5.20 Nootropics and Cognitive Supplements: Mechanisms, Evidence, and Risk

The brain-pill aisle runs on one trick: it tells you what a molecule does in a dish, then lets you assume it does the same in you.

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This article refuses the trick. One standard for everything: what happens to cognition or performance in reasonably designed trials of healthy adults — not what a compound does to a pathway in a cell culture.

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Hold that bar up and the wall of products collapses to two. Caffeine and creatine clear it, with small-to-moderate effects. L-theanine paired with caffeine earns a modest nod.

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Omega-3 has a reasonable case for correcting a genuinely inadequate intake, and a weak one for enhancing a well-fed brain. The herbal adaptogens rest on small, heterogeneous trials with a high risk of bias — plus real contamination and interaction concerns.

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Prescription compounds? Genuine effects, but they belong to medicine, and several are prohibited in sport. Stick around to the end and you’ll get a five-question checklist, plus the specific safety issues that matter most.

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Key takeaways

1. Caffeine is the best-evidenced compound here. Benefit plateaus around 3 to 6 milligrams per kilogram of body mass — about 210 to 420 mg for a 70 kg athlete, against a 400 mg daily ceiling for healthy adults — while side effects keep rising, so more isn’t better, it’s just jitterier.
2. Creatine delivers small but reasonably consistent cognitive effects. The clearest signals show up under sleep deprivation, or in people whose baseline stores are low.
3. Proprietary blends are a red flag. Hiding the doses conceals whether any ingredient is present at an amount actually used in research.
4. Supplement contamination is a documented, ongoing problem. If you are tested, third-party batch certification (Informed Sport, NSF Certified for Sport) is the best available risk reduction — but it cannot guarantee a product is clean, and strict liability means the athlete carries the consequence regardless.
5. “Natural” does not mean low risk. Herbal products carry real interaction potential, and some have documented safety signals.
6. Almost everything in this category was studied in clinical or impaired populations, where effects run much larger than they will in a healthy, rested adult like you.

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Beginner section: Why the brain-pill aisle mostly doesn’t work

There’s a structural reason the cognitive supplement market is mostly ineffective, and it’s worth thirty seconds of your attention — because it applies to every new product that will ever appear.

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The pathway story, and why your brain ignores it

Most supplements are sold on a simple pitch: swallow the raw material, or switch on the pathway, and your brain makes more of the good stuff. Feed the machine, get more output. Sounds fair.

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Except, as Article 5.10 sets out in detail, your brain is specifically built to resist that. The rate-limiting enzymes are already near saturation. The transporters into the brain are competitive — every compound queues for the same doors.

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And there are feedback loops whose entire purpose is to keep output stable, whatever you swallow. A mechanism is not a lever.

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Gym translation: pointing at a pathway is like pointing at a muscle chart and calling it a training programme. The chart is accurate. It still doesn’t lift anything.

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The small print: who was actually studied?

The second reason is sneakier. Most research on cognitive enhancers was done in people who were impaired — sleep-deprived, elderly, cognitively affected, or deficient in a nutrient.

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In those groups, effects are frequently real and sometimes substantial. In a healthy, rested, well-fed adult they’re much smaller, and often absent.

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Marketing does not distinguish the two. So before you buy anything, ask who the study tested — because if the answer is “someone sleep-deprived or deficient”, the honest fix is sleep or food, not the capsule.

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The whole market on one card

Here’s the entire category in six lines — mechanism, evidence in healthy adults, and the main catch for each.

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• Caffeine. Blocks adenosine receptors. Strong evidence for alertness and performance. The catch: tolerance builds, and it disrupts sleep if you take it late.
• Creatine. Buffers phosphocreatine energy in the brain, not just in muscle. Reasonably consistent small effects, largest under sleep loss or with a low baseline.
• L-theanine (with caffeine). Modulates attention and may reduce jitteriness. Support is modest and comes mostly from small acute studies — the effects are small and routinely over-claimed.
• Omega-3 (DHA/EPA). A structural membrane component. Weak for cognition in healthy, well-fed adults; the better case is correcting a deficient intake.
• Rhodiola, ashwagandha, bacopa. Mechanisms varied and poorly specified. Small, heterogeneous trials with high risk of bias — plus contamination and interaction risk, and liver concerns around ashwagandha.
• Racetams, modafinil, prescription stimulants. Genuinely psychoactive, with real effects — but studied in clinical populations, prescription-only, and several are prohibited in sport.

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Read that list top to bottom and the pattern jumps out: only caffeine and creatine have both a clear mechanism and reasonably consistent human evidence. Everything below them is weaker than its marketing suggests.

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The two that survive

Caffeine works, and works reliably — for alertness, and for performance in both endurance and strength work.

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Worked example, because you’ll want one: at the evidence-backed 3 to 6 milligrams per kilogram, a 70 kg lifter lands at roughly 210 to 420 milligrams, taken about 45 to 60 minutes before training. Watch the top of that range: 420 mg in one pre-workout dose already exceeds Health Canada's 400 mg/day maximum for healthy adults, before any coffee, tea or cola in the rest of the day. Start at the bottom of that range and see how you respond.

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Creatine brings its well-known physical effects plus reasonably consistent small cognitive ones. That cognitive payoff is largest when you’re sleep-deprived or your baseline stores are low — which is common in vegetarians.

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One-line recap: two compounds, both cheap, both boring, both actually supported. Everything else on the shelf is a maybe at best.

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A blunt safety point before we go compound by compound. Supplements are regulated far more loosely than medicines in most countries, and contamination with prohibited substances is a documented and continuing problem — not a scare story.

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And if you compete under anti-doping rules, a positive test is your responsibility regardless of intent. Third-party batch certification isn’t optional caution. It’s basic risk management.

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Advanced section: Compound by compound

Caffeine

Caffeine acts principally as a competitive antagonist at adenosine A1 and A2A receptors (Fredholm et al., 1999). Because adenosine accumulates with time awake and promotes sleep pressure, blocking its receptors reduces perceived fatigue. Downstream effects on catecholaminergic signalling follow from A2A antagonism in the striatum, which is part of why the subjective effect resembles stimulation rather than simply absence of tiredness.

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The performance evidence is among the strongest in sports nutrition. An umbrella review of meta-analyses found consistent benefit across endurance, muscular strength and endurance, jumping and sprinting, alongside effects on vigilance and reaction time (Grgic et al., 2020).

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Caffeine: Dose, benefit, and costGraph showing performance benefit and side-effect burden against caffeine dose per kilogram of body mass.Caffeine: Dose, benefit, and costPerformance benefitSide-effect burden02469+NoneModerateHighCaffeine dose (mg per kg body mass)Relative magnitudeBenefit plateaus here

Figure 2. Benefit plateaus at roughly 3 to 6 milligrams per kilogram — about 210 to 420 mg for a 70 kg athlete, against a 400 mg daily ceiling for healthy adults — while side effects continue to rise. Higher doses buy jitteriness, gastrointestinal upset and sleep disruption rather than more performance.

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• Dose. Commonly effective doses are roughly 3 to 6 milligrams per kilogram of body mass — 210 to 420 mg for a 70 kg athlete — taken around 45 to 60 minutes before exercise (Guest et al., 2021). Benefit plateaus in that range while side effects continue to increase, so higher doses generally buy jitteriness rather than performance. Count the daily total as well as the pre-session dose: Health Canada sets 400 mg/day as the maximum for healthy adults from all sources combined, and the top of the per-kilogram range reaches that on its own.
• Individual variation. Metabolism varies substantially, partly attributable to CYP1A2 genotype, and habitual intake affects the acute response (Guest et al., 2021). Some people experience anxiety or gastrointestinal upset at doses others tolerate easily.
• Timing versus sleep. The half-life is roughly five hours but varies widely (Fredholm et al., 1999). A randomised trial found that caffeine taken six hours before bed measurably reduced total sleep time (Drake et al., 2013). For anyone training in the evening, this is the dominant consideration, and the sleep cost can exceed the performance benefit.
• Withdrawal and tolerance. Regular use produces tolerance to some effects and a withdrawal syndrome including headache and low mood (Fredholm et al., 1999). Whether cycling off is worthwhile is not well settled; the evidence for withdrawal being unpleasant is much stronger than the evidence for cycling improving outcomes.

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Creatine, and the one genuinely interesting cognitive finding

Creatine is not a neurotransmitter precursor. It supports the phosphocreatine system, which buffers adenosine triphosphate (ATP) resynthesis, and this operates in brain tissue as well as muscle.

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Rae and colleagues reported improved working memory and processing speed with six weeks of supplementation in vegetarians, a group with low baseline stores (Rae et al., 2003). Subsequent systematic review of randomised trials in healthy people found small but reasonably consistent effects on memory measures, with the clearest signals in those with low baseline creatine and under conditions of stress such as sleep deprivation (Avgerinos et al., 2018).

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Doses used in cognitive research are sometimes higher than the standard 3 to 5 grams daily used for physical performance, and the evidence for higher doses is less mature. Standard doses have a long safety record in healthy adults; anyone with kidney disease or taking relevant medication should ask a clinician first (Kreider et al., 2017).

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The rest, in descending order of support

• L-theanine. An amino acid found in tea. Most of the reasonable evidence concerns its combination with caffeine, where small acute studies suggest improved attention and reduced subjective jitteriness relative to caffeine alone (Owen et al., 2008). Effects are small and the literature is thin. Low risk, low expected benefit.
• Omega-3 fatty acids. DHA is a structural component of neuronal membranes and adequacy matters. But trials of supplementation for cognitive enhancement in healthy, adequately fed adults have generally been unimpressive, and large trials in older adults for cognitive decline have largely been null (Sydenham et al., 2012). The reasonable position is to ensure adequate intake, principally from oily fish, rather than to expect enhancement.
• Bacopa monnieri. Some randomised trials suggest small improvements in memory measures over weeks to months, but studies are small, heterogeneous and often industry-funded (Kongkeaw et al., 2014). Gastrointestinal side effects are common.
• Rhodiola rosea. Studied mostly for fatigue in stressed or sleep-deprived populations, with small trials of variable quality. Not established as a performance aid in rested athletes.
• Ashwagandha. Popular for stress and sleep, with a number of small trials reporting effects on subjective stress and cortisol. Quality varies considerably. Importantly, there have been case reports and regulatory safety reviews concerning liver injury, and some national authorities have issued cautions (Björnsson et al., 2020). It also has plausible thyroid and immune interactions. This is not a benign herb and warrants a clinician conversation.
• Racetams. Piracetam and relatives are widely sold online in some jurisdictions and are prescription or unapproved medicines in others. Evidence in healthy adults is weak, mechanisms are poorly specified, and product quality is unregulated.
• Modafinil and prescription stimulants. These have genuine, well-documented effects on wakefulness and attention. They are prescription medicines with real side-effect profiles and dependence potential for the stimulants, and several are prohibited in sport in competition. Their use without a prescription is both a health risk and, for athletes, an anti-doping violation. This article does not provide guidance on obtaining or using them.
• Nicotine. Acts at nicotinic acetylcholine receptors and does have acute attentional effects in some studies. It is also highly addictive with cardiovascular considerations, and pouches and gum are not risk-free. Not recommended.

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Contamination, blends, and why the label is not the product

Three structural problems affect the entire category regardless of the compound.

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1. Contamination. Analytical surveys of sports supplements have repeatedly found undeclared substances, including anabolic agents and stimulants, in a meaningful minority of products (Martínez-Sanz et al., 2017). This has caused sanctions for athletes who did not intend to dope. Third-party batch certification programmes exist precisely because of this.
2. Proprietary blends. Listing ingredients without doses conceals whether anything is present at a researched amount. A blend containing twelve ingredients in a 500 milligram total cannot contain research doses of more than one or two of them.
3. Absence of trials on the finished product. Evidence for an ingredient at a particular dose in a particular population does not transfer to a different dose in a different formulation. Almost no consumer product has been trialled as sold.

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Questions to ask before taking anythingFive sequential checks before adding a supplement.Questions to ask before taking anythingIs there a trial onthe finishedproduct?Not on one ingredientin isolation, at adifferent doseIs the dosedisclosed?Proprietary blends hidewhether anything ispresent at an activedoseIs it third-partytested?Informed Sport or NSFcertification foranyone who competesDoes it interactwith anything Itake?A pharmacist or doctorquestion, not aninternet questionIs it prohibited inmy sport?Check the current WADAProhibited List, whichchanges annually

Figure 3. If a product fails any of these five checks, the mechanism story is irrelevant. Most products on sale fail at step two or step three.

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This is also the appropriate place to note that this article is educational and not medical advice. Supplements interact with medications, several affect blood pressure, clotting or thyroid function, and some are unsafe in pregnancy or with specific conditions. Discuss anything you are considering with a doctor or pharmacist who knows your full medication list.

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Practical section: A defensible approach

1. Fix the fundamentals first. Sleep, energy intake, protein, training consistency. No supplement in this article competes with any of them.
2. Consider only caffeine and creatine as first-line. These are the two with real evidence, low cost and long safety records at standard doses.
3. Dose caffeine deliberately, and count the daily total. Roughly 3 to 6 mg/kg, 45 to 60 minutes pre-session, with a firm cut-off eight to ten hours before bed. In absolute terms that is about 180–360 mg for a 60 kg athlete and 240–480 mg for an 80 kg athlete — so the upper end of the performance range can exceed Health Canada's 400 mg/day maximum for healthy adults on its own, before any coffee, tea or cola in the rest of the day. Lower ceilings apply in pregnancy and breastfeeding (300 mg/day) and for adolescents (2.5 mg/kg/day), and caffeine interacts with sleep, anxiety, cardiovascular conditions and several medications (Health Canada).
4. Use creatine monohydrate. Three to five grams daily. It is the cheapest and most studied form, and the exotic forms have no demonstrated advantage (Kreider et al., 2017).
5. Insist on lot-level third-party certification if you compete. Informed Sport or NSF Certified for Sport, checked batch by batch rather than brand by brand. This is meaningful risk reduction, not a guarantee: no supplement can be certified free of prohibited substances, and anti-doping strict liability still applies.
6. Reject proprietary blends. If the dose is not disclosed, the product cannot be evaluated.
7. Check the Prohibited List annually. It changes, and responsibility sits with the athlete.
8. Ask a pharmacist about interactions. Particularly with any psychiatric, thyroid, blood pressure or anticoagulant medication.

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One last framing point. The most reliable cognitive enhancers available to an athlete are a consistent sleep schedule, adequate food, regular exercise and reduced chronic stress. That is not a rhetorical flourish; it is what the effect sizes actually say.

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Sport applications

• Tested athletes at any level. Third-party batch certification is the single most important item in this article. Contamination has ended careers.
• Evening competitors. Caffeine timing becomes a genuine trade-off, since the sleep cost of a late dose can exceed the acute performance benefit.
• Vegetarian and vegan athletes. Lower baseline creatine stores mean creatine supplementation tends to produce larger effects, both physical and cognitive.
• Weight-class athletes. Stimulant use during energy restriction increases cardiovascular strain and worsens sleep at exactly the point where both matter most.
• Youth athletes. Supplement evidence in young people is thinner and the risks of establishing supplement-seeking behaviour early are real. Food first, and involve a qualified practitioner.

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Common mistakes

• Buying proprietary blends. Undisclosed doses make the product impossible to evaluate, and most cannot contain research doses of more than one or two ingredients.
• Assuming natural means safe. Herbal products have genuine interaction potential, and some have documented safety signals including liver concerns.
• Generalising from impaired populations. Most positive findings come from sleep-deprived, elderly or deficient groups. Effects in healthy rested adults are much smaller.
• Escalating caffeine dose to restore an effect. Benefit plateaus while side effects rise, and higher doses mainly worsen sleep and increase anxiety.
• Skipping third-party certification. Contamination is documented and strict liability applies to tested athletes regardless of intent.
• Taking supplements to compensate for poor sleep or intake. The effect sizes are not comparable, and the substitution never works.

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Coaching cues

• Sleep, food and consistency before any supplement.
• Caffeine and creatine are the only two with real evidence here.
• Three to six milligrams per kilogram of caffeine — about 210 to 420 mg for a 70 kg athlete, against a 400 mg daily ceiling for healthy adults — and a firm evening cut-off.
• If the dose is hidden, do not buy it.
• Batch-certified or nothing if you are tested.
• Ask a pharmacist about interactions, not a forum.

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FAQs

Do nootropics work?

Very few do in healthy, rested, well-fed adults. Caffeine works reliably. Creatine has reasonably consistent small effects, largest under sleep deprivation or with low baseline stores. L-theanine with caffeine has modest support. Beyond those, the trials are small, heterogeneous, frequently industry-funded and often conducted in impaired populations where effects are much larger than they would be in you. Prescription compounds do have real effects, but they are medicines with real risks and several are prohibited in sport.

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How much caffeine should I take before training?

Roughly 3 to 6 milligrams per kilogram of body mass, taken about 45 to 60 minutes beforehand, covers most of the evidence. Benefit plateaus in that range while side effects continue to rise, so going higher generally produces jitteriness and gastrointestinal upset rather than more performance. Individual tolerance varies substantially, so start at the lower end. Convert the per-kilogram figure into an absolute dose before you take it: for a 60 kg athlete 3–6 mg/kg is 180–360 mg, and for an 80 kg athlete it is 240–480 mg, against a recommended daily maximum for healthy adults of 400 mg from all sources combined. Pregnancy and breastfeeding (300 mg/day) and adolescence (2.5 mg/kg/day) carry lower limits again, and anyone with a cardiovascular condition, an anxiety disorder or regular medication should treat the dose as a clinician question. The more important variable for most people is the cut-off time: a dose taken six hours before bed has been shown to measurably reduce sleep.

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Is creatine actually good for the brain?

The evidence is genuine but modest. Creatine supports phosphocreatine energy buffering in brain tissue as well as muscle, and systematic review of randomised trials in healthy people has found small, reasonably consistent effects on memory measures. Effects appear clearest in those with low baseline stores, including vegetarians, and under stress such as sleep deprivation. It is not a dramatic cognitive enhancer, but it is the best-supported option in this category and it is inexpensive.

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Is ashwagandha safe?

It is widely sold and often described as benign, but that description is too comfortable. There have been case reports and regulatory safety reviews concerning liver injury, and some national authorities have issued cautions. It also has plausible interactions with thyroid medication, sedatives and immunosuppressants, and it is not recommended in pregnancy. If you are considering it, that is a conversation with a doctor or pharmacist who knows your medication list, not a purchase decision.

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Why do supplements get contaminated?

Because supplements are regulated far more loosely than medicines in most jurisdictions, manufacturing standards vary widely, shared production lines can cross-contaminate, and some manufacturers deliberately add undeclared active compounds to produce a noticeable effect. Analytical surveys have repeatedly found undeclared substances in a meaningful minority of sports supplements. For a tested athlete this matters enormously, because anti-doping operates on strict liability: The substance in your sample is your responsibility regardless of how it got there.

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Should I cycle off caffeine?

The evidence here is weaker than the confident advice suggests. Tolerance to some effects of caffeine clearly develops, and withdrawal produces headache and low mood, which is well documented. Whether periodic abstinence restores the acute performance benefit enough to justify the withdrawal period is not well established. A more defensible approach for most people is to keep habitual intake moderate and consistent, protect the evening cut-off, and reserve higher doses for competition rather than cycling repeatedly.

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Recommended videos

Each video below was chosen because it covers a specific part of this article in more depth than text alone allows.

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Related reading on FitXplor

• 5.10 Amino Acids and the Brain
• 5.18 Biohacking: What the Evidence Actually Supports
• 5.6 Neurotransmitters and Neuromodulators
• 5.17 Sleep, Circadian Biology, and Brain Recovery
• 5.9 Serotonin, Noradrenaline, and Acetylcholine

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References

Grgic, J., Grgic, I., Pickering, C., Schoenfeld, B. J., Bishop, D. J., & Pedisic, Z. (2020). Wake up and smell the coffee: caffeine supplementation and exercise performance — an umbrella review. British Journal of Sports Medicine, 54(11), 681–688.

Guest, N. S., VanDusseldorp, T. A., Nelson, M. T., et al. (2021). International society of sports nutrition position stand: caffeine and exercise performance. Journal of the International Society of Sports Nutrition, 18(1), 1.

Drake, C., Roehrs, T., Shambroom, J., & Roth, T. (2013). Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. Journal of Clinical Sleep Medicine, 9(11), 1195–1200.

Fredholm, B. B., Bättig, K., Holmén, J., Nehlig, A., & Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological Reviews, 51(1), 83–133.

Rae, C., Digney, A. L., McEwan, S. R., & Bates, T. C. (2003). Oral creatine monohydrate supplementation improves brain performance. Proceedings of the Royal Society B, 270(1529), 2147–2150.

Avgerinos, K. I., Spyrou, N., Bougioukas, K. I., & Kapogiannis, D. (2018). Effects of creatine supplementation on cognitive function of healthy individuals. Experimental Gerontology, 108, 166–173.

Kreider, R. B., Kalman, D. S., Antonio, J., et al. (2017). International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation. Journal of the International Society of Sports Nutrition, 14, 18.

Owen, G. N., Parnell, H., De Bruin, E. A., & Rycroft, J. A. (2008). The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutritional Neuroscience, 11(4), 193–198.

Sydenham, E., Dangour, A. D., & Lim, W. S. (2012). Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database of Systematic Reviews, (6), CD005379.

Kongkeaw, C., Dilokthornsakul, P., Thanarangsarit, P., Limpeanchob, N., & Norman Scholfield, C. (2014). Meta-analysis of randomized controlled trials on cognitive effects of Bacopa monnieri extract. Journal of Ethnopharmacology, 151(1), 528–535.

Björnsson, H. K., Björnsson, E. S., Avula, B., et al. (2020). Ashwagandha-induced liver injury: a case series from Iceland and the US Drug-Induced Liver Injury Network. Liver International, 40(4), 825–829.

Martínez-Sanz, J. M., Sospedra, I., Ortiz, C. M., Baladía, E., Gil-Izquierdo, A., & Ortiz-Moncada, R. (2017). Intended or unintended doping? A review of the presence of doping substances in dietary supplements. Nutrients, 9(10), 1093.

Health Canada. Caffeine in foods. canada.ca

Canadian Centre for Ethics in Sport. Supplements. cces.ca/supplements