Science Round-Up Seconds: 8 Nootropics to Combat Stroke, Alzheimer's & Co, Boost Cognitive Performance. Plus: 7 Unknown 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 ;-)

  • 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.
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