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 ESMO2013 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.

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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. 2013)... 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. 2013), 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.

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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. 2013).

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. 2013).

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. 2013)

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. 2013)

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...

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Figure 3: W/out arginine (Arg-) intestinal epithelial cells can't proliferate (graph based on Stadelmann. 2013)

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. 2013). 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)

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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.

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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...

• health related: "Vitamin D: We probably won't know before 2017, whether supplementation is advisable", "Aromatase inhibitors to treat endometriosis", or 
• muscle related: "The muscle sparing effects of CLA + Omega-3" and a true classic "Muscle mass gained on injectable testosterone is lost, when injections are seized", 

... 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. 2013 Sep 20.
• ESMO. Press releases related to the ESMO 2013 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. 2013 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. 2013; 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.

Fighting Body Fat W/ Green Tomatoes; Fasting, Exercise & Cognitive Performance; Potassium Citrate & Coconut Oil Strengthen the Bone; 25mg Clomid Double Testosterone

Image of the week: Golf-ball sized tumors from GMO corn and a >100% increase in mortality in female rodents are the results of the (at least in Europe) much debated study by Gilles-Eric Séralini et al. (Séralini. 2013)

I must admit that I got somewhat bored with writing the same, or at least very similar introductions time and again. So I decided to start each and every installment of On Short Notice with either a picture or a figure that impressed, amused, enraged or, as in this case, shocked me, when I hit on it. The image you see on the right shows the rodents from the French GMO corn study that made the news earlier this week. Females, to be precise. With golf-ball sized mammary gland tumors. Nasty and the result of a life on a 22% GMO or 22% GMO + Round-Up diet ... yeah, you read me right: 22% was enough. In fact, "the rate of mortality [...] reach[ed] a threshold at the lowest (11%) or intermediate (22%) amounts of GM maize" (Séralini. 2013), already, and that irrespective of whether the corn was or wasn't treated with round-up.

Quite a difference to the previous 13 week rodent study, which was obviously enough for the officials to allow the Frankenfood to be sold as "save for human consumption". But enough of those nasty tumors and pre-mature deaths and on to a short collection of recent science news from the world of health, nutrition, supplementation and medication (exercise news will follow in a couple of days, don't worry ;-)

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Red Tomatoes Are Good, But Green Ones Could Be Even Better - For weight Loss, At Least That's the simple message the results from a soon-to-be-published study on the AMPK- and PPAR-gamma mediated anti-obesity effects of 20 g/kg diet of red vs. green tomato water extracts (extraction took place at room temperature for 1h; Choi. 2013).

Figure 1: Significant benefits on weight gain, epididimal (=visceral) and liver fat were observed only with the dehydrotomatine, α-tomatine, trigonelline rich green tomato extract (based on Choi. 2013).

While both, the red (RTE) and green tomato extracts (GTE) did ameliorate the weight gain and fat accumulation of male C57BL/6 mice who received the RTE and GTE enriched chow after they had been pre-fattened on a "high fat diet" for 4-weeks, only the green tomato extract with its higher dehydrotomatine, α-tomatine and trigonelline extract had statistically significant effects on total body weight and visceral fat gain (see figure 1).

If you take a closer look at the photos of the rodents (small picture in figure 1), you will probably agree that judged by their physique the mice in the HFD + GTE appear to be the leanest. Now, it given the fact that "high" amounts of dietary fat and fatty livers are not exactly conducive to rodent health, the image may be misleading; and still, the fact that the purported "high fat" diet, had 4g more protein, 17g more fat and 23g less carbs per 100g, than the regular chow and thus a macronutrient composition of 24g / 41g / 24g makes me wonder if the control mice on the "healthy" low fat rodent chow would not have seen similar benefits from a few mg of GTE per day ;-)

As far as the underlying mechanisms are concerned the additional in-vitro experiments, Choi et al. conducted revealed that the anti-obesity effects were probably the result of concomitant increases of p-AMPK (to normal = control levels) and a profound suppression of the pro-adipogenic (=fat storage promoting) proteins PPAR-gamma, C/EBP-alpha and perillipin in the adipose tissue of the GTE treated animals. And with tomatine turning out to be the most potent (-80%) inhibitor of fat accumulation (vs. -10% for trigonelline), we eill probably soon see the first stanardized green tomato extracts being sold as dietary supplement. I mean, you all know how it works these days: If there is a single rodent study showing benefits, people will be willing to pay for it and since demand determines supply, it won't take long until you see the first 2xGTE based "fat burner" (featuring GTE as in green tea extract and GTE as in green tomato extract ;-) hit the shelves.

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Regardless of whether you are low-carbing or not, eggs could literally give you a head-start in the morning (click here to learn more about the good "bad" eggs)

Breakfast Counters Mental Fatique, Exercise curbs appetite - Regardless of Whether You "Break the Fast" or Not! That's what a group of researchers from Korea found, when they analyzed the effects of consuming or omitting breakfast on the physical and mental fatique, as well as the cognitive task performance, mood and appetite ratings of twelve healthy male participants during and after four different test conditions:

• no breakfast and rest, 
• breakfast and rest, 
• no breakfast and exercise and
• breakfast and exercise

On each of the four test days the participants went through the 'same' routine that consisted of "breakfast (or continued fast), a 2 h rest, an exercise (treadmill run at 60% VO2max to expend ~710 kcal) or an equivalent rest period, a liquid snack, a 90 min rest period and finally an ad libitum lunch" (Veasey. 2013).

As I already mentioned in the title of this item, the mental fatigue ratings were significantly higher during the fasted compare to the fed trials. Correspondingly consuming breakfast prior to resting increased speed on a Rapid Visual Information Processing task (RVIP) - an effect that was not observed, when the breakfast was supplied after the exercise. The treadmill exercise lead to a significant reduction in hunger ratings during and even temporarily after the exercise, irrespective of whether or not the subjects had had breakfast. The effect was however more pronounced in the fed condition.

Recent UK study says: Children learn better w/ breakfast The findings of a study that used an online questionnaire + test system to establish a connection between breakfast consumption and cognitive performance in 1386 children aged between 6 and 16 years, from schools throughout the UK, appears to confirm previous laboratory studies, suggesting that breakfast can help maintain attention and memory during the morning (Wesnes. 2013).

Now, though all this clearly suggests that skipping breakfast was a very bad idea, I would like to remind you of the "priming" or "programming" effect I have outlined in my recent post on "breaking the fast". Against that background, the scientists' conclusion that "consuming breakfast before exercise decreased mental fatigue ratings following cognitive task completion and exercise reversed the detrimental effects of breakfast consumption on RVIP reaction time" would have to be confirmed in a group of habitual "non-breakfast eaters", whose circadian rhythm is adapted to running on stored fuel in the morning, before we ascribe general validity to it.

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Potassium Citrate: Could the "Best Calcium Supplement" Contain No Calcium, At All? Usually the reason doctors will prescribe or tell people to take calcium supplements is that they are afraid their patients would otherwise pee out their bones - literally! Unfortunately, that does not reduce but will often rather exasperate the urinary excretion of calcium and thus belongs to the realms of counterproductive or at least incomplete text-book knowledge, which stands in contrast to a handful of studies of which the average physician usually has not heard, before (Harrington. 2003; Karp. 2009; Marangella. 2004, Sakhaee 2005; Taylor. 2010).

Figure 2: Changes in urinary calcium and calcium balance (mg/day), as well as serum parathyroid levels (PHT in pg/dl) after 6 months on 650mg calcium citrate (placebo) with or without 60 or 90mmol potassium citrate

The latter probably won't change with the soon-to-be-published paper that deals with the effects of potassium citrate supplementation on calcium balance in older men and women. And that despite the fact that the results could be of relevance for anyone following a high protein, high fat or SAD diet, as well - especially if he is like Adelfo's client Mr. C and "does not like his vegetables" ;-) After all, the main mechanism by which the administration of 60 or 90 mmol of potassium citrate improved the calcium balance of the subjects who had a low baseline calcium intake and a high phosporus load (556/1338 in the female and 618 / 1410 in the male subject) and a potassium intake 10-15% below the RDA of 3,500mg was the "complete neutraliz[ation]" of the dietary acid load, which can be a serious problem with far-reaching metabolic ramifications not just for the elderly (Mosele. 2013).

In the study at hand, the alkalizing effect of the potassium supplement went hand in hand with increases in urinary potassium (42.0 in the low and  67.3 mmol/day in the high dose arm) and profound decreases in urinary calcium loss. In conjunction with the elevated calcium intake from 630mg of supplemental calcium citrate, all subjects (placebo included) received, this induced a shift from a negative into a positive calcium balance and corresponding decreases in PTH, the hormone that will not just leach calcium out of the bones to keep your serum calcium levels steady (see figure 2), but has also been found to be associated with increased body fat levels (interestingly specifically fat and not other anthropometric markers like body weight!) and metabolic syndrome (Snider. 2005; Hjelmesaeth. 2009)

Is the dosage used in the study already dangerously high? No. 90mmol K-citrate are usually tolerated without problems (this assumes that you have healthy kidneys!), but must be spread across the day and are best ingested with food.

In view of what you've learned about the role of phosphorus in calcium and vitamin D metabolism ("Phosphor, Calcium and Vitamin D"), as well as the potential pitfalls of becoming overtly acidic (scroll down to figure 3) and what you can do to stay on the alkaline side of things, it is probably not necessary I remind you of the fact that you can avoid running into problems in the first place by simply eating a balanced whole foods diet without tons of grainy junk (whole or not) and convenience "foods". If you do that, the use of supplements should be unnecessary and could, if consumed in excess, have serious side effects, which range from gastrointestinal distress over low blood pressure, muscular warkness and dehydration (due to a low sodium : potassium ratio), up to cardiac arrhythmias and - in the worst case - sudden cardiac arrest.

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25mg Clomiphene Citrate Still a Good Choice For Non Testosterone Based TRT (or Restart) ... and as if that was not already enough, it will also maintain your bone health, when your testosterone can't do the job for you, or help you and your significant other if you have problems conceiving (see box "Clomiphene citrate?", below; Da Ros. 2013)

Clomiphene citrate? For those of you who have no idea, what clomiphene citrate aka "clomid" is: It's a SERM = selective estrogen receptor modulator - basically a molecule that looks and behaves similar to estrogen, but has only insignificant estrogenic effects, when it binds to the estrogen receptor. Originally developed for the treatment of breast cancer, SERMs have caught some attention within the bodybuilding community as the goto drug to "restart" the HPTA after the use of androgens. This works simply because estrogen, the last hormone in the steroid cascade has the most pronounced suppressive effect on steroid production. As soon as the respective receptors in the brain are blocked and the brain tricked to believe that there is almost no estrogen floating around it will ramp up the hormonal production again and the sex hormone levels will rise. Obviously, this does not work for former performance enhancing drug users, only, but also for men in whom the HPTA or testosterone production is suppressed for other reasons. And as if that was not astonishing enough, clomid has also been used with some success as a fertility drug for women (Zadehmodares. 2013).

In a prospective study the results of which have been published in the International Brazilian Journal of Urology Carlos Teodósio Da Ros and Márcio Augosto Averbeck were able to show that the (in bodybuilding circles probably laughed at) dosage of 25mg/day clomiphene citrate increased the testosterone levels of 125 men with hypogonadism and low libido (mean age was 62 years) from Serum T levels ranged from 309 ng/dL at baseline to 642 ng/dL within no more than 3 months.

What about the side effects? Well, the only ones the scientists observed were improvements in the
post-treatment Quality of Life (QoL) scores. Total cholesterol, HDL-cholesterol, triglycerides, fasting plasma glucose and prolactin did, if anything, improve (!) - statistically significant was yet only the -5% reduction in total cholesterol.

No serious adverse events were recorded. And if it were not for the absence of statistically significant improvements in sexual performance in the 26 men who had already passed the 71y age mark - you could probably say: "It worked like a charm" ;-)

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Curried Carrot Soup w/ coconut oil (DrAxe.com) - I doubt the chef who came up with this recipe was aware of a recent study by Conlon et al. which showed that coconut oil can increase carotenoid accumulation in tissue & serum of gerbils by up to 900%(!) over safflower control

Virgin Coconut Oil For Everything - Including Bone Strength! Sounds hilarious, but is true: Researchers from the Pharmacology Department at the Faculty of Medicine of the Universiti Kebangsaan Malaysia in Lumpur, Malaysia, have found that the addition of 8g /100g virgin coconut oil (VCO) to the diets of the ovariectomized rats (this is the standard rodent model of menopause), was more effective than calcium supplements in preventing the menopausal bone loss.

While calcium only prevented the reduction in trabecular separation but failed to increase the bone volume and trabecular number, the rodents in the VCO group had a significantly greater bone volume and trabecular number than the ovariectomized non-supplemented controls, as well.

The scientists speculate that the beneficial effects the coconut oil had on the bone-structure of the estrogen deficient rodents was most likely due its high amount of saturated fats, particularly the medium chain triglycerides (MCTs). At least in my humble opinion the the additional biologically active components like vitamins and polyphenols, probably played an almost as important role. At least, that's what their antiallergenic, antiatherogenic, anti-inflammatory, antimicrobial, antithrombotic, cardioprotective, and vasodilatory effects would suggest - I mean, why don't we simply add antiosteoperotic to that list ;-)

Hungry for more news? Visit the SuppVersity on Facebook!

That's it for today, but there will be more in the days to come... more short news and an article I have promised to write looooong ago. So stay tuned and don't forget to check out the SuppVersity Facebook page for a couple of even shorter news-items on the bone-obesity connection, the potential downsides to chronic high dose glutamine supplementation, why total LDL cholesterol number and even LDL particle size could be less important than we have thought and much, much more ;-)

References:

• Choi KM, Lee YS, Shin DM, Lee S, Yoo KS, Lee MK, Lee JH, Kim SY, Lee YM, Hong JT, Yun YP, Yoo HS. Green tomato extract attenuates high-fat-diet-induced obesity through activation of the AMPK pathway in C57BL/6 mice. J Nutr Biochem. 2013 Sep 10. pii: S0955-2863(12)00184-2.
• Conlon LE, King RD, Moran NE, Erdman JW Jr. Coconut Oil Enhances Tomato Carotenoid Tissue Accumulation Compared to Safflower Oil in the Mongolian Gerbil ( Meriones unguiculatus ). J Agric Food Chem. 2013 Aug 16.
• Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study. Int Braz J Urol. 2013 Jul;38(4):512-8.
• Harrington M, Cashman KD. High salt intake appears to increase bone resorption in postmenopausal women but high potassium intake ameliorates this adverse effect. Nutr Rev. 2003 May;61(5 Pt 1):179-83. 
• Hayatullina Z, Muhammad N, Mohamed N, Soelaiman IN. Virgin Coconut Oil Supplementation Prevents Bone Loss in Osteoporosis Rat Model. Evidence-Based Complementary and Alternative Medicine. 2013; 237236: 8 pages.
• Hjelmesaeth J, Hofsø D, Aasheim ET, Jenssen T, Moan J, Hager H, Røislien J, Bollerslev J. Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a cross-sectional study. Cardiovasc Diabetol. 2009 Feb 3;8:7.
• Karp HJ, Ketola ME, Lamberg-Allardt CJ. Acute effects of calcium carbonate, calcium citrate and potassium citrate on markers of calcium and bone metabolism in young women. Br J Nutr. 2009 Nov;102(9):1341-7. 
• Marangella M, Di Stefano M, Casalis S, Berutti S, D'Amelio P, Isaia GC. Effects of potassium citrate supplementation on bone metabolism. Calcif Tissue Int. 2004 Apr;74(4):330-5.
• Moseley K, Weaver C, Appel L, Sebastian A, Sellmeyer DE. Potassium citrate supplementation results in sustained improvement in calcium balance in older men and women. J Bone Miner Res. 2013 Sep 18.
• Sakhaee K, Maalouf NM, Abrams SA, Pak CY. Effects of potassium alkali and calcium supplementation on bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2005 Jun;90(6):3528-33. 
• Séralini GE, Clair E, Mesnage R, Gress S, Defarge N, Malatestab M, Hennequin D, de Vendômois JS. Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize. Food and Chemical Toxicology. 2013. Ahead of print.
• Snijder MB, van Dam RM, Visser M, Deeg DJ, Dekker JM, Bouter LM, Seidell JC, Lips P. Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab. 2005 Jul;90(7):4119-23.
• Taylor EN, Stampfer MJ, Mount DB, Curhan GC. DASH-style diet and 24-hour urine composition. Clin J Am Soc Nephrol. 2010 Dec;5(12):2315-22. 
• Veaseay RC, Gonazalez JT, Kennedy DO, Haskell CF, Stevenson CS. Breakfast consumption and exercise interact to affect appetite, cognitive performance and mood later in the day. Appetite 59 (2013) 618–638.
• Wesnes KA, Pincock C, Scholey A. Breakfast is associated with enhanced cognitive function in schoolchildren. An internet based study. Appetite. 2013 Aug 15;59(3):646-649.
• Zadehmodares S, Niyakan M, Sharafy SA, Yazdi MH, Jahed F. Comparison of treatment outcomes of infertile women by clomiphene citrate and letrozole with gonadotropins underwent intrauterine insemination. Acta Med Iran. 2013;50(1):18-20.

Calcium, Magnesium, Potassium & Co in Food, Water & Supps - Getting Enough is Easy, Knowing How Much Is Not!

Image 1: "Minerals? Yeah that's the stuff you need to avoid cramping" While this is certainly true, the mineral loss during "normal" workouts is largely overblown, the most important and actually only necessary ingredients in respective drinks, even for Ironman Triathletes, are salt, water and sugar and what's worse this prejudice conceals the importance of electrolytes for our general health.

While it is Thursday, it is plain to see that this is not Adelfo Cerame's weekly SuppVersity post. There have been a couple of issues with the promised workout videos and neither I nor Adelfo wanted to postpone them yet another week so that we decided to rather publish videos + Adelfo's weekly update tomorrow instead of a reduced snippet today. To make sure you have more than enough food for thought to bridge the time, I applied a coupe of tweaks to a longer snipped from the next installment of On Short News that dealt with the protective effects of high(er) intakes of calcium, magnesium and potassium on the incidence of vascular dementia (=dementia in response to low blood flow to / oxygenation of the brain) and Alzheimer's dementia (=dementia due to the build up of plaque in the brain). As you may already have seen, the result got somewhat epic, so let's not waste anymore time and get straight into the original data before it's too late and we have already become demented ;-)

Don't forget your minerals or they'll soon be just one of the many things you tend to forget

While the studies and reviews on the effects of minerals, especially calcium (and as of late also magnesium), on cardiovascular health is about as abundant as the assessments of their individual and joint benefits and / or pitfalls, their role in the etiology of another, quieter, but not less prevalent pandemic is still insufficiently studied. Against that background, the results Ozawa et al. present in a recently published paper in the Journal of the American Geriatric Society could well provide some novel insights on whether or not forgetting to keep an eye on your mineral intake now will make you forget more than just a couple of minerals in the more or less distant future - and that even if none of the 1081 community dwelling elderly (>60y) Japanese the scientists followed up for 17 years is even remotely related to you ;-)

Figure 1: Hazard ratios for all-cause, vascular and Alzheimer's dementia for patients in the lowest to highest quartiles of potassium (≤1,856 / 1,857–2,149 / 2,150–2,559 / ≥2,560), calcium (≤431 / 432–531 / 532–638 / ≥638) and magnesium (≤147 / 148–169 / 170–195 / ≥196) intake in mg/day (top) and difference in intake of selected foods in the highest vs. lowest quantile of overall mineral intake (bottom; all calculated based on Ozawa. 2013)

Aside from the general association of higher potassium, calcium, and magnesium intake with lower incidence of dementia, which was - given the overall low median intake - more or less to be expected, there are a couple of other very noteworthy things I want you to take note of (see figure 1; data adjusted for age; sex; low education; history of stroke; hypertension; diabetes mellitus; total cholesterol; body mass index; smoking; alcohol intake; regular exercise; and energy, vitamin C, cholesterol, saturated fatty acid, monounsaturated fatty acid, and polyunsaturated fatty acid intake):

• a higher mineral intake was had a more pronounced beneficial impact on vascular compared to Alzheimer's dementia (-77% vs. -46% max. reduction)
• for potassium and calcium the general rule of thumb is "the more, the better" (the deviation from that rule in the individual analysis for Alzheimer's is statistically nonsignificant), but I don't this is mediated by the overall low intake of both and thus only valid within the given range of ~700-900mg of calcium and ~2600-3000mg of potassium - intakes you can by the way easily get from your diets alone
• aside from the usual suspects, i.e. (green) vegetables, fruits and fish, dairy is among the most important source of minerals and high dairy eaters tend to be high mineral consumers, while low / no dairy eaters tend to be in the lowest quartiles of overall mineral intake

as well as a couple of things you cannot read off the graphs, e.g.:

• women had  significantly higher mineral intakes than men, i.e. 68.3% of the persons in Q4 for overall mineral intake were women
• age had no effect whatsoever on the overall intake of potassium, calcium and magnesium
• a low(er) education (<6 years of schooling) was a good predictor of low total mineral intakes, just as it is by the way in view of an overall worse diet quality (this is however less pronounced than conventional wisdom would suggest)
  
• intriguingly, people with diabetes had on average higher mineral intakes than people without diabetes, almost certainly a non-causative relationship that is probably mediated by supplements and nutritional counseling the diabetics received
• contrary to the US, there was no association between high salt and low Ca, Mg, or K intakes, this is also surprising because the "average" middle aged Japanese consumes way more than 5g of salt (Nagata. 2004) and thus 2x more than the US "tolerable upper intake level" of 2300 mg (Cogswell. 2013)

Apropos US, in view of a couple of other studies that have only recently provided support for the widely held, but in fact rarely scrutinized believe that, the lack of adequate amounts of potassium and magnesium, in particular, is associated not only with the age-related cognitive decline and even dementia, but also with such profane things as "simple" obesity, e.g. ...

• Donfrancesco et al. report higher potassium and magnesium intakes were associated with lower BMIs in 1168 men and 1112 women aged 35-79 yrs from 12 Italian regions (Donfrancesco. 2013)
• almost identical results in a study by Shay et al. that found associations with lower BMIs for potassium and magnesium 1794 men and women (ages 40-59 y) from 8 US population samples (Shay. 2013)

... it would unquestionably make sense to eventually stop bashing on sodium and start promoting the consumption of magnesium- and potassium-rich foods, instead.

Figure 2: Percentage of the population mineral intakes below the EAR for individuals aged ≥2y (data from NHANES 2003–2006; n = 16,110; Fulgoni. 2011).

Did you know that according to latest data from the CDC (Cogswell. 2013) less than 2% of US adults meet the dietary recommendations for potassium (≥4700 mg K/d) and that the lack of potassium was even more pronounced in the elderly (0.5% of the >72y-old US citizens meet the dietary requirements) and obese (0.7% meet the recommendations. With two out of five Americans also failing to meet even the required amount of magnesium in the diet, it appears more than questionable why the good-meaning (I don't doubt they are but too often they are mislead of have the good of the wrong people in mind) policy makers don't put magnesium and potassium into the water supply instead of toxic junk such as chlorine and fluoride...

I mean, you will probably remember from "On Short News on July 28, 2013" that each milligram of magnesium per liter drinking water could decrease the heart disease risk of people with an unbalanced mineral intake by 5%! But, alas, who am I to make such bold suggestions?

Now, while the importance of watching your dietary magnesium and potassium are pretty obvious and probably nothing you have not heard before, there is still one question left to be answered - a question that will point us away from RDAs and EARs and back to foods, which never contain only one of the aforementioned minerals in isolation. So here is the question: What do we make of calcium? In the Ozawa study it appeared to be clearly useful, but that was with intakes of >638mg/day in the highest quintile of the study population! The average European citizen, on the other hand, consumes roughly 1g = 1,000mg, i.e. 36% more than the Japanese and still we (us Europeans) are about as sick, if not sicker than the average Japanese? How come?  

Potassium, check; magnesium, check; calcium, ... wait a minute! What about phosphorus? 

Aside from the mere possibility that we could already be consuming way too much calcium (which is not supported by science as long as those 1,000mg come from your diet and not from supplements; cf. "Higher Calcium Intake Greater Fatty Acid Oxidation"), the most straight forward explanation would be an imbalanced intake of phosphorus. For the average European the latter is at about 1,675mg/day (mostly from dairy, cereals and meats - 27.9, 23.4, 17.4.% of daily intake, respectively) and thus clearly twice the amount our (the European) version of the well-meaning policy makers are telling us each and every one of us should be consuming on a daily basis.

Figure 4: Relative potassium intake in European countries according to source; note: with 4,110mg/day the average potassium intake in the Euopean Union is much higher than in the US, highest intakes were observed in Spain, lowest in Germany (Welch. 2009)

Did you know that the average magnesium intake in Europe (409mg/day) is much higher than in the US? And guess what, the usual suspects, i.e. dairy and cereals aside, non-alcoholic beverages are the #2 source (19% of total mg intake) of dietary magnesium in Europe! I would, an observation Welch et al. attribute just like the almost "optimal" (wrt to the US recommendations) average potassium intake of 4,110mg/day to the high quality tap and bottled mineral water, and other non-alcoholic beverages (and certainly not to reverse osmosis or the consumption of mineral-free distilled water, which is something you can use to satisfy the water requirements of your radiator or  iron, but not those of your body ;-).

Figure 3: Hazard risk analysis based on the Cholesterol and Recurrent Events (CARE) study (n = 4127; Tonelli. 2005)

In fact, we have broached on another of these imbalances in the context of the effects that were observed with higher magnesium : calcium ratios in drinking water (cf. red box above + "On Short News on July 28, 2013"), before. With phosphor we have yet another "antagonistic partner" of calcium, of which Ritz et al. have only recently argued that its increasing use as a food additive (check out the label of whatever processed food you buy, chances you find a XZY-phosphate on it are >50%) poses a serious health risk. To support their argument, the researchers cite data from a 2005 study by Tonelli et al. that indicates that even serum phosphor levels that are well within the normal range (2.0-4.0mg/dl) were associated with significantly increased CVD risks (cf. figure 3; suggested read: "Does Low Vitamin D Protect Us From Dietary Phoshporus Overload?").

These are only two selected examples of the available evidence that suggests that we are still totally underestimating the effects of "electrolytes", in general, and their ratios, in particular, on our neurological and metabolic health - and, even worse, doctors, policy makers, experts and gurus keep making mostly unwarranted recommendations to increase our intake of one and decrease the intake of another mineral, when in fact the lack of synergists (e.g. normal amounts of dietary magnesium to complement calcium) and absence or abundance of antagonists (e.g. potassium and magnesium for salt and calcium, magnesium and potassium for phosphorus) are the actual problems we are dealing with.

Figure 5: Don't forget that there are personal, regional and historical difference in total and relative mineral intakes and never supplement, high amounts of isolated minerals simply because Mr or Mrs average would benefit, without checking how "average" you actually are in terms of your solid, fluid and supplemental mineral intake (data for image based on Crawford. 1971; data on US water hardness according to the Water Research Center)

Implications: I guess based on all the information on the allegedly complicated interactions between the different minerals, you will by now have realized that statements like "everybody will benefit from taking 300mg of supplemental magnesium" let alone "everybody must take at least 300mg of supplemental magnesium" are about as useful as the constant advice to cut your salt, cut your fat and cut your calories people are confronted with on a daily basis. The chances that person X may benefit are probably high, but they are certainly much lower than the chances that you will survive the sting of a bee - and even that will still kill 53 US citizens per year.

Individualization, evaluation are therefore obligatory steps which must necessarily come before supplementation, which would - as some of the data in the figure 4 did already suggest - rarely be necessary, if the average inhabitant of the Western hemisphere did not top his sugary, salty and phosphate-laden fast-food diet with beverages that are either devoid of any minerals or will simply exasperate the existing imbalances.

Too many people (and I believe this is particularly true for the US) seem to have forgotten that we have not always been forced to filter all the minerals out of our water just to make the chlorinate, fluorinated, and "estrogenated" sludge that streams out of the faucet suitable for human consumption. Think of that and the data in figure 5, the next time the as of late often second-guessed recommendation that you got to have "at least X cups of water per day" resurfaces and of how little use each of them is, when it does not contain any of the electrolytes your body needs to handle the water appropriately.

References:

• Cogswell ME, Zhang Z, Carriquiry AL, Gunn JP, Kuklina EV, Saydah SH, Yang Q, Moshfegh AJ. Sodium and potassium intakes among US adults: NHANES 2003-2008. Am J Clin Nutr. 2013 Aug 1. 
• Crawford MD, Gardner MJ, Morris JN. Cardiovascular Disease and the Mineral Content of Drinking Water. Br. Med, Bull. 1971; 27,1: 21-24.
• Donfrancesco C, Ippolito R, Lo Noce C, Palmieri L, Iacone R, Russo O, Vanuzzo D, Galletti F, Galeone D, Giampaoli S, Strazzullo P. Excess dietary sodium and inadequate potassium intake in Italy: Results of the MINISAL study. Nutr Metab Cardiovasc Dis. 2013 Jul 24.
• Fulgoni VL 3rd, Keast DR, Bailey RL, Dwyer J. Foods, fortificants, and supplements: Where do Americans get their nutrients? J Nutr. 2011 Oct;141(10):1847-54.
• Ozawa M, Ninomiya T, Ohara T, Hirakawa Y, Doi Y, Hata J, Uchida K, Shirota T, Kitazono T, Kiyohara Y. Self-Reported Dietary Intake of Potassium, Calcium, and Magnesium and Risk of Dementia in the Japanese: The Hisayama Study. J Am Geriatr Soc. 2013 Aug 2. 
• Ritz E, Hahn K, Ketteler M, Kuhlmann MK, Mann J. Phosphate additives in food--a health risk. Dtsch Arztebl Int. 2013 Jan;109(4):49-55. Epub 2013 Jan 27. 
• Shay CM, Van Horn L, Stamler J, Dyer AR, Brown IJ, Chan Q, Miura K, Zhao L, Okuda N, Daviglus ML, Elliott P; for the INTERMAP Research Group. Food and nutrient intakes and their associations with lower BMI in middle-aged US adults:  the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). Am J Clin Nutr. 2013 Aug 1. 
• Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G; Cholesterol And Recurrent  Events Trial Investigators. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005 Oct 25;112(17):2627-33. 
• Water Research Center. Hard Water  Hardness Calcium Magnesium - Water Corrosion Mineral Scale. < http://www.water-research.net/hardness.htm > retrieved Aug 16, 2013.
• Welch AA, Fransen H, Jenab M, Boutron-Ruault MC, Tumino R, Agnoli C, Ericson U, Johansson I, Ferrari P, Engeset D, Lund E, Lentjes M, Key T, Touvier M, Niravong M, Larrañaga N, Rodríguez L, Ocké MC, Peeters PH, Tjønneland A, Bjerregaard L, Vasilopoulou E, Dilis V, Linseisen J, Nöthlings U, Riboli E, Slimani N, Bingham S. Variation in intakes of calcium, phosphorus, magnesium, iron and potassium in 10 countries in the European Prospective Investigation into Cancer and Nutrition study. Eur J Clin Nutr. 2009 Nov;63 Suppl 4:S101-21.

Hypothyroid, Cold, Tired & Depressed? Try Replacing 50µg of T4 With 12.5µg of T3 - Study Shows, 65% of Patients Would not Want to Go Back to Synthyroid (T4), Only!

Image 1: Are you taking copious amounts of synthyroid (levothyroxin, T4), already, and feel as if your hypothyroidism became rather worse than better? Does Your Dr tell you that your TSH is fine and you should just exercise more and eat less to stop gaining weight like mad? Than this post is for you!

The issue of optimal thyroid medication resurfaced as of late on the SuppVersity facebook wall, when I posted the link to a recently conducted retrospect study in patients who had undergone total thyroidectomy and were now receiving postoperative levothyroxin only hormone therapy by Ito et al. Not to my personal, but obviously to the researchers surprise, the textbook prescription of the "metabolically inactive"  T4 (essentially that is as almost 90% of "general knowledge about thyroid hormone metabolism incorrect as T4 can very well interact with thyroid receptors, it is though TR-alpha specific and has little metabolically activating effects, cf.  Koury. 2009) did not suffice to restore the circulating levels of the active thyroid hormone T3 to the preoperative levels (Ito. 2013). Only when so much T4 was administered that the thyroid stimulating hormone (TSH, also known as thyrotropin) were "suppressed" (as per textbook definition) the circulating T3 levels got back within the physiological normal range.

"Nurse, send the patient home and show me his lab report!"

The real-life consequences of treating lab values instead of patients and going by textbook prescriptions instead of the often debilitating symptoms of hypothyroidism which range from

• physical problems such as weight gain, constipation, constant cold, feeling of cold, blurred vision, nausea, sleepiness, low blood pressure, high cholesterol and blood glucose levels, etc. to
• psychological issues such as general cognitive decline, inability to concentrate, mental fatigue, anger, confusion and depression

and often become rather worse than better, when patients who still have their thyroid gland are going on "partial replacement" or start taking a "supportive" dose of synthyroid (levothyroxin, T4) to help a sluggish thyroid along.

Image 2: Ladies, you are lucky you got all that subcutaneous fat to absorb those lubricants and PCB laden cosmetics you are using and stash it away ... a pity it's all going to haunt you, when you want to get rid of those fatty, unaesthetic dumping grounds.

Weight loss and thyroid function: Beyond overdieting and undereating While those two, i.e. training like mad and eating like too little or only protein are unquestionably the main culprits, when it comes to diet-induced thyroid malfunction (in this cases thyroid medication is by the way counter-indicated; T4 would not work, T3 would simply burn away even more muscle mass), there is another interesting phenomenon you maybe have not heard about: Self-intoxication! Well, at least this is how I would call the sudden drop of thyroid function that is only one of the nasty effects the release of organochlorines, which have accumulated in the fat tissue of the dieters over years and are now liberated within months, in morbidly obese patients on "zero calorie" diets often weeks, has on the whole endocrine system of formerly big losers (Pelletier. 2002; Tremblay. 2004; Hue. 2006). Pelletier et al. for example found statistically significant negative correlations between the circulating levels of active thyroid hormone T3 and the amount of ...

• hexachlorobenzene (HCB), which was used as a pesticide until 1965 and was also used in the production of rubber, aluminum, and dyes and in wood preservation and is currently formed as a byproduct during the manufacture of other chemicals, mainly solvents and pesticides, and 
• PCB 156, one of the members of the olychlorinated biphenyl (PCB) family of chemicals that has now been banned from industrial insulators and lubricants, because of substantial evidence of its carcinogenic and neurotoxic effects.

... And you bet that this is only the tip of an iceberg. After all, fat is not just a storage site for useful energy, it is also the dumping ground for everything fat soluble you better lock away so that it cannot harm important organs; now, when you think about that, it stands to reason why the fat of animals that have been fed corn or whatever else that's been exposed to one or another of these compounds probably actually is, as common "wisdom" says, associated with an increased cancer risk and all sorts of other ailments.

What most doctors either don't know or simply ignore is the fact that the thyroid produces T3 and T4 at a very specific natural ratio of about 100/6 (I deliberately did not cancel the fraction, and wrote 50/3, instead, because 100/6 is the thyroid's daily production of T4/T3 in mcg, the rest of the approximately 20mcg of T3 come from local deiodinase processes at in other organs). Now, if we simply add say 50µg of T4, the corresponding decline in TSH will reduce the overall thyroid hormone output from the gland; and though the exact degree of "suppression" will depend on absorption kinetics, inter-individual differences, the presence / absence of inflammation and the specific activity of deiodinase enzymes which convert T4 to either T3 or reverse T3 (rT3) in the peripheral organs (esp. the liver and the kidneys), we will at this point simply assume that corresponding to the daily T4 output of 100µg the 50µg dose will suppress the total (T4+T3) output of thyroid hormones by ~50%:

Figure 1: Illustrative "calculation" of the effects of partial thyroid hormone replacement with 50mcg T4 only.

As my example calculation in figure 1 shows, this would equal a reduction of roughly -10% in terms of thyroid hormone activity and that despite the fact that the textbook will tell you that it would not make a difference. That I write "roughly" and not "definitively" is yet quite important, here, as there are too many confounding factors, such as the...

• possible increase in conversion of T4 to rT3 and thus "anti-thyroid" activity; the latter is especially prominent in insulin resistant individuals (Ruhla. 2011) and those receiving high doses of T4 (Clur. 1986)
  Note: this renders the recommendation to simply up the doses of T4 to levels with partially suppressed TSH levels Ito et al. make in the initially cited study pretty much nonsensical
• lack of enzymatic conversion at the level of the target tissue and consequently even lower thyroid activity; something that is often seen in patients who have a "sluggish thyroid metabolism" anyways and receive only a partial substitution

... which will eventually determine both, the hormone production, as well as its metabolic effects to make any clearcut statement. Unfortunately, the same is true, but rarely appreciated for the success of the standard (T4 only) treatment for hypothyroidism, the efficiacy of which will likewise vary from person to person and is even highly susceptible to fluctuations and changes in body weight, inflammation, macro- and micronutrient content of the diet etc.

Against this background, it stands to reason that the argument "but it works for most of my clients" you will often hear from your Dr. is of little significance for you as an individual and even a statement like "but didn't you feel better, when we initiated the treatment 2 months ago" could not just be missing the boat, altogether, but brings another commonly overlooked problem to mind: If you have been suffering from symptoms of hypothyroidism for a couple of years, you would probably feel "major improvements" if you went from a "1" as in "very bad" to a "3" as in "bad", without knowing that you may, just as the majority of the subjects in a study that's been published in The New England Journal of Medicine in 1999, feel even better if you received 12.5mcg of T3 instead of 50mcg of the T4 your Dr. has prescribed.

T4 + T3 therapy makes subjects feel better, 20/32 don't want to go back on monotherapy

The 31 hypothyroid patients who took part in the 10-week study during which the participants received in random order either their regular "T4 only" thyroid medication (e.g. 200mcg of T4) or an identically looking combination preparation in which 50mcg of the original T4 dosage had been replaced with 12.5mcg of T3 (e.g. 150mcg T4 + 12.5mcg T3). The patients, 31 women and 2 men with a mean age of 46 years and either autoimmune thyroiditis or thyroid cancer that was treated with baseline doses of 75±53 µg T4 per day  (range 100-300 µg), were closely monitored during the both of the 5-week interventions and biochemical, physiologic, and psychological tests were performed at the end of each treatment period.

Figure 2: Cognitive performance and psychological well-being of the 32 subjects of the Bunevicius study assessed by standardized tests on either regular T4 only or T4 and T3 combination protocols (based on Bunevicius. 1999)

A cursory glance at the subjects' "objectively" measured cognitive performance (figure 2, left) and pyschological well-being (figure 2, right) does already reveal that there were statistically improvements in a host of parameters that are of unquestionably greater importance to your daily life than an "optimal" level of thyroid stimulating hormone.

Figure 3: Mood and physical symptoms in the 32 subjects of the Bunevicius study assessed by straight forward questionnaires with visual analogue scales - this is the "how do yo actually feel" data (based on Bunevicius. 1999)

If you combine that with the information the patients provided on a visual analogue scale questionnaire on their perceived psychological and physiological well-being, where every single test result spoke in favor of the combination therapy(!), it is thus not very surprising that

[w]hen asked at the end of the study whether they preferred the first or second treatment, 20 patients preferred thyroxine plus triiodothyronine, 11 had no preference, and 2 preferred thyroxine alone (P=0.001).

These results were unrelated to the order of treatment and the two patients who preferred the T4 only treatment had probably ended up slightly hyperthyroid as they were complaining of feeling "slightly nervous during combined treatment" (Bunevicius. 1999). The others however emphasized that they "noticed that they were more energetic, had better concentration, and simply felt better" (ibid.) than on T4 alone.

The Bunevicius study in nuce

Protocol Reduce T4 intake by 4mcg per 1mcg of T3 you introduce; optimally reduce T4 intake by 50mcg and att 12.5mcg of T3 in.

Results Thyroid hormone levels staid in range (see table above), the +3beat/min increase in pulse rate is harmless and the non-significant drop of 6 and 2pts in systolic and diastolic blood pressure is nothing to speak of.

	T4	T4+T3
TSH (µU/ml)	0.8	0.5
TSH = 0*	7	5
T4 (µg/dl)	15.2	11.3
T3 (ng/dl)	87	117

Table 1: Serum levels of selected hormones and *# of patients with serum TSH <0.05µU/ml

Side Effects Two subjects felt slightly agitated on T4 + T3, no other side effect were reported

Useful for people who are taking high (>>50mcg) doses of T4 (only under supervision of your Dr!)

Not useful for people who don't need thyroid medication and simply suffer from low thyroid hormone due to overtraining, undereating or both (see links below).

Suggested reads

• (Over-)Motivational Orthorexia,
• Overtraining, Inflammation,
• Dietary Thyroid Treatment
• more on overtraining
• more on thyroid

Implications: Especially the usually overlooked effects on mood, cognitive function and "subjective" well-being, or rather the negative effects T4 only treatment has on these parameters, do speak in favor of putting the unwarranted prejudice against the "myotoxic" (=heart damaging) T3 overboard. We are, after all, not talking about the induction of full-blown hyperthyroidism, the detrimental effects of which on the hearts of rodents are essentially what brought the myth of the "dangerous T3" to live; we are just talking about doing our best to emulate the natural balance, which is not adequately and reliably measurable by taking the thyroid stimulating hormone (TSH) levels in the blood of a patient as your only reference.

Moreover, the notion of "just throwing in T4 and waiting for the target tissue to produce as much T3 from it as needed" is intrinsically flawed as it negates the established exogenous T3 requirements of the mammalian brain (~20% of the T3; cf. Silva. 1984), as well as the local downregulation of the T4 => T3 conversion in the brain upon exposure to elevated serum thyroxine (T4) levels (Silva. 1985), as they will occur whenever you simply "up the dosage" of levothyroxine in the false belief that this would help you to get rid of persistent symptoms of hypothyroidism. Against that background it appears to be rather the exception than the norm that you would be optimally functioning on T4 only and not end up

1. still systemically hypothyroid with even lower serum T3 levels (or T3-to-rT3 ratios), than before, or
2. now centrally (in the brain) hypothyroid despite "normal" or even suppressed TSH levels and adequate or high circulating thyroid hormone levels

Against that background, the researchers conclusion that the "ideal replacement regimen [especially] when thyroid-gland function is absent or nearly absent might consist of 10 µg of triiodothyronine daily in sustained-release form (because the hormone is rapidly absorbed and metabolized), along with enough thyroxine to ensure euthyroidism" (Bunevicius. 1999) does appear reasonable, although the necessity and value of "sustained" release formulas is certainly debatable, esp. for lower doses of T3.

References:

• Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999 Feb 11;340(6):424-9.
• Clur A. Reverse tri-iodothyronine as part of alpha 2 adrenergic receptors. Med Hypotheses. 1986 Nov;21(3):281-92.
• Hue O, Marcotte J, Berrigan F, Simoneau M, Doré J, Marceau P, Marceau S, Tremblay A, Teasdale N. Increased plasma levels of toxic pollutants accompanying weight loss induced by hypocaloric diet or by bariatric surgery. Obes Surg. 2006 Sep;16(9):1145-54. 
• Ito M, Miyauchi A, Morita S, Kudo T, Nishihara E, Kihara M, Takamura Y, Ito Y, Kobayashi K, Miya A, Kubota S, Amino N. TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol. 2013 Jun 18.
• Koury EJ, Pawlyk AC, Berrodin TJ, Smolenski CL, Nagpal S, Deecher DC. Characterization of ligands for thyroid receptor subtypes and their interactions with co-regulators. Steroids. 2009 Feb;74(2):270-6. 
• Ruhla S, Arafat AM, Weickert MO, Osterhoff M, Isken F, Spranger J, Schöfl C, Pfeiffer AF, Möhlig M. T3/rT3-ratio is associated with insulin resistance independent of TSH. Horm Metab Res. 2011 Feb;43(2):130-4. 
• Silva JE, Matthews PS. Production rates and turnover of triiodothyronine in rat-developing cerebral cortex and cerebellum: responses to hypothyroidism. J Clin Invest 1984;74:1035-49.
• Silva JE, Leonard JL. Regulation of rat cerebrocortical and adenohypophyseal type II 5'-deiodinase by thyroxine, triiodothyronine, and reverse triiodothyronine. Endocrinology 1985;116:1627-35.
• Tremblay A, Pelletier C, Doucet E, Imbeault P. Thermogenesis and weight loss in obese individuals: a primary association with organochlorine pollution. Int J Obes Relat Metab Disord. 2004 Jul;28(7):936-9.