Saturday, September 29, 2012

Caffeine Protects Brain Function Against Stress & SAD Diet; Coffee Withdrawal, Anxiety & More; Giardia, Messy Subtenant W/ Gusto For Arginine; Vit B6 & n6:n3 PUFA Ratio

19 Billion Euro that's the estimated 2011 financial burden due to lung cancer, alone, here in Europe and the On Short Notice figure of the week (information based on ESMO2012 press release)
Those of you who are also following the SuppVersity facebook news, will probably recognize the figure on the right: 16,000,000,000€ or $24,419,000,000, that's the estimated economical burden due to lung cancer, alone, here in Europe (cf. "Who cares if people are dying as long as the economy is thriving?"). An enormous financial loss, and still not the reason that this is my figure of the week. Rather than the financial damage, itself, it is the tragic fact that only the latter, yet not the fate of the patients and their families, would make a valid argument, when policy makers were debating a long overdue, total and all-encompassing public smoking ban... but now for a couple of more sciency, yet not less intriguing news from the past week.



Problems thinking straight? Guess what: 3-4 cups of coffee could help :-) According to a soon-to-be-published paper by scientists from the Jordan University of Science and Technology in Irbid, Jordan, the ingestion of the human equivalent of approximately 3.8mg caffeine per kg body weight or 3-4 cups of coffee per day, can inhibit both, the stress, related as well as diet induced (we are talking of the "typical" Western diet (WD), that's both high in carbohydrates and fat) cognitive impairments (Alzoubi. 2012)... well, at least in the researchers 3-months rodent study it worked like a charm
  • learning trial: animals in the caffeine/stress, caffeine/WD, and caffeine/stress/WD groups made fewer errors, than non-supplemented stressed or WD animals; overall their performance was comparable to those of the control
  • memory tests: treatment reduced the number of error and restored short-term memory and long-term memory during chronic stress and/or WD (P < 0.05) to normal levels
With respect to the underlying mechanisms the scientists speculate that caffeine may "act mainly by inhibiting adenosine receptors" (Alroubi. 2012), which has in turn been shown to to inhibit long term potentiation (LTP) in rat hippocampal slices and disrupt the process of learning and memory at the synaptic level by blocking release of glutamate (de Mendonca. 1994).

Additionally, caffeine has also been shown to increases the expression of hippocampal brain-derived neurotrophic factor (BDNF) and its receptor, which is impaired in response to chronic stress and a hypercaloric Western diet (Aleisa. 2006; Molteni. 2004) and leads to deteriorations in cognitive performance. In the long run those effects could also contribute to the anti-dementia and anti-Parkinson's effects, I mentioned in the recent SuppVersity post on the insulin sensitizing effects of coffee.



Figure 1: While the Hedonic tone and alertness reduced to baseline on day 5 of caffeine withdrawal, the habitual caffeine consumers had >15% higher anxiety scores on day 7 after giving up on their daily dose of methylxanthine (data calculated based on Smith. 2012).
Don't worry, caffeine will also work for humans. And what's best, upon short-term withdrawl (8 days) your cognitive performance is not going to suck - at least not as much as when you are stressed or living on pizza and French fries, only. All that and a couple of interesting other results have been published ahead of print in the online version of the Journal of Pharmacology (Smith. 2012).

To probe the effects of acute caffeine ingestion on cognitive performance and the influence of previous caffeine consumption and withdrawal, Andrew P Smith, Gary Christopher and David Sutherland recruited 70 volunteers (25 male, 45 female; mean age 22.8 years). The 35 consumers (>100mg caffeine /day, mean 300mg; range 110–600 mg) were put on withdrawal and tested on day 2, alone and without caffeine, and day 8 together with the non-consumers in a double-blind placebo-controlled fashion. During the caffeine challenge, the cognitive performance was tested twice, once before and once 30min after the provision of the caffeinated beverages.

Anxious, but smart: Caffeine gives you the edge

The results of the trial clearly indicate that the ingestion of 2 mg/kg of caffeine, which were served in decaffeinated coffee or tea 30min before the testing procedures, were associated with faster simple reaction times, fewer long responses, greater detection of targets in the cognitive vigilance task, and faster encoding of new information.
"The results confirmed previous findings, with ingestion of caffeine being associated with a faster simple reaction time, fewer long responses, more targets detected and faster encoding of new information. There were no main effects of consumer status, nor were there any significant interactions between caffeine and consumer status." (Smith. 2012)
Notwithstanding, I believe that many of you will probably be more interested in the effects of caffeine withdrawal on overall withdrawal symptoms (figure 1, top), as well as the alertness, hedonic tone and anxiety (figure 1, bottom) and the cognitive performance on day 2 of the withdrawal period (figure 2, left), than in any of the well-established performance cognitive performance boost, right?
Figure 2: Performance on day 2 of withdrawal phase (w/out caffeine) and on day 8 before (w/out caffeine) and after (w/ caffeine)the ingestion of decaffeinated tea or coffee with 2mg/kg caffeine in it (data based on Smith. 2012)
As you can see on the left-hand side of figure 2 there was a minimal performance decline on day 2 of the withdrawal phase, but the latter was statistically not significant and all measured markers of cognitive function had returned to normal on day 8 (remember longer response times = worse performance!), when the resumption or first time provision of caffeine spiked the reaction times and lowered the mistakes in all tests, irrespective of whether the subjects were former habitual consumers on withdrawal, or not.

Outside of controlled experiments "real" coffee and tea do at least as well

Since a large cup of coffee contains about the same amount of caffeine the scientists simply added to decaffeinated beverages, to ensure that the drinks could not be distinguished (by their smell for example), you can simply stick to your regular coffee and if you want to enjoy similar benefits. And to be honest, in view of the plethora of benefits of chronic low dose coffee consumption, I would not even think for a second about whether or not you may be missing out on the occasional boost, when you are not "going on withdrawal" from time to time...



Figure 3: W/out arginine (Arg-) intestinal epithelial cells can't proliferate (graph based on Stadelmann. 2012)
Giardia eats away your guts arginine supply and makes itself at home within an increasingly morbid digestive tract! As a group of scientists from Sweden and Argentina reports in their latest paper, the protozoan parasite, Giardia intestinalis, feasts on the arginine your gut cells need to proliferate (Stadelmann. 2012). This will lead to reduced polyamine levels and upregulated cell cycle inhibitory genes, which will eventually disrupt the the cell cycle of the intestinal epithelial cells. The reduced intestinal epithelial cell proliferation, on the other hand, allows the gut pathogen to thrive and will, in the long run, disrupt the intestinal tissue homeostasis and thus initiate the decay of the intestinal epithelium  - a central feature of so many of the wide-spread gut pathologies.

Provision of additional arginine + citrulline can help ... in the short run

Now, the good news about all that is that the in-vitro data in figure 3 clearly suggests and anecdotal, as well as the effective therapy of diarrhea patients with arginine/citrulline actually confirm that the provision of supplemental arginine (or citrulline) constitutes a cheap and readily available way to ameliorate the decay, until the bugs have been eradicated by antimicrobial drugs.

A pros pos, antimocrobial drugs, with regard to latter, Noa Tejman-Yarden and Lars Eckmann write in a recent review of the latest drug innovations, that despite the fact that metronidazole and other antimicrobials are usually effective, "treatment failures are common and antimicrobia resistance occurs" (Tejman-Yarden. 2011), so that it would appear as if complex derivatives of 5-nitroimidazole and benzimidazole, which form the core structure of the most widely used antigiardial drugs, will replace them in the short-run. At least for so long, until several new classes of antigiardial drug candidates that have already been identity by high-throughput screening of large compound libraries, will eventually hit the market (Tejman.Yarden. 2011)




More about vitamin B6: Helps with neurotransmitters synthesis; is involved in nerve function and necessary for normal brain development & function; influences mood, and melatonin production; effects circadian clock; is needed for B12 absorption and thus red blood cell production
When low: "Pins and needles" in extremities, mental disorders, seborrheic dermatitis, estrogenic PMS, dizziness, irritability, kidney stones, abnormal EEG, anemia, convulsions, edema (water retention), hypothyroidism, migraine-headaches, glossitis, lymphopenia
When high: Depression, suicidal tendencies, severe fatigue, mood swings, low blood sugar, migraine-headaches, heart palpitations, thyroid abnormalities (hyper- in the short, hypo in the long term), numbness in hands and/or feet, spinal / nerve degeneration, muscle spasms / cramps, osteoporosis, arthritis, higher blood pressure (short-term suppl.), lower blood pressure (long-term suppl.), mineral imbalances (high phosphor & magnesium vs. low sodium & calcium), restlessness, insomnia, vivid dreams, decreased estrogen & prolactin, depressive PMS.
RDA (adults): 1.3 mg*
*higher for pregnant women & >50y
Upper tolerable limit: 30-100mg*
*depending on the source of information
Food sources: chicken, turkey, tuna, salmon, shrimp, beef liver, milk, cheese, lentils, beans, spinach, carrots, brown rice, bran, sunflower seeds, wheat germ, and whole-grain flour
n6:n3 ratio does not depend on dietary intake alone: A marginal deficiency in vitamin B6 will skew your serum PUFA levels towards the N6-side That's the long and short of the results of a study that's going to be published in the October issue of the Journal of Nutrition.

Mei Zhao and her colleagues analyzed the fatty acid profiles in plasma, erythrocytes, and peripheral blood mononuclear cells (PBMC) of healthy men and women who had been fed a low-vitamin B-6 (pyridoxine) diet for 28 days and observed that contrary to the plasma HDL and LDL cholesterol concentrations, the amount of free fatty acids (FFA) in the blood and the erythrocyte and PBMC membrane fatty acid compositions, neither of which showed any statistically significant changes, the amount of all long-chain polyunsaturated fatty acids, i.e. arachidonic acid (n6) and EPA and DHA (n3) decreased from 548 ± 96 to 490 ± 94 μmol/L, 37 ± 13 to 32 ± 13 μmol/L, and 121 ± 28 to 109 ± 28 μmol/L, respectively.

The subsequent 8% increase in the total n6:n3 PUFA ratio from 15.4 to 16.6 is not alarming, but if this trend would continue linearly, it would certainly become problematic, in the long run. Moreover, the decrease in both n6 and n3 long-chain PUFAs (of which people tend to forget that the "inflammatory" arachidonic acid is as vitally important as its "anti-inflammatory" omega-3 counterparts) could provide an alternative / complementary mechanistic explanation for the increased cardiovascular disease risk that has been associated with vitamin B-6 deficiency.

In view of the fact that the RDA is not exactly high and can easily be achieved from dietary sources, along (as long as you follow a diversified whole foods diet), and considering the fact that high levels of B6 have been associated with more negative side-effects than B6 deficiency (see infobox on the right; please note that I collected the information on a couple of trustworthy websites on RDAs & co and did not verify the research on each of them!), I would however caution against the typical Western "more helps more" supplementation mentality.





Figure 4: Easy come, easy go - the mass you gain and the fat you lose by doing nothing than simply injecting testosterone is lost / regained within 6 months after discontinuation of the "testosterone therapy" (Forbes. 1992); read more about the role of testosterone in skeletal muscle hypertrophy in the Intermittent Thoughts on Building Muscle
In view of the fact that (a) today's short news items are pretty long(ish) and you still got a couple of interesting facebook news to check out, such as...
... and a plethora of additional gems from the realms of health, exercise, nutrition & supplementation, I will call it a day for today and save the exercise and a couple of other exciting On Short Notice items for later next week.


References:
  • Aleisa AM, Alzoubi KH, Gerges NZ, Alkadhi KA. Chronic psychosocial stress-induced impairment of hippocampal LTP: possible role of BDNF. Neurobiology of Disease 2006;22:453–62. 
  • Alzoubi KH, Abdul-Razzak KK, Khabour OF, Al-Tuweiq GM, Alzubi MA, Alkadhi KA. Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet. Behav Brain Res. 2012 Sep 20.
  • ESMO. Press releases related to the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.
  • Forbes GB, Porta CR, Herr BE, Griggs RC. Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA. 1992 Jan 15;267(3):397-9.
  • de Mendonca A, Ribeiro JA. Endogenous adenosine modulates long-term potentiation in the hippocampus. Neuroscience 1994;62:385–90.
  • Molteni R, Wu A, Vaynman S, Ying Z, Barnard RJ, Gomez-Pinilla F. Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor. Neuroscience 2004;123:429–40.
  • Smith AP, Christopher G, Sutherland D. Acute effects of caffeine on attention: a comparison of non-consumers and withdrawn consumers. J Psychopharmacol. 2012 Sep 19.
  • Stadelmann B, Merino MC, Persson L, Svaerd SG. Arginine Consumption by the Intestinal Parasite Giardia intestinalis Reduces Proliferation of Intestinal Epithelial Cells. PLoS ONE. 2012; 7(9): e45325. 
  • Tejman-Yarden N, Eckmann L. New approaches to the treatment of giardiasis. Curr Opin Infect Dis. 2011 Oct;24(5):451-6.

26 comments:

  1. This is absolutely in no way related to the article.

    I just thought it was important to remind you that you do an excellent job Professor Andro. I am personally grateful that I read about SuppVersity on MarksDailyApple. This place has been a non-stop learning experience for me, especially the comments to the articles. Keep up the great work!

    ReplyDelete
    Replies
    1. honestly, I am about as grateful as you are, since the one thing that motivates me most is positive feedback and people discussing the article and thinking beyond what I have already written and that's what YOU do :o)

      Delete
    2. As if off topic goes, I heartedly plead you to get a better microphone to use during SHM's podcasts. I am not native speaker and barely can make any sense of what being said by you because of the noise. Feels bad to miss any bits of precious information you seed over interwebz.

      Yours truly fatfree from vacation and passwords forgotten.

      Delete
    3. *lol* I will talk to Carl if we can to it via skype, as I cannot plug another mic into my phone and honestly am not sure if that would even help =)

      Delete
  2. How difficult is it to get too much b-6 even with supplementation. I have always been under the impression that the b-vitamins and their water solubility are easily excreted when consumed in excess.

    ReplyDelete
    Replies
    1. unfortunately water soluble does only mean that they don't accumulate in the tissue, but if you continuously take 500mg of B6 everyday you can expect dangerous side effects after a couple of weeks, with 100mg after years (cf. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1798481/) etc.

      many of the minor things listed are also attributable to imbalances, and interactions, which are not fully elucidated (there is only a single rodent study which does yet show that very high dose B6 will increase the excretion of B5)

      as long as you are well beyond the 100mg level per day, fatigue & co is probably the worst that can occur, though

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  3. A very nice informational blog. Keep on making such important blog post. Your work is really being appreciated by someone. human growth hormone

    ReplyDelete
  4. There are loads of studies that show caffeine has a positive effect on the hippocampus. I have found two negative studies.

    http://www.ncbi.nlm.nih.gov/pubmed/15174922
    http://www.ncbi.nlm.nih.gov/pubmed/17400186

    What do you make of these studies?

    The first study has a 0.3g/L dosage. What is the equivalent human dosage? I have seen a few caffeine studies with the 0.3g/L dosage. Do the rats drink the same amount of water in all studies with a g/l dosage?

    PS I hope this makes sense. My internet crashed and I have had to re-type the whole post.

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    1. rats consume 20-45ml water per day so 0.3g/L*35ml = 10.5mg / day which would translate (for an average weighed male rodent) to a human equivalent dose of ~6.2mg/kg or <100mg per day which is pretty low.

      Wrt to the first study, I see no detrimental effects mentioned

      wrt to the second, maybe the rodents were on low carb *rofl*

      in humans, at least caffeine + glucose = increased learning

      http://onlinelibrary.wiley.com/doi/10.1002/hup.1115/full


      rule of thumb disregard the busybodies, when 99% of the rest of the research says the exact opposite (esp. if the busybudies use rodents and strange dosing regimen)

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    2. This comment has been removed by the author.

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  5. This comment has been removed by the author.

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  6. You say the dose of a study is "3.8mg caffeine per kg body weight or 3-4 cups of coffee per day". The study uses the 0.3g/L dosage, which you told me is <100mg. What is the dose of this study?
    http://www.ncbi.nlm.nih.gov/pubmed/23000531

    Thanks

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  7. Chronic BDNF downregulates the Trkb receptor. - http://www.ncbi.nlm.nih.gov/pubmed/8752592

    This is true of caffeine as well. -http://www.ncbi.nlm.nih.gov/pubmed/22841916

    I think the downregulation of trkb stops BDNF from performing it's functions.

    ReplyDelete
    Replies
    1. why think laterally when simply typing BDNF caffeine into a search engine will yield dozens of studies showing beneficial effects ? http://www.ncbi.nlm.nih.gov/pubmed/23220362

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  8. My point is that I think the down-regulation of trkb stops BDNF from performing it's functions, like neuroprotection and neurogenesis.

    Could you answer my question on dosage above?

    Thanks

    ReplyDelete
  9. Never-mind my points on BDNF, as caffeine has been shown to increase neurogeneis in various studies.

    In this article, you say the dose of a study is "3.8mg caffeine per kg body weight or 3-4 cups of coffee per day". The study uses the 0.3g/L dosage, which you told me in these comments is <100mg. So which is the 0.3g/l dosage, <100mg or 3-4 cups of coffee? Do the mice drink the water all at once, or over the course of the day? I'm curious about this ,as I've seen the g/L dosage used in a few studies.

    http://www.ncbi.nlm.nih.gov/pubmed/23000531

    Thanks

    ReplyDelete
  10. You say the dose of a study is "3.8mg caffeine per kg body weight or 3-4 cups of coffee per day". The study uses the 0.3g/L dosage, which you told me is <100mg. Can you edit the post and change the dosage?

    "rats consume 20-45ml water per day so 0.3g/L*35ml = 10.5mg / day which would translate (for an average weighed male rodent) to a human equivalent dose of ~6.2mg/kg or <100mg per day which is pretty low."

    Isn't ~6.2mg/kg equivalent to 434 mg for a 70kg adult, which is 3-4 cups of coffee?

    Thanks

    ReplyDelete
    Replies
    1. ??? the rodents consume <100mg per day, not a human; I guess this is where I lost you, sorry for the misunderstanding

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  11. No problem. I'm just glad I understand the dosage now.

    If you combine that study with this one, it seems a higher dosage of caffeine is better for cognitive function. -http://boingboing.net/2011/11/21/caffeines-boosts-signals-in-th.html

    The only problem is that caffeine increase cortisol in a dose dependent manner, and augments cortisol response to physical or mental stress. - http://examine.com/supplements/Caffeine/#summary11-2

    Also, caffeine increases anxiety if you have the '1976T > C' genotype. These two things have always stopped me from intaking caffeine, and gaining the other benefits from tea and coffee.

    Is this increase in cortisol and anxiety enough to cut out caffeine intake? I do miss a cup of tea/coffee in the morning.

    ReplyDelete
    Replies
    1. A cup of tea/coffee in the morning wont hurt you in the least.

      Delete
  12. Thanks. If I started I would have 3-4 cups of tea/coffee spread out throughout the day. So probably about 250mg per day.

    I'm just looking at one of the studies on the examine page. How much are the p values rquivalent to in percentage? "Caffeine decreased heart rate (p less than .0001) and increased systolic blood pressure (p less than .005), diastolic blood pressure (p less than .0001), plasma cortisol levels (p less than .01)"

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    Replies
    1. The "p-value" is not related to percentages in the sense that you are using it. It is a measure of statistical significance and the lower the value the more correlated the two factors are.

      For example, using what you provided above, caffeine's effects are most significant on heart rate and diastolic blood pressure, followed by systolic, and finally cortisol.

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    2. So, can you get an exact figure from the "p-value" of how much the bp, heart rate and cortisol have changed? Or would that require access to the the full text?

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    3. I think you are still confusing clinical significance with statistical significance. In simple terms, p is the probability that the result was not by chance or how unlikely it would be not to be duplicated. If every subject's blood pressure went up. 000000001 mm, that would be statistically highly significant, but it would still mean diddly in terms of clinical effect. Someday, all studies will be required to post their raw data online. Then we'll have a better chance of separating out the nonsense.

      Delete
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