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Synephrine, arginine, citrulline - Which pre-workout ensures that you're "on fire"?

As I pointed out previously, my initial idea to cherry pick only the most interesting study results that were presented in form of of poster presentations at the Twelfth International Society of Sports Nutrition (ISSN) Conference and Expo in 2015 didn't work out. The number of interesting studies is is simply too much for a single waredownloadsoft article to discuss them all.

Accordingly, I am now posting the 2nd serving of what is going to be a multi-part series of articles with brief discussions of the most significant results of the >20 studies and short references to those that didn't make the waredownloadsoft cut in this, previous and future installments of this series for one reason or another.

• Synephrine More Ergogenic Than Thermogenic? There was not just one, but two poster presentations and a full paper that has been published only days ago on synephrine containing supplements at the ISSN meeting and on the ISSN website, respectively. Synephrine? Yes, that's the supplemental non-starter, ah... I mean allegedly powerful fat burner from orange peels. The one with promising fat loss results in rodents, but discouraging results in practice.
  
  Luckily, the studies that were presented in form of posters by scientists from the Texas A&M University (Jung. 2015 & Dalton. 2015) at the ISSN meeting did not deal with synephrine as fat burner. Rather than that, Jung et al. and Dalton et al. took a look at the short- and long-term safety of synephrine as a pre-workout. A pre-workout that contained either 3g beta alanine, 2g creatine nitrate, 2g arginine AKG, 300mg N-acetyl tyrosine, 270mg caffeine, and 15mg Mucuna pruriens, alone (PLA) or the same baseline ingredients and synephrine.
  

  Figure 1: Number of reps on sets 1-3 & 4-6 in the control and treatment conditions (Ratamess. 2015)

  Now, the fact that some synephrine in your preworkout won't kill you is not really exciting. I have to admit that. What is exciting... at least sort of, though is the fact that the questionable thermogenic turned out to be an effective ergogenic in the already published and thematically related study by Ratamess and colleagues (Ratamess. 2015). A study that shows that p-synephrine of which previous studies indicate that it is a potent, but highly selective β-3 adrenoreceptor may nor be the best fat burner (the good old ephedrine was a pan-receptor activator and clenbuterol & co target the β-3 receptor, maybe that's also why the fat loss results are rather disappointing) , but at least an underestimated ergogenic.

• As the data in Figure 1 goes to show you, the p-synephrine supplement, which was administered to twelve healthy, college-aged men at a dosage of 100mg either alone (S) or in conjunction with 100 mg caffeine (SCF) for three days. On the day on which the subjects participated in a standardized resistance exercise protocol consisting of 6 sets of squats for up to 10 repetitions per set using 80 % of their one repetition-maximum (1RM) with 2 min of rest in between sets, the supplement was ingested 45 minutes before the workout. In comparison to the placebo treatment synephrine alone triggered a significant increase in total repetitions and volume load. When synephrine was combined with 200 mg of caffeine, it also increased the mean power and velocity of squat performance. What did not change in response to either synephrine alone or caffeine and synephrine, though, were the blood lactate levels or the rate of perceived (RPE) exertion the subjects reported on the usual visual analogue scales.
  
  For me personally, that's a surprising result. For the scientists it "indicate[s that] supplementation with S and SCF can enhance local muscle endurance during resistance exercise" (Ratamess. 2015); and I have to admit: They are right. One thing you should keep in mind, though, is that unlike caffeine, where you often see reductions in RPE and thus an effect you will feel, synephrine will - even if it works - do its purported "magic" more subtly.
• The Latest on "Pump Supplements" - Creatine, Arginine, Citrulline, Nitrates -- To make sure that this series is not turning into a 12-part article, I will address the results of Moon's, Suzuki's and Vogel's results in one item (since Moon's paper basically summarizes the results of studies by Falcone and Joy, I won't discuss those separately) .
  
  

  Figure 2: Increases in blood flow volume (BFV) 33 minutes after the ingestion of 1.87g of RC, 3.67g of CP (citrulline content 1.87g), 1.87g of RA, or 3.07g of AP (arginine content 1.87g) before 3 sets of 15 arm curls (Moon. 2015).

  Moon et al.'s comparison of citrulline's and arginine's ability to increase the exercise-induced vasodilation and blood flow yielded unsurprising results that confirm that citrulline-based ingredients are more effective than arginine-based ingredients for modulating vasodilation and blood flow. Now that alone wouldn't be news-worthy if the scientists had not tested the effects of both, rawe L-citrulline (RC) and raw L-arginine (RA) and, citrulline and arginine bound to a whey peptide (CP and AP, respectively).
  
  I guess I am not going to surprise you, when I tell you that regular arginine was the worst vasodilator in this quartet. What is more surprising, though, is the extent to which the peptide bonding increased the vasodilating effects of regular citrulline and even arginine. With the the former producing 2x higher increases in vessel diameter and 9% higher increases in blood glow volume than regular citrulline (let's not even mention regular arginine | see Figure 2) the effects are pronounced enough to be potentially "feelable" and "visible" during a workout.
  
  

  Citrulline & Glutathione - GSH Amplifies & Prolongs CIT's NO Boosting Effects During + After Biceps Workout | learn more.

  Against that background I would be curious to see, whether the likewise recently reported performance enhancing effects of citrulline Suzuki et al.'s observed in twenty two well-trained young men who consumed 2.4 g / day of L-citrulline or placebo for 7 days and they took 2.4 g of L-citrulline or placebo 1 hour before 4 km cycling time trial on day 8 would be enhanced by bonding citrulline to whey peptides.
  
  I mean, if citrulline-whey-peptides appear to offer the same effects citrulline does, but at a higher efficacy, their beneficial effect on cycling time trial performance of which the Suzuki et al. argue that it was mediated by an up-regulation of plasma NO availability should be superior to that of raw citrulline, as well, right?
  
  And now that we are already talking about what really matters, i.e. performance enhancements, not increases in blood flow, it would also be interesting to see a follow up on the last "pump supplement" study to be mentioned in this installment of the ISSN Research Review: A study by Vogel et al.'s on the vasolidating effects of an arginine-nitrate based pre-workout supplements that shows significant increases in brachial artery diameter. Increases that are quantitatively similar to those Moon et al. observed for citrulline-whey-peptides in the previously discussed study. That does not mean, though that they are equally effective, though. To be able to say that we would need a study in which both agents are compared head-to-head. Unless this study is done and a follow up on Vogel's study proves that the increases in blood flow will actually produce significant performance gains, the only thing I can say about arginine nitrate is: It's interesting, but with respect to its ergogenic effects more studies have to be done.

References:

• Allison, D. B., et al. "Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain?." International journal of obesity 29.4 (2005): 443-446.
• Bouza, Brooke, et al. "Exercise and calorie information on menus is not enough to improve food choices in Hispanic adults." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P3.
• Dalton, R., et al. "Safety and efficacy of a pre-wrkout dietary supplement with and without synephrine." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P5.
• Falcone, Paul H., et al. "Acute hemodynamic effects of L-arginine, arginine nitrate, and arginine peptide on exercise-induced vasodilation and blood flow in healthy men." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P10.
• Joy, Jordan M., et al. "A comparison of raw citrulline and citrulline peptide for increasing exercise-induced vasodilation and blood flow." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P18.
• Jung, Y. P., et al. "Effects of 8 weeks pre-workout dietary supplement ingestion with and without synephrine on blood chemistry panel." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P4.
• Moon, Jordan R., et al. "A comparison of citrulline and arginine for increasing exercise-induced vasolidation and blood flow." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P6.
• O'Connor, A., et al. "Short-term powdered tart cherry supplementation encircling an acute endurance challenge potentially increases running performance and attenuates post-race markers of inflammation." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P7.
• Suzuki, Takashi, et al. "Oral L-citrulline supplementation enhances cycling time trial performance in healthy well-trained males." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P52.
• Vogel, Roxanne M., et al. "Acute hemodynamic effects of a multi-ingredient performance supplement on brachial artery vasodilation and blood flow volume following elbow flexion exercise in healthy young men." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P28.

If Yap et al. were right and only continuous and not accumulative physical activity mattered, activity trackers like the this would be useless. No one needs a device to remind him of the 30 min of brisk walking he did / skipped today.

In today's installment of waredownloadsoft "On Short Notice", we're going to take a closer look at a selection of recent papers from the European Journal of Applied Physiology. To be more specific, I will discuss the physiological and psychological effects of dietary nitrate and their potential significance for team athletes. From there we're taking a detour to glycogen resynthesis and its interaction with hydration - a topic that may be highly relevant for bodybuilders and at least interesting for everyone else. Before we then take a departing look at the differential effects of 5x10, 10x10 and endurance exercise on markers of protein synthesis and glucose uptake, we'll spend briefly review the claim that the cumulative physical activity (the one you measure w/ step counters) would lack the characteristic health benefits everyone expects from meeting his daily activity goals.

• Dietary nitrate improves sprint performance and cognitive function during prolonged intermittent exercise - While anyone of you should know that nitrate from beetroots can have significant physiological effects, the observations Thompson et al. made in their recent double-blind randomised crossover study are probably real news and above all practically relevant for some of you and/or your clients from various athletic domains (Thompson. 2015).
  
  To investigate the effects of dietary NO3(-) supplementation on exercise performance and cognitive function, the scientists had 16 male team-sport players consume NO3(-)-rich (BR; 140 mL/day; 12.8 mmol of NO3(-)), and NO3(-)-depleted (PL; 140 mL day/1; 0.08 mmol NO3(-)) beetroot juice for 7 days (these are the regular shots you can buy at supplement stores | if you want to drink regular beetroot juice, you need 3-4x the amount). With the nitrate supplement being consumed over a one week period we are thus not talking about the effects of acute, but about the effects of chronic supplementation. Keep that in mind, if you buy one shot and don't feel the results immediately.
  
  On the test day the subjects completed a prolonged intermittent sprint test (IST) protocol (two 40-min "halves" of repeated 2-min blocks consisting of a 6-s "all-out" sprint, 100-s active recovery and 20 s of rest) on a cycle ergometer during which cognitive tasks were simultaneously performed.

  Figure 1: Comparison of total work during the sprints and reaction times during cognitive decision making tasks designed to emulate the cognitive tasks during team sports (Thompson. 2015).

  As you can see in Figure 1 both, the total work done during the IST, as well as the reaction times that were measured during cognitive tasks in the second half of the IST, were improved in the beetroot vs. placebo trial.
  
  Even though, the scientists didn't find a difference in response accuracy, the findings are highly relevant for any athlete who has to (a) perform at high intensities, while (b) maintaining optimal cognitive performance and decision-making reaction times. Who is that? Well, I'd say almost every team sport athlete of whom previous studies have shown that his / her cognitive acuity suffers during prolonged intermittent exercise. 
• Extra water is not necessary for optimal glycogen replenishment after workouts - In fact, bodybuilders may want to avoid it... Avoid water? No, I am not saying you should not drink water at all, but if you look at the results of Valentín E. Fernández-Elías' recent "analysis of the relationship between muscle water and glycogen recovery after prolonged exercise in the heat in humans" you will see that too much water in the post-workout window may actually give you the 'watery' look some physique athletes like bodybuilders are trying to avoid.
  
  It is usually stated that glycogen is stored in human muscle bound to water in a proportion of 1:3 to 1:4 g. In their latest study, the scientists from the University of Castilla-La Mancha investigated this proportion in biopsy samples that were taken when their trained subjects recovered from prolonged exercise in the heat:

  "On two occasions, nine aerobically trained subjects (VO2max = 54.4 ± 1.05 mL/kg/min; mean ± SD) dehydrated 4.6 ± 0.2 % by cycling 150 min at 65 % VO2max in a hot-dry environment (33 ± 4 °C). One hour after exercise subjects ingested 250 g of carbohydrates in 400 mL of water (REHLOW) or the same syrup plus water to match fluid losses (i.e., 3170 ± 190 mL; REHFULL). Muscle biopsies were obtained before, 1 and 4 h after exercise" (Fernández-Elías. 2015).

  In contrast to what you may have expected, the muscle glycogen replenishment was not impaired by the lack of water in the REHLOW group. Ok, if you look at the data in Figure 2 right, there is a minimal advantage for the adequate water group, but this advantage is not statistically and almost certainly not practically relevant (79 ± 15 and 87 ± 18 g/kg dry muscle; P = 0.20).
  

  Figure 2: Muscle water content before and after dehydrating exercise and after 3 h recovery period (a). Muscle glycogen content before and after dehydrating exercise and after 4 h recovery period (b). Data is presented as mean ± SD. *Different from previous time point. †Different from REHFULL (P < 0.05 | Fernández-Elías. 2015).

  The thing that did differ between the adequat (REHFULL) and the inadequate (REHLOW) hydration trial, however, was the muscle water content which was significantly higher in the REHFULL than in the REHLOW trial (3814 ± 222 vs. 3459 ± 324 g/kg dm, respectively; P < 0.05; ES = 1.06).
  
  

  waredownloadsoft Suggested: "Hydrated or Dumb: Dehydration Affects Brain, Muscle and Other Vital Organs - Plus: 15+ Causes of Dehydration + Can the Color of Your Urine Tell You if You Drink Enough?" After reading this SV Classic and my recent article about the link between dehydration and type II diabetes you will probably stop thinking about using dehydration more than just occasionally.

  What's even more striking is that the scientists analysis of the ratio in which water and glycogen were stored in the two groups showed that subjects in the REHLOW trial stored the glycogen at the minimal 1:3 glycogen : water ratio, while their peers who got plenty of water exhibited a glycogen : water ratio of 1:17. Needless to say that this difference in water storage may be very important for bodybuilders during the last days and hours of their contest prep. In view of the importance of optimal hydration for your health, cognition and the hitherto unproven hypothesis that increases in cellular water may be involved in the hypertophy response to exercise (including the efficacy of creatine | Op‘t Eijnde. 2001), (non-)rehydration practices as they were used in the study at hand are nothing I would generally recommend. 
• Study says: Only continuous, not accumulated 30 min of walking will improve your glucose sensitivity - While step counters suggest that all you have to do to improve your health is to take "X" steps per day, the conclusion of a recent study from the DSO National Laboratories in Singapore refutes the simple and beautiful idea that you can distribute the X number of steps you would usually take during 30 minutes of brisk walking over three or more small "exercise servings" and see the same benefits as you'd see with 30 minutes of continuous brisk walking:

  "These findings demonstrate that 30 min of brisk walking is sufficient to improve insulin sensitivity in healthy, young Asians but only continuous and not accumulated walking provides this benefit. " (Yap. 2015).

  In said study, twenty-five healthy participants (12 males) participated in an oral glucose tolerance test (OGTT) the morning after: (i) accumulating three 10 min bouts of walking the previous evening; (ii) walking continuously for 30 min the previous evening or; (iii) resting the previous evening. Blood samples were taken in the fasted state and for 2 h post-OGTT. The subjects' insulin sensitivity was estimated from fasting blood glucose and insulin using the quantitative insulin sensitivity check index (QUICKI) and in response to the OGTT using an insulin sensitivity index (ISI-Matsuda).
  

  Figure 3: Changes in fasting glucose, insulin and insulin sensitivity (QUICKI) the morning after accumulated walking, continuous walking or a rest day; values expressed rel. to sedentary control (Yap. 2015).

  Now, as you've read a few lines above, the scientists say: Only the continuous walking is beneficial. Well, I don't know about you, but if I look at the study results in Figure 1, I wouldn't say that the data suggests that only continuous brisk walking would be beneficial. In fact, the early morning glycemia, which is by the way a pretty stupid measure of glucose tolerance anyway (cortisol rises in the AM and ruins the results), is very similar and the OGTT data in Figure 2 shows no practically relevant effect or difference either.
  

  Figure 4: Glucose (a), insulin (b) and insulin sensitivity index (ISI-Matsuda) (c) calculated from an oral glucose tolerance test the morning after three 10 min bouts of accumulated brisk walking, a 30-min continuous brisk walk or resting the previous evening. Values are mean (SD) (n = 25). Main effect of time for glucose (a) and insulin (b) (both P < 0.001). Main effect of trial for ISI-Matsuda (c) with Bonferroni post hoc t tests: accumulated walking vs. continuous walking (P = 1.000); accumulated walking vs. rest (P = 0.204); continuous walking vs. rest (P = 0.081 | Yap. 2015)

  With that being said, you can still rely on your step counter as a guide to a health-relevant amount of activity. What is important is that you get your physical activity in; and not that you do it in a continuous matter (even though that may offer small benefits in the study at hand). Plus, you will remember: Especially for those with some extra-weight on their hips "Increasing Physical Activity Just as Effective as Strength, Endurance or Combined Exercise to Lose Fat and Build Muscle" | re-read the SV article.

Does the vasodilatory effect of nitrates have a direct ergogenic effect that correlates with increases in blood flow?

If you are someone who actually reads the "product write-ups" (=ads) for NO boosters you will have heard the claim that the NO-induced vasodilation and the subsequent increase in blood flow will have significant performance enhancing effects. If you are a critical thinker, you will yet also have noticed that a "[citation]" (=reference) that would prove this claim is missing... with the publication of a recent study from the Université Droit et Santé Lille this may change in future write-ups.

In said study, Julien Aucouturier et al. tried to determine whether 3 days on NO3-rich beetroot juice would boost the tolerance to supra-maximal intermittent exercise.
To this ends, the French researchers had their subjects, who were not previously engaged in any form of intense endurance exercise perform a standardized exercise test, which consisted of 15-second exercise periods at 170% of the maximal aerobic power interspersed with 30-second passive recovery
periods, to failure.

Figure 1: Overview of the study design (Aucouturier. 2015).

All subjects performed the standardized testing procedure twice - at the same time of the day, but seperated by at least one, maximally two weeks. Once without after ingesting 680mg of NO3- for three days from beetroot juice, once after ingesting the low nitrate (<5mg/L) apple-black currant juice that was used as a placebo.

Figure 2: Individual data points for the increase in reps (=number of intervals to exhaustion) and markers of potential mechanisms that trigger this increase, i.e. ventilation (right, top) & oxygen uptake (right, bottom | Aucouturier. 2015)

The individual data points in Figure 2 (which are much more meaningful than group averages) show that the majority of the subjects experienced a measurable, some of them even a significant increase in exercise tolerance in response to the ingestion of 680mg of NO3- from beetroot juice over a three-day period.

Before we get back to the mechanism I hinted at in the introduction, already, I want to highlight one last thing that follows from the previously highlighted result: If "only" more than 50% of the subjects benefited from the NO3- almost 50% of them didn't benefit and that's not exactly news when it comes to beetroot juice and nitrate supplementation. Previous studies showed similarly conflicting results with some suggesting that the training status of the subjects may be a significant modifier (athletes may benefit less than couch potatoes), but the reason for the differentials response of the subjects is something to investigate in another study.
References:

• Aucouturier, Julien, et al. "Effect of dietary nitrate supplementation on tolerance to supramaximal intensity intermittent exercise." Nitric Oxide (2015).