9 Popular Supplements to Reconsider — What the Evidence Shows

Supplements are widely used across the world and range from simple vitamins and minerals to exotic plants and extracts to untested mixtures of unknown ingredients. Not all of them are worth taking — and some have evidence suggesting their risks outweigh any plausible benefit.

This article covers nine supplements where the clinical trial evidence raises meaningful concerns: either the supplement has failed to show benefit in human trials, or it actively interferes with beneficial physiological processes like exercise adaptation.

#1: Direct Antioxidants

The first category to reconsider is direct antioxidants — particularly when taken around exercise. Common examples include Vitamin A, high-dose Vitamin C, and Vitamin E.

Exercise creates oxidative stress in the body, and that stress is a feature, not a flaw. It signals cells to become more efficient, driving the adaptations that make exercise beneficial. Blunting that oxidative signal can blunt the results of training.

This is not just theoretical. A randomized, placebo-controlled trial of 54 healthy men and women found that supplementing Vitamin C and Vitamin E during a training programme blunted the positive adaptations to exercise. Multiple other studies have replicated this finding. A 2020 systematic review examining multivitamin and multimineral supplements found no benefit for these supplements in the prevention of cancer, cardiovascular disease, or all-cause death — https://pubmed.ncbi.nlm.nih.gov/35727272/

The harms extend beyond exercise. Research indicates that Vitamin A and Vitamin E may actually increase mortality rates by interfering with the balance between oxidants and antioxidants. There is also evidence linking Vitamin A supplementation to an increased risk of lung cancer.

Vitamin E specifically deserves additional attention, because there is a common counter-argument on social media: the argument that studies on Vitamin E used alpha-tocopherol when it is actually tocotrienols that matter. That is a hypothesis worth researching. But it does not justify dismissing the existing safety evidence — the current body of evidence is negative, and there is no established positive evidence for tocotrienols in humans to replace it.

This is also why a well-formulated evidence-based multivitamin deliberately excludes Vitamin A and Vitamin E, and uses only a low dose of Vitamin C. The indirect antioxidant approach is different: when glutathione — a powerful antioxidant — begins to decline in the body from around age 45 onwards, supporting the body's own antioxidant production through glycine (a glutathione building block) is a more targeted strategy than flooding the system with direct antioxidants.

#2: Anti-Inflammatories

The second group to reconsider are anti-inflammatory supplements like CoQ10 and PQQ. Similar to the antioxidant issue, exercise naturally inflames the body and produces oxidants — and this is the signal that drives muscle development and cardiovascular adaptation. Suppressing that inflammation blunts the training response.

A randomized trial found that CoQ10 supplementation after exercise dramatically reduced the benefits of training compared to a control group. Beyond exercise, there is no good evidence of benefit from CoQ10 in preventing cancer or heart disease. Importantly, the National Center for Complementary and Integrative Health (NCCIH) notes that CoQ10 research has not produced strong evidence for most of the conditions it is commonly marketed for. There is also good evidence that patients on statins do not receive any meaningful benefit from CoQ10 supplementation — a common belief driven by the fact that statins reduce CoQ10 blood levels, but the clinical relevance of that reduction has not been established in randomized trials.

#3: Resveratrol

Third on this list is resveratrol. Overall, there is no good evidence that resveratrol provides benefits in either animal models or humans. A study evaluating resveratrol on the lifespan of genetically heterogeneous mice found no lifespan extension. A Cochrane review of resveratrol in adults with type 2 diabetes found no clinically meaningful benefit on outcomes including glycaemic control, blood pressure, or body weight.

What the evidence does show is that resveratrol blunts the positive effects of exercise training, across multiple studies. One randomized controlled trial in aged men found that resveratrol supplementation specifically blocked the cardiovascular benefits that exercise training would otherwise produce. A second RCT found that exercise alone improved metabolic and inflammatory markers in skeletal muscle, but adding resveratrol negated several of those gains. Additionally, resveratrol supplementation has been shown to lower testosterone in women with polycystic ovary syndrome — a known hormonal effect with no established compensating benefit established in humans more broadly.

#4: Metformin (for non-diabetics)

Metformin is not a supplement, but it appears on this list because many people in the health optimisation space take it for so-called "health-span benefits." For context: in clinical practice, metformin is an important medication for people with type 2 diabetes or pre-diabetes, where the evidence is overwhelmingly positive. The concern here is about non-diabetics using it as a preventive measure.

The Diabetes Prevention Program — one of the most important trials in this area — followed over 3,000 non-diabetic adults for 21 years. Half received metformin, half received placebo. The result: no difference in all-cause mortality, cancer rates, or heart disease outcomes between the two groups.

Like resveratrol, there is also evidence of harm in this population. Across multiple studies, metformin in non-diabetic adults blocks the positive effects of exercise by as much as 50%, and also lowers testosterone.

#5: Iron

Iron is one of the most popular supplements worldwide, likely because fatigue is a common symptom and low iron or anaemia is a well-known cause. But that symptom-to-supplement connection is where the problem begins.

If blood iron levels have been tested and are confirmed low, an iron supplement is appropriate. But supplementing iron without confirmed deficiency is likely to cause more harm than good. Evidence shows that iron can impair zinc absorption, and supplementation without deficiency can cause gastritis and gastric lesions. A study involving over 50,000 people found that higher iron levels were associated with lower life expectancy — a concerning signal for unsupervised iron supplementation.

#6: Calcium

Calcium is among the most commonly purchased supplements. Some populations genuinely need it — people who avoid dairy or follow vegan diets may have difficulty meeting calcium requirements through diet alone. But outside of confirmed dietary insufficiency, supplemental calcium carries a different risk profile.

Current evidence does not support calcium supplementation (alone or combined with Vitamin D) for the prevention of bone fractures in otherwise healthy adults. At the same time, calcium supplements may contribute to kidney stone formation. There is also an ongoing concern — not yet settled — about whether supplemental calcium contributes to vascular calcification. Some studies have not found this effect; others suggest it is possible. Given the lack of demonstrated benefit and the potential for harm, routine calcium supplementation without dietary need is difficult to justify.

#7: High Dose Folic Acid

This category excludes pregnant women, for whom adequate folate is critical for fetal neural tube development. Outside of pregnancy, high folic acid intake raises separate concerns. Evidence suggests that high folic acid intake may accelerate the formation of pre-cancerous lesions and negatively affect immune function. There is also data indicating that high-dose folic acid may contribute to cognitive impairment in older adults.

The concern is not with adequate folate intake — achieving the RDI (400 mcg DFE) through a combination of diet and a moderate supplement is supported. The concern is with high-dose supplementation that significantly exceeds the RDI without a clinical indication.

#8: High Dose Niacin

Niacin is a form of Vitamin B3. A 2018 meta-analysis found that high-dose niacin supplementation is associated with a 10% increase in all-cause mortality. It also appears to increase new cases of diabetes, cause serious disturbances in blood sugar regulation, increase serious infection risk, and cause bleeding complications.

Other forms commonly marketed as alternatives — NR (nicotinamide riboside), NMN (nicotinamide mononucleotide), and NAM (nicotinamide) — are all converted in the gut into niacin. So despite the different branding, they are effectively the same substance once metabolised. There is also animal research (from mice) suggesting potential concerns with excessive NAD+ precursor supplementation, though direct human evidence on this specific question is limited. At adequate dietary intake, niacin is an essential B vitamin; the concerns here are specifically with high-dose supplementation as a health strategy.

#9: Fat Burning Supplements

Fat-burning supplements are the final category on this list. The active ingredient in most of these products is caffeine — and caffeine's effects on energy expenditure and performance are modest and achievable through ordinary coffee intake. The marketing typically overstates what these supplements deliver relative to a balanced diet and consistent exercise.

A pattern runs through this list: many of the supplements above — antioxidants, anti-inflammatories, resveratrol, and fat burners — interfere with the body's adaptive responses to exercise, diet, or adequate sleep. These three pillars of health generate their own beneficial biological signals. Supplements that suppress those signals in the name of short-cutting results can undermine the very outcomes people are seeking.

There are supplements with good evidence behind them. Creatine, for example, has a strong evidence base for supporting muscle performance, particularly in older adults. Omega-3 fatty acids have a meaningful evidence base for cardiovascular support. The key distinction is that well-evidenced supplements tend to work with physiological processes — they do not blunt or short-circuit them.

When evaluating any supplement, the useful questions are: what does the randomized controlled trial evidence actually show, and does taking it interfere with the body's natural adaptive responses? These nine examples each fail at least one of those tests.

Sources:

1. Vitamin and Mineral Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force: https://pubmed.ncbi.nlm.nih.gov/35727272/
2. Dietary Supplements for Exercise and Athletic Performance: https://ods.od.nih.gov/factsheets/ExerciseAndAthleticPerformance-HealthProfessional/
3. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007176.pub2/full
4. Tocotrienols: Vitamin E Beyond Tocopherols: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1790869/
5. Overview of vitamin E: https://www.uptodate.com/contents/overview-of-vitamin-e
6. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12767
7. Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses: https://pubmed.ncbi.nlm.nih.gov/12398937/
8. Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial: https://academic.oup.com/biomedgerontology/article/78/1/75/6668639?login=false
9. Coenzyme Q10: https://www.nccih.nih.gov/health/coenzyme-q10
10. Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association: https://pubmed.ncbi.nlm.nih.gov/30580575/
11. Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598361/
12. Resveratrol for adults with type 2 diabetes mellitus: https://www.cochrane.org/CD011919/ENDOC_resveratrol-adults-type-2-diabetes-mellitus
13. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810808/
14. Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001758/
15. Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial: https://pubmed.ncbi.nlm.nih.gov/27754722/
16. Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study: https://diabetesjournals.org/care/article/44/12/2775/138471/Effect-of-Metformin-and-Lifestyle-Interventions-on
17. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351883/
18. Effects of chronic metformin treatment on training adaptations in men and women with hyperglycemia: A prospective study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9321693/
19. Effect of Metformin on Testosterone Levels in Male Patients With Type 2 Diabetes Mellitus Treated With Insulin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740051/
20. Iron Fact Sheet for Health Professionals: https://ods.od.nih.gov/factsheets/Iron-HealthProfessional/
21. Genetically predicted iron status and life expectancy: https://pubmed.ncbi.nlm.nih.gov/32690432/
22. Calcium Fact Sheet for Health Professionals: https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/
23. Calcium and vitamin D supplementation in osteoporosis: https://www.uptodate.com/contents/calcium-and-vitamin-d-supplementation-in-osteoporosis
24. Folate Fact Sheet for Health Professionals: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
25. Supplemental Vitamins and Minerals for CVD Prevention and Treatment: https://www.sciencedirect.com/science/article/pii/S0735109718345601?via%3Dihub
26. Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors: https://www.uptodate.com/contents/low-density-lipoprotein-cholesterol-lowering-with-drugs-other-than-statins-and-pcsk9-inhibitors
27. Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345839/