Most Alzheimer’s drug headlines focus on anti-amyloid monoclonal antibodies: expensive intravenous therapies that can very modestly slow decline, but carry real risks (eg. brain bleeds), especially for people with the strongest genetic risk factor for Alzheimer’s: APOE4. (Fyi, ~25% of the population has APOE4, see my prior post here on it). But an exciting signal has emerged from a late stage cholesterol trial, and I think it deserves more attention.

The molecule is obicetrapib, an inhibitor of cholesteryl ester transfer protein (CETP). CETP inhibitors have a messy history—earlier drugs in the class failed for various reasons—but obicetrapib appears to be a cleaner, safer and more potent iteration. As a cholesterol drug alone it’s already notable: it dramatically lowers LDL cholesterol, raises HDL cholesterol (the “good” cholesterol), and meaningfully reduces Lp(a), a genetically driven cardiovascular risk factor that statins may actually increase (see my prior post here on Lp(a)—1/5 people have this).

But the cholesterol story is not the part that grabbed me. (To be clear, there are plenty of drugs on the market that already effectively lower LDL-C.) It was the impact this drug has on brain biomarkers that got me giddy with dork delight!

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The Alzheimer’s Biomarker Signal

A 2026 substudy published in the Journal of Prevention of Alzheimer’s Disease showed that obicetrapib significantly slowed the rise of p-tau217, one of the strongest blood biomarkers for Alzheimer’s pathology, compared to placebo across the full study population.

The results became even more striking when broken down by APOE genotype.

Among APOE4/E4 homozygotes—the highest-risk genetic subgroup with up to 12-fold increased risk of Alzheimer’s—obicetrapib reduced p-tau217 by nearly 8% while those taking placebo showed p-tau217 increase by nearly 13%. In other words, a 21% net biomarker ‘benefit’ from obicetrapib over just 12 months. This is HUGE.

For context, donanemab (Kisunla), one of only two FDA-approved disease modifying Alzheimer’s drugs in the US, achieved ~29% separation in p-tau217 versus placebo in its biomarker analysis—but over a longer time period. The other FDA approved drug, lecanemab (Leqembi), achieved ~ 21% separation in p-tau181 (another Alzheimer’s brain biomarker) over 18 months in its Phase 3 trial. These are the benchmarks.

And unlike obicetrapib’s once daily pill, donanemab and lecanemab require monthly IV infusions, have significant side effect risks and cost a fortune. The EU and UK have even excluded APOE4 homozygotes from using these treatments due to such elevated risk.

To be clear, obicetrapib has not “beaten” the antibody drugs. But in APOE4 homozygotes, a once-daily oral cholesterol pill produced a biomarker effect in a similar order of magnitude and without the infrastructure burden of an Alzheimer’s infusion program (estimated at $50k+-$80k per patient per year on average).

The NfL signal that may matter even more!

The most intriguing finding wasn’t even p-tau217. It was neurofilament light chain (NfL). (And no, I’m not talking about football—which I also have strong thoughts on… for another day!)

NfL reflects actual axonal injury—neurons being damaged. Amyloid and tau biomarkers tell us about Alzheimer’s pathology specifically; but NfL is closer to the question patients actually care about: are neurons being hurt right now?

In my scientific opinion, NfL may be a more important signal than amyloid clearing. Why? Because we have FDA approved drugs that slay when it comes to clearing amyloid plaques—yet they barely make a dent on cognitive decline. And more recent work highlights that amyloid removal by itself may explain very little variation in cognitive change for Alzheimer’s patients. For example, a new JAMA Neurology analysis found that when researchers looked at individual patients undergoing amyloid removal treatment (i.e. the Donanemab infusion drug), post-treatment amyloid explained only 3–4% of the variation in cognitive change, while a grouping method called quantile aggregation inflated that relationship to 87–99% (which is what the Donanemab drug company reported in headlines… eye roll). In other words, averaging people into neat amyloid buckets can make plaque clearance look far more predictive of cognitive benefit than it is in real patients—which helps explain why removing amyloid may be biologically relevant without being sufficient to halt the cognitive decline from the disease.

In the APOE4/E4 subgroup, obicetrapib significantly reduced NfL while those taking placebo showed an increase—a placebo-adjusted difference of over 17 percentage points. GFAP, another marker of neuroinflammation, also significantly improved.

This matters because the currently approved antibody therapies have NOT shown robust NfL lowering. In lecanemab’s pivotal trial, plasma NfL showed only a trend toward a difference at 18 months (P = 0.06—not statistically significant). Donanemab showed no significant impact on NfL levels either.

Obicetrapib, in the highest-risk genetic subgroup, showed statistically significant NfL reduction at 12 months. That’s an unusual combination: tau, neuroinflammation, amyloid directionality, and neurodegeneration markers all moving the right direction simultaneously… and in only 12 months. Imagine if a person at high risk for Alzheimer’s started on this drug in their 40s or 50s before significant damage accumulates? Could this stave off Alzheimer’s brain pathology entirely for APOE4 carriers?

Why This Is More Than Just “Lower Cholesterol”

A scrupulous reader should question whether the benefit of lowering LDL cholesterol could be responsible for these biomarker changes. I don’t think that’s the secret sauce and here’s why.

A 2025 Mendelian randomization study of over a million individuals found that genetic variants mimicking CETP inhibition (IOW, genetically mimicking a person taking obicetrapib for a lifetime) were associated with roughly 70% lower odds of all-cause dementia. 🤯

Mendelian randomization is a clever type of study that exploits the fact that you inherit your genes randomly at conception — long before any disease develops — which means genetic variants that mimic the effect of a drug or exposure are not confounded by lifestyle, diet (healthy user bias), or other factors that plague traditional observational studies. It’s clever because it lets researchers run what amounts to a natural, lifelong “randomized trial” that no ethics board could ever approve: comparing people who happened to be born with cholesterol-lowering gene variants against those who weren’t, and asking what decades of that difference did to their dementia risk.

Importantly, in that 2025 study, genetic variants mimicking PCSK9 inhibition (another cholesterol medication target, ie Repatha)—which lowers LDL cholesterol much more than CETP inhibition does—showed essentially no association with dementia risk.

That distinction is crucial. If the benefit were simply about lowering LDL cholesterol, PCSK9 inhibitors should work just as well or better. They don’t appear to.

This suggests the Alzheimer’s-relevant signal from CETP inhibition is probably less about LDL lowering and more about what CETP inhibition uniquely does: dramatically raising HDL cholesterol and improving HDL particle function.

Central to that is apolipoprotein A-I (APOA1) — the major structural protein of HDL particles, whose levels rise substantially with CETP inhibition. APOA1 is not merely a scaffold; it actively inhibits amyloid-beta aggregation, and animal studies have shown that boosting peripheral APOA1 preserves cognition, reduces neuroinflammation, and protects against cerebral amyloid angiopathy — the buildup of amyloid in blood vessel walls that contributes to both vascular dementia and Alzheimer’s.

The CETP/APOA1 angle is a fundamentally different mechanism than any currently approved Alzheimer’s therapy. And let’s be real—the currently approved Alzheimer’s therapies are, in my opinion, of laughable efficacy. (Sorry, Eli Lilly and Eisai!)

Why APOE4 Makes This Especially Interesting

APOE4 is the strongest common genetic risk factor for late-onset Alzheimer’s—and it is fundamentally a lipid-transport gene. The biological plausibility of a lipid-remodeling intervention is real in a way that’s easy to overlook if we think of Alzheimer’s purely as “amyloid plaque disease.” (Honestly, my former neuroscience training makes me want to SCREAM when someone says Alzheimer’s is primarily an amyloid plaque disease.)

There’s also a painful practical irony: the people at highest genetic risk from APOE4 are also the people at highest risk of serious side effects from antibody therapies. ARIA — brain edema and microhemorrhages detected on MRI — occurs in roughly 45% of APOE4 homozygotes treated with lecanemab (vs. 13% of non-carriers), and in 55% of homozygotes on donanemab.

A safe, oral therapy that could be taken before symptoms begin would be transformative for exactly the population that most needs alternatives.

The Caveats Are Real

This is not yet an Alzheimer’s prevention drug. It is a cholesterol drug with an Alzheimer’s biomarker signal in a cardiovascular patient population. The researchers did not test cognition. So we don’t yet know whether these biomarker changes translate to slower decline. Also, the APOE4/E4 subgroup was small—only 29 participants total—and small subgroups can exaggerate effects.

However, an earlier proof-of-concept, open-label Phase 2a trial evaluated obicetrapib in patients with early Alzheimer’s, finding it well-tolerated with no serious drug-related adverse events. And the manufacturer of Obicetrapib announced in January that they are planning to start a dedicated Alzheimer’s trial in 2026. I’m very excited to watch this data unfold.

Why I think the current FDA approved Alzheimer’s drugs are very Meh

The only two FDA approved disease modifying drugs for Alzheimer’s — lecanemab and donanemab — have been celebrated as historic breakthroughs, and in a narrow sense, they are: the first drugs to actually slow cognitive decline rather than just manage symptoms.

But here’s what the press releases glossed over. Lecanemab was approved on the strength of a headline number: 27% slowing of cognitive decline. That figure was real, but it was also an average that masked something the trial investigators buried in a supplementary appendix (see Figures S1–S4). When you break it down by sex, men experienced a 43% slowing — statistically significant. Women experienced a 12% slowing — statistically nonsignificant, meaning it could be noise.

So, this drug essentially may not work in women at the population level, and women make up two-thirds of all Alzheimer’s patients.

Donanemab looks somewhat better on the sex disparity front, possibly because its trial was designed to enroll people with lower tau burden to begin with — which is either smart science or a convenient way to stack your deck. The best current explanation? Women tend to accumulate tau pathology faster, and these drugs don’t clear tau — they only clear amyloid, which may be more of a bystander than a cause by the time symptoms appear.

Along those lines, I think the biggest issue is that these drugs hit the bullseye on the wrong target: amyloid plaques. Large meta-analyses show that 20–40% of cognitively normal elderly people already have significant amyloid plaque in their brains, and a recent study of centenarians — people who lived to 100 with intact cognition — found substantial amyloid pathology in many of their brains. If amyloid were the primary driver of Alzheimer’s, these people should have been demented, and they weren’t.

In any event, we have two very expensive, modestly effective, not-without-risk drugs that may work meaningfully for only a subset of patients, and we still don’t routinely screen for the biological factors that predict who that subset is. That’s not a breakthrough. That’s a starting line.

Wrapping it up and what I think the future holds for Alzheimer’s disease

If obicetrapib is approved for its cholesterol indication, it could become widely prescribed. If its Alzheimer’s biomarker findings replicate, it could represent something genuinely new: a preventive strategy aimed not at removing plaque after pathology is established, but at shifting lipid, vascular, and neuroinflammatory biology earlier in the disease course.

The antibody therapies (ie lecanemab, donanemab) remove amyloid plaques, yes; but by the time a patient walks into a memory clinic, the damage is already extensive. They slow the slide; they don’t restore what’s lost.

To get FDA approval for a prevention drug, you need to run trials in healthy people — people who may not develop the disease you’re trying to prevent for another 20 or 30 years. The studies have to be extraordinarily long, extraordinarily expensive, and you have to correctly identify who is actually at risk in the first place. The FDA, quite reasonably, will not approve a drug with serious side effects for use in a healthy person on the basis that they might get Alzheimer’s two decades from now. The risk-benefit calculation simply doesn’t work that way.

It’s an umbrella term for what is likely several different pathological processes that ultimately produce similar symptoms — vascular damage accumulating over a lifetime, insulin resistance and metabolic dysfunction in the brain (sometimes called type 3 diabetes), cholesterol mishandling driven by genes like APOE4, neuroinflammation, and likely combinations of all of these. And different causes will require different preventive strategies. A drug that works beautifully for APOE4 carriers with lipid dysregulation may do nothing for someone whose dementia risk is primarily vascular or metabolic in origin.

This is exactly why obicetrapib’s profile is so interesting from a prevention standpoint. It is not a drug being developed for Alzheimer’s. It is a cardiovascular drug with an excellent safety record, tested in thousands of patients, that happens to show a striking Alzheimer’s biomarker signal — especially in the highest-risk genetic subgroup. That matters enormously, because the most realistic path to Alzheimer’s prevention isn’t a dedicated prevention trial approved by regulators on the basis of a single hypothesis. It’s finding drugs that are safe enough, and beneficial enough for other established indications, that high-risk individuals can justifiably start them decades before symptoms appear. Then, as observational data accumulates over years and years of real-world use, the signal either strengthens or it doesn’t — and eventually, maybe, the evidence base becomes sufficient to support formal prevention labeling.

That is a slow and imperfect path. But it may be the only realistic one we have.

The antibody era matters. It is a genuine scientific achievement to slow the progression of a disease that has defeated every previous attempt at treatment. But antibodies given by IV infusion every two weeks to people who already have symptoms are not going to prevent the Alzheimer’s epidemic. For that, we need something cheap, safe, oral, and startable long before the first memory lapses. We need something that addresses the upstream biology — the lipid dysregulation, the vascular injury, the inflammation — before the cascade becomes irreversible.

Obicetrapib isn’t proven to be that. Not yet. But the signal is strong enough, the safety profile clean enough, and the unmet need large enough that this deserves serious attention from researchers, clinicians, and regulators alike.

The next major Alzheimer’s breakthrough may not come from a neurology clinic.

It may come from a lipid trial.

Stay tuned and subscribe for upcoming articles, including:

• Direct to Consumer Cancer Screening Roll Call! A Deep Dive on Prenuvo/Ezra, Grail (Galleri), Guardant (colon cancer), Auria (breast cancer) vs Standard of Care

• Sleep Meds and Supplements: the Good, the Bad, and the Useless

• Progesterone, HRT, and Cancer Risk — What’s Real and What’s Hype

• At some point… I will do a deep dive on peptides

Check out some prior articles if you’re new to Data Dosing and feel free to share:

• Most Americans have an Omega-3 Index in the “high-risk” category. But are fish oil supplements more helpful or harmful?

• Could a cheap, generic drug improve cancer outcomes in over a dozen tumor types?

• Two Simple Blood Tests That Could Rewrite Your Health Plan—How to order them and actionable insights

• DIY Supplement Vetting: A Guide to Quality Check any Brand

• Is Your Creatine Safe? A Deep Dive into Common Contaminants, How to Buy Safely, and Myths

• Does melatonin cause heart attacks?

• Two simple nasal sprays could keep Covid away

References

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2. Coughlan, G. T., Klinger, H. M., Boyle, R., Betthauser, T. J., Pichet Binette, A., Christenson, L., Chadwick, T., Hansson, O., Harrison, T. M., Healy, B., Jacobs, H. I. L., Hanseeuw, B., Jonaitis, E., Jack, C. R., Johnson, K. A., Langhough, R. E., Properzi, M. J., Rentz, D. M., Schultz, A. P., … Buckley, R. F. (2025). Sex differences in longitudinal tau-PET in preclinical Alzheimer disease: A meta-analysis. JAMA Neurology, 82(4), 364–375. https://doi.org/10.1001/jamaneurol.2025.0013

3. Davidson, M. H., Szarek, M., Scheltens, P., Vijverberg, E., Hsieh, A., Ditmarsch, M., Kling, D., Curcio, D., Nicholls, S. J., Ray, K. K., Cummings, J. L., & Kastelein, J. J. P. (2026). Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease. The Journal of Prevention of Alzheimer’s Disease, 13, 100394. https://doi.org/10.1016/j.tjpad.2025.100394

4. Flanders, M. D., Caunca, M., La Joie, R., Schneider, L. S., & Ackley, S. F. (2026). Methodological considerations for quantile aggregation in Alzheimer disease trials. JAMA Neurology. Advance online publication. https://doi.org/10.1001/jamaneurol.2026.1240

5. Honig, L. S., Sabbagh, M. N., van Dyck, C. H., Sperling, R. A., Hersch, S., Matta, A., Giorgi, L., Gee, M., Kanekiyo, M., Li, D., Purcell, D., Dhadda, S., Irizarry, M., & Kramer, L. (2024). Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease. Alzheimer’s Research & Therapy, 16(1), 105. https://doi.org/10.1186/s13195-024-01441-8 [4]

6. Jansen, W. J., Ossenkoppele, R., Knol, D. L., Tijms, B. M., Scheltens, P., Stam, C. J., Aalten, P., Visser, P. J., van Berckel, B. N. M., Verfaillie, S. C. J., Wink, A. M., Barkhof, F., van der Flier, W. M., & the Amyloid Biomarker Study Group. (2015). Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis. JAMA, 313(19), 1924-1938. https://doi.org/10.1001/jama.2015.4668

7. Kronenberg, F., Mora, S., Stroes, E. S. G., Ference, B. A., Arsenault, B. J., Berglund, L., Dweck, M. R., Koschinsky, M., Lambert, G., Mach, F., McNeal, C. J., Moriarty, P. M., Natarajan, P., Nordestgaard, B. G., Parhofer, K. G., Virani, S. S., von Eckardstein, A., Watts, G. F., Stock, J. K., & Tokgözoğlu, L. S. (2022). Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: A European Atherosclerosis Society consensus statement. European Heart Journal, 43(39), 3925–3946. https://doi.org/10.1093/eurheartj/ehac361

8. Lilly USA. (2025). Kisunla (donanemab-azbt) prescribing information. Eli Lilly and Company. https://pi.lilly.com/us/kisunla-uspi.pdf

9. McDade, E., Cummings, J. L., Dhadda, S., Swanson, C. J., Reyderman, L., Kanekiyo, M., Koyama, A., Irizarry, M., & Kramer, L. D. (2022). Lecanemab in patients with early Alzheimer’s disease: Detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimer’s Research & Therapy, 14(1), 191. https://doi.org/10.1186/s13195-022-01124-2 [5]

10. Nicholls, S. J., Nelson, A. J., Ditmarsch, M., Kastelein, J. J. P., Ballantyne, C. M., Barter, P., Bhatt, D. L., Boekholdt, S. M., Brennan, D., Guo, J., Lincoff, A. M., Nissen, S. E., & Ray, K. K. (2025). Safety and efficacy of obicetrapib in patients at high cardiovascular risk. New England Journal of Medicine, 393(1), 51–61. https://doi.org/10.1056/NEJMoa2415820

11. Nordestgaard, L. T., Hanson, A., Sanderson, E., Anderson, E., Walker, V., Tybjærg-Hansen, A., Davey Smith, G., & Nordestgaard, B. G. (2025). Cholesterol-lowering drug targets reduce risk of dementia: Mendelian randomization and meta-analyses of 1 million individuals. Alzheimer’s & Dementia, 21, e70638. https://doi.org/10.1002/alz.70638

12. Pontecorvo, M. J., Lu, M., Burnham, S. C., Schade, A. E., Dage, J. L., Shcherbinin, S., Collins, E. C., Mintun, M. A., & Skovronsky, D. M. (2022). Association of donanemab treatment with exploratory plasma biomarkers in early symptomatic Alzheimer disease: A secondary analysis of the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurology, 79(12), 1250–1259. https://doi.org/10.1001/jamaneurol.2022.3392

13. Rohde, S. K., Luimes, M. C., Lorenz, L. M. C., et al. (2025). Amyloid-beta pathology and cognitive performance in centenarians. JAMA Neurology. https://jamanetwork.com/journals/jamaneurology/article-abstract/2835759

14. Rosoff, D. B., Bell, A. S., Jung, J., Wagner, J., Mavromatis, L. A., & Lohoff, F. W. (2022). Mendelian randomization study of PCSK9 and HMG-CoA reductase inhibition and cognitive function. Journal of the American College of Cardiology, 80(7), 653–662. https://doi.org/10.1016/j.jacc.2022.05.041

15. Rubin, R. (2025). Trying to unravel why Alzheimer disease is more common in women. JAMA, 334(16), 1411–1413. https://doi.org/10.1001/jama.2025.16269

16. Sims, J. R., Zimmer, J. A., Evans, C. D., Lu, M., Ardayfio, P., Sparks, J., Wessels, A. M., Shcherbinin, S., Wang, H., Monkul Nery, E. S., Collins, E. C., Solomon, P., Salloway, S., Apostolova, L. G., Hansson, O., Ritchie, C., Brooks, D. A., Mintun, M., & Skovronsky, D. M. (2023). Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA, 330(6), 512–527. https://doi.org/10.1001/jama.2023.13239

17. Teipel, S. J., Tang, Y., & Khachaturian, A. (2025). Sex differences in treatment effects of lecanemab and donanemab: A Bayesian reanalysis of CLARITY-AD and TRAILBLAZER-ALZ2. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 11, e70155. https://doi.org/10.1002/trc2.70155

18. U.S. Food and Drug Administration. (2025). Leqembi (lecanemab-irmb) prescribing information.

19. van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., Froelich, L., Katayama, S., Sabbagh, M., Vellas, B., Watson, D., Dhadda, S., Irizarry, M., Kramer, L. D., & Iwatsubo, T. (2023). Lecanemab in early Alzheimer’s disease. New England Journal of Medicine, 388(1), 9–21. https://doi.org/10.1056/NEJMoa2212948

Let me start with three facts that should bother you.

Fact one: the amount of omega-3 fatty acids in your red blood cells predicts your risk of death in the next decade about as strongly as whether or not you smoke. 🤯

Fact two: About 89% of Americans have an Omega-3 Index in the "high-risk" category — meaning their red blood cell membranes contain so little EPA and DHA that their risk of dying from coronary heart disease is measurably elevated.

Fact three: A startling share of the fish oil capsules on store shelves are already rancid when you buy them.

In this article, I’ll walk you through:

1. Which forms of omega-3s to use (spoiler alert, plant based ALA does not have the same evidence base as EPA/DHA/DPA);

2. What the research actually says about omega-3 benefits and risks (much more nuanced than any of the health headlines imply);

3. How to know if you should even consider a supplement and why the Omega-3 Index is the gold standard;

4. Where to source quality omega-3 supplements, along with a list of my favorite brands that I’ve thoroughly vetted via third party testing. Never use SuppCo FYI.

Before we dive in, I open any article on supplements with this: No supplement is going to improve health outcomes anywhere near the magnitude of prioritizing diet (whole foods), lifestyle (exercise, social connection), and sleep. I’m not here to sell you supplements. I’m here to tell you which ones matter. With that said, let’s dig in . . . this one is a doozy!

The three long-chain omega-3s (and why plant omega-3 doesn’t substitute)

Most conversations lump “omega-3s” into a single category. Biologically, the differences between the fatty acids matter.

EPA (eicosapentaenoic acid) is the primary anti-inflammatory fatty acid. Your body uses it to manufacture resolvins and protectins — signaling molecules that actively shut down inflammation rather than just blocking it. EPA is the fatty acid most closely tied to reductions in cardiovascular events in high-dose intervention trials. Even though people commonly associate EPA with heart only benefits, the clinical research around depression consistently finds better support for EPA supplementation over DHA supplementation for treating depressive disorders.

DHA (docosahexaenoic acid) is the structural fat of brain and retinal tissue — it makes up a substantial fraction of neuronal membrane phospholipids and is critical for cognition and vision. Its role is architectural rather than anti-inflammatory: low DHA appears to reflect baseline neurological vulnerability rather than drive acute mood symptoms, which is probably why DHA-only supplementation doesn’t move the needle on depression (see more on this below). If you are an APOE4 carrier, see my prior post here for more info on DHA absorption — you may need higher doses earlier in life.

DPA (docosapentaenoic acid) is primarily converted from EPA, but can also be converted back into both EPA and DHA, serving as a metabolic intermediary and reservoir for these fatty acids. While it is often absent from supplement labels entirely, certain fish — wild sockeye salmon, Atlantic mackerel, herring — are rich sources. In the 17-cohort pooled analysis below, DPA independently predicted lower mortality at magnitudes similar to EPA and DHA.

ALA (alpha-linolenic acid) is the plant-based omega-3 from flax, chia, and walnuts. Your body can technically convert ALA into EPA and DHA, but the conversion is poor: about 5–10% efficiency to EPA, less than 1% to DHA. In the large biomarker studies, circulating ALA levels show little to no relationship with mortality as compared to DHA/EPA. Plant omega-3s are good nutrition (myriad other benefits!), but they are not a substitute for marine omega-3s.

The mortality evidence: a case for increasing omega-3 status

The largest analysis of the association between omega-3 status and all cause mortality appeared in Nature Communications in 2021. Harris and colleagues pooled data from 17 prospective cohorts — 42,466 adults, median 16 years of follow-up. After adjusting for age, sex, race, BMI, education, occupation, smoking status, physical activity, alcohol intake, diabetes, hypertension, and circulating omega-6 levels, people in the highest fifth of blood long-chain omega-3 levels had:

• 15–18% lower risk of dying from any cause

• 20% lower risk of cardiovascular mortality

• 13% lower risk of cancer mortality

• 18% lower risk of death from other causes

The 2018 Cardiovascular Health Study analysis (Lai et al., BMJ, 2018) followed 2,622 older adults across two decades and found that higher cumulative blood levels of seafood-derived omega-3s were associated with an 18% lower risk of unhealthy ageing — defined as dying early, developing a major chronic disease, or experiencing cognitive or physical decline.

In 2021, the Framingham Offspring Cohort study analyzed 2,240 participants with an 11-year follow-up. After adjusting for the usual cardiovascular suspects — age, sex, blood pressure, cholesterol, diabetes, and more — they asked how much life a 65-year-old would forfeit from various risk factors. Being a current smoker was predicted to cost roughly 4.7 years of life. Having a low Omega-3 Index rather than a high one cost essentially the same: about 4.7 years (McBurney et al., AJCN, 2021).

Can we trust the biomarker studies? The healthy-user problem.

A careful reader should ask: maybe people with high blood omega-3 levels just exercise more, eat more vegetables, and smoke less — and the omega-3 itself isn’t doing anything. This is “healthy user bias,” and it’s why observational nutrition findings on beta-carotene, vitamin E, and folate all collapsed when tested against placebo in randomized controlled trials (“RCTs”). The 2021 Framingham pooled analysis is harder to dismiss on those grounds, for three reasons:

1. The effect is large. A 15-18% all-cause mortality reduction from top to bottom quintile is in the range of smoking cessation or statin therapy — bigger than residual healthy-user confounding typically produces.

2. Fish oil supplement users weren’t driving the effect. A sensitivity analysis removing people already taking fish oil (the textbook healthy-user population) didn’t meaningfully change the findings.

3. Plant omega-3 (ALA) didn’t track with mortality. If high marine omega-3 levels were just a proxy for virtuous eating, ALA — from walnuts, flax, leafy greens, the whole health-food-store aesthetic — should have shown a similar association. It didn’t. Only the marine long-chain omega-3s predicted mortality.

My honest take: the biomarker evidence is consistent, survives adjustment for major confounders, and is harder to explain with pure healthy-user bias than most nutritional epidemiology.

The cardiovascular trials: where the data gets messy

Your cardiologist might say “clinical trials show fish oil doesn’t work.” On the other hand, Dr. Rhonda Patrick (PhD social media influencer) says “Everyone should supplement with fish oil.”

Both are wrong.

Here’s the actual landscape when it comes to cardiovascular health:

*MI=myocardial infarction aka heart attack; MACE= Major Adverse Cardiovascular Event

Messy, eh? But there are some distinct patterns that emerge…

The pattern.

Modest doses (~1 g/day) in mixed populations are largely null, and a Cochrane review of 79 trials concluded EPA+DHA has “little or no effect” on cardiovascular mortality (Abdelhamid, Cochrane Database, 2018). The catch is that averaging across populations obscures benefits at the individual level: VITAL’s null disappeared once you looked at people who weren’t getting much omega-3 from diet (low fish intake). There is more room for benefit with supplementation when you’re starting from a deficit.

The pattern repeats in the REDUCE-IT trial where omega-3 supplementations helped most where there’s the most room to help—in people at high risk for cardiovascular disease. The REDUCE-IT post-hoc analysis found that supplementation had significant benefit in patients with recent acute coronary syndrome, finding a number needed to treat (“NNT”) of just 11 (Gaba, Eur Heart J, 2024).

For context, the NNT is the number of people that must take the medication/intervention to see prevention of a single event (eg heart attack). For statins, the NNT to prevent one major cardiovascular event over 5 years is 60-100 moderate risk patients (e.g. no prior heart attack, but elevated cholesterol). So, an NNT of 11 with an omega-3 supplement is quite impressive.

The REDUCE-IT mineral oil caveat. REDUCE-IT used mineral oil as its placebo, which researchers argue was a harmful rather than neutral “control” (Bostrom, Circulation, 2021). That said, another trial using imaging to look at plaque in the heart in patients taking EPA vs mineral oil showed significant plaque regression in the EPA group, supporting that real benefit is happening with EPA (Budoff, Eur Heart J, 2020).

The atrial fibrillation (AFib) question.

In the REDUCE-IT randomized trial, 3.1% of the EPA group vs. 2.1% of placebo were hospitalized for AFib — a 1% absolute increase that skeptics inflate to a “48% relative risk increase” (ie 1% is 48% of 2.1%). However, a post-hoc subgroup analysis split participants by prior AFib history (Olshansky, JAHA, 2023): among the 91% without prior AFib, EPA raised AFib hospitalization by 0.6% while still reducing major cardiovascular events by 5.1% — a clearly favorable trade. The cardiovascular benefit was preserved whether or not patients developed AFib, and all-cause mortality stayed lower in EPA users even among those who developed Afib. Most cardiologists, in my experience, aren’t aware of the subgroup nuance.

A 2024 cohort study adds important nuance on the observational side: in the general population without cardiovascular disease, regular fish oil users had a small ~13% increase in AFib risk and a ~5% increase in stroke risk that just barely reached statistical significance (HR 1.05, p=0.050). But in people with established cardiovascular disease, fish oil supplementation tracked with meaningfully better outcomes: ~15% lower risk of progressing from AFib to myocardial infarction, ~12% lower risk of dying after developing AFib, and ~9% lower mortality in those with heart failure (Chen, BMJ Medicine, 2024). Again, omega-3 supplementation appears to help most where there’s the most room to help — in people who already have cardiovascular disease.

What the cardiology societies actually recommend (and where I think they undershoot).

The American College of Cardiology (ACC) and American Heart Association (AHA) do not recommend over-the-counter fish oil for cardiovascular prevention in the general population — their support is reserved for prescription EPA (Vascepa, 4 g/day) in statin-treated patients with high triglycerides and high cardiovascular risk (Virani, JACC, 2021), with fish oil considered only “reasonable” for secondary prevention after a heart attack (Siscovick, Circulation, 2017). That blanket guidance averages across regular fish-eaters and the genuinely deficient — two very different patient populations — and benefit gets diluted when you mix them together; stratify by who was actually deficient (VITAL participants eating less than 1.5 fish servings/week, low baseline EPA in REDUCE-IT, the bottom-quintile Omega-3 Index across cohorts) and the signal sharpens considerably. “Fish oil supplements don’t prevent heart disease” is defensible on average, but the strongest practical takeaway is to measure your Omega-3 Index before deciding (more on how below).

In any event, if you have a history of AFib or other heart rhythm disturbances, this is a supplement situation where consulting a cardiologist before exceeding 1 g/day is genuinely warranted because the randomized trial data strongly suggests that the AFib signal is dose-dependent.

Beyond the heart: inflammation, cancer, mental health

There are other potential health benefits of omega-3 supplementation outside of the cardiovascular realm. Here are a few supported by research, though the quality of the evidence base is questionable in a number of these studies. .

1. Autoimmune and inflammatory disease

In a prospective cohort of 32,232 women followed for an average of 7.5 years, consistent intake of more than 210 mg/day of long-chain omega-3s from fish was associated with a 52% lower risk of developing rheumatoid arthritis, an autoimmune disease (Di Giuseppe, Ann Rheum Dis, 2014). The VITAL trial (over 25,000 older adults) found that 1 g/day of EPA+DHA was associated with a 15% lower incidence of autoimmune disease, though this did not reach statistical significance; exploratory subgroup analyses suggested larger apparent reductions for thyroid disease and rheumatoid arthritis (Hahn et al., BMJ, 2022). Meta-analyses of randomized trials have found that marine omega-3s modestly reduce pain in rheumatoid arthritis, though recent reviews rate the quality of this evidence as low-to-moderate (Senftleber, Nutrients, 2017; Gkiouras et al., Crit Rev Food Sci Nutr, 2023).

A 2026 systematic review and meta-analysis across 96 clinical trials adds important mechanistic context here — and reinforces the same pattern we saw with cardiovascular disease (Khabir et al., 2026). When EPA and DHA enter circulation, they compete directly with arachidonic acid (AA) — a pro-inflammatory omega-6 fatty acid — for incorporation into cell membranes. The more EPA and DHA that get embedded in those membranes, the fewer AA-derived inflammatory molecules (like prostaglandin E2 and leukotriene B4) get produced (Calder, 2010). Critically, these AA reductions were most pronounced in people who already had something to fight: those with cardiovascular disease, metabolic conditions, and cognitive or mental disorders. The same selectivity held for the key inflammatory markers — TNF-α, CRP, and IL-6 — which were significantly reduced by EPA+DHA supplementation in people with underlying disease, but barely budged in healthy populations (Khabir et al., 2026). This is consistent with a growing body of evidence that individuals with higher baseline inflammation are simply more responsive to omega-3 supplementation (Xin et al., 2012). Similar to cardiovascular disease, omega-3 supplementation seems to help inflammation most where there’s the most room to help.

Another angle on inflammation comes from studies looking at the impact of Omega-3 supplementation on vagal tone and heart rate variability (HRV).

A secondary analysis of the VITAL trial showed that 1g/day of omega-3s meaningfully improved RMSSD (a proxy measure of HRV) compared to placebo over two years. A separate crossover RCT using a higher dose of 3.4g/day saw RMSSD climb by nearly 10% over eight weeks relative to placebo. A meta-analysis of fish oil studies also found significant improvements in another marker of vagal tone. The benefits appear to scale with dose and tend to be stronger in people who already carry elevated cardiovascular risk. This could explain part of the double edged sword with these supplements: increased vagal tone and slower AV conduction may lower inflammation on one the one hand; but on the other hand, the slowing of intra-atrial conduction raises Afib risk.

2. Cancer

To understand whether Omega-3s actually prevent cancer, you have to look past the “all-or-nothing” headlines. While some massive studies had unimpressive results, smaller dives into the data reveal specific groups and combinations where these fats seem to make a real difference. For example, the VITAL randomized trial followed over 25,000 people and found that taking 1 gram of Omega-3 daily didn’t significantly lower the overall risk of getting cancer for the general healthy population (Manson, NEJM, 2019). However, when researchers looked closer at specific groups, the story changed. For example, a subgroup analysis found that African-American participants who took the supplement actually had fewer precancerous polyps (growth that can lead to colon cancer) compared to those who didn’t (Song, JAMA Oncol, 2020).

There is also a “survival” signal in the omega-3- cancer literature. One study of people already diagnosed with colorectal cancer found that those with a high Omega-3 intake (at least 300 mg/day) appeared to have a 41% lower risk of dying from the disease compared to those who ate very little, although the result was just shy of statistical significance (Song, Gut, 2017).

The DO-HEALTH trial gave adults over 70 a triple combination of omega-3s, Vitamin D, and a simple at-home exercise program. Omega-3s alone showed a trend toward a 30% lower risk of invasive cancer, though this result was not statistically significant (HR: 0.70, CI: 0.44–1.09). When combined with Vitamin D and exercise, the risk of invasive cancer dropped by a massive 61% which was statistically significant (Bischoff-Ferrari, Front Aging, 2022).

The data for specific cancers is also a bit of a mixed bag. A large review of 21 different studies found that women with a high intake of marine omega-3s had a 14% lower risk of breast cancer (Zheng, BMJ, 2013). Meanwhile, the data for prostate cancer remains genuinely mixed, with no clear consensus on whether it helps, hurts, or does nothing at all.

3. Depression and anxiety

For major depression, EPA-predominant omega-3 formulations (≥60% EPA of total EPA+DHA) have the strongest evidence of any nutritional supplement for adjunctive treatment — meaning, taken alongside an antidepressant rather than instead of one. A meta-review of 33 meta-analyses concluded that among all nutrient supplements studied for mental health, EPA-dominant omega-3s have the most robust support, particularly when combined with SSRIs (Firth, World Psychiatry, 2019). DHA-predominant or DHA-only formulations consistently fail to show antidepressant effects in trials (Liao, Translational Psychiatry, 2019) — so the ratio genuinely matters. The optimal dose appears to be 1–2 g/day of EPA, with a dose-response meta-analysis suggesting a U-shaped curve peaking around 1.5 g/day and no additional benefit above 2 g/day (Norouziasl, Br J Nutr, 2024). The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends omega-3s as second-line monotherapy for mild-to-moderate depression and as adjunctive therapy for moderate-to-severe depression. Nevertheless, a 2021 Cochrane review rated the overall certainty of evidence of benefit for omega-3s in depression as “very low,” noting that the small pooled effect size may not be clinically meaningful (Appleton, Cochrane, 2021). So my take: real signal, particularly with EPA-dominant formulations alongside an SSRI, but not a replacement for established treatments.

For anxiety, the evidence is more preliminary but growing. A 2024 dose-response meta-analysis of 23 trials found a significant reduction in anxiety symptoms at 2 g/day, though certainty of evidence was rated very low (Bafkar, BMC Psychiatry, 2024). An earlier meta-analysis of 19 trials found anxiolytic effects concentrated in clinical populations rather than subclinical samples (Su, JAMA Network Open, 2018). Treat the anxiety evidence as suggestive rather than established.

4. Cognition

The cognition story requires separating two questions that often get conflated:

• Does having high omega-3 levels in your blood correlate with better brain health?

• Does taking an omega-3 supplement improve cognition?

The answer to the first question is a fairly consistent yes. The answer to the second is: it depends on who you are, and probably not by much if at all.

On the biomarker side, the observational data are reasonably consistent. I On the biomarker side, the observational data are reasonably consistent. In the UK Biobank (440,750 participants), people whose plasma omega-3 was meaningfully above average (one standard deviation higher — roughly the difference between someone in the middle of the distribution and someone in the top sixth) had 10% lower dementia risk (He, GeroScience, 2023). The Three-City Study (1,279 participants, 17 years of follow-up) found a similar 13% lower dementia risk for each comparable step up in plasma EPA+DHA, alongside slower cognitive decline and less medial temporal lobe atrophy on serial MRI (Thomas, Alzheimer’s & Dementia, 2020). The WHIMS-MRI study (n=1,111) found higher Omega-3 Index correlated with greater total brain and hippocampal volume (Pottala, Neurology, 2014). These biomarker findings are harder to dismiss as healthy-user bias because the exposure is an objectively measured blood level, not a self-reported behavior.

Self-reported data are weaker on that front: a 2023 meta-analysis of 48 longitudinal studies (103,651 participants) found ~20% lower dementia risk with higher dietary DHA intake, while long-term omega-3 supplement users in one cohort had a striking 64% lower AD risk (Wei, AJCN, 2023). But both of these findings are exactly the kind of associations where healthy-user bias likely does most of the work (these studies did not control well for other healthy user behavior like the 2021 Harris study did), since people who report eating lots of fish or consistently taking supplements often have other health promoting habits that could lower dementia risk.

Intervention trials are more complicated. In healthy older adults, results are largely null — VITAL-Cog (3,424 participants on 1 g/day for ~2.8 years) found no cognitive benefit (Kang, Alzheimer’s & Dementia, 2022). Trials in established Alzheimer’s have also been null: a Cochrane review of three RCTs found no benefit on cognition (Burckhardt, Cochrane, 2016). The exception is mild cognitive impairment (MCI), where roughly two-thirds of trials report positive cognitive outcomes (Andriambelo, Ageing Res Rev, 2023), and a 2025 dose-response meta-analysis of 58 RCTs found significant improvements in attention, memory, and global cognition per 2 g/day omega-3 (Shahinfar, Sci Rep, 2025).

The discordance between observational and trial data probably comes down to 1. timing (observational studies capture decades of exposure, while RCTs run months to a few years); 2. healthy user bias (observational fish eaters or supplement takers likely have other healthy habits); and 3. effect modifiers (gender, genetics, etc). For example, the relationship may be modified by APOE4 status: evidence suggests E4 carriers may benefit most from DHA supplementation before cognitive decline begins, but less so once Alzheimer’s is established, possibly because E4 carriers show accelerated DHA breakdown that’s compensable early but overwhelmed by advanced disease (Yassine, JAMA Neurology, 2017; Ebright, Trends Endocrinol Metab, 2024). See my prior post on APOE4 here if you don’t know if you are 1 in 4 people who carry that genetic allele.

Caveat potential benefits with this sobering 2026 study: a longitudinal analysis from the Alzheimer’s Disease Neuroimaging Initiative found that omega-3 supplement users showed faster cognitive decline and reduced brain glucose metabolism compared to matched non-users (Liao et al., J Prev Alzheimers Dis, 2026). More on this study in the “Rancid Fish Oil” section below.

My honest take: high blood omega-3 levels are consistently associated with better brain health across dozens of cohorts; supplementation may offer a modest protective effect if started early enough; but swallowing low-quality fish oil capsules is not the same thing as having a high Omega-3 Index — and rancid supplements may actually cause harm in certain populations.

How to check your own omega-3 status

By now, you’ve seen the Omega-3 Index referenced throughout this piece — so let’s actually explain what it is and how you can measure yours.

The Omega-3 Index is the percentage of EPA and DHA actually incorporated in the membranes of your red blood cells (RBCs). RBC membranes are slower-turnover tissue. They are a better reflection of your omega-3 status over the last several months — not what you had for breakfast, and not whether you swallowed fish oil for a couple days before your lab draw.

Harris and von Schacky pulled together data from the Physicians’ Health Study, the Cardiovascular Health Study, the Seattle cardiac arrest study, and several European trials, and drew two cut points of omega-3 index that still guide the field:

• ≥ 8%: “cardioprotective” range — associated with the lowest risk of dying from coronary heart disease.

• ≤ 4%: highest risk — associated with up to roughly a 10-fold higher risk of sudden cardiac death compared to the protective range.

• 4–8%: intermediate zone where most Americans actually live.

Annoyingly, not every “omega-3 blood test” is the same. You want to know the proportion of omega-3s incorporated into your RBC membranes, not just floating in your serum (fluid that surrounds the blood cells).

If going through Quest, the “OmegaCheck” is at least in the right neighborhood — it measures whole-blood EPA + DPA + DHA and correlates strongly with the proportion of omega-3s incorporated into RBCs (though it is NOT the same as the omega-3 index). You can request this lab from your doctor by asking for “OmegaCheck with Test ID 92701” or order it directly yourself here for $79.

If you are below <8% on the OmegaQuant or the combined EPA+DPA+DHA value on OmegaCheck, consider incorporating more fatty fish into your weekly diet and recheck in 6 months. (The Quest reference range says optimal is >5.4%— but based on the above research, I aim for >8%.) Alternatively, you could consider supplementing with fish oil, but please read below if doing so because the fish oil market is fraught with oxidized supplements.

Why rancid fish oil isn’t just gross — it may be actively harmful

A meaningful fraction of fish oil on the market is oxidized before you ever open the bottle.

That’s because fish oil—and especially DHA—is inherently unstable. The same polyunsaturated structure that makes omega-3 fatty acids biologically valuable also makes them highly susceptible to oxidation. When these oils oxidize, they form lipid peroxides and reactive aldehydes—compounds that can impair mitochondrial function and promote oxidative stress. The industry does have voluntary standards (peroxide value, anisidine value, and total oxidation aka ‘TOTOX’), but compliance is inconsistent, and consumers rarely have visibility into product quality.

Independent testing consistently shows that oxidation is not rare:

• A 2015 Canadian analysis reported ~50% of products exceeded voluntary limits.

• GOED’s own 2020 analysis of 48 top-selling U.S. products found that of the 17 products that could be fully evaluated for all quality parameters, nearly half failed at least one oxidation criterion or label claim.

• International surveillance has reported rates exceeding 80% in some markets.

• ConsumerLab (April 2026): 3 of 14 products failed for rancidity. And to be honest, I think ConsumerLab standards here were overly generous where they gave products a “Pass” with a TOTOX level of 26, but I would not recommend a product to friends or family with a TOTOX level over 15– in that case 7 of 14 products would fail. One product they tested reached a TOTOX of 109.9, with others exceeding limits despite being well within shelf life. The longer fish oil sits on the shelf or is exposed to heat, the more likely TOTOX levels creep up.

• ConsumerLab testing (2023 analysis of 72 products) found that 45% of supplements tested positive for rancidity using standard criteria. Using more conservative thresholds that I would recommend (TOTOX < 15 rather than < 26), this number would be MUCH higher. One product from their 2026 testing reached a TOTOX of 109.9—oxidation levels 4x the industry standard—despite being well within its stated shelf life.

Caveat: Larger analyses have found that more than 85% of fish oils on the market meet industry oxidation standards, suggesting the quality problem may be less universal than smaller studies indicate (e.g. De Boer et al., Food Chemistry, 2018). However, this would still leave ~15% of products on shelves that are genuinely super oxidized before use. And industry standards only flag a TOTOX above 26 (very high!) upon opening with oxidation accelerating unpredictably during further storage.

But the more important question is — does rancid fish oil harm you?

Well, the biologist in me says it certainly cannot be good for your health to ingest reactive aldehydes. The human clinical trial data are more mixed, but point to Yes.

A double blind randomized controlled trial, healthy adults were assigned to either fresh or deliberately oxidized fish oil (same labeled dose: 1.6 grams EPA+DHA per day for only 7 weeks) (Rundblad, Br J Nutr., 2017). The results diverged sharply:

• Fresh oil: low-density lipoprotein (LDL aka “bad cholesterol”) decreased by 6%

• Oxidized oil: LDL increased by 19%

Same fatty acids, same dose — opposite physiological effect.

In contrast, another randomized controlled trial (Ottestad et al., Br J Nutr., 2012). measuring different oxidative biomarkers in health adults found no significant differences after 7 weeks of consuming oxidized fish oil. But it’s important to point out that short-term studies in young, healthy individuals are the least likely to detect harm.

The study that is most concerning to me is the 2026 Alzheimer’s study that followed the cognitive trajectory of adults aged 55-90 yo for 5 years.

If your parents are anything like mine, that fish oil was probably low quality Walgreens fish oil sitting on the shelf (not refrigerated) with an expiration date possibly passed. In other words, it’s very possible many of these older study subjects were ingesting oxidized fish oil for years. Because the cognitive decline in the study did not track with traditional Alzheimer’s markers, the researchers hypothesized that the brain results “may be mechanistically linked to oxidative stress and mitochondrial dysfunction…. The resulting peroxidation products [from fish oil] can directly compromise mitochondrial membrane integrity, inhibit oxidative phosphorylation, impair energy metabolism, and paradoxically exacerbate reactive oxygen species production…” (Liao et al., J Prev Alzheimers Dis, 2026). That pattern is compatible with what we might expect from chronic exposure to oxidized lipids in rancid fish oil.

The study itself does not prove that rancid fish oil—or omega-3s themselves—caused the decline. With observational studies, a cautious reader should always query if reverse causation could contribute to findings, e.g. are people at a higher risk of dementia more likely to start fish oil supplements? Maybe.

Or healthy user bias, e.g. are healthy people less likely to supplement with fish oil? Doubt it — healthy user bias would more likely predict cognitive improvements for people deciding to take a fish oil supplement because those types of people tend to engage in other healthy behaviors as well.

In any event, this study should give anyone pause before making general recommendations for random fish oil supplementation over whole food fatty fish in elderly patients.

A word on contamination (the news is mostly good).

As far as heavy metal contamination, the common concern about mercury doesn’t apply here. Mercury binds to protein, not fat, and the purification process used to produce fish oil removes protein effectively. Independent testing has consistently found negligible mercury levels in fish oil supplements (e.g. Foran, Arch Pathol Lab Med., 2003).

Polychlorinated biphenyls (PCBs) and related contaminants are present at trace levels but typically far below regulatory thresholds—and far below what you’d get from eating comparable amounts of fatty fish (e.g. Lee, Internatl Journ Food Sci & Tech, 2016).

How to pick a fish oil supplement and my fav brands

I wrote a post a couple months ago with step by step instructions for vetting quality control and 3rd party testing of any supplement, including fish oil: Here. If your brand is not listed below, feel free to use that post to vet your own brand. Do not rely on SuppCo.

TLDR quick tips:

1. Look for IFOS certification. Go here to see if your brand is listed with the “IFOS” blue oval icon; then look at TOTOX and peroxide levels on the CoA report. I aim for TOTOX under 15 and peroxide < 5 meq/kg.

2. Prefer the triglyceride (TG) form over ethyl ester (EE) where possible. Re-esterified triglyceride preparations raise the Omega-3 Index more reliably than ethyl esters do, at least in head-to-head comparisons (Neubronner, Eur J Clin Nutr, 2011). Most prescription products are ethyl esters; many premium supplements are triglyceride.

3. Don’t obsess over total fish oil milligrams. Read the EPA, DHA and DPA (if listed) numbers specifically. A 1,000 mg fish oil softgel with 180 mg EPA and 120 mg DHA is mostly 700 mg of “other stuff.” For the EPA:DHA ratio— the science is unsettled on this and likely domain dependent (i.e. EPA dominant formulations clearly win for cardiovascular disease, but DHA dominant formulations may improve certain inflammatory markers better). Stay tuned for a follow-up post on the EPA:DHA ratio.

4. Store it right. Keep it cool, keep it dark, keep it sealed. I store all fish oil supplements in the fridge unless I am traveling with them. Never buy fish oil supplements off Amazon, see why here. I purchase directly from the manufacturer or from iHerb.com (no affiliation) because all of their supplements are stored in temperature controlled facilities to avoid rancidity.

With those filters applied, five brands I recommend for fish oil (not vouching for any other supplements from these brands):

1. Carlson: IFOS certified, triglyceride form, consistently low TOTOX and peroxide values, and one of the most reasonably priced high quality fish oils on the market. I alternate between Omega3 D+K and Cod Liver Oil personally. And the liquid form makes it easy for me to give to my older kiddos (occasionally!) as a dietary buffer:

   • Omega3 D+K: high DHA liquid option which can be helpful for those with difficulty swallowing a pill. 1430mg/5ml total omega 3s, 890mg DHA, 360 mg EPA. I also like the K2 added here as most people don’t get enough K2 specifically from diet (as opposed to K1). I alternate a high DHA version because of my personal APOE4 status (see the 2nd half of this article here if you have APOE4).

   • Cod Liver Oil: 1100 mg/ 5ml of total omega 3s, 370 EPA, 500 DHA liquid option. Caution with Vitamin A content in cod oil–this is one NOT to be taken every day as fat soluble vitamins can accumulate!

   • Elite Omega-3: a balanced 2:1 EPA: DHA ratio with 700 mg/capsule of total omega 3s, 400 mg EPA, 200 mg DHA. A recent batch had Peroxide at 1.34 meq/kg and TOTOX at 9.68 (very good levels).

2. Life Extension: IFOS certified, triglyceride form, reasonably priced, good ratios.

   • Super Omega 3

3. Sports Research: IFOS certified, triglyceride form, high potency, liquid forms available, very reasonably priced.

   • Omega-3 Triple Strength, 690 mg EPA, 310 mg DHA. I have my Dad on this one because it’s higher EPA and optimizing for cardiovascular benefits for him.

   • A recent batch had Peroxide at 0.94 meq/kg and TOTOX at 6.86 (very good levels!).

4. Metagenics: IFOS certified, triglyceride form, premium brand (more expensive), higher EPA and DHA ratios.

   • Metagenics is also one of the few companies that provides full a CoA for all supplements. If you like feeling fancy, go with this brand—but honestly the quality is just the same with the above listed brands.

5. Pure Encapsulations: Not IFOS certified, but I have their Omega3 CoA for this product, which consistently shows levels of Peroxide of <5 meq/kg and TOTOX of <10. This brand is more expensive, but I respect that they also provide CoAs for all products. See why here.

Brands I avoid:

• Thorne: not IFOS certified and will not provide their 3rd party testing.

• Nordic Naturals: not IFOS certified and the flavoring interfered with ConsumerLab’s attempted 3rd party testing for their oxidation levels while peroxide levels were above 5. I have a message out to their legal—may revise this note after I hear back with a CoA.

Lastly, don’t waste your money on omega-3 supplements for kids—just use the liquid Carlson or Sports Research version for adults at ½ dose (or even better, get them to eat fish…I’m not keen on giving children fish oil supplements on the regular). And gummy omega-3s have horrible quality control that I would not personally trust.

Wrapping it all up.

Omega-3 fatty acid supplementation is not a one-size-fits-all health recommendation. The strongest signal in the science is this: having high blood levels of marine omega-3s (EPA, DHA, and DPA) is consistently associated with meaningfully lower risk of dying from heart disease, cancer, and all causes combined — and a low Omega-3 Index rivals smoking as a predictor of premature death. For most Americans, who sit in the “high-risk” zone below 8%, that gap is worth closing.

The smartest first step is to measure your own Omega-3 Index — not guess based on how much fish you think you eat — and then prioritize whole food sources like wild salmon, mackerel, sardines, and herring before reaching for a bottle. For healthy adults already eating oily fish several times a week and testing at or above 8%, the evidence does NOT support supplementation — and the risk of consuming oxidized lipids is real enough to argue against it. For those with established cardiovascular disease, or a genuinely low Omega-3 Index, the benefit-to-risk ratio of high-quality supplementation is favorable and supported by multiple lines of converging evidence.

And if you do supplement, the supplement matters: rancid fish oil is not just inert — emerging evidence suggests it may actively harm some people. Choose brands based on my guidelines above.

This article is intended for general education and is not medical advice. If you take blood thinners, have a bleeding disorder, are pregnant, or are planning surgery, always talk to your doctor before starting or continuing on an omega-3 supplement as they can have blood thinning effects.

Stay tuned and subscribe for upcoming articles, including:

• I Read Every Collagen Study So You Don’t Have To

• Sleep Meds and Supplements: the Good, the Bad, and the Useless

• Progesterone, HRT, and cancer risk — what’s real and what’s hype

Please feel free to share with friends and check out some prior articles if you’re new to Data Dosing:

• Could a cheap, generic drug improve cancer outcomes in over a dozen tumor types?

• Two Simple Blood Tests That Could Rewrite Your Health Plan

• DIY Supplement Vetting: A Guide to Quality Check any Brand

• Is Your Creatine Safe? A Deep Dive into Common Contaminants, How to Buy Safely, and Myths

• Does melatonin cause heart attacks?

• Two simple nasal sprays could keep Covid away

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Naltrexone is an FDA-approved drug used at 50 mg daily to treat opioid and alcohol addiction (It is an opioid antagonist, not an agonist — so it carries no abuse potential). It has been on the market since 1984 and has decades of safety data. It costs pennies a day.

At much lower doses — typically 1.5 to 4.5 mg taken once daily — naltrexone appears to do something entirely outside the addiction arena. A growing body of research suggests this “low-dose naltrexone” (LDN) may slow cancer growth, enhance the effectiveness of chemotherapy, and help manage cancer-related pain. When my mom was diagnosed with a treatment resistant lymphoma 2 years ago, one of the first things I advocated for was LDN in conjunction with the standard of care treatment. (She is doing well btw!)

This article walks through what the published, peer-reviewed research actually shows. I’ll cover the cancers where LDN has shown benefit, the evidence for its safety, how it might work mechanistically, and — critically — why getting the dose wrong could produce the opposite of the intended effect. I’ll also provide a practical script you can bring to your doctor if you want to discuss trying LDN.

(Image: Ciwun, 2024)

This is not medical advice. Nothing in this article should replace a conversation with your medical team.

The Evidence: Cancers Where LDN Has Shown Benefit — and Why It’s Safe Even When Benefit Is Unclear

The key takeaway from the entire LDN-cancer literature is this: we have varying degrees of evidence — from cell lines to animal models to case reports to small clinical trials — showing promising anti-cancer benefits across a remarkably wide range of cancer types. Even in the studies where a clear anti-cancer benefit was not demonstrated, LDN was consistently safe, free of serious adverse events, and well tolerated.

Before diving in, it’s worth addressing the elephant in the room: why, if the preclinical evidence is this broad, don’t we have large definitive clinical trials? The answer is largely structural. Naltrexone is off-patent and available as a generic. LDN must be compounded by a pharmacy because there is no FDA-approved 1.5–4.5 mg product. Large clinical trials require industry backing, and there is no patent-protected product to recoup the cost of a large randomized controlled trial. This is not unique to LDN — it’s a well-known structural problem in drug development affecting many potentially useful repurposed generics (e.g. lidocaine for breast cancer).

With that context, here is what the research shows.

In Vitro (Cell Culture) Studies — A Broad Range of Cancer Types

Numerous in vitro studies have shown intermittent LDN reduces cancer cell numbers across a remarkable range of cancer types: ovarian, colorectal, pancreatic, breast, lung, prostate, glioblastoma, neuroblastoma, melanoma, hepatic, esophageal, gastric, renal, leukemia, myeloma, sarcoma and head and neck squamous cell carcinoma, among others (see systemic review here Liubchenko et al., 2021).

A note on dosing translation: in vitro concentrations don’t translate directly to human doses, but the human LDN dose of 1.5 to 4.5 mg produces transient blood levels in a comparable low-nanomolar range used in these in vitro studies. The key point is that these effects were seen at low concentrations of naltrexone, not at the standard therapeutic concentrations used for addiction treatment. (See the mechanism of action section below to understand why low doses have a seemingly opposite effect to regular doses.)

Animal Studies

Animal studies have consistently shown strong controlled evidence for LDN’s anti-cancer effects, and they have been instrumental in establishing the critical importance of dosing schedule.

Neuroblastoma: Mice injected with neuroblastoma cells and receiving LDN once daily (blocking receptors for ~4–6 hours) had only a 20% tumor incidence versus 100% cancer incidence in controls, with a 10–24% increase in survival time (Zagon & McLaughlin, 1984).

Colon cancer: Mice with human HT-29 colon cancer receiving LDN daily showed a 2.4-fold delay in tumor appearance, with 80% of treated mice tumor-free at the point when 100% of controls had tumors (Hytrek et al., 1996).

Ovarian cancer: LDN markedly reduced the number and weight of tumor nodules in mice transplanted with human SKOV-3 ovarian cancer cells, with the mechanism directed at inhibiting proliferation and angiogenesis, and the combination of LDN with cisplatin producing additive anti-tumor effects (Zagon, Donahue & McLaughlin, 2013).

Head and neck squamous cell carcinoma: LDN increased the latency from visible to measurable tumors up to 1.6-fold, and markedly reduced tumor volume, weight, and DNA synthesis in mice bearing human squamous cell carcinoma tumors (McLaughlin, Stucki & Zagon, 2012).

Colorectal cancer: LDN given every 2 days significantly reduced both tumor volume and tumor weight in mice bearing human colorectal cancer xenografts after 19 days of treatment, with no obvious toxicities or side effects (Ma et al., 2020).

Cervical cancer: LDN significantly inhibited tumor growth in nude mice bearing human cervical cancer xenografts, showing significant tumor growth inhibition and tumor weight reduced compared to controls (Liu et al., 2021).

Ehrlich solid carcinoma: LDN reduced tumor weight and volume in mice, and the combination of LDN with 5-fluorouracil produced significantly greater tumor reduction than either agent alone (Aboalsoud et al., 2020).

Human Case Reports — Dramatic but Anecdotal

Published case reports describe striking outcomes in patients with advanced cancer who used LDN, though none of these can establish causation on their own.

Pancreatic cancer: Berkson et al. reported multiple patients with stage IV pancreatic adenocarcinoma and liver metastases treated with LDN at 4.5 mg once daily combined with intravenous alpha-lipoic acid. One patient was alive 78 months after diagnosis — a disease with a typical prognosis of 3 to 6 months. Two additional patients achieved PET-confirmed radiological remission. After stopping the protocol, one of these patients relapsed within a month (Berkson et al., 2006; Berkson et al., 2009).

B-cell lymphoma: A 61-year-old man with biopsy-proven follicular lymphoma, stage III, refused conventional chemotherapy (I am not recommending this!) and was treated with LDN 3 mg daily only. Within 6 months, all pathological lymph nodes — including baseball-sized nodes in the cervical region and left groin — showed complete resolution on PET/CT imaging. The patient reported remaining symptom-free one year after his last imaging (Berkson et al., 2007).

Tongue cancer (adenoid cystic carcinoma): A 58-year-old man with T4N0M0 adenoid cystic carcinoma of the tongue base who refused the recommended surgical removal was treated with LDN at 3 to 4 mg daily plus vitamin D3 at 10,000 IU daily. He achieved long-term remission (Khan, 2014).

Lung cancer: A 50-year-old male with non-small cell lung cancer and a history of prostate cancer experienced prolonged survival while using LDN among other medications (Miskoff & Chaudhri, 2018).

Renal cell carcinoma: A 64-year-old with stage IV renal cell carcinoma had stable disease with disappearance of signs and symptoms for 9 years following an integrative approach that included LDN at 4.5 mg at bedtime combined with IV alpha-lipoic acid (Berkson, 2018).

Prostate cancer: Dalgleish and Liu reported a case series of 6 prostate cancer patients managed with immune modulation including LDN as part of a multi-agent approach (Dalgleish & Liu, 2022).

Human Clinical Trials

There are no large placebo-controlled randomized controlled trials (RCT) of true low-dose naltrexone (1.5–5 mg) for cancer outcomes in any cancer type, likely owing to the structural problems around generic drug development discussed above.

The only placebo-controlled, double-blind RCT is a Duke University glioma trial (Peters et al., 2022) which looked at the effect of LDN on quality of life (QoL) and fatigue during concurrent chemotherapy and radiation, not cancer outcomes. While it found no statistically significant difference in QoL or fatigue between LDN and placebo groups, the researchers noted that LDN may have allowed a meaningful “clinical” difference in fatigue post concurrent radiation therapy and chemotherapy. The study was not designed or powered to evaluate cancer survival as an endpoint, but noted that the LDN median survival was 20.9 months vs placebo 18.1 months (difference not statistically significant). Crucially, the adverse event profiles were indistinguishable between LDN and placebo, and the two grade 5 (fatal) adverse events in the trial both occurred in the placebo arm—demonstrating a remarkable safety profile of LDN.

Two smaller human studies — the 2025 MD Anderson cancer pain case series (20 cancer patients, LDN 1.5–4.5 mg) and the 2014 metabolic treatment case series (10 patients with chemo-resistant metastatic cancers, LDN 4.5–5 mg at bedtime) — both also confirmed that LDN was safe and well tolerated, with no serious adverse events attributable to LDN. The MD Anderson series found an 80% positive response rate for cancer pain at first follow-up, with particular benefit in patients with neuropathic pain.

In the metabolic treatment case series, ten patients with chemoresistant advanced metastatic cancer and life expectancy of 2-6 months were treated with a combination of lipoic acid, hydroxycitrate, and LDN (5 mg). Most patients achieved disease stabilization or slowed progression, though two patients died of progressive disease within two months. The authors noted that the results suggest the probable efficacy of metabolic treatment in chemoresistant advanced carcinoma and/or enhancement of chemotherapy efficacy. Caveat: This case series involved a combination of metabolic treatments, so the effects cannot be attributed solely to LDN.

A Phase I study is also underway evaluating naltrexone plus propranolol in combination with standard immunotherapy in patients with advanced melanoma (ClinicalTrials.gov: NCT05968690).

Outside of cancer, LDN has separately exhibited potential use in human trials or case studies for other diseases that have a component of immune dysregulation and/or inflammation, e.g. multiple sclerosis, Crohn’s disease, fibromyalgia, HIV, autoimmune thyroid disease, hyperinsulinemia-related insulin resistance, Sjogren’s syndrome, psoriasis, Stiff-Person syndrome, and Long Covid.

Safety: The Consistent Finding Across ALL Studies

Across every study — whether LDN showed anti-cancer benefit or not — it was safe and well tolerated at 1.5 to 4.5 mg doses. LDN is non-addictive — it is an opioid antagonist, not an agonist — so it carries no abuse potential.

Side effects reported across clinical trials in cancer and non-cancer conditions are consistently mild and transient: vivid dreams (not usually reported as unpleasant), transient headache, and brief insomnia during the first few days after initiation.

There is a breast cancer phase II trial worth noting here as well, though it used standard-dose naltrexone (escalated from 10 to 25 to 50 mg daily), not low dose naltrexone. Even at this much higher dose, naltrexone had an excellent safety profile. The study showed only modest anti-cancer activity — one partial response out of eight evaluable patients. The limited efficacy at standard dose is consistent with the broader literature's emphasis that brief, intermittent receptor blockade — not continuous high-dose blockade — is what drives anti-cancer effects (see more on “How LDN works” below).

The Cancer Pain Angle: A Practical Entry Point

If you are a cancer patient interested in trying LDN, the most practical way to start the conversation with your oncologist may not be to lead with “I want to try an anti-cancer drug”, but rather to frame it as a pain or fatigue management discussion.

LDN is already used off-label for a range of chronic non-cancer pain conditions, including fibromyalgia, complex regional pain syndrome (CRPS), and neuropathic pain, with published evidence supporting its use in these settings.

A Script for Your Doctor

If you’d like to raise LDN with your doctor, here is a template you can adapt and send to your doctor before your appointment. When advocating for yourself, it’s always best to first send requests in writing and then follow up with discussion at your appointment.

“Dear Dr. [Name],

I’d like to discuss trying low-dose naltrexone (LDN) as an addition to my current treatment plan. I’ve been reading published peer-reviewed research on this and wanted to share a few points:

LDN refers to naltrexone at doses of 1.5 to 4.5 mg taken once daily — much lower than the standard 50 mg dose used for addiction. At this low dose, naltrexone has a mechanism that is fundamentally different from, and in some respects opposite to, the continuous receptor blockade produced by the standard dose.

A 2025 case series from MD Anderson Cancer Center (Malik et al., Journal of Pain and Symptom Management) found that LDN was safe and showed an 80% positive response rate for refractory cancer-related pain, with only minor side effects.

A 2022 placebo-controlled, double-blind, randomized trial in 110 high-grade glioma patients at Duke (Peters et al., Supportive Care in Cancer) found that LDN’s adverse event profile was indistinguishable from placebo over 16 weeks. No serious adverse events were attributed to LDN.

Multiple review papers — including Ciwun et al. (Cancers, 2024), Liu & Dalgleish (Expert Review of Anticancer Therapy, 2022), and Liubchenko et al. (Advances in Therapy, 2021) — summarize robust preclinical evidence for anti-cancer properties of LDN as well in a wide range of cancers (e.g. ovarian, colon, breast, lung, prostate, glioblastoma, neuroblastoma, melanoma, liver, gastric, lymphoma, leukemia, renal, sarcoma, thyroid), though clinical trial data remains limited. There are also several published case reports (see Berkson, 2007-2010) of notable outcomes in patients with advanced cancer using LDN. I understand these are anecdotal case reports, not controlled trials, but they are published in peer-reviewed journals and consistent with the preclinical evidence.

I also understand this is off-label and that the evidence for anti-cancer effects is still preliminary. I’m primarily interested in it for [pain management / as a low-risk adjunct / quality of life]. Given its favorable safety profile and low cost, would you be open to a trial of LDN starting at 1.5 mg nightly?

I’m not currently on any opioid pain medications [OR: I understand the timing would need to be coordinated with my current pain medications].

I’m happy to share the published papers with you if that would be helpful.”

I am aware that LDN can also be easily obtained from Telehealth providers that use compounding pharmacies (e.g. Midi, AgelessRx); but please see Cautions below and never add a medication from another healthcare provider without also informing your Primary Care Provider and/or Oncologist.

How LDN Works: From Cellular Growth Inhibition to Opioid Protection

LDN’s anti-cancer mechanism centers on a counterintuitive trick of timing. When taken once daily at 1.5 to 4.5 mg, naltrexone blocks opioid growth factor receptors (OGFr) for only about 4 to 6 hours. The body responds to this brief blockade by overproducing both opioid growth factor (OGF, a naturally occurring peptide also known as met-enkephalin) and OGFr as a compensatory rebound effect. When LDN wears off, the increased OGF binds to the increased OGFr and acts as a brake on cell division. Beyond this direct growth-inhibitory effect, LDN also reshapes the immune environment — enhancing Natural Killer (NK) cell activity, shifting macrophages from the tumor-promoting M2 type to the anti-tumor M1 type, blocking Toll-like receptors to reduce inflammation, and priming cancer cells to become more sensitive to chemotherapy drugs like oxaliplatin, gemcitabine, and cisplatin (Liu et al., 2016; Ma et al., 2020; Liu & Dalgleish, 2022).

(Image: Qu, 2021)

Critically, this mechanism may also provide a “shield” against the potential pro-cancer effects of conventional opioid therapy. Emerging research suggests that mu-opioid receptor (MOR) agonists like morphine (painkiller) can inadvertently fuel cancer progression by stimulating tumor cell proliferation, promoting angiogenesis (the growth of new blood vessels to feed the tumor), and suppressing the activity of NK cells. Because many tumors—including breast, lung, and pancreatic cancers—overexpress the mu-opioid receptor, the use of standard opioids for pain management has become a point of concern for some researchers.** By serving as a non-addictive, non-opioid adjunct for pain, LDN may allow patients to significantly reduce their reliance on conventional narcotics. In doing so, it potentially offers a secondary cancer benefit by sparing the body from the immunosuppressive and mitogenic (growth promoting) “side effects” of chronic opioid use.

**Major oncology and pain societies (e.g., American Society of Clinical Oncology, ASCO) still recommend opioids as first-line therapy for moderate-to-severe cancer pain. No randomized controlled trials have demonstrated that standard opioid use worsens cancer outcomes; but importantly, no randomized human trials have directly evaluated long-term opioid use versus no opioid use on cancer progression or survival.

Caveats, Disclaimers, and Cautions

LDN Is Not a Replacement for Standard Cancer Treatment

Every review paper in the literature emphasizes LDN as a potential adjuvant — something added alongside standard care, not a substitute for surgery, chemotherapy, radiation, or immunotherapy. No regulatory body anywhere in the world has approved LDN for cancer treatment and you should not take preclinical evidence or case reports to advocate for LDN replacing whatever standard of care treatment your oncologist recommends.

Low Dosing May Be Critical and Higher Dosing Could Be Harmful (in the Cancer Context)

Critically, the anti-cancer benefits from LDN seem to depend on the dosing being low enough so that the Opioid Growth Factor receptor (the target of LDN) is only blocked intermittently. True low dose naltrexone (1–5 mg) typically blocks opioid receptors for only 4–6 hours, triggering a beneficial “rebound effect” of increased endogenous opioids and receptors that can inhibit tumor cell replication.

On the other hand, continuous blocking of these receptors can flip the biological switch, potentially facilitating cancer progression. The foundational 1984 Zagon and McLaughlin study showed that when 0.1 mg/kg of naltrexone was given once daily (4–6 hours of receptor blockade, human equivalent dosage <1mg), only 20% of mice injected with neuroblastoma cells developed tumors — compared to 100% of untreated mice. But when given four times daily (creating 24 hours of continuous blockade), 100% of the treated mice developed tumors and survival decreased. This has been confirmed at the molecular level: Liu et al. (2016) showed that low-dose and standard-dose naltrexone activate completely different gene expression profiles, with genes that promote programmed cancer cell death (BAD and BIK) switched on only at low doses of naltrexone. A 2021 bladder cancer study further demonstrated that continuous naltrexone exposure actually promoted cancer cell proliferation and migration. This dose-direction principle also likely explains why the only human breast cancer naltrexone trial — which used standard-dose 50 mg daily, producing continuous blockade — showed only modest results and the drug was ultimately discontinued because of tumor progression in all cases.

The bottom line: the same drug can either fight cancer or potentially promote it, depending entirely on whether the receptor blockade is brief and intermittent or continuous.

A note on holistic and functional medicine practitioners: While the functional medicine community has correctly identified LDN as a versatile tool for conditions like fibromyalgia, multiple sclerosis, and Long Covid, there is a troubling trend toward “more is better” dosing. Especially on social media, some practitioners encourage patients to escalate doses to 10 mg/day and higher, multiple times a day, often for periods spanning many years. This is a dangerous misunderstanding of naltrexone’s pharmacology. While numerous human studies have found that doses up to 5 mg were remarkably safe, there is a total lack of long-term human safety data for long term use of higher doses with respect to cancer risk. Until large-scale trials prove otherwise, touting 10mg+ as having the same “remarkably safe” profile as 1-5mg is scientifically irresponsible. (To my knowledge, no one has specifically studied whether patients on >25 mg naltrexone long-term— aka >1 year —have higher cancer rates compared to patients not on naltrexone or an opioid agonist.)

Drug Interactions and Practical Considerations

LDN must not be taken with opioid pain medications without careful timing and coordination — it will block their analgesic (painkilling) effects. Also, naltrexone inhibits the cytochrome P450 enzymes CYP1A2, CYP2C9, CYP2D6, and CYP3A4 when metabolized, creating potential for drug interactions that should be reviewed with your physician.

Compounding Pharmacies

LDN must be compounded, meaning even if the prescription comes from Stanford Hospital (commonly used in their Long Covid clinic) or another reputable medical institution, it still needs to go through a compounding pharmacy. Compounded medications bypass the standard FDA review process, which carries a higher risk of potency errors and contamination—especially with injectables where sterility is non-negotiable (e.g. peptides can be high risk—more on this in a later post!).

So, when a provider prescribes a compounded medication, you should verify that the pharmacy is PCAB-accredited (Pharmacy Compounding Accreditation Board), which serves as the gold standard for safety and quality in the industry, and ensure the facility is a 503A or 503B pharmacy (503B look up here). Any provider using a compounding pharmacy should also be able to answer these questions regarding the pharmacy they use. Paid Subscribers can also direct message me a Compounding Pharmacy in question and I can help with feedback on their 503 status. Stanford Hospital uses Apothecary compounding pharmacy FYI.

In Summary

The robust preclinical data and striking case reports of LDN in cancer provide a compelling rationale for its use as a safe, affordable adjunct to standard care. The research community recognizes both the potential and the limitations of LDN. As the Ciwun et al. 2024 review concluded: “The current state of knowledge regarding the use of LDN in cancer treatment indicates that this drug has high therapeutic potential, particularly as an adjuvant for both traditional chemotherapy and new treatment methods, such as immunotherapy. The multifaceted action of LDN, leading to the inhibition of cancer progression, represents a new perspective in the therapy of oncological diseases.”

If you are a cancer patient interested in LDN, the cancer pain angle — per the 2025 MD Anderson study — may be the most practical conversation-starter with your oncologist. When navigating my mom’s care, I realized that most doctors had no idea that naltrexone at low doses has a completely different mechanism of action from the regular dose “addiction protocol” naltrexone. So, use the script above and bring the research citations.

Lastly, I wouldn’t be a good lawyer if I did not start and end with … this article is for informational purposes only and does not constitute medical advice. Always consult with your oncologist or medical team before making changes to your treatment plan. :)

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There are two highly prevalent, genetically determined risk factors that every human should test for: Lipoprotein(a) and APOE4. If you have them, your standard medical advice may be outdated. But more importantly, if you know you have them, there are highly specific, actionable steps you can take today to protect your heart and your brain.

Below, I’ll walk you through:

• What it means if you have elevated lp(a) (Part 1) or an APOE4 allele (Part 2);

• Which interventions have evidence based support and which interventions look promising, but still need more research before they are widely recommended; and

• How to ask your doctor to order relevant tests (or how to order yourself) along with scripts ready to cut and paste at the end of this article.

My lawyer hat: This is a research review, not medical advice! :)

Part 1: Lipoprotein(a) — The Stealth Heart Disease Driver

What it is and why it matters.

Lp(a) is an LDL-like particle that carries cholesterol and other lipids in the blood. Unlike LDL-C (typical measure of cholesterol), lp(a) is bound to an additional protein called apolipoprotein(a) which gives it biological properties that make it particularly dangerous; it not only deposits cholesterol in artery walls but also carries highly inflammatory oxidized phospholipids and interferes with normal clot breakdown, making it a uniquely potent driver of atherosclerosis and thrombosis. European and U.S. lipid groups now recommend measuring lp(a) at least once in adulthood, because a high value can materially change how proactively you and your doctor should manage the rest of your cholesterol.

A quick terminology overview:

• Total Cholesterol: Aggregate of all cholesterol, good and bad, in your body–not a precise measure of cardiovascular risk.

• LDL-C (most common lab doctors order): the total mass (ie amount) of cholesterol carried within LDL particles, which does not necessarily reflect how many atherogenic particles are circulating.

• ApoB: a direct measure of the number of atherogenic lipoprotein particles (each particle contains one ApoB), making it one of the most accurate markers of cardiovascular risk–more accurate than LDL-C.

• lp(a): the genetically determined LDL-like particle discussed above.

• HDL: a lipoprotein involved in reverse cholesterol transport (which is generally good), though higher levels do not always translate to lower cardiovascular risk.

• Triglycerides: a type of fat carried in lipoproteins (especially very-low-density lipoproteins) that often reflects metabolic health and insulin resistance, with elevated levels associated with increased cardiovascular risk.

Unfortunately, diet and exercise barely move Lp(a) numbers. Therefore, the action item when you have elevated lp(a) is to more aggressively reduce ApoB (and hence, LDL-C) and triglycerides, if elevated.

Interventions

While major groups (American College of Cardiology, American Heart Association, National Lipid Association) do not define unique LDL-C or ApoB targets specifically for Lp(a) carriers, they recommend that elevated lipoprotein(a) should prompt earlier or more intensive cholesterol lowering to reduce overall atherosclerotic cardiovascular disease risk. The National LIpid Association specifically recommends ApoB thresholds below 70 ng/dl for “high risk” individuals. Therefore, targeting ApoB below <70 mg/dl (rather than the normal reference range of <90-130 mg/dl depending on the lab) is a reasonable goal to discuss with your doctor.

In addition, current guidelines recommend early, intensive management of the other cardiovascular risks you can modify — not just ApoB-related burden, but also blood pressure, diabetes, and overall vascular risk. A high Lp(a) result also makes family screening more sensible, because the trait clusters in families and cascade testing can uncover relatives who are flying blind.

How to lower ApoB when you have elevated lp(a)

While lp(a) is fairly impermeable to diet and exercise, ApoB (and LDL-C) are indeed modifiable by diet (low saturated fat, high fiber!). I’m not going to lie though—lowering ApoB to less than 70 ng/dl may not be possible with diet and exercise alone.

The most common cholesterol medications (statins, ezetimibe, and bempedoic acid) do not lower lp(a); but they do mitigate cardiovascular risk from lp(a) by significantly lowering other atherogenic particles (ie ApoB). Always aim for the lowest effective dose with a medication. Statins have many benefits and save lives; but they can also increase insulin resistance at higher doses (more common in women than men) and are neutral or may even nudge lp(a) upward slightly. Therefore, asking your doctor if combining a lower dose statin with ezetimibe rather than immediately escalating statin dose is a valid question.

PCSK9 inhibitors (e.g. evolocumab/Repatha or alirocumab/Praluent or inclisiran/Leqvio) are another great option for lowering ApoB and lp(a) for those without cost constraints (difficult to get insurance coverage for these classes of newer medications). FYI, if you are intolerant to statins (e.g. try two different statins and develop muscle pain), insurance may then cover Repatha.

There are also Lp(a)-targeted siRNA drugs currently in clinical trials (e.g. Pelacarsen, olpasiran, lepodisiran) which have shown very large Lp(a) reductions in phase 2 testing, with phase 3 development underway. The important caveat is we still need data on whether lowering Lp(a) itself (independent of LDL-C impact) reduces heart attacks, strokes, or valve disease enough to justify widespread use.

How to lower triglycerides

Triglycerides are very susceptible to dietary intervention. Lowering carbohydrate intake—especially refined carbs and sugar—is one of the most effective ways to reduce triglycerides, often lowering levels by 20–50% in controlled studies. If needed after dietary interventions have failed, fibrates are a class of medication that reliably lowers triglycerides. Levels below 150 mg/dL are generally recommended (some clinicians consider <100mg/dl optimal). Discuss with your doctor.

A word on Vitamin B3 (aka Niacin)

I also often get asked about Vitamin B3 (aka niacin) effects on cholesterol. Yes, niacin lowers Lp(a), and the best pooled RCT data suggest the reduction can be substantial. But niacin is a classic example of a therapy that can improve a biomarker without proving it improves the outcome that matters— i.e. cardiovascular disease. Large trials failed to show clinical benefit from Vitamin B3, and the 2024 National Lipid Association update explicitly says it is not recommended to reduce atherosclerotic cardiovascular risk through Lp(a) lowering. That does not mean B3 is biochemically inert. It means “the lab moved” is not the same as “people did better.”

Part 2: APOE4 — The Alzheimer’s Accelerator

What it is and why it matters.

About 1 in 4 people carry at least one copy of the APOE4 variant — the single strongest genetic risk factor for late-onset Alzheimer’s disease. It disrupts how your brain clears amyloid-beta, how it transports fats and cholesterol, and how its immune cells (microglia) behave. It also makes your blood-brain barrier naturally leakier, which matters for almost everything below.

However, it’s important to note that many APOE4 carriers never develop Alzheimer’s, and many Alzheimer’s patients don’t carry APOE4. Genetics loads the gun; lifestyle can pull the trigger with this variant.

If you are an APOE4 carrier, research shows the same average lifestyle is simply less forgiving than it is for non-carriers. But there is strong data to show that the right interventions can dramatically reduce your risk.

APOE4 Interventions

The 2024 Lancet Commission concluded that nearly half of all dementias could theoretically be prevented through modifiable risk factors. For APOE4 carriers, those levers work harder — in both directions.

🩺 The Big Three (Highest Impact)

1. Control Your Blood Pressure — Aggressively. A 26-year longitudinal study found that treating high blood pressure in APOE4 carriers reduced their relative risk for cognitive decline from 13x down to 1.9x — an 85% risk reduction. This is probably the single most impactful thing you can do. High blood pressure damages the blood-brain barrier (BBB), which is already naturally more permeable (”leaky”) in APOE4 carriers. Maintaining a lower BP helps preserve this critical defensive barrier. Aim for BP at or below 120/80 mmHg.

2. Control Your Cholesterol — Earlier Than You Think. APOE4 carriers tend to run higher LDL-C, higher ApoB, and a more atherogenic lipid profile. A 2025 Mendelian randomization study of over 1 million people found that lifelong genetic lowering of non-HDL cholesterol was associated with roughly a 70–80% reduction in dementia risk. The key word is lifelong — this isn’t a “fix it at 60” situation. Emerging therapeutic data further strengthen the link between cholesterol and Alzheimer’s pathology in APOE4 carriers: the cholesterol drug obicetrapib (a CETP inhibitor not yet approved in the USA) not only lowers LDL-C, but in a phase 3 substudy, it significantly attenuated progression of Alzheimer’s biomarkers, including p-tau217, with the largest effects seen in APOE4 carriers. Another 2024 study found that Ezetimibe use was associated with over sevenfold lower risk of Alzheimer’s and related dementias. Interestingly, the researchers hypothesized this was unique to Ezetimibe’s mechanism of action (blocking sticky protein interactions in the brain), not solely due to cholesterol lowering. In any event, if you have an APOE4 allele, you should talk to your doctor about your lipid targets now.

3. Exercise. Seriously, Exercise. Beyond the usual cardiovascular benefits, aerobic exercise increases circulating Klotho, a protein associated with reduced cognitive decline, by up to 30%. And Klotho may have unique protective effects for APOE4 carriers. A JAMA Neuro study found that APOE4 carriers with a separate genetic variant that naturally increases Klotho (KL-VS) have a 25-35% reduction in Alzheimer’s risk; but this Klotho variant did not appear to reduce Alzheimer’s risk in non-carriers. Therefore, exercise (and the associated increases in Klotho) may be an even more potent dementia mitigator for the APOE4 population.

🥗 Diet

Go Mediterranean. A 2025 Nature Medicine study found that APOE4 homozygotes (two copies) who followed a Mediterranean diet lowered their dementia risk by 35%. Non-carriers? Only 5%. The diet appears to work harder for carriers.

Omega-3s. Eat more fatty fish! Some researchers hypothesize that APOE4 carriers may have more difficult shuttling DHA into the brain. That said, the brain’s dedicated DHA transporter (Mfsd2a) preferentially shuttles DHA in phospholipid form, not the free DHA found in most standard fish oil supplements. This is why fatty fish, krill, or phospholipid-bound DHA formulations are worth prioritizing. Also see below on Omega3 supplementation.

Consider Eating More Unprocessed Meat. This one surprised me. A 15-year cohort JAMA study published this month found that higher meat consumption was associated with slower cognitive decline and lower dementia risk — but only in APOE4 carriers. At the highest intake levels, APOE4 carriers no longer declined faster than non-carriers, which is a meaningful finding. The mechanism isn’t fully clear, but the authors speculate APOE4 carriers may extract B12, taurine, and creatine more efficiently from meat. Important caveat: this was based on food frequency questionnaires. And the benefit appeared to be driven by unprocessed meat — processed meat was associated with worse outcomes across all genotypes.

🧪 Monitor Metabolism Early

Watch Insulin — Not Just Glucose. APOE4 isn’t a major diabetes risk factor on its own, but insulin resistance independently increases Alzheimer’s risk — and metabolic dysfunction can develop years before your fasting glucose or Hba1c (most common glucose lab ordered by doctors) rises. Ask your doctor to check a fasting insulin level. The goal isn’t just staying under the diabetes cutoff; it’s keeping your HbA1c in the low-normal range, ideally well below 5.6%.

🔥 Tame Inflammation

The Framingham Heart Study found that APOE4 carriers with chronic inflammation faced a 6.63x higher risk of Alzheimer’s compared to APOE4 carriers without inflammation. Get a high-sensitivity CRP test (hsCRP) and aim for under 1.0 mg/L.

Manage Stress. Psychological stress directly increases neuroinflammation. This isn’t soft advice — it’s one of the most mechanistically direct levers you have on brain immune function. And if you carry APOE4, the stakes are measurably higher. Multiple human studies have found that the cortisol-cognition relationship is steeper in E4 carriers — the same level of chronic stress produces more cognitive damage.

Sleep. Sleep is one of the most potent anti-inflammatory interventions available to APOE4 carriers. Poor sleep drives up CRP, IL-6, and TNF-α, the same inflammatory markers that appear to accelerate amyloid accumulation in genetically susceptible brains. Sleep is also when the brain’s glymphatic system is most active, physically clearing metabolic waste — including amyloid-beta — through a process that relies on slow-wave sleep in particular. APOE4 carriers already have impaired glymphatic clearance at baseline; chronic sleep deprivation compounds that deficit directly. (Follow-up post coming on the myriad sleep medications and supplements available and which are safe vs harmful for your brain.)

Omega-3s (1–2g/day). DHA supports neuronal membrane integrity and reduces inflammatory signaling. There is robust data to support these anti-inflammatory systemic benefits. For cognition, the overall RCT evidence for omega-3 supplementation is inconsistent —likely due to different study groups (collapsing APOE4 carriers and noncarriers), stages of dementia, and form of omega3. A 2024 randomized trial in JAMA followed older adults with white matter lesions and suboptimal omega-3 levels for three years. APOE4 carriers who received omega-3 had a dramatic reduction in neuronal integrity breakdown, with the effect appearing within the first year of treatment; there was no benefit in the overall group. Other trials in people with mild cognitive impairment have shown meaningful benefits, while trials in established Alzheimer’s dementia have been largely negative — consistent with the hypothesis that timing matters enormously. APOE4 may also accelerate DHA turnover with one study showing carriers have a 77% shorter whole-body DHA half-life compared to non-carriers, meaning you’re burning through it faster. I am paying close attention to Lysoveta as well, an LPC-bound DHA designed to use the brain’s dedicated MFSD2A transporter which may allow greater DHA transport into APOE4 brains. (As of this post, the dosage is too low and price to high for it to be a practical recommendation imo.) Anywho, as an APOE4 carrier myself, I aim for somewhat higher levels of Omega-3s. Carlson’s is my favorite high DHA fish oil (3rd party testing vetted here). I can also give a half spoonful to my kids a couple times/week when I struggle to get those salmon dinners down. 😊 (FYI, I have a dedicated omega 3 post coming soon because fish oil supplements have notoriously horrible quality control.)

B Vitamins. Folate (B9), B12, and B6 lower homocysteine, a metabolite linked to dementia risk and brain atrophy. Benefits appear strongest if your homocysteine is actually elevated. The benefit also may be contingent on Omega-3 status: one study found the protective effect on brain atrophy was entirely concentrated in those with higher baseline EPA and DHA. The proposed mechanism: B vitamins are required for the synthesis of phospholipids that carry DHA into the brain. Without enough DHA to work with, the B vitamins have less to do. Caution: Most B-complex supplements contain absurdly high (and potentially toxic) levels of B6 and B12. I prefer Sports Research B-Complex for reasonable dosing and solid third-party testing. Or just use a sensible multivitamin. Naturelo has good RDA-level nutrients and quality third party testing. See my prior post here on how to quality check other supplements.

Lithium Orotate (1–5 mg), Worth Considering in Older Age. Animal models show lithium reduces microglial activation, lowers pro-inflammatory cytokines, and slows tau and amyloid accumulation. Small human studies with low-dose lithium carbonate have shown hints of cognitive stabilization. This is not settled science — no RCTs on orotate specifically; but the safety profile at low dosage of the OROTATE form is reassuring. I think it’s a reasonable consideration for APOE4 carriers as they age, when amyloid pathology tends to accelerate. Note that lithium orotate more readily crosses the BBB at lower doses, avoiding serious safety concerns that come with higher dosing needed for lithium carbonate. Discuss with your doctor and always let them know if you are adding even OTC supplements like lithium orotate. Also see from JAMA this month: “Lithium for Alzheimer Disease—Pilot Study Sets the Stage for Larger Trials.”

Low-Dose Naltrexone (LDN, 1–4.5 mg). LDN reduces microglial activation and inflammatory cytokines in animal and human inflammatory disease models. Direct evidence in Alzheimer’s is still lacking, but the mechanism is compelling and safety at low doses is well-established. LDN is a fascinating molecule and the mechanism(s) of action are very distinct from regular dose naltrexone.

Note: On supplements generally — no Omega-3 or LDN pill will move the needle on dementia risk the way sleep, exercise, and stress reduction do. Don’t major in the minors if your fundamentals aren’t locked in.

🍷 Alcohol: Tighter Rules Apply

A study tracking older adults found that moderate alcohol consumption improved learning and memory in non-APOE4 carriers — but produced the opposite effect in E4 carriers, where it was associated with greater cognitive decline. The researchers proposed a likely mechanism: alcohol raises LDL cholesterol more in E4 carriers than in non-carriers, and elevated midlife cholesterol is itself a known risk factor for Alzheimer’s. This finding is consistent with the broader literature: across multiple independent cohorts, alcohol consumption that appears neutral or protective in non-carriers shows a dose-dependent increase in dementia risk specifically among E4 carriers. I still enjoy a glass of red wine, so am keeping my LDL cholesterol low to hedge my bets. 😅

👩‍⚕️ For Women: HRT Timing Matters

The “critical window” hypothesis has real data behind it: initiating hormone replacement therapy earlier in menopausal transition is associated with better cognitive outcomes; starting after 65 may be neutral or harmful. In the EPAD cohort, APOE4 women on HRT had better delayed memory scores and measurably larger entorhinal and amygdala volumes. And estradiol may modulate Alzheimer’s pathology in APOE4 carriers—one study showed midlife APOE4 carriers using transdermal estradiol showed reduced amyloid-beta plaque load compared to those on placebo or oral conjugated equine estrogens; this benefit was not observed in noncarriers. Nevertheless, a recent meta-analysis found HRT was statistically neutral (no benefit or harm) for APOE4 carriers although it reduced Alzheimer’s risk ~35% in non-carriers. So the picture is genuinely complex and muddied by outdated data in women’s health (e.g. the Women’s Health Initiative used synthetic hormones largely not in use today, but is still cited for modern day HRT outcomes). Bottom line: If you are a candidate for HRT and choose to pursue it, do not wait until after full blown menopause to start.

The APOE4 & Lp(a) Advanced Blood Work Cheat Sheet

Standard lipid and metabolic panels were designed for the general population. If you carry APOE4 or high lp(a), you should advocate for more advanced testing.

When you go to your doctor, ask for these specific tests by name and CPT code. I will include risk factors that make it more likely for insurance to cover the test in the doctor scripts below.

1. For lp(a)

• Lipoprotein(a) / Lp(a). CPT Code: 83695.

  • A result >50 mg/dL is considered elevated and may indicate you have the genetic risk factor.

• Apolipoprotein B (ApoB). CPT Code: 82172

  • If lp(a) is elevated, target: <70 ng/dL.

• NMR LipoProfile (LDL-P). CPT Code: 83704 (often ordered alongside a standard lipid panel, CPT 80061); aka “Quest Cardio IQ.”

  • Note: Small particles are much more atherogenic and your doctor may want to be more aggressive with cholesterol treatment if your elevated cholesterol consists of more small particles vs large particles.

• Homocysteine. CPT Code: 83090.

• If Lp(a) is elevated, ask for a follow-up Calcium Score (CAC / Heart Scan). CPT Code: 75571.

  • This is a quick, non-invasive low dose radiation CT scan that looks for calcified plaque in the coronary arteries. It will also inform how aggressively your doctor may want to manage the rest of your lipid profile.

2. For APOE4

• APOE Genotype test. CPT Code: 81401. To determine if you carry 0, 1, or 2 of the E4 alleles.

  • Insurance coverage is inconsistent, but more likely to be covered if ordered in the context of cardiovascular risk. You can also look up your APOE genotype if you have raw data from 23andMe or a similar genetic testing kit. Comment on this article if you have trouble finding your SNPs.

• All of the lipid panels under #1.

• High-Sensitivity C-Reactive Protein (hs-CRP): CPT Code: 86141. Ask for the high sensitivity one specifically, not general CRP.

  • APOE4 Target: Optimally <0.5 mg/dL

• Homocysteine: CPT Code: 83090

  • APOE4 Target: Optimally <10 umol/L.

• Fasting Insulin. CPT Code: 83525

  • APOE4 Target: Optimally <5.0 uIU/mL (”normal” allows up to 25).

• Omega-3 Index. Do not assume your fish oil is working. Measure your omega 3 index and adjust dietary intake of fish or fish oil accordingly. This is often a specialty test (like OmegaQuant Basic) and may not have a standard CPT code covered by insurance, but it is worth the roughly $50 out-of-pocket cost.

  • APOE4 Target: Optimally >8% (higher is better).

Remember that there is a massive gap between current research and the standard of care. A systematic review found that it takes an average of 17 years for research evidence to reach everyday clinical practice. Your brain and your heart cannot afford to wait until 2043 for your doctor to catch up, so you need to advocate for yourself.

The Scripts: How to Talk to Your Doctor

Doctors are incredibly busy, and many operate under a system that penalizes them for ordering “unnecessary” tests outside of standard guidelines. Be polite, be firm, and make it easy for them.

Start here: Request for lp(a) and APOE4 testing:

“Hi Dr. [Name],

I’ve been reviewing my long-term cardiovascular and neurological health goals, and I’d like to request two specific labs to help refine my risk profile: Lipoprotein(a) and APOE genotyping.

I’m asking for these specifically for the following reasons:

• Given that Lp(a) is a highly heritable and independent risk factor for premature cardiovascular disease, I’d like to establish my baseline. Since current guidelines (like those from the ESC/EAS) suggest testing every adult at least once, and because I have [mention any family history of early heart disease/stroke here, even if it’s distant], I believe this is necessary for a complete risk assessment. If my levels are elevated, it would certainly influence how aggressively we manage my other lipid markers. [Note that insurance is more likely to cover this test if there is a family history of premature heart disease (Men <55, Women <65)]

• I am interested in understanding my APOE status to better tailor my lifestyle, specifically regarding lipid metabolism and long-term cognitive health [and given I have a family history of dementia]. Knowing if I carry the E4 allele would motivate more rigorous adherence to preventative protocols (diet, exercise, and sleep) that are shown to be particularly impactful for that genotype. [Note that this test is much more difficult to get insurance coverage for; but DTC options are listed below]

I’m hoping we can code these in a way that reflects [choose one: a family history of heart disease / a history of lipid disorders] to help with insurance coverage. If insurance won’t cover them, I’m still interested in proceeding and would appreciate you ordering them so I can have the results in my clinical record.

Best, [Patient]”

If lp(a) or APOE4 positive, follow-up with:

1. Request for Advanced Testing.

   “Hi Dr. [Name]. Because of my genetic profile and/or family history of [heart disease/ diabetes/ dementia / all of the above], I’m taking a very proactive approach to my cardiovascular and cognitive health. Standard lipid and metabolic panels don’t give me enough peace of mind. Also, data shows that LDL cholesterol does not always reflect the number of atherogenic particles in circulation, and ApoB—which directly measures particle number—often tracks cardiovascular risk more accurately. For this blood draw, I’d like to add an ApoB, an NMR LipoProfile, fasting insulin, homocysteine, and a high sensitivity CRP (not the regular CRP). I have the CPT codes here to make the ordering process easier for your staff.”

2. Firm Rebuttal (If They Push Back).

   Doctor: “Your LDL and glucose look fine, we don’t need to run those extra tests. Insurance probably won’t cover them.”

   You: “I understand that my standard markers look okay, but research shows that as an [APOE4/lp(d) carrier], my disease risk is highly sensitive to particle count and chronic inflammation, not just total cholesterol mass. Given my elevated [dementia/ cardiovascular] risk, I aim to offset other modifiable risk factors—particularly insulin resistance—by monitoring fasting insulin, which often rises years before fasting glucose or HbA1c become abnormal. I also want to ensure other inflammatory markers (e.g. hsCRP and homocysteine) are kept in check. [Lastly, I am concerned about my B vitamin tissue status as I’ve been very tired lately.]** I am willing to pay out of pocket if insurance denies it. Could you please put the orders through with the appropriate diagnostic codes for my family history?” **Optional push for adding homocysteine if you have any fatigue.

3. Out-of-Pocket Bypass.

   Sometimes, a doctor simply will not order the tests, or the insurance hoops are too exhausting. If this happens, use a direct-to-consumer lab service. All of these tests can also be ordered directly through Quest here if you opt to self-pay. Or Ulta Lab tests here (via Labcorp). Ulta Labs has APOE genotype test, but Quest does not at this time. You pay cash (often cheaper than insurance copays for specialized tests) and walk into a local Quest or Labcorp to get your blood drawn with the lab slip. 23andMe genetic testing will also give you your APOE genotype.

Summary

We used to view our genetics as a crystal ball—a fixed, unchangeable destiny. Today, we know better. Your genes are one variable in a much larger equation, and your environment, metabolism, and daily choices carry more weight in that equation than most people realize. So the interesting question is not “Can I change my genes?” It is “What should I do sooner, harder, or more consistently once I know what I’m carrying?”

High Lp(a) should make you more aggressive about cardiovascular prevention now. APOE4 should make you more disciplined about dementia prevention now. In both cases, the goal is the same: stop treating “normal for the average person” as good enough when your inherited biology may be asking for tighter risk control.

I have a family member with early Alzheimer’s and I will be doing a separate post on more experimental things we are trying with this family member. In the past year, we have been able to decrease her p-tau217 significantly without the help of amyloid monoclonal antibody infusions (the only currently approved disease modifying treatment for Alzheimer’s, which barely works if we’re being honest).

Stay tuned and subscribe for upcoming articles, including:

• I Read Every Collagen Study So You Don’t Have To

• Sleep Meds and Supplements: the Good, the Bad, and the Useless

• My Top 5 WORST Quality Controlled Supplements— Consumers Beware!

And check out some prior articles if you’re new to Data Dosing:

• DIY Supplement Vetting: A Guide to Quality Check any Brand

• Is Your Creatine Safe? A Deep Dive into Common Contaminants, How to Buy Safely, and Myths

• Does melatonin cause heart attacks?

• Two simple nasal sprays could keep Covid away

References

Yes, I read all of these (not just abstracts). Yes, it took many hours. 😊

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Erickson, C. M., Schultz, S. A., Oh, J. M., Darst, B. F., Ma, Y., Norton, D., Betthauser, T., Gallagher, C. L., Carlsson, C. M., Bendlin, B. B., Asthana, S., Hermann, B. P., Sager, M. A., Blennow, K., Zetterberg, H., Engelman, C. D., Christian, B. T., Johnson, S. C., Dubal, D. B., & Okonkwo, O. C. (2019). KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology, 92(16), e1878–e1889. https://doi.org/10.1212/WNL.0000000000007323

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For years now, people have been coming to me asking, “Is supplement XYZ legit”? I have a whole treasure trove of Certificates of Analyses* from dozens of supplement companies (e.g. Pure Encapsulations, Life Extension, Thorne, NOW Foods, Metagenics, Momentous, Double Woods, Ritual, etc.).

The truth is: Most supplement companies are garbage. They are not regulated by the FDA and have very little enforcement for false advertising or adulterated products. So be scrupulous, skeptical, and cautious when diving into a new supplement.

First, I’ll walk you through 3 DIY ways to quality check any supplement. Then, I’ll walk you through the 6 most common quality “seals” (USP, NSF, Clean Label Project, ConsumerLabs, USDA Organic, IFOS) and what they actually mean.

TLDR: your best assurance is a CoA, not a quality seal. Avoid Lead Safe Mama and SuppCo for supplement vetting.

Three DIY ways to quality control check a supplement:

1. Directly request a Certificate of Analysis (CoA)

A CoA is a legally binding technical record that confirms a specific batch of product meets the quality standards and technical specifications promised by the manufacturer. Anyone can directly email the supplement company to ask for a CoA. If there is not an email address listed on the Contact website of a brand or if you do not get a response after emailing the “Contact” email, you can find an email that will go to their legal department by clicking on either the company’s “Terms and Conditions” link or their “Privacy Terms” link (usually at the very very bottom of the product page). Then, Ctrl + F the ‘@’ symbol to find an email address that legally must go to a real person. Here is the script to send:

Hi there,

Do you perform third party testing of the product linked here? [URL OF PRODUCT] If so, could you please provide a CoA from a batch of this product manufactured in the past year?

Yours Truly,

Cautious Consumer

2. Get a subscription to Consumerlabs.com (no affiliation)

ConsumerLabs is a treasure trove of third-party testing. It is $99/ year; but if you take multiple supplements, you can join and look up a lifetime of products and then cancel after the first year. Money well-spent imo if you are on the supplement bandwagon! One tiny (because I genuinely LOVE Consumerlabs) word of caution— they do not test all products for heavy metals (e.g. Creatine). And for those that are tested for heavy metals, ConsumerLabs is more lenient than Prop 65 Safe Harbor levels (California thresholds) for some products. More on this below.

3. Check for heavy metals

If you are only interested in a product’s heavy metal levels (e.g. lead, arsenic, cadmium, mercury), here is a script you can send to the company (use above to find company email address):

Hi there,

There was a Prop 65 warning regarding this product: [URL of Product]. I am a consumer in the state of California and therefore, you are legally required to disclose the ingredient triggering the warning for this product.

1. Which specific chemical(s) (e.g., Lead, Cadmium, Arsenic, or Mercury) triggered the Prop 65 warning for this product?

2. What are your internal “Pass” specification levels (limits) for heavy metals for this product? (e.g., what is the maximum ppm allowed for a batch to be approved for sale)

Please provide a copy of the most recent Certificate of Analysis (COA) for this item if you perform 3rd party testing.

Yours Truly,

Cautious Consumer

If you want to use the conservative California thresholds, look for dosing that will give you <0.5 µg/day for lead, <4.1 µg/day for cadmium, <10 µg/day for inorganic arsenic and <0.3 µg/day for mercury. (You can use AI to convert ppb levels based on the gram amount of the supplement in question or drop me a comment and I’ll help.) If the company responds something squirrelly without giving concrete numbers, red flag alert! For example: “This is simply a legal requirement that has been introduced by the state of California, meaning that this warning is commonly found on most supplements.”… or…. “When it comes to plant-based products like ours, heavy metals are naturally occurring in [any] amounts that are not harmful.” (Ora Organics, Hiya, Gruns, I’m looking at you!)

Quality Certifications

Many people think because a supplement has a feel good sounding label, they are in the clear. Unfortunately, that is not always the case. And not all supplements are created equal. There are some supplements that are easy to manufacture, fairly shelf stable, and not prone to adulteration (e.g. Vitamin D). These products are less brand sensitive and the most reasonably priced one may be the best option. On the other hand, there are some supplements that have notoriously horrible quality control. In these instances, you are wasting money at best because the product degrades (e.g. Vitamin C, probiotics) or just never had the amount stated on the label to begin with (e.g. most NAD supplements). At worst (and this is scary!), you are doing more harm than good by taking certain adulterated supplements (e.g. oxidized fish oil, heavy metal contaminated minerals such as Magnesium, MultiVitamins with iron or calcium, and Ashwaghanda).

More details below, but here’s a quick summary of what you get from the most common 3rd party testing labels…

As you can see, some of these certifications are quite expensive and additionally require recurring annual costs for testing and licensing. That said, a smaller brand could have zero of these certifications due to cost constraints but still perform quality third party testing. That is why I think a CoA should be the gold standard when reviewing a supplement for quality control.

1. U.S. Pharmacopeia (USP) (my favorite)

The USP is an independent, non-profit scientific organization that sets the official public standards for both drugs and dietary supplements in the United States. Unlike the FDA, which generally investigates products after they are on the market, the USP verification process is a voluntary audit that a company pays for to prove they are following the highest standards.

USP Certification (“Verified or Certified”) guarantees:

• Label Claim: the product contains ingredients listed on the label and at the specific potencies claimed. To be certified, a product must contain between 90% and 110% (up to 150% for high volatility vitamins such as Vitamin C) of the declared amount of a specific ingredient.

• Contaminants: USP tests for heavy metals (lead, mercury, etc.), pesticides, and microbes (like E. coli or mold), and guarantees they are below a certain pre-specified threshold. For many heavy metals, the USP threshold is multiples higher than the Prop 65 Safe Harbor levels (which is why I always still ask for a CoA for any supplement I’ll be taking regularly). USP also does not test for every pesticide. For example, dicamba, a nasty pesticide linked to a whole host of health issues (which was just approved by the current administration for widespread use on crops), is not tested by USP audits.

• Proper Dissolution: tests for proper dissolution which proves the pill will actually break down and dissolve in your body within a specific timeframe so your system can absorb the nutrients, rather than passing through the whole digestive tract intact.

• Sanitary Manufacturing: The facility meets the FDA’s Good Manufacturing Practices (GMP) regarding cleanliness and process.

2. National Sanitation Foundation (NSF)

NSF International is an independent, third-party public health and safety organization that developed NSF/ANSI 173, a set of standards for testing and certifying dietary supplements. While USP focuses on pharmaceutical-grade precision, NSF is often the preferred choice for athletes and high-performance brands because of its specialized screening for prohibited substances (e.g. steroids, stimulants) in sports.

NSF Certification (“Verified or Certified”) guarantees:

• Label Claim: the product contains ingredients listed on the label and at the specific potencies claimed. However, unlike USP Certification, NSF only guarantees a product contains at least the amount listed on the label. It could have levels of an ingredient much higher (as long as not in the toxicity range) and still pass certification. This could be dangerous, especially if you consume these ingredients from other sources as well. I do not rely on NSF for this reason.

• Contaminant Screening: Like USP, NSF tests for heavy metals (lead, arsenic, cadmium, mercury), pesticides, and microbes (Salmonella, E. coli, and mold). However, NSF limits can be even more lenient than USP for certain heavy metals; for instance, NSF allows up to 10 µg/day of Lead, which is double the USP limit and 20 times higher than the California Prop 65 Safe Harbor level.

• Banned Substance (Certified for Sport): A specialized tier of NSF certification screens for substances banned by major athletic organizations (like the NFL, MLB, and WADA).

• Proper Dissolution: NSF does not perform the more intense dissolution testing that USP does. But it does require all pills to pass a Disintegration test. This is a Pass/Fail check to see if the supplement physically falls apart within a set time (usually 30 minutes).

• Sanitary Manufacturing: The facility meets the FDA’s GMP regarding cleanliness and process.

3. ConsumerLab.com (CL)

CL is unique because it acts more like an independent watchdog rather than a standard certification body. While USP and NSF are largely funded by the manufacturers who pay for audits, CL is primarily funded by consumer subscriptions. CL buys samples anonymously from store shelves, which avoids the possibility of the manufacturer cherry-picking a super clean batch for testing.

ConsumerLab Certification (“Approved Quality”) guarantees:

• Label Claim: the product contains ingredients listed on the label and at the specific potencies claimed. CL is much stricter than NSF but not as strict as USP. To be approved, a product must contain at least 100% and no more than 165% of its claimed amount of oil soluble index vitamins, no more than 150% of its claimed amount of water soluble index vitamins and no more than 125% of the index minerals.

• Contaminant Screening: CL screens for different contaminants based on the product ingredients (e.g. minerals are screened for heavy metals; green powders screened for pesticides/microbes, etc). For heavy metals, a CL “Pass” typically defaults to California’s Prop 65 Safe Harbor levels per gram of product; however, many products such as powders have more than 1 gram in a serving and heavy metals can then easily exceed Prop 65 levels and still get a “Pass” from CL. Nevertheless, CL is much stricter on heavy metals than either USP or NSF.

• Disintegration: CL uses the same disintegration testing as NSF for most of its products. But for enteric-coated, time-release, or sustained-release products, it uses the stricter USP dissolution testing.

• Sanitary Manufacturing: Unlike USP and NSF, a standard ConsumerLab “Pass” does not include a physical audit of the manufacturing facility’s cleanliness or GMP records. They focus entirely on the finished product in the bottle.

4. Clean Label Project (CLP)

The Clean Label Project is a national non-profit focused on environmental contaminants like heavy metals and pesticides that migrate from soil and water into our food supply. Like ConsumerLab, they primarily use unannounced retail sampling. A product can be either CLP Certified or have the CLP “Purity Award”, with the latter being the most common seal you see from CLP. While CLP Certification has decent rigor with respect to contaminant screening, the CLP “Purity Award” is essentially a useless label. To get the Purity Award, the product must rank in the top 33% (the cleanest third) of its specific category. But so many supplement categories are already very dirty. For example, in a category that is naturally heavy in metals (like chocolate, protein powders, mineral supplements, green powders), a product could potentially have high levels of lead and still win a Purity Award if the rest of the industry is significantly worse. For this reason, I do not put stock in this label.

Clean Label Project Certification (NOT “Purity Award”) guarantees:

• Label Claim (Potency): Not tested.

• Contaminant Screening: CLP tests for bisphenols (aka BPA and BPS), glyphosate, heavy metals (arsenic, cadmium, lead, and mercury), pesticides (over 300 residues), and phthalates (BBP, DBP, DEHP, and DHP). Additionally, acrylamide testing is conducted for products that undergo heat processing during manufacturing. For certification, heavy metal levels must be below the Prop 65 Safe Harbor Levels.

• Proper Dissolution: No testing.

• Sanitary Manufacturing: Like CL, not applicable here.

5. International Fish Oil Standards (IFOS) Certified (Omega 3 must!)

IFOS is the only program that tests fish oils batch-by-batch. They check for three specific things:

• Potency: Does it actually have the EPA/DHA it claims?

• Purity: Is it free of *PCBs, dioxins, and mercury?

• Freshness: Is the oil rancid (oxidized)? The upper limit of TOTOX should be < 26 (The Global Organization for EPA and DHA, a trade group for the omega-3 supplement industry, recommends this as the ceiling). Because I take fish oil regularly and plan to long term, I err on the more conservative threshold of only buying brands with a TOTOX value below 10.

You can go here to look up whether your fish oil brand is IFOS certified and then download the batch testing results to check TOTOX levels and other contaminants.

I think IFOS certification is the most important certification for Omega-3s because fish oil is notoriously prone to rancidity and heavy metal accumulation. *More on PCBs in My Top 5 Worst Quality Controlled Supplements post coming soon…

6. USDA Organic (mostly worthless)

The United States Department of Agriculture (USDA) Organic seal tells you nothing about the supplement quality. It solely signals a paperwork audit of a farming process, not a laboratory test of purity, contamination, or safety. The seal guarantees that for the last 3 years, the land where the ingredients were grown had no synthetic pesticides, herbicides, or fertilizers applied to it. But soil can still be contaminated by industrial runoff of pesticides from 50 years ago. Or, if the farm next door is spraying dicamba or glyphosate and the wind blows it onto the organic crop, that crop is still “Organic” despite having pesticide residues. With respect to glyphosate (a probable carcinogen), our country is now prioritizing its domestic production, with legislation** in 2026 labeling glyphosate as essential for “national security.” While this doesn’t make glyphosate “Organic,” it ensures that the US food system will be more saturated with it than ever, including in Organic products subject to soil drift.

In addition, as of 2025, the EPA has approved several new PFAS-based pesticides (”forever chemicals”) for use on conventional food crops. These chemicals are designed to never break down. So even if an organic farmer doesn’t use them, these persistent chemicals are now entering the water table and soil at a faster rate and can easily migrate into organic food without ever triggering a violation.

Lastly, “Organic” tells you nothing about heavy metal contamination. Many supplements have plant-based ingredients (e.g. rice, hemp, pea, cacao) that are heavy metal bioaccumulators; they suck up lead, arsenic, and cadmium from the earth like a vacuum. Independent testing by the Clean Label Project has actually found that organic plant proteins often have HIGHER heavy metal counts than conventional ones.

Overall, Organic is essentially a useless label when it comes to supplements.

A word on Lead Safe Mama

Lead Safe Mama (LSM) is an advocacy site run my a mom with no background in science or toxicology. LSM uses arbitrary “Action Levels” to flag products as unsafe, but these standards are often scientifically detached from actual human risk and bordering on fear-mongering. While LSM primarily relies on an “Action Level” of 5 ppb (parts per billion) for lead as a ‘fail’ threshold, this concentration is roughly 100 times stricter than the California Proposition 65 Safe Harbor level of 0.5 µg/day when applied to a standard supplement dose. For example, a 1g pill testing at 5 ppb contains only 0.005 µg of lead; so a consumer would have to swallow 100 of those pills in a single day just to reach the Prop 65 limit, which is already set 1,000 times lower than the level where actual physiological harm is observed.

In addition, the method LSM uses for testing heavy metals—XRF technology (a surface-scanner designed for industrial paint and solid housewares), is notoriously inaccurate for measuring the complex chemical matrix of an ingestible supplement. This misapplication of science creates toxic paralysis for consumers, leading them to discard safe, high-quality products based on data points that carry no practical clinical significance.

Lastly, none of LSM testing confirms label accuracy, meaning you could be paying for an expensive choline supplement that has low levels of heavy metals but virtually zero choline in the product. Or alternatively, you could be getting toxic levels of Vitamin A or iron from a multivitamin that still “passes” as safe under LSM standards.

Avoid SuppCo like the plague

SuppCo 3rd party testing is rigged and they mostly promote brands of investors that have co-invested in the promoted supplement. For example, AG1 supplement gets the highest score of 10 — even though we have multiple third party reports that AG1 has extremely high levels of lead, the probiotics are present in such tiny amounts that you’re better flushing your money in the toilet, and the rest of the ingredients are essentially a crappy multivitamin selling at 10x the price of other quality multivitamins. But guess what? A top influencer sponsor of AG1 is Mark Hyman (he makes money when you buy AG1). And Mark Hyman is also a SuppCo partner who decides what “score” different supplements get. Is it just a coincidence that brands failing every third-party test somehow receive a top-tier rating from SuppCo? Nope. It’s a racket.

Summary

In summary, quality seals/certifications do not always guarantee a quality product. The gold standard will always be a CoA (and if a company does not provide CoAs to consumers, that can be a litmus test for sketchiness). If I had to rank certifications based on the quality assurance they provide, it would be: 1. USP; 2. ConsumerLab; 3. NSF; and for fish oil supplements, IFOS is a must.

Later this month, I’ll be doing a deep dive on the worst quality controlled supplements out there and how to be extra cautious if you do choose to partake (as some of these “bad” supplements can have health benefits if quality sourced!). I’ll also list out the brands that I have personally vetted.

And next month, stay tuned for a deep dive on two genetic variants that every human should test for because there are ACTIONABLE things that mitigate risky alleles if started early enough in life. These tests are an easy blood draw from Quest that you (via QuestHealth) or your doctor can order.

**2026 Glyphosate legislation

FYI on Glyphosate: The administration invoked the Defense Production Act (DPA)—a law usually reserved for wartime or national emergencies—to prioritize glyphosate. The government’s logic follows two tracks:

1. The Military Connection: Glyphosate requires elemental phosphorus, which is also a critical precursor for semiconductors, lithium-ion batteries, and military incendiary/smoke devices. By securing the phosphorus supply chain for “Roundup,” the administration argues it is simultaneously securing the supply chain for high-tech weaponry.

2. The Food Security Argument: The White House now officially classifies glyphosate as a “cornerstone of national productivity.” The order asserts that any interruption in its supply would “critically jeopardize” the U.S. food system, making its production a matter of national defense.

What do you think about this logic? Feel free to leave thoughts in comments!

Creatine is having a moment. Once reserved for bodybuilders and sprinters, it is now being heralded as a critical tool for muscle strength, cognitive health, and menopause support. (Check out Part 1 of this post HERE where I dish the scoop on which of these benefits are real vs hype.)

But with popularity comes scrutiny. If you’ve been hesitant to add that white powder to your morning routine because you’re worried about heavy metals, hair loss, or kidney stress, you aren’t alone. And honestly, you should be asking questions—just make sure they are the right ones.

Here is the science-backed guide to vetting your creatine, debunking the myths, and understanding why quality matters more than you think.

The “Dirty” Truth: Contaminants Are Real

First, the bad news. Not all creatine is created equal. Cheap, poorly manufactured creatine can be a trojan horse for industrial by-products and neurotoxic contaminants.

When creatine is synthesized in a lab (often in facilities with loose regulations), the chemical reaction can leave behind “process impurities.” The two big ones to watch out for are:

• Dicyandiamide (DCD): A residue from the starting materials.

• Dihydro-1,3,5-triazine (DHT): An impurity from the manufacturing process (note: this is not the hormone dihydrotestosterone linked to hair loss—it just shares an unfortunate acronym).

The European Food Safety Authority (EFSA) suggests conservative limits for these (DCD ≤ 50 mg/kg and DHT should be undetectable). Unfortunately, many high end brands don’t even test for them at all (e.g. Promix, Thorne).

How common is contamination? Higher than you might think. A study analyzing 33 samples of creatine on the market found that 15% were contaminated with DHT/DCD and 44% had significant breakdown (not inherently harmful, but means you are not actually getting creatine).

You might think, “I’ll just buy a brand with an NSF Certified for Sport seal.” While NSF is great for ensuring a product is free of banned substances (vital for athletes), certification does not even test for DHT or DCD. It also does not guarantee that heavy metal levels are below the conservative Prop 65 Safe Harbor levels set by California. These “safe harbor” thresholds are exposure per day, not simply “product contains some amount.” For lead, the Prop 65 Maximum Allowable Dose Level (MADL) for reproductive toxicity is 0.5 micrograms/day. A product can have low lead per kilogram, but your daily dose determines whether you exceed that exposure.

In other words, a supplement can be NSF certified but still contain DHT, DCD, and higher levels of lead or arsenic. Prop 65 Safe Harbor levels are admittedly conservative, but if there is a supplement you are taking daily (or giving to teens!), I always check specifically that heavy metal levels are below those thresholds.

The Solution: buy “Creapure” and/or ask for a CoA

If you want to bypass the guesswork, you can simply buy a creatine brand that only uses the ingredient called “Creapure®” (no affiliation). Creapure is creatine monohydrate manufactured in a dedicated facility in Germany by Alzchem. Creapure is rigorously tested to meet specifications that often exceed international standards. Crucially, they specifically test for DHT to be non-detectable; DCD below 30 mg/kg; and strictly controlled levels of heavy metals.

In any event, it is always a good idea to ask the brand manufacturer for a Certificate of Analysis (CoA) for any supplement that you will be taking on a regular or long-term basis (which is the case for many creatine users). Don’t settle for a “pass/fail.” Ask to see the actual numerical values for DCD, DHT, and heavy metals for the specific lot you are buying.

FWIW, heavy metal contamination is much less a concern for creatine than other supplements (e.g. protein powders) because it is a synthetically produced compound rather than one extracted from plants grown in soil. But I have found some brands that had alarmingly high levels of lead. I have yet to find a brand using Creapure that is above the Prop 65 Safe Harbor levels for heavy metals– but always happy to be proved wrong! Feel free to send me brands to vet.

Myth Busting: Kidneys, Hair, Coffee, and Weight

Once you have a clean product, the next hurdle is the “bro-science” fears that have persisted for decades. Let’s clear the air.

1. “Creatine hurts your kidneys.” (False Alarm)

This is the most common medical misunderstanding regarding creatine. Doctors often estimate kidney filtration using blood creatinine and estimated Glomerular Filtration Rate (eGFR), a proxy for kidney function. Creatinine is partly a breakdown product of creatine stored in muscle, so taking creatine can raise creatinine a bit—even when kidney function is normal—making creatinine-based eGFR look falsely low. If this happens, ask your clinician to confirm kidney function with cystatin C (or a combined creatinine + cystatin C estimate), which is far less affected by muscle and creatine intake. For healthy adults with normal kidney function, there is no credible evidence that creatine supplementation harms kidneys. A 2025 systematic review of 21 studies concluded that creatine does not cause kidney damage in healthy people when used at recommended doses (3-5 grams/day). However, for anyone with kidney disease, or reduced kidney function (kidney transplant, one kidney), these studies are not applicable. There are isolated case studies where creatine use was associated with kidney damage (these cases may have been confounded by other supplements or pre-existing undiagnosed kidney disease). On the other hand, a small open-label 2025 study suggested that patients already on hemodialysis may have slight benefit in certain physical task dimensions without adverse effects to kidney health. That said, you should always discuss adding any supplement with your doctor.

2. “Creatine causes hair loss.” (Unlikely)

A single study in 2009 on rugby players (10 subjects in creatine group) showed a rise in the hormone DHT (dihydrotestosterone) after creatine use. That study didn’t actually measure hair loss. Furthermore, over 12 subsequent studies have failed to replicate those results. So the current scientific consensus does NOT support that creatine causes hair loss.

3. “Caffeine and/or hot liquids kill the benefits.” (It’s Complicated, but mostly Fine)

There was an old belief that caffeine somehow “cancels out” creatine’s benefits. The research doesn’t support this. A 2016 study specifically tested creatine mixed with coffee versus creatine alone and found no significant performance differences. Caffeine and creatine work through completely different pathways in your body. They don’t interfere with each other’s absorption or effectiveness. The only potential issue? Some people report stomach upset when combining the two, likely because both can be rough on digestion in high doses.

For hot liquids, there’s a kernel of truth buried under exaggeration. Creatine can degrade into creatinine when dissolved in hot, acidic liquids. But the key word is can—the process takes hours even in very hot temperatures, not minutes. And as a dry powder, creatine is remarkably stable. Studies show no detectable degradation even at 104°F after three years. At 140°F, only trace amounts of breakdown products appeared after 44 months.

4. “Creatine will make me gain weight.” (This one is actually true—sort of.)

It is true that many users experience an initial weight increase of 2 to 4 pounds within the first week of starting creatine. This freaks people out; but it’s not fat. It’s not even the “bloating” people imagine. Creatine is what scientists call “osmotically active.” When creatine enters your muscle cells, water follows. This water retention is likely the underlying “weight gain” that many experience when first starting creatine. It usually normalizes as cells adjust and it is fully reversible if you stop supplementing.

Vetted Brands and Where to Buy Them

If you only take one thing away from this article, I hope it is this: Never buy supplements off of Amazon. When you buy creatine (or any supplement!) from Amazon, you’re rolling the dice on how it was stored before it reached your door. These warehouses and delivery trucks often aren’t climate-controlled, exposing the powder to the heat and moisture that causes creatine to break down into creatinine. While this byproduct isn’t harmful to your health, it is completely useless for your muscles, meaning you’re essentially paying for a supplement that has lost its power before you even break the seal. Unlike creatine, there are other supplements that when broken down or oxidized in heat, actually cause more harm than good.

That said, I always purchase supplements directly from the manufacturer website or from iherb.com (no affiliation). While mass-market retailers often treat supplements like any other piece of plastic, specialty distributors like iHerb utilize GMP-registered, climate-controlled warehouses kept at a steady 75°F to ensure your creatine remains stable and effective.

I have personally vetted nearly a dozen creatine brands for quality control and most of them do NOT test for DCD or DHT. Many test for heavy metals, but few provide a CoA (the third party testing document to verify heavy metal levels) when requested. The brands that have high levels of heavy metals and/or do not test for DCD/DHT include: Promix, Thorne, Warrior, Sports Research, NOW Foods (though I otherwise love this very reasonably priced brand for many other supplements which I have vetted).

The brands that came out the cleanest with most transparent testing: Momentous, BluePrint, and Pure Encapsulation. All 3 of these brands are well below Prop 65 thresholds and clear on DCD and DHT. BluePrint was the cleanest and the cheapest (I do think Bryan Johnson is a bit bonkers, although I like his intensity).

Price per 5 gram serving (no affiliation with any of these):

1. Momentous: $0.44

2. Blueprint: $0.40

3. PureEncapsulations: $0.58

I am not vouching for any other supplements by these brands (for example, I know Pure Encapsulations has had quality control issues with B12 and Ashwagandha supplements.)

Next up, I’ll be diving into creatine use in women specifically with attention to creatine in pregnancy, postpartum, and menopause. Stay tuned..

Subscribe for other upcoming articles, including:

• Supplement Vetting: How to Know Which Supplements (if any!) to Trust?

• Kids MultiVitamins: How to Choose and Do Kids Even need a Multi?

• Statin Chattin’ — Ask your Doctor about THIS if going on a Statin

• My Top 5 WORST Quality Controlled Supplements— Consumers Beware!

• Sleep meds and supplements: The good, the Bad, and the Useless

• Estrogen and Mitochondria

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References

• Alzchem Trostberg GmbH. (n.d.). Quality & Manufacturing. Creapure®. Retrieved January 29, 2026, from https://www.creapure.com/en/creapurer/quality-manufacturing/

• Bernales-Delmon, W., et al. (2025). Oral creatine in hemodialysis patients increases physical functional capacity and muscle mass, an open label study. PLoS One, 20(7), e0328757.

• European Food Safety Authority (EFSA) Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC). (2004). Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC) on a request from the Commission related to creatine monohydrate for use in foods for particular nutritional uses. EFSA Journal, 36, 1–6 (adopted 17 February 2004).

• Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease (CKD) Work Group. (2024). KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International, 105(4S), S1–S193.

• Moret, S., Prevarin, A., & Tubaro, F. (2011). Levels of creatine, organic contaminants and heavy metals in creatine dietary supplements. Food Chemistry, 126(3), 1232–1238.

• Naeini, E. K., Eskandari, M., Mortazavi, M., Gholaminejad, A., & Karevan, N. (2025). Effect of creatine supplementation on kidney function: A systematic review and meta-analysis. BMC Nephrology, 26(1), Article 622.

• NSF International. (n.d.). Certified for Sport® Program. Retrieved January 29, 2026, from https://www.nsf.org/consumer-resources/articles/certified-for-sport-program

• Trexler, E. T., Smith-Ryan, A. E., Roelofs, E. J., Hirsch, K. R., Persky, A. M., & Mock, M. G. (2016). Effects of coffee and caffeine anhydrous intake during creatine loading. Journal of Strength and Conditioning Research, 30(5), 1438–1446.

• van der Merwe, J., Brooks, N. E., & Myburgh, K. H. (2009). Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clinical Journal of Sport Medicine, 19(5), 399–404.

This is Part 1 of a 3 part series. In Part 2, I’ll flag dangerous contaminants to watch out for, common concerns, and how to buy and consume creatine safely.

TLDR

Popular claims for creatine include increased muscle strength and cognitive benefits.

In general, if you’re a healthy adult taking creatine for muscle gains or cognitive benefits, you’re most likely paying for expensive urine at best; or a hearty dose of lead, DHT and DCD, at worst.

Nevertheless, there are specific use cases where creatine may confer clearer benefits—for example, in stressed or deficient states (i.e. hypoxia, sleep deprivation, vegetarian diet) and states of altered energy metabolism (i.e. statin users, MTHFR mutations, elevated homocysteine, mental health conditions).

Here’s the scoop . . .

First, what is creatine and how much do we need?

Creatine is a small molecule your body naturally makes each day from the three amino acids, arginine, glycine, and methionine. Creatine is taken up into tissues and helps recycle and shuttle adenosine triphosphate (aka ATP, the cell’s energy “currency”) efficiently to where the body needs it.

Interestingly, there are no creatine receptors in the human body (at least that we know of yet)so the system is entirely transporter and enzyme‑driven. However, creatine is being studied as a potential neurotransmitter that may interact with other receptors, such as GABA and glutamate receptors. Cool stuff.

More than 90% of creatine is stored in skeletal muscle, so people with more muscle have larger pools but, in turn, higher daily losses. A typical 70-kilogram adult with normal muscle mass loses (uses up in bodily processes + excretes) about 2 grams of creatine per day. The body endogenously makes about 1 gram of creatine per day, so the other 1 gram must come from diet to keep the total body pool topped up. (Some research suggests getting 2 grams/day from diet to maintain body stores.)

Creatine is found almost entirely in animal muscle: meat and fish. Dairy and eggs have tiny amounts, and plant foods have effectively zero. This means vegans and vegetarians get virtually no dietary creatine.

To get 1-2 g/day creatine strictly from food, you would need to eat ½ to 2 pounds of meat per day, with red meat and fatty fish having more creatine and poultry having less. That’s around 4 to 7 servings (4 oz) of holiday turkey for context! And if you are aiming to get the 5 gram creatine range (most commonly cited in studies, see below), that would be around 17 servings of turkey per day.

How you cook meat matters! When thinking about how much creatine you get from diet, cooking method matters. Cooking meat at high temperatures can degrade creatine, with high-heat methods (grilling, frying, barbecuing) causing roughly 30–50% loss of creatine. If optimizing for creatine content, opt for gentle methods (boiling, steaming).

Now, on to the claims . . .

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Muscle size and strength

Claim:

“Creatine is one of the most reliable tools for muscle strength.” -Dr. Robert Silverman ( ~600k followers on IG and owns a creatine supplement line).

Reality:

Creatine supplementation may help you do a couple more reps in the gym and those extra reps then provide tiny benefits in muscle strength; but supplementing with creatine alone (not paired with strength training) is a big Nothing Burger for muscle and strength gains.

The Full Scoop:

Creatine’s primary claim to fame is muscle strength improvements. But creatine is not some silver bullet building muscle while you sit on the couch. Its muscle building properties come from increased energy buffering, allowing some people to work out [a tiny bit] harder or longer, and it’s those increased reps that really drive strength gains.

When participants of studies used creatine without any exercise intervention, the changes in lean body mass were extremely small and mostly reflected increased total body water (creatine draws water into muscles), not true muscle fiber hypertrophy. There are several studies that looked specifically at muscle protein synthesis (MPS) without exercise intervention and there was NO increase in MPS. Therefore, combining creatine with strength training is key to seeing any benefit on the muscle front.

But even in studies that combine exercise with creatine, results are inconsistent and small — some still found no added benefit of creatine for muscle protein synthesis (MPS). When reviewing the literature (or watching Instagram reels from wellness influencers), it’s important to note that DEXA scans cannot distinguish between intracellular water and actual muscle protein. An increase in “lean mass” on a DEXA scan is often misinterpreted as muscle growth when it is really just increased water in the muscles.

However, one thing that cannot be underrated is the real power of placebo! If you add creatine into a pre-workout drink and “feel” energized (even if it’s all in your head), you train harder, build more muscle, and that’s a win! Given the great safety profile of well-sourced creatine (see Part 2 on dangerous common contaminants), go for it!

Cognitive benefits

Claims:

“Taking creatine regularly can sharpen your memory, help you process information faster, and even improve how quickly you pay attention to things better.” -Dr. Will Cole (>800,000 IG followers and owns a creatine supplement line)

And Dr. Mark Hyman (>3.6 million IG followers and sells creatine):

Reality:

Creatine may have modest benefits in stressed or aging states, but the biggest crossover study to date in healthy adults found no cognitive benefits.

The Full Scoop:

Meta-analyses from 2022–2025 conclude that creatine supplementation may offer modest benefits for memory or attention during acute stressors like sleep loss or hypoxia, aging associated changes in physiology (e.g. elderly, menopause), and deficient states (e.g. vegetarians); but even those results are inconsistent.

In a 2006 study, mega dose creatine supplementation (20 g/day) given to super sleep deprived people modestly improved cognitive scores in certain dimensions (e.g. spatial memory and reaction times). In traumatic brain injury and hypoxia models, there is also data to support a potential small brain benefit from high doses. In 70-80 year olds, 20 g/day for 1 week improved certain recall tasks (forward number and spatial recall); but findings were null in other dimensions (e.g. random number generation, backward number recall). In chronic fatigue syndrome (a condition commonly associated with “brain fog” and immune dysregulation), 16 grams of creatine/day for 6 weeks improved reaction times and reduced fatigue scores (caveat, very small trial with no placebo arm). And a few months ago, a small industry sponsored study (9 subjects per group) in perimenopausal and menopausal women found lower dose creatine hydrochloride (different from the typical creatine supplements) increased brain creatine levels in certain regions and slightly improved reaction times, but failed to improve mental and physical fatigue. There were a number of issues with this study that I’ll be discussing in a later post.

In any event, even the largest randomized controlled study to date on creatine and cognition found NO cognitive benefits in well rested healthy adults. Wildly, the study authors concluded: “Our study…implies that creatine might have a small beneficial effect [on cognitive performance].” You’d think the conclusion, given zero significant findings, would be the opposite, right? This is why it’s important to always read the actual underlying study and data rather than taking abstract conclusions at face value. Sexy conclusions generate press (and potentially funding); but null findings generate crickets.

Side note/pet peeve: Fwiw, null findings can be immensely helpful for scientific progress and I wish there were more journal publications calling them out. Publishing only positive results distorts the map of reality in many fields. We get mountains of “significant” findings and suspiciously few “look this thing does NOTHING, isn’t that interesting?!” This is called “publication bias” and it’s something to be mindful of when reading a seemingly sensational study abstract. Also, the above study was critiqued by some researchers (e.g. here) for concerns regarding the methodological rigor of the analysis.

Nevertheless, it is possible we would see greater cognitive effects with longer term and higher dosing. But even at 20 grams/day, some studies show that we still only see a modest increase in total brain creatine (~8.7% when averaged over brain regions, ranging from 4.7% to 14.6%). What would be interesting to see, and I don’t think anyone has studied this — is whether those increases in brain creatine after mega loading doses could be sustained after dropping down to lower dosing of 3-5 grams/day.

Altered energy metabolism

Claim:

“Creatine supplementation can improve energy metabolism by sparing methyl groups for other bodily processes.” -Me, after doing a literature review :)

Reality:

This is true; BUT probably only has a functional impact when the body is short on methyl groups to begin with.

The Full Scoop:

This brings me to what I think is the best use case scenario for creatine supplementation — states of altered energy metabolism. The body uses methyl groups to generate creatine, so production of creatine can be very taxing on the methylation cycle. By adding exogenous creatine, one can free up extra methyl groups which are needed for many bodily processes, including turning on/off gene activity through DNA methylation.

Here are some groups that might see benefit from creatine supplementation:

1. Statin users

   A number of common medications directly alter energy metabolism in a way that may benefit from creatine supplementation. For example, statins block HMG-CoA reductase (the rate-limiting enzyme in the mevalonate pathway). This can alter the way mitochondria process electrons in the transport chain by depleting CoQ10 (aka ubiquinone/ubiquinol), which is essential for cellular energy production. Several studies indicate that statins can reduce muscle mitochondrial capacity in vivo (humans) and also mechanistically. That said, there is a biological basis where creatine could confer extra benefit in statin users.

   Indeed, a small study in statin users showed benefits from creatine at lower doses. In another pilot study (no placebo), patients with statin-associated muscle symptoms who supplemented with a lower dose of creatine (3g/day) experienced a significant reduction in myopathy (muscle pain) scores. A big confounder for the prior studies was that there was no placebo blinding. Other in vitro work also indicates creatine has mechanistic potential to mitigate statin-induced muscle atrophy. This suggests that adding creatine may allow patients who experience muscle pain on statins, a very common side effect, to tolerate this potentially life-saving therapy.

   Big caveat: a randomized, double-blind trial in healthy adults on a very high-dose statin (80 mg/day) found 10 g/day creatine monohydrate for 4 weeks did not reduce post-exercise creatine kinase rise, soreness, or pain versus placebo. That said, effects seem to be highly individual and may be contingent upon degree of muscle damage. (Deep dive on statins and other cholesterol medications in a future post.)

2. MTHFR mutations

   Another source of potentially altered energy metabolism where creatine might be beneficial is in people with the MTHFR (Methylenetetrahydrofolate reductase) polymorphism. This genetic variation limits the conversion of dietary folate to its active form (5-MTHF), creating a bottleneck in the methylation cycle. The polymorphism impacts approximately 30–40% of the population, approximately 10–15% of which carry two copies of the variant which results in significantly reduced enzyme activity. Because extra methyl donors are needed when the methylation cycle is strained, and endogenous creatine production consumes roughly 40–50% of the body’s available methyl groups—supplementing with creatine may gently relieve this bottleneck. While large-scale clinical trials are still needed, this hypothesis is strongly supported by mechanistic work in animal physiology and a specific human case study where creatine supplementation in a homozygous (677TT) patient reduced homocysteine levels by nearly 50%.

3. Elevated homocysteine

   People with elevated homocysteine may also benefit from creatine supplementation. The body uses methyl donors to eliminate homocysteine. When supplementing with creatine, your body can therefore spare some methyl donors to go towards clearing homocysteine levels. Elevated levels of homocysteine are associated with vascular inflammation, oxidative stress, and increased cardiovascular risk. While studies looking at lowering homocysteine directly have not shown cardiovascular benefit, we know homocysteine in and of itself is an inflammatory molecule. (BTW, if your doctor has never checked your homocysteine levels, it’s a lab I think everyone should have a baseline of every couple of years because there are easy actionable things you can do to lower homocysteine.)

   Several randomized controlled trials do indeed show that creatine supplementation lowers homocysteine in people with elevated levels—though findings were null in healthy adults without elevated homocysteine, again echoing the theme that creatine helps most when there are aberrations in baseline physiology. That said, creatine’s methyl-sparing benefit has limits: in advanced chronic disease, such as heart disease patients or those on hemodialysis, creatine fails to lower homocysteine and may even raise it. Severe metabolic dysregulation appears to overwhelm any sparing effect. The pattern holds: creatine can optimize what’s suboptimal, but it’s not a fix for advanced disease.

4. Neurological conditions

   Emerging research increasingly frames psychiatric disorders not just as neurotransmitter imbalances, but as states of altered energy metabolism in the brain (and elsewhere). While higher dosing of creatine is typically needed to elevate brain levels in healthy adults, several studies show that smaller doses (i.e. 3- 5 grams) are sufficient to raise brain creatine in people with depression. This effect may be more pronounced in women; one randomized controlled trial found that female participants taking 5 grams daily alongside an SSRI achieved remission rates double that of the placebo group. (Caveat: small sample size, lead researcher has creatine patents, and this result has not been consistently replicated in men or larger, independent populations.)

   Nevertheless, creatine does not appear to be a universal panacea for all mental health conditions. Rigorous trials in schizophrenia and bipolar disorder have largely produced null findings, failing to show statistically significant improvements in symptom scores despite similar dosing protocols. While creatine failed to lower average depression scores across the group in bipolar disorder, it did produce a significant increase in remission rates. However, creatine triggered mania in some study subjects, so always talk to your doctor first especially if trying creatine with a medical condition.

   In addition to psychiatric disorders, chronic fatigue syndrome (CFS), an illness marked by fatigue and “brain fog”, may also see benefit from creatine supplementation. A plausible mechanism for this benefit in CFS is that creatine provides a buffer for ATP, which helps stabilize cellular energy homeostasis in tissues with high energy demands that may be compromised in this condition. One study found significantly lower creatine levels in the anterior cingulate cortex area of the brain in CFS subjects compared to healthy controls. In a small CFS study, researchers found that high-dose supplementation (16g/day) resulted in a significant reduction in subjective fatigue scores, though the study’s uncontrolled, non-placebo design requires these improvements to be interpreted with caution.

   Long Covid has many overlapping features of CFS and recent research highlights the importance of creatine deficiencies in organs affected by this condition too. One study showed substantial reductions in both skeletal muscle and brain creatine in individuals with post-COVID fatigue syndrome, with decreased creatine levels associated with greater symptom severity. Small trials have demonstrated that moderate doses (4-6 grams) of creatine can lead to statistically significant reductions in “brain fog” compared to placebo; but effects on fatigue have been mixed. For example, one study found that a 6g/day dose was effective for reducing fatigue, whereas an 18g/day dose produced null results. It’s possible that the higher dose was too much for potentially stressed mitochondria to process effectively. The signal is intriguing but dosing protocols and endpoints remain heterogeneous and underpowered, so it’s too early to declare an optimal dose. But given the general safety profile of creatine (if purchased from a properly third-party tested brand), it may be worth trying. There are also registered ongoing studies in this space for those interested, e.g. ClinicalTrials.gov identifier NCT06992414.

5. Pregnancy and menopause

   While pregnancy and menopause can alter energy metabolism, I’ve decided to make a dedicated Part 3 to cover creatine as it relates to women’s health because there are extra considerations (and risks) for this group. Stay tuned.

So, in summary. . .

Creatine supplementation may offer tangible benefits for people in stressed or deficient states and in those with disrupted energy metabolism. Conversely, for healthy young adults seeking marginal muscle or cognitive gains, supplementation may result in little more than high-cost excretion or, more concerning, exposure to industrial contaminants like lead, dicyandiamide (DCD), and dihydro-1,3,5-triazine (DHT).

This brings me to Part 2, which I’ll be sharing next week--- A deep dive into common contaminants and myths around creatine safety. I’ll also be sharing brands I have personally vetted. By the way, NSF certification does not test for most of these contaminants.

Stay tuned and subscribe for upcoming articles, including:

• Creatine: Common Contaminants and Myths

• Supplement Vetting: How to Know Which Supplements (if any!) To Trust?

• Kids MultiVitamins: How to Choose and Do Kids Even need a Multi?

• Statin Chattin’ — Ask your doctor about THIS before going on a statin

• To HRT or not to HRT: Hot Flashes, Cold Facts on Hormone Replacement Therapy

• My Top 5 WORST Quality Controlled Supplements— Consumers Beware!

  Thanks for reading Data Dosing! Subscribe for free to receive new posts and support my work.

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This is Part 1 of a series on sleep aids. Subscribe to make sure you get Part 2 where I do a deeper dive on the gamut of sleep polypharmacy from herbals and over-the-counters to newer FDA approved drugs like DORAs.

A study discussed this month at the American Heart Association (AHA) conference stated that those that use melatonin have “about a 90% higher chance” for incident heart failure. Holy smokes!! This has generated a flurry of scary headlines in the past few days (some from health influencers with millions of followers), e.g. “When Sleep Aids Backfire: Melatonin Tied to Heart Risks in Major Study” and “Melatonin and Heart Risks: Is anything safe anymore?” etc.

Enter Huge Eye Roll and My Blood Pressure Rising over so much garbage ‘science’ reporting these days.

Shame on AHA for such a flawed study design and shame on news outlets and influencers spewing headlines that will likely discourage those with legitimate insomnia from taking one of the safest sleep aids we currently have available (i.e. melatonin, a robust, natural anti-inflammatory molecule in neurons).

TLDR

1. The control group in the AHA study only included people who have NEVER been prescribed a sleep aid, including melatonin. (The study was run in the UK, where melatonin requires a prescription.)

2. Thus, the control group only included people who we could say have very mild insomnia, since anyone with even moderate insomnia has likely tried a sleep aid.

3. We know from decades of research (see sources below) that the severity of sleep disturbances strongly predicts increased risk of cardiovascular events.

4. Therefore, the severity of insomnia could very likely be a factor causing heart events rather than melatonin.

5. We cannot make any conclusions about melatonin and heart event risks either way, the data and confounders in this study create too much noise.

This is a great reminder that correlation does NOT equal causation.

To be clear, I don’t think melatonin should be taken like candy or in pre-pubescent children who are very vulnerable to minor shifts in hormones (until we have more data in this age group specifically). But if an adult suffering from insomnia (which increases not just heart failure risk, but may also be linked to increased risk of all-cause mortality) can improve sleep with *low dose* melatonin vs something like ambien or just NOT sleeping through the night for weeks on end, I would bet my house that such a person is having a net health benefit with melatonin on board.

What the AHA study really says (and doesn’t)

At a conference earlier this month, the AHA highlighted a preliminary study (a conference abstract, not a peer-reviewed paper) that looked back at five years of electronic health records from 130,828 adults with insomnia. People who had a documented melatonin prescription (in the UK, melatonin requires a prescription) for ≥12 months had higher five-year rates of new heart failure (4.6% vs 2.7%), hospitalization for heart failure (19% vs 6.6%), and death from any cause (7.8% vs 4.3%) than “non-melatonin” patients. The official press release phrases this as “about a 90% higher chance” for incident heart failure and “twice as likely to die” over the 5 year time period, which comes from an adjusted model.

When a headline says “twice as likely to die” if you take X, it’s important to look at absolute risk of taking X, not just relative risk. For example, in this study, participants in the melatonin group were nearly “twice as likely to die” from any cause than those in the non-melatonin group (7.8% melatonin users died vs. 4.3% non-melatonin users died). The absolute risk increase here is 3.5%. Not as scary sounding as “twice as likely,” eh?

But the biggest issue with this study, in my opinion, boils down to what we call “spurious correlation” or the third variable problem. This occurs when an external factor, known as a confounding or lurking variable, influences both of the other variables, creating a misleading association that is not a direct cause-and-effect relationship. For example, hot weather can cause both an increase in ice cream sales and an increase in drowning incidents, making it seem like ice cream sales cause drownings when the two are only correlated due to the third variable of hot weather. Here, those with a melatonin prescription had more heart events than those without any sleep medication prescription. The “third variable” here could be severity of insomnia — those with severe insomnia seek out melatonin prescriptions while those with mild insomnia don’t require any medication. More severe insomnia (not melatonin use) is actually the variable causing increased heart events.

We know from many lines of research that even short bouts of insomnia (even a single night of sleep deprivation!) can significantly lower insulin sensitivity and disrupt the immune system which can cause a whole host of acute negative sequelae for the metabolic and vascular systems as well.

Another clue that this melatonin connection is a red herring: those with documented 1 prescription of melatonin had a 90% higher chance for heart failure, but those with documented 2 prescriptions of melatonin had an 82% higher chance. Appropriate dose responses are often a great way to poke holes in “causal” links. If X causes Y, then more X should cause more Y. Not so here. On the other hand, if we look at dose response relationships between sleep problems and cardiovascular events, we see clear dose-response patterns: the worse the sleep problem (more symptoms, more irregular timing, or the combination of insomnia with objectively short sleep), the higher the risk of events such as heart attack, stroke, or heart failure. Also, if melatonin helps alleviate a person’s insomnia, then in theory, the more melatonin prescriptions, the fewer sleep disturbances, and thus fewer heart attacks. So maybe melatonin actually reduces heart attacks! (To be clear, we don’t know the answer and absolutely cannot draw that conclusion either — but you see what I’m getting at here by saying this study should be thrown out with the garbage.)

In addition, the study design is ripe for other confounders. For example, the “non-melatonin” group likely contained many over-the-counter (OTC) melatonin users whose purchases never hit their medical chart — the study did not actually survey these study participants; it was just a records review. How many people don’t tell their doctor about an OTC medication? Exactly. Potential misclassification makes all of this data noisy.

Anywho, this is one of the oldest traps in science communication: association in a health-record study gets reported as causation in the media. Whenever you see a strong claim from an abstract, stash it under “interesting, not definitive,” and look for the peer-reviewed paper (or send me the headline!) rather than buying into sensational influencer headlines.

Some fun facts on melatonin to geek out on with me!

• Potential cognitive benefits. There’s early evidence for cognitive benefits from melatonin in Mild Cognitive Impairment. Pooled results from a large meta-analysis just this month indicated that melatonin for 13-14 weeks significantly improved cognitive function in adults with cognitive impairment. More studies needed to confirm this early finding and the dosages used in these studies were HIGH (0.15 mg/kg… so about 10.5 mg/night in a 70 kg person for one study and 25 mg/night in another earlier study).

• Potential gut health benefits. The gut makes and stores lots of melatonin— possibly hundreds-fold more in the GI tract than in the pineal gland (brain source of melatonin) and the intestine also expresses melatonin receptors. Cool! There are several lines of research showing potential benefit in IBS, GERD, and ulcers when melatonin is added to standard of care treatment. Mostly small studies, but a biological mechanism is plausible given the inflammatory nature of the aforementioned conditions, melatonin’s antioxidant properties, and the presence of melatonin receptors in GI system.

• Melatonin tends to decrease with age. Kids and teens have the highest melatonin levels and young adults usually maintain robust peaks. But after midlife (50s), average amplitude fades, and by the 70s–80s typical peaks are roughly half (or less) of young-adult values. Numerous studies have looked at levels throughout the lifespan and the data is admittedly noisy with big interindividual variability. There is some data indicating very healthy older adults can still show “youthful” melatonin levels in controlled lab settings. In any event, given the usual decline with age, I have my parents (70s) take low dose melatonin every night irrespective of sleep issues.

• Impact on endogenous production. Even long-term nightly use does not appear to suppress the body’s own melatonin in trials that measured it. In adults using 12 for months, stopping melatonin did not reduce urinary 6-sulfatoxymelatonin (the main melatonin metabolite) and did not trigger rebound insomnia. If you are looking for a physiological dose (matching what the body would naturally make), stick with ~0.3 mg dose.

• Migraine help. A growing body of research indicates melatonin may be helpful in migraine treatment. For example, in chronic migraine, an 8-week double-blind trial compared melatonin 3 mg to valproic acid 200 mg and placebo as *add-on* therapy. Melatonin performed about as well as valproate and better than placebo on headache outcomes. (Note: this was add-on therapy, meaning that the patients stayed on other migraine baseline medication so external validity is limited.) There are several other headache studies showing modest benefits as well.

• Less can be more for sleep. There is some research showing 0.3 mg melatonin can improve sleep efficiency and restore normal-night melatonin levels just as well as 3 mg and without next-day grogginess sometimes seen with higher doses. Evidence supports starting low (~0.3–1 mg immediate-release or 2 mg extended-release) and then titrating up if needed. A 2024 dose-response meta-analysis of 26 randomized controlled trials found benefits generally peaked around ~4 mg/day, with no clear advantage above that. The fact that so many supplement lines ONLY have dosages 5 mg or higher is a complete marketing scam imho to make you feel like you’re getting more bang for your buck. (If you have Rem Behavior Disorder or other rare conditions, there is data supporting higher dosing above even 10 mg but that is a very unique use case and does not apply to the general population.)

If you are interested in trying melatonin after discussing with your doctor, these are several brands that I have vetted for good quality controlled third party testing data (no affiliation with any of these or any supplements for that matter):

• Life Extension, 0.3 mg (aka 300 mcg)

• Life Extension, 1.5 mg, Immediate + Extended Release Combo

• NOW Foods, 3 mg (they also have a Sustained Release 5 mg here for those who find they do need a stronger dose after trying lower increments)

It is also important to note that there are plenty of trials showing melatonin did NOT improve sleep more than placebo; so while it may help for certain individuals, it is definitely not a panacea for all sleep issues!

Which leads me to Part 2 of this post where I’m going to do a deep dive on what the research says on other sleep aids — from ashwagandha and herbal remedies to Ambien and the latest dual orexin antagonists (my favorite!). Teaser… most sleep aids have the potential to be no bueno for your brain *if used chronically*. However, there are a few that actually improve sleep architecture which could plausibly reduce long term risk of dementia and cognitive decline. Subscribe here if you want the download on these . . .

As always, none of this is medical advice. You should talk with your doctor before starting any medication or supplement, even over the counter ones!

Stay tuned and subscribe for upcoming articles, including:

• Supplement Vetting: How to Know Which Supplements (if any!) To Trust?

• Kids MultiVitamins: How to Choose and Do Kids Even need a Multi?

• Statin Chattin’ — Ask your doctor about THIS before going on a statin

• To HRT or not to HRT: Hot Flashes, Cold Facts on Hormone Replacement Therapy

• My Top 5 WORST Quality Controlled Supplements— Consumers Beware!

Sources:

• Nnadi, E. E., Fox, S., Kanagasingam, T., & Rahimi, L. (2025). Effect of Long-term Melatonin Supplementation on Incidence of Heart Failure in Patients with Insomnia. Circulation, 152(Suppl 3), A4371606. Presented at the American Heart Association Scientific Sessions 2025.

• Laugsand, L. E., Strand, L. B., Platou, C., Vatten, L. J., & Janszky, I. (2014). Insomnia and the risk of incident heart failure: A population study. European Heart Journal, 35(21), 1382–1393.

• Huang, T., Mariani, S., & Redline, S. (2020). Sleep irregularity and risk of cardiovascular events: The Multi-Ethnic Study of Atherosclerosis. Journal of the American College of Cardiology, 75(9), 991–999.

• Chaput, J.-P., Biswas, R. K., Ahmadi, M., Cistulli, P. A., Rajaratnam, S. M. W., Bian, W., St-Onge, M.-P., & Stamatakis, E. (2024). Sleep regularity and major adverse cardiovascular events: A device-based prospective study in 72,269 UK adults. Journal of Epidemiology & Community Health, 79(4), 257–264.

• Sofi, F., Cesari, F., Casini, A., Macchi, C., Abbate, R., & Gensini, G. F. (2014). Insomnia and risk of cardiovascular disease: A meta-analysis of cohort studies. International Journal of Cardiology, 176(3), 1044–1047.

• Bertisch, S. M., Pollock, B. D., Mittleman, M. A., Buysse, D. J., Bazzano, L. A., Gottlieb, D. J., & Redline, S. (2018). Insomnia with objective short sleep duration and risk of incident cardiovascular disease and all-cause mortality: Sleep Heart Health Study. Sleep, 41(6), zsy047.

• Liu, X., Li, C., Sun, X., Yu, Y., Si, S., Hou, L., Yan, R., Yu, Y., Li, M., Li, H., & Xue, F. (2021). Genetically predicted insomnia in relation to 14 cardiovascular conditions and 17 cardiometabolic risk factors: A Mendelian randomization study. Journal of the American Heart Association, 10(15), e020187.

• Lange, T., Perras, B., Fehm, H. L., & Born, J. (2003). Sleep enhances the human antibody response to hepatitis A vaccination. Psychosomatic Medicine, 65(5), 831–835.

• Vgontzas, A. N., Papanicolaou, D. A., Bixler, E. O., Kales, A., Tyson, K., & Chrousos, G. P. (1999). Circadian interleukin-6 secretion and quantity and depth of sleep. The Journal of Clinical Endocrinology & Metabolism, 84(8), 2603–2607.

• Leung, L.YL., Tam, HL., Asiamah, N. et al. Effect of melatonin on cognitive function in adults with cognitive impairment: a multi-dimensional meta-analysis of randomized trials. Alzheimer’s Research & Therapy 17, 238 (2025).

• Gonçalves, A. L., Martinez, D., Bacaltchuk, J., et al. (2016). Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. Journal of Neurology, Neurosurgery & Psychiatry, 87(10), 1127–1132.

• Alstadhaug, K. B., Odeh, F., Salvesen, R., Stjern, M., & Bekkelund, S. I. (2010). Prophylaxis of migraine with melatonin: A randomized, double-blind, placebo-controlled crossover study. Neurology, 75(17), 1527–1532.

• Ebrahimi-Monfared, M., Sharami, S. R., Ghavami, Y., et al. (2017). Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial. Restorative Neurology and Neuroscience, 35(4), 385–393.

• Gelfand, A. A., Kroon Van Diest, A. M., McDonald, J. C., et al. (2023). Melatonin for migraine prevention in children and adolescents: A randomized, double-blind, placebo-controlled trial after single-blind placebo lead-in. Headache: The Journal of Head and Face Pain, 63(9), 1314–1326.

• Peres, M. F. P., Zukerman, E., da Cunha Tanuri, F., Moreira, F. R., & Cipolla-Neto, J. (2017). The role of melatonin in the treatment of primary headache disorders. Headache: The Journal of Head and Face Pain, 57(7), 1093–1108.

• Rizk, H., Mohamed, S. A., & El-Sayed, S. M. (2022). Melatonin as a treatment for migraine sufferers: A systematic review. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 58(1), 82.

• Cruz-Sanabria, F., Bruno, S., Crippa, A., et al. (2024). Optimizing the time and dose of melatonin as a sleep-promoting drug: A systematic review of randomized controlled trials and dose–response meta-analysis. Journal of Pineal Research, 76(5), e12985.

• Song, G. H., Leng, P. H., Gwee, K. A., Moochhala, S. M., & Ho, K. Y. (2005). Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: A randomised, double-blind, placebo-controlled study. Gut, 54(10), 1402–1407.

• Faghih Dinevari, M., Jafarzadeh, F., Jabbaripour Sarmadian, A., Abbasian, S., Nikniaz, Z., & Riazi, A. (2023). The effect of melatonin on irritable bowel syndrome patients with and without sleep disorders: A randomized double-blinded placebo-controlled trial. BMC Gastroenterology, 23, 135.

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Peak travel and peak viruses love each other. Two old-school nasal sprays—one antihistamine (azelastine) and one seaweed-derived barrier (iota-carrageenan)—now have randomized human data suggesting they can lower the risk of infection when used regularly during high exposure events (such as air travel, parties, etc).

Azelastine nasal spray (allergy spray):

A phase 2 randomized, double-blind controlled trial (my favorite kind of trial!) gave azelastine 0.1% nasal spray three times daily and SARS-CoV-2 infections fell by about 67% versus placebo spray. Azelastine spray also reduced rhinovirus (common cold) infections by ~71%. Not bad! JAMA Network, Nov 2025.

How people can get it:

• United States**: Azelastine 0.15% (brand Astepro Allergy) is over-the-counter (OTC) for allergies.

• Europe: Allergodil 0.1% is widely sold in pharmacies (often pharmacy-only, no prescription needed in many countries).

** While OTC is available, it is important to note that the study used a lower dosage than OTC. The lower dosage is available by prescription only. The COVID prophylaxis is likely bolstered by repeated use rather than 1x/day (keep the mucosal lining coated as often as possible). So it may be better to have lower dosing to allow more frequent sprays.

Here is a draft note I wrote to my doctor in case it is helpful for you to have a discussion with your doctor:

Dear Doctor,

I am having seasonal allergies. Could you please call in a prescription for azelastine nasal spray .1% (137 mcg per spray /generic Astelin/Astepro 0.1%) PRN for sneezy itchy nose/ [indication XX—FYI, seasonal allergies help here 😉]?

I know extra strength is available OTC, but if I will use it more regularly, I want the lowest effective dose of 0.1% rather than .15%.

Also, I just read this study: https://pubmed.ncbi.nlm.nih.gov/40892398/. The COVID prophylaxis may be bolstered by repeated use rather than 1x/day which could be helpful during the significant work travel coming up in the next few weeks.

Thanks,

Yours Truly.

And if you do get Covid this holiday season, there are signals that early intervention with azelastine nasal spray may also reduce viral load. That could mean less sick days and more egg nog days ahead!

Iota-carrageenan nasal spray (seaweed-derived barrier):

A multicenter, double-blind RCT asked hospital workers to use an iota-carrageenan spray 4 times daily for 21 days. PCR-confirmed symptomatic COVID-19 fell by ~80% compared to placebo spray.

How people can get it:

• United States: ePothex Saline Nasal Spray with Iota Carrageenan. (no affiliation; also on Amazon)

• Europe: Boots Dual Defence (no affiliation, others are available online).

I typically alternate between iota-carrageenan spray and azelastine spray throughout the day when traveling.

Caveats!

• Saline vs Above Nasal Sprays?

  • My hunch is that the placebo vehicle spray in these studies might have offered a small barrier effect independent of “drug” (i.e. azelastine / iota-carrageenan) — we have seen this with other nasal sprays such as Xylitol and even plain ‘ol saline rinses. That said, perhaps differences between intervention vs no intervention would have been even more pronounced if the “placebo” were not a nasal spray. But if you can’t afford or get access to either of the above products, there is a plausible argument that saline nasal spray alone could provide some protection (no studies document this however).

• Side effects?

  • Azelastine can cause a bitter/metallic taste (common) and less commonly: drowsiness, nasal discomfort, nose bleeds.

  • Carrageenan sprays can burn a little when it hits those sniffers but generally well tolerated. Some report mild nasal irritation, dryness, sneezing — rates similar to saline placebo in trials.

• Study weaknesses?

  • Azelastine: Single center; relatively young, mostly vaccinated participants; low event counts; the spray’s bitter taste could partially unblind but placebo also had metallic flavor added. A correction to the paper (figure and a sentence) was issued on November 3, 2025. Findings need confirmation in larger, multicenter trials. JAMA Network

  • Iota-carrageenan: Trial ran in 2020 unvaccinated healthcare workers (unique population) with symptom-triggered PCR, and follow-up was short (21 days)—so generalizing to today’s vaccinated travelers and community transmission patterns is imperfect. Larger modern trials were registered but results have not been published.

None of this is medical advice. You should talk with your doctor before starting any medication or supplement, even over the counter ones!

Sources

• Efficacy of a Nasal Spray Containing Iota-Carrageenan in the Postexposure Prophylaxis of COVID-19 in Hospital Personnel Dedicated to Patients Care with COVID-19 Disease. Int J Gen Med. 2021;14:6277-6286

• Lehr T, Meiser P, Selzer D, et al. Azelastine Nasal Spray for Prevention of SARS-CoV-2 Infections: A Phase 2 Randomized Clinical Trial. JAMA Intern Med. 2025;185(11):1309–1317.

• Klussmann JP, Grosheva M, Meiser P, Lehmann C, Nagy E, Szijártó V, et al. Early intervention with azelastine nasal spray may reduce viral load in SARS-CoV-2 infected patients. Scientific Reports. 2023;13:6839.

• Meiser P, Flegel M, Holzer F, Groß D, Steinmetz C, Scherer B, Jain R; CARVIN-II Study Group. Azelastine Nasal Spray in Non-Hospitalized Subjects with Mild COVID-19 Infection: A Randomized Placebo-Controlled, Parallel-Group, Multicentric, Phase II Clinical Trial. Viruses. 2024;16(12):1914.

Stay tuned and subscribe for upcoming articles, including:

• Melatonin causes heart attacks?!? Bad science and the sleep-aid maze

• Supplement Vetting: How to Know Which Supplements (if any!) To Trust?

• Kids MultiVitamins: How to Choose and Do Kids Even need a Multi?

• Statin Chattin’ — Ask your doctor about THIS before going on a statin

• To HRT or not to HRT: Hot Flashes, Cold Facts on Hormone Replacement Therapy

• My Top 5 WORST Quality Controlled Supplements— Consumers Beware!