Omega-3 Supplements May Increase Risk of Cognitive Decline, Scientists Warn

#51

In the uk it is not a prescription drug

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#52

It is: https://www.medicines.org.uk/emc/product/12964/smpc

#53

Yes and I posted a critique of the study but you simply ignore anything that doesn’t fit your agenda. Also, quite hard to believe you feel a significant effect from a single fish oil capsule. Does eating salmon make you lazy and depressed as well? I’m sorry but a single fish oil capsule doesn’t move the needle strong enough 1 way or another for me to truly believe someone feels the effect of it. Long term I can believe it. Single pill… nope. There are several studies showing fish oil benefits depression as well as meta-analysis but you haven’t posted any of those in your quest to report the unbiased science.

Massive doses in mice and shaking their brains doesn’t negate the bulk of epidemiologic, prospective/retrospective data, and meta analysis arguing that fish oil may have a benefit or perhaps no/minimal effect. Furthermore, a lot of longevity “experts” in this space and I don’t see anyone else sharing your view? If anything, they are exposing the flaws of the recent study that you haven’t commented on. Dementia study not looking at vascular heath? Education? Hypertension? LDL? Socioeconomic status? Past medical history? Sounds well controlled…

Your hypothesis was generated because the google autofill of sleepy was in the top hits and there’s a Reddit thread about it? Thank you for recommending Reddit to me.

#54

Yeah, that’s exactly why I’ve said before that Omega-3s are the most complicated anti-aging compounds out there. You’d probably need to sift through hundreds of papers just to make the right call, and you have to scrutinize every single one of them. A meta-analysis just can’t cut it for this kind of thing.

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#55
#56

What are you saying? I’m talking about the dozens of studies that point to detrimental effects of DHA supplementation that I posted here: Omega-3 Supplements May Increase Risk of Cognitive Decline, Scientists Warn - #2 by adssx

My own experience with DHA supplementation is purely anecdotal and it’s just what led me to dig deeper into that compound. What matters is the evidence above.

Regarding so-called “experts”. I emailed some of them the above papers and most did not answer (even though they were answering before when I was telling them things aligned with their views). I emailed Matt Kaeberlein and he said first “I don’t really disagree with your position, although I don’t find the evidence against DHA to be all that convincing. Having said that, I haven’t closely read all the latest literature in this space, mostly because of time constraints and also because I get frustrated at how poorly many of these studies are designed and/or analyzed. […] I do agree the evidence for benefit from supplementation tilts toward EPA for many outcomes, at least for now. The one I take is 3:1 EPA:DHA.” I then sent more evidence and he said: “You’ve convinced me I need to become more informed on this topic. Now I just need to find the time to do it!” I think later on he mentioned rapamycin.news in a podcast (@RapAdmin might know better) and said he was changing his view on omega 3 supplementation thanks to interactions here (iirc).

Regarding other “experts”, think about what Charlie Munger said: “Show me the incentive and I’ll show you the outcome.” Do you think someone who has recommended omega 3 supplementation for years if not decades to thousands of followers has an incentive to look at the evidence against omega 3 supplementation? Even worse for those “experts” who sell omega 3 supplements or include them in their own branded supplements.

So you can make up your own mind by looking at the raw data: the original papers. Instead of blindly following “experts” whose incentives might not be aligned with yours.

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#57

I tried getting Gemini and Claude to review the studies referenced on this thread and to expend the potential sources for making an informed conclusion for when and if EPA or DHA supplementation is supported.

TL;DR - sometimes EPA helps, maybe skip it outside those few areas.

Oral omega-3 supplementation must be strictly tailored by clinical phenotype, as standard commercial use is often ineffective or potentially harmful.

Summary of Key Findings on Omega-3 Suitability

When Appropriate:

  1. Secondary Cardiovascular Prevention: High-dose purified EPA (4 g/day icosapent ethyl) is indicated on a statin background for patients with elevated triglycerides (\ge 150 mg/dL) and established cardiovascular disease or diabetes.
  2. Prodromal Alzheimer’s Disease (MCI): Isolated omega-3 fails, but structured multinutrient formulations (Fortasyn Connect/Souvenaid) providing DHA and EPA alongside uridine, choline, and antioxidants show significant slowing of cognitive-functional decline and brain atrophy over 36 months by synergistically feeding the Kennedy pathway.
  3. Major Depressive Disorder: EPA-predominant formulations (\ge 1 g/day) serve as effective clinical adjuncts.
    When Neutral or Harmful:
  4. Primary Prevention & Cognitive Decline: Standard supplementation does not prevent cognitive aging in healthy older adults. In the ADNI cohort, late-life omega-3 supplement use was associated with accelerated cognitive decline mediated by longitudinal FDG-PET cerebral glucose hypometabolism, potentially due to docosahexaenoic acid hydroperoxide (DHA-OOH) lipid peroxidation inducing mitochondrial dysfunction.
  5. Genetic Subgroups (APOE4): High-dose DHA (2 g/day) successfully increases brain DHA but shows no cognitive or structural benefit in cognitively unimpaired $APOE\ \varepsilon4$ carriers.[1]
  6. Brain Trauma / TBI: High-dose EPA is contraindicated following repetitive mild TBI; it suppresses post-injury angiogenic signaling and impairs microvascular repair, triggering blood-brain barrier instability and cortical perivascular tauopathy.[2, 3]
  7. AF & Longevity Risk: Doses >1 to 1.5 g/day increase atrial fibrillation risk in high-CVD populations.[4] Furthermore, fish oil fails to extend lifespan in rigorous heterogeneous mouse models (ITP).

The 20 Most Important Studies for Omega-3 Efficacy & Safety

  1. REDUCE-IT (2019)
  • Findings: Established that 4 g/day of pure EPA (icosapent ethyl) reduces major adverse cardiovascular events (MACE) by 25% in statin-treated patients with elevated triglycerides.
  • Link:(ClinicalTrials.gov)
  1. STRENGTH (2020) [4]
  1. JELIS (2007) [5]
  1. RESPECT-EPA (2024) [4]
  1. ASCEND (2018)
  1. VITAL (2019)
  1. VITAL-Cognitive Substudy (2022)
  1. AREDS2 Cognitive Substudy (2015)
  1. MAPT (2017)
  1. Liao et al. (ADNI Analysis, 2026) [6]
  1. Albayram et al. TBI Study (2026) [2, 3, 7]
  1. PreventE4 (2025) [1]
  1. ADCS DHA Clinical Trial (Quinn et al., 2010) [8, 9]
  1. Karolinska OmegAD Trial (Freund-Levi et al., 2006)
  1. OmegAD CSF Study (Freund-Levi et al., 2014)
  1. LipiDiDiet 36-Month Trial (Soininen et al., 2021) [10]
  1. NIA Interventions Testing Program (Strong et al., 2016)
  • Findings: Standard medical-grade fish oil failed to extend lifespan in genetically heterogeneous mice, with the high-dose (50,000 ppm) actually shortening male lifespan by 18% at one site due to lipid peroxidation.
  • Link:(Fish oil supplements, longevity and aging - PMC)
  1. Gencer et al. Atrial Fibrillation Meta-Analysis (2021) [4]
  1. Rancho Bernardo Study (Lopez et al., 2011)
  • Findings: Long-term observational data showing that high dietary and plasma DHA levels were associated with a 72% to 73% lower risk of all-cause dementia and Alzheimer’s disease.
  • Link:(Checking your browser - reCAPTCHA)
  1. Witte et al. Clinical Trial (2014) [11]
  • Findings: 2.2 g/day fish oil for 26 weeks improved executive functions, enhanced hippocampal grey matter volume, and preserved white matter microstructural integrity in healthy older adults.
  • Link:(Checking your browser - reCAPTCHA)
#58

Thanks @John_Hemming this is exactly my point: they market it as EPA only but in reality check the ingredients they added 100 mg DHA. This the case for all the “pure EPA” / “Mega EPA” / whatever seems EPA only that I found in EMEA. Sometimes the same brand sells real EPA only in the US (and you can import it from iHerb) but in Europe they sell those ersartz. My assumption is that EPA only in Europe got some kind of protection due to the existence of that Rx product. I might be wrong but I don’t see any other explanation.

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#59

Even more so when the vast majority of papers looking at “omega 3” are low-quality small studies from Iran, China or else (with all due respect to those countries). Meta-analysis: Garbage in, garbage out.

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#60

Thanks a lot @zebit0 for doing the work! I’ll do it later with ChatGPT 5.5 and send the link. I agree with Gemini’s and Claude’s conclusion (unfortunately!).

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#61

The research review left me thinking: maybe get my omegacheck or omega quant test done (since I’m mostly plant based and eat zero fish), but unless well out of or quite low range, then I’m not getting more Sport Research fish-oil for now on.

#62

The issue on medicines is that if something is sold as a medicine then it is subject to the medicinal regulations. I had not spotted that the pure EPA contained also about 10% DPA. To what extent that is reasonable I don’t know. I would think most people have some DPA in their diet and taking too much might be an issue.

My guess is that with distillation it becomes hard to get below 10% DPA.

#63

No: in the US there are plenty of pure EPA only products with 0 DHA. Sometimes the same brand sells pure EPA in the US only and 90% EPA in Europe only.

Is that an issue? Maybe not.

#64

Regarding other “experts”, think about what Charlie Munger said: “Show me the incentive and I’ll show you the outcome.” Do you think someone who has recommended omega 3 supplementation for years if not decades to thousands of followers has an incentive to look at the evidence against omega 3 supplementation?

Similar for your stance. You’ve selected only negative studies to support your view since obviously this is something you feel strongly about. Unfortunately, that’s not the entire picture and honestly nobody knows the answer. Had you presented an argument with equal emphasis on both sides of the data I’d be less critical of your approach. There is a big gap between arguing lack of benefit vs actual harm. Especially when your basis is a rat study with massive doses in an artificial environment and a poorly controlled human study with previous study from the same database showing the exact opposite. Everyone is tearing apart the Stanfield study for its shortcomings, but this ADNI PET study is being taken as the fact. I spent an entire 10 minutes grabbing the studies below. Not that hard to show the data isn’t as lopsided as you present.

It’s not hard to cherry pick studies:

“DHA supplementation improved both memory and reaction time in healthy young adults: a RCT.” 2013

“Oxidative stress in endurance cycling is reduced dose-dependently after 1 month of re-esterified DHA supplementation.” 2020 - Doesn’t seem very pro-oxidant in this study?

Effects of DHA supplementation on hippocampus volume and cognitive function in older adults with MCI. 12 month double blind RCT. 2017. DHA improved test scores, hippocampus volume, global cerebral volume

Modulation of blood cell gene expression by DHA supplementation in hypertriglyceridemic men." 2011

Association of DHA supplementation with Alzheimers disease stage in APOE4 carriers. A Review." 2017

A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: the Comparing EPA to DHA (ComparED) Study. DHA more effective at modulating inflammation than EPA.

Dietary Docosahexaenoic Acid-Rich Supplementation Decreases Neurotoxic Lipid Mediators in Participants with Type 2 Diabetes and Neuropathic Pain. 2024

The effect of omega-3 fatty acids on a biomarker of head trauma in NCAA football athletes: a multi-site, non-randomized study. 2021.

#65

This is exactly what I did. As you can see here I was initially thinking that one should supplement with DHA or EPA based on the omega 3 test and that both were beneficial: Omega 3 for neuroprotection: EPA vs DHA? (I later updated that post)

I changed my mind after a careful review of the literature.

Of course you can find papers pointing to the other direction. But not all papers are equal. A large, long, high-quality RCT done by Tier 1 institutions and published in a Tier 1 journal such as VITAL-DEP will always be better than an old low-quality association study for instance.

For instance you cited Effects of DHA Supplementation on Hippocampal Volume and Cognitive Function in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized, Double-Blind, Placebo-Controlled Trial

This was a randomized, double-blind, placebo-controlled trial in Tianjin, China. 240 individuals with MCI aged 65 years and over were recruited and equalized randomly allocated to the DHA or the placebo group. Participants received 12-month DHA supplementation (2 g/day) or corn oil as placebo.
A total of 219 participants (DHA: 110, Placebo: 109) completed the trial. The change in mean serum DHA levels was greater in the intervention group (+3.85%) compared to the control group (+1.06%). Repeated-measures analyses of covariance showed that, over 12 months, there was a significant difference in the Full-Scale Intelligence Quotient (ηp2 = 0.084; p = 0.039), Information (ηp2 = 0.439; p = 0.000), and Digit Span (ηp2 = 0.375; p = 0.000) between DHA-treated versus the placebo group. In addition, there were significant differences in volumes of left hippocampus (ηp2 = 0.121, p = 0.016), right hippocampus (ηp2 = 0.757, p = 0.008), total hippocampus (ηp2 = 0.124, p = 0.023), and global cerebrum (ηp2 = 0.145, p = 0.032) between the two groups.

2016, tier 2 (or 3) Chinese university (back then) but great journal.

They used corn oil as placebo which had been criticized in some cardiovascular trials.

But since then we have the larger (n=365) and longer (2y), done by USC that found… Nothing! 2g/day of DHA for 2 years has no impact on cognition or hippocampal volume (placebo was “50% corn oil and 50% soy oil”, I don’t know how much better that is vs 100% corn oil)

And we have other meta-analyses and papers that found… Nothing! Or even detrimental impact. So this 2016 paper is mostly discarded (unless you come up with a theory explaining why the 2016 one found benefits while all others did not, could be the enrolled population, the genes, the product used, etc.).

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#66

Btw you cited “Association of DHA supplementation with Alzheimers disease stage in APOE4 carriers. A Review.” 2017", authored by Hussein N Yassine, the lead PI behind the failed PreventE4 trial. It seems that now Yassine has given up on omega-3 supplementation.

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#67

  1. Fish oil, omega-3s: Many studies were subsidized and heavily promoted by both the fish industry and the supplement industry. Mainly derived from observations that many long-lived populations ate a lot of fish. Then, making the leap, it must be the Omega-3s.

  2. The negative consequences could make you worse off than taking none at all.

  3. Just eat more fish; this is a more proven benefit without the negative consequences.

  4. Look at your supplement list. Do you want to add one more iffy supplement?

My point is that there is insufficient evidence of any benefit to warrant adding it to my supplement list, especially since the consequences could be detrimental to my aging brain if the “good” studies turn out to be wrong.

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#68

Here’s ChatGPT 5.5 Thinking Extended Deep Research. It took 58 minutes and 401 searches to output the result. I specifically mentioned the studies you listed @Shady. I mentioned others on the “anti-omega 3” side but I forgot VITAL-DEP and PreventE4 (I later mentioned them). Still, the conclusion is roughly aligned with what I said: ChatGPT - Omega-3 and Mental Health

Bottom line: EPA may have a niche role in depression treatment; DHA/fish oil for cognition or dementia prevention remains unproven.

For a supplement that is so hyped and has been studied for years, if not decades, this shows it’s useless.

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#69

@zebit0 I also don’t eat fish (and am apoe3/4), so I’m forever feeling overwhelmed re this topic. Based on all of Adssx’ good work, if I ate fish, I don’t think I’d even supplement at this point….but I don’t, so as you suggest, I suppose the omega index should be our guide (me guessing).

In his recent omega YouTube, Brad Stanfield mentioned the issue with oxidation and how it causes harm. I asked Claude Opus and ‘he’ said algae oil is much less likely to oxidize. But having said that, there is only one source of epa only algae oil… so here I stand between a rock and hard place.

I did start taking Accentrate LPC which is fish oil, but I’ve since learned it is not a slam dunk, so I’m not sure I’ll repurchase.

#70

Honestly it makes sense bc of how massively PUFA they are - at least supplement with choline and nexlizet instead…