2g/day of DHA for 2 years has no impact on cognition or hippocampal volume

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@CronosTempi

But there was the opposite argument that this increased “efficiency” is not necessarily beneficial, because we have the example of how less efficient mitochondria (or intentionally slightly hobbled mitochondria) promote longevity (purported mechanism for metformin) - less efficient mitochondria generate less ROS.

Any thoughts on this @John_Hemming ?

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@relaxedmeatball

IMO, if they continue this out to 5 years, then I’ll totally rule it out as having any effect.

Then you have the VITAL-DEP trial: almost 20k people over more than 5 years and they found an increased risk of depression. So based on your own stop criteria you should stop.

@relaxedmeatball

For me personally (38y male), I take DHA and EPA (combined, as fish oil) at a modest dose, simply to address potential deficiency (because I have almost zero seafood in my diet). I don’t personally take a view that there’s anything magical about it, and if there’s any conclusive evidence that taking it is a net negative, then I’ll stop. I have no ideological position on this. That said, I think all the studies you shared above showing negative correlations and links to diseases are really interesting, and tend to get lost in all of the hype. Thanks for sharing.

I had the same reasoning as yours until I read the evidence:

• Vegans who eat 0 fish don’t have a higher risk of CVD or dementia (actually their risk is lower)
• The risk is only higher for people with zero fish intake and a low quality diet (“American diet”)
• For DHA there is evidence that it is a net negative: trend towards shorter lifespan in the ITP + trend towards detrimental for CVD in Mendelian randomization + slightly increased risk of depression in the very very large VITAL-DEP trial.
• Please also consider that there is a HUGE publication bias in academia: only papers showing a positive association tend to be published. And on top of that there’s a huge hype bias: only positive results (“omega 3 extends lifespan”) are shared by bullshit influencers such as Peter Attia and Rhonda Patrick. They don’t share “Hundreds of MR studies found that omega 3 were useless for hundreds of diseases”. So when reviewing the literature you should give way more weight to negative results.
• There are also unknown risk when you take any kind of supplements: supply chain issue, production issue, pollutants or heavy metals in the supplements, wrong dose, wrong compound, etc.
• And of course there’s the opportunity cost: instead of taking supplement X (and spending time and money to find the best one, read the literature, etc.), what else could you do?

So here again, based on your own stop criteria, you should stop supplementing.

[AnUser]

“We absolutely do not recommend people universally take fish oil … fish oil have very few robust indications, based on the REDUCE-IT trial, we recommend EPA only fish oil for certain individuals meeting criteria with type 2 diabetes, certain cardiovascular risk factors and high triglycerides, other than that, we do not recommend fish oil. Fish oil can actually increase the risk of bleeding, increase your risk of arrhythmia, things like atrial fibrillation, so although the research is very clear that eating fatty fish two times a week, substituting red meat for eating fatty fish, salmon, mackarel, like that, incredibly healthy, multitude of cardiovascular benefits, but taking fish oil is not necessarily going to be beneficial, and can actually raise your LDL cholesterol” - Danielle Belardo.

Doctor Blocks Me For Correcting Him

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[relaxedmeatball]

Very, very interesting. Thanks for sharing. I’m going to do some more reading and take this into consideration and I may end up stopping supplementation. You are definitely right about the publication bias and hype bias. I’m in academia (though basic research, not clinical studies) so I know how that side of things goes. However, I definitely trusted opinions of Attia, Bill Harris etc. (Thinking about this, now I realise Bill has assays, RBC omega index etc to sell…) As you said, it’s just not possible to read everything for myself, and everybody, everywhere is saying fish oil is great, anti-inflammatory, anti-fibrotic, reduces clotting risks etc etc, and it’s in everybody’s stack. Thus, it becomes a no brainer that I honestly never thought to question.

So, aside from VITAL-DEP, what else should I read? I saw a related JAMA study that DHA also failed for dry eye disease. Can you please link me to the MR studies?

[adssx]

I put the gist of my anti-DHA diatribe here (RCTs + MR + animal + mechanistic): Vitamin O (Omega 3) for athletes - #4 by adssx

Like you, I believed trusted opinions and some association studies, so I started supplementing with EPA + DHA until I realized it made me depressed. So I stopped it and did my own research. Bill Harris is definitely biased as he’s selling his bullshit tests. I emailed + tweeted to OmegaQuant some of the above results and they never got back to me (they got back to me on other things before so they definitely got my email ). Peter Attia does not strike me as particularly intelligent but I assume that, if presented with the results, he would change his mind. Although it’s hard when you told people to do something for years to suddenly say “Actually what I said before was harmful, don’t do it!”. Better to just say nothing.

[relaxedmeatball]

Also, in fairness to Attia, this is what he said in the latest “AMA” which came out March 17th 2025. He does mention the negative trials, says VITAL used too low of a dose, didn’t check omega 3 levels. But the cognitive studies are negative across the board, though he continues to recommend high does for APOE4+ patients. The main supporting evidence seems to be this meta analysis of observational studies: https://www.sciencedirect.com/science/article/pii/S0002916523463204

Any thoughts?

Attia show notes below:

Closing the Omega-3 Deficiency Gap: Observational Study Findings

• A study examined Omega-3 index levels in individuals with varying fish intake and supplementation habits.
• Findings:
  • Individuals consuming no fish & no supplements → Average Omega-3 Index ~4.1%
    • Many people fall into this category due to dietary preferences or aversions.
  • Individuals consuming fish 3x per week & taking some Omega-3 supplements → Average Omega-3 Index ~8.1%
    • These individuals fall within the recommended range (8-12%).
• Takeaway:
  • Even three meals of fish per week may not be enough to reach optimal Omega-3 levels without supplementation.
  • Higher-risk individuals (e.g., those with APOE4 genetic variant) may benefit from aiming toward 12% Omega-3 Index through dietary intake or supplementation.

Importance of EPA vs. DHA: Unclear Optimal Ratios

• The Omega-3 Index is the sum of EPA & DHA—the test provides a breakdown of both levels.
  • Example: 8.1% total Omega-3 Index
    • DHA: 5.1%
    • EPA: 3.0%
• Unclear ideal targets for DHA vs. EPA individually
  • APOE4 carriers may benefit from higher DHA levels
  • DHA is crucial for brain health and membrane integrity, particularly for Alzheimer’s prevention.
• Clinical Approach:
  • For higher-risk patients, the goal is to reach 12% Omega-3 Index (via diet or supplements).
  • No preference for EPA vs. DHA-heavy supplements—as long as the total Omega-3 intake reaches recommended levels.

Mechanism of Action: How Omega-3s Work in Disease Prevention

• Primary benefits come from anti-inflammatory & oxidative stress pathways.
• Key Mechanisms:
  • Inhibits NF-κB pathway (reduces inflammation).
  • Reduces VLDL (very low-density lipoprotein) production and enhances hepatic fatty acid oxidation.
  • Lowers triglycerides, but less important today
    • Pharmacologic interventions (e.g., prescription drugs) are more effective for triglyceride reduction.
    • Dietary strategies to reduce excess energy intake are also effective.
• Cardiovascular Benefits:
  • Enhances nitric oxide production → increases vasodilation (widening of blood vessels).
  • Acts as a mild blood thinner → reduces platelet aggregation (lower clotting risk).

Fish Oil for Cardiovascular Disease (CVD): What the Data Says

• Two types of studies:
  • EPA + DHA combination supplements
  • EPA monotherapy (pharmaceutical-grade EPA only)
• Evidence supports secondary prevention, but primary prevention is less clear.
  • Secondary prevention (people with existing CVD):
    • Fish oil supplementation reduces major adverse cardiac events (MACE).
    • Per a 2021 analysis, EPA monotherapy showed an 18% reduction in mortality (but based on only three trials).
    • REDUCE-IT trial: One of the key studies, but its placebo (mineral oil) may have skewed results.
    • Even after excluding REDUCE-IT, data suggests a ~20% reduction in CVD risk.
  • Primary prevention (people without known CVD):
    • VITAL and ASCEND trials found no clear benefit.
    • Potential issue: Studies used only 1 gram of fish oil—may not be a sufficient dose.
    • Lack of biomarker tracking: Studies didn’t adjust dose based on individual Omega-3 levels.

Fish Oil for Cognitive Decline & Alzheimer’s Disease

• Alzheimer’s prevention is difficult to study in RCTs due to the slow onset of disease.
• Mixed results in small clinical trials:
  • OmegAD Study (200 participants, 6 months):
    • DHA: 1.7 g/day, EPA: 0.6 g/day.
    • No overall cognitive benefit except in patients with mild Alzheimer’s.
  • PUFA Trial (100 participants, 3 years):
    • EPA: <1 g/day, DHA: ~0.75 g/day.
    • No reduction in white matter lesions.
    • APOE4 carriers showed better neuronal integrity.
• Observational studies show a 20% reduction in dementia risk with higher Omega-3 intake.
  • Potential confounders:
    • People who eat more fish or take supplements tend to be more health-conscious.
    • Difficult to isolate Omega-3 effects from other lifestyle factors.
• APOE4 Carriers & DHA:
  • APOE4 reduces the ability to increase plasma DHA levels from supplementation.
  • DHA Brain Delivery Pilot Trial:
    • 2+ g/day of DHA led to a 28% increase in CSF DHA levels (shows high doses may be necessary).
  • Ongoing study (PreventE4 by Hussein Yassine):
    • Testing 2 g/day of DHA in APOE4 carriers before dementia onset.
    • Results could clarify long-term cognitive benefits.

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@relaxedmeatball

The main supporting evidence seems to be this meta analysis of observational studies: https://www.sciencedirect.com/science/article/pii/S0002916523463204

Chinese study from a tier 2 university, observational, from 2023. Since then we have MR studies that show that most likely this is not causal.

Thanks for this summary. I started to supplement based on that. However, what is not mentioned (and that made me change my mind):

• VITAL: 1 g/day is not that low, especially over 5 years, and still they found a negative outcome (on depression)
• No mention that vegans with a healthy diet have no problems at all.
• No explanation how the “optimal” or “recommended” omega-3 levels are defined
• No evidence that people with APOE4 benefit more (there’s actually evidence against it, “Higher levels of docosahexaenoic acid in plasma were associated with a greater rate of MCI-to-AD progression.”)
• Mechanisms of action: no mention that dietary DHA self-inhibits its biosynthesis and blunts the benefits of EPA.
• Since then, PreventE4 was published and it’s a total failure despite taking into account the previous criticisms (DHA only, higher dose, longer duration, with vitamin B)
• Also this trial: ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial: 3 years, 975 mg EPA + 650 mg DHA, suggesting that EPA (not DHA) might benefit people with APOE4.
• No mention at all of MR studies that show that DHA and EPA are useless for dementia prevention. That’s, to me, the strongest evidence.

[Virilius]

So what is your conclusion from all of this? Supplement only EPA? Don’t supplement with omega 3 at all? Only take omega 3 with very low DHA?

[adssx]

My conclusion so far:

• DHA: useless at best, detrimental at worst => avoid.
• EPA: might have some benefits for mental health and CVD so if you don’t eat much fish and/or if your omega 3 index is low and/or if you feel better while taking it then 500 mg to 1g/day of pure EPA (in Europe only available as a prescription drug) might be a safe option.
• Otherwise, just eat more fish?

[AnUser]

@relaxedmeatball

fish oil is great, anti-inflammatory, anti-fibrotic, reduces clotting risks etc etc, and it’s in everybody’s stack

Mechanistic speculation, is like the number one sign of quackery for complex diseases. I guess many of us fell for it when we didn’t for other places where it’s commonly used.

It seems like resveratrol on steroids and people having a Mandela effect that we saw some good data in the past, or something. But I might be wrong. The RCT and MR data don’t look too good?

[Olafurpall]

Look into increased expression of uncoupling proteins. Increased uncoupling of mitochondria reduces their efficiency but tends to reduce ROS generation, because oxidative phosphorylation creates ROS as a byproduct. This is thought to be one of the explanation for why some small animal species live longer than some larger ones, despite having increased metabolic rate. Here is one study on this: Mitochondrial uncoupling, ROS generation and cardioprotection - PubMed

[Rapan]

@adssx

Again, they expected an effect size of at least 0.5 SD. That’s why they powered the trial as they did:

Does this make sense? An effect size of at least 0.5 would translate into a “medium” effect as indicated by previous studies. Are there any previous studies which indicated a “medium effect” of DHA on on cognition or hippocampal volume? I don’t think so, but I didn’t research it.

Nevertheless, the absolute effect size in the lecanemab trial (monoclonal antibody medication used for the treatment of Alzheimer’s) was only about 0.2, so “small effect”.

Therefore the estimation (or probably better guess) of at least 0.5 sounds unreasonable to me for a prevention trial using a fatty acid as therapeutic agent.

[dicarlo2]

I would agree. Seems like there was some, or perhaps even a lot, of observational data that indicated benefit, along with mechanistic explanations for almost two decades. Unfortunately, it appears this has not panned out in more rigorous testing via RCTs and MRs.

Add in years of recommendations from authorities (AHA, government, etc), and this is probably more entrenched than Resveratrol.

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@dicarlo2

Add in years of recommendations from authorities (AHA, government, etc), and this is probably more entrenched than Resveratrol.

I don’t know in the US but in Europe health authorities don’t recommend omega 3 supplementation. They just recommend to eat fish. Omega 3 (EPA-only or EPA + DHA) are only approved in people with high triglycerides.

[DeStrider]

To be fair, Omega-3 has reduced my triglycerides. Due to your provided information, I am going to look for a supplement with more EPA and less DHA. I’ll try to avoid DHA as much as possible. Thanks @adssx

[relaxedmeatball]

@adssx

Chinese study from a tier 2 university, observational, from 2023. Since then we have MR studies that show that most likely this is not causal.

Again, thank you for the response and spelling out the evidence.

That said, I think you need to be careful with statements like this one. Yes, I am absolutely distrustful of research from China - especially basic science research. But a meta analysis is something where the source institution shouldn’t matter too much, and the peer review quality of the journal matters more. i.e. whether reviewers bothered to actually check things.

I say this because we’ve already seen how trusting authoritative/prestigious sources with big credentials can be problematic - Attia (Stanford and NIH), Rhonda, Bill Harris etc - because they have more conflicts, biases and staked reputations.

[AnUser]

@adssx

EPA: might have some benefits for mental health and CVD so if you don’t eat much fish and/or if your omega 3 index is low and/or if you feel better while taking it then 500 mg to 1g/day of pure EPA (in Europe only available as a prescription drug) might be a safe option.

What’s a low omega-3 index? This older study suggests that 4.4% is adequate to not be associated with brain aging (lower vs. higher was) ( surrogate? endpoint):

Analyses using the omega-3 index yielded similar results: there was no linear relation to any of the brain MRI measures but low values (Q1 vs Q2–4; below vs above 4.4%) were inversely associated with TCBV [total cerebral brain volume] in all 4 models and positively associated with WMHV [white matter hyperintensity volume] in model A.

Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging 2012

What omega-3 index is adequate, and does EPA only supplement to increase this Omega-3 index enough work, and is it consistent with the optimal amount in association studies or similar with regards to composition of omega-3 index? E.g do we need to look at the EPA and DHA portions of our final omega-3 index and compare it with what’s determined to be optimal, or is it only total index that matters independent of composition?

[AnUser]

I’ve also heard about this before, that the placebo in the Vascepa trial might’ve been harmful. So it’s not a slam dunk for EPA and cardiovascular disease unlike other RCT’s for other compounds. Of course if someone’s indicated then I would of course take it, it’s still good evidence, just takes it down a notch maybe.

The icosapent ethyl group had minimal changes in levels of these biomarkers, whereas the mineral oil placebo group had significant increases, including, at 12 months, 11% for oxidized LDL, 22% for hs-CRP, and 29% for interleukin-1β. At 12 and 24 months, the between-group differences were higher for the biomarkers, including 39% for hs-CRP at 24 months.

https://www.jwatch.org/na55103/2022/07/14/reduce-it-trial-result-doubt

[adssx]

Yes the placebo was shit but I think other trials found similar results and it’s confirmed by Mendelian randomization and association studies. Also seen in animal models. That’s why I’m more confident regarding EPA.