By Robert Schinetsky

Pre-workout supplements are as ubiquitous as they are diverse, which is to say there are hundreds (if not thousands) of pre-workout supplements from which to choose. The caveat is that the vast majority of pre-workout supplements are simply a rinse and repeat of other (often more successful) pre-workouts, which only shows that most companies aren’t developing their products according to scientific research.

To help you navigate the pitfalls and follies that is the ever-expanding pre-workout market, here is a list of the best pre-workout nutrients as well as several common pre-workout supplements that may not be an optimal choice to use.

Let’s get started with…

Controversial Pre-Workout Nutrients

Huperzine A

Huperzine A is a naturally occurring alkaloid found in several plants, including toothed clubmoss (huperzia serrata). It has gained prominence in pre workouts, nootropics, and productivity supplements due to its ability to enhance acetylcholine levels – huperzine A inhibits the enzyme the metabolizes acetylcholine (acetylcholinesterase). This should promote stronger, longer-lasting levels of acetylcholine – delivering greater exercise performance, stronger focus, and better exercise performance.

However, as previously discussed, scientific research demonstrates that huperzine A does not improve exercise performance. Other consideration factors are that huperzine has a relatively long half-life (16-20 hours, depending on the dose), which means that supplementing with huperzine A regularly (e.g., using a stimulant pre-workout, stim-free pre-workout, sleep aid, etc.) can lead to an excess of huperzine, which encourages sustained acetylcholine levels. In theory, this should enhance focus, memory, and learning, but (anecdotally) too many huperzine-containing supplements can lead to brain fog, ringing in the ears, synesthesia, and headaches. Furthermore, consuming high amounts (or even low amounts) of huperzine A (>100-200mcg/day) has not been studied in young, healthy individuals without cognitive decline.

Kanna

Kanna (sceletium tortuosum) is a traditional South African “feel-good” herb that is commonly used to help relieve stress and support greater cognitive function (e.g., improved executive function and cognitive flexibility). It primarily works by increasing serotonin levels via its SSRI activities, and other research indicates it may inhibit PDE4 (fyi, common male enhancement pharmaceuticals inhibit PDE5, which encourages greater blood flow to various regions of the body).

Despite reductions in stress and improvements in mood, increased serotonin levels can actually lead to greater feelings of fatigue. Additionally, there is no demonstrable body of research investigating the potential benefits of kanna in regard to exercise performance. High doses of kanna are also known to lead to GI upset in certain individuals, particularly when using the ingredient, the first few times.

Agmatine Sulfate

Derived from L-arginine, agmatine sulfate is commonly included alongside L-citrulline to prolong and intensify nitric oxide production, blood flow, and muscle pumps. The reason for this is due to some research indicating that agmatine may indirectly support nitric oxide production via inhibition of arginase – the enzyme that breaks down arginine – as well as stimulation of endothelial nitric oxide synthase (eNOS) – the enzyme that catalyzes NO production in the body.1

Theoretically, by limiting arginase activity, blood levels of arginine should remain elevated longer promoting stronger, longer-lasting NO production, blood flow, and muscle pumps. However, research demonstrating the NO-boosting effects of agmatine when consumed orally in humans is severely lacking.

There is some research suggesting that agmatine may have some neurological and endocrine benefits, including a reduction in perceived pain, but in terms of boosting blood flow and/or athletic performance, the evidence just isn’t there yet.2

Glycerol Powder

Glycerol is a simple polyol (organic compound containing multiple hydroxyl groups) composed of a sugar alcohol surrounded by three hydroxyl groups, which makes it highly soluble in water. It’s naturally occurring in the human body as a component of triglycerides and serves as an intermediate in carbohydrate and lipid metabolism. Glycerol accumulates in all bodily fluids, except the ones circulating in your brain and eyeballs, where it helps to increase osmotic pressure, and as a result, enhances the total volume of water in the body. In other words, glycerol improves the cells’ ability to store more water, which is beneficial for improving stamina, endurance, and performance.

Research has shown that glycerol ingestion may increase exercise tolerance in terms of time by approximately 24% as well as the length of time that can be spent exercising, because of the improvement in physical endurance. Additionally, heart rate during exercise appears to be significantly lower following ingestion of glycerol.3,4,5

However, other research has found that hyperhydration with glycerol compared with hyperhydration with water alone does not improve performance.6,7,8

Moreover, the doses of glycerol used in these studies (between 0.5-1.5g/kg of bodyweight) far exceed the paltry 1-3 grams of “high-yield” glycerol (65% glycerol-containing supplements) present in current pre-workout supplements.

Another potential concern of powdered glycerol supplements is the silica content. How does this impact glycerol supplements?

Well, glycerol is extremely hygroscopic, meaning it loves water, and to prevent the glycerol from clumping, glycerol liquid is dried into a powder and mixed with copious amounts of silicon dioxide.

The FDA has set upper limits on the consumption of silicon dioxide not to exceed 2% of food total weight. This is mainly because amounts higher than these limits haven’t been sufficiently studied.

It’s also worth mentioning that animal studies suggest that consumption of glycerol monostearate (GMS) increases the exposure to phthalate esters, which have been shown to reduce testosterone levels.9

Choline Precursors C

Choline precursors are typically included in pre-workout supplements to boost levels of “the learning neurotransmitter” (acetylcholine), which impacts multiple processes in the body, including memory, learning, and the mind-muscle connection. Based on these biological actions, it’s believed that supplementing with choline-based supplements (choline bitartrate, choline citrate, Alpha-GPC, etc.) may enhance exercise performance; however, human clinical trials are lacking on the ergogenic potential of choline donors. It warrants mention that a few small human trials have found modest improvement in performance with varying dosages of Alpha-GPC (between 150-1,000mg per day).10,11,12,13

One thing to consider is that the studies aren’t crystal clear as to the dosage used in the study. Clinical trials list a dosage in the study, but many of the choline supplements available to consumers offer between 22-50% choline by mass – this becomes increasingly confusing when delving into the Alpha-GPC research. Alpha-GPC by itself is 40% choline by mass; however, several studies simply list the dosage (150, 250, 300, 1,000mg, etc.) but without knowing the concentration or form of alpha-GPC used in the study, it is difficult to discern exactly what choline-delivering supplement/concentration is used – is it a branded Alpha-GPC supplement providing 50% alpha-gpc (a la AlphaSize, which means you’re getting half of the listed Alpha-GPC dose on the label…i.e., 300mg AlphaSize, supplying 150mg Alpha-GPC…which provides only 40% of bioavailable choline)...or is it 300mg “active” alpha-gpc…hence, 600mg Alpha-GPC (50% yield).

All of this is to say that brands and ingredient providers should be exceedingly clear as to the amount and standardization included in their respective products.

One other thing that hasn’t been touched upon yet are the downstream concerns of consuming choline-donating supplements, particularly alpha-GPC. A 2021 study appearing in the International Journal of Molecular Sciences concluded that “GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.”68

A separate 10-year cohort study demonstrated that Alpha-GPC supplementation was significantly associated with a 10-year incident stroke risk in a dose-responsive manner. To be more precise, individuals supplementing with α-GPC vs. not supplementing with it had a 46% higher risk of stroke.67

The increased cardiovascular risks of alpha-GPC stem from its metabolism in the body.

Trimethylamine N-oxide (TMAO) is a metabolite generated from the metabolism of certain nutrients, including choline and carnitine (which will be discussed soon). Under certain conditions (such as osmotic stress), TMAO can be used by cells to maintain cell volume, which is a beneficial trait.

However, TMAO can also activate various inflammatory molecules, including the proinflammatory cytokines IL1-β and IL-18 as well as vascular endothelial cell MAPK and NFκB signaling. A growing body of research also finds an association between TMAO and risk of cardiovascular disease and stroke. A newly published review in the February 2023 issue of Frontiers in Endocrinology noted that TMAO may also directly contribute to platelet hyperreactivity and enhanced thrombosis as well as cholesterol accumulation and endothelial dysfunction.14,15

A separate review, appearing in Frontiers in Cardiovascular Medicine, also noted a causal relationship between elevated levels of choline and valvular disease (damage to any heart valve). Researchers also reported that higher choline levels were linked to higher risk of myocardial infarction as were increased levels of carnitine.16

Uridine

Uridine is a component of RNA that also supports carbohydrate metabolism, glycogen synthesis, and brain function. It’s naturally produced in the body and can also be found in dietary supplements. Uridine can be used to create CDP-choline as well as phosphatidylcholine (PC).

As a supplement, uridine has experienced popularity with biohackers and nootropic enthusiasts.

Uridine is known to enhance dopamine levels in the body (which given the benefits of dopamine for exercise, make it seem enticing), but the uridine → dopamine link is shown only in animal studies.17

Human research on uridine supplementation is sparse, and recently published research indicates that supplementing with uridine monophosphate (500mg 2x/day) increases circulating uridine levels as well as enhances hunger and caloric intake proportionally to an individual’s basal energy requirements.18

While this may benefit individuals interested in bulking as well as those with poor appetites, for those trying to lose weight/maintain weight, supplementing with uridine may not be a wise choice.

One other cause for concern is that high circulating levels of uridine is associated with several adverse health conditions.19,20,21

Carnitine

Carnitine is an amino acid derivative that supports energy production and “fat burning” by way of acting as the biological taxi for fatty acids. Long-chain fatty acids (LFCAs) cannot enter the mitochondria on their own. They require the services of carnitine to transfer them into mitochondria for subsequent beta-oxidation (the burning of fatty acids for energy).22

Based on the roles of carnitine in the body, it’s thought that supplementing with additional carnitine can improve exercise performance, fat burning, and weight loss. However, the research doesn’t really pan out as the results are mixed. Some studies find benefit, while others find no performance or lean mass improvements at all.23,24,25

A 2020 review on carnitine supplementation also concluded that:26

“Theoretically, carnitine supplementation should increase carnitine muscle content thus improving fatty acid oxidation and exercise function in healthy humans. However, so far, no scientific basis supports improvement in exercise performance for healthy individuals or athletes after carnitine supplementation.” Another 2020 systematic review, including 11 studies, noted that: “Twenty-four weeks of LC supplementation did not affect muscle strength in healthy aged women, but significantly increased muscle mass, improved physical effort tolerance and cognitive function in centenarians.”

Furthermore, research indicates that healthy individuals do not need to consume supplemental L-carnitine, as the liver and kidneys are capable of generating sufficient amounts from the essential amino acids lysine and methionine to meet daily needs.27,28

It’s also worth noting that L-carnitine suffers from poor bioavailability (between 5-15%).

Basically, carnitine may be helpful to those individuals who do not consume enough protein and/or animal products (vegans, vegetarians, elderly), but healthy individuals do not appear to need and/or benefit from L-carnitine supplementation.

There’s also the carnitine-TMAO link to consider as well.

TMAO (trimethylamine-N-oxide) is considered to be an independent and dose-dependent risk factor for cardiovascular disease (CVD). Long-term supplementation of L-carnitine has been noted to induce an increase of fasting plasma trimethylamine-N-oxide (TMAO) levels.

However, other studies in humans have noted that while L-Carnitine does increase TMAO levels, it doesn’t increase markers of atherosclerosis, inflammation, or oxidative stress. Regardless, given the conflicting evidence regarding exercise performance coupled with the growing concerns about TMAO and its potential role in cardiovascular health, consumers should be cautious when considering the implementation of L-carnitine into their supplementation regimen.

Unproven Stimulants

Feeling that rush of energy, motivation, and euphoria is a primary reason individuals use pre-workout supplements. Caffeine has been extensively studied across a wide range of doses across diverse age groups in both men and women. However, some pre-workout supplements use additional stimulants beyond caffeine – stimulants that are vastly under-researched in humans, not to mention unproven, unsafe, and/or not classified as “dietary supplements.” Examples of such stimulants are:

• Higenamine

• Hordenine

• Phenylethylamine (PEA)

• Isopropylnorsynephrine

• DMAA

• DMHA

• DMBA (AMP Citrate)

• Theophylline

• Dendrobium extract

• Eria Jarensis (N-phenethyl dimethylamine)

These stimulants, and the potential issues (side effects) they may impart, have been discussed at length in previous articles titled:

• Stim Hype! Show Me the Science

• NEW HARVARD STUDY! HIGENAMINE CONCERNS! Stimulant In Some Pre-Workouts And Fat Burners!

Suffice it to say that the aforementioned stimulants lack extensive safety/performance research in healthy human subjects. There is also the concern that supplements listing these ingredients on their respective Supplement Facts Panel don’t actually meet label claims, which is backed up by studies showing just that.29,30,31,32

The Best Pre-Workout Supplements

Caffeine

Building off of the previous point about stimulants that are under-researched (and potentially hazardous), we start off the list of the best pre workout supplements with the most rigorously studied stimulant of all time – caffeine.

Quite simply, it is the king of psychostimulants!

Caffeine antagonizes adenosine (a neurotransmitter that promotes feelings of fatigue and sleepiness) while increasing dopamine, which increases feelings of reward, mood, motivation, motor control, and decision-making.

There are no shortage of studies investigating the safety and efficacy of caffeine, particularly regarding sports performance. More specifically, caffeine has been noted to consistently improve performance regarding:

• sport-specific endurance33

• power-based sports34

• resistance exercise35

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 of which 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.36,37

If you suffer with poor 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.38

Caffeine can even boost central drive and has the potential to increase strength or muscular endurance performance.

Caffeine + p-Synephrine

p-Synephrine is an alkaloid found in citrus aurantium (bitter orange) that is structurally similar to ephedrine but doesn’t present with the same cardiovascular concerns due to its affinity for beta-3 receptors as opposed to beta-1 and beta-2 receptors (which is a good thing).

Supplementing with p-synephrine has been found to improve energy expenditure, fat oxidation (“fat burning”) and post-exercise oxygen uptake. Other research suggests stacking caffeine with 100mg p-synephrine may provide greater benefits in terms of performing faster, more powerful repetitions with no additional perceived exertion or lactate accumulation.70,71

Citrulline/Citrulline Malate

Citrulline is an amino acid found in a number of foods (including watermelon) that has been shown to be a superior supplement for increasing blood levels of arginine than even L-arginine supplements. This is noteworthy because arginine is the “fuel” that the body uses to produce nitric oxide – an important signaling molecule that causes vasodilation, which encourages greater blood flow, oxygen and nutrient delivery to working muscles.

Note: Greater NO production also supports better muscle pumps and 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.39,40,41,42,43

Citrulline malate may also promote better recovery and relieve muscle soreness, too.

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. But, truth be told, so long as you’re getting a research-verified dose of L-Citrulline (2.4-10 grams), you should derive some benefits.

Most citrulline malate supplements on the market are either 1:1 (meaning they supply equal amounts of citrulline and malic acid) or 2:1 (two parts citrulline to one part malic acid).

Creatine Monohydrate

Much like caffeine is the most well-researched stimulant in human history, creatine monohydrate is the most well-studied (and consistently shown effective) supplement in the history of sports nutrition for improving athletic performance and lean mass gains.

Creatine monohydrate combined with resistance training has been shown to provide greater results compared to resistance training alone in regard to:44

• Energy production

• Power

• Strength output

• Lean mass gains

Creatine also supports recovery by reducing muscle damage following exercise.45

The International Society of Sports Nutrition also noted in its position paper on creatine supplementation that:44

“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.”

Betaine Anhydrous

Betaine is an organic compound derived from choline that is naturally produced within our bodies and found in a number of foods, including beets (from which betaine derives its name).

Concerning exercise performance, betaine improves cell volumization and hydration via its actions as an osmolyte. Betaine also aids biosynthesis 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 may enhance performance – better hydration and improved creatine production.

Human studies indicate that supplementing with 2.5 grams of betaine/day may increase:46,47,48,49

• Muscle protein synthesis

• Power output (bench press and vertical jump)

• Force production

• Muscular endurance

• Lean mass gains

• Reductions in fat mass

Via its osmolytic properties, betaine can increase intracellular water47, which encourages cell volumization and cellular swelling. This supports muscle growth by way of stimulating muscle protein synthesis.

Beta-Alanine

Beta-alanine is most commonly associated with improving resistance to fatigue and boosting endurance due to its ability to act as an intracellular buffer. By increasing intracellular levels of carnosine, beta-alanine improves a muscle’s capacity to buffer H+ ions and delay 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 enhance:50,51

• Muscle endurance

• Muscle growth

• Resistance to fatigue

• Time-to-exhaustion

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.

Dopamine Precursors

Dopamine is the neurotransmitter that impacts feelings of reward, mood, motivation, memory, learning, and motor control. Most recently, we’ve discussed the benefits of L-Tyrosine for Mental Performance. In that article, newly published research demonstrated that supplementing with 2,000mg (2g) of L-Tyrosine helped individuals maintain greater cognitive performance in light of a stressful environment.69

During particularly stressful situations (such as intense physical activity), dopamine levels can decline, thereby reducing motivation and performance while simultaneously accelerating the onset of fatigue.52

It stands to reason, then, that staving off declining dopamine levels (by supplying the nutrients used in dopamine synthesis) would help 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.

Key nutrients that support dopamine, in addition to L-Tyrosine, include mucuna pruriens and folic acid.

PEAK ATP®

ATP (adenosine triphosphate) is the cellular currency of energy production, and the body’s ability to rapidly replenish ATP reserves is critical to sustaining a high level of performance.

Various ATP supplements have been developed and investigated over the years in an attempt to increase blood levels of ATP; however, the vast majority of them have been shown to be ineffective due to a lack of bioavailability, even when dosed as high as 5,000mg.53,54,55

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:56,57

• 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.58,59,60

Polyphenols

Polyphenols are chemicals found in plants that offer a number of health-promoting benefits, including:

• Glycemic support

• Cardiovascular support

• Cognitive function

• Digestive health

Grapes 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:61

• enhancing vascular function (e.g., vasodilation, vasorelaxation, nitric oxide production)

• limiting oxidative damage during exercise by upregulating endogenous antioxidant capacity

Research has demonstrated that using a polyphenol-rich extract significantly increased average power developed (5%), maximal peak power output (3.7%), and total power output (5%).62

A 2019 review on the influence of polyphenol supplementation for performance and recovery found that:63

• “acute supplementation with ~ 300 mg 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 > 1000 mg polyphenols per day for 3 or more days prior to and following exercise will enhance recovery following muscle damage via antioxidant and anti-inflammatory mechanisms.”

Electrolytes

Electrolytes are a critical component for athletic performance, not to mention optimal cardiometabolic health and cognitive function. They impact nerve impulse, muscle contraction/relaxation, hydration, blood flow and core temperature regulation.

Deficiencies in any one of the main electrolytes (sodium, magnesium, and potassium) can impair performance and accelerate the onset of fatigue. Many individuals simply don’t consume sufficient amounts of potassium and/or magnesium each day. Also, be aware that athletes and even casual gym rats who regularly perform intense physical activity have increased requirements of these key minerals.

A 2021 meta-analysis, including 17 studies with a total of 889 participants, found that magnesium supplementation increased nitric oxide levels as well as reduced markers of c-reactive protein (CRP).64

Earlier studies have also noted that magnesium increases eNOS activity, resulting in vasodilation, and potassium can soften the endothelium and increase nitric oxide production.65,66

While there are many forms of electrolyte supplements, citric acid salts (citrate forms) of potassium and magnesium have been shown to offer superior bioavailability, and citric acid, in particular, has also been noted to improve exercise performance by buffering lactic acid buildup in muscle tissue.

Together, these minerals complement the NO-enhancing effects of Citrulline Malate and polyphenols, supporting cardiovascular health as well as greater blood vessel dilation, blood flow, and exercise performance.

What About Nitrates?

Nitrates are regarded among the bodybuilding community as one of the best pump supplements. They stimulate a separate (yet equally powerful nitric oxide pathway than L-Citrulline/Citrulline Malate) and have been shown to improve VO2 kinetics and exercise performance as well as reduce the oxygen cost of exercise.

Like many supplements, nitrates can be obtained from various foods (spinach, beet root, kale, arugula, etc.) as well as dietary supplements. Advanced Molecular Labs (AML) has recently released NITRATE NO3 BOOSTER capsules, which provides 2,000mg Citrulline Nitrate (supplying 540mg nitrates) as well as polyphenols and vitamin C, the latter of which has been shown to attenuate nitrate tolerance.

While nitrates have been shown to improve exercise performance, their effects are most pronounced 90-120 minutes after ingestion…most people consume a pre-workout supplement (at most) 30-60 minutes pre-workout. Therefore, nitrates can be viewed as a daily dual cardiovascular supplement/ergogenic aid. It can be taken 1-2 hours pre workout or any other time of time to support nitric oxide and circulation.

Takeaway

When it comes to choosing your pre-workout supplement, understand you have a lot (perhaps too many) of options. Before reaching for the product with the shiniest-looking label or cheapest price, check out the supplement facts panel and see what ingredients and dosages of those ingredients are included in the product.

AML pre-workouts and productivity supplements, including PreWorkout, PreWorkout X-treme, Dopa Rush Pre-Workout and Dopa Rush Cocktail, contain full dosages of the best pre-workout nutrients outlined above to offer the greatest benefits for mental and physical performance in the gym, on the field, and in the office!

© Published by Advanced Research Media, Inc. 2023

© Reprinted with permission from Advanced Research Media, Inc.

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