Magnesium Could be in Charge of Your Vitamin D Levels: Supplements Lower High and Increases Low 25OHD Levels

D3 and Mg Supplements not mandatory w/ sun + balanced diet

If you subscribed to the @SuppVersity Facebook Page, you will have read the news, already: "Magnesium status and supplementation influence vitamin D status and metabolism" (Dai 2018) - that is both the title and the main results of a recent study from the Vanderbilt University that is important enough to make it from the short format on Facebook to a detailed SuppVersity article of its own - the article at hand ;-)

The 25OHD-balancing effects Dai et al. observed in their 180 participants (aged 40–85 y) could after all do much more than point towards a reason why everyone and his mama seems to be D-ficient - it could force us to redefine what "optimal" 25OHD levels are - significantly below those many Internet "health experts" recommend.

Learn more about vitamin D at the SuppVersity

How Much Vitamin D Shall You Take?

Leucine, Insulin, Vitamin D and Your Gainz

Vitamin D Speeds Up Exercise Recovery

One Svg of Fish or Eggs Satisfy Your Needs?

Vitamin D an Essential Supp For Athletes?

New Dosing Suggestions for Mr./Mrs. Average

The study is a National Cancer Institute independently funded ancillary study, nested within the "Personalized Prevention of Colorectal Cancer Trial" (PPCCT), which enrolled 250 participants at risk of developing colorectal cancer. The PPCCT is a double-blind 2 × 2 factorial randomized controlled trial conducted in the Vanderbilt University Medical Center.

Customized supplementation with magnesium glycinate brought the subjects' total magnesium into the range of the RDA (men 400-420 mg/d, women 310-320 mg/d)

What makes the study stick out is that doses for both magnesium and placebo were customized based on baseline dietary intakes - in other words: The less magnesium in the diet, the more was supplemented. Furthermore, the scientists tested not just 25OHD (which is what your doctor will test if you ask for a "vitamin D test") but also changes in plasma 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2 [25(OH)D2], 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] - all by liquid chromatography–mass spectrometry.

Based on the somewhat disappointing observation that vitamin D was not related to cardiovascular disease in the recent VITAL trial (Kubiak 2018) - even in subjects with baseline vitamin D insufficiency(!) - the researchers whose current main objective is to elucidate the role that magnesium may play with cancer as part of the previously mentioned "Personalized Prevention of Colorectal Cancer Trial" speculated that "magnesium supplementation differentially affects vitamin D metabolism dependent on baseline 25-hydroxyvitamin D [25(OH)D] concentration" (Dai 2018).

In previous experiments, the scientists had already observed that people's ability to synthesize "vitamin D" depended on their magnesium status.

About both, the US's vitamin D and magnesium status, co-author Martha Shrubsole, Ph.D., research professor of Medicine, points out in the corresponding press release:

Magnesium is at the center of vitamin D metabolism - as part of CYP, cytochrome P450 enzymes (dark gray indicates deactivating enzymes, and light gray indicates activating enzymes | Dai 2018)

"Vitamin D insufficiency is something that has been recognized as a potential health problem on a fairly large scale in the U.S. A lot of people have received recommendations from their health care providers to take vitamin D supplements to increase their levels based upon their blood tests. 

In addition to vitamin D, however, magnesium deficiency is an under-recognized issue. Up to 80 percent of people do not consume enough magnesium in a day to meet the recommended dietary allowance (RDA) based on those national estimates" (from Vanderbilt press release). 

[Worth mentioning:] "Shrubsole stressed that the magnesium levels in the trial were in line with RDA guidelines, and she recommended dietary changes as the best method for increasing intake. Foods with high levels of magnesium include dark leafy greens, beans, whole grains, dark chocolate, fatty fish such as salmon, nuts and avocados." (ibid.). 

Incidentally, the hypothesis that these two deficiency nutrients may interact is not even new. You can go back as far as 50 years and will find (rodent) studies showing how vitamin D affects not just calcium but also magnesium levels (Harrison 1964). Hitherto, though, this interaction has often been ascribed to the ability of vitamin D to increase Mg absorption irrespective of one's vitamin D status.

Having high(er) 25OHD levels was found to be associated with 11-13% reduced all-cause mortality hazards in a 2013 study using data from NHANES 2001-06 - for those of the subjects that consumed high(er) amounts of magnesium the hazard reduction compared to D-ficient levels of <20ng/ml was 23%-30% and the overall HRs up to 20% lower (Deng 2013).

The opposite, i.e. putative effect of magnesium on vitamin D, on the other hand, has been largely ignored - despite the fact that more recent studies, such as Deng et al. 2013, in which the authors analyzed NHANES data from 2001 to 2006 seem to suggest that there's a two-way interaction of magnesium and vitamin D in relation to risk of both vitamin D deficiency and insufficiency - with literally life-threatening/saving implications (Deng 2013).

Which Mg is best? Plasma an bone (primary axis) as well as red blood cell (RBC; 2ndary axis(!)) content after 14 days of supplementation with identical amounts of magnesium in different organic and inorganic forms (Coudray. 2005 | learn more) - unfortunately, the study was conducted in rodents and used only gluconate, not glycinate as it was used in the PPCT trial.

Now, we shouldn't forget that, in Deng's study, we're talking about correlations/associations of which Zittermann in a 2013 writes that it "provides important findings concerning potential metabolic interactions between magnesium and vitamin D and its clinical relevance.

In 10 lab-workers, the mean serum 25(OH)D varied widely [from 17.1 (4.6) to 35.6 (5.2) ng/ml; P < 0.005] between laboratories (error bars represent SEM). B, Similarly, marked within-individual variation was observed in 25(OH)D measurement in different laboratories. This means: Whether an individual has hypovitaminosis D (threshold = dashed line) depends on which laboratory was used. 

I've heard the vitamin D test is inaccurate - Is that accurate or #fakeNews? Accurate. As Holick points out in a 2009 paper, "the first assays for 25(OH)D used the competitive protein binding format with the vitamin D binding protein (DBP) as the binder" - advantage: recognizes 25(OH)D2 equally as well as 25(OH)D3; disadvantage: the assay will also measure all sorts of D-metabolites including 24,25-dihydroxyvitamin D [24,25(OH)2D], 25,26-dihydroxyvitamin D and the 25,26-dihydroxyvitamin D -26, 23-lactone, which reduces the accuracy by ~10-15%.

The same issue(s) exist(s) for the radioimmunoassay (RIA | Diasorin@) which "typically overestimated 25(OH)D levels by approximately 10-20%" (ibid). Moreover, IDS has recently developed an RIA "which has a 100% specificity for 25(OH)D3 and only 75% specificity for 25(OH)D2 (ibid) and could thus be a more accurate alternative (still, if you're D-ficient or not often depends on which lab you're using (see Figure on the right | from Binkley 2004)

So how do you get the absolute accurate levels? You don't... well, actually you don't have to. Scientists, on the other hand, should use liquid chromatography tandem mass spectroscopy (LC-MS) to measure 25(OH)D in human serum, directly. This assay quantitatively measures both 25(OH)D2 and 25(OH)D3.

However, results should be considered preliminary since biochemical data on individual magnesium status were lacking, [and] confounding cannot be excluded" (Zittermann 2013). That's in contrast to the more recent observations by Dai et al. whose data come from a tightly controlled clinical trial - a trial that clearly suggests this link could be mechanistic.

The relationship between 25OHD and magnesium is complex and probably U-shaped

Mechanistic, but not simplistic, to be more precise: In the latest study by Dai et al. the relations between magnesium treatment and plasma concentrations of 25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 were significantly different depending on the baseline concentrations of 25(OH)D, and significant interactions persisted after Bonferroni corrections (meaning including statistical correction of multiple comparisons which increase the likelihood of false positives). More specifically, the subjects from the "Personalized Prevention of Colorectal Cancer Trial" whose data the Vanderbilt scientists analyzed revealed that ...

• 

  The main result of the study: The provision of adequate (RDA) amounts of magnesium seems to help balance the 25OHD levels of the subjects in the PPCCT trial at ~30ng/ml.

  magnesium supplementation increased the 25(OH)D3 concentration when baseline 25(OH)D concentrations were close to 30 ng/mL, ...
• but decreased the levels of 25(OH)D3 when the baseline 25(OH)D was higher (from ∼30 to 50 ng/mL | insufficient data to reliable statements about even higher concentrations);
• moreover, at higher baseline 25OHD concentrations, other 25OHD metabolites, i.e. 25-hydroxyvitamin D2 [25(OH)D2], and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were likewise affected by magnesium supplements, how and at which levels this affects the hitherto often ignored ratio of these D-metabolites and hence our health will have to be elucidated in future studies, though (see figure below).

Overall, the provision of (sufficient =RDA) magnesium seems, as the authors from Vanderbilt University rightly point out, to allow our bodies to keep our 25OHD levels within the middle range of a previously established and repeatedly confirmed U-shaped curve that illustrates the general or specific cardiovascular disease risk as a function of serum 25OHD levels (Ross 2011; Abraham 2011).

Somewhat surprising for the "more is more" proponents, high 25OHD3 and 24,25(OH)2D3 decreased with magnesium supplementation; the often derided 25(OH)D2, on the other hand, increased (Dai 2018).

In the discussion of the results, Dai et al. (2018) write that "magnesium supplementation may not only accelerate the metabolism and degradation of 25(OH)D3 but also shift CYP3A4 to selectively degrade vitamin D3 over vitamin D2 when plasma 25(OH)D is high" - it doesn't take a scientists to realize that the findings of the study at hand thus "provide the first evidence that adequate magnesium status could potentially prevent vitamin D–related adverse events" (Dai 2018).

The existence of such a "comfort zone" is also in line with some recently published paper in the Journal of Steroid Biochemistry and Molecular Biology in which Mohammed S. Razzaque highlights that "Vitamin D status is more likely to be a consequence rather than a cause of a disease" (Razzaque 2018). That magnesium may help keeping your levels within this "comfort zone" may hence be either the results of direct interactions or simply the consequence of the well-proven cardiovascular and metabolic benefits of getting enough of the precious mineral in your diet.

More Than a Diet Myth? Dark Chocolate/Cacao Won't Get You Jacked, but it May Help Maintain a Slim Waist Over Time | read the whole SuppVersity Classic

Another reason to eat more chocolate... just kiddin', although Dai et al. rightly point out that, in spite full-blown deficiency intakes in  79% of US adults (NHANES), sufficient amounts of magnesium can be easily consumed with our diet if the latter contains copious amounts of foods with high levels of magnesium include dark leafy greens, beans, whole grains, fatty fish such as salmon, nuts, avocados and dark chocolate!

In this context, it seems appropriate to remind you that the overall result of the study at hand underlines the futility of the Western concept "more helps more", which doesn't seem to hold for vitamin D. In fact, it may well fail you when it comes to magnesium supplementation, too... and I am not just talking about magnesium (and other nutrient) losses due to the laxative effects of the Internet's favorite macromineral, here (noteworthy in this context: 1st study on transdermal magnesium + Mg-bioavailability).

From a mechanistic perspective, the interaction could be a result of the previously illustrated role of magnesium in vitamin D metabolizing enzymes: 1α-hydroxylase (i.e., CYP27B1) and 24-hydroxylase (i.e., CYP24A1), which synthesize and metabolize 25(OH)D and 1,25(OH)2D, respectively. In that, the study at hand is the first large(r)-scale study to (a) be done in people w/out severe Mg-deficiency and to (2) show that normalizing magnesium will not simply increase 25OHD, but seems to modulate it towards ~30-40ng/ml. This warrants mentioning that similar interactions do/could exist with calcium & phosphorus (Harrison 1958; Gray 1977), as well as potassium (Bikle 1978; Rafferty 2008) and salt (Breslau 1982). And guess what: One of them, i.e. calcium or rather a Ca:Mg ratio of ≥2.6, which has previously been found in >76% of the US general adult population, is also characteristic of the subjects in the study at hand - whether high Ca:Mg diets actually 'cause the vitamin D deficiency epidemic will yet have to be elucidated in future studies | Comment!

References:

• Abraham, Paul S., et al. "The vitamin "D-bate": what vascular risk in geriatric inpatients?" Journal of the American Geriatrics Society 59.8 (2011): 1556-1558.
• Bikle, Daniel D., and H. Rasmussen. "A biochemical model for the ionic control of 25-hydroxyvitamin D3 1alpha-hydroxylase." Journal of Biological Chemistry 253.9 (1978): 3042-3048.
• Binkley, N., et al. "Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization." The Journal of Clinical Endocrinology & Metabolism 89.7 (2004): 3152-3157.
• Breslau, Neil A., et al. "The role of dietary sodium on renal excretion and intestinal absorption of calcium and on vitamin D metabolism." The Journal of Clinical Endocrinology & Metabolism 55.2 (1982): 369-373.
• Dai, et al. "Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial." The American Journal of Clinical Nutrition, 108.6(1) (2018).
• Deng, Xinqing, et al. "Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III." BMC medicine 11.1 (2013): 187.
• Gray, Richard W., et al. "The importance of phosphate in regulating plasma 1, 25-(OH) 2-vitamin D levels in humans: studies in healthy subjects, in calcium-stone formers and in patients with primary hyperparathyroidism." The Journal of Clinical Endocrinology & Metabolism 45.2 (1977): 299-306.
• Harrison, Helen C., Harold E. Harrison, and Edwards A. Park. "Vitamin D and citrate metabolism: effect of vitamin D in rats fed diets adequate in both calcium and phosphorus." American Journal of Physiology-Legacy Content 192.2 (1958): 432-436.
• Harrison, Harold E., and Helen C. Harrison. "The interaction of vitamin D and parathyroid hormone on calcium phosphorus and magnesium homeostasis in the rat." Metabolism-Clinical and Experimental 13.10 (1964): 952-958.
• Holick, Michael F. "Vitamin D status: measurement, interpretation, and clinical application." Annals of epidemiology 19.2 (2009): 73-78.
• Kubiak, Julia, et al. "Vitamin D supplementation does not improve CVD risk factors in vitamin D-insufficient subjects." Endocrine connections 7.6 (2018): 840-849.
• Rafferty, Karen, and Robert P. Heaney. "Nutrient effects on the calcium economy: emphasizing the potassium controversy." The Journal of nutrition 138.1 (2008): 166S-171S.
• Ross, A. Catharine, et al. "The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know." The Journal of Clinical Endocrinology & Metabolism 96.1 (2011): 53-58.
• Tuohimaa, Pentti, et al. "Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case‐control study in the Nordic countries." International Journal of Cancer 108.1 (2004): 104-108.
• Zittermann, Armin. "Magnesium deficit-overlooked cause of low vitamin D status?." BMC medicine 11.1 (2013): 229.

AM Cardio for Fat Loss W/ 25g Casein vs. 25g Whey Isolate, 25 g Maltodextrin Preload, or Truly Fasted - What's "Best"?

Don't believe a word when someone tells you that a new study would show that you can burn extra body fat if you consume a casein shake before your (by then no longer fasted) AM cardio workouts.

While the scientific evidence doesn't seem to confirm the superiority of fasted AM cardio (learn more), there's no doubt that it can help you shed body fat if the energy you expend on treadmill ergometer, or rowing machine helps you sustain a >10% energy deficit over the next 24h.

What is highly debated, though, is whether you got to take precautions in form of protein powders (or BCCAs) to protect your muscle from falling apart.

A final answer to this question has yet to be found, but with the results of a recent study by Bradley T. Gieske and colleagues from the Lindenwood University (Gieske 2018), this ostensibly super-important question *rofl* may become redundant, anyway...

Learn more about building muscle and strength while losing fat with www.suppversity.com

Acutely Increased Hormones Don't Grow Muscle?

Protein vs. Carbs 4 Glycogen, BFR & Recovery ...

Pre-Exhaustion Exhausts Your Growth Potential

Exercise not Intensity Variation for Max. Gains

Battle the Rope to Get Both, Ripped and Strong

Study Indicates Cut the Volume Make the Gains!

... How's that? Well, in their study, the US scientists write that "[p]rotein consumption before fasted moderate-intensity treadmill exercise significantly increased post-exercise energy expenditure compared to maltodextrin ingestion and tended to be greater than control" (Gieske 2018). 

For the naive supplement nerd this sounds like "you can have your protein and eat it, too"

SuppVersity readers, on the hand, have learned too much about the futility of post-exercise excess oxygen consumption (aka EPOC) and its (ir-)relevance in terms of fat loss to buy into premature supplement advice a la "Ingest 30.3g of casein 32.4 minutes before your AM cardio workout".Ah... and that's not just Gieske's randomized, double-blind, placebo-controlled, crossover study tested not 30.3g/session, but rather...

• 25g protein in form of 25 g of similarly colored and flavored whey protein isolate, of casein protein (real micellar casein, no cheap caseinates), and compared the effects of this protein preload to 25 g of maltodextrin, or a non-caloric control. 

After the ingestion of the supplement, the participants sat quietly for 30 min before completing a standardized warm-up protocol consisting of whole-body dynamic movements that lasted approximately ten minutes. Hence, the actual testing session, a medium-to-low intensity 30-minute 'cardio' session on the treadmill (55% heart rate reserve) took place 40 minutes after the bolus ingestion of casein, whey, maltodextrin or the zero-calorie control drink. 

Figure 1: Acute exercise-induced (kcal total on the primary axis) and extrapolated post-exercise 24h energy expenditure (kcal/kg/day on the secondary axis) in the study by Gieske et al (2018).

In conjunction with the 15 minutes, it took for the subjects to get their resting metabolic rate post workout (re-)assessment started, the data in Figure 1 was thus generated at roughly T=60 minutes in the early postprandial phase (note: don't forget that the exercise itself will have slowed down the digestion significantly).

"The postprandial phase is not exactly where you'd expect fat oxidation to peak, no?"

Well, in terms of bro-science the above question seems to be very reasonable. As the pros (here Gieske et al.) point out, though, anyone who knows a thing or two about the metabolic effects of protein and the potential issues w/ training fasted will be hardly surprised to see that 

the researchers' hypothesis "that pre-exercise protein ingestion would increase post-exercise energy expenditure and fat oxidation compared to both carbohydrate and fasting conditions" (Gieske 2018)...

... was confirmed when the data from the eleven healthy, college-aged males (23.5 ± 2.1 years, 86.0 ± 15.6 kg, 184 ± 10.3 cm, 19.7 ± 4.4% fat | recreationally active, doing both cardio and weights, being active most of the days - but no athletes) was analyzed. In that it's important to note the following:

• Dietary standardization in form of a replication of the average four-day diet composition reported by participants prior to Visit 1 was as follows: 2446 ± 800 kcal (28.44 ± 9.30 kcal/kg), 132 ± 56 g (1.53 ± 0.65 g/kg) protein, 235 ± 101 g (2.73 ± 1.17 g/kg) carbohydrate, 99 ± 37 g (1.15 ± 0.43 g/kg) fat on the remaining test visits was successful.
• Exercise standardization as measured using one-way ANOVA revealed no significant differences (p = 0.743) in intra-exercise heart rate, rating of perceived exertion (p = 0.985), or oxygen consumption (p = 0.993) between conditions, suggesting that intensity was sufficiently standardized across all testing sessions.
• And the pre-treatment and pre-exercise rates of energy expenditure (Absolute: 1873 ± 189 kcal/day, Relative: 22 ± 2 kcal/kg/day) were not significantly different across conditions (p > 0.99). 

All three factors can thus not explain why the scientists found visible (Figure 1) and statistically significant inter-trial differences between the pre-treatment/exercise energy expenditure and post-exercise energy expenditure. More specifically, the researchers were able to show that, ... 

• 

  #Evidence: Meta-analysis says: "Fasted AM Cardio - No Measurable Physiological Benefits in Terms of Fat Loss & Body Composition" | more

  the energy expenditure after consuming the whey protein isolate (WPI | 3.41 ± 1.63 kcal/kg) was significantly greater (p < 0.05) than the within-group change in REE following consumption of maltodextrin (MAL | 1.57 ± 0.99 kcal/kg, p = 0.010) and tended to be greater than the non-feeding control group (2.00 ± 1.91 kcal/kg, p = 0.055); 
• similarly, the energy expenditure after consuming the casein protein (CAS | 3.38 ± 0.82 kcal/kg) was greater than those following consumption of MAL (p = 0.012) and tended to be greater than the non-feeding control group (p = 0.061) 

About the trend towards statistically significant effects of whey vs control the scientists write that it "is notable, as 73% of the participants during the WPI condition exhibited a change in REE toward the direction of significance" (Gieske 2018 | note: the success rate in terms of being able to observe beneficial effects on energy expenditure was yet highest in the casein group, where 9 out of 11 subjects vs 6 out of 11 participants in the WPI group saw significant increases). 

The researchers calculated within-condition effect sizes for each nutrient (WPI, CAS, and MAL) - with effect sizes for WPI and CAS being moderate to large compared to MAL and CON.

So far, so good, now for the bad news: With a total intra-exercise EE of 345 ± 31 kcal, 362 ± 32 kcal, and 349.17 ± 70 kcal, the increase in energy expenditure compared to the control trial (293 ± 37 kcal) is below the amount of energy, circa 100kcal, in the protein/carbohydrate supplements. 

Figure 2: Individual effects on energy intake and expenditure (left) and corresponding net effect (right).

You can see that very well if you check out the subjects' energy balance right after the workout (Figure 2, left); and things don't look much better if we assume that the post-workout increase in energy expenditure persists, i.e. that the scientists' calculated "increase in energy expenditure" remains stable (or whatever they assumed it did, when they used the data from 20-25 minutes after the workout and extrapolated it to 24h), and calculate the effect of consuming whey, casein, or maltodextrin on the net energy balance.

Do not get me wrong, though... AM cardio aids fat loss!

#Popular: "Ever Wondered Why the Fat Keeps Falling Off When You Embark on Intermittent Fasting Regimens? Calories, Bro!" | read more

I've experienced that repeatedly, myself. For me, personally, doing AM cardio means doing cardio at all. If I postpone it to "later", it is not unlikely that I don't do it at all and fail to burn those extra 300-500kcal which are then not missing from my net energy balance - a balance I deliberately keep in the red while dieting, 'cause there's no metabolic magic in AM cardio that would make the fat fall off, it is pretty much like "fasting": It's all about calories ... well, calories, coffee ('cause you always need it ;-) and weight training + enough protein to optimize your lean mass retention aka "keep your gainz" ;-)

No, no, and no: It does not make a difference! It makes no difference if you consume whey or casein or any other form of protein before your low-to-moderate intensity AM cardio. While the insulin spike from whey may blunt the fat oxidation during the initial 5 minutes of your training that's not relevant for your real-world fat loss.

The same goes for the 14.42kcal difference in the NET energy balance between whey and casein and the overall difference to control, of which we (a) do not even know if those 75-90kcal wouldn't simply be compensated for at lunch or dinner, and/or (b) nullified by potential compensations in REE later in the day (which were not measured).

So what's the verdict, then? In the absence of practically relevant changes in energy expenditure, let alone net energy balance, it would be stupid to expect to lose more body fat if you consume 25g of either whey or casein before your by then no longer "fasted" AM cardio sessions.

What's more, the measurable, but overall small and medium effects (Cohen's d) of casein and whey protein isolate on the subjects' intra- and post-workout total fat oxidation and respiratory exchange rate (ratio of carbohydrates to fats that are used to fuel your metabolic requirements), respectively, are likewise irrelevant when it comes to the alleged "fat burning effects" of AM cardio.

In the end, it's just a zero-sum-game! One of which I can guarantee, however, that it is going to be completely misinterpreted on the average bodybuilding and physique boards, though... especially with the scientists' imho somewhat unfortunate emphasis on the "significantly increased rates of post-exercise fat oxidation and energy expenditure with casein" and "the reduction in [...] total fat oxidized during the exercise bout [with WPI preingestion] compared to casein" in the first paragraph of the discussions | Leave a comment on Facebook!

References:

• Gieske, et al. (2018). "Metabolic impact of protein feeding prior to moderate-intensity treadmill exercise in a fasted state: a pilot study." Journal of the International Society of Sports Nutrition 15:56.

Sodium-/Potassium-Bicarbonate (+Mg, +Ca) Supplement ➡ Improved 6x30m Sprint Time, Lactate, Magnesium & More | Plus: Enterically Coated NaHCO3 Tablets - Where are They?

The stack (ingredients on the right) was ingested twice daily.

It has been a while since the last study on sodium bicarbonate's usefulness has found its way to the SuppVersity.

And, technically speaking, the latest RCT by scientists from the Department of Sports Training at the Jerzy Kukuczka Academy of Physical Education in Katowice, Poland, and colleagues from the Miller School of Medicine, at the University of Miami is a "bicar-bonate", but not a "sodium bicarbonate" study.

How's that? Well, the scientists did exactly what some of you have already suggested: They combined sodium- and potassium-bicarbonate (the authors write di-carbonate, which is obviously the same) at a dosage of 3g, each, to achieve a balance between the two macro-minerals and topped the bicarbonates up with 1000 mg (600 mg + 400 mg) calcium phosphate and calcium citrate, 1000 mg potassium citrate, and 1000 mg magnesium citrate.

Mineral water will contain some K and Mg, too - and it will have other benefits:

Hydrogen Rich Water = Quackery?

Glass of Water Before Meals as Diet Tool

Every Sip of Water Cuts 'ur T2DM Risk

Chilled Water Also Serves as a Nootropic + More

2.5 lbs/8wks of Weight Lost W/ Plain Water

Mineral Water Supercharges 'ur Performance?!

This Na/K-Bicarb + Ca/K/Mg-Citrate super-stack (or placebo) was consumed twice a day by N=26 well-trained soccer players, who compete at the elite Polish league, during an 11-day training camp in Spain. Unfortunately, the exact details about the way the supplement was administered is not adequately described in the FT, where it says:

"The players from the experimental group ingested a single dose of 3000 mg sodium di-carbonate, 3000 mg potassium di-carbonate (6 caps containing 500 mg each), 1000 mg (600 mg + 400 mg) calcium phosphate and calcium citrate, 1000 mg potassium citrate, and 1000 mg magnesium citrate twice a day, 90 min before each practice session. The control group ingested identical capsules containing cornstarch. Supplements were taken with plenty of water (600 mL). The supplementation protocol included an additional dose of di-carbonates and minerals, 90 min before the exercise test protocol and the day before the test" (Chycki 2018).

Only in conjunction with the information from the following "study protocol"-section it becomes clear - or I should say it is my interpretation that ...

• ...the performance tests [Running-Based Anaerobic Sprint Test (RAST) protocol which involved 6 × 30 m maximal sprint efforts, separated by 10 s of active recovery] were carried out at baseline and after 9 days of supplementation, 
• ... the supplements were consumed 90 minutes before the regular AM and PM training (or "practice", as Chycki et al. call it) on day 2-7, i.e. chronically(!),
• ... on day 8 the subjects consumed only one serving of the macromineral stack (or cornstarch placebo) and there was either no soccer training at all or, at least, no PM session, so that they would have rested for 24h before the performance test on day 9,
• ... on the testing day, the subjects reported to the lab in the AM fasted and consumed another mineral stack 90 minutes before the RAST protocol,

So, basically one macromineral stack 90 minutes before each training for 9 days - with the last "training" actually being the sprint test. With "only" 6g of sodium- and potassium-bicarbonate the stacks were dosed comparatively low compared to the 0.3g/kg protocols that have been used in many of the preview studies. The dosage is, however, in line with previously discussed "serial-loading" studies where NaHCO3 was administered in repeated smaller doses over 24h or several days (see this previous article) to achieve the desired alkalizing effect with a reduced risk of gastrointestinal distress.

Yes, the diet was standardized: The participants were placed on an isocaloric (3455 ± 436 kcal/day) mixed diet (55% carbohydrates, 20% protein, 25% fat) prior to and during the investigation. The pre-trial meals were standardized for energy intake (600 kcal) and consisted of carbohydrate (70%), fat (20%) and protein (10%). The participants did not take any medications and substances not prescribed by the supplementation protocol for 3 weeks before and during the study.

The latter was further reduced in the study at hand by administering the supplements in 500mg capsules - a practice of which I've previously pointed out that it seems to (a) limit the gastrotestinal distress an (b) help those of you who hate the salty taste of pure NaHCO3.

Table 1: The authors found statistically significant differences between baseline and post-intervention period at rest, post ingestion, and after exercise for the experimental group for all parameters| Note: d, effect size (≥ 0.5 = LARGE effect - found for all parameters); p, statistical significance; F, value of analysis of variance function (Chycki 2018).

Next to the performance test, Chycki et al. (2018) also tested the subjects' lactate concentration (LA), acid–base equilibrium and electrolyte status, the following variables were evaluated: LA (mmol/L), blood pH, pCO2 (mmHg), pO2 (mmHg), HCO3− act (mmol/L), HCO3− std, (mmol/L), BE (mmol/L), O2SAT (mmol/L), ctCO2 (mmol/L), Na+ (mmol/L), K+ (mmol/L), and Ca2+, Mg2+. The measurements were performed from fingertip capillary blood samples at rest and after 3 min of recovery... and guess what!? "Large effects" (Cohen's d > 0.5) were observed for all of these.

You have to read the captions carefully, though...

because, otherwise, you will miss that the data in Table 1 shows the intra-group change of the given parameters. In other words: After having ingested the macro-mineral-stack the lactate levels, the pH, the HCO3 and Mg2+ content, as well as the performance n the 6x30m sprint test improved compared to baseline. Large effects compared to placebo were observed "only" for:

• lactate immediately after the workout (d = 0.884 |large; p = 0.0001)
• blood pH at rest (d = 0.780 | large; p = 0.0001), and 
• the HCO3− content of the subjects' blood at rest (d = 0.989 | large; p = 0.0001)

Those of you who haven't read that many SuppVersity articles, yet, must also be aware that "Cohen's d" as a measure of the effect size does not say that this is "large" = "practically relevant" difference.

The paper has issues in terms of data reporting: As pointed out in the main body of this article, the figure with the sprint times does not align with the values reported in the text of the paper. For the given reason (unrealistic improvements, hardly legible captions, etc.) I rely on the explicitly stated sprint times in the experimental and an extrapolation of the corresponding data in the placebo trial. I believe that this represents the data appropriately, but I cannot guarantee that.

I have to emphasize once more While this can be (and often is) the case, it only tells you that the inter-group difference was large even when the standard deviations are considered.

Figure 1: Sprint performance times in seconds before and after the 9-day training + supplementation intervention in the experimental vs. placebo group; left: with a similarly messed up vertical axis scale as in the original from the study / right: with a transparent vertical scale that shows that the statistical "effect size" is large, the relative improvement, on the other hand, rather low [†Note: I cannot guarantee that the data is 100% accurate, because the plotted and discussed data in the stud at hand contradict each other and I had to extrapolate the non-reported absolutes for the placebo group].

I guess I'll simply show you the subjects' actual sprinting performance, ...because the graph illustrates that very nicely. While you're looking at Figure 1, there are yet two things you should be aware of:

1. Since the scientists' plot of the data is totally messed up (click here to see it), I had to redo the graph for the sprint times based on the values given in the text, i.e. the 6 × 30 m running test improved from by 2.3% 25.09 s to 24.53 s (p = 0.00001) in the experimental group and by only non-significant 1% in the control group (I extrapolated the absolute values in the control group, which were not reported from inter-group difference in the scientists' own IMHO wrongly labeled graph).
2. Furthermore, I decided to give you both, the equivalent of the scientists' own plot which uses a scale that totally exaggerates the improvement (Note: the original captions cannot be correct, because then, the sprint times would have improved by ~50% - that's unrealistic and not in line with any of the other data reported in the text) and my "fair" plot, from which you can see that the real-world effect is not exactly as large as a misinterpretation of "large effect sizes" would suggest.

If you keep that in mind, you may be somewhat disappointed, ... I know, "only" 2% - true: that's not super impressive but the study still adds significantly to our knowledge of bicarbonate buffering as an ergogenic aid for anaerobic exercise (like sprinting or hypertrophy training) - and here's why...

Innovation, anyone? Enterically coated Na-HCO3 tablets could make you rich ;-)

I actually wonder that acid resistant NaHCO3 tablets have not been marketed, already, as a more stomachable al-ternative to classic powders or caps, which will release their content in the gut where it will react with the stomach acid and produce bloating or worse.

Moreover, with the publication of a recent study from the Univer-sity of São Paulo in which the scientists investigated the buf-fering effect of NaH-CO3 in post-gastric bypass patients and found (a) sign. reduced side effects and (b) a signif. increased effect on blood pH, we do have initial evidence that allowing the tablets to pass through the stomach undigested, may not just avoid the runs, it may also re-duce the dosage you need to see an effect, signif. - or, as the authors put it: "Maximal bicarbonate increases were well above those shown previously, with minimal side effects, indicative of minimal neutralization of bicar-bonate in the stomach." (de Olivera 2018).

What does the study tell us? Yes, the 2% performance benefit doesn't sound like much, but during an actual soccer match those +2% sprint performance can make the difference between getting and missing a long ball and hence scoring a goal or seeing the goalkeeper punt.

The performance increase isn't really news, anyway. Bicarbonate is, after all, one of the few proven ergogenics ("apparently effective and generally safe" - Kreider 2010). What is new, however, is this:

(1) This is the first study to show that you can take sodium and potassium bicarbonate at a 1:1 ratio and still see ergogenic effects as they've previously been observed with baking soda, alone. That's an important and (IMHO) novel finding, because the tendency of serum potassium levels to increase significantly in response to strenuous exercise (from the muscle) would have suggested that additional potassium could impair the muscle contractile properties - at least when it is combined with Ca + Mg, however, this is not the case. Plus: Even though sodium bicarbonate doesn't have the blood pressure increasing effect of regular salt in healthy individuals (Luft 1990), SuppVersity readers know that some extra potassium will rarely hurt ;-)

(2) This is the first study to suggest that chronic K-/Na-bicarbonate supplementation may enhance the training effect trained athletes can derive from a relatively short training camp. This does also suggest that buffering effects of bicarbonates, phosphates, and citrates do not impair (keyword: "hormesis"), but rather promote the training effect.

(3) This is the first study to suggest that addition of the magnesium and calcium citrate, both deficiency nutrients in the general population, doesn't impair the performance benefits of bicarbonates. Why would it? Well If you've ever tried to mix bicarbonates and citrates you will know that the two will react with each and release carbon-dioxide. This, in turn, would leave less bicarbonate to pass into the bloodstream to work its buffering magic there (note:  in the absence of a KHCO3+NaHCO3 only group, it's still possible the that either the reaction between bicarbonates and citrates or the mere presence of Mg and Ca could have reduced the performance effects of the bicarbonate stack).

For those of you who didn't notice that already - the use of the word "suggests" in (2)+(3) does exactly what it means: it "suggests" that future studies should investigate individual and synergistic effects of the dynamic macronutrient quartett w/ Na, K, Ca, and Mg | Comment!

References:

• Chycki, Jakub, et al. "Chronic Ingestion of Sodium and Potassium Bicarbonate, with Potassium, Magnesium and Calcium Citrate Improves Anaerobic Performance in Elite Soccer Players." Nutrients 10.11 (2018): 1610.
• Luft, Friedrich C., et al. "Sodium bicarbonate and sodium chloride: effects on blood pressure and electrolyte homeostasis in normal and hypertensive man." Journal of hypertension 8.7 (1990): 663-670.

5% Faster W/ 135ml of Red Blood Cells - Transfusion Works Within 2h! Plus: ~1.5g/kg = Optimal PWO Protein Intake for Protein Synthesis in Females - SV November Short News

Welcome to today's installment of "on short notice"

You may remember from the SuppVersity news on Facebook that the use of cobalt supplements can indeed (as it has long been touted and doubted) have similar effects as EPO (Hoffmeister 2018). Yet while the study by Hoffmeister et al. showed that the VO2max correlated significantly with the 2% increase in Hemoglobin in response to the ingestion of  5 mg of ionized Co2+ for 3 weeks, an acute performance-enhancing effect was neither tested nor observed in the German study.

That's in contrast to autologous (=your own) blood infusions. A simple injection of only ~135 ml of red blood cells that were previously isolated from 450 ml of your own blood 2h before training or competition will improve your endurance performance by 5%, ... according to the latest study from the University of Copenhagen (Bejder 2018).

High-protein diets are much safer than some 'experts' say, but there are things to consider...

Practical Protein Oxidation 101

5x More Than the FDA Allows!

More Protein ≠ More Satiety

Satiety: Casein > Whey? Wrong!

Protein Timing DOES Matter!

High Protein not a Health Threat

And if you're rather into lifting weights than cycling, running, or triathlons, today's research update also discusses the results of a recent small-scale study by Malovany et al. (2018), which puts a(t least a preliminary) number on the usefulness of escalating post-workout protein intakes from high to very high. Sounds interesting? Well, then let's start with the "blood doping" study by Bejder, et al.

+ + + The "blood doping study" + + +

• Instant (2h post) 5% performance boost in athletes w/ 135 ml of red blood cells (#RBCs) from a single 450 ml phlebotomy (Bejder 2018) -- While you all will have heard about "blood doping" and the infusion of autologous (=their own) blood and/or isolated red blood cells (#RBCs) in cyclists and other endurance athletes, I bet that you will be as surprised as I was that a single injection of 135 ml of red blood cells (#RBC) from a rather small amount of your own blood (450 ml) will improve your endurance performance by 5% - and that only 2h after you injected the RBCs.

• Study type: Randomized, double-blind, placebo-controlled crossover study
• Comparison: placebo = sham phlebotomized vs. blood transfusion-trial
• Subjects: N=9 (=small scale) young men w/ >1year resistance training (all major muscle groups | training at least twice a week) experience who didn't do more than 30 minutes "cardio" per exercise session and were able to life 0.7x and 2.3x their bodyweight on the bench press & leg press, respectively; no supplement use, general health, you know it...
• Outcomes: Hb, Hct, RBC, and Ret% 1wk before phlebotomy, 3 days before transfusion, 2 h post 135 ml transfusion and 3 days post 135+235 ml transfusion
• Performance tests: (1)Two 650kcal time-trial three days and 2h after receiving either ~50% (135 ml) of the RBCs or a sham transfusion on subsequent days + (2) One 4×30 s all-out cycling sprint interspersed by 4 min of recovery was performed six days before and three days after a second autologous blood transfusion (235 ml).

• What the scientists found was that the subjects' mean power in the time trial (TT) to was increased in time trials from before to after transfusion (P<0.05) in BT (213±35 vs. 223±38 W; mean±SD) but not in PLA (223±42 vs. 224±46 W | see Figure 1, left).
  

  

  Figure 1: Mean power in the TT and during the 4x30s sprints in the active and placebo trial (Bejder 2018).

  For the four 30 s sprint bouts that were performed not 2h, but three days later no effect was observed [BT (639±35 vs. 644±26 W) and PLA (638±43 vs. 639±25 W) | see Figure 1, right].

The Vampire Approach to Longevity - Young Blood Revives Muscle, Brain & More | Plus: 6+ Less 'Horrific' Alternatives | read more

What does the "blood doping"-study tell us? The study shows that there is an instant increase in endurance performance that's practically highly relevant for athletes competing in various sports from a relatively small amount of RBCs (~135 ml) you can extract from a single phlebotomy.

Improvements in sprint/anaerobic performance, on the other hand, seem unlikely. After all, despite a second (larger = 235ml) injection of RBCs the subjects' performance during the 4x30s bouts of all-out cycling on day 3 after the initial transfusion was not increased - in the presence of elevated RBCs, that is (5.03 ± 0.28 versus 4.58 ± 0.17x10^12/L blood) | Comment!.

 + + + The "protein ceiling" study + + +

• Optimal post-workout protein intake for max. protein synthesis over 8h in resistance-trained women is 1.5-2.0g/kg - More will just  be burned as fuel (Malovany 2018) -- For men we've known this all along: There's a threshold value not to how much protein we can in- and digest in one serving, but rather to the amount of protein that can be used to fuel skeletal muscle protein synthesis after workouts (Humayun 2007; Jäger 2017). And while they certainly have to be considered preliminary due to the small sample size of N=9, Malovany et al.'s (2018) latest study shows that a similar threshold exists for female resistance trainees, too.

• Study type: randomized sequential study of the effect of different amounts of PWO protein ranging from deficient to excess (0.2-2.90 g/kg)
• Subjects: N = 8 healthy females w/ regular menstrual cycles, who perform whole-body resistance exercise regularly, had trained each major muscle group (i.e., chest, back, and legs) at least twice per week consistently for at least one year prior to recruitment, didn't do more than 30 min of continuous endurance training per exercise session, and whose 1RM on the bench press and leg press of 0.7 and 2.3 × bodyweight, respectively.
• Outcomes: steady state whole body phenylalanine rate of appearance (Ra), oxidation (Ox; the reciprocal of protein synthesis, PS) and net protein balance protein synthesis measured via minimally-invasive indicator amino acid oxidation (IAAO) technique (protein synthesis) and urinary Urea: Creatinine ratio (protein oxidation), respectively
• Exercise standardization: 2d prior to each metabolic trial, all participants were required to complete a prescribed but self-monitored whole-body resistance exercise session - the workout was identical to the workout they would do on the test day, i.e. i) barbell bench press, lat pulldown superset; ii) standing overhead barbell press and seated cable row superset; iii) leg press; and iv) leg extension; each exercise was performed at 75% 1RM for 4 sets of 8-10 repetitions with ~90s rest intervals between sets
• Dietary standardization: 2-d adaptation diet containing 1.2 g/kg/d of protein during the 2-d controlled training period prior to each metabolic trial
• Testing days: ingestion of liquid carbohydrate beverage (1 g/kg as a 1:1 ratio of maltodextrin: Gatorade® Endurance) 1h before std. workout (see exercise standardization); each participant completed 6-7 metabolic trials (n = 50 for total trials completed) during the luteal phase, which was defined as the second half of the menstrual cycle.
• Supplementation: 8x hourly meals providing a randomized test protein intake (0.2-2.9 g/kg) as crystalline amino acids, modeled after egg protein, with constant phenylalanine (30.5 mg/kg) and excess tyrosine (40.0 mg/kg)

• As you can see in Figure 2 (left), the scientists observed a ceiling effect for the protein synthesis with protein intakes >1.5g/kg body weight - the horizontal nature of the linear trend for the values clearly indicates this.
  
  
  The rate of protein oxidation, which was estimated via the urinary Urea: Creatinine ratio, on the other hand, increased linearly with increasing protein intakes (Figure 2, right) - without a threshold effect, i.e. the more protein, the more is going to be oxidized (see bottom line for discussion of what would happen w/ bolus vs. 8x1/h ingestion).

Protein Wheysting?! No Significant Increase in PWO Protein Synthesis W/ 40g vs. 20g Whey, But 100% Higher Insulin, 340% More Urea & 52x Higher Oxidative Amino Acid "Loss" | read more

What does the "protein ceiling"-study tell us? Due to its small scale (N=9) and very specific participant characteristics (young, healthy, resistant-trained women), the results of the study at hand have to be considered as good, but preliminary evidence for the existence and quantity of a protein synthesis threshold (~1.5g/kg/8h) during the first 8h after a workout.

In that, it is important to point out that this effect was achieved by the sequential ingestion of a total amount of 0.2-2.9 g/kg of protein every hour. It is not just likely, but almost certain that taking the ingestion of a single bolus of the amino acid mix immediately after the workout (for 1.5g/kg that would have been 100g per subject) would have yielded different results. More specifically, one could speculate that the protein oxidation would have increased, while the net protein synthesis would have decreased w/ dose-escalating bolus ingestion (compared to the sequential ingestion protocol used in the study at hand) - a result I've reported for whey in a 2013 article from the archives.

Speaking of whey: It is not clear to which extent the results can be generalized to different protein sources, like whey (concentrate, isolate, hydrolysate), micellar casein, whey+casein mixes, actual egg protein, etc. as both, their digestion kinetics, as well as their amino acid and functional peptide content differ significantly. Still, the recommendation to consume 1.5-2.0g/kg protein within the 8h window after a workout to optimize protein synthesis in healthy, resistance-trained young women is the best we have as far as "one-size-fits-'em-all" recommendations are concerned | Comment!

References:

• Bejder, J. "Time Trial Performance Is Sensitive to Low-Volume Autologous Blood Transfusion." Medicine & Science in Sports & Exercise: November 6, 2018 - Volume Publish Ahead of Print
• Hoffmeister, Torben, et al. "Effects of 3 weeks of oral low-dose Cobalt on hemoglobin mass and aerobic performance." Frontiers in physiology 9 (2018).
• Humayun, Mohammad A., et al. "Reevaluation of the protein requirement in young men with the indicator amino acid oxidation technique–." The American journal of clinical nutrition 86.4 (2007): 995-1002.
• Jäger, Ralf, et al. "International society of sports nutrition position stand: protein and exercise." Journal of the International Society of Sports Nutrition 14.1 (2017): 20.
• Malowany, Julia M., et al. "Protein to Maximize Whole-Body Anabolism in Resistance-trained Females after Exercise." Medicine & Science in Sports & Exercise (2018).

Peak & Mean Power + Power Capacity Increase (5-8%) in 11 Trained Women W/ OTC Rhodiola Extract in Non-Sponsored Cross-Over Trial ++ Review of Evidence from Other Studies

While there's some evidence that other plants from the genus "Rhodiola" may have similar effects, you want to rely on the std. exctracts from "Rhodiola Rosea" that were used in several studies if you want to try it | for dosage recommendation, see bottom line.

Some of you will probably remember that "Rhodiola" aka"Golden Root" is a putative adaptogen, i.e. a "nontoxic [sic!] substance and especially a plant extract that is held to increase the body's ability to resist the damaging effects of stress and promote or restore normal physiological functioning" (Merriam-Webster Medical Dictionary)...

No? Well, I remembered "Rhodiola Rosea", as I should have written before to avoid confusion with other plants from the same genus, when I saw a recent post by Jason Cholewa on Facebook.

The link to a study that was attached to the post didn't just remind me of this almost forgotten herb (ten years ago it was used in many more 'kitchen-sink supplements' than today); It drew my attention to a recent paper by scientists from the Samford University in Birmingham, USA (Ballmann 2018).

Bicarbonate can help you train at intensities that promote VO2_Max gains even on an 'elite' level:

Caffeine + Bicarb Make Champions

Bicarb + Asp = Muscle Magic!?

NaCHO3 & Leg Days're a Breeze

+100% Anaerobic Endurance

Bicarb Buffers Creatine

Instant 14% HIIT Boost

In the conclusion of their abstract, the scientists, ..., write about the standardized Golden Root Extract (#GRE) that they tested in N=11 physically active college-aged females (=accruing at least 150 minutes/week of moderate physical activity) in a within groups counterbalanced placebo-controlled trial that...

"GRE [more specifically, 3x500mg of a std. Rhodiola extract per day for three days and 500mg in the AM on the test day,] may possess ergogenic benefits and findings hold important implications for boosting anaerobic performance in repeated anaerobic bouts of exercise" (Ballmann 2018).

Needless to say that this sounds interesting for all sorts of sports and athletes ranging from sprinters over team sports athletes to the average gymrat. And, if we take the large effect sizes into account, I would speculate that your next question is:

"Where can I buy this stuff?" 

Summary of the study design: The study tested the effects of a standardized (3% total Rosavins and 1% total Salidroside | NOW Foods) Rhodiola supplement or placebo on anaerobic performance of 11 trained, college-aged female subjects by the means of 3x15s Wingate tests (watch video) in a blinded, randomized, and counter-balanced manner.

The supplement was administered thrice a day for three days (3x500mg/g) and once 30 minutes before the warm-up/testing procedures (1x 500mg/d). Each 15-second all-out-pedaling bouts during the Wingate test was followed by a 2 minute active recovery rest period, in which subjects pedaled at their own pace against an unloaded pedal resistance.

The good news is: While it is a special product that is standardized for 3% total rosavins and 1% salidroside, you can, much in contrast to a dozen other promising herbal supplements, buy it (almost) everywhere - even the exact product that was used in the study at hand, i.e. NOW Food's 500mg caps which go by the simple name "Rhodiola".

This makes the study at hand particularly interesting for you, me, and everyone else who's always on the look-out for safe and still functional performance boosters that are actually available on the market (vs. some exotic extracts you would have to order from a research supplier such as Sigma Aldrich).

In that, it is not clear if a 'loading phase' as the scientists used it in the study at hand is even necessary. Other studies, I am about to cite later in this article seem to suggest that an effect can be seen immediately (~1h) post ingestion and evidence of a cumulative effect is - as of now - not available and warrants further research (see red box on potential anti-hormetic effects, too).

Disclaimer: It may be important to point out that I am pretty sure that there are similar products from other manufacturers on the market (before you buy, make sure it's standardized to at least 3% total rosavins and 1% salidroside, though) and that neither I nor the authors (at least according to their declaration in the full-text of their study) received any kind of compensation for mentioning NOW in our articles.

It is thus very well possible that the actually measured effect in Ballmann's study was due to the single 500mg cap the subjects took before the Wingate test. This, in turn, would imply that you would use Rhodiola in similar ways as caffeine or other (no longer available) stimulants like DMAA or ephedra.

"So, I'll take 500 mg 30-60 minutes before workouts, right? Won't more help more?

If this is not your first visit at suppversity.com, you should know by now that "more helps more" is as invalid for supplements and exercise performance as it has been shown to before money and happinesss (Easterlin 1973).

Figure 1: In Noreen's 2013 study, the provision of R. rosea at a dosage of 3mg/kg  only once, 1 hour before the 6k-cycling trial, yielded significantly improved time-trial times (left) and reduced rates of perceived exertion (RPE | p = 0.04), as well as RPE/power (right | p = 0.007) compared to a carbohydrate placebo (adapted from Noreen 2013).

Moreover, studies like Noreen et al. (2013 | see Figure 1) or Duncan & Clarke (2014) seem to suggest that an even lower dosage of 3mg/kg of the same standardized extract taken 1h before (in those studies albeit aerobic) exercise tests will have significant ergogenic effects, too.

Overall, it has to be said, though that the optimal dosing strategy is still in the open, though, because: (a) we do not have any studies comparing different dosing regimens directly, and (b) we do not even know how Rhodiola Rosea does whatever it is, it does. If we knew (b), we could at least speculate about the optimal timing and potential dosing thresholds, but as of yet, there are only various unconfirmed and often disputed hypotheses as to how Rhodiola works.

"Will the anti-oxidant effects of Rhodiola ruin my gains - keyword: #hormesis?" It is impossible to say whether the anti-oxidant effects of Rhodiola may impair your long-term gains, at this point. My educated guess however, would be that the answer to this question people ask me all the time is "no" - not the least because the creatine kinase (CK) and hence muscle damage in a 2004 study by Abidov et al. was not blunted by the provision of a supplement, of which the scientists say that it contained "30 mg active substances [rosavine, rosarine, rosine, salidroside, rhodalgin, acetylrhodalgin, rosiridine, and rosiridol]", the levels only recovered significantly faster over the 5-day follow-up.

Figure 2: When it comes to choosing whether and at which dose to use of ROS scavengers you must consider hormetic dose-response relationship between stress exposure (X-axis) and adaptational response (Y-axis). Stimulatory effects occur in the low-dose region at the left of the no-observed-effects-level (NOAEL), whereas adverse effects occur in the high-dose region at the right of the NOAEL - first published in July 2018

A long(er)-term (=4 week) study, in which the Polish Rowing Team received 100 mg of a non-specified "R. rosea concentrate", found increases in total plasma antioxidant capacity and a reduced superoxide dismutase activity in erythrocytes directly after and 24 hr after an exhaustive bout of exercise was also observed in rowers by Skarpanska-Stejnborn et al (2009) - both effects that are relatively unlikely to translate to a reduction in the adaptive response to exercise. Due to the fact that we're talking about highly trained athletes, it is also not that surprising that the already marginal (and everything but statistically significant) increases in performance markers the scientists observed over time showed no inter-group differences.

Needless to say that "additional research is necessary" (I know I hate this sentence, too ;-) to finally answer your question, but as previously pointed out, I consider it unlikely that the regular use of Rhodiola, in a similar fashion as caffeine, would have negative effects on your gains.

These hypotheses include, most prominently, the 'ATP hypotheses'. Unfortunately, researchers from the Air Force Research Laboratory (Walker 2007) found in their 2007 study that the significant increases in ATP-turnover/resynthesis that had been observed in a previous rodent study (Abidov 2003) doesn't seem to occur in humans.

Walker et al. (2007) had used the same dosing scheme as Ballmann, but relied on what I would call a pretty odd performance test: wrist curls. Be that as it may,... their measurement of the ATP kinetics by phosphorus 31 nuclear magnetic resonance spectroscopy, revealed absolutely zero effects of the rhodiola supplement - whether that's simply due to the hardly exhaustive nature of the exercise protocol in this Air Force study, is not clear, but I certainly wouldn't discard the possibility of muscle-physiological/-metabolic effects completely with high(er) intensity exercise, yet.

The actual mechanism is not clear, but it could be of metabolic, muscle-physiologic or neuro-physiologic origin... or, obviously, a combination of all three!

If we look for other potential mechanisms, the previously cited study by Noreen et al (2013) comes to mind. The scientists Gettysburg College found significant performance improvements, in this case, improved 6-km cycle times (Figure 1, left), they ascribe to a reduced perception of effort (Figure 1, right). Similar beneficial effects on RPE were observed by Duncan & Clarke (2014), who tested the effects of 3mg/kg BW in ten young men, who completed two 30-minute cycling trials at an intensity of 70% of VO2Max in a double-blind, crossover design trial. Together these two studies seem to suggest that - at least during endurance exercise - the mechanism of action could, in fact, be of central neurological vs. peripheral muscle-physiological nature.

Figure 3: Mean anaerobic performance variables over all three WAnTs (for individual data see Figure 4). Data are presented as mean ±SD. * indicates significantly different from placebo (p < 0.05 | Ballmann 2018)

Since tests that would be able to confirm this hypothesis were not conducted in the Ballmann study, and the mean fatigue index (Figure 3, bottom right) was non-significantly elevated, not decreased, it does yet seem very unlikely that this is what triggered the beneficial effects Rhodiola had in this most recent study on the effects of Rhodiola on anaerobic exercise performance.

Speaking of adaptogens: Ashwaghanda may be for gymrats, too | Human study showed significant body composition improvements in 2015. 

Could hormonal changes explain the benefits? You may remember the 2016 installment of the #ShortNews, in which I addressed a study showing significant increases in testosterone levels in response to 7x higher doses of a non-standardized Rhodiola product in exercise-trained mice (learn more).

Rhodiola is also said to have cortisol-lowering effects - a claim that corresponding product write-ups try to prove by citing studies like Jurcău et al. (2012), or Ross et al. (2014), which did, however, not investigate the cortisol response to exercise but other forms of stressors.

Studies that investigated the effects in conjunction w/ physical exercise found inconclusive effects w/ one study that used a combination of Rhodiola + carnitine showing a significant time, but no treatment effect (Muñiz-Pumares 2011). The same goes for the previously cited study by Noreen et al (2013), as well as a dose-escalation study in rodents that found no effect on either testosterone or cortisol of exercised mice on dosages of up to 300mg/kg (that's already the human equivalent) of a mixed Rhodiola, Astragalus and Radix Paeoniae Alba extract (Chen 2017).

Figure 4: Results from the study under review (Ballmann 2018) - Anaerobic performance outcomes compared from 1st, 2nd, and 3rd 15-second Wingate Anaerobic Tests (WAnT); Data are presented at mean ±SD; * indicates significantly different from 1st WAnT, # indicates significantly different from 2nd WAnT (p < 0.05).

As far as the observed effects are concerned, it is worth mentioning that we're talking about a cumulative effect, which occurred in the absence of significant effects in the individual 15s-bouts of all-out cycling (see Figure 4).

This is in line with the previously hinted at observation that there are more 'Rhodiola studies' using aerobic vs anaerobic outcomes to gauge its efficacy; and, more importantly, that the former are also more likely to report performance increases than studies that used (ultra-)short bouts of high-intensity exercises, such as the 3x15s Wingate tests.

Even if Rhodiola was more of an endurance supplement, though, this would not change the results of the study at hand: There's a statistically significant cumulative effect over "only" 3x15s high-intensity cycling bouts in the study under review, which thus provides convincing evidence that:  Athletes competing in sports that require intermittent all-out sprinting or other forms of intermittent high-intensity exercise may benefit from standardized Rhodiola extracts.

Figure 5: Graphical illustration of the relative improvements in mean and peak power (blue) and anaerobic capacity and power (orange) with Rhodiola vs placebo; all differences that are shown were statistically significant (p < 0.05) in the cumulative analysis (i.e. considering all three bouts) and the individual effect sizes (Cohen's d) are provided in the captions.

In that, it is still not clear, whether the benefits, which I have summarized and plotted once more for you in Figure 5 (figure shows relative differences between Rhodiola and placebo), would occur with the 3mg/kg (for the ladies in the study at hand that would be ~200mg) dosage of the standardized extract that both, Duncan & Clarke (2014) and Noreen et al (2013), administered only once ~1h before the performance tests would be identical.

How safe is rhodiola? While Rhodiola Rosea is not just easily available, but also classified as generally recognized as safe (GRAS), it should be mentioned that studies on potential supplement-drug interactions are ambiguous. While there's evidence of competition for CYP2C9 (Thu 2016 & Thu 2017) and other CYP enzymes, and hence potential interactions with NSAIDs, certain diabetes meds, angiotensin II inhibitors (blood pressure), SERMs (tamoxifen) and even sildenafil, Noeldner et al. and Panossian et al. write that the IC50 for interactions with drug metabolizing enzymes is too high to be physiologically relevant for the proprietary dry extracts WS® 1375 and SHR-5, respectively... if you take any meds, though, it makes perfect sense to check with your doctor before you trial any Rhodiola supplement.

Another thing we have to keep in mind, though is that in a situation where we have almost no clue about the underlying mechanism of the effects, it is not warranted to blindly generalize the results from one exercise context (aerobic | Noreen 2013) to another (anaerobic | Ballmann 2018).

Sex differences are possible but unlikely in either, exercise-, or psychophysiological contexts.

Speaking of methodological differences, you may have noticed that Ballmann et al. as well as Naureen conducted their studies in healthy, college-aged, recreationally active women, not - as most studies do - in healthy, college-aged recreationally active men. This raises the question: Could the efficacy of Rhodiola be sex-specific? Well, while this cannot be completely ruled out, the previously referenced results from Duncan & Clarke (2014) do at least suggest that it works in males, too.

Figure 6: Illustration of observed benefits (not all unambiguous, though) of Rhodiola Rosea supplementation in exercise (blue) and psycho-physiological contexts (orange); based on a 2011 review by Hung et al.

This, i.e. an absence of significant inter-sex differences, can also be seen in the studies Hung et al. summarized in their 2011 review in Phytomedicine, which lists, on top of the exercise-related benefits that are the topic of the article at hand, additional psycho-physiological effects that range from the reduction of depressive symptoms, over general anti-stress and well-being effects to very practical reductions in work-related fatigue - even after night duty in both male and female subjects.

Other studies, reviewed by Ponassian & Wikman in Pharmaceuticals in 2010 found evidence supporting the benefits I've illustrated in Figure 6 and suggest the following related/additional benefits...

• CNS-stimulating effects and downstream benefits in physical & cognitive performance,
• Neuroprotective, hepatoprotective, and cardioprotective effects,
• general antioxidant, as well as radioprotective effects,
• anti-inflammatory/-allergic and immunotropic effects, as well as
• the previously hinted at antidepressive and anxiolytic.

Unfortunately, the methodology of the pertinent studies in this 2010 review is even more heterogeneous than in the exercise-related studies, I discussed in quite some detail. Hence, it's impossible to use them to refine the previously made statements about different timing and dosing regimen. A pattern that emerges, however, is that the dosages are mostly within a range of 100-500mg of standardized Rhodiola extracts (often identical to the one Ballmann et al. used) and that the supplement was administered, in most cases, only on the day the tests were conducted.

If that's what your PWO meal looks like, you're doing it right. Learn more about the role of protein in post-workout glycogen synthesis, as well as the effects of combined resistance + HIIT training on your satellite cells and the effects of blood flow restriction on exercise recovery in this 2018 article.

The two things (a)+(b) we can be certain of are: (a) in young, healthy, physically active women, Rhodiola Rosea, administered at a dosage of 3x500mg for three days and an extra 500mg of the std. extract w/ 3% total rosavins and 1% salidroside ca. 30 min before the testing procedures, will have 'medium' to 'large' cumulative ergogenic effects on 3x15s bouts of all-out cycling (+5-8%); and (b) similarly beneficial effects, mostly in form of an increased time-to-exhaustion, have been reported with a single dose of Rhodiola in other studies for aerobic exercise tests.

We also know with decent certainty that (i) the effects are not hormonally-mediated (see infobox) and probably not sex-dependent. Moreover, (ii) the minimal dosage of the std. extract to yield benefits seems to be below the 500mg used in the study at hand (~3mg/kg), and a loading period doesn't seem to be necessary. In fact, it seems to be likely that (iii) Rhodiola has 'immediate' (30-60min) ergogenic effects, the underlying mechanisms of which (iv) are still unknown.

If you do want to give Rhodiola a try, it would seem smart to obtain a supplement that contains 300-500mg of an extract that is standardized to 3% total rosavins and min. 1% salidroside (this is what the majority of studies that report details on the product seem to have used) and take one to two capsules approximately 30-60 min before your workouts. 'Loading' and/or the use on non-exercise days seems unnecessary.

Do not expect too much, though: Based on my personal experience with adaptogens and the inter-individual difference in the response to Rhodiola in Noreen's study (Figure 1, left), where ~30% even performed worse in the Rhodiola trial, you will have to accept that Rhodiola may be one of those 'hit or miss'-supplements that work for some, but by no means everyone | Comment!

References:

• Abidov, M., et al. "Effect of extracts from Rhodiola rosea and Rhodiola crenulata (Crassulaceae) roots on ATP content in mitochondria of skeletal muscles." Bulletin of experimental biology and medicine 136.6 (2003): 585-587.
• Abidov, M., et al. "Extract of Rhodiola rosea radix reduces the level of C-reactive protein and creatinine kinase in the blood." Bulletin of experimental biology and medicine 138.1 (2004): 63-64.
• Andersen, Mark B., Penny McCullagh, and Gabriel J. Wilson. "But what do the numbers really tell us?: Arbitrary metrics and effect size reporting in sport psychology research." Journal of sport and exercise psychology 29.5 (2007): 664-672.
• Ballmann, Christopher G., et al. "Effects of short-term Rhodiola Rosea (Golden Root Extract) supplementation on anaerobic exercise performance." Journal of sports sciences (2018): 1-6.
• Chen, Zichao, and Shanshan Li. "Study on the Effects of the Rhodiola Reagent on Improving Exercise Endurance and Exercise Fatigue Resistance." Revista de la Facultad de Ingeniería 32.4 (2017): 421-426.
• Duncan, Michael J., and Neil D. Clarke. "The effect of acute Rhodiola Rosea ingestion on exercise heart rate, substrate utilisation, mood state, and perceptions of exertion, arousal, and pleasure/displeasure in active men." Journal of Sports Medicine 2014 (2014).
• Easterlin, Richard A. "Does money buy happiness?." The public interest 30 (1973): 3.
• Hung, Shao Kang, Rachel Perry, and Edzard Ernst. "The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials." Phytomedicine 18.4 (2011): 235-244.
• Jurcău, Ramona, Ioana Jurcău, and Cristian Bodescu. "Anxiety and salivary cortisol modulation in exercise induced stress, using a phytotherapic product containing Rhodiola Rosea." Palestrica of the Third Millennium Civilization & Sport 13.3 (2012).
• Muñiz-Pumares, D., et al. "Effects of acute supplementation with Rhodiola rosea and L-carnitine on exercise performance, cognitive function and cortisol in healthy active volunteers." Br J Sports Med 45.15 (2011): A1-A1.
• Noeldner, M., et al. "Preclinical investigations of possible drug interactions with WS® 1375, a proprietary dry extract from Rhodiola rosea roots." Planta Medica 76.12 (2010): P620.
• Noreen, Eric E., et al. "The effects of an acute dose of Rhodiola rosea on endurance exercise performance." The Journal of Strength & Conditioning Research 27.3 (2013): 839-847.
• Panossian, Alexander, et al. "Pharmacokinetic and pharmacodynamic study of interaction of Rhodiola rosea SHR‐5 extract with warfarin and theophylline in rats." Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives 23.3 (2009): 351-357.
• Panossian, Alexander, and Georg Wikman. "Effects of adaptogens on the central nervous system and the molecular mechanisms associated with their stress—protective activity." Pharmaceuticals 3.1 (2010): 188-224.
• Ross, Stephanie Maxine. "Rhodiola rosea (SHR-5), part I: a proprietary root extract of Rhodiola rosea is found to be effective in the treatment of stress-related fatigue." Holistic nursing practice 28.2 (2014): 149-154.
• Skarpanska-Stejnborn, Anna, et al. "The influence of supplementation with Rhodiola rosea L. extract on selected redox parameters in professional rowers." International journal of sport nutrition and exercise metabolism 19.2 (2009): 186-199.
• Thu, Ole Kristian, Odd Georg Nilsen, and Bent Hellum. "In vitro inhibition of cytochrome P-450 activities and quantification of constituents in a selection of commercial Rhodiola rosea products." Pharmaceutical biology 54.12 (2016): 3249-3256.
• Thu, Ole Kristian Forstrønen, Olav Spigset, and Bent Hellum. "Noncompetitive inhibition of human CYP 2C9 in vitro by a commercial Rhodiola rosea product." Pharmacology Research & Perspectives 5.4 (2017): e00324.
• Walker, Thomas B., et al. "Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men." Metabolism 56.8 (2007): 1111-1117.