Research

What studies say about common supplement ingredients

Plain-English summaries of what peer-reviewed studies found about common supplement ingredients. We start with six and update this page as we add reviews. Each finding says who was studied and ends with a numbered reference. Findings describe ingredients, not specific products.

How we pick sources: position stands and guidelines from professional societies, systematic reviews and meta-analyses of randomized trials, large trials, and NIH fact sheets. We flag studies that are small, short or old.

This is general information, not medical advice. See our Medical Disclaimer.

How to read our evidence grades

Grades are our editorial summary of the evidence for the use described, not a medical review.
A: Strong and consistent. Several meta-analyses or a position stand agree on a benefit.
B: Good but limited. A real benefit, but small, mixed or limited to certain groups or doses.
C: Weak or inconsistent. Small or low-certainty trials with mixed results.
D: Little or no support for the use being marketed.

Creatine monohydrate
Evidence grade: A

Bottom line: With resistance training, creatine monohydrate reliably adds a small extra gain in strength and lean mass, and it has a strong safety record in healthy people at studied doses.

• The International Society of Sports Nutrition (ISSN) concludes that creatine consistently raises muscle creatine stores, which may help explain improvements in high-intensity exercise performance. [1]
• Across 35 randomized trials (1,192 people without specific diseases), creatine plus resistance training added about 1.1 kg of lean mass versus controls, regardless of age. Overall, men gained about 1.46 kg with creatine, while the 0.29 kg gain in women was not statistically significant. Creatine without exercise had no significant effect. [2]
• In adults with average ages of 57 to 70 (22 trials), creatine plus resistance training added about 1.37 kg of lean tissue versus placebo, plus small extra strength gains. [3]

Doses used in studies: 5 g four times a day for 5 to 7 days, then 3 to 5 g a day [1], or 3 to 5 g a day without loading for at least 4 weeks [4].

Forms studied: Monohydrate in nearly all research. Other forms, such as creatine ethyl ester, buffered creatine and creatine nitrate, have not been shown to be retained better. [1]

Safety and who should ask a doctor first: Up to 30 g a day for up to 5 years has been safe and well tolerated in healthy people; weight gain is the only consistently reported side effect [1]. Creatine can raise blood creatinine, which can complicate kidney tests [4]. Ask a doctor first if you have kidney disease, take kidney-affecting medicines, are pregnant or breastfeeding, or have a chronic condition.

Whey protein
Evidence grade: B

Bottom line: Whey is a convenient way to reach a daily protein target, and with resistance training, extra protein adds a small boost to strength and muscle. Once total intake reaches about 1.6 g of protein per kg of body weight a day, more adds little for muscle growth.

• The ISSN says 1.4 to 2.0 g of protein per kg a day, from food or supplements, is enough for most exercising people. [5]
• In 49 trials (1,863 healthy adults doing resistance training), protein supplements added about 2.5 kg to one-rep-max strength and 0.3 kg of fat-free mass, with no further fat-free-mass gain above about 1.6 g/kg a day. [6]
• Whey-specific results are small and mixed: small extra lean-mass gains in resistance-trained adults, though not statistically clear for whey alone [7], and only a small lower-body strength gain in adults 60 and older who also did resistance training. [8]

Doses used in studies: About 20 to 40 g of protein per serving, every 3 to 4 hours [5]. Trials lasted at least 6 weeks [6].

Forms studied: Whey concentrate or isolate, alone or with carbohydrate or creatine [7]. These studies did not compare isolate with concentrate.

Safety and who should ask a doctor first: In 28 trials of adults without kidney disease, higher-protein diets did not adversely change kidney filtration [9]. Whey is a milk protein, so avoid it with a cow's-milk allergy. Ask a doctor first if you have kidney disease, have been told to limit protein, or are pregnant or breastfeeding.

Magnesium
Evidence grade: C

Bottom line: Magnesium may help some adults fall asleep a little faster, but sleep trials are small and inconsistent. Its blood-pressure effect is small (about 2 mmHg) but more consistent.

• A 2026 systematic review of 12 randomized trials in adults found inconsistent, low- to very-low-certainty sleep results and concluded the evidence does not support routine use for insomnia. [10]
• In older adults with insomnia (3 small trials, 151 people), magnesium cut the time to fall asleep by about 17 minutes versus placebo, without significantly changing total sleep (low- to very-low-quality evidence). [11]
• In 155 adults reporting poor sleep, 250 mg of elemental magnesium a day as bisglycinate lowered self-rated insomnia severity slightly more than placebo at 4 weeks, a small effect. [12]
• Across 34 double-blind trials (2,028 adults), a median of 368 mg a day lowered blood pressure by about 2 mmHg systolic and 1.8 mmHg diastolic versus placebo. [13]

Doses used in studies: 320 to 729 mg of elemental magnesium a day in the older-adult sleep trials, above the 350 mg supplement upper limit in two of three [11]; 250 mg in the bisglycinate trial [12]; a median of 368 mg for blood pressure [13].

Forms studied: Oxide, citrate and bisglycinate [11][12]. In one small study, citrate and an amino-acid chelate were absorbed better than oxide. [14]

Safety and who should ask a doctor first: The US upper limit for magnesium from supplements is 350 mg a day, set because of diarrhea [15]. Severe high blood magnesium occurs almost only with substantially reduced kidney function and high intake [16]. Magnesium can reduce absorption of tetracycline and fluoroquinolone antibiotics, so space doses as a pharmacist directs [17]. Ask a doctor or pharmacist first if you have kidney disease; take antibiotics, bisphosphonates, blood-pressure medicines or diuretics; are pregnant; or plan to exceed 350 mg a day.

Vitamin D3
Evidence grade: B

Bottom line: Vitamin D3 reliably raises blood vitamin D, but in a large trial of generally healthy adults 50 and older, 2,000 IU a day did not reduce fractures.

• The Endocrine Society's 2024 guideline suggests healthy adults under 75 not exceed the Dietary Reference Intakes, and suggests vitamin D for adults 75 and older, in pregnancy and for high-risk prediabetes. [18]
• In the VITAL trial (25,871 generally healthy US adults, median 5.3 years), 2,000 IU a day did not lower total, nonvertebral or hip fractures versus placebo. [19]
• Vitamin K2, often paired with D3: in postmenopausal women it improved spine bone density, but most trials used a drug-level MK-4 dose (45 mg a day), not the microgram MK-7 amounts in typical products, and the fracture result was not significant. [20]

Doses used in studies: The RDA is 600 IU a day for ages 1 to 70 and 800 IU from 71. The upper limit, 4,000 IU a day, is not a target intake [21].

Forms studied: D3 (cholecalciferol) raised blood vitamin D more than D2 (ergocalciferol) overall, but not significantly with daily dosing [22]. K2 mostly as MK-4 [20].

Safety and who should ask a doctor first: Too much vitamin D can cause high blood and urine calcium [23]. In 18 healthy volunteers on a warfarin-type blood thinner, 45 mcg a day of MK-7 lowered INR, a clotting measure, by about 40% [24]. Ask a doctor first if you take warfarin or a similar drug (avoid K2 unless your prescriber approves); have kidney disease, high blood calcium or kidney stones; are pregnant; or are considering over 4,000 IU a day or large weekly or monthly doses.

Omega-3 fish oil
Evidence grade: B

Bottom line: Fish-oil omega-3s reliably lower triglycerides. In large trials they did little or nothing for overall cardiovascular events or death, and higher doses were linked to more atrial fibrillation.

• A Cochrane review of 86 trials (162,796 adults) found little or no effect on death from any cause or cardiovascular events (high-certainty evidence) and about a 15% drop in triglycerides. [25]
• Prescription omega-3 at 4 g a day lowers very high triglycerides by 30% or more, per an American Heart Association advisory [26], but in the STRENGTH trial (13,078 high-risk adults), the same dose of prescription EPA+DHA did not reduce major cardiovascular events. [27]
• In 7 cardiovascular-outcome trials (81,210 people), omega-3 supplements were linked to a 25% higher risk of atrial fibrillation, more so above 1 g a day. [28]

Doses used in studies: 0.5 g to more than 5 g a day [25]; 4 g a day in prescription trials, whose results should not be assumed for store-bought fish oil [26][27].

Forms studied: Fish-oil EPA+DHA, prescription EPA+DHA and purified EPA [25][26][27]. In one small 2-week study, 600 mg a day of DHA from algal-oil capsules raised blood DHA about as much as the same DHA dose from cooked salmon. [29]

Safety and who should ask a doctor first: Across 11 trials (120,643 patients), omega-3 did not significantly increase overall bleeding [30]. Ask a doctor first if you take blood thinners or antiplatelet drugs, have a heart-rhythm problem such as atrial fibrillation, have very high triglycerides, have a fish or shellfish allergy, are pregnant, or have surgery scheduled.

Melatonin
Evidence grade: B

Bottom line: In trials, melatonin shortened the time to fall asleep by minutes, not hours. Its best-supported use is jet lag after flights across five or more time zones.

• In 19 placebo-controlled trials (1,683 people with primary sleep disorders), melatonin cut the time to fall asleep by about 7 minutes and added about 8 minutes of sleep, effects the authors called modest. [31]
• A 2022 meta-analysis of 24 trials in chronic insomnia found no significant improvement in time to fall asleep, total sleep or sleep efficiency in adults. [32]
• A 2002 Cochrane review found that melatonin taken near bedtime at the destination reduced jet lag after flights across five or more time zones in 9 of 10 trials. [33]
• Low dose or higher: in a small trial of adults over 50, 0.3 mg restored sleep efficiency in poor sleepers [34], but a 2024 dose-response analysis found effects rising up to about 4 mg a day, so it is not settled that lower is better. [35]

Doses used in studies: 0.1, 0.3 and 3 mg taken 30 minutes before bed [34]; 0.5 to 5 mg for jet lag, with doses above 5 mg no more effective [33].

Forms studied: Oral melatonin. Label accuracy is a documented problem: 22 of 25 melatonin gummy products sold in the US were inaccurately labeled. [36]

Safety and who should ask a doctor first: NCCIH (part of NIH) says short-term use appears safe for most people, but long-term data are lacking; mild side effects include headache, dizziness, nausea and sleepiness [37]. Store it out of children's reach: the CDC estimated about 11,000 emergency visits in 2019 to 2022 for unsupervised melatonin ingestion by children 5 and under [38]. Ask a doctor first if you take prescription medicines, especially blood thinners; have epilepsy; are pregnant or breastfeeding; are an older adult, particularly with dementia; or have ongoing insomnia.

References
1. Kreider RB, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017. PMID: 28615996. https://pubmed.ncbi.nlm.nih.gov/28615996/
2. Delpino FM, et al. Influence of age, sex, and type of exercise on the efficacy of creatine supplementation on lean body mass: A systematic review and meta-analysis of randomized clinical trials. Nutrition. 2022. PMID: 35986981. https://pubmed.ncbi.nlm.nih.gov/35986981/
3. Chilibeck PD, et al. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis. Open Access J Sports Med. 2017. PMID: 29138605. https://pubmed.ncbi.nlm.nih.gov/29138605/
4. Antonio J, et al. Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? J Int Soc Sports Nutr. 2021. PMID: 33557850. https://pubmed.ncbi.nlm.nih.gov/33557850/
5. Jäger R, et al. International Society of Sports Nutrition Position Stand: protein and exercise. J Int Soc Sports Nutr. 2017. PMID: 28642676. https://pubmed.ncbi.nlm.nih.gov/28642676/
6. Morton RW, et al. A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med. 2018. PMID: 28698222. https://pubmed.ncbi.nlm.nih.gov/28698222/
7. Naclerio F, Larumbe-Zabala E. Effects of Whey Protein Alone or as Part of a Multi-ingredient Formulation on Strength, Fat-Free Mass, or Lean Body Mass in Resistance-Trained Individuals: A Meta-analysis. Sports Med. 2016. PMID: 26403469. https://pubmed.ncbi.nlm.nih.gov/26403469/
8. Al-Rawhani AH, et al. Effectiveness of whey protein supplementation on muscle strength and physical performance of older adults: A systematic review and meta-analysis of randomized clinical trials. Clin Nutr. 2024. PMID: 39303495. https://pubmed.ncbi.nlm.nih.gov/39303495/
9. Devries MC, et al. Changes in Kidney Function Do Not Differ between Healthy Adults Consuming Higher- Compared with Lower- or Normal-Protein Diets: A Systematic Review and Meta-Analysis. J Nutr. 2018. PMID: 30383278. https://pubmed.ncbi.nlm.nih.gov/30383278/
10. Lopresti AL, et al. Magnesium Supplementation for Sleep in Adults: A Systematic Review of Randomized Controlled Trials. J Diet Suppl. 2026. PMID: 42661485. https://pubmed.ncbi.nlm.nih.gov/42661485/
11. Mah J, Pitre T. Oral magnesium supplementation for insomnia in older adults: a Systematic Review & Meta-Analysis. BMC Complement Med Ther. 2021. PMID: 33865376. https://pubmed.ncbi.nlm.nih.gov/33865376/
12. Schuster J, et al. Magnesium Bisglycinate Supplementation in Healthy Adults Reporting Poor Sleep: A Randomized, Placebo-Controlled Trial. Nat Sci Sleep. 2025. PMID: 40918053. https://pubmed.ncbi.nlm.nih.gov/40918053/
13. Zhang X, et al. Effects of Magnesium Supplementation on Blood Pressure: A Meta-Analysis of Randomized Double-Blind Placebo-Controlled Trials. Hypertension. 2016. PMID: 27402922. https://pubmed.ncbi.nlm.nih.gov/27402922/
14. Walker AF, et al. Mg citrate found more bioavailable than other Mg preparations in a randomised, double-blind study. Magnes Res. 2003. PMID: 14596323. https://pubmed.ncbi.nlm.nih.gov/14596323/
15. Costello R, et al. Perspective: Call for Re-evaluation of the Tolerable Upper Intake Level for Magnesium Supplementation in Adults. Adv Nutr. 2023. PMID: 37487817. https://pubmed.ncbi.nlm.nih.gov/37487817/
16. Van Laecke S. Hypomagnesemia and hypermagnesemia. Acta Clin Belg. 2019. PMID: 30220246. https://pubmed.ncbi.nlm.nih.gov/30220246/
17. Ogawa R, Echizen H. Clinically significant drug interactions with antacids: an update. Drugs. 2011. PMID: 21942976. https://pubmed.ncbi.nlm.nih.gov/21942976/
18. Demay MB, et al. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2024. PMID: 38828931. https://pubmed.ncbi.nlm.nih.gov/38828931/
19. LeBoff MS, et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults. N Engl J Med. 2022. PMID: 35939577. https://pubmed.ncbi.nlm.nih.gov/35939577/
20. Ma ML, et al. Efficacy of vitamin K2 in the prevention and treatment of postmenopausal osteoporosis: A systematic review and meta-analysis of randomized controlled trials. Front Public Health. 2022. PMID: 36033779. https://pubmed.ncbi.nlm.nih.gov/36033779/
21. Ross AC, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011. PMID: 21118827. https://pubmed.ncbi.nlm.nih.gov/21118827/
22. Tripkovic L, et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012. PMID: 22552031. https://pubmed.ncbi.nlm.nih.gov/22552031/
23. Rizzoli R. Vitamin D supplementation: upper limit for safety revisited? Aging Clin Exp Res. 2021. PMID: 32857334. https://pubmed.ncbi.nlm.nih.gov/32857334/
24. Theuwissen E, et al. Effect of low-dose supplements of menaquinone-7 (vitamin K2) on the stability of oral anticoagulant treatment: dose-response relationship in healthy volunteers. J Thromb Haemost. 2013. PMID: 23530987. https://pubmed.ncbi.nlm.nih.gov/23530987/
25. Abdelhamid AS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020. PMID: 32114706. https://pubmed.ncbi.nlm.nih.gov/32114706/
26. Skulas-Ray AC, et al. Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation. 2019. PMID: 31422671. https://pubmed.ncbi.nlm.nih.gov/31422671/
27. Nicholls SJ, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020. PMID: 33190147. https://pubmed.ncbi.nlm.nih.gov/33190147/
28. Gencer B, et al. Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation. 2021. PMID: 34612056. https://pubmed.ncbi.nlm.nih.gov/34612056/
29. Arterburn LM, et al. Algal-oil capsules and cooked salmon: nutritionally equivalent sources of docosahexaenoic acid. J Am Diet Assoc. 2008. PMID: 18589030. https://pubmed.ncbi.nlm.nih.gov/18589030/
30. Javaid M, et al. Bleeding Risk in Patients Receiving Omega-3 Polyunsaturated Fatty Acids: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Am Heart Assoc. 2024. PMID: 38742535. https://pubmed.ncbi.nlm.nih.gov/38742535/
31. Ferracioli-Oda E, et al. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013. PMID: 23691095. https://pubmed.ncbi.nlm.nih.gov/23691095/
32. Choi K, et al. Efficacy of melatonin for chronic insomnia: Systematic reviews and meta-analyses. Sleep Med Rev. 2022. PMID: 36179487. https://pubmed.ncbi.nlm.nih.gov/36179487/
33. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002. PMID: 12076414. https://pubmed.ncbi.nlm.nih.gov/12076414/
34. Zhdanova IV, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001. PMID: 11600532. https://pubmed.ncbi.nlm.nih.gov/11600532/
35. Cruz-Sanabria F, et al. Optimizing the Time and Dose of Melatonin as a Sleep-Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose-Response Meta-Analysis. J Pineal Res. 2024. PMID: 38888087. https://pubmed.ncbi.nlm.nih.gov/38888087/
36. Cohen PA, et al. Quantity of Melatonin and CBD in Melatonin Gummies Sold in the US. JAMA. 2023. PMID: 37097362. https://pubmed.ncbi.nlm.nih.gov/37097362/
37. National Center for Complementary and Integrative Health. Melatonin: What You Need To Know. NCCIH, National Institutes of Health. Last updated May 2024. https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know
38. Freeman DI, et al. Notes from the Field: Emergency Department Visits for Unsupervised Pediatric Melatonin Ingestion - United States, 2019-2022. MMWR Morb Mortal Wkly Rep. 2024. PMID: 38451863. https://pubmed.ncbi.nlm.nih.gov/38451863/

Last updated: September 24, 2026