TeaCrine®, Tribulus, Cordyceps, ALA, Sesamin, Fish Oil & More - The Latest Supplement Science (November 2016)

Many currently available supplements lack sufficient scientific backup.

It has been a while since I published the last supplement science update - the recent release of the latest edition of the Journal of Dietary Supplements reminded me of that. In issue 1 of volume 14 of this journal that "addresses important issues that meet a broad range of interests from researchers, regulators, marketers, educators, and healthcare professionals" (Aims & Scope according to the publisher) you will find studies on (you already know that from the headline) "TeaCrine®, Tribulus, Guarana, ALA, Sesamin, Fish Oil & More", studies the design and results of which I will briefly summarize for you in the following paragraphs:

Read about rather exercise-related studies at the SuppVersity

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Study Indicates Cut the Volume Make the Gains!

• TeaCrine® performs again: New data on safety, dosing and time course of effects (Ziegenfuss. 2016) -- You've read about theacrine (not to be confused with l-theanine although both are naturally occurring in tea) in previous SuppVersity articles. It's a purported cognitive and physical performance enhancer and its patented variety, which is extracted from Camellia assamica variety kucha tea, is now part of many pre-workout formulas.
  
  In their latest study, Ziegenfuss et al. (2016) who generated most of the currently available TeaCrine® (TC) research examined the "subjective dose–response, daily changes in cognitive and psychometric parameters, and changes in gas exchange and vital signs" (Ziegenfuss. 2016).  As the authors point out, these particular study outcomes "were chosen to better ascertain the previously reported animal and human outcomes involving theacrine administration" (ibid.).
  

  

  Figure 1: Relative changes (calculated based on arithmetic mean of 95% confidence interval) in self-reported fatigue, focus, and willingness to exercise in the chronic administration trial (Ziegenfuss. 2016).

  The study had two parts: Part 1 (chronic administration) was a randomized, open-label, dose–response investigation in nine healthy participants  (3F, 6M) who consumed either 400 mg TC per day or 200 mg TC per day and recorded the subjective changes in cognitive, psychometric, and exercise attributes using 150-mm anchored visual analog scale (VAS) before, and 1, 4, and 6 hours after ingestion every day for 7 consecutive days.
  
  Part 2 (acute administration) had a different design, with 15 healthy subjects (7F, 8M)
  participating in a randomized, double-blind, placebo-controlled, crossover investigation in which all participants ingested a single 200 mg dose of TC or Placebo (PLA).
  Just like in part 1 (results see Figure 1), VAS questionnaires were used to detect subjective changes in various aspects of physical and mental energy along with changes in gas exchange and hemodynamic parameters before, and 1, 2, and 3 hours after acute ingestion.
  
  What the scientists found was a similar increase in energy, focus, and concentration with both dosages of theacrine. Interestingly enough, the subjects' willingness to exercise, anxiety, motivation to train and libido increased only in the low-dose group receiving 200mg/d for 7 days while it was unchanged in the higher-dose group who took 400 mg of the supplement on a daily basis.
  

  

  Figure 2: Graphical summary of the most important take-home messages of the study at hand.

  Now this, i.e. the U-shaped dose-response curve (cf. Figure 1) is yet only one of three important insights into how you should supplement with this natural purine molecule: It can be derived from (a) Ziegenfuss' et al.'s acute administration study that you (A) don't have to take theacrine chronically for a week (or longer) before you see beneficial effects. On the other hand, the results from the long(er)-term study show (B) no habitation effect, i.e. the dreaded decrease in efficacy you see with other stimulants such as caffeine.
  
  Speaking of which, since theacrine does not have any of caffeine's (mild) adverse side effects such as increased heart rate or changes in systemic hemodynamics (more safety data can be found in Hayward. 2015), theacrine could, in fact, make a good adjunct to caffeine in pre-workout supplements or fat loss adjuvants. To award teacrine the "SuppVersity seal of ergogenic approval", it would yet be nice to see independent research on the combination of the two, i.e. caffeine and theacrine - research that would prove that theacrine does, indeed, add meaningfully to the benefits of caffeine when it's co-consumed with the world's favorite stimulant. For l-theanine there's some such evidence, as you've learned earlier this year at the SuppVersity, for theacrine, on the other hand, the one study that investigated the potential nootropic effects of this combination found only subjective, yet no objective benefits (Kuhman. 2015).
• Tribulus disappoints again: No beneficial effects in men with unexplained infertility (Roach. 2016) -- With their latest study, researchers from the Cairo University in Egypt add to the confusion over the efficacy of tribulus terrestris supplements. Unlike the others of other recent studies, Roaiah, et al. didn't find any measurable benefits in the 30–50-year-old patients with unexplained infertility who participated in their three-months study.
  

  

  Figure 3: The relatively low dose of regular tribulus powder didn't have a measurable effect on the hormone levels of the infertile men in the 3-months study at hand (Roaiah. 2016).

  The authors, themselves, attribute the different study outcomes primarily to differences in the dosage regimen with studies yielding positive results using twice the amount that was used in the study at hand (meaning 1,500 mg/day instead of 750 mg/day in three divided doses). Personally, however, I would suspect that the type of the supplement [raw powder vs. saponin extract as it was used in Wilk, et al. (2016)] may better explain the sign. inter-study differences. If that's indeed the case it wouldn't make sense to pick up the next best TT supplement at your local GNC and hope for results. Rather than that, it would be wise for studies to finally settle if it's the product quality and, more specifically, the saponin content and composition that makes all the difference.
• Cordyceps (militaris) surprises again: Study finds performance benefits during high-intensity exercise tests w/ chronic supplementation (Hirsch. 2016) -- Cordyceps is not just the third purported ergogenic in today's installment of the SuppVersity Supplement Research Update, it's also one of those supplements where we simply don't have enough evidence to be sure that it's worth the significant amount of money you have to pay for a monthly supply of 4g/day of this peculiar mushroom.
  
  With the data in Figure 1 and the fact that it is now offered in bulk at prices that would allow you to get a one-month supply for less than $15, cordyceps may be a candidate for your "next supplement to test-drive"-list.
  

  

  Figure 4: Phase II changes in performance measures (A) maximal oxygen consumption (VO2max), (B) ventilatory threshold (VT), and (C) time to exhaustion (TTE) presented as 95% confidence intervals (Mean ± (1.96 × SEM)) | ∗indicates a significant improvement, as determined by 95% CI (Hirsch. 2016).

  You should be aware, though, that it took Hirsch et al. the analysis of 95% confidence intervals and thus some statistical shenanigan to be able to report significant improvements in total time to exhaustion (TTE) after one (+28.1 s) and three weeks (+69.8 s) and three weeks before the small, but measurable increases in VO2max (+4.8 ml/kg/min) and ventilatory threshold (+0.7 l/min) surfaced. If cordyceps does indeed work it is thus, just like creatine, whey and other better-proven ergogenics, a thing that has to be consumed chronically - unlike caffeine and its stimulating cousins' (including theacrine, see above) whose immediate effects are probably the reason why they are so popular.

While it is no longer a popular fat burner ingredient sesamin may be an anti-inflammatory, blood glucose management improving adjunct to the supplement regimen of any type II diabetic according to a new human study (Mohammad. 2016).

What else have we got? Alright, with the three most interesting studies being discussed in detail we can turn to the noteworthy, but not exactly super-interesting studies on guarana, ALA, carnitine, magnesium and fish oil. And no, we're not talking about stacking them. Rather than that, the latest research from scientists all around the world suggests that there are (A) no benefits of 2x50mg /day of guarana in neck cancer patients during chemotherapy (Martins. 20016), (B) potential benefits of carnitine and alpha lipoic acid (ALA) may prevent the onset of diet-induced type II diabetes in humans just like they did in a recent rodent study (Abdelkarem. 2016), (C) significant benefits of sesamin (you may remember this oil from various OTC fat burners) as an anti-inflammatory T2DM supplement (see Figure to the right) and (D) small but significant reductions in muscle soreness in response to resistance training after one week on 6g of fish vs. soybean oil (Tinsley. 2016) | Comment!

References:

• Abdelkarem, Hala M., Laila H. Fadda, and Abeer AG Hassan. "Potential Intervention of α-Lipoic Acid and Carnitine on Insulin Sensitivity and Anti-Inflammatory Cytokines Levels in Fructose-Fed Rats, a Model of Metabolic Syndrome." Journal of Dietary Supplements (2016): 1-11.
• Habowski, S. M., et al. "The effects of Teacrine TM, a nature-identical purine alkaloid, on subjective measures of cognitive function, psychometric and hemodynamic indices in healthy humans: a randomized, double-blinded crossover pilot trial." Journal of the International Society of Sports Nutrition 11.1 (2014): 1.
• Hayward, Sara, et al. "Safety of Teacrine®, a Non-Habituating, Naturally-Occurring Purine Alkaloid Over Eight Weeks of Continuous Use." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P59.
• Hirsch, Katie R., et al. "Cordyceps militaris Improves Tolerance to High-Intensity Exercise After Acute and Chronic Supplementation." Journal of Dietary Supplements (2016): 1-13.
• Kuhman, Daniel J., Keanan J. Joyner, and Richard J. Bloomer. "Cognitive performance and mood following ingestion of a theacrine-containing dietary supplement, caffeine, or placebo by young men and women." Nutrients 7.11 (2015): 9618-9632.
• Martins, Suelen Patrícia dos Santos, Cynthia Lemos Ferreira, and Auro del Giglio. "Placebo-Controlled, Double-Blind, Randomized Study of a Dry Guarana Extract in Patients with Head and Neck Tumors Undergoing Chemoradiotherapy: Effects on Fatigue and Quality of Life." Journal of Dietary Supplements (2016): 1-10.
• Mohammad Shahi, Majid, et al. "Effect of Sesamin Supplementation on Glycemic Status, Inflammatory Markers, and Adiponectin Levels in Patients with Type 2 Diabetes Mellitus." Journal of Dietary Supplements (2016): 1-12.
• Roaiah, Mohamed Farid, et al. "Prospective analysis on the effect of botanical medicine (Tribulus terrestris) on Serum testosterone level and semen parameters in males with unexplained infertility." Journal of Dietary Supplements (2016): 1-7.
• Tinsley, Grant M., et al. "Effects of Fish Oil Supplementation on Postresistance Exercise Muscle Soreness." Journal of dietary supplements (2016): 1-12.
• Wilk, Michał, et al. "Endocrine Responses to Phys^ical Training and Tribulus Terrestris Supplememtation in Middle-Age Men." Central European Journal of Sport Sciences and Medicine 13.1 (2016): 65-71.
• Ziegenfuss, Tim N., et al. "A Two-Part Approach to Examine the Effects of Theacrine (TeaCrine®) Supplementation on Oxygen Consumption, Hemodynamic Responses, and Subjective Measures of Cognitive and Psychometric Parameters." Journal of dietary supplements (2016): 1-15.

ALA, Berberine, Metformin, Resveratrol, AICAR & Co - Are AMPK Mimetics & Activators Good or Bad for Athletes?

Unless you're planning to just sit, instead of cycle on your spinning bike, it is by no means sure if your performance well benefit or maybe even suffer from the use of AMPK mimetics and activators.

Recently someone asked me on Facebook, whether AMPK activators like Lipoic acid (ALA), Berberine, Metformin, AICAR & Co wouldn't make excellent performance boosters. I pondered that question for some time and said: "If you are about to compete in a highly glycolytic sport, the opposite is probably the case."

There's little question that supplements like lipoic acid are useful if you are an overweight type II diabetic. But let's be honest: How many of you fall into this category? As healthy, active individuals or even athletes, on the other hand, you should be aware that the ability of these agents to increase the glucose uptake and block the glyconeogenic pathways in the liver may easily make you run out of fuel during anaerobic activities like lifting or sprinting.

Learn more about hormesis and how antioxidants can also impair your gains

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Antiox. & Health Benefits Don't Correlate

This does not negate the fact that AMPK activators, by their ability to increase the use of free fatty acids as a substrate, may be of interest to endurance runners or athletes competing in other sports, where the lion's share of the energy they use during their workouts and competitions are carboxylic acids with a long aliphatic tail (chain), i.e. fatty acids.

Against that backround it is hardly surprising that the few pertinent studies that exist are - at least in parts - contradictory. Shortly before the last Olympic Games in Beijing, for example, a study was published that showed that the research chemical and AMPK activator AICAR (5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide) increased the running capacity of mice without any training. But let's be honest: Do you think athletes would be looking for agents that work without training... well, obviously they would, but AICAR - as potent as it may be - will never replace the blood, sweat and tears athletes have to invest to be successful. That's for sure.

Which AMPK activators are actually prohibited by the WADA? The WADA list of prohibited substances lists only "AMP-activated protein kinase (AMPK), e.g. AICAR; and Peroxisome Proliferator Activated Receptor δ (PPARδ) agonists e.g. GW 1516" which is pretty unspecific and leaves me questioning whether other natural AMPK activators like ALA, berberine, chlorogenic acid or the most widely used one, i.e. metformin, would be illegal, too.

Nevertheless, the observation Narkar et al. (2008) made was enough for the World Anti-Doping Agency (WADA) to include certain AMPK activators in the list of forbidden drugs - for all, not just endurance sports, obviously.

Table 1: Adenosine monophosphate-activated kinase activators and their impact on exercise capacity (Niederberger. 2015)

Actual experimental evidence of performance enhancing effects exists for several natural and synthetic AMPK mimetics and activators (see Table 1). If you look closely, however, you will notice that all those "enhacnements" and "increases" have been in rodent models and/or non-athletes.

What does the latest review say? As usual, the special needs of Olympic-lifters, bodybuilders, sprinters and all other athletes who are competing in anaerobic sports are ignored by the authors of the latest and - as far as I know - first review of the impact of the activation of AMPK on sports performance.

It's the increase in the total time and endurance as well as VO2 in a injection only (no training) rodent study observed by Narkar et al. in 2008 that is behind all the hype around AICAR as a "potent doping agent". I wonder if the athlete who use is even know that the mice in the study didn't even train. Whether the effect is additive is thus highly questionable.

In spite of their unfortunate ignorance of sports-specific differences, Niederberger et al. (2015) produce a neat overview of the available research on AMP mimetics like AICAR, pharmacological drugs like metformin, salycilic acid, thiazolidinediones, Phenobarbital and Telmisartan, and natural AMPK activators like green tea, capsaicin, resvertrol and co. Of these, none has been tested in athletes, though, even the applauded AICAR helps only in theory (!). Unlike Niederberger's review suggests, the performance enhancing effects in studies like (Hayashi. 1998; Cuthbertson. 2007; Narkar. 2008) were after all observed in the absence of baseline training and are thus not representative of what would happen in athletes who won't be dumb enough to believe that they don't even have to train if they are abusing AICAR.

The lack of relevant evidence for performance benefits in athletes that would be induced by AMPK mimetics, as well as the existing evidence that AMPK promoters like resveratrol, which don't target AMPK primarily, but must be thought of as potent antioxidants instead, entail the risk of anti-hormetic effects (e.g. the attenuation of the positive effects of endurance exercise on inflammatory and oxidative stress markers in aged men in response to 250mg resveratrol day in Olesen et al.'s 2014 study) put a huge "?" behind the actual usefulness of AMPK mimetics and promoters as athletic performance enhancers..

In the absence of experimental evidence from both rodent and human studies that involve AMPK activators and anaerobic exercise, we have to use our brains to find out whether sprinters, bodybuilders, or weight lifters and athletes competing in team sports that have both an aerobic and an anaerobic component would benefit as well. In this case the extensive research on alpha lipoic acid (ALA) can help us, but we should not forget that the effects may differ from one agent to the other.

Due to the previously mentioned potentially negative effect on blood glucose in insulin sensitive individuals that is mediated primarily by increases in whole body glucose oxidation, increased glycolysis (wasting of the glycogen reserves| Barnes. 2004) and a reduced ability to produce new glucose "on demand" (via gluconeogenesis, which is AMPKs main of glucose control according to Zhang et al. 2009), athletes competing in anaerobic sports may in fact run the risk of running low on blood sugar and thus compromising their performance and/or being even more reliant on sugary high carbohydrate beverage.

In insulin sensitive muscle cells ALA reduces the rate of glycogen synthesis (Dicter. 2002). This should remind you of this simple truth: What's good for your obese neighbor, ain't necessarily good for you. Plus: ALA ain't the only supplement with different, often opposite effects in lean vs. obese.

What's good for the obese is rarely good for athletes: The reduced protein synthesis (Figure 1) is only one of several undesirable side effects of high doses of ALA. One that people usually won't even believe exists is an impairment of glycogen synthesis in insulin sensitive skeletal muscle. While ALA is famous for partly restoring the whole body (including body fat) glucose uptake in insulin resistant individuals, studies like the one by Dicter et al. (2002) indicate that it will reduce the insulin-induced glycogen synthesis if the muscle in question is not insulin resistant, but sensitive. That's an effect that may occur only at higher dosages of ALA (and other potent AMPK activators), but still one that no athlete can ignore.

If you don't care about blood glucose, you may be intrigued to hear that AMPK will not act on your glucose metabolism, alone. Increasing levels of AMPK will also suppress skeletal muscle protein synthesis (Figure 1), which is a side effect that's probably even worse than the remote risk of hypoglycemia, specifically in athletes competing in anaerobic sports.

Figure 1: Changes in p-AMPK and nutrient-induced protein synthesis in myotubes from the EDL muscle (Saha. 2010).

Now, some of you may argue that I personally wrote in an older article in the Intermittent Fasting Series that the rise in AMPK due to exercise would not be a problem.

If you'd read that article carefully, though, you'd also know that this is because exercise triggers the release of a specific form of AMPK that's different from the one that's released during fasting and in response to regular AMPK activators. It is thus not unlikely that high(er) intakes of ALA as they would probably be abused by athletes, who (falsely) believe they'd benefit from it, can impair the protein synthesis to a similar extent as it was observed by Saha et al. in their 2010 study in rodent EDL muscles.

Furthermore animal studies show that chronic administration of albeit very high doses of ALA, equivalent to ~5g/day for a human being, will actually trigger significant reductions in lean mass (Shen. 2005) - something almost every athlete who's competing in anaerobic sports will want to avoid.

The answer to the question in the headline is - as so often: "It depends!" If you are an endurance athlete, the acute, yet not the chronic consumption of the AMPK mimetics (=acts just like) like AICAR and maybe some of the less potent AMPK activators could improve your endurance. Without studies where the rodents (or even better men and women) are actually trained, even this assumption is speculative.

Figure 2: While the last word has not been spoken, yet the impaired adaptive response to stressors in older subjects supplementing w/ 250mg/day resveratrol Olsen et al. observed in 2014 is further evidence that the chronic consumption of potent antioxidants (which happen to be AMPK promoters in this and other cases like ALA) must not be recommended unconditionally for athletes based on the available evidence.

If, on the other hand, you're competing in sports where anaerobic performance, i.e. power, speed and other parameters that will critically depend on the availability of glucose, you will probably see no beneficial and, in the worst case, detrimental effects.

These detrimental effects could also occur in response to the chronic ingestion of AMPK promoters like lipoic acid due to their potentially negative effect on protein synthesis and glycogen repletion, as well as in response to the chronic use of potent anti-oxidants for which evidence exists that they impair the hormetic response to exercise and may thus be detrimental for athletes competing in both anaerobic and aerobic sports.

If you take small amounts of berberine, ALA, resveratrol, or other agents that have been shown to exert their health benefits via AMPK, though, it is very unlikely that the previously discussed unwanted side effects surface (don't expect direct ergogenic effects, though). Moderation is - as so often - the key to perfect happiness | Comment on FB!

References:

• Barnes, Brian R., et al. "The 5′-AMP-activated protein kinase γ3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle." Journal of Biological Chemistry 279.37 (2004): 38441-38447.
• Cuthbertson, Daniel J., et al. "5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men." Diabetes 56.8 (2007): 2078-2084.
• Hayashi, Tatsuya, et al. "Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport." Diabetes 47.8 (1998): 1369-1373.
• Narkar, Vihang A., et al. "AMPK and PPARδ agonists are exercise mimetics." Cell 134.3 (2008): 405-415.
• Niederberger, Ellen, et al. "Activation of AMPK and its Impact on Exercise Capacity." Sports Medicine (2015): 1-13.
• Olesen, Jesper, et al. "Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men." The Journal of physiology 592.8 (2014): 1873-1886.
• Saha, Asish K., et al. "Downregulation of AMPK accompanies leucine-and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle." Diabetes 59.10 (2010): 2426-2434.
• Shen, Q. W., et al. "Effect of dietary α-lipoic acid on growth, body composition, muscle pH, and AMP-activated protein kinase phosphorylation in mice." Journal of animal science 83.11 (2005): 2611-2617.
• Zhang, Bei B., Gaochao Zhou, and Cai Li. "AMPK: an emerging drug target for diabetes and the metabolic syndrome." Cell metabolism 9.5 (2009): 407-416.

Circadian Clock Normalization as Novel Mechanism Behind the Health Benefits of ALA in NAFLD & Diabesity | Plus: ALA For Athletes & the Obese - Yes/No + When to Take It?

Yes, you can buy alpha lipoic acid as bulk powder, but if you still have intact mucosa and want to keep it intact, I suggest you swallow pills.

Alpha lipoic acid aka "ALA" is a natural AMPK agonist that works similar to metformin. Developed by BASF and others as an anti-diabetes medication in the late 20th century, it's now a popular supplement that is prescribed as a "drug" to type II diabetics only rarely and only in Europe, yet not in the US.

Based on the currently available evidence its anti-diabetic effects are comparable but far inferior to metformin. In view of the fact that lipoic acid is also non-patentable and thus not exactly profitable, it's no wonder that it has disappeared from the radar of the medical establishment over the past decade.

Learn more about lipoic acid here at the SuppVersity

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A recent study from the Linus Pauling Institute may yet well put the naturally occurring power-antioxidant, which is found at higher levels in organ meats and leafy vegetables such as spinach and broccoli, back onto the research agenda of top scientists all around the world.

Lipoic acid appears to reset and synchronize circadian rhythms, or the "biological clock" found in most life forms. The ability of lipoic acid to help restore a more normal circadian rhythm to aging animals could explain its apparent value in so many important biological functions, ranging from stress resistance to cardiac function, hormonal balance, muscle performance, glucose metabolism and the aging process.

Figure 1: ALA had no direct weight loss effect, but it reduced the abnormal cortisol excursions and the increase in postprandial fatty acid synthesis in the old rodents (Keith. 2014)

The findings were made by biochemists from the Linus Pauling Institute at Oregon State University, and published in Biochemical and Biophysical Research Communications, a professional journal.

"This could be a breakthrough in our understanding of why lipoic acid is so important and how it functions. Circadian rhythms are day-night cycles that affect the daily ebb and flow of critical biological processes. The more we improve our understanding of them, the more we find them involved in so many aspects of life, "said Tory Hagen, the Helen P. Rumbel Professor for Healthy Aging Research in the Linus Pauling Institute, and a professor of biochemistry and biophysics in the OSU College of Science

Almost one-third of all genes are influenced by circadian rhythms, and when out of balance they can play roles in cancer, heart disease, inflammation, hormonal imbalance and many other areas, the OSU researchers said. Of particular importance is the dysfunction of circadian rhythms with age.

"In old animals, including elderly humans, it's well-known that circadian rhythms break down and certain enzymes don't function as efficiently, or as well as they should," said Dove Keith, a research associate in the Linus Pauling Institute and lead author on this study.

If lipoic acid offers a way to help synchronize and restore circadian rhythms, this could be a quite significant result. In that it is yet important to know if the effects, the researchers observed only in the liver, are mediated by effects that are independent of the anti-oxidant effects of lipoic acid - or, to put it differently, if lipoic acid has direct or just indirect effects which are mediated by the blockade of pro-oxidant disturbances of the "circadian clock" of the liver.

Figure 2: AMPK expression in white & brown fat and muscle (top, based on Prieto-Honta. 2012), and implications (bottom)

I guess it would be pretty unsatisfying if I passed on this opportunity to review a handful of recent studies on the benefits of alpha lipoic acid, right? Well, then... I guess you will remember that I am skeptical about its usefulness as a nutrient partitioner, right? Although we have only rodent data to support this hypothesis the increase in AMPK expression that would come at a very unfavorable moment, if you take your "repartitioning supplement" shortly before or with a meal did after all leave the rodents in the previously discussed study by Prieto-Hontoria et al (2012) lighter and less muscular (see Figure 2, as well as previous article "Lean & Muscular W/ Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out "Nutrient Repartitioner"!" | read more).

That obviously doesn't mean that ALA was useless. In a different scenario - e.g. for someone with a high(er) baseline inflammation - alpha lipoic acid may well have beneficial "nutrient repartitioning effects". Examples? What about the seminal paper by Ko et al. (2011)?

In said study, 360 obese individuals (body mass index [BMI] ≥30 kg/m2 or BMI 27-30 kg/m2 plus hypertension, diabetes mellitus, or hypercholesterolemia) were randomized to alpha-lipoic acid 1200 or 1800 mg/d or placebo. The supplement was consumed in three doses of 600mg timed 30 minutes before a meal. Now in my past articles, I have often pointed out that supplement timing may be overrated. In the case of ALA, it does yet make perfect sense for diabetics and insulin resistant obese people (!) to take it before a meal, in order to benefit from the insulin sensitizing effects of the AMPK activator alpha lipoic acid.

Figure 3: Weight loss during 4-week induction and 16-week follow up in the placebo, 1,200mg and 1,800mg ALA groups (left) and relative weight loss at the end of the study in all "completers" (Koh. 2011)

As you can see in Figure 3, the timely use of 600mg of alpha lipoic acid before each of the meals lead to significantly increased weight loss, specifically in the latter phase of the 20 week trial, in the course of which the subjects had to consume 600kcal less - but at least 1,200kcal/day - than their habitual diet would provide. Quite an impressive result of which the researchers from the University of Ulsan College of Medicine in Seoul say that its efficacy and safety (compared to other anti-obesity drugs) would "suggest that alpha-lipoic acid may be effective as an adjunctive medication for obesity" (Koh. 2011) - a medication, and you can see that in Figure 3, that helps with both: weight and fat loss!

Whether ALA is or isn't for hard-training athletes / gymrats remains to be seen

Unfortunately, studies on athlete subjects are quasi-non-existent. What we know is that alpha-lipoic acid can be used to increase the accumulation of creatine in the muscle (learn more | baking soda is probably more effective, though) and that it diminishes the exercise induced oxidative damage without having significant beneficial (or negative) effects on exercise performance in the short run (Zembron-Lacny. 2009).

ALA or R-ALA? There is no reliable evidence that R-ALA would produce superior effects in vivo studies. The often cited study by Streeper et al. (1997), for example, was conducted on isolated, insulin resistant rat muscle in the Petri dish and is thus hardly representative of trained athletes. In fact, the vast majority of studies reporting metabolic benefits from the use of alpha lipoic acid used the racemic mixture of the R- and the allegedly "toxic" S- isomer of alpha lipoic acid. If you still insist on R-ALA make sure it's bound to sodium (Na), because the unbound version won't even make it into your bloodstream (Carlson. 2007).

Otherwise, you will find patent after patent with hilarious, scientifically unverified claims about "muscle building", "body recompositioning" and "performance enhancing" effects of ALA in athletes.

Reliable evidence that any of these effects exist in athletes who follow a clean, whole foods based high(er) protein diet, however, is absent. If anything, one could cite a relatively exotic rodent study that was published in the Journal of Shaanxi Normal University (Natural Science Edition) in 2006. In said study, the Chinese scientists observed a glycogen preserving effect of ALA in rats who were trained to exhaustion (Xiong. 2006). Whether or not these or other benefits outweigh a potentially reduced adaptive response to exercise as it was observed for n-acetyl-cysteine (NAC) by Michailidis et al. in 2013 remains questionable, though.

Figure 3: Highly significant increases in PPAR-alpha are partly responsible for the reduced hepatic fatty liver synthesis and should help prevent NALD (Keith. 2014)

Let's get back to the "clock issue": It remains to be seen if similar effects on the clock genes in the liver can be observed in older humans, as they have now been reported for rodents with the standard 600mg/day servings of alpha lipoic acid of which previous studies show that it can help with diabetes and non-alcoholic fatty liver disease.

Until we don't know the exact mechanism by which alpha lipoic acid works its restorative magic on the clock genes of your liver, we cannot tell if it has to be timed appropriately, either. For melatonin, which is a cyclically produced hormone correct timing is a must. For lipoic acid it's probably irrelevant... at least if its effects are in fact mediated by the powerful antioxidant effects of lipoic acid | Comment!

References:

• Carlson, David A., et al. "The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects." Alternative Medicine Review 12.4 (2007): 343.
• Dove Keith, Liam Finlay, Judy Butler, Luis Gómez, Eric Smith, Régis Moreau, Tory Hagen. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age. Biochemical and Biophysical Research Communications, 2014
• Koh, Eun Hee, et al. "Effects of alpha-lipoic acid on body weight in obese subjects." The American journal of medicine 124.1 (2011): 85-e1.
• Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Martínez JA, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr. 2012 Jun 5. [Epub ahead of print]
• Streeper, Ryan S., et al. "Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle." American Journal of Physiology-Endocrinology And Metabolism 273.1 (1997): E185-E191.
• Xiong, Zheng-ying, and Hai-bin LIU. "Effects of alpha-lipoic acid on glucose reserve and moving capacity of training rats [J]." 
• Zembron-Lacny, A., et al. "Assessment of the antioxidant effectiveness of alpha-lipoic acid in healthy men exposed to muscle-damaging exercise." J Physiol Pharmacol 60.2 (2009): 139-43.

Supplemental NAFLD (Non-Alcoholic Fatty Liver Disease) Protection for Everyone! Regular Alpha Lipoic Acid (300mg) & Vitamin E (700IU) For Less Than $20 Do the Trick!

You don't have to look at the liver of this person to know that he / she is suffering from NAFLD - just like an ever-increasing minority (soon majority) of US citizens

You may asking yourselves what "looking good naked" has to do with obesity and diabetes right now, but if you think about it, the things you have to achieve the one (don't tell me you don't care if you look good naked, liar!) and avoid the others are actually not too different and what's commonly overlooked: The liver is of pivotal importance for both! Looking healthy and being healthy.

In spite of the fact that I am going to get back to the "liver <> diabetes" connection later in the article, I would like to invite you to take a closer look at a previous article on that topic "Liver Enzymes the #1 Marker of Insulin Resistance!? Plus: What Does the Correlation Bettwen HbA1C & ALT, AST and GPT Tell Us About Diabesity?" to catch up!

You can learn more about NAFLD at the SuppVersity

6 Bananas A Day = No Problem For the Liver!

Can We Blame NALFD on Fructose?

Insulin Sensitivity is Determined in the Liver

Saturated Fat & NAFLD - Is there a Link?

Snack Your Way to a Non-Alholic Fatty Liver

No Choline, No Healthy Liver, But Heart Attacks

Now that we are on common grounds in regards to the importance of liver health, it's about time to drop the bomb. Believe it or not, you can help your liver along tremendously with commonly available dietary supplements - and if I am not totally mistaken that will cost you - at most - 20 bucks a month. Certainly not bad in view of the fact that the stack of alpha lipoic acid (regular, not R-ALA) and - you won't believe it - regular vitamin E has just been shown to A

• 

  CLA always with DHA | learn why

  improve inflammatory cytokine levels, 
• reduce steatosis scores, 
• improve homeostasis model assessment scores, and 
• lower triglyceride levels 

withing only 6 months significantly in comparison to the baseline levels of the to 155(!) patients that were enrolled in the study.

ALA & Vitamin E work - both in conjunction and on their own

In pairs of m=40, the subjects had been randomly allocated to receive either ALA 300 mg, vitamin E 700 IU, or ALA 300 mg plus vitamin E 700 IU, the poor 35 patients who were left were randomized to treatment with placebo.

Figure 1: Changes in selectet parameters of metabolic health over the 6-months study period (Basu. 2014)

As the data in Figure 1 clearly indicates, this was ill fate. Compared to their peers who were treated with alpha lipoic acid and / or vitamin E, they saw significantly less pronounced health improvements in spite of similar lifestyle changes (participants were allowed to consume 1600 calories per day and to participate in moderate exercise, consisting of walking 150 minutes per week at the rate of 100 steps per minute).

No, I would not be scared of vitamin E! If you have NAFLD, there is no doubt that you can benefit from additional antioxidants. Things may look different, for lean athletes like yourself, who tend to fall for the false promises of "nutrient repartitioners" | learn more.

Bottom Line: They are cheap, they can be bought all over the Internet and at every supplement store round the corner and they are effective. Alpha lipoic acid (regular) and vitamin E will boost your efforts to reverse the damage you've inflicted on your liver over the past couple of years and this will have pronounced effects on your overall metabolic health, your lipid and glucose metabolism, your heart disease and cancer risk ("Liver Cancer Kills US Citizens" | learn more) and - of course - the way you look and feel. Not too bad for 100% sage supplements that are worth less than $20 per months, right? Just make sure you don't overdo it. If 300mg + 700IU work, this does not mean that 1,200mg + 2400IU will work better ;-)

Reference

• Basu, Patrick P., et al. "Effect of Vitamin E and Alpha Lipoic Acid in Nonalcoholic Fatty Liver Disease: A Randomized, Placebo-Controlled, Open-Label, Prospective Clinical Trial (VAIN Trial)." Open Journal of Gastroenterology 4.05 (2014): 199.

No Magic Numbers: The Omega-3:Omega-6 (N3/N6) Ratio - Higher is Better, But as Part of the Standard American Diet Even a 1:1 Ratio Won't Protect You Against Diabesity

Eating "like an American" makes you fat and sick. No matter what the omega-3 to omega-6 ratio of your diet may be.

It is a pity. Yeah, if the latest study from the University of South Carolina was a human study, it would finally provide a definitive answer to the question how much omega-3 we actually need. Well, I should clarify: It would provide an answer to the question how much omega-3 we need with a given baseline omega-6 intake.

In view of the fact that the study duration was 20 weeks, it would yet take more than 60 (human) years to find out, whether the ratio of n-3/n-6 in the diet is in fact as irrelevant as the reslts Reilly T. Enos et al. present in their latest paper would suggest.

You can learn more about omega-3 & co at the SuppVersity

Fish Oil Makes You Rancid?

Are All Fats Bad For You?

Fish Oil & GLA vs. Acne

MUFA & Fish Oil Don't Match

Fish Oil Doesn't Help Lose Weight

Rancid Fish Bad 4 Health

Over those 20 weeks the scientists from the Departments of Pathology and Chemistry and Biochemistry fed their previously healthy C57BL/6 mice diets that contained either the regular rodent chow or one out of four high fat diets with omega-3 to omega-6 ratios of 1:1, 5:1, 10:1, and 20:1. As the scientists point out, the percentage of calories provided by each of the three macronutrients and the ratio of monounsaturated FAs (MUFAs) to PUFAs (MUFA:PUFA) were identical for the HFDs and were designed to be similar to the standard American diet.

Table 1: Diet composition of treatment diets.SFAs, Saturated Fatty-Acids; MCSFAs, Medium-Chain Saturated Fatty Acids; LCSFAs, Long-Chain Saturated Fatty Acids; USFAs, Unsaturated Fatty Acids; MUFAs, Monounsaturated Fatty Acids; PUFAs, Polyunsaturated Fatty Acids (Enos. 2014)

The only significant difference among the HFDs was the omega-6:omega-3 (The control diet (AIN-76A Mod) was used in order to match the MUFA:PUFA and omega-6:omega-3 of the 20:1 HFD.)

Ok, the rodent thing is not the only problem

None of the diets contained any long-chain omega-6 or omega-3 FAs. In human terms this would mean that we are not testing a high fish, high grass-fed beef, but a high omega-3 vegetarian diet with tons of alpha linolenic, but no Docosahexaenoic acid (DHA) or Eicosapentaenoic acid (EPA), which is the "stuff" (=long-chain omega-3 fatty acids) you would find in meats of grass-fed beef and, of course, fish.

Figure 1: Changes in body weight, visceral fat weight and adipocyte size during 20 weeks on modified "standard American diet" w/ different ratios of omega-3 to omega-6 fatty acids (Enos. 2014)

And still, based on the current paradigm, the scientists expected to see significant differences in metabolic health parameters between the high and low omega-3 to omega-6 ratio groups - at best even a complete revision of the metabolic damage the rodents suffered due to consuming a high energy + high fat diet.

It does not always work that way.

In reality, though, any therapeutic benefit produced by reducing the omega-6:omega-3 was evident only when comparing the 1:1 to 20:1 HFD. Yep, that's true, the mice on the 1:1 HFD had a lower total to HDL (TC:HDL-C) ratio and a decreased adipose tissue CXCL14 gene expression and adipose tissue macrophage infiltration, both of which would indicate that they had a lower risk cardiovascular disease.

As a SuppVersity reader you know very well that "A Meta-Analysis Says: Fish Oil Does Not Help You Lean Out!" you do yet also know that the there are also a bunch of arguments "Why It's Still Worth Having Fatty Fish 1-2x/Week" | more

But there were benefits, weren't there? Yes, there were! In fact, there was even a direct link between higher EPA:AA (AA: arachidonic acid, the allegedly inflammatory and thus "bad" long-chain omega-6 fatty acid) and DHA:AA in the adipose tissue phospholipids. 

The net outcome on the other hand, was profoundly disappointing: "[...]despite these effects, and independent of the omega-6:omega-3, all HFDs, in general, led to similar levels of adiposity, insulin resistance, and AT [adipose tissue] inflammation" (Enos. 2014) - in short, it's a sad, but actually not surprising fact that the standard American diet (SAD) will make you fat and diabetic, no matter how much omega-3 fatty acids you are shoveling down.

References

• Enos, Reilly T., et al. "Reducing the Dietary Omega-6: Omega-3 Utilizing α-Linolenic Acid; Not a Sufficient Therapy for Attenuating High-Fat-Diet-Induced Obesity Development Nor Related Detrimental Metabolic and Adipose Tissue Inflammatory Outcomes." PLOS ONE 9.4 (2014): e94897.