Stronger & Leaner or Fatter & Less Muscular W/ 4,000IU Vitamin D3 - What if Abstract and Data Tell Different Stories?

Image 1: The gap between the purported and the real world effects of vitamin D3 supplementation remains about as wide as the Grand Canyon - if not wider... and it takes a lot of ignorance towards your own study results to fill this divide up :-o

It is astonishing how fast things can change, only last Thursday I said on the SuppVersity Science Roundup on SHR, that hitherto trial after trial with supplemental vitamin D in the form of cholecalciferol (vitamin D3) failed to produce the desired results. And what do I have to tell you today? A group of researchers from the Purdue University and the College of Charleston have just published a study that appears to make it necessary for me, to at least rectify the previous assessment by stating: "With the exception of a recent trial from the Purdue University ..." Upon having a closer look at the actual data, it did yet turn out that the gap between what the abstract, on the one hand, and the real data, on the other hand, is about as wide as the still existent divide between the purported benefits from vitamin D supplementation and the real-world outcomes of respective trials.

It sounds as if Carillo et al. had finally done, what no one else has done before them, ...

Figure 1: Rel. odds ratio you make it to 100, 90-99, 80-89 yrs instead of dying before your 80th birthday - the results are based on a 44-year prospective study investigating the relation between midlife muscle strength and human longevity and found that "centenarians belonged 2.5 times  more often to the highest third of grip strength in midlife" (Rantanen. 2012)

... i.e. it sounds as if they had observed at least parts of the beneficial effects that are constantly being ascribed to vitamin D supplementation in 23 overweight and obese young men and women (age: 26.1 ± 4.7 y; BMI: 31.3 ± 3.2 kg/m²) with low, but not (officially) deficient 25-hydroxyvitamin D (25OHD) levels of 19.3 ± 7.2 (the official normal rage is between 9-80ng/ml):

"Vitamin D supplementation in overweight and obese adults during resistance training induced an early improvement in peak power, and elevated vitamin D status was associated with reduced waist-to-hip ratio." (Carillo. 2012)

So, according to the conclusion both strength and body composition improved n the course of the 12-week training intervention, which consisted of a 5min warm-up + light stretching (see also "Stretching Before Workouts Makes You Weak!"), followed by 8 machine-based (Kaiser Equipment) resistance exercises, namely

• leg extensions, leg flexions, leg presses, 
• hip adductions & hip abductions, 
• chest presses, seated rows & lat pull downs,

at a progressively increasing intensity, starting with 70%RM in the first weeks and 80% of the 1RM for three sets of 8 repetitions (or "momentary muscular failure"), right? Sounds like that, I should say!

Serious training + serious nutrition = serious gains... but what about vitamin D?

Moreover, with the additional protein shake (360 kcal; 8 g fat, 54 g carbohydrate, 20 g milk protein isolate, 100IU vitamin D and 300mg of calcium) every participant had to consume during the hour following the exercise sessions, the scientists rightfully call their experimental protocol "anabolic". It is thus no wonder that aside from ostensible weight loss and strength gain, both of which you would expect in formerly sedentary subjects, the subjects in both groups did also increase their lean mass (see figure 2, right) .

Figure 2: The hushed up truth Part I => "Gain less muscle and more fat with vitamin D" (right) and have a statistical significant, but real world highly questionable correlation between 25OHD and waist-to-hip ratio of R²=0.205, yet not vitamin D3 supplementation (small, insert; all data based on Carillo. 2012)

What the scientist didn't tell you in the afore-cited conclusion to their abstract, though, is that the group which received an additional 4000 IU vitamin D3 instead of the microcrystalline placebo, did gain less lean mass and more fat mass than their peers. And while the inter-group difference for each of these parameters is statistically not significant, I would bet that their ratio, i.e. the ratio of lean mass to fat mass gains, in this case 5.6 kg muscle per 1kg fat in the placebo vs. 1.8kg muscle per 1kg fat in the vitamin D3 group, were! A difference, by the way, which is not simply a result from the greater increase in energy intake in the vitamin D3 group (see figure 2, left), as the latter should have increased both, lean and fat mass gains. What it effectively did, however was exactly the same as a vitamin D supplement in a rodent study it worked as a "fat-synthesizer" (see "Vitamin D3 a "Fat Synthesizer"!? Rodent Study Shows +33% Increased Fat Deposition in Vitamin D3 Supplemented Mice.")

"Something is rotten is rotten, here, and I can tell you Horatio heaven did not direct it"* 

* I hope you like Shakespeare ;-)

Figure 3: If you want lower PTH vitamin D may be worth it, if not, you get only a non-significant worsening of your glucose metabolism; in addition to increases in body fat and lower lean mass gains (cf. figure 2) obviously (Carillo. 2012)!

The fact that we see only increased fat but not muscle gains, however, only adds to a whole list of observations which show that irrespective of how cleverly the abstract tries to make this look like the "break-through study" about the benefits of vitamin D supplementation, we are yet dealing with nothing more but another confirmation of the futility of vitamin D3 supplements. After all, the 4,000 IU of D3 were not even able to increase the levels of 25OHD to a statistically significant (inter-group differences!) degree (see figure 2). If you also take into consideration that

• contrary to the actual vitamin D levels shown in figure 2 (small insert), the provision of 4,000IU/day of D3 did not (!) correlate with a reduction in waist-to-hip ratio,
• the vitamin D3 supplement did not increase serum calcium (see figure 3, top), and
• the participants who received the active supplement, exhibit an allegedly non significant, but still existent worsening of their glucose metabolism (cf figure 3, bottom) 

it must be allowed to ask whether the -34% reduction in PTH, which is the only blood parameter that exhibited a statistically significant inter-group difference, is reason enough to take an otherwise at best ineffective supplement.

"But it does make you stronger!" - Nope, that's another trick!

The latter is all the more true, because the participants in the vitamin D arm of the study may have increased their peak power faster (see figure 3), but the did not increase their overall strength on any of the exercises to a greater extend than the men and women in the placebo arm of the study.

Figure 4: Relative (left) and absolute strength gains (middle) as well as time course of peak power changes
(calculations based on Carillo. 2012)

The notion that this was the case, is simply a consequence of selective reporting (or in this case "highlighting") of study outcomes (cf. Chan. 2004); or, in other words, we are (mis-)lead by the overemphasis Carrillo et al. put on the early (first 4-weeks) increase in peak power, and their corresponding nonchalant surreptitious reference to the fact that "[n]o other improvements were observed with supplementation" (Carillo. 2012). In short, there is a ballyhooed increase in "peak strength" in the early weeks, but this does not change the fact that the participants in the vitamin D3 arm of the study ended up gained more fat and less muscle, and were - at the end of the trial - neither stronger nor leaner (neither in terms of their body fat %, nor in terms of their waist-to-hip ratio, which was not associated with supplementation!)

From a mere statistical perspective, you could even argue that nothing happened. And let's be honest does that vindicate vitamin D supplementation? I don't think so! If you want to make a change, get big and buffed or strong and sexy, get your lazy ass off the couch and out in the sun, work out regularly, prepare your own nutritious food and drop all useless supplements (see "Three Simple Rules of Smart Supplementation") ... but you know all that, already, right?

Image 2: Does "doing science" come down to presenting only those facts that are in line with the orig. research hypothesis, these days? (img. geekology.com)

Some more general remarks: Now, I could hardly care less that this is yet another study showing that vitamin D3 is a supplemental non-starter., but there is one thing that really drives me up the walls and this is the fact that you as an intelligent and critical SuppVersity reader who is determined and willing to question what he reads on the Internet, but in 99% of the cases won't have access to full-texts of papers like this, are being mislead by abstracts, which are written for the sole purpose to tailor to the original research hypothesis

"[...] that vitamin D supplementation during resistance training would result in greater gains in muscle mass and function as well as improved glucose tolerance compared to exercise training alone." (Carillo. 2012)

and that irrespective of the fact that the actual data disproves this hypothesis!

References

• Carillo AE, Flynn MG, Pinkston, C, Markofki MM, Jian Y, Donkin SS, Teegarden D. Impact of vitamin D supplementation during a resistance training intervention on body composition, muscle function, and glucose tolerance in overweight and obese adults. Clinical nutrition (Edinburgh, Scotland) 3 September 2012.
• Chan AW, Hróbjartsson A, Haahr MT, Gøtzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA. 2004 May 26;291(20):2457-65
• Rantanen T, Masaki K, He Q, Ross GW, Willcox BJ, White L. Midlife muscle strength and human longevity up to age 100 years: a 44-year prospective study among a decedent cohort. Age (Dordr). 2012 Jun;34(3):563-70. Epub 2011 May 4.

Vitamin D & PUFA - Is There an Overlooked Antagonism Between Polyunsaturated Fatty Acids and Vitamin D3?

Image 1: Do not write off all the "good"
foods until you read the full blogpost,
including my comment at the end
(image by ADAM)

Hah... I knew a newsitem the title of which joins everybody's contemporary "pet supplements", would get your attention. Quasi as a byproduct of one of the hilarious vitamin D + calcium trials in which scientists seek to prevent bone loss and fracture in men and women age 65 and older by supplementation with 700IU (no I am not missing a "0", here) and 500mg calcium per day, Sathi Niramitmahapanya and his colleagues from the  U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University found an interesting and previously not thought of negative correlation between their subjects' plasma levels of 25-hydroxyvitamin D (25OHD) levels and the ratio of poly- to monounsaturated fatty acids in their diets (Niramitmahapany. 2011). Could it be that you have to choose, when it comes to high vitamin D or PUFA intake?

Since this was not a specifically designed experiment, Niramitmahapany et al. had to rely on the data that had already been gathered in a 3-year, randomized, double-blind, placebo-controlled trial, originally designed to determine the effect of supplemental vitamin D + calcium on rates of  bone loss and fractures in 152 men and women (age >65years). Consequently, the study relies heavily on the accuracy of complex regression analysis, by the means of which the Tuft researchers tried to figure out which of the handful of confounding variables they had surveyed, had the greatest influence, or I should say statistically measurable explanatory value for the effect of vitamin D3 supplementation on serum 25-hydroxyvitamin D levels in their elderly subjects.

In essence a regression model consists of a system of several sets of loosely predefined partial differential equations (e.g. logarithmic, linear, polynomial, etc.), the scientists, or rather their computers (in this particular study, the SPSS software package was used for statistical analyses) solve using the experimentally established data. Although statistical analyses like this allow for literally unlimited adjustments for confounding variables, such as body weight, total energy intake, etc., the underlying models are still in and out of themselves theoretical constructs that are based on certain hypothesis and assumptions. Thus, any "associations" of parameter A and outcome B, which are usually expressed in the form of regression coefficients (larger coefficient = greater explanatory power), are valid only if all the underlying assumptions hold true.

Out of the parameters Niramitmahapany et al. evaluated, the only independent variable with a significant impact on the effect of supplemental vitamin D3 on serum levels was the composition (not the absolute amount!) of the fats in the subjects' diets.

Figure 1: Statistically modeled regression coefficients of total fat intake and MUFA/PUFA ratio; adjusted for baseline BMI, 25OHD levels, total energy intake (data adapted from Niramitmahapany.. 2011)

As the regression coefficients in figure 1 clearly show, neither the absolute amount of fats nor the absolute amount of an individual type of dietary fat (monounsaturated, MUFA; polyunsaturated, PUFA; saturated fatty acids, SFA) are adequate predictors of serum 25OHD levels. The ratio of monounsaturated to polyunsaturated fatty acids (MUFA / PUFA ratio) on the other hand turned out to be a pretty reliable predictor of the amount of active vitamin D in the sera of the study participants. This was all the more the case if possible influences of saturated fatty acids were taken into account in the model, as well.

Now, statistics and "associations" are one thing, mechanisms and "causations" are yet another; and obviously the latter, i.e. cause-and-effect relations and determinisms, are what humans, in general, and natural scientists, in particular, have been striving for even before the early days of natural science in the ancient times. Thus, I assume you will be interested to hear, what the scientists have to say with regard to the underlying mechanisms of the statistical "association" they observed:

The mechanisms by which fatty acid intake may influence vitamin D3 absorption have not been completely delineated. Most of the available evidence comes from early work by Hollander and colleagues (Hollander. 1981). Their gut perfusion studies in the rat revealed that vitaminD3 is absorbed by passive diffusion in the proximal jejunumand the distal
ileum (10). Absorption of physiological doses of vitamin D3 in rats was reduced by 30%in the presence of a 4-fold increase in luminal fat (Hollander. 1978; 1981), and consistent with our findings, the PUFA, linoleic and linolenic acids, were particularly effective in decreasing vitaminD3 absorption (Hollander. 1978). Hollander offered several potential explanations for why these fatty acids impaired vitamin D3 absorption. They may have increased the solubility of vitamin D3 in the micelles and changed the partition coefficient such that the vitamin D3 stayed in the micelle. Alternatively, they may have increased the size of the micelle and thereby reduced its diffusion rate and increased its difficulty in crossing the unstirred water layer lining the intestinal mucosa. 

I suppose, what you just read about how dietary fat impairs the absorption of vitamin D goes against all you have hitherto heard from the same "experts" and "gurus" who have been telling you to take 20g of fish oil and 20.000IU of vitamin D, each day. Well, in their defense, it should be said that small amounts of dietary fat are actually beneficial, probably even essential for the uptake of the so-called "fat-soluble" vitamins A, D, K (and probably even E), BUT its obviously not the fat that "drives" or "carries" the vitamins into your blood stream, but the bile acid that is secreted in order to digest the former, which helps with / is necessary for the absorption of these, in the true sense of the word, vital nutrients. Moreover, as Niramitmahapanya et al. state, even evidence for the general accepted claim that vitamin D from small amounts of fish oil "produced a greater increment in 25OHD than vitaminD3 as a powder or dissolved in ethanol" is "inconclusive", ...

because the starting 25OHD levels, study durations, and dosing schedules in the available studies weren’t matched and because increment in 25OHD rather than absorption of parent vitamin D3 was measured.

And studies by Holvik (2007) and Maalouf (2008) which compared identical doses of vitamin D as a powder or in ethanol vs. vitamin D in oil found no difference.

The authors of the study at hand obviously did not look close enough at the data of the Maalouf study, because they state that Maalouf had "found the serum 25OHD increment to be greater with the oil vehicle", which may be correct, but the difference was small and mainly the result of a single 'hyperresponder' within the small study population (N=9 in the respective group). The "greater increment" in the oil group of the Maalouf study is thus statistically irrelevant.

So, while it appears quite clear that the general effect of large amounts of fat taken with physiological doses of vitamin D is a negative one, the scientists cannot explain why mono-unsaturated fatty acids seem to be an exception to the way the other fats (and PUFAs in particular) appear to negatively affect micelle content or migration rate of fat-soluble vitamins in the intestines. Yet, whatever the mechanism may be, an increase or, after all, a reduced decrease in vitamin D3 absorption from the gut may yet be another of the hitherto established health benefits of the long-overlooked mono-unsaturated fatty acids.

Dr. Andro's comment: If you want my personal assessment of these results, take them with an appropriate amount of skepticism. After all, eating meat, fish, liver, eggs, dairy etc., all rich sources of dietary fat and fat soluble vitamins, is the way nature intended us to get part (remember we would synthesize most of our vitamin D from sun exposure) of our vitamin D. So, the only way it would make sense that fat reduces its absorption would be the close association of cholesterol, which is the building block our body uses to manufacture vitamin D, and fatty foodstuff. It would thus be more prudent to say that "fat starvation", which would naturally be associated with low cholesterol intake, is a signal for you body to increase vitamin D uptake, in order to save the valuable cholesterol for the production of other hormones. Instead of avoiding fatty foods, you should thus rather get your lazy ass off the couch and into the sun to put the cholesterol from your 10-egg-breakfast-omelet to good use ;-)

Strengthless Gains: HMB+Arginine+Lysine Build Muscle. Strength Gains Require Vitamin D Levels >30mg/mL

Image 1: I wonder, why
gerontologists don't use
plain BCAAs - too convenient?

If, as I hope, you are a regular visitor of the SuppVersity, you know that in this day and age of vitamin-D3-loving, I am an outspoken skeptic, as far as the "magic" of supplementing with the undreestimated bone-building vitamin is concerned. That being said, I am all the more happy that after thousands of worthless epidemiological studies, scientists eventually begin to conduct well-controlled clinical trials, which provide factual information instead of dodgy hypothesis on the complex mechanisms by which our vitamin D status modulates a number of metabolic processes which reach far beyond the health of our bones.

Did you know that the most recent studies on the effects of vitamin D on weightloss (Soares. 2011) and type 2 diabetes (Mitri. 2011) conclude that "[c]urrent evidence from RCTs [randomized controlled studies] did not consistently support the contention that calcium and vitamin D accelerated weight or fat loss in obesity" and that, in the majority of hitherto published, well-powered studies "no effect of vitamin D supplementation on glycemic outcomes" was seen "among participants with normal glucose tolerance at baseline and in three small underpowered (n=32–62) trials of patients with established type 2 diabetes". The obvious discrepancy between the euphoria, or I should say, hype the unreliable epidemiological trials brought about and the disillusioning results of real science, which will always go beyond mere observation, should remind you of the ease with which you can design or (mis-)interpret epidemiological studies in order to prove whatever hypothesis you want - I do not have to remind you of the "fat lies" related to the detrimental effects of saturated fats on heart health, do I?

But let's get back to the topic at hand - strengthless muscle growth. In a year-long double-blinded, controlled study (Fuller. 2011) John C. Fuller, Jr. and his colleagues from Iowa State University and the Vanderbilt University Medical Center provided 39 elderly women and 38 elderly men (age 76+/-1.6 years) with an amino acid supplement which contained either a blend of HMB + Arginine + Lysine (2.0 g CaHMB, 5.0 g arginine, and 1.5 g lysine) or an isocaloric non-essential amino acid placebo (alanine 5.6 g, glutamic acid 0.9 g, glycine 3.1 g, serine 2.2 g). The supplement, of which the heavier participants (>65kg) consumed 1.5x the amount of their lighter age-mates, was to be taken each day, with breakfast. Based on previous research by Vukovich (2001) and Flakoll (2004), Fuller et al. hypothesized that the intake of the HMB-containing amino acid blend would result in statistically significant gains in both strength and size of the muscles of their elderly participants.

In fact, HMB has been shown to stimulate protein synthesis and reverse its inhibition by lowering proteolysis-inducing factor, lipopolysaccharide, tumor necrosis factor α, and angiotensin II via an upregulation of the mTOR / p70S6k pathway. By attenuating the activation of caspases-3 and -8, HMB supplementation may also decrease the formation of reactive oxygen species and the activation of the ubiquitin-proteosome degradation pathway. If you asked me, however, you would probably see the very same benefits from supplementing with HMB's way cheaper precursor leucine - keep that in mind before you waste your money on a hardly palatable amino acid derivative your body will synthesize on its own, if you just provide the right substrate, i.e. l-leucine from BCAAs, EAAs or just plain whey protein.

In view of the fact that in a previous study by the same group (Baier. 2009) an identical amino acid supplement had failed to elicit  significant strength increases in a similar subject group, and based on previous findings by various scientists on the detrimental effects of full-blown vitamin D deficiency (<15ng/mL 25OHD3) on muscle strength, Fuller et al. speculated that there could be a synergy (which does not equal "vitamin D builds strength) or interdependence between the provision of the leucine metabolite HMB, the vitamin D status of a person and the ensuing improvements in muscle size and strength.

Figure 1: Relative changes in lean body mass in 77 elderly subjects after one year on a HMB+Arginine+Lysine supplement (calculated based on data from Fuller. 2011)

The results of their study (cf. figures 1-2) suggest that 'adequate' vitamin D levels (25OH-D3 > 30ng) are not required for the HMG + Arginine + Lysine amino acid mixture to work its muscle building magic on elderly subjects.

Figure 2: Increase in total leg strength [in ft-lbs] as measured by the sum of knee extension and flexion at 60 and 120 degrees/s in 77 elderly subjects after one year on a HMB+Arginine+Lysine supplement (data adapted from Fuller. 2011)

Yet, in subjects with 25OH-D3 levels <30ng was this increase in muscle mass also accompanied by strength gains, which were approximately 4x higher than in the unsupplemented control group (cf. figure 2).

Vitamin D and muscular strength in the elderly: Bischoff-Ferrari et al. (2004) found continued improvements in lower extremity function up to 40ng 25OH-vitD3/mL, a level well above what has been previously thought necessary for maximum benefit. Although this does not sound much, clinical trials such as the one Andres Ernesto Carillo conducted as part of his dissertation (Carillo. 2010) show that supplementation with 4.000 IU VitD3, which is way beyond what conservative physicians would deem tolerable, raised vitamin D in 23 previously deficient individuals (25OHD levels = 19.3ng/ml; age 26.1 +/- 4.7yrs) levels by no more than + 2.7ng/mL over control.

A word of caution before you ramp up your supplemental vitamin D intake to a bottle a day: Although this was a "double-blind controlled" trial, the controlled parameter was not vitamin D supplementation, but the HMB+Arginine+Lysine mixture the elderly subjects received - as far as the vitamin D status was concerned, the study was merely observational. That being said, the study may have higher significance than the unreliable epidemiological guesswork, you will hear about in the news almost daily, it does not allow, however, any (not even preliminary) conclusions regarding the potential effect supplemental vitamin D would have had on the outcome of the study. If the low vitamin D level was just corollary to or caused by some other underlying conditions, for example, it would be very unlikely that even 100.000IU of vitamin D would have had a significant effect on the muscular performance of the subjects.

There Are Two Sides to Each Coin: Vitamin D Increases Insulin Sensitivity in Obese, Yet Decreases it in Lean Mice

I am probably repeating myself, but I cannot emphasize enough that a common fallacy of medical research is the focus on pathologies. A recent example with respect to the "omnipotency" (that's what the Internet news could make you believe) of vitamin D comes from researchers at George Town University (GU. Press Release).

The scientists were able to replicate the results of previous studies, where high dose vitamin D supplementation had "significantly reduced development of estrogen receptor-positive (ER+) breast cancer", but for estrogen receptor-negative (ER-) breast cancer they found either no effect (lean mice) or even an increased rate of cancerous growth in the group of obese mice.

What's yet even more interesting that a similar contradiction was evident with respect to vitamin D's widely perpetuated beneficial effects on insulin resistance. In the pathologic model of the obese mice, vitamin D @ 15-25k IU per day was in fact able to ameliorate insulin resistance, in the lean, naturally insulin sensitive mice, however, insulin sensitivity was reduced by supplemental vitamin D.

As I've discussed it in the context of the most recent fish oil study (and will probably repeat for other "super nutrients"), in 99.9% of the cases the effect of - especially high dose - supplementation with ostensibly harmless "vitamins" or "nutrients" vary enormously depending on the subjects current nutritional and health status. To derive one-size-fits-it-all recommendations from individual studies and to transfer results obtained from a pathological model without further scientific investigations to a healthy one is careless and may turn out to be very dangerous.

9.600 IU Vitamin D Required to Get 97.5% of a Study Population to Serum 25(OH)D Levels of At Least 40ng/ml

I refrained from posting each and every study on vitamin D that has been published within the past weeks - nothing new or exciting there + way too much hype, if you want my opinion... BUT now, finally, there is some additional large-scale scientific data on the issues of how much is enough and how much is too much of supplemental vitamin D!

In the latest issue of Anticancer Research Garland et al. (Garland. 2011) published a study in which self-reported supplemental vitamin D intake in a cohort of 3,667 men and women from different ethnic backgrounds was assessed and corresponding serum vitamin D levels were measured.

Figure 1: Reported daily intake of vitamin D vs. measured serum 25(OH)D levels in study cohort of 3,667 subjects (Garland. 2011)

Unsurprisingly, "serum 25(OH)D rose as a function of self-reported vitamin D supplement ingestion in a curvilinear fashion", but other than some fear mongers would have us believe, ...

no intakes of 10,000 IU/d or lower producing 25(OH)D values above the lower-bound of the zone of potential toxicity (200 ng/ml).

While you, as a regular visitor of the SuppVersity, already knew that doses up to 10,000 IU are generally save, this is probably the first time you read a reliable number on how much supplemental vitamin D it takes to bring 25(OH)D levels to >=40ng/ml (which is even below the concentration of 60-80ng/ml, where scientists believe the anti-cancer effects of vitamin D set in):

The supplemental dose ensuring that 97.5% of this population achieved a serum 25(OH)D of at least 40 ng/ml was 9,600 IU/d.

In view of the authors conclusion that even "universal intake of up to 40,000 IU vitamin D per day is unlikely to result in vitamin D toxicity", and under the assumption that your vitamin D levels, as measured by blood tests, are low, you better invest in some high dose vitamin D supplements if you do not want to pop dozens of pills everyday.