The 10 Best Muscle-Building Supplements: A 2021 Science-Based Review

There’s no getting around it, if you want to build muscle, you need to be eating and training right. In fact, if you're not challenging yourself both in the kitchen and the weight room, it’s going to be very difficult to build any size or strength at all.

But even with your diet and workout routine dialed in, it can still be tough to achieve the kind of gains in lean body mass that many folks are after.  Ultimately, that’s one of the main reasons people looking to build muscle become interested in dietary supplements.

The only issue is that there are hundreds of supplements out there with all sorts of different claims as to their benefits.  So what are the best muscle-building supplements? To answer this question, we’ve developed an efficacy rating system we call ‘Does it Work’,or DIW for short.         

Determining the Best Muscle-Building Supplements

Our rating system ranges from 1 to 4, with 1 representing the least effective supplements and 4 representing those that are most effective for muscle growth. Each supplement’s rating is determined by a couple of different factors.

First, we’ve taken into consideration the number of randomized, prospective, and blind studies that have been published on each substance. If there aren’t many studies on a particular supplement, the overall rating for that substance will be lower and vice versa.

Secondly, we consider the results of the studies. If most studies on a particular supplement demonstrated positive effects with high significance, that supplement would rank highly. If numerous studies demonstrated only modest improvements, the ranking would be lowered somewhat. If there is a high degree of mixed results in the studies-- i.e. some of the studies are positive, while others are not -- it lowers the DIW score further.

Now that we’ve covered how we actually came up with our ratings, let’s get into our evaluation of the best muscle-building supplements.

What Are the Best Muscle-Building Supplements?

1. Whey Protein

What is it?

Whey is a dairy-based protein.  Milk consists of two types of protein: whey and casein.  Whey is a faster-digesting protein, meaning that it is more rapidly absorbed in comparison to casein.  While supplementing with casein may also have some benefits, particularly when it comes to recovery, it’s hard to deny that whey protein is the best muscle-building supplements.  

As far as proteins go, whey is categorized as a complete protein because it contains all of the 9 essential amino acids that your body can’t make on its own.  On top of that, it contains more of the BCAAs leucine, isoleucine, and valine than any other complete protein source.

How does it work?

All of the muscles throughout your body are going through a constant state of turnover.  At the cellular level, they’re made up of proteins, which are constantly being broken down by physical stressors.  Your body also naturally breaks down proteins to be used in other important bodily processes as well.

Muscle protein breakdown (MPB) which is also known as protein degradation,  happens to all of us on a daily basis. Luckily though, it’s only half of the equation.  In response to this natural process, your body uses dietary protein to repair and rebuild the damaged proteins in your muscles, which is known as muscle protein synthesis (MPS).         

MPS is the key to muscle growth.  In the most basic of terms, muscle growth happens when the amount of protein synthesized within your muscles eclipses the amount that is broken.  In order for that to happen though, your body needs an adequate supply of dietary protein.

While you can get all of the protein you need from solid food sources like meats, many may find it difficult to do so.  Building muscle requires a high-protein intake, oftentimes at or above 1g of protein per pound of body weight each day.  

So, if you’re 180 lbs, that’d be around 180g of protein per day, which would be quite a lot of meat. For example, that’d translate to over 20 ozs of chicken per day.  

However, that’s where supplementing with whey comes into the picture.  One serving of most high-quality whey products contains around 25g of protein, which can be effortlessly mixed in with water.  Adding a couple of scoops of whey into your daily diet makes hitting your protein goal that much easier day in and day out.

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It’s not just the ease of use that makes whey protein such a popular supplement either; it also has a rapid absorption rate.  On top of that, a number of studies have demonstrated that whey produces greater spikes in MPS than just about any other type of complete protein.    

Scientists have revisited these results in a variety of tests, and have consistently found that on average, whey produces more muscle biosynthesis in comparison to other complete protein sources.  

• Whey References
  1. "Endocrine responses following exhaustive strength exercise with and without the use of protein and protein-carbohydrate supplements."Wilk, M., Michalczyk, M., Golas, A., Krzysztofik, M., Maszczyk, A., Zajac, A. Biology of Sport. Dec. 2018.
  2. "Effect of whey protein isolate on strength, body composition and muscle hypertrophy during resistance training" Hayes, A., Cribb, P.J. Clinical Nutrition and Metabolic Care. Jan. 2008.
  3. "Effect of protein/essential amino acids and resistance training on skeletal muscle hypertrophy: A case for whey protein" Hulmi, J.J., Lockwood, C.M., Stout, J.R. Nutrition and Metabolism. Jun. 2010.
  4. "Functional properties of whey, whey components, and essential amino acids: mechanisms underlying health benefits for active people (review)" Ha, E., Zemel, M.B. The Journal of Nutritional Biology. May. 2003.
  5. "Effects of Whey Isolate, Creatine, and Resistance Training on Muscle Hypertrophy" Cribb, P., Williams, A., Stathis, C., Carey, M., Hayes, A. Medicine and Science in Sports and Exercise. Feb. 2007.
  6. "Ingestion of whey hydrolysate, casein, or soy protein isolate: effects on mixed muscle protein synthesis at rest and following resistance exercise in young men." Tang, J.E., Moore, D.R., Kujbida, G.W., Tarnopolsky, M.A., Phillips, S.M. Journal of Applied Physiology. Jul. 2009.
  7. "Activation of mTOR signalling in young and old human skeletal muscle in response to combined resistance exercise and whey protein ingestion" Farnfield, M., Breen, L., Carey, K., Garnham, D. Cameron-Smith, D. Applied Physiology, Nutrition, and Metabolism. Sep. 2011.
  8. "Activation of mTOR signalling in young and old human skeletal muscle in response to combined resistance exercise and whey protein ingestion" Farnfield, M., Breen, L., Carey, K., Garnham, D. Cameron-Smith, D. Applied Physiology, Nutrition, and Metabolism. Sep. 2011.
  9. "Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men." Hulmi, J.J., Tannerstedt, J., Mero, A.A. Journal of Applied Physiology. 2009.
  10. "Effects of leucine and whey protein supplementation during eight weeks of unilateral resistance training." Coburn, J.W., Housh, D.J., Malek, M.H., Beck, T.W., Cramer, J.T., Johnson, G.O., Donlin, P.E.Journal of Strength and Conditioning Research. May. 2006.
  11. "Amino acid absorption and subsequent muscle protein accretion following graded intakes of whey protein in elderly men" Pennings, B., Groen, B., de Lange, A., Gijsen, A.P., Zorenc, A.H., Senden, J,M., van Loon, L.C. American Journal of Physiology, Endocrinology and Metabolism. Feb. 2012.
  12. "Whey protein stimulates postprandial muscle protein accretion more effectively than do casein and casein hydrolysate in older men" Pennings, B., Boirie, Y., Senden, J.M., Gijsen, A.P., Kuipers, H., van Loon, L.C. The American Journal of Clinical Nutrition. May. 2011.
  13. "Whey Protein Supplementation During Resistance Training Augments Lean Body Mass" Volek, J.S., Volk, B.M., Gomez, A.L., Kunces, L.J., Kupchak, B.R., Freidenreich, D.J. Journal of the American College of Nutrition. Jun. 2013.
  14. "The Effect of Whey Isolate and Resistance Training on Strength, Body Composition, and Plasma Glutamine" Cribb, P.J., Williams, A.D., Carey, M.F., Haynes, A. International Journal of Sport Nutrition and Exercise Metabolism. Oct. 2006.
  15. "Ingestion of whey hydrolysate, casein, or soy protein isolate: effects on mixed muscle protein synthesis at rest and following resistance exercise in young men." Tang, J.E>, Moore, D.R., Kujbida, G.W., Tarnopolsky, M.A., Phillips, S.M. Journal of Applied Physiology. 2009.

2. BCAAs

What are they?

Branched-chain amino acids (BCAAs) are like the name implies, amino acids (AAs). There are two kinds of AAs: essential and non-essential.  Your body can produce non-essential amino acids all on its own, whereas essential AAs can only be obtained through food sources.

There are 9 different essential amino acids, 3 of which are classified as BCAAs due to their molecular structures.  The 3 BCAAs are leucine, valine, isoleucine.

How Do They Work?

BCAAs play an important role in muscle protein synthesis.  Leucine, in particular, helps to set off a series of signaling events in your body designed to kick start the rebuilding process within your muscle cells.  

It directly activates what’s known as the mTOR cascade, which is the process responsible for stimulating muscle growth.  mTOR, which is short for the mammalian target of rapamycin, refers to a series of signaling pathways within your body that help to coordinate the transportation of protein and other nutrients to your muscles.  

While leucine does appear to play the most critical role when it comes to muscle growth, research shows that all 3 BCAAs have synergistic effects when taken together.   When combined with isoleucine and valine, leucine produces greater spikes in MPS compared to when taken on its own.

It is important to point out though that some researchers have argued that BCAAs may not be as effective at stimulating muscle protein synthesis when compared to whey protein.  However, most studies have found that supplementing with BCAAs before and/or after a workout helps to decrease exercise-induced muscle damage.

BCAAs are oxidized by your muscles during exercise and your muscles’ store of them can be easily depleted by an intense workout.  Without an adequate supply of BCAAs, your muscles won’t be able to kick start the process to repair and rebuild after your workout.

• BCAA References
  1. "Novel metabolic and physiological functions of branched chain amino acids: a review"Zhang, S., Zeng, X., Ren, M., Mao, X., Qiao, S. Journal of Animal Science and Biotechnology. Jan. 2017.
  2. "Effect of central and peripheral leucine on energy metabolism in the Djungarian hamster (Phodopus sungorus)"Koch, C.E., Göddeke, S., Krüger, M., Tups, A. Journal of Comparative Psychology B. Jul. 2012.
  3. "Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise"Blomstrand E, Eliasson J, Karlsson H.K., Köhnke R. The Journal of Nutrition. Jan. 2006.
  4. "Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans"Jackman, S.R., Witard, O.C., Philp, A., Wallis, G.A., Baar,K., Tipton, K.D. Frontiers in Psychology. Jun. 2017.
  5. "Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?"Lai L., Lu Y., Kong Z., Ma X., Bai, H., Zhang, X., Xu H., Gao S. Yi, N. Journal of Beijing University of Physical Education. Mar. 1994.
  6. "The Effects of Oral BCAA on Players of Force Antagonistic Events"Lai L., Lu Y., Kong Z., Ma X., Bai, H., Zhang, X., Xu H., Gao S. Yi, N. Journal of Beijing University of Physical Education. Mar. 1994.
  7. "Nutraceutical Effects of Branched-Chain Amino Acids on Skeletal Muscle"Shimomura, Y., Yamamoto, Y., Bajotto, G, Sato, J., Murakami, T., Shimomura, N., Kobayashi, H., Mawatari, K. The Journal of Nutrition. Feb. 2006.
  8. "Effect of BCAA supplement timing on exercise-induced muscle soreness and damage: a pilot placebo-controlled double-blind study."Ra, S.G., Miyazaki, T., Komine, S., Ishikura, K., Kawanaka, K., Honda, A., Matsuzaki, Y., Ohmori, H. Journal of Sports Medicine and Physical Fitness. Nov. 2018.
  9. "Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans"Jackman, S.R., Witard, O.C., Philp, A., Wallis, G.A., Baar, K., Tipton, K.D. Frontiers in Physiology. Jun. 2017.
  10. "Signaling Pathways and Molecular Mechanisms through which Branched-Chain Amino Acids Mediate Translational Control of Protein Synthesis"Kimball, S.R., Jefferson, L.S. THe Journal of Nutrition. Jan. 2006.

3. Creatine

What is it?

Creatine is a naturally occurring amino acid-like substance that’s produced in small amounts in the human body.  Minimal quantities can be obtained through certain food sources as well.

It’s also one of the most popular, most well-researched, and best muscle-building supplements on the market.  That's because numerous studies have demonstrated that creatine has positive effects on both exercise performance and muscle growth in a wide variety of different test subjects.  

How does it work?

One way creatine works is by increasing your body’s levels of adenosine triphosphate (ATP).  ATP is an energy-providing biochemical that plays an important role in muscle contractions.  More available energy in your muscles during your workout ultimately translates into more training volume.  Adding more sets, reps, and weight into your routine, leads to significant increases in size and strength over time.   

Some research shows that creatine may also help to increase levels of insulin-like growth factor (IGF) in your muscles during exercise.  IGF plays an important role in muscle growth and those with higher concentrations of IGF in their muscles, on average, demonstrated significantly greater gains in lean body mass.  

• Creatine References
  1. "Effect of Creatine Supplementation and Resistance-Exercise Training on Muscle Insulin-Like Growth Factor in Young Adults" Burke, D.G., Candow, D.G., Chilibeck, P.D., MacNeil, L.G. Human Kinetics Journal. Aug. 2008.
  2. "Increased IGF mRNA in human skeletal muscle after creatine supplementation." Deldicque, L., Louis, M., Theisen, D., Dehoux, M., Thissen, J.P., Rennie, M.J., Francaux, M. Medicine and Science in Sports and Exercise. May. 2005.
  3. "Creatine and β-hydroxy-β-methylbutyrate (HMB) additively increase lean body mass and muscle strength during a weight-training program" Jowko, E., Ostaszewski, P., Jank, M., Sacharuk, J., Zieniewicz, A., Wilczak, J., Nissen, S. Nutrition. Aug. 2001.
  4. "Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training" Olsen, S., Aagaard, P., Kadi, F., Tufekovic, G., Verney, J., Olesen, J.L., Suetta, C., Kjaer, M. The Journal of Physiology. May. 2006.
  5. "Skeletal muscle adaptation and cell cycle regulation." Yan, Z. Exercise and Sports Science Reviews. Jan. 2000.
  6. "Dietary creatine monohydrate supplementation increases satellite cell mitotic activity during compensatory hypertrophy." Dangbott, B., Schultz, E., Mozdziak, P.E. International Journal of Sports Medicne. Jan. 2000.
  7. "Effects of creatine supplementation on muscle power, endurance, and sprint performance." Izquierdo, M., Ibanez, J., Gonzalez-Badillo, J.J., Gorostiage, E.M. Medicine and Science in Sports and Exercise. Feb. 2002.
  8. "Combined creatine and sodium bicarbonate supplementation enhances interval swimming." Mero, A.A, Keskinen, K.L., Malvela, M.T., Sallinen, J.M. Journal of Strength and Conditioning Research. May. 2004.
  9. "Creatine supplementation improves sprint performance in male sprinters." Skare, O.C., Skadberg. Wisnes, A.R. Scandinavian Journal of Medicine and Science in Sports. Apr. 2001.
  10. "The effect of longer-term creatine supplementation on elite swimming performance after an acute creatine loading." Theodorou, A.S., Cooke, C.B., King, R.F., Hood, C., Denison, T., Wainwright, B.G., Havenetidis, K. Journal of Sports Sciences. Nov. 1999.
  11. "Creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players." Claudino, J.G., Mezencio, B., Amaral, S., Zanetti, V., Benatti, F., Roschel, H., Gualano, B., Amadio, A.C., Serrao, J.C. Journal of The International Society of Sports Nutrition. Jun. 2014.
  12. "Effects of creatine supplementation on body composition, strength, and sprint performance." Kreider, R.B., Ferreira, M., Wilson, M, Grindstaff, P., Plisk, S., Reinardy, J., Cantler, E., Almada, A.L. Medicine and Science in Sports and Exercise. Jan. 1998.
  13. "Effect of creatine supplementation on body composition and performance: a meta-analysis." Branch, J.D. International Journal of Sports Nutrition and Exercise Metabolism. Jun. 2003.
  14. "Creatine supplementation during college football training does not increase the incidence of cramping or injury" Greenwood, M., Kreider, R.B., Melton, C., Rasmussen, C., Lancaster, S., Cantler, E., Milnor, P., Alamanda, A. Molecular and Cellular Biochemistry. Feb. 2003.
  15. "Putting to rest the myth of creatine supplementation leading to muscle cramps and dehydration" Dalbo, V.J., Roberts, M.D., Stout, J.R., Kerksick, C.M. British Journal of Sports Medicine. Jul. 2008.
  16. "Effects of Long-term Creatine Supplementation on Liver and Kidney Functions in American College Football Players" Mayhew, D.L., Mayhew, J.L., Ware, J.S. Human Kinetics Journal. Dec. 2002.
  17. "Few adverse effects of long-term creatine supplementation in a placebo-controlled trial." Groeneveld, G.J., Beijer, C., Veldink, J.H., Kalmijn., S., Wokke, J.H., van den Berg, L.H. International Journal of Sports Medicine. May. 2005.

4. Beta-Alanine

What is it?

Beta-alanine (BA) is a non-essential amino acid, meaning it’s produced in small amounts in the human body.  It can also be found in some food sources. Beta-alanine plays a direct role in your body’s production of the molecule carnosine.  

And with a sizeable and growing body of evidence as to its significant effects on the muscle-building process, beta-alanine also has to be considered one of the best muscle-building supplements currently on the market.

How does it work?

Carnosine plays a buffering role within your muscles cells, helping to block the build-up of lactic acid during intensive exercise.  Reducing the amount of lactic acid in your muscles ultimately helps you to work at higher intensities for longer periods of time, thus increasing the time you have before exhaustion sets in.  

A number of studies have demonstrated that BA supplementation significantly improves exercise performance.  Researchers have found positive effects on populations ranging from those with no previous training experience all the way up to top-level athletes.  

On top of that, other research has also demonstrated that over time, study participants who supplemented with beta-alanine on average also saw significantly greater gains in lean body mass compared to those who were given only a placebo.            

• Beta-Alanine References
  1. "Role of beta-alanine supplementation on muscle carnosine and exercise performance." Artoli, G.G., Gualano, B., Smith, A., Stout, J., Lancha, A.H. Medicine and Science in Sports and Exericse. Jun. 2010.
  2. "Muscle buffer capacity and aerobic fitness are associated with repeated-sprint ability in women." Bishop, D., Edge, J., Goodman, C. European Journal of Applied Physiology. Aug. 2004.
  3. "Effect of beta-alanine supplementation on muscle carnosine concentrations and exercise performance" Sale, C., Saunders, B., Harris, R.C. Amino Acids. Dec. 2009.
  4. "Effects of Beta-Alanine on Muscle Carnosine and Exercise Performance: A Review of the Current Literature" Culbertson, J.Y., Kreider, R.B., Greenwood, M., Cooke, M. Nutrients. Jan. 2010.
  5. "International society of sports nutrition position stand: Beta-Alanine" Trexler, E.T., Smith-Ryan, A.E., Stout, J.R., Hoffman, J.R., Wilborn, C.D., Sale, C., Kreider, R.B., Jager, R., Earnest, C.P., Bammock, L., Campbell, B., Kalman, D., Ziegenfuss, T.N., Antonio, J. Journal of the Internationl Society of Sports Nutrition. Jul. 2015.
  6. "Effect of beta-alanine supplementation on muscle carnosine concentrations and exercise performance" Sale, C., Saunders, B., Harris, R.C. Amino Acids. Dec. 2009.
  7. "Beta-alanine supplementation, muscle carnosine and exercise performance" Blancquaert, L., Everaert, I., Derave, W. Current Opinions in Clinical Nutrition and Metabolic Care. Jan. 2015.
  8. "beta-Alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters." Derave, W., Ozdemir, M.S., Harris, R.C., Pottier, A., Reyngoudt, H., Koopo, K., Wise, J.A., Achten, E. Journal of Applied Physiology. Nov. 2007.
  9. "Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity." Hill, C.A., Harris, R.C., Kim, H.J., Harris, B.D., Sale, C., Boobis, L.H., Kim, C.K., Wise, J.A. Amino Acids. Feb. 2007.
  10. "β-Alanine Improves Sprint Performance in Endurance Cycling" Van Thienen, R., Van Proeyen, K., Eynde, B., Puype, J., Lefere, T., Hespel, P. Medicine and Science in Sports and Exercise. Apr. 2009.
  11. "Effects of β-alanine supplementation during a 5-week strength training program: a randomized, controlled study." Mate-Munoz, J.L., Lougedo, J.H., Garnacho-Castano, M.V., Veiga-Herreros, P, Lozano-Estevan, M.E.C., Garcia-Fernandez, P., de Jesus, F., Goudemar-Perez, J., San Juan, A.F., Dominguez, R. Journal of International Sports Nutrition. Apr. 2018.
  12. "International society of sports nutrition position stand: Beta-Alanine" Trexler, E.T., Smith-Ryan, A., Stout, J.R., Hoffman, J.R., Wilborn, C.D., Sale, C., Kreider, Richard, B., Jager, R., Earnest, C.P., Banncokc, L., Campbell, B., Kalman, D., Ziegenfuss, T.N., Antonio, J. Journal of the International Society of Sports Nutrition. Jul. 2015.
  13. "International society of sports nutrition position stand: Beta-Alanine" Trexler, E.T., Smith-Ryan, A., Stout, J.R., Hoffman, J.R., Wilborn, C.D., Sale, C., Kreider, Richard, B., Jager, R., Earnest, C.P., Banncokc, L., Campbell, B., Kalman, D., Ziegenfuss, T.N., Antonio, J. Journal of the International Society of Sports Nutrition. Jul. 2015.
  14. "Effects of twenty-eight days of beta-alanine and creatine monohydrate supplementation on the physical working capacity at neuromuscular fatigue threshold." Stout, J.R., Cramer, J.T., Mielke, M., O'Kroy, J., Torok, D.J., Zoeller, R.F. Journal of Strength and Conditioning Reserach. Nov. 2006.

5. HMB

What is it?

HMB, which is short for β-hydroxy-β-methylbutyrate, is a metabolite of the BCAA leucine.  Although it may share some similar functions with leucine, HMB plays its own unique role within the body.  Somewhere around 5% of the leucine that is consumed through your daily diet is ultimately converted by your body into HMB.       

In recent years, it's continued to grow in popularity as a muscle-building supplement do to the growing body of evidence that taking HMB may lead to greater gains in size and strength compared to diet and exercise alone.

How does it work?

HMB plays a buffering role in your muscles’ metabolism, preventing the build-up of enzymes that directly contribute to muscle protein breakdown (MPB).  It’s also believed to stimulate MPS through the activation of certain biochemical pathways within your body.

In particular, HMB is believed to activate the mammalian target of rapamycin (mTOR) pathways. Once activated, these pathways help to facilitate the delivery of fresh nutrients to damaged muscle tissues during protein synthesis, helping to replace old broken down muscle proteins with fresh new ones.  

• HMB References
  1. "Effects of leucine and its metabolite β‐hydroxy‐β‐methylbutyrate on human skeletal muscle protein metabolism" Wilkinson, D.J., Hossain, T., Hill, D.S., Phillips, B.E., Crossland, H., Williams, J., Loughna, P., Churchward-Venne, T.A., Breen, L., Phillips, S.M., Etheridge, T., Ratchmacher, J.A., Smith, K., Szewczyk, N.J., Artherton, P.J. The Journal of Physiology. Apr. 2013.
  2. "Effect of leucine metabolite β-hydroxy-β-methylbutyrate on muscle metabolism during resistance-exercise training" Nissen, S., Sharp, R., Ray, M., Rathmacher, J.A., Rice, D., Fuller Jr., J.C., Connelly, A.S., Abumrad, N. Journal of Applied Physiology. Nov. 1996.
  3. "Signaling pathways initiated by β-hydroxy-β-methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli"Eley, H., Russell, S.T., Baxter, J.H. Mukerji, P., Tisdale, M.J. American Journal of Physiology. Oct. 2007.
  4. "Effects of leucine and its metabolite β‐hydroxy‐β‐methylbutyrate on human skeletal muscle protein metabolism" Wilkinson, D.J., Hossain, T., Hill, D.S., Phillips, B.E., Crossland, H., Williams, J., Loughna, P., Churchward-Venne, T.A., Breen, L., Phillips, S.M., Etheridge, T., Ratchmacher, J.A., Smith, K., Szewczyk, N.J., Artherton, P.J. The Journal of Physiology. Apr. 2013.
  5. "Mechanism of the Attenuation of Proteolysis-Inducing Factor Stimulated Protein Degradation in Muscle by β-Hydroxy-β-Methylbutyrate" Smith, H.J., Wyke, S.M., Tisdale, M.J. Cancer Research. Dec. 2004.
  6. "β-Hydroxy-β-methylbutyrate free acid reduces markers of exercise-induced muscle damage and improves recovery in resistance-trained men" Wilson, J.M., Lowery, R.P., Joy, J.M., Walter, J.A., Baier, S.M., Fuller, J.C., Stout, J.R., Norton, L.E., Sikorski, E.M., Wilson, S.M., Duncan, N.M., Zanchi, N.E., Rathmacher, J. British Journal of Nutrition. Aug. 2013.
  7. "Efficacy of β-hydroxy-β-methylbutyrate supplementation in elderly and clinical populations" Fitschen, P.J., Wilson, G.J., Wilson, J.M., Wilund, K.R. Nutrition. Oct. 2012.
  8. "Body Composition in 70-Year-Old Adults Responds to Dietary β-Hydroxy-β-Methylbutyrate Similarly to That of Young Adults" Vukovich, M.D., Stubbs, N.B., Bohlken, R.M. The Journal of Nutrition. Jul. 2001.
  9. "Nutritional supplementation of the leucine metabolite β-hydroxy-β-methylbutyrate (hmb) during resistance training" Panton, L.B., Rathmacher, J.A., Baier, S., Nissen, S. Nutrition. Sep. 2000.
  10. "The effects of 12 weeks of beta-hydroxy-beta-methylbutyrate free acid supplementation on muscle mass, strength, and power in resistance-trained individuals: a randomized, double-blind, placebo-controlled study" Wilson, J.M., Lowery, R.P., Joy, J.M., Anderson, J.C>, Wilson, S.M., Stout, J.R>, Duncan, N., Fuller, J.C., Baier, S.M., Naimo, M.A., Ratchmacher, J. European Journal of Applied Physiology. Mar. 2014.
  11. "Nutritional role of the leucine metabolite β-hydroxy β-methylbutyrate (HMB)" Nissen, S.L., Abumrad, N.N. The Journal of Nutritional Biochemistry. Jun. 1997.
  12. "β-Hydroxy-β-Methylbutyrate (HMB) Supplementation in Humans Is Safe and May Decrease Cardiovascular Risk Factors" Nissen, S., Sharp, R.L., Panton, L., Vovovich, M., Trappe, S., Fuller Jr., J.C. The Journal of Nutrition. Aug. 2000.
  13. "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)" Wilson, J.M., Fitschen, P.J., Campbell, B., Wilson, G.J., Zanchi, N., Taylor, L., Wilborn, C., Kalman, S., Stout, J.R>, Hoffman, J.R>, Ziegenfuss, T.N., Lopez, H.L., Krdider, R.B., Smith-Ryan, A.E., Antonio, J. Journal of the International Society of Sports Nutrition. Feb. 2013.
  14. "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)" Wilson, J.M., Fitschen, P.J., Campbell, B., Wilson, G.J., Zanchi, N., Taylor, L., Wilborn, C., Kalman, S., Stout, J.R>, Hoffman, J.R>, Ziegenfuss, T.N., Lopez, H.L., Krdider, R.B., Smith-Ryan, A.E., Antonio, J. Journal of the International Society of Sports Nutrition. Feb. 2013.
  15. "Creatine and β-hydroxy-β-methylbutyrate (HMB) additively increase lean body mass and muscle strength during a weight-training program" Jowko, E., Ostaszewski, P., Jank, M., Sacharuk, J., Zieniewicz, A., Wilczak, J., Nissen, S. Nutrition. Jul. 2001.

6. HICA

What is it?

Alpha-hydroxy-isocaproic acid, or HICA, is a naturally occurring amino acid metabolite.  It’s also sometimes referred to as DL-α-hydroxy-isocaproic acid, leucic acid or DL-2-hydroxy-4-methylvaleric acid.   

Like HMB, it’s produced during the metabolism of the BCAA leucine.  80% of the leucine absorbed in your diet is used to make muscle proteins. The remainder is metabolized in the muscle into α-ketoisocaproate (α-KIC) and β-hydroxy-β-methylbutyrate (HMB). Along the α-KIC pathways, some of the KIC is also converted into HICA, although it’s a pretty small amount.

How does it work?

HICA works as an anti-catabolic agent, inhibiting certain enzymes that contribute to the degradation of muscle tissues and a number of experimental and clinical studies have found that it helps to prevent muscle protein breakdown in both animal and human subjects.

Some research has also demonstrated that HICA may increase muscle protein synthesis as well.  Like it’s closely related cousin HMB, it’s also believed to activate mTOR pathways, although through different mechanisms than HMB.  

While the findings up to this point seem to be promising, there simply hasn’t been as much research on HICA as there has been on other supplements like creatine.  Some believe it will eventually surpass HMB as a muscle-building supplement and at half the dose required by HMB. Yet without the depth of clinical research, it’s a little more difficult to make definitive conclusions about its effectiveness on muscle growth.  

• HICA References
  1. "Effects of alfa-hydroxy-isocaproic acid on body composition, DOMS and performance in athletes" Mero, A.A., Ojala, T., Hulmi, J.J., Puurtinen, R., Karila, T., Speala, T. Journal of the International Society of Sports Nutrition. Jan. 2010.
  2. "Chronic α-hydroxyisocaproic acid treatment improves muscle recovery after immobilization-induced atrophy." Lang, C.H., Pruznak, A., Navaratnarajah, M., Rankine, K.A., Deiter, G., Mange, H., Offord, E.A., Breuille, D. American Journal of Physiology, Endocrinology and Metabolism. Aug. 2013.
  3. "Effects of Alpha-hydroxy-isocaproic acid upon Body Composition in a Type I Diabetic Patient with Muscle Atrophy - A Case Study." Teixeira, F.J., Matias, C.N., Monteiro, C.P., Howell, S.L., Kones, R. Yale Journal of Biology and Medicine. Jun. 2018.

7. Phosphatidic Acid

What is it?

Another promising muscle-building supplement is Phosphatidic acid (PA), a natural compound and important signaling lipid found throughout most of your body’s cells.   PA plays a critical function in mTOR signaling, which in turn helps to regulate cell growth throughout your entire body.

How does it work?

mTOR plays a central role in muscle protein synthesis (MPS), helping to set off a series of signaling events drawing nutrients and oxygen into muscle tissues in need of repair.  

Researchers have found a positive correlation between PA and the activation of mTOR signaling pathways, which are directly involved in MPS.  Several double-blind studies have found that supplementing with PA lead to significantly greater increases in lean muscle mass compared to a placebo.

In fact, several studies evaluating high-intensity training protocols that typically lead to net muscle loss found that those who supplemented with phosphatidic acid not only avoided losing muscle, they actually saw some net gains.  

• Phosphatidic Acid References
  1. "Growth factor-like action of phosphatidic acid" Moolenaar, W.H., Kruijer, W., Tilly, B.C., Verlaan, I., Bierman, A.J., de Laat, S.W. International Journal of Science. Sep. 1986.
  2. "Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling" Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A., Chen, J. Science. Nov. 2001.
  3. "Signaling functions of phosphatidic acid" Wang, X., Devaiah, P., Zhang, W., Weli, R. Progress in Lipid Research. May. 2006.
  4. "The role of diacylglycerol kinase ζ and phosphatidic acid in the mechanical activation of mammalian target of rapamycin (mTOR) signaling and skeletal muscle hypertrophy." You, J.S>, Lincoln, H.C>, Kim, C.R>, Frey, J.W., Goodman, C.A., Hornberger, T.A. The Journal of Biological Chemistry. Jan. 2014.
  5. "The role of phosphoinositide 3‐kinase and phosphatidic acid in the regulation of mammalian target of rapamycin following eccentric contractions" O'Neil, T.K., Duffy, L.R., Frey, J.W., Hornberger, T.A. The Journal of Physiology. Jul. 2009.
  6. "Efficacy of phosphatidic acid ingestion on lean body mass, muscle thickness and strength gains in resistance-trained men" Hoffman, J.R., Stout, J.R., Williams, D.R., Wells, A.J., Fragala, M.S., Mangine, G.T., Gonzalez, A.M., Emerson, N.S., McCormack, W.P., Scanlon, T.C., Purpura, M., Jager, R. Journal of the International Society of Sports Nutrition. Oct. 2012.
  7. "Phosphatidic acid enhances mTOR signaling and resistance exercise induced hypertrophy" Joy, J.M., Gundermann, D.M., Lowery, R.P., Jager, R., McCleary, S.A., Purpura, M., Roberts, M.D., Wilson, S.M., Hornberger, T.A., Wilson, J.M. Nutrition and Metabolism. Jun. 2014.
  8. "Phosphatidic acid enhances mTOR signaling and resistance exercise induced hypertrophy" Joy, J.M., Gundermann, D.M., Lowery, R.P., Jager, R., McCleary, S.A., Purpura, M., Roberts, M.D., Wilson, S.M., Hornberger, T.A., Wilson, J.M. Nutrition and Metabolism. Jun. 2014.

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8. Testosterone Boosters (D-Aspartic Acid, ZMA & NMDA)

What is it?

Testosterone plays a key role in muscle growth and numerous studies have demonstrated that boosting testosterone levels can have positive effects on both exercise performance and overall body composition.  So much so that taking substances like steroids and human growth hormone has become a banned practice in pretty much all major sport.

How Does it Work?

With that being said, some supplements claim to boost your testosterone the natural way.  Several substances, such as d-aspartic acid, ZMA, and NMDA have been said to be ‘natural testosterone boosters’, with several different supplements touting them as “muscle-building” ingredients.

However, there simply isn’t any scientific evidence to support these kinds of claims.  Up until this point, there has been no clear evidence to support the basic premise behind the idea of a “natural testosterone booster”.

• Testosterone Booster References
  1. "Heavy Resistance Training and Supplementation With the Alleged Testosterone Booster Nmda has No Effect on Body Composition, Muscle Performance, and Serum Hormones Associated With the Hypothalamo-Pituitary-Gonadal Axis in Resistance-Trained Males" Willoughby, D.S., Spillane, M., Schwarz, N. Journal of Sports Science and Medicine. Jan. 2014.
  2. "Effects of Zinc Magnesium Aspartate (ZMA) Supplementation on Training Adaptations and Markers of Anabolism and Catabolism" Wilborn, C.D., Kerksick, C.M., Campbell, B.I., Taylor, L.W., Marcello, B.M., Rassmussen, CJ., Greenwood, M.C., Almada, A., Kreider, R.B. Journal of the International Society of Sports Nutrition. Dec. 2004.
  3. "d-Aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men" Willoughby, D.S., Leutholtz, B. Nutrition Research. Oct. 2013.

9. Arginine

What is it?

Arginine is an amino acid that aids in your body’s production of nitric oxide, which plays an important role in cell signaling.  Arginine synthesis begins in your intestines, where citrulline is formed. From there, citrulline is transported to your kidneys where it’s converted into arginine and sent back out into your bloodstream.  

How Does it Work?

Several studies have shown that in its supplemental form, arginine is poorly absorbed by the intestinal tract.  Some research has also found that arginine supplementation may lead to stomach pain and discomfort for some.

Furthermore, there doesn’t appear to be any scientific evidence to support the claim that arginine is an effective muscle-building supplement.  Researchers have generally found that its effects are minimal when taken as a supplement and no study has clearly demonstrated a significant correlation between arginine supplementation and muscle growth.  

• Arginine References
  1. "No effect of short-term arginine supplementation on nitric oxide production, metabolism and performance in intermittent exercise in athletes" Liu, T., Wu, C., Chiang, C., Lo, Y., Tseng, H., Chang, C. The Journal of Nutritional Biology. Jun. 2009.
  2. "Influence of Chronic Supplementation of Arginine Aspartate in Endurance Athletes on Performance and Substrate Metabolism" Abel, T., Knechtle, B., Perret, C., Eser, P., von Aux, P. Knecht, H. Physiology and Biochemistry. 2005.
  3. "Chronic arginine aspartate supplementation in runners reduces total plasma amino acid level at rest and during a marathon run" Colombani, P.C., Bitzi, R., Frey-Rindova, P., Frey, W., Arnold, M., Langhans, W., Wenk, C. European Journal of Nutrition. Dec. 1999.
  4. "Effects of L-arginine supplementation on exercise metabolism" McConell, G.K. Clinical Nutrition and Metabolic Care. Jan. 2007.

10. Citrulline

What is It?

Citrulline is a naturally occurring amino acid.  When taken in the supplemental form, citrulline is converted by your body into arginine (and ornithine).  Research has clearly demonstrated that citrulline is more effectively absorbed by your body than arginine when taken as a supplement.  

How Does it Work?

Some studies have demonstrated that citrulline may help to improve aerobic and/or anaerobic endurance in athletes.  However, its effects on muscle growth have yet to be fully demonstrated.

Athletes primarily supplement with nitric oxide boosters for the vasodilation effect they produce in the muscles.  This effect is often referred to as the “pump”. While it’s a sensation many gym-goers may enjoy, there isn’t much scientific evidence that a more intense pump leads to greater gains in size and strength.    

• Citrulline References
  1. "l-Citrulline-malate influence over branched chain amino acid utilization during exercise" Sureda, A., Cordova, A. Ferrer, M.D., Perez, G., Turn, J.A., Pons, A. European Journal of Physiology Sep. 2010.
  2. "Leucine and Citrulline: Two Major Regulators of Protein Turnover" Cynober, L., de Bandt, J.P., Moinard, C. Nutrition in Intensive Care Medicine: Beyond Physiology. 2013.

wrap up

While a number of different natural substances have been touted as muscle-building supplements, the research shows that some ingredients work better than others.  Amongst them, whey protein and creatine are without a doubt the most well-researched supplements, with numerous studies highlighting their positive effects on muscle growth.

Along with whey and creatine, there also appears to be a substantial body of evidence that beta-alanine, HMB, and phosphatidic acid can have significant effects on the size and strength of your muscles as well.

Although BCAAs have been extensively studied, there is still some debate when it comes to their effectiveness on muscle protein synthesis.  Some researchers argue that compared to BCAAs, whey protein is far more effective at stimulating MPS. Even so, there is ample evidence to suggest that BCAAs play an important role in preventing the breakdown of muscle tissues.     

While there is a growing cache of research on the positive effects of HICA, there simply haven’t been as many studies on it to make the same kind of conclusions we were able to make for substances like HMB.  

For other supplements like testosterone boosters and arginine, there is little if any reliable scientific evidence to suggest that they are effective substances for increasing the size and strength of your muscles.  Most studies demonstrating positive findings appear to have conflicts of interest.