Best Pre-Workout Nutrients: Research Review
By Robert Schinetsky
Creatine is, quite simply, the most well-studied and consistently shown effective supplement for improving athletic performance and lean mass gains. It stands alone and is the metric by which all other sports nutrition supplements are measured. In no specific order, supplementation with creatine, in combination with resistance training, has been shown to lead to better outcomes (compared to resistance training alone) in:1
- Energy production
- Strength output
- Lean mass gains
Creatine also supports recovery by reducing muscle damage following exercise.2 The International Society of Sports Nutrition also remarked about creatine in its position paper:1
“Creatine monohydrate is the most effective ergogenic nutritional supplement currently available to athletes with the intent of increasing high-intensity exercise capacity and lean body mass during training…
“Creatine monohydrate supplementation is not only safe, but has been reported to have a number of therapeutic benefits in healthy and diseased populations ranging from infants to the elderly. There is no compelling scientific evidence that the short- or long-term use of creatine monohydrate (up to 30 g/day for 5 years) has any detrimental effects on otherwise healthy individuals or among clinical populations who may benefit from creatine supplementation …
“At present, creatine monohydrate is the most extensively studied and clinically effective form of creatine for use in nutritional supplements in terms of muscle uptake and ability to increase high-intensity exercise capacity.”
Regarding the “best” time to take creatine, there is some data that suggests that post-workout may be slightly better than pre-workout, but the much more important factor is that creatine monohydrate is consistently taken. Again, remembering to take your creatine supplement each day will have much more impact than getting mired down in fretting over the most optimal time to take it.
Citrulline is an amino acid found in a number of foods, watermelon in particular, that has been shown to be a superior supplement for increasing blood levels of arginine than even L-arginine supplements.
Why is this beneficial?
Arginine is the “fuel” that the body uses to generate nitric oxide – an important signaling molecule that affects numerous aspects of physiology. The most pertinent of these, at least in terms of athletic performance, is vasodilation (the “widening” of blood vessels), which allows for greater blood flow, oxygen and nutrient delivery to working muscles. Note: Greater NO production also supports better muscle pumps! The end result is a greater work capacity. In fact, studies note that supplementation with citrulline malate or L-Citrulline may help improve VO2 kinetics, boost energy production, enhance time to exhaustion, and increase the number of repetitions performed while also reducing an individual’s rate of perceived exertion (RPE) versus placebo.3,4,5,6,7 Citrulline malate may also promote better recovery and relieve muscle soreness, too.5
Now, much of the focus on citrulline/citrulline malate centers around increasing NO production; however, citrulline also serves as an important part of the urea cycle (along with l-ornithine and l-arginine). The urea cycle helps remove metabolic waste products generated from intense exercise, including lactate, hydrogen (H+ ions) and ammonia. As these byproducts accumulate, fatigue builds and ultimately forces you to end your set. Citrulline supplementation may help increase buffering capacity of skeletal muscle, helping you delay fatigue and complete more total work during your training session (i.e., progressive overload).
There is some debate as to which form of citrulline is “superior” – Citrulline Malate or L-Citrulline. Truth be told, so long as you’re getting an efficacious dosage of L-Citrulline (between 2.4-10 grams), you’re good. Research supports the inclusion of 8-10 grams of Citrulline Malate in pre-workout supplements to boost resistance training performance.
Most citrulline malate supplements on the market are either 1:1 (meaning the supply equal amounts of citrulline and malic acid) or 2:1 (two parts citrulline to one part malic acid).
AML Pre Workout X-treme supplies 10,000mg of Citrulline Malate 2:1, yielding 6,620mg (>6grams) of L-Citrulline.
Did you really think you’d get through an article on the best pre-workout supplements for 2022 without seeing the king of psychostimulants?
Caffeine is as synonymous with pre-workout supplements as training montages in ‘80s movies – they belong together and are made better when used together.
As you likely know, caffeine increases feelings of wakefulness and alertness. This occurs via antagonism of adenosine (a neurotransmitter that promotes feelings of lethargy and sleepiness).
But, that’s not all.
Caffeine also stimulates the release of dopamine, which increases feelings of reward, mood, motivation, motor control and decision-making.
There’s also no shortage of studies investigating the safety and efficacy of caffeine, particularly regarding sports performance. Specifically, caffeine has been noted to consistently improve performance regarding:
- Sport-specific endurance8
- Power-based sports9
- Resistance exercise10
In fact, caffeine has not only been found to be beneficial for sports performance when dosed between 3-6mg/kg, but also safe (the same cannot be said of other stimulants sometimes found in pre-workout supplements).
Moreover, doses as high as 9mg/kg (upwards of 900mg caffeine for a 100kg athlete!) have been studied and found to benefit performance; however, doses ranging between 3-6mg/kg have been studied more frequently.12,13
If you’ve had a bad night’s sleep, caffeine may also be helpful as it has been shown to reduce poor training performance due to sleep deprivation as well as exhaustive exercise.11
Caffeine may also enhance central drive and has the potential to increase strength or muscular endurance performance.
As we just mentioned above, dopamine is the neurotransmitter that’s most often associated with feelings of reward; however, it also affects a variety of other things, including mood, motivation, memory, learning and motor control.
Dopamine can also play an important role in exercise and sports performance. And, as you can tell if you’ve spent even a modicum of time reading AML’s article section, we’re fans of dopamine and helping the body make the most of this primetime neurochemical. During very stressful situations (such as intense physical activity), dopamine can become depleted, leading to a decline in motivation and performance while simultaneously accelerating the onset of fatigue.14
In fact, researchers have noted that fatigue is due, in part, to an increase in serotonergic activity and a decrease in dopaminergic activity. Moreover, administration of dopamine reuptake inhibitors can prolong the time to fatigue and help individuals maintain power output during exercise as well as improve performance in hotter environments.15
It stands to reason that by staving off this reduction in dopamine (by supplying the body with the nutrients it needs to support dopamine synthesis), you would be able to delay the onset of fatigue, maintain a high level of performance, increase time to exhaustion, and attain new heights in strength, power and athleticism.
For these reasons, AML Preworkout and Preworkout X-treme (as well as our entire DopaRush lineup) include prominent dopamine-support agents, including:
- Velvet bean (mucuna pruriens)
- Folic Acid
Betaine is an organic compound derived from choline that is both naturally produced by our bodies and found in a number of foods, beets being the best known (from which betaine derives its name).
In regards to exercise performance, betaine helps increase cell volumization and hydration via its actions as an osmolyte. Betaine also supports the body’s production of creatine via its methylation of homocysteine to methionine – one of the amino acids the body uses to produce creatine. This provides two mechanisms by which betaine can enhance performance – better hydration and improved creatine production.
Human research has noted that supplementation with 2.5 grams of betaine per day may increase:16,17,18,19
- Muscle protein synthesis
- Power output (bench press and vertical jump)
- Force production
- Muscular endurance
- Lean mass gains
- Reductions in fat mass
As stated above, betaine (as an osmolyte) can increase intracellular water17, which encourages cell volumization and cellular swelling. This supports muscle growth by way of stimulating muscle protein synthesis.
Similar to creatine monohydrate, there is some discussion as to the “most optimal” time to consume betaine – pre-workout, post-workout, first thing in the morning, etc. As discussed above, the most important thing is to take it consistently as the body of research to date investigates the consistent intake of betaine daily over the course of several weeks. Therefore, when you consume betaine during the day is secondary to actually taking it each day.
Beta Alanine is the supplement most often associated with improving resistance to fatigue and boosting endurance exercise performance. This is because supplementation with beta-alanine has been found to increase levels of the intracellular buffer, carnosine.
This ultimately improves a muscle’s capacity to buffer H+ ions and delays the onset of fatigue, thereby helping athletes complete more repetitions and more total work before succumbing to fatigue.
Research notes that daily supplementation with beta-alanine may lead to improvements in:20,21
- Muscle endurance
- Muscle growth
- Resistance to fatigue
It should be noted that beta-alanine is most beneficial to those individuals who engage in endurance activities or those who perform repeated bouts of effort with limited rest (<60 seconds), as the endurance-boosting effects are typically best experienced when physical demand exceeds >60 seconds of effort.
As for the “best” time to take beta-alanine, it’s similar to creatine and betaine. Its effects are cumulative, which means that it needs to be taken consistently in order to derive benefit. The saturation dose of beta-alanine is 179, which means if you’re supplementing with between 2.4-6.4 grams per day (the dosage range used in research studies), it will take between 4-8 weeks to reach the 179 gram threshold, at which point the carnosine content of your muscles will be improved enough to boost performance.
Listen to enough commercials and you’ll be inundated with the word “polyphenols” and the myriad of benefits they offer. But, how many individuals actually know what the heck polyphenols actually are?
To keep things simple, polyphenols are a large family of bioactive compounds naturally occurring in plants. There are over 8,000 polyphenols, and they can be subdivided into four groups, including:
- Flavonoids (e.g., quercetin, catechins, anthocyanins, etc.)
- Phenolic acids (e.g., stilbenes, lignans, etc.)
- Polyphenolic amides (e.g., capsaicin)
- “Other” polyphenols (e.g., ellagic acids, resveratrol, curcumin, etc.)
Polyphenols offer a number of health-promoting benefits, including:
- Glycemic support
- Cardiovascular support
- Cognitive function
- Digestive health
Grape and beetroot are among the richest sources of polyphenols (both of which are commonly included in pre-workout supplements).
Polyphenols may benefit exercise performance through two main mechanisms:22
- Enhancing vascular function (e.g., vasodilation, vasorelaxation, nitric oxide production)
- Limiting oxidative damage during exercise by upregulating endogenous antioxidant capacity
Research from 2017 found that supplementation with a polyphenol-rich extract significantly increased average power developed (5%), maximal peak power output (3.7%) and total power output (5%).23
A 2019 review on the influence of polyphenol supplementation for performance and recovery found that:24
“acute supplementation with polyphenols 1-2 h prior to exercise may enhance exercise capacity and/or performance during endurance and repeated sprint exercise via antioxidant and vascular mechanisms.”
“supplementation with polyphenols for 3 or more days prior to and following exercise will enhance recovery following muscle damage via antioxidant and anti-inflammatory mechanisms.”
ATP (adenosine triphosphate) is the cellular currency of energy production, and the body’s ability to regenerate ATP lies at the heart of sustaining a high level of performance.
Certain supplements over the years have been investigated in an attempt to increase blood levels of ATP; however, the vast majority of them have been found to be ineffective due to a lack of bioavailability, even when dosed as high as 5,000mg.25,26,27
Peak ATP is a clinically researched, patented form of adenosine 5’-triphosphate (ATP) disodium that is identical in structure to human ATP. Research has shown that Peak ATP supplementation not only is bioavailable, but it may also improve athletic performance and body composition. This occurs via its ability to support increased blood flow, muscular excitability and recovery.
Studies note that Peak ATP can provide benefits after just a single dose, and has been shown in human studies to result in:28,29
- 147% increase in strength
- 30% increase in power
- 96% greater muscle thickness
Supplementation may also help reduce protein breakdown and prevent performance drop-off as an individual gets deeper into their workout.30,31,32
p-Synephrine is an alkaloid found in citrus aurantium (bitter orange) that is structurally similar to ephedrine but comes without the adverse cardiovascular effects due to its lack of affinity for Beta-1 and Beta-2 receptors in the body (which is a good thing).
P-synephrine does show affinity for beta-3 receptors, which has been noted to increase:
- Energy expenditure
- Fat oxidation (“fat burning”)
- Post-exercise oxygen uptake
This leads to improvements in repetition performance and volume load during training. Other research indicates there is an additive effect when stacking p-synephrine with caffeine (as is the case with AML Preworkout X-treme).33,34 Specifically, the combination of caffeine with 100mg p-synephrine was found to help athletes achieve faster, more powerful repetitions with no additional perceived exertion or lactate accumulation!33 To top it off, p-Synephrine may also help reduce food intake, benefiting those seeking weight loss.
©Published by Advanced Research Media, Inc. 2022
©Reprinted with permission from Advanced Research Media, Inc.
- International Society of Sports Nutrition Position Stand: Safety and Efficacy of Creatine Supplementation in Exercise, Sport, and Medicine. Journal of the International Society of Sports Nutrition.
- Cooke, M.B., Rybalka, E., Williams, A.D. et al. Creatine supplementation enhances muscle force recovery after eccentrically-induced muscle damage in healthy individuals. J Int Soc Sports Nutr 6, 13 (2009). https://doi.org/10.1186/1550-2783-6-13
- Wax, B., Kavazis, A. N., Weldon, K., & Sperlak, J. (2015). Effects of supplemental citrulline malate ingestion during repeated bouts of lower-body exercise in advanced weightlifters. Journal of Strength and Conditioning Research, 29(3), 786-792. https://doi.org/10.1519/JSC.0000000000000670
- Glenn, J. M., Gray, M., Wethington, L. N., Stone, M. S., Stewart, R. W. J., & Moyen, N. E. (2017). Acute citrulline malate supplementation improves upper- and lower-body submaximal weightlifting exercise performance in resistance-trained females. European Journal of Nutrition, 56(2), 775-784. https://doi.org/10.1007/s00394-015-1124-6
- Perez-Guisado, J., & Jakeman, P. M. (2010). Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. Journal of Strength and Conditioning Research, 24(5), 1215-1222.
- Bailey SJ, Blackwell JR, Lord T, et al. L-citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. J Appl Physiol 119: 385-395, 2015
- Suzuki T, Morita M, Kobayashi Y, Kamimura A. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover study. J Int Soc Sports Nutr 13: 6, 2016.
- Ganio MS, Klau JF, Casa DJ, Armstrong LE, Maresh CM. Effect of caffeine on sport-specific endurance performance: a systematic review. J Strength Cond Res. 2009;23(1):315–324. doi: 10.1519/JSC.0b013e31818b979a.
- Astorino TA, Roberson DW. Efficacy of acute caffeine ingestion for short-term high-intensity exercise performance: a systematic review. J Strength Cond Res. 2010;24(1):257-265. doi: 10.1519/JSC.0b013e3181c1f88a.
- Davis JK, Green JM. Caffeine and anaerobic performance. Sports Med. 2009;39(10):813. doi: 10.2165/11317770-000000000-00000.
- Goldstein ER, Ziegenfuss T, Kalman D, et al. International society of sports nutrition position stand: caffeine and performance. J Int Soc Sports Nutr. 2010;7(1):5. doi:10.1186/1550-2783-7-5
- Pickering C, Grgic J. Caffeine and Exercise: What Next?. Sports Med. 2019;49(7):1007-1030. doi:10.1007/s40279-019-01101-0
- Pasman WJ, van Baak MA, Jeukendrup AE, de Haan A. The effect of different dosages of caffeine on endurance performance time. Int J Sports Med. 1995;16(4):225-230. doi: 10.1055/s-2007-972996.
- Selasi Attipoe, Stacey A. Zeno, Courtney Lee, Cindy Crawford, Raheleh Khorsan, Avi R. Walter, Patricia A. Deuster, Tyrosine for Mitigating Stress and Enhancing Performance in Healthy Adult Humans, a Rapid Evidence Assessment of the Literature, Military Medicine, Volume 180, Issue 7, July 2015, Pages 754-765, https://doi.org/10.7205/MILMED-D-14-00594
- Cordeiro LMS, Rabelo PCR, Moraes MM, et al. Physical exercise-induced fatigue: the role of serotonergic and dopaminergic systems. Braz J Med Biol Res. 2017;50(12):e6432. Published 2017 Oct 19. doi:10.1590/1414-431X20176432
- Lee EC, Maresh CM, Kraemer WJ, Yamamoto LM, Hatfield DL, Bailey BL, Armstrong LE, Volek JS, McDermott BP, Craig SA: Ergogenic effects of betaine supplementation on strength and power performance. J Int Soc Sports Nutr. 2010, 7: 27-10.1186/1550-2783-7-27.
- Hoffman JR, Ratamess NA, Kang J, Rashti SL, Faigenbaum AD: Effect of betaine supplementation on power performance and fatigue. J Int Soc Sports Nutr. 2009, 6: 7-10.1186/1550-2783-6-7
- Trepanowski JF, Farney TM, McCarthy CG, Schilling BK, Craig SA, Bloomer RJ: The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men. J Strength Cond Res. 2011, 25: 3461-3471. 10.1519/JSC.0b013e318217d48d.
- Cholewa JM, Hudson A, Cicholski T, Cervenka A, Barreno K, Broom K, Barch M, Craig SAS. The effects of chronic betaine supplementation on body composition and performance in collegiate females: a double-blind, randomized, placebo controlled trial. J Int Soc Sports Nutr. 2018 Jul 31;15(1):37. doi: 10.1186/s12970-018-0243-x. PMID: 30064450; PMCID: PMC6069865.
- Smith AE, Walter AA, Graef JL, Kendall KL, Moon JR, Lockwood CM, Fukuda DH, Beck TW, Cramer JT, Stout JR. Effects of beta-alanine supplementation and high-intensity interval training on endurance performance and body composition in men; a double-blind trial. J Int Soc Sports Nutr. 2009 Feb 11;6:5. doi: 10.1186/1550-2783-6-5. PMID: 19210788; PMCID: PMC2649036.
- Trexler ET, Smith-Ryan AE, Stout JR, Hoffman JR, Wilborn CD, Sale C, Kreider RB, Jäger R, Earnest CP, Bannock L, Campbell B, Kalman D, Ziegenfuss TN, Antonio J. International society of sports nutrition position stand: Beta-Alanine. J Int Soc Sports Nutr. 2015 Jul 15;12:30. doi: 10.1186/s12970-015-0090-y. PMID: 26175657; PMCID: PMC4501114.
- d'Unienville NMA, Blake HT, Coates AM, Hill AM, Nelson MJ, Buckley JD. Effect of food sources of nitrate, polyphenols, L-arginine and L-citrulline on endurance exercise performance: a systematic review and meta-analysis of randomised controlled trials. J Int Soc Sports Nutr. 2021;18(1):76. Published 2021 Dec 29. doi:10.1186/s12970-021-00472-y
- Cases J, Romain C, Marín-Pagán C, et al. Supplementation with a Polyphenol-Rich Extract, PerfLoad®, Improves Physical Performance during High-Intensity Exercise: A Randomized, Double Blind, Crossover Trial. Nutrients. 2017;9(4):421. doi:10.3390/nu9040421.
- Bowtell J, Kelly V. Fruit-Derived Polyphenol Supplementation for Athlete Recovery and Performance. Sports Med. 2019;49(Suppl 1):3-23. doi:10.1007/s40279-018-0998-x
- Arts, I.C., Coolen, E.J., Bours, M.J. et al. Adenosine 5′-triphosphate (ATP) supplements are not orally bioavailable: a randomized, placebo-controlled cross-over trial in healthy humans. J Int Soc Sports Nutr 9, 16 (2012). https://doorg/10.1186/1550-2783-9-16
- Coolen EJ, Arts IC, Bekers O, Vervaet C, Bast A, Dagnelie PC. Oral bioavailability
of ATP after prolonged administration. Br J Nutr. 2011;105:357-66
- Herda TJ, Ryan ED, Stout JR, Cramer JT. Effects of a supplement designed to increase ATP levels on muscle strength, power output, and endurance. J Int Soc Sports Nutr. 2008;5:3.
- Wilson JM, et al. Effects of oral adenosine-5’-triphosphate supplementation on athletic performance, skeletal muscle hypertrophy and recovery in resistance-trained men.Nutrition and Metabolism. 2013, 10:57.
- Lowery RP, et al. Oral ATP administration improves blood flow responses to exercise in both animal and human training models.Presented at 10th Annual ISSN Conference. Colorado Springs, CO. June 2013.
- Rathmacher JA, et al. Adenosine-5’-triphosphate (ATP) supplementation improves low peak muscle torque and torque fatigue during repeated high intensity exercise sets. Journal of the International Society of Sports Nutrition. 2012, 9:48.
- Martin Purpura PhD, John A. Rathmacher PhD, Matthew H. Sharp MS, Ryan P. Lowery MS, Kevin A. Shields MS, Jeremy M. Partl MS, Jacob M. Wilson PhD & Ralf Jäger PhD, MBA (2017): Oral Adenosine-5′-triphosphate (ATP) Administration Increases Postexercise ATP Levels, Muscle Excitability, and Athletic Performance Following a Repeated Sprint Bout, Journal of the American College of Nutrition, DOI: 10.1080/07315724.2016.1246989
- Ratamess NA, Bush JA, Kang J, et al. The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance. Journal of the International Society of Sports Nutrition. 2015;12:35. doi:10.1186/s12970-015-0096-5.
- Ratamess NA, Bush JA, Kang J, et al. The Effects of Supplementation with p-Synephrine Alone and in Combination with Caffeine on Metabolic, Lipolytic, and Cardiovascular Responses during Resistance Exercise. J Am Coll Nutr. 2016;35(8):657-669. doi:10.1080/07315724.2016.1150223.
- Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Longev. 2011;2011:1. doi: 10.1155/2011/482973.