Maximizing Hypertrophy (Muscle Growth)

In the primer, we established a few rough parameters that can be improved through strength training.  To recap, they include hypertrophy (muscle size), neural adaptation (efficiency), and strength-skill improvement (getting better at a particular movement).  There's plenty more that strength training can improve, but those are our points of interest.

Today we're talking about hypertrophy, AKA how to grow big muscles. 

Right now you might be thinking that the subject has been done to death.  Humor me and read through it, because I'd put money down that you aren't squeezing every drop of growth out of your training program.

*please note that the following article is dedicated entirely to muscle size, thus any training recommendations will be made in a vacuum where the only thing the trainee cares about is packing on muscle.

What Is Hypertrophy?
Muscular hypertrophy is the growth of either muscle mass, cross-sectional area, or both.  Simple enough, right?  Something worth mentioning is that not all hypertrophy is of the same quality.  You'll often see discussions on the difference between myofibrillar and sarcoplasmic hypertrophy, with some protocols claiming a chance of spurring the elusive hyperplasia.  The debate between big versus strong, or functional versus non functional muscle size has been raging for decades.

In real life, hypertrophy is never so compartmentalized.  Size can come from synthesis and addition of new contractile proteins, stuffing in more glycogen/sarcoplasm, water retention from certain supplements, and so on.  Personally, I don't think it's worth worrying about.  I've found that the only people who ever truly guilty of being massively big yet laughably weak are those who forego any semblance of functional training and/or are roided up to to their eyeballs (usually they go hand in hand).

How Hypertrophy Works
Let's say you live with your girlfriend in a two bedroom house (if you're a female, sorry.  Pretend you're a guy).  Then one day, you come home from work to find your girl sitting alone in the bathroom.  Her pallid face frames a gaze that is fixed gravely on a plastic, urine soaked stick with two pink lines on it.

Once you recover from the shock, you realize that you've got 9 months to do some serious planning.

So you take a look at your finances and go over your options.  If you've got the cash, you could build a third room for junior. If not, then he'll just have to cramp your style for a few years and sleep in your room.  If you find yourself in a panic about how you're going to afford this kid, maybe you move all your crap and rent out the second bedroom.  If you're really well off, you might build junior a whole new floor, with a race car bed, a basketball court, and a zip line to the breakfast table.

Growing bigger muscle is a lot like convincing your body that it can afford to spend the money on that basketball court and zipline.  When you get in the gym and train, you're telling your body that there's a novel stressor in your life, and it needs to find a way to handle it.  The time you spend in the gym does NOT dictate how your body chooses to adapt to the issue.  

Here's the keystone: muscle growth above baseline is expensive and noncritical to survival.  You must understand that bigger muscles are a luxury that will ONLY be built if the body is fully capable of safely and comfortably spending the resources needed.  This article will focus on providing practical information on how you can signal your body to go ahead and start construction.

Factors That Govern Growth

1) Stress
In the context of training, this stress comes from our resistance exercise.  Physical stress sets the stage for muscle growth by placing a new demand on the body, and thus a subsequent need for adaptation.  It's extremely important to understand that stress equals potential.  Even highly experienced lifters sometimes forget that what they do in the gym merely creates the potential for growth; whether or not it happens depends on many other factors.  The question for this section then becomes, what stress maximizes growth potential?

It turns out that as far as muscle growth is concerned, it doesn't matter.

Intensity
You read right.  Multiple recent studies confirm that the type and intensity of exercise makes no difference whatsoever in terms of hypertrophy.  All that matters is whether or not you've recruited the entirety of muscle fibers, and that sufficient volume is reached.  This information equates to an astounding shift in common training methodology.

A study by Phillips et al, 2012, placed 18 20-22 year old men in 3 training groups and had them perform unilateral lower leg strength training programs for 10 weeks, 3 times a week.  What is remarkably interesting is that they had each subject perform 2 of the 3 programs on each separate leg.  Each subject performed a session of 3 sets to fatigue at 30% of 1RM (one repetition maximum), 3 sets to fatigue at 80% of 1RM and 1 set to failure at 80% of 1RM.

The results?  The 3@30% 1RM group and the 3@80% of 1RM group experienced nearly identical hypertrophy, with the 30% group gaining slightly more.  The 1@80% of 1RM group experienced some hypertrophy, but far less than the other two groups.  Keep in mind that responder/nonresponder issues were largely eliminated because these results were compared leg to leg across the same individual - same person, two programs, two different outcomes.

The take home point is that once you've selected a weight that CAN take you to failure (usually >25-30% of 1RM), and performed enough reps that you're fatigued enough to not be able to do another, you've automatically hit maximal recruitment.

How can that be?  How can a set at 30% of 1RM possibly recruit as many fibers as one at 80% of 1 RM, given that the body is adept as recruiting more or less exactly as many fibers as needed to perform a lift (this is why you don't smash yourself in the face when picking up a gallon of milk, etc.).  The answer is that during exercise, the smallest slow twitch fibers will be recruited first, but as they fatigue to the point where they cannot contract, recruitment will then progress to larger fast twitch fibers.  This continues until every fiber has been exhausted and work can no longer continue.  With a higher % of 1RM, more fibers are recruited earlier on and the newer ones are recruited more rapidly; with a lower %, less are utilized at first and newer fibers are recruited more slowly.  This is known as Henneman's size principle.  The end result is the exact same, regardless of how hard you think you've worked.

Note that there is an intensity cutoff.  A study by Holm, et al. had a similar set up, with 12 sedentary men performing unilateral quadriceps exercises 3x/wk, with one lifting at 15.5% of 1RM for 36x3 and one lifting at 70% of 1RM for 8x3.  The average growth for the 70% of 1RM group was  ~15%, while the 15.5% of 1RM group's growth was only ~5%.  I have issues with how this study handled nutrition, but the point is that there's a point where too little intensity and too many reps is sub-optimal for growth.  That line appears to be around the ~30% of 1RM mark.  I imagine that this threshold represents the line that separates training a muscle for strength/ hypertrophy and oxidative capacity and mitochondrial size.  

It turns out that any notions of perceived effort or high intensity are completely meaningless as far as size is concerned.  Pick a muscle(s) you want to get bigger, pick an exercise that hits that muscle, do literally any rep scheme you want until fatigue is reached, take a rest, and do it two more times.  You've just hit your maximum potential for muscle growth within that muscle.

Note: before anyone asks, yes, progressive overload is still crucial.  Your body still needs to be continually challenged for growth to occur.  What this means is that either reps need to increase or weight needs to increase regularly.  If using the high end of the rep scale, eventually weight will become too light (<30% 1RM) and will need to be increased.

Volume
Volume is a strange animal. We all know that volume is necessary to produce hypertrophy, and the results of hundreds of studies corroborate that fact that more volume leads to more growth, to a point. The problem is, there's a huge lack of science on the subject of exactly how much load is ideal.

We know that 3 sets produces more growth than 1 set. We also know that at a certain point, no further growth can be potentiated and in fact is detrimental. Where does that point lie? When do we stop gaining benefits out of additional sets? No one knows for sure, and it likely varies significantly from person to person. The author's opinion is that for most people, it's probably best to stick to 3 work sets per exercise.

Frequency
Proper training frequency is directly related to recovery ability.  Recovery ability is influenced by a lot of factors, which makes giving generic guidelines quite difficult.  In fact, recovery ability varies day to day and week to week depending on not only the mechanical stress, but also the emotional stress, levels of sleep, and nutrition profile.

In reality, this is where top level trainers earn their bread; keeping tight control of their athlete's volume and frequency and making sure they're always ready to hit their super compensation window (a topic for another day).  

For most, waiting ~48 hours between training the same muscle group seems to be the sweet spot.  Understand that your recovery is specific to YOU; just because your buddy can get away with training 6x/wk, it doesn't mean doing the same won't put you on a one way train to snap city.  

If you legitimately feel like crap or are too tired to get up and go, you're probably better suited to just take a rest day ("legitimately" being the operative term).  When in doubt, you really can't go wrong with 3x/wk.  

2) Inflammation
We've probably all heard that resistance training, especially the eccentric portion, causes micro-trauma.  This trauma has to be healed like any other wound, which is where the inflammation process comes in.

Immediately after a training bout, the process begins by flooding the damaged muscle tissue with macrophages.  Without getting too in depth, macrophages sweep in, eat up all the cells that are dead or damaged beyond repair through apoptosis, then secrete cytokines.  These cytokines mark the muscle tissue for repair, stimulate satellite cell response (more on this next section), and downregulate myostatin (a powerful inhibitor of muscle growth).

In practical terms, a depressed immune system means two things: A poor ability to initiate inflammation, and delayed inflammation response.  An inhibited or weakened immune system degrades the body's ability to perform an appropriate post exercise immune response significantly.  By the same token, chronic inflammation tends to have the same effect as induced immune depression, simply because resources are constantly being used to combat the source of perpetual inflammation.  The take home point is that sub optimal  immune function yields poor healing, which significantly impacts your ability to grow new muscle.

The obvious question is, how do we maintain an optimal immune system?  I'm going to assume that if you're reading this, you probably already engage in resistance training, eat a paleo-ish diet with the inclusion of fruits and vegetables which afford at least a marginal amount of anti-oxidants and micro nutrients, and that you already have a relatively healthy body weight.  The most common mistakes serious trainees make are A) not getting enough sleep, and B) training too frequently and interrupting the inflammation/healing process before it has a chance to finish.

Inadequate sleep has a number of very serious side effects which are detrimental to overall health and specifically to muscle growth.  If you're the type that thinks they can "get away" with 6 hours of sleep a night, then you can expect a depressed immune system, compromised ability to heal, down regulation of highly beneficial growth hormones, and heavily diminished muscle growth.

While we're on the subject, Brad Pilon has been doing a lot of research on the effects of chronic inflammation and muscle growth.  If it interests you, check out more on inflammation and muscle growth.

An issue you'll sometimes hear about is whether it's okay to take NSAIDs such as ibuprofen or naproxen sodium for muscle soreness.  Many argue that if acute inflammation response is critical to growth, then anything which inhibits that response must also inhibit growth.  There's a study by Mikkelson et al, 2009 which indicated that NSAIDs did inhibit growth pathways, but they used the NSAID idomethacin and administered it locally with a catheter.  Not exactly the same thing as popping two ibuprofen.  If you are so brutally sore from DOMS that you NEED something for the pain, then I wouldn't worry about it too much.

3a) Satellite Cell Activation
Human skeletal muscle is fairly unique in that it has the capacity for multiple nuclei.  Satellite cells are oligopotent stem cells which typically lie dormant on the surface of muscle tissue; when activated, they develop, split, and donate a new nucleus to existing muscle tissue.  This nucleus donation is required for regeneration and growth of muscle tissue.

I have no idea who made this image originally, and my Photoshop skills aren't good enough to make something comparable.  If anyone knows where it's from, please inform me so I can ask their permission to use it. 

There's a slew of information out there regarding the relationship between hypertrophy and stem cell activation.  A study by Petrella et al, 2008, had 66 healthy, untrained adults aged 20-75 perform a 16 week, 3x/week lower body resistance program consisting of x8-12 knee extension, leg press, and squats.  At the conclusion of the program, they  measured the contribution of satellite cells to hypertrophy.  Here's what they had to say about it:

In this relatively large cohort of 66 human subjects, the three-cluster model provides compelling evidence to support the concept that extreme myofiber hypertrophy is facilitated by satellite cell proliferation 

These cells come into play throughout our life cycle, as skeletal muscle is more or less constantly being damaged through normal activity.  The question is, how do we maximize satellite cell response to encourage not only repair, but growth of new tissue?

First and foremost, satellite cells respond proportionally the level of stress, and by extension, the level of damage within the muscle fiber.

Chen et al, 2005, notes that satellite cells are also a downstream target of androgens including tesosterone, though the mechanisms behind this relationship aren't fully understood.  The study cites quite a number of experiments involving animals and humans in which increased levels of testosterone are positively associated with a greater number of satellite cell activations.  It also does the same for other growth factors, including IGF-1.  Though we may not know at this time exactly how it works, we can safely conclude that upregulating testosterone and other growth hormones will also improve satellite cell response, and consequently, muscle regeneration and growth.

There's a relatively new, though fairly robust, body of information supporting the theory that creatine supplementation upregulates satellite cell activation in combination with resistance training.  Studies by Olsen, et al. and a few others have shown evidence supporting this claim.  I won't get into the nitty-gritty because I figure 90% of you already supplement with creatine; just consider it an added bonus.  

3b) mTOR/AMPK
The balance mTOR/AMPK is a huge topic that will be discussed in depth in future articles that deal with the larger scope of overall body recomposition.  For now, I'm going to keep this simple for the sake of brevity, but stay tuned if this topic interests you (which it should, it's extremely important).

The protein mTOR (mammalian target of rapamyacin) and its signaling pathway, the Insulin/PI3K/Akt/mTOR, is a downstream regulator of protein synthesis.  Downstream of what, you ask?  Chiefly insulin, amino acid availability, cellular energy status, and oxygen levels. Consider mTOR as a storage and synthesis anabolic pathway. 

AMPK (5' adenosine monophosphate activated protein kinase) is an enzyme which counterbalances mTOR.  It has a great many functions in the body, but we'll focus on AMPK's role in fat mobilization and oxidation, and that it stops protein synthesis cold.  Counter to mTOR, AMPK acts as a catabolic, lipolytic (fat burning), synthesis inhibiting pathway.

Really, the take home on the relationship between mTOR and AMPK parallels the relationship between most anabolic and catabolic hormones/pathways.  In healthy, disease free populations, mTOR and AMPK work in cyclic, oscillating conjunction to balance tissue synthesis and tissue removal.  As one goes up to perform a specific job, the other gracefully gets out of the way.  In diabetic/obese individuals, mTOR is chronically "turned on", while AMPK is chronically inhibited; interchange leptin/ghrelin, insulin/cortisol, and you start to get the picture that no hormone/enzyme/pathway isinherently good or bad, rather they each have their time and place.

For muscle growth, you need to inhibit AMPK and maximize mTOR involvement, period.  Please do not take that as me telling you mTOR=good and AMPK=bad, because that it is not the case.  Simply understand that after you've created the conditions for muscle growth via a training session, mTOR needs to come into play and AMPK needs to get lost. 

Maximizing mTOR
As stated, the mTOR pathway is activated by cellular energy status, nutrient availability, and growth factor availability.  What this realistically means is that post workout, you'll want to get essential aminos, particularly adequate leucine, into your body.  So, protein after a workout - quite the revelation, eh?

Obvious stuff aside, protein input is one component of mTOR.  Unfortunately, ignoring the other components causes mTOR activation to suffer significantly.  The other important triggers are the input of growth factors.  You'll want to do the following to maximize mTOR:

• Spike insulin - simple sugars and fast proteins post workout are great for this
• IGF1/2 - synthesized by downstream uptake of growth hormone
• Growth hormone
• upregulated by fasting, grhelin, sleep, hard exercise
• inhibited by stress hormones - chiefly chronic cortisol - sleep deprivation

Where green arrows indicate activation, and red lines indicate inhibition.  Also shown: as ATP levels fall, AMPK levels increase.
 
Starting to make sense?  It might be hard to swallow, but adequate deep sleep and management of chronic daily stressors has just as much involvement with muscle growth as your lifting program and protein supplements.

mTOR is a metabolically costly process.  Positive cellular energy status is crucial for activating mTOR.  Simply put, you need to eat in significant excess of your maintenance calories.  On top of that, mTOR/AMPK are closely tied to ATP levels; if ATP goes down, AMPK goes up, which is quite undesirable during the growth window.  We've probably all heard that nutrient availability is crucial to muscle growth.  Actually, it's mandatory.  A Study by Oshiro et al. 2004, strongly indicates that without adequate resources, mTOR remains dormant.  In other words, don't even bother going to the gym without getting a pre workout and post workout in.

I don't want to get too much into the topic of fasting, but one of the largest benefits to intermittent fasting (I feel dirty even mentioning this without referring you to Martin Berkhan's Intermittent Fasting for more information) is that it paradoxically appears to up-regulate growth hormone AND AMPK.  AMPK is no surprise considering the complete absence of calories (obviously a catabolic state), but the growth hormone is a bit of a head scratcher.  Purely in the author's opinion, this seemingly conflicting signaling is likely due to the fact that when a person adjusts to intermittent fasting schedule, ghrelin entrains (a hunger hormone) to peak prior to the feeding window and growth hormone is maximized in anticipation of a huge input of calories- prime conditions for storage and growth with desirable calorie partitioning.  

The real dilemma is that exercise is a tricky stimulus.  On the one hand, it increases growth hormone and causes the micro-trauma necessary for satellite cell activation - and that's great for muscle growth.  On the other hand, it's also catabolic in that it increases AMPK and inhibits mTOR.  As strange as it may sound, to maximize growth you MUST arrest the catabolic effects of training and switch your body into a state where mTOR is cranking and AMPK is out of the way.

Lastly, let's discuss cardio.  Cardio increases AMPK, no way around it - and that's fine so long as it isn't during your growth period.  Do it earlier in the day, on a rest day, or even right after your workout  if you have to.

Putting It All Together
 Maximizing muscle growth comes down to your ability to consistently meet the following needs:

• Mechanical stress - sufficient repetitions to achieve failure, sufficient volume (generally 3 work sets), compounds to maximally upregulate growth hormones including GH and test.
• Requires progressive overload through perpetual increase of load or reps.

• Emotional stress - get rid of it as much as humanly possible.  Daily stressors chronically upregulate cortisol and downregulate hormones which positively impact both growth and calorie partitioning including GH, test. 

• Sleep - requirements vary, but if you're waking up tired each day or burning the candle at both ends, kiss your gains goodbye.  Same problems as emotional stress, but specifically poor sleep->low GH->less IGF1/2->mTOR inhibition.

• Immune health - not always controllable, but ties in with stress management, adequate sleep, comprehensive diet, and preventing chronic inflammation.

• Aminos - you probably already knew this, but never skip pre and post workout nutrition.  No aminos->no mTOR->catabolic environment.

• Insulin - don't buy into insulin and carb fear mongering; if you want muscle growth, you want a big insulin spike post workout, and that means simple carbs and fast protein.

• Recovery - varies, but in general  don't screw with it by training the same muscle group more than once every ~48 hours; if inflammation is still happening, you're doing more harm than good.

• Energy status - insufficient calories inhibits anabolism; you simply won't grow without enough food.  Carbs are required to signal adequate glucose/glycogen availability for mTOR activation.

• Supplements - most aren't worth the time, but get your creatine and a multivitamin/mineral in.

Notes And Causes For Pointless Worry
Here's something no one wants to hear: for an untrained individual, the first month or two of strength training generally doesn't contribute very much to muscle growth.  From your body's standpoint, there's simply no need for it.  It's much easier and more cost efficient to respond to the new stress through neurological adaptation.  The only answer is to keep on training and have faith that hypertrophy will follow nervous system adaptations.  

Let's return to the study by Palakal involving the 66 healthy, untrained adults.  25% of them were non or delayed responders.  It's a tough pill to swallow - the idea that a person is simply not genetically geared towards hypertrophy.  Furthermore, they reported the following:

No differences were found among the clusters in average training intensity, training volume, or program adherence; and the IIx-to-IIa myofiber type shift typical of resistance training was induced equally among all three clusters (4). Despite these similarities, the propensity for myofiber hypertrophy was vastly different.

It sucks, but response to a training program is nowhere near as predictable as many would have you believe.  We can design programs that are intended to give you the most growth potential, but there are so many genetic wildcards at play that it's simply impossible to truly know.  Why are some people non/less/delayed responders?  Maybe they have higher baselines levels of myostatin; maybe it's a relatively low satellite cell count, an unusual distribution of fiber types that don't hypertrophy all that well, a chronically elevated cortisol level, or any other number of mind boggling variables that exist within the body.  The harsh reality is that we control what's in our power to understand and manipulate, and the rest is up to the black box that is the inner workings of your unique human body.

While we're on the subject of sub optimal response to training, let's talk about age.  To make a long story short, growing muscle becomes harder as we age.  This happens for a great many reasons; down regulation of growth hormones, impaired healing response, and so on.  One factor that often goes unconsidered is degradation of the mechanisms which mediate satellite cell response.  The study by Chen et al, 2005 notes the following:

Striking differences can be observed in skeletal muscle between the adult and the aged in terms of muscle size and strength. One mechanism could be the decrease in the number of satellite cells with aging (Nnodim 2000). Another explanation is that the loss of muscle mass that occurs with aging is likely to reflect changes to the in vivo microenvironment required for the efficient activation and differentiation of satellite cells 

Another topic you'll hear discussed every now and again is that of myofascial bounding.  The first time I ever heard of this was reading over Dante Trudel's Doggcrapp training protocol, but there's a number of trainers who think it's crucial for hypertrophy.  The basic premise is that the tough membrane which surrounds muscle tissue,  your myofascia, needs to be stretched to keep it from constricting muscle growth.  Some even say that it can lead to hyperplasia (the growth of entirely new muscle cells, a very rare thing indeed).  They often cite a study done by Davis and Gonyea, 1989, which showed mild hyperplasia following significant hypertrophy in bird wings when they were stretched very far for lengthy periods.  Subsequent studies have neither confirmed nor dis-confirmed this effect, whether avian or human.  I honestly have no idea if there's any truth behind this extreme stretching business, but I'm mentioning it here if any adventurous spirit wants to give it a shot.



Note:  I welcome any and all feedback, both positive and negative.  Please feel free to comment with any suggestions below.

References
Oshiro N., Yoshino, K., Hidayat, S., Tokunaga, C., Hara, K., Eguchi, S., Avruch, J., and Yonezawa, K. 2004. Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells 9: 359-366.

Shadrach, Jennifer L. ; Wagers, Amy J. Stem cells for skeletal muscle repair. PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Volume: 366 Issue: 1575 Pages: 2297-2306 DOI: 10.1098/rstb.2011.0027 Published: AUG 12 2011

L. Holm, S. Reitelseder, T. G. Pedersen, S. Doessing, S. G. Petersen, A. Flyvbjerg, J. L. Andersen, P. Aagaard, and M. Kjaer.  Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity.  doi: 10.​1152/​japplphysiol.​90538.​ 2008.

Chen, Y ; Zajac, JD ; MacLean, HE. Androgen regulation of satellite cell function. JOURNAL OF ENDOCRINOLOGY Volume: 186 Issue: 1 Pages: 21-31 DOI: 10.1677/joe.1.05976 Published: JUL 2005

Steen Olsen, Per Aagaard, Fawzi Kadi, Goran Tufekovic, Julien Verney, Jens L. Olesen, Charlotte Suetta and Michael Kjær1.  Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training.  2006, doi:10.1113/jphysiol.2006.107359.  June 1, 2006 The Journal of Physiology, 573, 525-534.

Petrella J., Kim J., Mayhew D., Cross J., Bamman M. Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. Epub 2007 April 18.

Mikkelsen UR, Langberg H, Helmark IC, Skovgaard D, Andersen LL, Kjaer M, Mackey AL. Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise. J Appl Physiol. 2009 Nov;107(5):1600-11. Epub 2009 Aug 27.

Alway, S. E., P. K. Winchester, M. E. Davis, and W. J. Gonyea. Regionalized adaptations and muscle fiber proliferation in stretch-induced enlargement. J. Appl. Physiol. 66(2): 771-781, 1989

Hay N., Sonenberg N. Upstream and downstream of mTOR. 10.1101/gad.1212704 Genes & Dev. 2004. 18: 1926-1945

Fielding, RA, Manfredi TJ, Ding W, Fiatarone MA, Evans WJ, and Cannon JG. Acute phase response in exercise. III. Neutrophil and IL-1 accumulation in skeletal muscle. Am J Physiol Regulatory Integrative Comp Physiol 265: R166-R172, 1993.

Shih, Michael. "keletal Muscle Hypertrophy Is Regulated via AKT/mTOR Pathway. BioCarta. Web. 21 Mar. 2011.

Cameron J. Mitchell, Tyler A. Churchward-Venne, Daniel W. D. West, Nicholas A. Burd, Leigh Breen, Steven K. Baker, and Stuart M. Phillips. 2012. Resistance exercise load does not determine training-mediated hypertrophic gains in young men

A Primer on Size, Strength, and Skill

Let me begin this article with a quick apology about the gap between this article and the last few.  I have a good reason - my daughter being born!  While this has easily been the happiest time of my entire life, it's also been one of the busiest.  Hopefully now that we're all settling into a bit more of a routine, I'll be able to get back to it.

Anyway, there's a few articles I'll be posting soon that shed light on what exactly drives hypertrophy, strength, where they overlap, and where they differ.  The ultimate goal of these articles is to discuss how we can optimally train these two components of fitness.  These topics do require a cursory understanding of muscle physiology to be useful, so let's start with the basics.

Your Body, the Electrician
Imagine your bicep muscle as thousands of little electric winches all strung together in parallel.  These winches, which represent individual muscle fibers (NOT your entire "muscle", but the individual strands that make up a muscle) can only pull or release, which is to say that they can only create tension by pulling inwards.

To operate a winch, you need to have power, which is where your motor neurons come in.  Motor neurons are essentially power cables that power a group of winches.  Generally speaking, the finer the muscle movement must be, the closer the ratio of winches to cables.  The very small muscles that direct eye movement have a much higher ratio of winches to cables, where a larger muscle responsible for gross movement pattern have a much lower ratio.  In either case, one single cable (nerve) and all the winches (fibers) that it powers (innervates) is called a motor unit.  

Its important to understand that a single fiber contracts at a variable frequency, but is ultimately either flexing or relaxing.  A muscle can and does have varying intensity of contraction and force production, but a single muscle fiber is binarily on or off.  Each contraction of an individual muscle fiber is known as a twitch.

The Contraction
The force of a muscle contraction can be modulated in a few different ways.  The nervous system can call on a higher percentage of available motor units, recruiting more fibers which participate and add to overall force production.  This is known as recruitment, or the amount of cables sending power to each group of winches.

Secondly, the nervous system can stimulate each motor unit with a stronger or higher frequency signal, causing each fiber to twitch more frequently.  This is can be thought of as an individual cable sending more power to each group of winches so that they pull and release at a faster rate.

Ultimately, a muscle can increase force production by altering how many winches are used at one time, as well as how frequently the winches are pulling and releasing.  

There's a lot more to it, but this is enough for now.

Differentiating Strength, Size, and Skill
All other variables held equal, a larger muscle will produce more force than a smaller muscle.  This is generally due to the increase in contractile proteins within the fiber, which can be thought of as increasing the amount of winches.  The bottom line is that force production is influenced by the cross-sectional diameter of a muscle.  Simply put, bigger muscles equal a stronger contraction.

In contrast, a muscle can produce more force through improvements in neural efficiency.  More motor units can be utilized, fiber recruitment increases, transmission speed increases, and force production improves.  It must be understood that the nervous system will only allow a contraction that it deems is safe.  Just as a stretching program signals the body that it's safe to increase ROM over time,  a strength training program conditions the nervous system that it won't rip your muscle off its attachment site if it allows you to use a higher percentage of your maximal strength.

These are the two primary adaptations to strength training.  The body also makes improvements in fuel delivery - intramuscular capillary concentration increases, glycogen (sugar) storage and fuel oxidation improves, and so on.

The last factor I want to mention is improvement to motor pattern efficiency, an often unspoken but very important topic.  In the context of strength training, this is the strength-skill connection.  In reality, it's the improvement of any skill as a result of getting better at the skill itself, not from any improvement in a physical attribute.  This phenomenon accounts for a much larger portion of gains than most trainees ever realize.  The bottom line is that strength is a skill; squat 5x a week and you'll get exceptional at squatting, but you won't be exceptional at even quite similar skills.  An 8 week squat program that yields a 15% increase in squat performance does not confer anywhere near a 15% increase in pure strength.  Much of that 15% comes from improvements in the skill of squatting. 

Motor pattern adaptation is more specific than we in the fitness world would like to think it is, but it's a readily observable occurrence.  Throw an untrained individual in a pool seven days a week and have them only breaststroke - that person would get somewhat faster at all swimming strokes and become a slightly better all around "swimmer", but would make far and away the most dramatic progress in solely the breaststroke.  Even more so, those general improvements would taper off severely once the person has a few months of training under their belt.  Generally speaking, the more the individual progresses, the less "global" their training benefits become. 

For now, it's enough to understand that when you get in the weight room and train, you get stronger, but you also get good specifically at whatever lifts you are performing.  This increase in skill accounts for a difficult to quantify but very significant portion of your gains.  The more advanced you become, the less general strength and size you gain.

Future Topics
We use the word "gains" loosely.  It should be obvious by this point that no training program can maximize gains in hypertrophy, neural efficiency, and strength-skill efficiency.  In the next article(s), we'll dive into how the body responds to various training protocols, and what you're really getting out of different types of training. 

The science might surprise you.  Some of it surprised the hell out of me. 

An In Depth Look At Pre Workout Supplements

The topic of today's discussion is pre workout supplementation.  Let's talk about some fluorescent drinks.

Can they really give the performance benefits supplement companies claim?  Are they safe?  What exactly is in this stuff?  Why do I need a master's in molecular chemistry to read the labels?  Are they a total waste of money?  Who comes up with the ridiculous names?  Will they really give you the Xtreme Bionic Gorilla Nightmare Zone Skin Rupturing Muscles you've always wanted?

Let's take a close look at exactly what goes into these products, how they can benefit your performance, and what claims they fail to live up to.

Note: this article examines pre workout supplements in the context of resistance training.  No discussion will be made on endurance or aerobic exercise.  Similarly, the purpose and effect of these ingredients will be looked at only in the scope of performance enhancement.  Many of the following have additional applications, side effects, drug interactions, additional medical considerations, and so on.  This article is not intended to thoroughly discuss the entire cadre of potential effects from any of the following substances.  Lastly, this article will only examine the effects of supplementation past normal baseline, with the assumption that no deficiency is present unless otherwise noted.  This is, as you will see later, critical in understand/disproving certain claims made by supplement companies.

What Are Pre Workout Supplements?

There's lots of different supplements that could be labeled as "pre workout".  This article specifically focuses on products that market themselves as pre workout supplement cocktails which contain a mixture of a whole bunch of stuff thrown into one jar.

They come in many different varieties.  Some of the more popular choices include Jack3d, N.O. Xplode, Superpump Max, Craze, Cellucor C4, Black Powder, Animal Rage, The Curse, White Flood, Nano Vapor, N.O. Monster, XPand, and many more.

An important factor is that these products contain many or all of the same ingredients in varying amounts, with the remainder being some kind of proprietary or "special" ingredient. Each one is a bit different from its peers.  Some are fairly standard, and some throw in very potent chemicals (that tend to be banned before too long, as in the case of ephedrine/DMAA and so on)

Therefore, we will examine the most common ingredients and a few of the less common ones.  This article will NOT examine every ingredient ever put in any pre workout supplement.  I would advise you to track down a specific ingredient list before making a purchase and see for yourself if there's anything questionable therein.

What's In This Stuff?

Let's take a look at a few common choices:

A quick look will reveal that there's some common ingredients, some that only a few share, and some that are unique to certain brands.  The remainder of the article will look at exactly what these ingredients do for sure, what they may do, and what they absolutely do not do.

Ingredients (Alphabetical)

Adenosine-5'-Triphosphate Disodium
This is just plain old ATP in oral supplement form.

Let's nip this one right in the bud:  oral ATP is not bioavailable.  A study by Coolen et al, 2011 and other similar studies conclude that oral supplementation of ATP fail to increase ATP levels.  It's simply broken down in the small intestine.  Even at very high doses, far above what you'd find in a pre workout supplement, it still does nothing.

Oral ATP just doesn't work.

Arginine, Nitric Oxide

Discussion of arginine must be prefaced with a brief primer on nitric oxide.

Nitric oxide is a gas which serves a host of functions in the body. As far as performance enhancement goes, we're concerned with it's vasodilative properties. Similar to how nitroglycerin or Viagra work, nitric oxide causes the relaxation and opening of blood vessels. The idea is that increasing nitric oxide levels will aid in inducing hyperemia (increased blood flow, the "pump") in muscle tissue.

Unfortunately, it isn't that simple.  Blood pressure, smooth muscle (blood vessel) tone, and cardiac output are tightly regulated processes.  Even if nitric oxide production was upregulated, your body has plenty of ways to return blood flow to whatever it thinks it should be at, which is generally commensurate with your activity level at the time.  In other words, you aren't likely to fool your body into diverting 25% more blood than it needs to your biceps.

A fairly comprehensive symposium/review by Tschakovsky and Joyner, 2008 on multiple iterations of research all based on this topic indicates that the body is just too damned good at compensation.  Increased levels nitric oxide are generally counteracted by changes elsewhere to keep blood flow on point.  Even in studies where direct infusions were used, it was concluded that nitric oxide does not increase vasodilation during exercise or hyperemia in muscle tissue. 

All of that being said, the premise of arginine supplementation is that it is a precursor to nitric oxide production, and that supplementation will upregulate nitric oxide.  A study by Alvarez et al, 2012, showed that arginine supplementation does not increase nitric oxide production. 

There's a healthy body of research on nitric oxide's effects and arginine's inability to upregulate production.  In short, there's no evidence that nitric oxide causes hyperemia, and even if it did, there's no evidence that arginine supplementation increases nitric oxide.

On a related note, there's quite a few compelling studies which indicate that repeat dose dietary nitrates do in fact offer performance benefits.  A review by Ferreria and Behnke, 2010, examine quite  a few studies which all show that daily supplementation of dietary nitrates, most commonly in the form of beetroot juice, does in fact lower blood pressure, reduce the O2 and ATP cost of exercise, and may give the benefits people were looking for all along from nitric oxide based pre workout supplements.

The mechanisms through which this happens appear to be unclear; acute/single dose supplementation seems to do nothing, but daily use for 5-7 days does appear to offer marked performance benefits.  Though none of the studies have been done on high intensity resistance exercise per se, the results remain promising.

...dietary NO₃⁻, administered in the form of beetroot juice (500 ml/day for 6 days), decreases resting systolic blood pressure (SBP) and O₂ consumption during walking and running.

 ...authors selectively remove NO₃⁻ from beetroot juice to produce a NO₃⁻-free juice as placebo. There was no placebo effect in any of the variables measured. Thus the decrease in O₂ uptake and SBP in their investigations can be assigned to dietary NO₃⁻, rather than other compounds present in beetroot juice (e.g., polyphenols and/or quercetin). Moreover, the responses occurred in the absence of changes in phosphocreatine (PCr) recovery kinetics (estimate of mitochondrial oxidative capacity). Lastly, the effects of dietary NO₃⁻ occurred within 2.5 h and promoted an increase in exercise tolerance (11). Whether dietary inorganic NO₃⁻ is given as beetroot juice (1, 2, 11) or pharmacologically (12), the responses are seemingly consistent across different exercise modalities, although the precise mechanisms remain unclear.

This is an interesting topic, and one I may do more writing on later.  Note that a few pre workout supplements do contain beetroot extract/quercetin, but I have no idea if that would emulate the effects of daily beetroot juice, especially in such small quantities.  I doubt it, since the effective dosage of beetroot juice in clinical studies seems to be rather high (high enough to cause red stools and tooth staining).

B3

B3 will come in the form of niacin, nicotinamide, or niacinamide, or inositol hexanicotinate.

B3 is purported as a mood elevator, depression fighter, and fatigue reducer.  The entire theory behind  B3 supplementation it that it improves the availability of NAD/NADH, which are co-factors in ATP production.  They also play a role in neurotransmitter production, including dopamine and adrenaline.

A study by Forsyth, et al, 1999, indicated that oral NADH could be an effective in treating chronic fatigue syndrome.  Perhaps the most significant for our purposes are studies by Kay et al, 2000 and Moline et al, 2001, which showed some promise for NADH as counteracting the effects of sleep deprivation and jet lag.

It must be understood that these are pilot studies.  They're simply a peek into whether or not there's a possibility or response to supplementation.  None of them were conclusive enough to make any statements, and to my knowledge there's not a single quality study done on the subject of NADH/NAD as a performance enhancer.  Furthermore, most of the studies that do exist used a sublingual (under the tongue) delivery method as opposed to the oral supplementation found in pre workouts, and also used NADH directly, instead of the niacin or nicotinamide found in pre workout supplements.

Does B3 supplementation offer any benefit to athletic performance, mental focus, or energy production?  No one really knows.  The cursory studies might indicate that B3 is an energy booster under the conditions of significant fatigue/sleep deprivation, but no one really knows at this point.  The science is simply not there in any capacity.

B6

This will usually show up as pyridoxine hydrochloride or pyrodoxal-5'-phosphate.

Like B3, B6 is a co-factor in energy production, specifically in regards to the conversion of glycogen to glucose. It also plays a role in the production of dopamine, serotonin, and adrenaline.

The supposed benefit of supplementation is more efficient usage of carbohydrates/glycogen, as well as an upregulation of neurotransmitter production (mood enhancement, motivation, focus).

A scientific review of multiple studies by Malouf and Evans, 2003, revealed that there was no statistical difference in cognitive function between placebo and B6 groups.  A similar review by Balk et al, 2006, showed the same findings.

To my knowledge, there is a complete absence of research on the subject of B6 as an improver of glycogenolysis, carbohydrate utilization, or anything of that nature.

There is literally not a single quality study on B6 as a performance enhancer of any kind.  What the supplement companies seem to be calling this is a mood enhancer/motivator and glucose liberator; what science they're basing that on is completely absent.  There's no evidence whatsoever that glycogenolysis is somehow improved, or that neurotransmitter production is upregulated. 

The research would suggest that B6 as a performance enhancer is completely bunk.

B12 

B12 will usually be in the forms of cyanocobalamin and methylcobalamin.

B12 is involved in the production of red blood cells, and appears to play a role in the maintenance of the myelin sheath that covers nerve cells.  B12 supplementation is primarily used to treat b12 deficiency, pernicious anemia, and cyanide poisoning.  I haven't seen evidence that it does much of anything when supplemented above normal values and below dangerous levels.

The same reviews by Malouf and Evans, 2003 and Balik et al, 2006, indicates that supplementation offers no cognitive improvement in normal populations. Studies by Lukaski, 2004, Hvas et al, 2004 and quite a few others show no cognitive function improvement compared to placebo.

This one is a head scratcher. I don't even understand what this is supposed to do, let alone if it lives up to claims. Are supplement companies claiming this will enhance mood or neurological function? There is absolutely no research to suggest that it does.

It has been said elsewhere, but it bears repeating that supplementation to cure deficiency and supplementation above normal values are two very separate things.

Beta Alanine/Carnosine

Beta alanine is an amino acid which serves as a precursor to carnosine production.  Carnosine is a dipeptide which has a prominent role in buffering H+ ions/pH during intense activity.

The idea is that oral supplementation increases substrate availability for caronosine production, which in turn elevates muscle carnosine concentrations.  This would allow increase work output at a high intensity  From a meta-analysis by Hobson et al, 2012 :

...further support for the buffering role of carnosine in skeletal muscle comes from the higher concentrations found in fast-twitch muscle fibres (Harris et al. 1998), which experience the greatest levels of H+ accumulation during extreme physical work. In isolated muscle, the absence of carnosine as a buffering agent leads to fatigue due to acidification, which does not occur when carnosine is present in the surrounding medium (Severin et al.1953).

The meta-analysis, a comprehensive review of current literature by Culbertseon et al, 2012, a study by Caruso, 2010, and plenty of others all conclude that beta alanine supplementation does improve intramuscular carnosine availability and help buffer muscle acidity, granting considerable anaerobic/resistance exercise performance benefits.

That being said, the exact mechanisms at play, the measurable effect, proper dosing, and what activities it most aids are all in need of more research.

Somewhat similar to creatine, beta alanine supplementation allows for a bit more work output during all out activity, potentially letting you get that extra rep or that couple more seconds of hard sprinting.  Whereas creatine allows for a prolonged stay in the ATP-PC energy pathway, carnosine staves off muscle acidity from all out activity.

Since fatigue from muscle acidity tends to set in a bit after the switch from the ATP-PC energy system to the glycolytic energy system, you can expect beta alanine supplementation to come into play just after creatine.  In terms of resistance training, you might have creatine supplementation exerting its effects on the 1-3 rep range, and carnosine doing so on a higher rep range. 

 

Caffeine

Every pre workout supplement not marked caffeine free will contain caffeine.  I won't spend much time on this one as the performance benefits of caffeine are extremely well documented and you probably already know exactly how you respond to it.

What merits discussion is the variance of caffeine dosage between supplements, as it can be significant.  The average dose per serving is around ~130mg; the highest of the lot is SCREAM, with 300mg.  For reference, the average 7 oz cup of coffee contains between 100-130 mg depending on brew method, and some serving suggestions recommend up to 3 scoops at a time.  Be aware that if you switch from coffee or one pre workout to another, the caffeine dosage can vary considerably.

Many companies won't disclose the amount of caffeine in their product, or label it as a proprietary blend.  There's really no reason for this and I have no idea why it happens.  A good rule of thumb would be to expect between 100mg-300mg per serving.

Carnitine/Tartate
Carnitine is an acid required for the transport of fatty acids to mitochondria for oxidation, and is often paired with tartate to boost absorption.

A study by Volek et al, 2001, indicates that carnitine+tartate supplementation offers benefits in mitigating tissue damage, perceived muscle soreness, and other exercise induced catabolic biomarkers following a 5 set, 15-20 rep squat protocol.

A review by Sahlin, 2011, indicates that supplementation standalone carnitine supplementation reduces lactic acid build up, which increases work capacity and delays fatigue. The kicker is that it took six months of consistent supplementation to do anything. Note that this was without the addition of tartate.

Most research more or less denounces oral carnitine supplementation as ineffective under normal circumstances, because who's going to supplement something for six months for minor improvements? Tartate seems to greatly improve carnitine uptake by muscle tissue, and necessitates the need for new research. It seems that carnitine may in fact offer quite a few performance and recovery benefits when paired up with tartate, but more research is needed.

Understand that carnitine supplementation alone is not particularly bioavailable. Be wary of pre workout supplements that don't also include tartate.

Creatine

Creatine is a proven enhancer of short term, maximal intensity performance.  Like caffeine, its effects are extremely well documented.  Supplementation increases the intramuscular availability of phosphocreatine, which acts as a phosphate reservoir for ATP synthesis.  This allows the body to churn out more ATP as needed to power the ATP-PC energy system just a little bit longer to get out that extra bit of intense effort.  If you'd like to know more about creatine as a standalone supplement, there's an extensive article in the nutrition section.

It has very few known side effects, especially at the dosages seen in pre workout supplements, and can largely be considered quite safe. The only concerns may be minor gastrointestinal irritation, bloating, and water retention.  As with many other ingredients, creatine behooves adequate hydration to minimize the occurrence of side effects.

The amount of creatine per serving ranges from 1g to 3g.  Depending on the amount of servings ingested, this is a relatively modest amount.  If you use creatine as a standalone supplement in conjunction with pre workout supplements, care should be taken to avoid excess.  Though excess creatine will be excreted, too much can increase the risk of dehydration and gastrointestinal problems.  Establish how much creatine is in your pre workout supplement and either make up the difference or avoid standalone supplementation altogether.

Citrulline/Malate

Similar to premise of nitric oxide/arginine, citrulline is proposed to be a vasodilator/stimulator of hyperemia. It must be pretty powerful stuff considering bodybuilding.com labels it as an "Insane Pump and Vascularity Initiator" in their SCREAM product.

Citrulline is prone to the same logic as arginine; even if it did increase arginine availability/upregulate nitric oxide (possible), would the downstream effect ultimately increase vasodilation/cause muscle hyperemia? (no).

There isn't enough research to make a statement on the former. The only research available on citrulline as a nitric oxide upregulator involves rats and not humans, and even then, the rats had various deficiencies or metabolic conditions. There's no quality research directly measuring the effects of citrulline supplementation on nitric oxide regulation or vasodilation/hyperemia during exercise.

Personally, I wouldn't get my hopes up on this stuff giving you Xtreme Skin Ripping Pumps and Garden Hose Vascularity.

Glucoronalactone
Glucoronalactone is a molecule that plays a structural role in connective tissue.

Some have claimed that it has detoxifying, liver protecting properties, as well as some energy/cognition benefits.

There's practically no real information or study on glucoronalactone anywhere. What research there is has been done on animals, and what little information there is on its effects is entirely anecdotal.

Could it possibly be an ergogenic aid? Perhaps a better question is; why are companies throwing in a practically unstudied compound into a product?

Glutamine
Glutamine is a non-essential, naturally occurring amino acid.

The proposed benefit of glutamine supplementation is that it helps counteract proteolysis/gluconeogenesis of muscle tissue (muscle breakdown), particularly during intense activity, and helps provide aminos for protein synthesis (new muscle construction).  Glutamine is also utilized by the organs responsible for immune system health.  It's been postulated that supplementation supports immune function indirectly since hard training increases the demand on glutamine by the muscles, and by extension, reduces the availability for the organs responsible for immune function.

A study by Gleeson, 2008, showed that there were no significant improvements in immune health, anabolic growth, or protein sparing, even when paired with heavy resistance exercise.

In regards to immune function, the study indicates that though glutamine plasma concentrations are increased with supplementation, glutamine concentrations are practically never low enough to depress immune function in the first place, even under the conditions of severe burns or wounds.  Even so, it was shown that glutamine plasma concentrations fall only under very long bouts of prolonged exercise (3+ hours), and actually increased in response to acute, high intensity exercise.

As stated in the study, protein synthesis requires sufficient levels of essential amino acids, not the presence of non-essential forms.  In other words, if there's plenty of the 9 essentials, throwing some glutamine on top isn't going to do a whole lot. 

As with many pre workout ingredients, there's a huge void of credible science backing any claims.  What little there is suggests that glutamine supplementation is ineffective as a performance enhancer, anabolic agent, immune system booster, or protein sparer.

Lastly, there's been claims that glutamine "increases growth hormones by 400%".  This is a great example of an absurd statistic looked at in a vacuum.  While a large dose of glutamine may in fact do just that, a bout of resistance exercise will increase growth hormones by up to 20,000%.

Leucine/Isoleucine/Valine (Branched Chain Amino Acids)
Branched chain amino acids are a subset of essential amino acids.  It's practically common knowledge at this point that ensuring adequate essential BCAA's both before and after a workout goes a long way in promoting protein synthesis, signaling mTOR, and combating muscle catabolism.

One example study by Gran and Cameron-Smith, 2011, delineates the benefits of BCAA's and there's plenty of other research to back it up.  The overall benefits of adequate BCAA's are well established at this point, but is there any reason supplement with them pre workout?

First, it's important to realize that BCAA's come packaged along with many protein sources, being as they're essential.  Whey protein is about 22% BCAA's, egg whites are about 70% BCAA's.  Most hard trainers are getting plenty of BCAA's through maintaining adequate dietary protein either way.  If you're eating in the ballpark of 1-1.5g protein per pound of body weight, there's pretty much no possible way you aren't getting plenty of BCAA's through your diet.

In that light, are BCAA's useful pre workout?  By now, most know that training in a completely fasted, protein absent state is not a smart choice.  You could supplement with 5-10g BCAA's pre or post workout, or just eat a couple egg whites/have a protein shake.

I see BCAA supplementation as having a very specific application for those who enjoy training on an empty stomach, but understand that they really shouldn't be training on an empty stomach.  As mentioned on his site, this is a method Martin Berkhan recommends for those using Intermittent Fasting and training in the fasted window.

Magnesium, Phosphorus, Calcium, Vitamin C, Sodium, Potassium
I lump all of these into the same category, though they of course serve different functions in the body. These are all essentially vitamins and minerals that have been shown to often be somewhat deficient in a hard training population.

You can get them here, through diet, from a multivitamin/mineral, or direct supplementation.  What should be recognized is that bioavailability varies greatly between forms of vitamins/minerals.  For instance, the magnesium in these supplements is usually either undisclosed, or magnesium citrate. This form is far less bioavailable than magnesium oxide or hydroxide.

If you're looking for something that implicitly adresses vitamin/mineral deficiency, I wouldn't rely on a pre workout supplement to do it.

Stimulants (Non-Caffeine)
These come and go as legal climates change. The supplement business has a laundry list of quite powerful and potentially quite dangerous stimulants that have ended up on the banned substance list, including ephedrine and other -phedrines, amphetamines, 1,3-dimethylamylamine (DMAA), and many, many others.

Many pre workout supplements contain only caffeine and a few other ingredients that are supposed to be cognitive/focus/energy enhancers, such as the ones that have already been discussed. Less frequently, they may contain more powerful stimulants that are not (yet) banned.

This varies company to company and changes all the time. I would advise always looking under the stimulant section (or whatever ridiculous descriptor the company uses) for unrecognized substances and looking into them before use.

Taurine
Taurine is a prevalent organic acid found naturally in the body, and has been a very common food additive in recent years, most notably in energy drinks.  It's involved in a great deal of biological processes, most notably osmoregulation and bile salt production.

It's been suggested by a few pilot studies that taurine paired with caffeine improve cognitive function, and that taurine alone may improve athletic performance.  However, the research and evidence on the effects of taurine, if any, are practically non-existent.

Almost every study involving taurine has been done on energy drinks as a whole,  or treatment to specific disease such as congestive heart failure, which renders them useless in discussing standalone taurine as a sports supplement.  Despite its widespread use, there's not a whole lot known about taurine supplementation.  Though research has discovered no side effects from supplementation, there's no studies on any long term effects either. 

A study by Galloway et al, 2008, showed that oral taurine supplementation does elevate plasma taurine levels significantly (13 fold), but fails to elevate intramuscular taurine concentrations or effect carbohydrate or fat oxidation, PCr content, VO2 max, blood glucose and free fatty acid concentrations, or any other relative performance biomarkers.  However, the study did show that post exercise concentration of threonine, an essential amino acid, was elevated, and that there may be some effect on BCAA interaction.  On the whole, nothing too dramatic.

Lack of evidence prohibits a definitive statement, but cursory studies makes me very doubtful that taurine offers much of anything performance-wise..  The bottom line is that you get a lot of taurine in your diet, and it's shown to simply be excreted when taken in excess.  I very seriously doubt that supplementation does much of anything at all.

Tyrosine

Tyrosine is a common nonessential amino acid which plays a role in protein synthesis and neurotransmitter production.

Similar to the B vitamins, tyrosine supplemention is propsed as a cognitive function and energy booster.  It's usually labelled under some kind of Xtreme Mental Lasor HyperFocus Initiation Protocol Formula, which really just means it's grouped with the stimulants. 

The only two studies which test tyrosine as an ergogenic aid to exercise, performed by Struder et al, 1998, and Chinevere et al, 2001, showed no benefits or difference from placebo. 

Similar to many other ingredients in pre workouts, what we're seeing here is that research suggested  tyrosine supplementation could improve healthy neurotransmitter production under times of great or chronic stress, in which those neurotransmitter can run low or be depressed.  There is no evidence to suggest that it offers any benefit to a healthy, non-clinically depressed, non-sleep deprived individual.

If you're serious enough to get gym time, then you're almost certainly serious enough to not absoluely neglect recovery, in which case tyrosine will likely offer no benefit. 

Notable Issues With Pre Workout Supplements 

The efficacy of each ingredient notwithstanding, we've got some shady practices that all of these supplement companies are guilty of, to varying degrees.

The most concerning is the inclusion of practically unstudied compounds. You can bet that every substance in a pre workout is safe enough for acute use, that there would likely never be a dosage of anything high enough to cause real problems, and that there will be 50 different warnings on not overdosing. In an industry where word of mouth is (unfortunately) everything, the last thing a supplement company wants is a bad reputation. That being said, there's ingredients in most pre workout supplements which have absolutely no research on long term effects or chronic use, if any relevant research at all.

Secondly, much of the labeling is just flat out false advertising. You probably don't need me to tell you that supplement companies sometimes exaggerate claims, but a thorough examination shows that it's perhaps more serious. How is it even remotely ethical or honest to label something as "Insane Pump and Vascularity Igniter" when there is no evidence whatsoever to even suggest such a thing? Companies have access to the exact same studies that we all do, and probably a lot more. Much of the advertisements and claims are no more than blatant lies.

It's a double-edged sword that supplement companies aren't strictly regulated by the FDA. On one hand, they have the legal latitude to market all sorts of potentially (but probably not at all) beneficial ingredients without legal scrutiny or prescription use. They're free to call something a "blood flow amplifier" or, "cell voluminizing and growth complex" and base it off of, at best, conjecture. Bottom line, don't trust the companies, know your ingredients and their specific dosages and interactions, do research on proprietary blends or fishy substances.

Another consideration is the balancing act between different ingredients. For instance, does your pre workout supplement have higher or lower levels of creatine or beta alanine relative to caffieine or other stimulants?  What if you're looking for 4-6g of creatine, but that entails ingesting another half a gram of caffeine to get it?  This should absolutely influence your decision making process, as it's quite easy to be forced into taking a large dose of stimulants in order to get enough of the other ingredients you want. 

Lastly, a somewhat unscrupulous practice that practically all of these companies use is renaming an innocuous or mundane sounding compound as something sexy and exotic. For instant, Gaspari labels their Peak ATP as containing adenosine 5'-triphosphate disodium and WOW, that sure sounds fancy! Except Adenosine 5'-triphosphate disodium is really just plain old ATP, the same stuff you make 100+ lbs of every day in your own liver and kidneys. Another example is N.O. Xplode listing 20 different subtypes of creatine, when it's all just creatine. It isn't "wrong", just a somewhat disingenuous marketing strategy.

Safety
Safety is a very difficult thing to quantify. It is of course possible to experience uncommon reactions to any substance, and there's a whole lot of different ingredients in pre workouts. In that regard, any such cocktail probably increases the risk of adverse reactions and makes it nearly impossible to determine exactly what could be causing problems.  I haven't seen any particular ingredients that have acute side effects substantial enough to be labeled "unsanfe".  Apart from that, if I were forced to comment I would say that pre workout supplements are generally safe for most users, provided they have some common sense on dosing and know how to read a label.

The words "pre workout supplement" and "addiction" often go hand in hand. I think addiction is a pretty strong word, but I could certainly see them being habit-forming. This isn't unique to pre workout supplements per se, but more specifically attributable to their relatively high stimulant concentration. If you enjoy a pleasant buzz from caffeine, then sure, anything you can get upwards of 7 cups of coffee's worth of caffeine from at a whack is likely to hook you.

Apart from that, there's probably a marginal risk of psychological addiction in that if you buy into them doing everything they're advertised to do, then you'll probably have a hard time going without that "extra edge". This is probably the most common complaint of chronic users; when they don't have their precious miracle juice, they just "feel weaker".

Note: these statements implicitly exclude any companies that sneak in potent stimulants or banned substances.

Summary
What you'll find in pre workout supplements is a mixture of ingredients that are more or less proven, possibly beneficial, flat out bunk, and even some that are just big question marks.

Are pre workout supplements worth using?  That depends entirely on you.  Are you the type who only wants to drop money on something proven effective/doesn't like the idea of putting unknowns into their body?  If so, you're probably better off cherry picking bulk ingredients yourselfl.  If you're a "can't hurt, might help" kind of person or you don't mind spending a bit extra for the convenience/good taste, then pre workout supplements are probably what you're after.

Understand that the majority of the claimed benefits are based off of corollary or unfounded conclusions often drawn from research that's been manipulated, taken out of context, or based off of practically nothing.  It's often times a "One isolated study done on rats showed that XYZ could possibly elevate mood in those with depression/other conditions/a serious deficiency, so we threw in 5000% of your RDA cuz energy" approach.

Also, be aware that companies can list ingredients in various ways.  For instance, some label B3, B6, and B12 with RDA's; others just throw them under an energy blend in undisclosed amounts and use  more exotic terminology.  I don't understand why companies do this, but they do.  It's probably for the same reasons that Ultra Anabolic Sodium Chloride Hydration Absorptive Bulking Complex sounds sexier than table salt.

Lastly, know that often times, a less bioavailable/effective form of a substance will be used, probably because they're the cheaper.  For instance, magnesium will often be of the citrate form and not oxide; yohimbe will usually be bark extract and not HCl, etc.  If this concerns you, obtain the preferred form separately. 

References

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Kay GG, Viirre E, Clark J. Stabilized NADH as a countermeasure for jet lag. Presented at: 48th International Congress of Aviation and Space Medicine; September 17-21, 2000; Rio de Janeiro, Brazil.

Moline ML, Rebeta JL, Flye BL, et al. Effectiveness of NADH in alleviating effects of sleep deprivation in healthy middle-aged adults. Abstract presented at: The First International Conference on Mechanisms of Action of Nutraceuticals; October 2001.

Malouf R, Grimley Evans J. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev 2003:CD004393.

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Hvas AM, Juul S, Lauritzen L, Nexø E, Ellegaard J. No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord 2004;81:269-73

Thiago S Alvares, Carlos A Conte-Junior, Joab T Silva, and Vânia Margaret F Paschoalin. Acute L-Arginine supplementation does not increase nitric oxide production in healthy subjects, 2012. doi:10.1186/1743-7075-9-54

Michael E Tschakovsky and Michael J Joyner. Nitric oxide and muscle blood flow in exercise. Applied physiology of nutrition and metabolism, vol 33, pp 151-161, 2008.
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