6 Controversial Pre-Workout Supplements
By Robert Schinetsky
Here is a Review on 6 Controversial Pre Workout Supplements...
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 (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.
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 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.”34
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.33
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 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 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.
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:
- Phenylethylamine (PEA)
- DMBA (AMP Citrate)
- 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
- 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
© Published by Advanced Research Media, Inc. 2023
© Reprinted with permission from Advanced Research Media, Inc.
- Mun CH, Lee WT, Park KA, Lee JE. Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain. Anat Cell Biol. 2010;43(3):230-40.
- Keynan O, et al. Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial- PubMed - NCBI." National Center for Biotechnology Information.
- Burelle Y, Massıcotte D, Lussıer M, Lavoıe C, Hıllaıre-Marcel C, Peronnet F. Oxidation of [13C] glycerol ingested along with glucose during prolonged exercise. J Appl Physiol. 2001;90:1685–1690.
- Montner P, Stark DM, Riedesel ML, Murata G, Robergs R, Timms M, Chick TW. Pre-exercise glycerol hydration improves cycling endurance time. Int J Sports Med. 1996;17:27–33.
- Coutts A, Reaburn P, Mummery K, Holmes M. The effect of glycerol hyperhydration on Olympic distance triathlon performance in high ambient temperatures. Int J Sport Nutr Exer Metabol. 2002;12:105–119.
- Pense M, Turnagöl H. Effects of Glycerol-Induced Hyperhydration on Cardiovascular Functions and Endurance Performance in Athletes During the Course of Treadmill Exercise Performed at High Temperatures. World Appl Sci J. 2011;12:1114–1124.
- Inder WJ, Swanney MP, Donald RA, Prickett TC, Hellemans J. The effect of glycerol and desmopressin on exercise performance and hydration in triathletes. Med Sci Sports Exer. 1998;30:1263–1269.
- Magal M, Webster MJ, Sistrunk LE, Whitehead MT, Evans RK, Boyd JC. Comparison of glycerol and water hyperhydration regimens on tennisrelated performance. Med Sci Sports Exer. 2003;35:150–156.
- Gao HT, Xu R, Cao WX, et al. Food Emulsifier Glycerin Monostearate Increases Internal Exposure Levels of Six Priority Controlled Phthalate Esters and Exacerbates Their Male Reproductive Toxicities in Rats. PLoS One. 2016;11(8):e0161253. Published 2016 Aug 30. doi:10.1371/journal.pone.0161253
- Ziegenfuss T, Landis J, Hofheins J. Acute supplementation with alpha-glycerylphosphorylcholine augments growth hormone response to, and peak force production during, resistance exercise. J Int Soc Sports Nutr. 2008;5(Suppl 1):P15. Published 2008 Sep 17. doi:10.1186/1550-2783-5-S1-P15
- Marcus L, Soileau J, Judge LW, Bellar D. Evaluation of the effects of two doses of alpha glycerylphosphorylcholine on physical and psychomotor performance. J Int Soc Sports Nutr. 2017 Oct 5;14:39. doi: 10.1186/s12970-017-0196-5. PMID: 29042830; PMCID: PMC5629791.
- Bunn J.A., Crossley A., Timiney M.D. Acute ingestion of neuromuscular enhancement supplements do not improve power output, work capacity, and cognition. J. Sports Med. Phys. Fit. 2017;58:974–979.
- Hoffman JR, Ratamess NA, Gonzalez A, Beller NA, Hoffman MW, Olson M, et al.. The effects of acute and prolonged CRAM supplementation on reaction time and subjective measures of focus and alertness in healthy college students. J Int Soc Sports Nutr (2010) 7:39. doi: 10.1186/1550-2783-7-39
- Olma A, Streb W, Lazar M. TRIMETHYLAMINE OXIDE - FACTOR IN THE DEVELOPMENT OF ATHEROSCLEROSIS AND A POTENTIAL TARGET FOR DIETARY AND PHARMACOLOGICAL INTERVENTIONS. Pol Merkur Lekarski. 2023;51(1):54-58. doi: 10.36740/Merkur202301108. PMID: 36960901.
- Zhen J, Zhou Z, He M, Han HX, Lv EH, Wen PB, Liu X, Wang YT, Cai XC, Tian JQ, Zhang MY, Xiao L, Kang XX. The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseases. Front Endocrinol (Lausanne). 2023 Feb 7;14:1085041. doi: 10.3389/fendo.2023.1085041. PMID: 36824355; PMCID: PMC9941174.
- Jing W, Huang S, Xiang P, Huang J, Yu H. Dietary precursors and cardiovascular disease: A Mendelian randomization study. Front Cardiovasc Med. 2023 Feb 9;10:1061119. doi: 10.3389/fcvm.2023.1061119. PMID: 36844729; PMCID: PMC9947469.
- Hanssen R, Rigoux L, Albus K, Kretschmer AC, Edwin Thanarajah S, Chen W, Hinze Y, Giavalisco P, Steculorum SM, Cornely OA, Brüning JC, Tittgemeyer M. Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Rep Med. 2023 Jan 17;4(1):100897. doi: 10.1016/j.xcrm.2022.100897. PMID: 36652907; PMCID: PMC9873946.
- Braun OO, Lu D, Aroonsakool N, Insel PA. Uridine triphosphate (UTP) induces profibrotic responses in cardiac fibroblasts by activation of P2Y2 receptors. J Mol Cell Cardiol. 2010 Sep;49(3):362-9. doi: 10.1016/j.yjmcc.2010.05.001. Epub 2010 May 13. PMID: 20471392; PMCID: PMC2917486.
- Hoebertz A, Mahendran S, Burnstock G, Arnett TR. ATP and UTP at low concentrations strongly inhibit bone formation by osteoblasts: a novel role for the P2Y2 receptor in bone remodeling. J Cell Biochem. 2002;86(3):413-9. doi: 10.1002/jcb.10236. PMID: 12210747.
- Longo N, Frigeni M, Pasquali M. Carnitine transport and fatty acid oxidation. Biochim Biophys Acta. 2016;1863(10):2422-2435. doi:10.1016/j.bbamcr.2016.01.023
- Shannon CE, Ghasemi R, Greenhaff PL, Stephens FB. Increasing skeletal muscle carnitine availability does not alter the adaptations to high-intensity interval training. Scand J Med Sci Sports. 2018 Jan;28(1):107-115. doi: 10.1111/sms.12885. Epub 2017 May 12. PMID: 28345160.
- Koozehchian MS, Daneshfar A, Fallah E, et al. Effects of nine weeks L-Carnitine supplementation on exercise performance, anaerobic power, and exercise-induced oxidative stress in resistance-trained males. J Exerc Nutrition Biochem. 2018;22(4):7-19. doi:10.20463/jenb.2018.0026
- Sawicka, A.K., Renzi, G. & Olek, R.A. The bright and the dark sides of L-carnitine supplementation: a systematic review. J Int Soc Sports Nutr 17, 49 (2020). https://doi.org/10.1186/s12970-020-00377-2
- Gnoni A, Longo S, Gnoni GV, Giudetti AM. Carnitine in Human Muscle Bioenergetics: Can Carnitine Supplementation Improve Physical Exercise?. Molecules. 2020;25(1):182. Published 2020 Jan 1. doi:10.3390/molecules25010182
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- Cohen PA, Travis JC, Keizers PHJ, Deuster P, Venhuis BJ. Four experimental stimulants found in sports and weight loss supplements: 2-amino-6-methylheptane (octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA). Clin Toxicol (Phila). 2018 Jun;56(6):421-426. doi: 10.1080/15563650.2017.1398328. Epub 2017 Nov 8. PMID: 29115866.
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- Lee G., Choi S., Chang J., Choi D., Son J.S., Kim K., Kim S.M., Jeong S., Park S.M. Association of L-alpha Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years. JAMA Netw. Open. 2021;4:e2136008. doi: 10.1001/jamanetworkopen.2021.36008
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