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.

L-Arginine - 6g/Day Boost Cholesterol- & Non-Esterified Fatty Acid Lowering Effects of Resistance Training. Are Classic Pre-Workouts Actually "Health Supplements"?

Lifting will improve your blood lipids, l-arginine will boost the effect.

In the spirit of Tuesday's post on the potential negative effects of nitrate supplements on weight loss (learn more + see box below for some important clarifications), I would like to invite you to take a look at the effects of "short-term  L-arginine  supplementation  on  lipid  profile  and  inflammatory proteins after acute resistance exercise in overweight men" as they are about to be reported in one of the future issues of e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism by Nascimento et al. (Nascimento. 2014) - it's not essentially new, but actually quite a nice reminder of the fat that what I said about l-arginine in the nitrate article was not all made up.

An addendum to the nitrate study: Even a persistent 5% reduction in RMR would not necessarily inhibit weight loss + you can argue that your body needs less energy / oxygen, because it works more effectively and contrary to common believe that's what a true ergogenic should do!

In the introduction to the said article, I already hinted at and linked to the potential weight loss benefits of l-arginine. In spite of the fact that it is literally useless as an NO-booster (remember without increase in NOS, the enzyme that produces NO from arginine, simply piling up more arginine in your blood will only lead to increases in uric acid), previous studies have already shown that L-arg improves the metabolic profile of people with suboptimal health status.

• Schulze et al.. for example, observed that l-arginine speed up the triglyceride-lowering effect of simvastatin in patients with elevated plasma triglycerides (Schulze. 2009)

• El-Kirsh et al. found that both, L‐arginine and L‐citrulline supplementation ameliorated the biochemical parameters and blunted arthesclerotic lesions in high‐fat and high‐cholesterol‐fed rats (El-Kirsh. 2011)

Other studies report beneficial effects on blood pressure and - as discussed in the anti-diabetes series - an ameliorating effect on the blood glucose levels of diabetic and/or insulin resistant individuals (McKnight. 2010; Dong. 2011).

So, the results of this most recent study don't really come as a surprise

In view of what we already knew about l-arginine, the results of the Nascimento study, i.e. reductions in  LDL cholesterol and NEFA levels, in response to the ingestion of 3x2g of pure l-arginine per day in this double blind, randomized crossover study don't come as a surprise.

Figure 1: Changes in triglycerides, total & LDL cholesterol and NEFA levels in response to exercise, only (control) and exercise + arginine (arginine) supplementation; figures in boxes ind. inter-group diff. (Nascrimento. 2014)

What's "news", though, is the interaction with exercise that sheds a whole new light the good old NO-Xplode (learn more, but keep in mind that one characteristic feature of this products is and was being totally underdosed) and its identical clones! I mean, who would have expected that he was buying a health supplement that potentiates the beneficial effects of exercise, in this case...

• 

  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?

  four acute, machine-based resistance training sessions
• stretching + general warm-up and cool down before / after sessions
• three sets of 12 repetitions; 60% of the 1RM; 60s rest between sets
• starting with large, ending with small muscle groups
• large muscle groups: Chest press, leg press, pull down, leg extensions
• small muscle groups: Deltoid machine, leg curl, biceps curl, triceps pulley

...on the potentially artherogenic low-density lipoprotein (LPL) and the amount of pro-diabetic non-esterified fatty acids in his bloodstream? You did? Well... I should have anticipated that, Mr & Mr Smar Alec ;-)

There is one question left to answer: What exactly is the mechanism here? I know that some of you won't care - as long as it works - but let's be honest, wouldn't it be nice to know? Well, acute and chronic exercise increase have already been shown to increase the activity of lecithin-cholesterol aciltransferase (L- CAT), the enzyme responsible for the cholesterol ester transfer to HDL, which will then evacuate the cholestrol from the circulation. If this effect is either increased or the transport facilitated by l-arginine, this would explain the reduction in LDL the researchers observed in the study at hand.

Figure 2: The short-term improvements in adiponectin Nascrimento et al. observed stand in line with the well-known long-term improvements in blood glucose management.

Moreover, studies by Tan et al. (2011) suggest that L-arginine will have direct effects on the expression of fat-metabolic genes in skeletal muscle and white adipose tissue, which favor lipogenesis in the muscle (not a problem if those lipids are subsequently burned as fuel during workouts) and a reduced storage of fat in the adipose organ. In conjunction with its proven ability to stimulate mitochondrial biogenesis and brown adipose tissue development (McKnight. 2010) and the previously discussed effects on WAT,  hyperphagia,  improved insulin sensitivity and - much contrary to nitrate (learn more) - increased energy expenditure (albeit only on low protein diets; Clemmensen. 2012). In sum these effects would appear to be profound enough to explain the observations in the study at hand, and those I reported in previous SuppVersity articles on l-arginine - specifically those discussing the potential fat burning (more) and anti-diabetic / glucose lowering effects (more).

Whether that's reason enough for you to begin supplementing again, is yet probably a question of your current metabolic state... if you are by no means like the seven overweight, hypertensive men, non-smoking and sedentary with a mean age of 46±5 yrs and a body weight of 93.1±12.0 kg, ain't insulin resistance, or have high cholesterol levels, it's pretty unlikely that you will see huge benefits.

References:

• Clemmensen, Christoffer, et al. "L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances." Amino acids 43.3 (2012): 1265-1275.
• Dong, Jia-Yi, et al. "Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials." American heart journal 162.6 (2011): 959-965.
• El‐Kirsh, Amal Ashmawy Ahmed, et al. "The effect of L‐arginine or L‐citrulline supplementation on biochemical parameters and the vascular aortic wall in high‐fat and high‐cholesterol‐fed rats." Cell biochemistry and function 29.5 (2011): 414-428.
• McKnight, Jason R., et al. "Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health." Amino acids 39.2 (2010): 349-357.
• Schulze, Friedrich, et al. "L-Arginine enhances the triglyceride-lowering effect of simvastatin in patients with elevated plasma triglycerides." Nutrition research 29.5 (2009): 291-297.
• Tan, Bie, et al. "Dietary L-arginine supplementation differentially regulates expression of lipid-metabolic genes in porcine adipose tissue and skeletal muscle." The Journal of nutritional biochemistry 22.5 (2011): 441-445.

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.