Synephrine More Ergogenic, Than Thermogenic? Pump Supps Revisited - L-Arginine, L-Citrulline and Respective Whey-Peptides & -Nitrates | ISSN Research Review '15 #2

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 SuppVersity 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 SuppVersity cut in this, previous and future installments of this series for one reason or another.

Read more about ISSN and other studies at the SuppVersity

Vitargo, Red Bull, Creatine & More | ISSN'15 #1

Pump Supps & Synephrine & X | ISSN'15 #2

High Protein, Body Comp & X | ISSN'15 #3

Keto Diet Re- search Update | ISSN'15 #4

The Misquantified Self & More | ISSN'15 #5

BCAA, Cholos-trum, Probiotics & Co | ISSN'15 #6

• 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.

Is p-synephrine different from synephrine? That's a good question without a clear question. Most supplements that list synephrine on the label actually contain P-hydroxy-α-{methylaminomethyl}-benzylalcohol aka p-synephrine, a protoalkaloid compound that differs from m-synephrine and o-synephrine structurally and comes in form of to stereoisomers in most supplements - the l-enantiomer and the d-enantiomer as the racemate d,l-synephrine. While the latter have been shown to be present in bitter orange, other forms, like the m,s-isomer may are suspected to be adulterations from synthetic phenylephrine supplement producers use to "spike" (Allison. 2005) their products (I assume this was not the case with the samples the researchers in the study at hand used, but the chaos wrt to the types of synephrine puts a huge "?" behind the assumption that you'll see the same effects from any given synephrine or synephrine + caffeine supplement. 

• 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.

You don't believe citrulline can do anything for you? Check this out: 8g/day Citrulline Increase Leg Workout Performance - More Reps on Leg Press, Hack Squat & Leg Ext. in Exp. Gymrats (more)! It is thus by no means useful for "cosmetic pumps", only 

Studies that didn't make the cut in this issue are Brooke Bouza et al.'s study on the exercise and calorie information on menus (Bouza. 2015) as well as O'Conner et al.'s tart-cherry study (O'Connor. 2015). That's not because there were methodological issues or something. It's much simpler: The notion that "exercise and calorie information on menus is not enough to improve food choices in Hispanic adults" (Bouza. 2015) is about as unsurprising as the word "potentially" (O'Connor. 2015) in the conclusion of O'Connor's study is daunting. And by the way, now that you know that tart cherry "potentially increases running performance and attenuates post-race markers of inflammation" you actually know the most relevant finding of O'Connor's study, right? | Comment on Facebook!

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.

Ask Dr. Andro: Are There NO Changes in the New N.O.-Xplode 2.0 Advanced Strength Formula?

The official SuppVersity Supplement Shoot-Out!
The longstanding veteran, NOXplode AVPT,
is challenged by a clone of its own, 
NOXplode 2.0 Advanced Strength -
which will be the last pre-workout standing?

Question Dr. Andro: What the... is BSN trying to scam costumers? At first sight the labels of the old and the new Advanced Strength version of N.O.-Xplode seem to be absolutely identical.

Answer Dr. Andro: I am usually not soliloquizing, but in this case I thought that many of you may have had the same thought, when they spotted the new(?) BSN N.O-Xplode 2.0 - Advanced Strength in the "new products" column of their favorite supplement vendor: a lot of boastful claims in the product description, but no eye-catching changes in the actual formula.... Reason enough to devote a few hours of my precious time to scrutinize the labels of the old N.O.-Xplode AVPT and the purportedly "new" N.O.-Xplode 2.0 Advanced Strength.

N.O.-Xplode AVPT vs N.O.-Xplode 2.0 - Fight!

Well, let's start with the most obvious. The packaging got redesigned! I would not mind, but actually I find the new "darker" design looks a little cooler... well, I guess the ugly blue "now 25% more" sticker was bordering unfair competition, anyway. After all, BSN has been selling this "value" *lol* edition of the AVPT version of NOXplode for years now. So, if you are looking for a nice-looking addition to your supplement stash and red is your favorite color, the new BSN NOXplode 2.0 container could be just what you've always been waiting for  :-)

If, on the other hand, you are more interested in the content of the fancy new container, I suggest you follow my lead, click at the image above and have a look at the labels... let's see, what have we got here?

The basics - Calories, Carbs, Vitamins and Co.

The FDA approved nutritional information is the part of the label that - the information on the carb content aside - will interest people the least, I guess. Nevertheless, I had hoped to see improvements in the types of vitamins the guys from BSN used. An adequate dose of methylcobalamine (B12), some pyridoxal-5-phosphate instead of the inactive pyridoxine HCL, we are bombarded with in all protein containing supplements, anyways, and some active methyl-tetrahydrofolate instead of the folic acid that the FDA is forcing upon you in each in every foodstuff you eat, would have been nice, yet obviously too expensive improvements (cf. table 1)

	AVPT	NOXplode2.0	Dr. Andro's thoughts
Total calories	25kcal	25kcal	identical
Total carbs	6g	6g	identical
Total sugars	0g	0g	wtf! As if a glucose polymer was no sugar
Vitamin B6 from pyridoxine HCL	25mg	20mg	instead of reducing the amount BSN had better invested in some P5P, the bioactive version of pyridoxine
Folate from folic acid	400mcg	300mcg	obviously someone @BSN got wind of the studies which show that the cheap folic acid (in excess) does more harm than good... I guess you know why they did not replace it with a reasonable dose of the active methyl-tetrahydrofolate
Vitamin B12 from cyanocobalamine	120µg	120µg	identical, but still not absorbable (cf. "Want B12? Drink Milk")
Calcium from Calcium Phosphate	75mg	75mg	identical & insignificant
Phosphor from various phosphates	535mg	200mg	someone got wind that the average Western diet already contains way too much phosphate and that the phospates in the original formula were the reason for diarrhea in some people
Magnesium from various phosphates	360mg	60mg	in view of the lack of magnesium in typical Western diets, the higher dose in the old formula was better - as long as your stomach could tolerate it ;-)
Sodium from various phosphates	235mg	300mg	well, isn't that great? Cut down magnesium, ramp up sodium... I guess its more stomach friendly, but is it also healthier?
Potassium from various phosphates	75mg	75mg	it is unfortunate and ridiculous that the FDA does not allow more than this amount per serving
Table 1: Comparison of the fundamental nutrients, vitamins and minerals in the formula (based on nutritional information from BSN and a major online vendor)

The Problem... ahh, I mean "Proprietary" Blend ;-)

Now, things are getting a little complicated. How do you evaluate a supplement where you know that something is in there, but have no clue in which amount? Well, I guess this would not matter if we were talking about the FDA-invented difference between sugar and glucose polymers (isn't it interesting that the FDA let's the supplement companies make a difference, here?), it is however of tremendous importance to know whether the undisclosed overall amount of the AVPT or ASPM (Advanced Strength & Performance Matrix) part of the 18.0g and 19.6g proprietary blend in NOXplode AVPT and NOXplode 2.0 Advanced Strength contain 90% or 30% glucose polymers. With the latter being the first ingredient on the label, we can only be sure that it is the major ingredient in this part of the formula and since we know that we get 6g of non-sugar carbs, there probably is little room for the additional working ingredients in this part of the formula, anyway.

I hope you understand the problem we are facing here. The one (and only) thing, we can do, is to compare the order in which the ingredients are listed (the latter complies to the relative amount of the individual ingredient, with those ingredients with the highest amounts being listed first) and evaluate whether the changes BSN has made in terms of the specific ingredients and their ratios do make sense.

	AVPT	NOXplode2.0	Dr. Andro's thoughts
Total weight of proprietary blend	18.0g	19.6g	this means that BSN has generously rounded up the +1.6g diffrence in what they advertise as "2 more grams of active ingredients" (cf. BSNOnline)
N.O. Meta-Fusion	L-Arginine AKG, L-Citrulline Malate, RC-NOS™ (Rutacarpine 95%), L-Citrulline AKG, L-Histidine AKG, NAD (Nicotinamide Adenine Dinucleotide), Gynostemma Pentaphyllum (Leaves & Stem) (Gypenosides 95%)	L-Arginine-Alpha Ketoglutaric Acid, L-Citrulline-Malic Acid Interfusion, L-Citrulline-Alpha Ketoglutaric Acid, L-Histidine-Alpha Ketoglutaric Acid, NAD (Nicotinamide Adenine Dinucleotide), Gynostemma (90% Gypenosides) (Leaves & Stem)	BSN has removed the rutacaropine, which induces vasodilation via CGRP (Duan. 2007) and added a lower amount of l-histidine AKG which does of course figure in the generation of NO, but has of yet not been shown to independently induce vasolidation; maybe the BSN-guys thought it would fit well with the (probably) extended amount of beta alanine, since β-alanyl-L-histidine, i.e. carnosine is what we actually want
AVPT / ASPM	Modified Glucose Polymers (Maltodextrin), Di-Creatine Malate, Trimethylglycine, Creatine Ethyl Ester -Beta-Alanine Dual Action Composite (CarnoSyn®), Sodium Bicarbonate, Sodium Creatine Phosphate Matrix, Creatinol-O-Phosphate-Malic Acid Interfusion, Glycocyamine, Guanidino Proplonic Acid, Cinnulin PF® (Aqueous Cinnamon Extract) (Bark), Ketoisocaproate Potassium, Creatine AAB (Creatine Alpha-Amino-N-Butyrate)	Modified Glucose Polymers (Maltodextrin), Beta-Alanine (CarnoSyn®), Di-Creatine-Malic Acid Interfusion, Betaine HCL, Sodium Bicarbonate, Creatine-Sodium Phosphate Matrix, Creatinol-O-Phosphate-Malic Acid Interfusion, Glycocyamine, Creatine Ethyl Ester HCL, Guanidino Propionic Acid, Cinnamon Extract (Bark) (Cinnulin PF®), Ketoisocaproate Potassium, Creatine-Alpha-Aminobutyric Acid Matrix (Creatine AAB™)	the same fancy creatines without any substantial research supporting their superiority over creatine monohydrate as in AVPT (personally I see no reason to boast with the slogan "no creatine monohydrate", after all CM is the only form of creatine that has proven in scientific studies time and again that its working!); it seems, though, as if the beta alanine content increased - while this would be a good thing, its mere speculation based on its position within the list of ingredients in the proprietary blend; why BSN replaced the 'real' betaine (trimethylglycine) with the 'digestive aid' betaine HCL eludes me
Ener-Tropic Xplosion™	L-Tyrosine, Taurine, Glucuronolactone, Methylxanthine (Caffeine), L-Tyrosine AKG, MCT's (Medium Chain Triglycerides)[Coconut], Common Periwinkle Vinpocetine 99%, Vincamine 99%, Vinburnine 99% (Whole Plant)	L-Tyrosine, Taurine, Glucuronolactone, Methylxanthine (Caffeine), L-Tyrosine-Alpha Ketoglutaric Acid, MCT's (Medium Chain Triglycerides), Lesser Periwinkle (95% Vinpocetine, 98% Vincamine, 98% Vinburnine [Whole Plant])	BSN is trying to trick you on this one by just using a different name for the same ingredient - the common and the lesser periwinkle denote the same plant, the only difference is that the purportedly improved NOXplode 2.0 contains an inferior extract
Phospho-Electrolyte Replacements / Composite	Di-Calcium Phosphate, Di-Potassium Phosphate, Di-Sodium Phosphate	Di-Calcium Phosphate, Di-Potassium Phosphate, Di-Sodium Phosphate	its telling that the "replacement" in the AVPT became a "composite" in NOXplode 2.0 - I already alluded to the inferior mineral composition of the "new" version in table 1
Glycerol Hydrating Polymers™ / Glycerol Polymer Complex	Potassium Glycerophosphate, Magnesium Glycerophosphate, Glycerol Stearate	Potassium Glycerophosphate, Magnesium Glycerophosphate, Glycerol Stearate	I suppose BSN changed the name to "polymer complex", because it sounds way more sophisticated; in fact, its the same stuff as in the AVPT version
Table 2: Detailed analysis and comparison of the ingredient profile of the proprietary blends of NOXplode AVPT and NOXplode 2.0 Advanced Strength (based on nutritional information from BSN and a major online vendor)

As you can see from the juxtaposition of the ingredient profiles in table 2, the changes are mediocre at best and the potential increase in the beta alanine content is the only improvement I can find... what about you?

Conclusion - Love It or Hate It!

I guess, some of you are expecting me to rip BSN's marketing coup apart. Well, I guess I could, but let's be honest, obviously there was and still is a huge amount of trainees out there who loved the old formula and kept buying it even when everybody told them that arginine was not working, the new XY was all the rave and their first generation pre-workout would not be worth the cost of its container. In case you are one of those patrons who made the old NOXplode the best-selling preworkout supplement of all times, chances are you will like its almost identical twin, as well. If, on the other hand you, you hated the old version and/or are satisfied with your current pre.workout regimen, I see no reason to invest the 35.99$ into a professionally redesigned redesigned red plastic container.

Beet Root Juice Supplementation Improves Exercise Performance. Nitrate Content of the Beets Decreases ATP Turnover in High Intensity Exercise.

Nitrates have long been decried as toxic and dangerous and I bet, before their latest appearance to the supplement market, none of you would even have remotely considered to consciously increase his/her dietary nitrate supply. Yet, recent scientific studies confirm that nitrate (in moderate doses) is not only safe, but also has, its effects on vasodilation aside, quantifiable effects on exercise performance.

A group of scientists from the UK tried to find out the underlying mechanisms of the ergodicity of supplemental nitrate (Baily. 2011). Following a six day supplementation period in the course of which seven males (aged 19-38 yr) consumed 500 mL per day of either nitrate-rich beetroot juice (~300mg nitrate content) or placebo (PL, with negligible nitrate content). What they observed is best described as a "tuning effect" that was observable both, in the course of high, as well as in the course of low intensity exercise training.

During low intensity exercise, the pulmonary VO2 amplitude and thus the oxygen need during this kind of aerobic exercise decreased by -7%. An even more profound effect of nitrate supplementation was observed during high intensity activity (knee extensor exercises) where the ATP turnover decreased by -25%. These results stand in line with an overall increase in exercise tolerance of +25% in the nitrate supplemented group over placebo.

Other than a some other researchers had speculated, Baily et al. did not find any indications of a changed phosphate vs. oxygen (P/O) ratio in the muscle. The changes in ATP turnover a 6-day loading phase with dietary nitrate from beet root juice triggers, must thus be considered the underlying mechanism of the ergogenic effect of nitrates, which, as you may have notices, appear in various forms (amino acid nitrates, creatine nitrates, etc.) in recently released supplements - not without reason, as it turns out.

2g Arginine /Day Induce Vasolidation and Increase VO2Max in Male Soccer Players

Regular readers of the SuppVersity will know that - despite the recent bashing of arginine by the some supplement producers - I like this universal amino acid AND studies supporting the notion of athletes being able to benefit from arginine supplementation keep coming. The most recent one was done by Kamil et al. (Kamil. 2010) and investigated the effect of 2g pure l-arginine on vasolidation and VO2Max in soccer players. Their findings were as follows:

Oral supplementation of L-arginine significantly (p<0.01) decreased blood pressure indices and increased VO₂max (p<0.01), blood flow (p<0.05), femoral artery diameter (p<0.05) and urea levels (p<0.05). There was no change in blood lipid levels (p<0.05). No significant changes were noted in the placebo and control groups.

The increase in VO2Max, as shown in Table 1 was relatively low, though. Yet, it's statistical significance stands out of question.

	L-Arginine	Placebo	Control
Pre	56.43 ± 3.7	57.85 ± 6.8	56.52 ± 3.3
Post	57.15 ± 3.3 **	57.48 ± 6.9	56.55 ± 3.1

Table 1: Mean (±SD) pre- and post-study values of VO₂max (ml/kg/min) in male soccer players

If this is no reason not to dump your good old "1st generation"-preworkout products (e.g. NO Xplode, White Flood, Super Pump 250, VPX Shotgun), the main working ingredient of which is - guess what: arginine.On a side note: After trying about every of the new "super-mega NO-booster" from PreSurge-Unleashed to Anadraulic State GT, I have just returned to MHPs Dark Rage, which, to my mind, is still among the most comprehensive and effective pre-workout products on the market - you already knew it: an arginine-based product, as well.