adssx
#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.
So your strategy to take omega 3 in the evening might be the correct one @hamida_abdenour!
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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.
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Digby9
#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.
adssx
#64
That’s my fear as well. I’ll give it a try though…
DHEA also enhances the cholinergic system. Could be the reason?
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Digby9
#65
Looks like I need to do more research, thanks.
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adssx
#66
I switched to:
- 1,000 pure EPA in the morning
- 325 mg EPA + 225 mg DHA in the evening
After a few days, it seems okay: no more lethargic/depressed state compared to 325 mg EPA + 225 mg DHA in the morning. Wait and see…
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adssx
#67
@matthost FYI this Chinese paper found slower aging with EPA only: Omega-3 PUFAs slow organ aging through promoting energy metabolism 2024
So, could it be that EPA is also best for anti-aging? 
They used a massive dose, though: 4% => 40,000 ppm of pure EPA (98%). If I’m correct, the human equivalent dose would be about 30 g EPA/day. So, way more than the ITP, as the ITP used 50,000 ppm of fish oil, which has EPA + DHA in lower quantities.
@John_Hemming: does high-dose EPA make sense given your theory of aging?
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I think the argument for Omega 3 relates to more functional cellular membranes. That will feed into almost any theory of aging.
It may be that they help mitochondria as well, but I don’t know.
Personally I think 30g or EPA is pushing it. There are arguments about risks at higher levels.
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adssx
#69
Yes I don’t think anyone is taking 30 g of EPA or promoting that. It was just the crude HED conversion. However, some people take ~10 g EPA+DHA/day and claim amazing results, for instance: x.com
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Thanks do you have a link to the claim itself. Obviously improving membranes is a good thing.
adssx
#71
A few of her tweets on this:
adssx
#72
Omega-3 fatty acids and major depression: a Mendelian randomization study 2024
Genetically predicted total omega-3 fatty acids reduced the odds of MDD (ORIVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93–0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OREPA 0.92; 95% CI 0.88–0.96; p = 0.0002).
Two recent prevention trials have not identified any benefit of omega-3 fatty acids above placebo on MDD incidence. In fact, the VITAL-DEP trial identified an increased risk of MDD from 1 g fish oil per day over 5 years (HR 1.13 (1.01–1.26), p = 0.03, n = 9171), although the authors acknowledged the EPA dose (465 g) and ratio (<2:1) as a limitation. Similarly, the omega-3 arm of the MooDFOOD trial found no significant improvement of 1412 mg of EPA and DHA (3:1 ratio) on depressive symptoms in 682 participants over a 12-month follow-up compared to placebo.
VITAL-DEP used 465 mg EPA + 375 mg DHA: Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial 2021
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Ambient
#73
Interesting findings. Some random thoughts/questions on depression and well being.
I don’t recall your current stack or other stuff you have tried except lithium and telmisartan IIRC.
You ever tried alpha gpc or cdp-choline?
If not, those might be worth trying one day as they do more than just choline effects.
Those can also be paired with various amino acids for drive/boost etc (l-dopa or tyrosine or phenylalanine or dlpa, acetyl-l-carnitine).
There are various combo product called ‘mr happy stack’ that uses something like dha, uridine, alpha gpc or cdp choline, and some add in various b vitamins.
Not sure if you ever tried various neurotransmitter re-uptake inhibitors(individual) to see what neurotransmitter you might feel helps most but they are also good (dopamine, serotonin, noradrenaline).
Others get good effects from various monoamine oxidase inhibitors.
I’ve even seen people use both(maoi + reuptake inhibitors), which might cause many issues for others.
Maybe a triple neuro reuptake combo. Or a various agonist/antagonist combo.
Inverse type stuff seems interesting also and way over my head.
Not sure if you ever use cannabis/thc, but could look to boost endocannabinod system with non-cannabis products. Maybe pair fish oil with lecithin (1g to 10g/day).
I also got big cannabinoid effects from four sigmatic coffee. Not sure if it was the lions mane, rhodiola or chaga mushroom or all 3.
Other various non-psychoactive extracts that can activate that system.
Other supplements that combine like an all in 1 type in pills or powders.
From pre-workout’s to cognitive & memory formulas.
Could be more gaba/glutamate/glycine stuff that helps you instead of monoamines or a combo of all. Stuff that is stimulating or non-stimulating.
Maybe hormonal (dhea, testosterone, thyroid) or peptide like oxytocin, vasopressin, pomc, endorphins etc.
adssx
#74
I don’t know enough about all the things you mentioned and I must say I’m not really willing to try. I like to have a biomarker to optimize with a clear target (ApoB, blood pressure, HbA1c, omega 3 index, etc.) and then choose the “best” available intervention to reach that target. Unfortunately for mood/depression there’s no easy way to measure it other than “how do I feel now?” and it doesn’t seem that there’s a “best” intervention. It might be because depression varies a lot in its causes from one person to another and you need to pinpoint the cause to find the best treatment. I don’t want to do trial and error with all these compounds (quality of the supplements, potential drug interactions with other things I’m taking, inability to assess the efficacy independently, etc.). That being said I’m more and more willing to give a try to low-dose selegiline (1.25 mg/day 4 days a week, oral, not sublingual, MAO inhibitor): I was initially skeptical but the ITP selected it in its latest batch so they must be convinced by its potential (although why only now? Did they get new data? Or are they just desperate?), and data in Parkinson’s looks okay, I sponsored some selegiline concentrations in Ora Biomedical’s challenge. Wait and see…
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Ambient
#75
That is understandable. It is challenging to measure mood. Could also have the potential interactions etc.
I’ve tried selegiline. At around 5-10mg/day. It was ok.
If you want to stick to ITP stuff, protandim is a good option to try if you don’t like selegiline.
As I’ve tried all the protandim ingredients separately but never as the actual product.
Ashwaghanda and bacopa are probably the products that would affect mood the most.
Forskolin is also currently being tested with ITP, which raises cAMP (maybe boosting thyroid and testosterone?), and might boost dopamine or other chemicals which has some ability to boost mood.
I’ve seen some products with it mixed with various herbal extracts similar to protandim.
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adssx
#76
You’re right. +7% lifespan in males is not a lot but at least it shows it’s safe (in mice). Components are turmeric, milk thistle, bacopa, ashwagandha, and green tea. I wonder which one is the top contributor to life extension. Out of these 5, which one is best for depression? Sleep? Anxiety? Here again there’s not a lot of data about these compounds, what the optimal is, when to take them, etc.
Ambient
#77
Indeed.
I saw that the ITP tested green tea extract, and curcumin (tumeric). Those did not increase life span.
So it’s either milk thistle, bacopa, or ashwagandha. Or maybe some interesting synergy with all 5 products together doing something.
From personal experience it would be ashwaghanda extract: 5% withanolides for sleep, and anxiety.
Ashwaghanda seems to have quite a few different extracts out on the market and many people seem to like/dislike various ones.
Some people say ashwaghanda worsens depression, and some say it works. So it’s very individual.
A quality product is key as many fake or under-dosed products out on the market.
Bacopa might be better for some with depression or memory issues. Or combining the 2 products.
I’ve seen people report various dosages with the different extracts.
Probably best to start low and slowly build up.
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adssx
#78
Good point. If you look at the details green tea and curcumin increased both median and max lifespan but it wasn’t statistically significant:
So it could just be that they all individually increase lifespan a bit but not enough to move the needle much unless combined.
That’s another issue with supplements. That’s why I prefer drugs. At least you’re sure of the quality. Even for omega 3 I’m considering switching to pharma-grade Vascepa (pure EPA) or Omacor (EPA + DHA) instead of whatever brand bought from Amazon with no supply chain control, potential contaminations, etc.
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Neo
#79
I remember testing my neurotransmitter levels more than a decade ago when I started to get into health optimization. Was def experimental, but might have advanced more since then. So might be with looking into.
At a glance
Neurotransmitter testing is an approach that assesses the levels of various neurotransmitters in the body, offering insights into the neurochemical balance. Common types of neurotransmitter testing include urine and blood tests, each providing distinct advantages. Urine tests, such as the Comprehensive Neurotransmitter Profile - 24 Hr by Doctor’s Data, measure the breakdown products of neurotransmitters to assess how the body synthesizes and metabolizes them. Blood tests, on the other hand, directly quantify the levels of neurotransmitters circulating in the bloodstream, offering real-time information.
These tests may play a role in assessing mental health by uncovering potential imbalances in neurotransmitter levels. For instance, mood changes may be associated with low levels of certain neurotransmitters. Selective serotonin reuptake inhibitors (SSRIs) are a class of medication often used to increase the amount of circulating serotonin. However, they may not be effective for mood changes associated with other neurotransmitter imbalances.
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Neo
#80
Haven’t read the paper (and know other papers has additional data), from the part you quoted we also have
The best responders were those with higher (aggregate) initial levels
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.
And the best responders were those who ended up with the highest index levels
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 one simplified framework could also be:
-
even if higher than average levels of Omefa3 index you may want to supplement if depression
-
if you supplement, you may want to do it to above average levels
Not sure if that means that one should skip supplementing with EPA or DHA if that one is high at the outset (- based on this study)
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