Do creatine, fish oil, vitamin D and magnesium work? What trials show in healthy adults

Does creatine work? Modest, consistent gains when paired with training

Creatine trials in older adults so far report no consistent harms^{1, 3}. Vitamin D also didn’t reduce fractures in a study within its large trial¹¹. For magnesium, correcting a diagnosed deficiency is a separate question from routine use¹².

FDA doesn’t approve or test supplements before sale, so an independent quality seal is one of the few outside checks that the label matches the contents^{13, 16, 17}. A seal still doesn’t mean a product is safe or effective¹⁴.

A 2017 meta-analysis pooled 22 randomized trials in 721 older adults, with mean ages of 57 to 70¹. Participants did resistance training two or three days a week for 7 to 52 weeks while taking creatine or a placebo¹. The creatine groups gained about 1.37 kg more lean tissue mass (95% CI 0.97 to 1.76)¹.

Strength gains were also slightly larger with creatine, but the effects were small: standardized mean differences of 0.35 for chest press and 0.24 for leg press¹. The NIH Office of Dietary Supplements (ODS) says creatine helps the body adapt to structured, increasing training loads over weeks to months³. It adds that responses vary from person to person³.

Cognition is an emerging area. A 2024 meta-analysis pooled 16 randomized trials with 492 adults aged about 21 to 76, most of them healthy². It found a small improvement in memory (standardized mean difference 0.31, moderate certainty)². Times on attention and processing-speed tasks were also faster, though that finding is low certainty². There was no significant effect on overall cognitive function or executive function, and the authors called for larger, more rigorous trials².

The muscle results come from trials that added creatine to resistance training, so they say little about creatine without training¹. The pooled outcomes were lean mass and strength tests, not falls, fractures or day-to-day independence¹. For cognition, the authors note that the relatively small sample sizes limit the statistical power and generalizability of their conclusions².

On safety, most trials in the 2017 meta-analysis reported no creatine-related adverse effects¹. Four reported gastrointestinal events and two reported muscle cramping, but none of these led participants to withdraw¹. The five trials that checked liver or kidney function found no adverse effects¹. Still, the authors cautioned that about 700 participants is too few to detect rare harms, and they noted case reports of kidney impairment in young men¹.

ODS reports no consistent side effects apart from weight gain, which can reach 1 to 2 kg in a month alongside strength training³. It lists nausea, diarrhea and other stomach upset, muscle cramps and heat intolerance among anecdotal reactions³. The International Society of Sports Nutrition is a professional society, not a regulator⁴. It concludes that intakes of up to 30 g a day for up to five years have been safe and well tolerated in healthy people⁴.

Omega-3 fish oil: supplement doses didn’t prevent major cardiovascular events in healthy older adults

VITAL randomized 25,871 US adults with no previous heart attack, stroke or cancer: men aged 50 and older and women aged 55 and older^{5, 9}. They took 1 g a day of marine omega-3 (460 mg EPA and 380 mg DHA) or a placebo for a median of 5.3 years^{5, 9}. Fish oil didn’t lower major cardiovascular events (hazard ratio 0.92, 95% CI 0.80 to 1.06)⁵. It didn’t lower invasive cancer either (hazard ratio 1.03, 95% CI 0.93 to 1.13)⁵.

Total heart attacks, a secondary outcome, were lower (hazard ratio 0.72, 95% CI 0.59 to 0.90)^{5, 9}. ODS notes larger reductions in heart attacks among Black participants and among people who ate less than 1.5 servings of fish a week⁹. But secondary and subgroup results like these point to questions for future trials rather than settled benefits⁹. ODS also reports no significant reduction in stroke or cardiovascular death⁹.

Prescription icosapent ethyl is a different case. REDUCE-IT tested 4 g a day of icosapent ethyl, a prescription ethyl ester of EPA alone^{6, 10}. Its 8,179 participants were statin-treated adults with fasting triglycerides of 135 to 499 mg/dL^{6, 10}. They also had cardiovascular disease, or diabetes plus other risk factors^{6, 10}. Over a median of 4.9 years, the main composite of cardiovascular events fell from 22.0% to 17.2% (hazard ratio 0.75, 95% CI 0.68 to 0.83)⁶.

REDUCE-IT has two catches. The placebo was mineral oil, which ODS says isn’t a neutral placebo and may have made the difference between groups look larger^{6, 9}. And Amarin, the drug’s maker, funded the trial^{6, 10}.

STRENGTH tested a high-dose EPA-plus-DHA formulation instead: 4 g a day of omega-3 carboxylic acids⁷. Its 13,078 participants were high-risk, statin-treated patients with high triglycerides and low HDL cholesterol⁷. It found no benefit over a corn-oil comparator (12.0% vs 12.2%; hazard ratio 0.99)⁷.

The icosapent ethyl label limits its cardiovascular use to adults on maximally tolerated statins with triglycerides of 150 mg/dL or more¹⁰. They must also have either established cardiovascular disease or diabetes with two or more other risk factors¹⁰. A typical 1,000 mg fish oil capsule supplies about 180 mg EPA and 120 mg DHA⁹. So the REDUCE-IT result doesn’t transfer to over-the-counter fish oil.

These trials don’t show that routine fish oil at supplement doses prevents heart attacks, strokes or cancer in healthy adults⁵. REDUCE-IT applies to one prescription drug at 4 g a day, in statin-treated, high-risk patients with raised triglycerides^{6, 10}. In STRENGTH, a high-dose EPA-plus-DHA formulation didn’t reproduce that result⁷.

On safety, a 2021 meta-analysis linked marine omega-3 supplementation with a higher risk of atrial fibrillation (hazard ratio 1.25, 95% CI 1.07 to 1.46)⁸. It pooled 7 cardiovascular outcome trials with 81,210 participants⁸. The risk was greater in trials using more than 1 g a day (hazard ratio 1.49) than in those using 1 g or less (hazard ratio 1.12)⁸. It rose by about 11% for each additional gram⁸.

In REDUCE-IT, hospitalization for atrial fibrillation or flutter was 3.1% with icosapent ethyl vs 2.1% with placebo^{6, 10}. The drug’s label also warns of more bleeding (12% vs 10%; serious bleeding 3% vs 2%)¹⁰. In STRENGTH, gastrointestinal side effects affected 24.7% of the omega-3 group vs 14.7% of the comparator group⁷. ODS reports that FDA considers supplements supplying no more than 5 g a day of EPA and DHA safe when used as recommended⁹. It adds that supplement labels shouldn’t recommend more than 2 g a day⁹.

Vitamin D: fixing a deficiency isn’t the same as routine use

VITAL also tested vitamin D. Its 25,871 participants were randomized to 2,000 IU (50 mcg) of vitamin D3 a day or placebo for a median of 5.3 years¹¹. Vitamin D didn’t significantly change rates of breast, prostate or colorectal cancer¹¹. It didn’t significantly reduce heart attacks, strokes or cardiovascular deaths either¹¹. And in a 2022 ancillary study, it didn’t reduce total, hip or nonvertebral fractures¹¹.

Deficiency is a separate question from routine use. The National Academies consider people at risk of deficiency when blood 25-hydroxyvitamin D is below 30 nmol/L (12 ng/mL)¹¹. They consider 50 nmol/L (20 ng/mL) or more sufficient for most people¹¹. The adult RDA is 600 IU (15 mcg) a day through age 70 and 800 IU (20 mcg) after that¹¹.

As summarized by ODS, the Endocrine Society recommends routine supplementation for adults 75 and older, pregnant women, adults with prediabetes, and children and teens¹¹. It doesn’t recommend it for healthy adults aged 19 to 74¹¹. It says everyone should follow the RDA, and it advises against routine blood testing in healthy people¹¹. The US Preventive Services Task Force found insufficient evidence to weigh the benefits and harms of screening adults without symptoms¹¹.

The large trials don’t show that taking vitamin D routinely prevents cancer, cardiovascular disease or fractures in generally healthy older adults¹¹. These results concern routine use. They aren’t a verdict on treating a diagnosed deficiency, which is a decision for a clinician.

The adult tolerable upper intake level is 4,000 IU (100 mcg) a day¹¹. ODS says vitamin D toxicity almost always comes from supplements and causes high blood calcium¹¹. In extreme cases, it can lead to kidney failure, abnormal heart rhythms and death¹¹. In the Women’s Health Initiative, 36,282 postmenopausal women were randomized to 1,000 mg of calcium plus 400 IU of vitamin D a day, or placebo¹¹. The supplement group had a 17% higher risk of kidney stones over seven years than the placebo group¹¹.

Magnesium: low intake is common, symptomatic deficiency isn’t, and sleep benefits aren’t established

About 48% of Americans get less magnesium from food and drinks than the estimated average requirement, based on 2013 to 2016 national survey data¹². But ODS says symptomatic deficiency from low dietary intake is uncommon in otherwise healthy people, because the kidneys limit how much magnesium is lost in urine¹². It lists the groups more likely to have inadequate status: people with gastrointestinal diseases such as Crohn’s or celiac disease, type 2 diabetes or alcohol dependence, and older adults¹². The adult RDA is 400 to 420 mg a day for men and 310 to 320 mg for women¹².

A low intake on a dietary survey isn’t the same as a deficiency¹². Blood magnesium hasn’t been measured in the national nutrition survey since 1974, so current magnesium status in the US isn’t known¹². As for sleep, the ODS fact sheet for health professionals doesn’t discuss sleep or insomnia¹². None of the sources reviewed for this page establish a sleep benefit from magnesium in healthy adults.

The 350 mg tolerable upper intake level applies to magnesium from supplements and medicines, not to magnesium in food¹². High supplemental doses can cause diarrhea, nausea and abdominal cramping¹². The risk of toxicity rises when kidney function is impaired¹².

Magnesium also interacts with some medicines. It can reduce the absorption of oral bisphosphonates and some antibiotics¹². Loop and thiazide diuretics can increase magnesium loss in urine, while potassium-sparing diuretics reduce it¹². Proton pump inhibitors taken for long periods, typically more than a year, can cause low blood magnesium¹².

Why third-party testing matters

FDA doesn’t approve dietary supplements before they’re sold, and it doesn’t test them before they reach consumers¹³. Manufacturers and distributors have the initial responsibility for making sure their products are safe¹³. Testing has turned up problems. ODS describes a 2013 analysis of six deer antler velvet supplements³. Five contained no deer IGF-1, and four were adulterated with human IGF-1³.

More recently, in March 2024, the supplement maker NOW said it had tested 12 creatine gummy brands bought on Amazon or brand websites¹⁵. It reported that five contained little to no creatine, while the other seven met their label claims¹⁵. NOW is a competitor, though, and the results weren’t independently verified¹⁵. That’s because none of the third-party labs NOW typically uses said they were able to test the gummies¹⁵.

Independent seals check different things. The USP Verified Mark means a product contains the listed ingredients in the declared amounts and has no harmful levels of specified contaminants¹⁷. It also means the product breaks down within a set time and was made under FDA good manufacturing practices¹⁷. NSF Certified for Sport checks the label against the contents and screens for unsafe contaminants and 290 substances banned by major athletic organizations¹⁶. It also requires a GMP-certified manufacturing site, which NSF audits annually or bi-annually depending on its grade¹⁶.

Informed Sport tests every batch for substances banned in sport before release¹⁸. Its home page doesn’t say that it verifies potency¹⁸. ODS stresses that quality seals don’t guarantee a product is safe or effective¹⁴.

What to look for

None of these supplements replaces the habits the trials were built around, such as the resistance training in the creatine studies¹. Supplements can also interact with some medicines¹⁴. ODS advises getting a health care provider’s approval before taking supplements in place of, or in combination with, prescribed medicines¹⁴. If you’re weighing one, these checks follow from the evidence above.

• Creatine: check the creatine per serving, not the number of gummies, given the 2024 gummy test results¹⁵. The cognition trials used creatine monohydrate². ODS describes a typical regimen of a 5- to 7-day loading phase followed by 3 to 5 g a day³.
• Fish oil: look for EPA and DHA amounts in milligrams on the label. Typical supplement amounts are far below the 4 g a day prescription regimen^{9, 10}. In trials, atrial fibrillation risk rose with higher intakes⁸.
• Vitamin D: the adult upper limit is 4,000 IU a day¹¹. The Endocrine Society guidance summarized by ODS doesn’t recommend routine supplementation for healthy adults aged 19 to 74¹¹. It says everyone should follow the RDA¹¹.
• Magnesium: more than 350 mg a day from supplements exceeds the upper limit¹². Impaired kidney function raises the risk of toxicity¹².
• A seal you can look up: search the certifier’s own database for the exact product, and use the batch search where there is one¹⁸.
• Claims that sound like treatment: a supplement marketed with a disease or cure claim is a warning sign. Only a drug can legally claim to diagnose, treat, cure or prevent a disease, and FDA doesn’t determine whether supplements work before they’re sold^{13, 14}.

Sources

1. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis Open Access Journal of Sports Medicine (Dove Medical Press), 2017 · meta-analysis
2. The effects of creatine supplementation on cognitive function in adults: a systematic review and meta-analysis Frontiers in Nutrition, 2024 · meta-analysis
3. Dietary Supplements for Exercise and Athletic Performance: Fact Sheet for Health Professionals NIH Office of Dietary Supplements · regulator
4. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine Journal of the International Society of Sports Nutrition, 2017 · guideline
5. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer (VITAL) New England Journal of Medicine, 2019 · randomized trial
6. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (REDUCE-IT) New England Journal of Medicine, 2019 · randomized trial
7. 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 · randomized trial
8. Effect of Long-Term Marine Omega-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis Circulation (American Heart Association), 2021 · meta-analysis
9. Omega-3 Fatty Acids: Fact Sheet for Health Professionals NIH Office of Dietary Supplements · regulator
10. VASCEPA (icosapent ethyl) capsules: prescribing information DailyMed, US National Library of Medicine, 2026 · regulator
11. Vitamin D: Fact Sheet for Health Professionals NIH Office of Dietary Supplements · regulator
12. Magnesium: Fact Sheet for Health Professionals NIH Office of Dietary Supplements · regulator
13. Questions and Answers on Dietary Supplements US Food and Drug Administration, 2026 · regulator
14. Dietary Supplements: What You Need to Know NIH Office of Dietary Supplements · regulator
15. NOW tests creatine gummies, finding almost half to be severely understrength SupplySide Supplement Journal, 2024 · news
16. What Our Mark Means NSF Certified for Sport · certifier
17. USP Verified Mark US Pharmacopeia · certifier
18. Informed Sport LGC Group · certifier