so (over-)hyped like fish oil or vitamin D that rings an alarm with me and when I hear "experts" on popular podcast say things along the lines of "as long as you take your fish oil that can compensate for a whacky diet", this is totally burning me up. Yes, there is conclusive evidence that for someone who has damaged his/her body by years and years of omega-6 over-consumption the inclusion of even "high" dose (I consider 5-6g high!) fish oil supplements can make sense, but NO, it will neither allow you to keep eating the same crap that has brought you to where you are at now, nor (and I think this is even more important for most of the SuppVersity readers) is there conclusive evidence that a healthy, active and lean human being is not way better off by limiting his total PUFA intake instead of popping grams of highly oxidizable n-3 fatty acids from fish oil caps.

Highly oxidizable? Yes! Dangerous? Surprisingly not!

A pros pos "highly oxidizable", the argument that polyunsaturated fatty acids (PUFAs) are readily oxidized not only in your body, but even at the shelves of your nutrition store, is one of the few possible caveats of fish oils supplementation even fish oil enthusiasts will acknowledge. After all previous animal studies have shown that diets rich (5%) in rancid (=oxidized) fish oils lead to increases in thiobarbituric acid-reactive substances (TBARS) levels and elevate liver specific transaminases, as well as the alkaline phosphatase (ALP) levels in the plasma of rats (detrimental effects which can by the way be ameliorated by taurine supplementation, cf. Hwang. 2000). The results of a recent study by Inger Ottestad and colleagues from Norway may thusly surprise the "pro-fish oil"-faction about as much as they surprised me (Ottestad. 2011): The ingestion of 8g of oxidized (peroxide value: 18mEq/kg; ansidine value: 9) fish oil (1.6g EPA+DHA) did not have any unfavorable short term-effects in previously healthy individuals.

Figure 1: Serum (left, 8-iso on secondary axes was measured in urine) and erythrocyte (right, GPx on secondary axes) markers of oxidative stress in 68 healthy subjects who were randomly assigned to ingest 8g of "fresh" fish oil, oxidized fish oil or high oleic-acid sunflower oil per day for before (pre) and after (post) the 7 week intervention (data adapted from Ottestad. 2011)

If you take a closer look at the measured levels of serum (4-hydroxy-2-hexenal: 4-HHE, 4-hydroxy-2-nonenal: 4-HNE, alpha-tocopherol,  high-sensitive C-reactive protein: hsCRP and 8-iso-PFG2a, the latter in urine) as well as erythrocyte (total GSH, 4-hydroxy-2-nonena: GR, CAT and glutathione peroxidase: GPx) markers of oxidation before and after the 7-week intervention (cf. figure 1), it is quite obvious that there were no statistically significant oxidation-related changes in the concentrations of the measured markers of oxidative stress, of which the scientists state that they are the current, yet debatable, "gold standard" for in vivo studies.

Figure 2: Changes in n-3 and n-6 levels and the n-6/n-3 ratio (small graph) in the course of the study period (data calculated based on Ottestad. 2011)

It is thus not really surprising that both fish oil groups experienced virtually identical (and highly favorable) -50% reductions in the ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids. Moreover, ...

[a]fter 3 and 7 weeks of intervention, the plasma level of EPA, docosapentaenoic acid and DHA were significantly increased in both fish oil groups compared to the HOSO group, but no significant difference in EPA, doc-osapentaenoic acid and DHA between the FO and oxFO groups was observed.

The scientists are thusly right to conclude that their results do not support the often-heard hypothesis that higher intakes n-3 long-chain fatty acids could increase in vivo lipid peroxidation and more importantly, that ...

[...] the content of hydroperoxides in fish oil supplements, even with a PV that exceeds the European Pharmacopeia for marine n-3 oils, does not apparently influence the plasma level of n-3 FA.

With regards to the obvious differences to previous animal studies, the scientists state that secondary oxidation of hydroperoxides, which are then absorbed in the intestine has until now been observed in animal and cell studies. In view of the relative short duration of the study and the reliance on healthy subjects, it is also questionable whether identical results would have been achieved, when sick patients (the usual customer group at least for the pharma-grade n-3 supplements) had been treated with the same product for years.

Oxidized fats in fish oil and beyond

It is also worth mentioning that Ottestad et al. are not sure, whether their "aritifically oxidized" fish oil (oxidation was achieved by sparkling pure oxygen through the oil for 20 min twice a day for 21 d) was an appropriate model for commercially available (oxidized) fish oils. After all, there could be major differences in the composition of the oxidation products, when the oils go rancid over months or get damaged by heat etc. While I obviously cannot answer this question without setting up my own lab, I can however tell you that another recent study by Halvorsen et al. who examined the peroxide and alkenal (one of the major products of secondary oxidation) content of fish and vegetable oils, found average peroxide levels in 33 commercially available fish oil products (mean PV: 3.61mEq/kg) that were ~500% below the ones of the oxidized fish oil (18mEq/kg) in the Ottestad study.

Figure 3: Mean peroxide and alkenal values of 33 commercially available fish and 35 vegetable oils (Halvorsen. 2011).

In this regards, fresh vegetable oils, obviously are way in front, as the data from a study by Bente Lise Halvorsen and Rune Blomhoff clearly shows, that they have lower peroxide and much lower alkenal levels than fish oils (cf. figure 3). Interestingly, vegetable oils are also less prone to being oxidized during storage, something Halvorsen and Blomhoff conclude based on the absence of the "negative correlation (r=−0.557, p<0.001) [...] between the number of days until expiry and the PV [peroxide value]" they observed in the marine omega-3 oils.

Figure 4: Peroxide (PV in mEq/kg) and alkenal (in nM/ml) levels in fresh vegetable oils and after being heated for 25 minutes at 225°C in an oven (data adapted from Halvorsen. 2011); solid red line - maximal peroxide value for olive oils, dotted red line - maximal peroxide values for fish oils as suggested by Turner et al. (Turner. 2006)

Contrary to fish oils, which are usually taken "fresh" and in a capped form, the main fate of vegetable is however to be (ab-)used as cooking / frying oils. During the heating process, the amount of secondary lipid oxidation products, the alkenals, doubles or quadruples depending on the type of oil (cf. figure 4). In that, it may at first seem counterintuitive that, when the scientists heated the samples for 25 minutes at 225°C in an oven, the amount of primary oxidation products was slightly reduced in most, but not all (e.g. soy bean oil) of the 11 vegetable oils. If you do yet take into consideration that the latter are the "raw material" for the secondary oxidation products, it becomes quite clear that this is not a desirable process ;-)

Image 3: Extra virgin olive oils (EVOOs) have generally higher peroxide values than the cheap refined stuff, and yet, EVOOs and not refined oils have been shown to exhibit numerous health benefits.

Putting peroxide values (PV) into perspective: All potential health hazards aside, it may be interesting to know that the general "rule of thumb" says that a fat is rancid when the PV is about 10 meq/kg (the fish oil in the study with PV=18 was thusly "rancid"). A fresh and refined product on the other hand should have PV below 1 meq/kg (Gunstone. 1996). That being said, it may surprise you that for high quality extra virgin olive oils, the PV limit is 20meq/kg, while for "regular" olive oil it is only 10 meq/kg. If you know look at studies related to the health benefits of refined vs. extra virgin olive oil, you will have to admit that - quite obviously - fish oil apparently is not the only oil, where increased peroxide levels do not negate the beneficial health effects of the oil.

So, if pure vegetable oils are generally "fresher" than fish oils does that mean that as long as you do not heat them, they are the better choice? No, they are not! I mean, look at the research that is out there... the abundance of n-6 fatty acids in the "healthy" vegetable oils that are getting pimped especially by the US government, is at the heart of an epidemic of which the authorities still claim that it was caused by high cholesterol levels. Instead banning all saturated fats from YourPlate (which should never look like the governments MyPlate ;-), you should rather incorporate more coconut oil and saturated fats from butter, beef etc. into your diet. Select (vegetable) oils that are relatively high in mono-unsaturated fatty acids, like extra virgin olive oil (don't care about its high peroxide value, cf. red box above) and try to reduce the amount of n-6 fats you ingest - you will get more than enough even from grass-fed meats, olive and other oils and any processed foods that may still be part of your diet, anyway.

Image 4: Not all Omega-3 are created equal. We know for some time that DHA (not EPA) is what your brain needs and a recent study from Norway suggest that eicosapentaenoic acid (EPA) is actually pro- not anti-inflammatory at a cellular level. It may yet well be that this in turn triggers a beneficial hormetic response which would support my "fish oil = exercise in a pill hypothesis"

Although this is not directly related to the topic of oxidation I still want to add that another study appears to confirms my long-cherished skepticism towards EPA (most fish oils have a 2:1 EPA to DHA ratio), which, as a recent study from Norwegian scientists shows (Myhrstad. 2011), is not really "beneficial super-antioxidant" people are led to believe. In their trial the scientists fed 14 healthy female volunteers test meals. The cakes the participants ate were enriched with either flaxseed, cod liver or coconut oil and the intention of the study was to elucidate differential effects of meal fatty acid composition on inflammatory markers. Not to my, but probably to the scientists surprise the "evil" saturated fat from the coconut oil turned out to be similarly benign as the flaxseed cake. Only the EPA-laden cod liver oil cake produced a statistically significant increase in IL-8 mRNA levels 6h post ingestion. Similarly, incubation of peripheral blood mononuclear cells with EPA, yet not ALA lead to >3x increase in IL-8 and >2x increases in IL-6 mRNA expression.

While I am not quite sure what to make of these observations, these results stand in line with previous studies reporting differential effects of EPA vs. DHA rich fish-oils, where across the board, the DHA appeared to be the major driving force of the beneficial health effects people hope to be getting from their fish oil caps (e.g. brain health, Engström. 2009).

Fish oil caps can be a good addition to this regimen specifically for those who are just about to start out on a low omega-6 diet to offset the skewed n-6 to n-3 ratio (something that takes its time). They are yet by no means obligatory for someone who eats fish on a regular basis and invests the extra bucks into grass-fed beef and eggs from pastured chicken. If you thusly satisfy your (anyway low) dietary DHA requirements... and most importantly, taking fish oil will not compensate for eating shitloads of processed foods and lack of exercise, even if the aforementioned pro-inflammatory effects of EPA support my previously uttered hypothesis that fish oil has some resemblance to "exercise in a pill".

Theanine or Caffeine? Soda, Black or Green Tea? What's Going to Get Your Brain Going? Plus: What About Sleep?

Caffeinated soft drink, coffee or tea, caffeine alone or caffeine + l-theanine what's going to yield the desired afterburner effect for your brain? The answer to this question came out probably less straight forward than you'd expected.

"L-theanine, coffee or both? What's going to get your brain going?" That's the question form the title of today's SuppVersity article and it's a question with an astonishingly simple answer:  Both!

I guess you will be well aware that both caffeine and l-theanine have scientific evidence to support their usefulness as cognitive enhancers (Quinlan. 2000; Hindmarch. 2000; Nathan. 2006). Their interactions however have not been studied that extensively.

It's thus worth to take a closer look at the data Hira Zameer et al. collected for their most recent paper in the International Journal of Endorsing Health Science Research - data on the effects these agents can have on the cognitive performance and reaction times of 87 healthy young women (18-19 years), when they are consumed as part of hot and cold beverages (Zameer. 2013)

Compare to caffeine, which is literally on everyone's lips, only few people actually know what l-theanine is. Quite often you will see it being mislabled as the "the caffeine in tea" and that despite the fact that it is not even a methylxanthine, but (as the "L-" already suggests) an amino acid. Against that background it appears prudent to start today's SuppVersity article with a mini-summary of the the (astonishingly few) things we know about gamma-glutamylethylamide or 5-N-ethyl-glutamine, an amino acid and a glutamic acid analog that's - who would have guessed that - primarily found in tea.

L-theanine - the "tea caffeine"!?

L-theanine has gained quite some attention in the field of neuroscience. Kakuda et al., for example report significant neuroprotective effects in their 2002 paper. Protection is however not the only thing l-theanine can do for you. Previous studies have shown that it has direct beneficial effects on the activity of alpha frequency band (8–14 Hz), the cellular pacemaker of the human body (Kobayashi, 1998; Juneja, 1999).

Not to be confused: L-Theanine vs. theacrine as in "Theacrine Will Get You Going - Every Day! Camellia Kucha Alkaloid Acts via Dopamine and Adenosine" | more

In this context it's important to know that l-theanine has, in contrast to many other agents, the ability to cross the blood-brain barrier. It does so relatively easily, but not rapidly: Based on the current scientific evidence it takes ca. 30 minutes from the moment of its ingestion, before the first changes in neurotransmitter levels can be observed.

Structurally, L-theanine is similar to the excitatory neurotransmitter glutamic acid (Nathan. 2006). Consequently, L-theanine has the ability to antagonizes the central effects of glutamate by inhibiting glutamate reuptake and blockade of glutamate receptors in the hippocampus (Kakuda. 2002). This process goes hand in hand with an increased release of the "calming" neurotransmitter GABA and a concomitant decline norepinephrine levels.

In view of its GABA-ergic effects, it's not really surprising that L-theanine has also been found to ameliorate the blood pressure rising effects of caffeine and tone down the CNS responses (Eschenhauer. 2006) - quite a neat effect for an agent you get for free with your daily dose of caffeine in tea, isn't it?

Don't be fooled - tea will also mess with your sleep quality, but as data from an Y2K study by Hindmarch et al. shows, "day-long tea consumption produces similar alerting effects to coffee, despite lower caffeine levels, but is less likely to disrupt sleep." During the study (results see figure on the left), the drinks were administered on four occasions during the day (0900, 1300, 1700 and 2300 hours).

In subjects who had to perform a standardized series of stressful tasks, L-theanine has been shown to reduce the heart rate and salivary immunoglobulin A release via direct inhibition of the excitation of cortical neurons (Kimura. 2007). With the close connection between stress exposure, the activation of the sympathetic nervous system and the ensuing release of vasoconstricting hormones, it is not unlikely to assume that L-theanine's blood pressure lowering effects are a simple result of its ability to buffer the CNS activity and reduce the adrenergic tone (Kulkarni. 1998; Matthews. 2004).

Enough of the past, let's get to the most recent results

Now that you are in the know about some of the most prominent effects of l-theanine consumption, let's see how it fares in a direct comparison to everyone darling - caffeine!

Figure 1: Effects of soda, (black) tea and green tea ingestion on reaction time, concentration test performance, blood pressure and heart & pulse rate (Zemeer. 2013)

I already mentioned that the subjects, 87 young adult females (18-19 years of age) were randomly assigned to three groups

• Group A consumed a cold beverages in the form of soft drinks (caffeine only)
• Group B consumed a serving of black tea (caffeine + l-theanine)
• Group C consumed a serving of green tea (min. caffeine + l-theanine)

Before and 45 min after the beverage ingestion the scientists monitored the cardiovascular and neurophysiological responses. After the "immediately post" data had been collected, all participants engaged in a series of standardized reaction time and concentration tests that yielded astonishingly similar results:

• Both tea preparations "proved to be more sufficient in enhancing concentration and focusing power of the individuals by reducing the distractions during a task at hand" (Zemeer. 2013)
• The concentration levels during a passage reading task in the tea condition were likewise significantly higher (p < 0.05) than in the soft drink condition, which had only marginal effects on the subjects' ability to focus.

The analysis of the cardiovascular parameters, on the other hand, showed that all groups experienced a decline in systolic blood pressure, surprisingly,

Ever wondered about the "exact" pharmacology of caffeine? Tom Edwards captured it in 1990.

"[...] a significant reduction in systolic blood pressure by 13 and 19 mm Hg was evident amongst the candidates of group A and C who were assigned for the intake of soft drink (caffeine) and green tea (L-theanine), respectively (p < 0.05) as compared to individuals who were belonged to tea (caffeine + L theanine) consumption group. Similarly, a considerable decline in diastolic blood pressure by 12 mm Hg was more noticeable among the participants who were subjected to consume soft drink (caffeine) and green tea (L-theanine) (p < 0.05) as compared to the group B, tea consumers.

Physiological rise in the heart rate of the individuals was observed when their basal heart rates were taken before and after consumption of hot and cold beverages. But a less significant rise in heart rate by 1bpm was remarkable among group C (L-theanine) candidates (P=0.31). In contrast to heart rate, a significant increase in pulse rate by 10 bpm was reported within the members of group C, green tea (L-theanine) consumers (P=0.01). " (Zemeer. 2013)

If you look back at my brief summary of the current data on l-theanine in the upper part of this article, you will probably find the increase in blood pressure and the modulatory effects on the heart rate of the subjects odd - in the end, it is however perfect evidence that the effects of neurotransmitters and agents that can influence their levels and ratios are hard, if not impossible to predict. As with GABA (see "SuppVersity Science Round-Up: Paradoxical Effects of GABA. Plus: GABA-Alternatives" | read more) it may thus well be that tea really psyches you up and a "simple" coffee, where caffeine runs the whole show, is much better suited for you than a huge cup of black or green tea.

SuppVersity Suggested Read: "Green Tea Extracts for Building Strength & Size and Losing Weight - Fact or Fraud? Or, Why It is Always Worth Taking a Look at the Data that Is NOT in the Abstract. " | read more

So what do we make of these results, if the effects are so "difficult to predict"? Unlike the prediction the answer to this question is actually surprisingly straight forward, because all uncertainties aside, the study at hand did eventually confirm what most people know from their own experience: Tea, unlike coffee has a stimulatory, yet calming effect and is thus slightly more useful, whenever you are looking for focus and mental clarity.

If you want to tear down the gym, the rather aggressive and agitating effects of "unbuffered" (=no l-theanine around) of caffeine should be your first choice - unless, of course, the agitation turns into anxiety and instead of hammering away curl after curl you find yourself sitting on the bench shivering of negative excitement.

References:

• Eschenauer G, Sweet BV. Pharmacology and therapeutic uses of theanine. Am J Health Syst Pharm. 2006 Jan 1;63(1):26, 28-30.
• Hindmarch I, Rigney U, Stanley N, Quinlan P, Rycroft J, Lane J. A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality. Psychopharmacology (Berl). 2000 Apr;149(3):203-16.
• Nathan PJ, Lu K, Gray M, Oliver C. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006;6(2):21-30. 
• Kakuda T, Nozawa A, Sugimoto A, Niino H. Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors. Biosci Biotechnol Biochem. 2002 Dec;66(12):2683-6. 
• Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007 Jan;74(1):39-45.
• Kulkarni S, O'Farrell I, Erasi M, Kochar MS. Stress and hypertension. WMJ. 1998 Dec;97(11):34-8. Review.
• Kuriyama S, Shimazu T, Ohmori K, Kikuchi N, Nakaya N, Nishino Y, Tsubono Y, Tsuji I. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA. 2006 Sep 13;296(10):1255-65.
• Quinlan PT, Lane J, Moore KL, Aspen J, Rycroft JA, O'Brien DC. The acute physiological and mood effects of tea and coffee: the role of caffeine level. Pharmacol Biochem Behav. 2000 May;66(1):19-28.
• Zameer et a.. Comparative Effects Of Caffeine & L-Theanine Consumption On Subjective Cardiovascular Signs And Neurophysiological Responses. International journal of endorsing health science research. 2013; 1(1): 38-42.

Measuring Overtraining; Phosphatidic Acid to Potentiate the mTOR Effects of Leucine? Plus: Built-in Serm in Menopausal HRT Blocks Breast Cancer, Creatine Bumps Up Performance Not Body Weight, Estrogen Timing & Brain NDMA Toxicity

Weight-supported sports such as cycling precipitate overtraining

"20%", that's the SuppVersity figure of the week. It tailors directly to the first item in today's installment of On Short Notice and denotes the amount of professional athletes who exhibit symptoms of overtraining syndrome at any given time in their career.

"The prevalence varies by sport and is thought to be highest in endurance sports requiring high volume intense training, such as swimming, triathlon, road cycling, rowing and, to a lesser extent, distance running."  (MacKinnon. 2000)

What all those sports (except for distance running) have in common are long training hours on 6 days per week for several months without appreciable time off. Notably, the chances of overtraining also increase, when the equipment supports your body mass. With weight-bearing activities, such as distance running, on the other hand, the risk of musculoskeletal injury limits training volume and therefore reduces the chance of "running" (literally) into overtraining.

Overall, there is however no group of athletes that is immune to training too long, too hard and without appropriate recovery times. And yes, this goes for power sports, such as weight lifting and judo, as well (cf. Callister. 1990, Fry. 1994)!

Identifying overtraining by psychomotoric evaluation  

When you come to think of it, it does actually stand to reason: Static and dynamic tasks for finger, hand, and arm movements, as they are assessed during a  series of tests to assess motor performance are a way better yardstick to determine the stress (over-)load on the central nervous system (CNS), than simply looking at "how much ya bench". Why? The nasty, creepy and easy to overlook form of overtraining happens largely in your head and your nerves, it's not muscular. Your skeletal muscle can be fully rested, while your central nervous system is at the verge of collapsing.

What does the motor-skill test measure? (1) steadiness (one or both hands) - assesses hand unrest, tremor; (2) inserting long pins (one or both hands) - assesses rate of arm and hand movements, precision of arm-hand movements, manual and digital dexterity; (3) tapping (one or both hands) - assesses wrist-finger speed

Usually the latter goes hand in hand with other not exactly exercise related stress symptoms such as nervousness, and the inability to cope with the imposed stress and piling-up difficulties. Therefore Paul et al. required that all the one-hundred 18-25y athletes (M=65, F=35; university to international level) from various athletic backgrounds, i.e.

• hockey (14%), volleyball (14%), basketball (13%), handball (12%), football (6%), cricket (2%),
• cycling (13%),  running (11%), kabaddi (8%),  swimming  (5%),  gymnastics (1%), and sprinting (1%)

to fill out a "classic" Training Stress Scale (TSS) questionnaire as well. The TSS is a 19-item scale to check the symptoms of acute overtraining which includes a subset of questions designed to assess  the ability of bouncing back mentally after setbacks and mistakes (REB).

Figure 1: Motor performance (steadiness error duration; inserting long pins task duration; tap hits) in 100 athletes grouped into low (LS), medium (MSG), and high (HSG) groups according to their scores on the TSS test (calculated based on Paul. 2012)

As you can see in figure 1 the results of the motor performance test did not just correlate with the data from the stress test questionnaire, they also depict a very good picture of the state of the nervous system, with highly significant difference between the highly stressed and almost certainly overtrained athletes (green) and their lightly stressed peers (figure 1, blue; stress data was assessed by the aformentioned TSS test).

Professional athletes rarely end up  like Christian Bale in the Machinist but as I discussed at length in a previous post, overtraining was one of the two pillars of the crazy regimen the actor used to starve himself into a state that hardly allowed him to perform in front of the camera.

Aside from the high correlation and the confirmation of the hypothesis that psychomotoric tests could prove a valid tool to access the training status of athletes and ambitious gymrats, the investigation yielded the following main results:

• The athletes with lowest training stress symptoms showed the highest reboundability (resilience) from their mistakes. 
• Increased intensity of training stress symptoms indicates attention deficit leading to poor psychomotor performance.
• Along with physical training, psychological training has to be considered as one of the eminent aspects of overall development of an athlete.

In order to maximize athletic performance, it is therefore more or less obligatory to "carefully and timely diagnose for any signs and symptoms for physical and psychological distress" (Paul. 2012). Needless to say that the combination of the TSS and psychomotor performance test offers a way to do just that - to monitor, control and optimize the training routine.

Phosphatidic acid a novel 'mTOR potentiator' for superior gains?

I somehow forget this one in the last installment of On Short Notice, but before the first supplements are going to hit the market (two of the authors have already filed a patent back in 2011 that hasbeen  published in June 2012; see De Ferra. 2012), I thought I'd briefly discuss the results of a recently published study on the potential ergogenic and muscle building effects of phosphatidic acid (PA) by Hoffman et al. (Hoffman. 2012).

The study that was published online in the Journal of the International Society of Sports Nutrition evaluated the effects of an 8-week resistance training on 16 resistance-trained men who had been randomly assigned to consume either 750 mg of PA or a placebo.

Figure 2: Effect of 8 weeks of strength training + post-wporkout amino acid supplementation with and without  750mg phosphatidic acid  per day (left) and ratio of beneficial, trivial and negative effects of supplementation on the respective outcome parameters (Hoffman. 2012)

As the data in figure 2 goes to show you, the supplementation regimen had beneficial effects almost all of the (except for the pennation angle, btw. where greater the angles of pennation, means translates to a smaller amount of effective force transmitted to the tendon), however not a single statistical significant difference was observed. And while the scientists assessment that the overwhelmingly beneficial effect of PA supplementation on lean mass gains is "very likely beneficial", this does not change that the 750mg of PA did not add to allegedly highly beneficial effects of the workout regimen.

Figure 3: Training protocol and amino acid content (in g/100g) of the post-workout supplement (identical in both groups).

Since all particpants had taken part in identical 4-day per week, split routine resistance training programs for 8-weeks (70% of their 1-repetition maximum (1-RM) for all exercises;  90-s rest period was required between each set, for all exercises; for the exercises check out figure 3) and were advised to consume a standardized post-workout protein formula (containing 36-g amino acid and collagen protein blend) mixed in a 500 ml commercial sports drink within 30 minutes post-exercise, the supplemental confounding factors were pretty tightly controlled. If anything but the consumption of the PA supplement would have been responsible for the inter-group differences this would therefore have to be related to

• the non-supervised training sessions at the subjects respective local gyms (training logs regardless of whether they are evaluated by "certified personnel", or not, can obviously be faked), and
• the absence of a prescribed nutritional regimen (the participants kept 3-day food-logs and were advised to stay on their habitual diet; no significant differences in total intake ~3,200kcal/day; according to Hoffman et al. likewise not statistical significant, but wrt to the the changes in body composition maybe noteworthy, were the -17% lower carb and +18.2% higher protein intake in the active = PA arm of the study)

Both the missing supervision, as well as the absence of a fixed nutritional protocol would however pertain to both groups and are thus likely to average out. Plus, they actually make the study more realistic. After all, you are interested in what happens if the average strength trainee (in this case young men with a mean age of ~23years, at least 1 year of training experience and a BMI of 27.7kg/m²) and not to 10 identical clones, don't you?

"So this stuff is not useful, right?"

Figure 4: Exogenous phosphatidic acid is metabolized to lysophosphatidic acid (LPA) in the body and LPA has been shown to work synergistically w/ leucine to increase mTORC1 activity (in vitro data from Winter. 2010).

Despite the "likely" and "very likely beneficial" effects on lower body power and lean body mass, of which only the latter could maybe have reached statistical significance with a larger number of participants (with only 20 subjects, i.e. 10 per group differences need to be more pronounced to reach statistical significance). It should be quite obvious that PA is probably not the next creatine.

Maybe the increased mTORC1 expression Winter et al. have observed upon co-incubation of leucine with LPA are not pronounced enough (figure 4). Or simply not necessary with enough leucine and insulin in the blood stream. After all, the Winter study also showed that basically identical effects were observed when the cells were incubated with leucine + insulin, instead of LPA + insulin (data not shown in figure 4).

So even if oral PA acts just like in-vitro LPA synergistically with leucine to activate the mTOR pathway (Fang. 2001; Winter. 2010; figure 4), the real world benefits in the study at hand are probably about as significant as the hypothetical 500g increase in net protein retention I discussed in he protein timing news earlier this week. Whether this may change with higher and/or more frequent doses in future studies remains to be seen, though. It does at least not appear to be impossible...

Additional news

• 'Built-in SERM' could help making post-menopausal estrogen replacement breast cancer proof At least this is what the results of a recent rodent trial that was conducted by researchers from the Division of Endocrinology at the Department of Medicine of the University of Virginia Health System in Charlottesville would suggest. Even in the absence of a progestin, which does have some ameliorative effects on the pro-carcinogenic effects of estrogen, the addition of the tissue-specific selective estrogen receptor modulator bazedoxifene (BZA) to the allegedly questionable, yet still widely prescribed conjugated equine estrogen (CEE) blocked the CEE- and, in a second control study, even the more potent E₂-stimulated ductal and terminal end bud growth of mammary gland and the corresponding estrogen-responsive gene expression (Song. 2012). 

• 

  Just like any athlete, man or woman who is interested in increasing his / her athletic performance, German Olympic lifter Julia Rohde could benefit from taking regular creatine monohydrate without necessarily running the risk of having to compete in a higher weight class (img sportzentrum-flora.de)

  5g creatine monohydrate (CM) per day helps soccer players to improve their game - or, more precisely, the time they needed to complete a standardized sprint running and dribbling test. And while you will probably not be surprised that CM supplementation did not affect the accuracy of their shots, you may very well be surprised that it did neither induce greater weight gain or any other changes in body composition (Mohebbi. 2012).
  
  The latter may also be interesting for athletes competing in sports where increased muscle mass can become an issue. After all, the results Mohebbi et al. present in the latest issue of the Middle-East Journal of Scientific Research would suggest that unless your training is geared towards increased muscle gain (which is obviously shouldn't be if that would be an issue for you) regular creatine, i.e. not the sugar laden 'cell-volumizers', can help you increase your performance in the absence of the (again, only for certain people) disadvantageous weight gain.
• Whether estrogen will save your brain cells or actually exacerbate the damaging effect of NMDA exposure depends on timing I guess you will all have heard of the protective effects of estrogen against N-methyl-d-aspartate (NMDA) toxicity. Now, a group of researchers from the University of Catania and the University of Rome Sapienza,both obviously in Italy, found that only pretreatment with estrogen will provide these beneficial effects, while the co-incubation or subsequent administration of estrogen will only potentiate the NMDA-induced cell death (Spampinato. 2012)

Have a nice weekend, everyone! As far as the On Short Notice items go, that's it for today. If you want more, just check out the SuppVersity Facebook Wall. I must forewarn you, though, since I am pretty busy this weekend, I am not sure if there will be another installment of the Athlete's Triad Series, tomorrow. If that's not the case, you will however get a regular news item, so don't worry you won't get bored ;-)

References:

• Callister R, Callister RG, Fleck SJ, Dudley GA. Physiological and performance responses to overtraining in elite judo athletes. Med. Sci. Sports Exerc. 1990; 22: 816–24.
• Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J: Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 2001, 294:1942–1945.  
• De Ferra L, Heuer M, Hagerman S, Purpura S, Jäger R. Method for increasing muscle mass and strength. Filed November 23, 2011. US 2012/0141448 A1. Published on June 7, 2012.
• Fry AC, Kraemer WJ, van Borselen F et al. Performance decrements with high-intensity resistance exercise overtraining. Med. Sci. Sports Exerc. 1994; 26: 1165–73. 
• MacKinnon LT. Special feature for the Olympics: effects of exercise on the immune system: overtraining effects on immunity and performance in athletes. Immunol Cell Biol. 2000 Oct;78(5):502-9.
• Mohebbi H, Rahnama N, Moghadassi M, Ranjbar K. Effect of Creatine Supplementation on Sprint and Skill Performance in Young Soccer Players. Middle-East Journal of Scientific Research. 2012; 12 (3): 397-401.
• Paul M, Khenna N, Sandhu JS. Psychomotor analysis of athletes under overtraining stresss. Serb J Sports Sci. 2012;6(3): 95-10.
• Song Y, Santen RJ, Wang JP, Yue W. Effects of the Conjugated Equine Estrogen/ Bazedoxifene Tissue-Selective Estrogen Complex (TSEC) on Mammary Gland and Breast Cancer in Mice. Endocrinology. 2012 Oct 15.
• Spampinato SF, Merlo S, Molinaro G, Battaglia G, Bruno V, Nicoletti F, Sortino MA. Dual Effect of 17β-Estradiol on NMDA-Induced Neuronal Death: Involvement of Metabotropic Glutamate Receptor 1. Endocrinology. 2012 Oct 17.
• Winter JN, Fox TE, Kester M, Jefferson LS, Kimball SR: Phosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway. Am J Physiol Cell Physiol 2010, 299:C335–C344.