#46

It’s rare to find negative reports on the use of fish oils (other than from Brian Peskin the PEO guy), so I thought I should mention mine. Over the years I have tried fish oils 4 times, trying to source the best of the best out of concerns for rancidity and mercury. Each time I was fine for about 3 days before getting hit with severe fatigue, unable to function and on the couch.

I never thought of it as depression as there did not seem to be any mental/emotional component other than the fear that it might not go away. Stopping the fish oil always resolved the fatigue within 24 to 36 hours. I’ve never been able to find a mechanism of action for this effect. Glad it’s being discussed!

3 Likes
#47

Yes, I don’t know if depression is the best word to describe this, but for me, it’s the same: lethargic and doing nothing. Also resolved after 24–48 hours. I ordered EPA only. I’ll see if it’s better.

3 Likes
#48

For close to two decades, I’ve been consuming one tablespoon of ground flaxseeds 5 times a week. I’ve also been a once/week salmon/sardine consumer. Then about a year ago, I started supplementing with small amounts of EPA, and smaller yet of DHA. Stupidly, I never got my omega-3 index checked before supplementing with the EPA/DHA, which I now regret greatly. I do intend to check it some time not too long from now.

I started with the EPA/DHA because I was worried that I might not be getting enough of DHA:

But recently I came across this, and I’m somewhat conflicted:

1 Like
#49

Make sure you do the most expensive “Complete” test to get the EPA and DHA breakdown.

I would look at more recent papers. n=37 RCT from 2006…

1 Like
#50
4 Likes
#51

@Digby9 @hamida_abdenour @Satchel @Davin8r: as you experienced kind of similar symptoms, do you know you APOE status? (related to this: Omega 3 for neuroprotection: EPA vs DHA? ) I’m E2/E4.

Also, this paper (High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels 2019) concludes:

Interestingly, EPA group improved less than placebo group in impulsivity (commission errors), both overall and in youth with the highest baseline EPA levels, who also showed less improvement in other ADHD and emotional symptoms. […] In conclusion, EPA treatment improves cognitive symptoms in ADHD youth, especially if they have a low baseline endogenous EPA level, while youth with high EPA levels may be negatively affected by this treatment.

Could it be the same for DHA? If already high baseline then supplementing might be detrimental? It would explain the mixed results if you need to supplement based on your baseline + APOE4 status.

3 Likes
#52

I’m negative for ApoE variants.

Omega-3 Fatty Acids 6.82%
Omega-3 Index 5.00%
Alpha-Linolenic (18:3n3) 2.16%
Eicosapentaenoic (EPA, 20:5n3) 0.64%
Docosapentaenoic-n3 (22:5n3) 1.43%
Docosahexaenoic (DHA, 22:6n3) 2.59%

Since this test (May of 2024, I’ve been supplementing with Carlson pure EPA, 1 gram 4 days/week for the past several months (less than 1g/day so that I don’t increase risk of afib). I’ll repeat the test soon.

2 Likes
#53

I also have also experienced depression with omega (dha/epa), and tend to lean towards the choline vs adrenergic hypothesis that you posted about (@adssx) .
There might be more going on with other chemicals, neurotransmitters, signaling stuff etc.
As I have also taken choline bitartrate (w/inositol 250mg each) before and had a similar feeling as I did with epa/dha oil.
Felt like it was inhibiting or lowering some good feeling chemical(s).

Some of the other choline products seem to have good reviews such as citicoline or alpha gpc.
Some brands have products that stack a choline precursor product with L-dopa(or tyrosine) and acetyl-l-carnitine.
So it appears they want to boost choline with dopamine and noradrenaline.
Kind of like activating both the parasympathetic and sympathetic nervous system.
Some of those choline precursor products might be doing a few different things besides targeting choline.

Those were interesting posts you had with Dr Alo vs Dr Lipid on twitter in regards to heart disease.
Too much omega 3, and my blood get’s too thin and it takes much longer to heal from cuts.

In regards to neuroprotection, fish oil might be boosting choline as acetylcholinesterase inhibitor medicines are used for anti-dementia. Maybe it’s doing something else.

5 Likes
#54

Thanks, so we’re similar: average omega-3 index, low EPA, and high DHA. So could DHA supplementation in people with already high baseline DHA be detrimental? :man_shrugging: Is it about the EPA:DHA ratio?

2 Likes
#55

I would say the choline and neurotransmitters idea makes sense because i take modafinil and i feel the fall of dopamine in me as a crash after 6h of moda intake so i bought some tyrosine for that to test it next week and I’m interested in rising dopamine levels with safinamide a MAO-B inhibitor for Parkinson @adssx hint to you if you want to do a deep dive in it and also lately im taking a nicotine 4mg mouth pouche for direct antagonist for the cholinergic preceptors and it saves me from the crash ofter modafinil for the rest of the day plus a super night of lucid dreaming xd

4 Likes
#56

I think I got this from choline. I started supplementing it and just became sad which was continous, like the moment of consciousness before falling sleep was sadness, and still being the case right the moment waking up. That was wild as usually a good night’s sleep would help. It disappeared after quitting it. choline = sad boi for me.

But I don’t think I have noticed anything from EPA/DHA, in fact I used to take high doses while drinking green tea. It felt stimulatory and like I got high, slightly euphoric, colors becoming a bit more vivid, music sounding better. I took like 5-6 grams at a time. There was an examine article on this phenomena way back.

“Sir, no I did NOT inhale. I just took 6 capsules of fish oil”.

4 Likes
#57

Right on. Interesting to hear about the modafinil and dopamine connection. I do recall hearing one of modafinils actions is of a dopamine reuptake inhibitor. Let us know how the tryosine/moda combo goes.

So safinamide, modafinil and tyrosine all together? or just safinamide?

@AnUser Thanks for sharing. It stinks to feel those things from a product that helps many others.
I should have mentioned that I didn’t always get depressive symptoms from EPA/DHA. It might have been from doing various choline products or foods in the same day. Or something else that I am unaware of.
As I don’t always get depressed from choline products either.

Now that you mention the well being feelings(euphoric etc) from EPA/DHA, it might have been related to endocannabinoid system(maybe anandamide or something else).

I’ve also experienced a craving for thc/cannabis after doing various supplements (epa/dha with lecithin, various herb extracts etc).
Which did boost mood but not as high/euphoric as thc would. But I can see various people get the high/euphoric effects as you did.
The craving would last a long time also, like 12-36 hours. Sometimes I’d give in and sometimes I was able to ride it out.
Not a huge thc fan, but do partake at times over the course of a year.

1 Like
#58

I too have always gotten depressed from any kind of cholinergic agonist supplementation that I’ve tried over the years, without fail, starting with lecithin (phosphatidylcholine) when I worked at a health food store in the 1990s. It was supposed to improve my memory and be a “smart drug” but just made me feel depressed.

3 Likes
#59

After a lot of research, I found this paper: Baseline blood levels of omega-3 and depression remission: a secondary analysis of data from a placebo-controlled trial of omega-3 supplements 2017

Journal of Clinical Psychiatry + Washington University, so fairly high quality, although dating a bit. They found:

The percentages of EPA, DHA, and the omega-6 arachidonic acid (AA) were measured in RBCs at baseline and post-treatment in 122 participants with DSM-IV major depression who were randomized between May 2005 and December 2008 to receive either 50 mg/day of sertraline and 930 mg EPA/750 mg DHA/day or sertraline plus placebo. Associations between baseline RBC omega-3 levels and remission of depression (HAM-D≤7) were analyzed by treatment arm.
Among participants in the omega-3 arm, baseline RBC levels of EPA + DHA (P = .002) and the EPA + DHA:AA ratio (P = .003) were significantly higher among those whose depression subsequently remitted compared with those whose depression did not remit. No associations were detected in the sertraline plus placebo arm. Baseline levels of EPA (P = .03) and the EPA + DHA:AA ratio (P = .04) moderated the relationship between treatment arm and depression outcomes.
High baseline RBC levels of EPA and DHA and a high EPA + DHA:AA ratio predict favorable depression outcomes in patients receiving omega-3 supplements. Omega-3 supplementation may be an effective treatment for depression, but the requisite dosage and duration of treatment may depend on the patient’s baseline level of omega-3 fatty acids.
High baseline levels of EPA and DHA may result from a diet high in these omega-3 fatty acids. It is also possible that participants with higher omega-3 levels at baseline incorporate these fatty acids into RBCs and other tissues more efficiently than do those with lower levels of omega-3, and are therefore better able to utilize the omega-3 provided by the supplements. There are large individual differences in the plasma and RBC uptake of omega-3, even with an identical diet. In both short-and long-term studies, a fixed daily dose of omega-3 produces substantial individual variability in omega-3 blood levels37, which may be explained in part by genetic polymorphisms. Lower blood and tissue uptake of omega-3 may help to explain the lower levels of EPA and DHA found in depressed patients, and may even have etiological significance.
In three studies comparing EPA+DHA in RBCs in individuals with major depression and healthy controls, the mean percentages of RBC of omega-3 in depressed patients were 3.6, 3.6, and 3.8, vs. 6.3, 5.4, and 4.8 in the non-depressed participants.
These findings suggest that a level of 5-6% in RBCs might be a reasonable target for therapeutic efficacy. However, patients whose depression did not remit in the present study nevertheless increased their omega-3 RBC levels to an average of 7.2%, compared to 8% for the remitters. Further analysis of these data revealed that the probability of remission was highest in the participants in the omega-3 arm who had the highest blood levels after treatment, in the range of 9-10%, and these participants also had the highest blood levels before the trial began. This finding is similar to that reported in a review of trials of omega-3 to improve cardiovascular outcomes which concluded that the beneficial effects of omega-3 on cardiovascular outcomes in clinical trials were achieved by the patients who reached the highest blood levels of omega-3, which in many cases were higher than those typically observed in healthy controls.

So this aligns with my theory: baseline EPA and DHA levels matter, and you should supplement accordingly:

  • Low EPA and high DHA: EPA only?
  • High EPA and low DHA: DHA only?
  • Both low: trial and error?
  • Other situations: 60% EPA + 40% DHA? :man_shrugging:
4 Likes
#60

I will start on the tyrosine side of the equation because i believe I’m on the fast metabolite Comt genes side ( I’m ADHDish person i should do the test for sure ) then trying the combination with safinamide just to see how every path feels like for me and the interesting part to me is the direct antagonist of the cholinergic receptors with nicotine gives me a good mental boost.I become more sharp and on the task and it doesn’t have the depressing effect like the omegas 3 used to have on me when i take them on day time if it was about the cholinergic effect in the brain.

1 Like
#61

Digging more on this topic I found that Rhonda Patrick takes 2 g EPA in the morning and 2 g DHA in the evening: What's Rhonda Patrick's guidance on omega-3 supplementation? | Ask Huberman Lab

She didn’t explain why, but could it be because of this “lethargic” effect of DHA that some of us experienced? The literature seems to confirm that:

This British paper compared DHA to EPA, taken at bedtime. They found something surprising: Differential Effects of DHA- and EPA-Rich Oils on Sleep in Healthy Young Adults: A Randomized Controlled Trial 2021

Compared to placebo, improvements in actigraphy sleep efficiency (p = 0.030) and latency (p = 0.026) were observed following the DHA-rich oil. However, these participants also reported feeling less energetic compared to the placebo (p = 0.041), and less rested (p = 0.017), and there was a trend towards feeling less ready to perform (p = 0.075) than those given EPA-rich oil. A trend towards improved sleep efficiency was identified in the EPA-rich group compared to placebo (p = 0.087), along with a significant decrease in both total time in bed (p = 0.032) and total sleep time (p = 0.019) compared to the DHA-rich oil.
It should be noted that although participants in the EPA-rich oil group reported the shortest sleep times, this did not appear to lead to any reduction in the quality of sleep. In fact, a trend towards a significant increase in sleep efficiency, compared to placebo, was observed along with no increases in the time spent awake, number of awakenings, or decreased ratings of subjective sleep quality. This might potentially suggest that EPA is beneficial for regulating a healthy sleep cycle and could help protect against suboptimal sleep (i.e., too little or too much sleep), which is known to be detrimental for health.

This Japanese paper found improved sleep with 576 mg DHA + 284 mg EPA, but they didn’t report subjective evaluation: Effect of Docosahexaenoic Acid and Eicosapentaenoic Acid Supplementation on Sleep Quality in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Trial 2022

DHA has been reported to induce melatonin secretion in mice. Thus, DHA may increase melatonin levels by altering the membrane phospholipid composition of the pineal gland.

(poke @John_Hemming given your current focus on melatonin)

There might be sex and age differences: Sex- and age-dependent associations of EPA and DHA with very short sleep duration in adults: a cross-sectional analysis 2024

The associations of EPA and DHA with very short sleep duration are sex- and age-dependent. In males under the age of 32, a significant positive correlation exists between dietary EPA intake and very short sleep duration. For women above 44 years of age, an increase in DHA intake can notably ameliorate issues of very short sleep duration.

Plasma DHA Is Related to Sleep Timing and Duration in a Cohort of Mexican Adolescents 2020

Plasma DHA was associated with earlier sleep timing and longer weekend sleep duration in Mexican adolescents. Whether DHA supplementation improves sleep in adolescent populations deserves consideration in randomized trials.

Association of omega-3 levels and sleep in US adults, National Health and Nutrition Examination Survey, 2011-2012 2022

Relative to normal sleep, adults with very short sleep had lower levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and sum of LC omega-3 fatty acids. Differences remained significant (p < .05 for all) with adjustment for sociodemographic factors. No associations were observed with difficulty falling sleeping or sleep disorder.

image
image1380×856 96.7 KB

So your strategy to take omega 3 in the evening might be the correct one @hamida_abdenour!

4 Likes
#62

It was just common sense, take it when you can’t feel the mood effects but get the benefits and im also 29yo so maybe the rise of melatonin production affected my awaking sleep cycles from DHA that’s why i got the lethargy.

2 Likes
#63

I’m negative for the ApoE variants based on 23 & me. I tested for Omega 3/6 levels years ago and don’t remember my levels other than I was very low on Omega 3 and a little high on 6. I reduced seed oils but I haven’t retested. The effects of fish oils lasts longer than a night’s worth, so it wouldn’t help me to take DHA at night.

This may seem off topic but FWIW, I get a very similar effect when I take DHEA as a topical cream with my Testosterone. I can’t imagine a connection but the feeling is the same and it takes about the same amount of time to kick in.

#64

That’s my fear as well. I’ll give it a try though…

DHEA also enhances the cholinergic system. Could be the reason?

1 Like
#65

Looks like I need to do more research, thanks.

1 Like