Direct answer
Four supplements have strong RCT evidence for healthy adults: creatine monohydrate (3-5 g/day, ~8 % strength gain, cognitive effects under sleep deprivation), omega-3 EPA/DHA (2-4 g/day, clinically relevant triglyceride reduction), magnesium (in deficiency: better sleep quality), vitamin D (in documented deficiency, not prophylactically). The wider rest — multivitamins, greens powders, most adaptogens — shows no relevant effects in healthy adults.
What counts as "actually works"?
We judge a supplement on three criteria: evidence level (meta-analysis > RCT > cohort > animal > anecdote), effect size (clinically relevant or only statistically significant), and reproducibility (multiple independent research groups with consistent findings). A supplement that scrapes a p-value under 0.05 in a 4-week n=30 trial is not "proven" — it's a signal that needs more data.
Then there's context: a supplement that corrects a deficiency almost always works. Vitamin D works when deficient. Iron works in iron-deficiency anemia. Magnesium works in documented deficiency. The interesting question is: does it also work without a deficiency? That's where the evidence thins out fast.
The four with the best evidence
Creatine monohydrate — the world's most-studied supplement
Over 1000 published studies and clear effects: max strength +5-15 % in trained athletes, muscle mass +1-2 kg over 8-12 weeks of training, sprint performance improved. The position stand of the International Society of Sports Nutrition (Kreider 2017, PMID 28615987) summarizes the evidence: 3-5 g monohydrate per day, ongoing, with or without loading. Loading (20 g/day, 5-7 days) fills muscle stores faster but is unnecessary.
Safety profile: good. Kidney markers (creatinine) rise measurably without actual kidney function being impaired — standard lab values are falsely flagged as "kidney issue" in people supplementing creatine.
Beyond the sports world, creatine shows cognitive effects in smaller studies under sleep deprivation or in vegetarians (whose baseline creatine stores are lower). The evidence here isn't as dense as in strength training but is consistently positive.
Omega-3 EPA/DHA — triglyceride lowerer, not panacea
In people with elevated triglycerides (> 150 mg/dl), 2-4 g EPA/DHA per day lower them by 15-30 %, clinically relevant (Skulas-Ray 2019, American Heart Association Scientific Statement, PMID 31476893). For very high triglycerides (> 500 mg/dl), prescription high-dose preparations (icosapent ethyl) are standard of care.
What omega-3 does not reliably do: cardiovascular primary prevention in healthy adults with normal values. The major megatrials of recent years (VITAL, ASCEND) found no clear reduction of hard endpoints without risk factors. Taking fish oil primarily against heart attack without having elevated triglycerides is optimizing for an uncertain effect.
Dose rule of thumb: 2-3 g EPA+DHA combined per day, low oxidation (TOTOX < 10), with the largest fat-containing meal.
Magnesium — clear in deficiency, debatable otherwise
A double-blind study in elderly adults with primary insomnia showed significant improvement in sleep quality (PSQI), sleep latency, and early awakening with 500 mg magnesium per day (Abbasi 2012, PMID 23853635). Effect size was moderate; participants had subclinical deficits.
In younger adults without deficiency, effects are weaker and less consistent. Bioavailability depends heavily on form: bisglycinate (bound to glycine) is well absorbed and stomach-gentle. Citrate is cheap, well absorbed, mildly laxative at higher doses. Oxide has bioavailability below 5 % — useful almost only as a laxative, not for replacement.
Daily dose 300-500 mg elemental magnesium, in the evening. Max safe: 350 mg from supplements on top of diet (EFSA UL for adults).
Vitamin D — yes in deficiency, unclear prophylactically
In Central Europe, 40-80 % of adults have suboptimal 25(OH)D levels depending on the season. With documented deficiency (< 20 ng/ml), supplementation improves bone mineral density, reduces fall and fracture risk in older adults, and normalizes calcium homeostasis.
In non-deficient adults, effects are unclear. The VITAL trial (n=25,871, 5.3-year follow-up) found no significant reduction of cancer or cardiovascular events with 2000 IU vitamin D per day (Manson 2019, PMID 30415629). Hopes for vitamin D as a longevity lever have not been confirmed in the large trials.
Empirical standard without blood test: 2000-4000 IU/day, with the largest meal (fat-soluble). Above 4000 IU/day long-term should be monitored with blood tests.
Where the market lies loudest
Multivitamins: The Physicians' Health Study II (n=14,641, 11 years) found no significant effect on cardiovascular endpoints or all-cause mortality (Sesso 2012, PMID 23117275). As insurance against multiple subclinical deficiencies they may be reasonable — as a performance or longevity intervention they are not supported.
Greens powders: Marketed as "vegetables in powder form." RCTs on relevant endpoints essentially don't exist. Polyphenols and micronutrients from real plant food are better absorbed via matrix effects — powders are convenience, not a substitute.
Adaptogens (ashwagandha, rhodiola, eleuthero): Mechanistically plausible, with some encouraging short-term studies on stress or sleep endpoints. Problems: small n, short duration (4-12 weeks), heterogeneity of preparations. Ashwagandha has the most robust evidence; even so, long-term data are thin and interactions with thyroid medication are documented.
High-dose antioxidants: Beta-carotene at high doses raises lung cancer risk in smokers (CARET, ATBC trials). Vitamin E above 400 IU/day correlates with higher all-cause mortality in meta-analyses. "More antioxidant = better" is a refuted heuristic.
Methodology — how we evaluate supplements
We use a four-tier system: meta-analysis > RCT > observational study > mechanism/animal. Every substance on this list has an evidence score derived from the number of independent RCTs, the consistency of findings, and effect size. When the evidence is weak, we say so explicitly — and we distinguish between "does not work" (evidence against) and "unclear" (insufficient data). No affiliate links, no hype, no hallucinations.
Sources
- Kreider RB et al. 2017 — International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine PMID 28615987
- Skulas-Ray AC et al. 2019 — Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association PMID 31476893
- Abbasi B et al. 2012 — The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial PMID 23853635
- Manson JE et al. 2019 — Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease (VITAL trial) PMID 30415629
- Sesso HD et al. 2012 — Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial PMID 23117275