by Jack Norris, RD, LD
- Introduction to the Omega-3 Fatty Acids
- Essential Fatty Acids: ALA and LA
- Long-chain Omega-3 Fatty Acid Blood Levels of Vegetarians
- Conversion of ALA to EPA and DHA
- ALA Supplementation Results in Little Increase in Blood DHA
- EPA and DHA Correlate between Plasma and the Heart but not the Brain
- Tissues Contain Enzymes that Convert Omega-3s
- Dietary DHA Reduces ALA Conversion
- Lower Omega-6 Intake is Associated with Higher Serum EPA and DHA
- DHA Supplementation in Vegetarians
- Omega-3 Recommendations for Vegans
- Vegetarian Pregnancy and Children
- Omega-3s and Chronic Disease
- Omega-3s and Cardiovascular Disease
- Omega-3s and Cognition
- Omega-3s and Depression
- Omega-3s and Increased Risk of Disease
- Appendix A: Biomarkers of DHA Status
- Appendix B: Evolutionary Arguments for a Dietary Requirement for DHA
- Crawford, 2006 and Crawford et al., 2022
- Bradbury, 2011
- Langdon, 2006
- Burdge, 2022
- Conclusion to Evolutionary Arguments for a Dietary Requirement for DHA
Introduction to the Omega-3 Fatty Acids
There are two questions regarding vegetarians and omega-3s: Do vegetarians have negative health consequences from not eating fish and should vegetarians supplement with omega-3s?
For our purposes, there are four important omega-3 fatty acids:
- alpha-linolenic acid (ALA) – short-chain (18 carbon) omega-3 fatty acid. Found in small amounts in animal flesh, in very small amounts in a variety of plant products, and in relatively large amounts in soy, walnuts, canola oil, flaxseeds and their oil, hempseed oil, camelina oil, and chia seeds. The human body cannot make its own ALA; it must be obtained through the diet.
- eicosapentaenoic acid (EPA) – long-chain (20 carbon) omega-3 fatty acid. Found mostly in fatty fish, in small amounts in eggs, and in very small amounts in seaweed that can be concentrated into supplements. Some EPA is converted into series 3 eicosanoids which can reduce blood clotting, inflammation, blood pressure, and cholesterol. The human body can produce EPA from ALA and possibly from DHA.
- docosapentaenoic acid (DPA) – long-chain (22 carbon) fatty acid. There is both an omega-3 and omega-6 version of DPA. The omega-3 version is an intermediary between EPA and DHA.
- docosahexaenoic acid (DHA) – long-chain (22 carbon) omega-3 fatty acid. Found mostly in fatty fish, in small amounts in eggs, and in very small amounts in seaweed that can be concentrated into supplements. DHA is a major component of the gray matter of the brain, and also found in the heart, retina, testis, sperm, and cell membranes. The body can convert EPA into DHA.
A chart showing the conversion pathways for the omega-3 fatty acids can be found in The Fatty Acids.
See the video below for an excellent overview of omega-3 fatty acids from omega-3 researcher Dr. Richard Bazinet of the University of Toronto (2021).
Essential Fatty Acids: ALA and LA
The Institute of Medicine considers there to be a dietary requirement for two fatty acids for people age 1 year and older:
- alpha-linolenic acid (ALA) – the short-chain omega-3 (described above) which can be low in some vegan diets.
- linoleic acid (LA) – the short-chain (18-carbon) omega-6, which is prevalent in most vegan diets due to being abundant in vegetable oils.
Because they’re essential fatty acids, there’s a daily dietary reference intake (DRI) for both ALA and LA:
- ALA: 1.6 g (males age 14+), 1.1 g (females age 14+)
- LA: 17 g (men age 19-50), 12 g (women age 19-50)
Burdge (2022) reports that an overt deficiency of ALA has never been fully isolated from LA and fat-soluble vitamin deficiencies in adult humans in order to clearly demonstrate that ALA is an essential fatty acid.
Essential Fatty Acid Intakes of Vegans
The table below shows the weighted averages of studies measuring vegan ALA intakes. Calculations and citations are in our ALA Intakes spreadsheet.
The World Health Organization and Food and Agriculture Organization (2010) recommend an LA intake between 2.5-9% of calories, saying that the lower number prevents deficiency and the higher end of the range reduces the risk for heart disease.
Although vegans who don’t ensure sources of ALA tend to have a high ratio of omega-6 to omega-3 fats, their percentage of calories as LA has been shown to be 5.1% (Pinto, 2017, United Kingdom), 7.3% (Allès, 2017, France), 8.5% (Kornsteiner, 2008, Austria), and 9.3% (Rizzo, 2013, USA), well within the range recommended by the WHO. Because of this, we’re hesitant to recommend that vegans avoid LA.
Long-chain Omega-3 Fatty Acid Blood Levels of Vegetarians
Summary: The differences in long-chain omega-3 blood levels between vegans, lacto-ovo-vegetarians, and omnivores aren’t obviously physiologically significant, especially with regard to omnivores who don’t regularly eat fish. Red blood cell DHA of vegetarians and vegans is roughly 72-75% of that of omnivores, but it’s not clear if this has clinical significance.
There is no standardized method for measuring omega-3 fatty acids: no one knows what levels of fatty acids in any given medium represent a deficient, healthy, or optimal level. It could even be that blood levels of fatty acids have little bearing on omega-3 fatty acid status. The purpose of this section is to determine whether vegans do indeed have lower blood levels of long-chain omega-3 fatty acids than omnivores. Early studies found that vegans have lower EPA and DHA blood levels, but these studies were conducted on very few people; more recent studies haven’t shown nearly the difference.
As of early 2022, we’ve tracked 27 studies measuring the blood levels of omega-3 fatty acids in vegetarians. We list these studies and their measurements in the Cross-sectional tab of our spreadsheet, Omega-3s Part 2: Research.
The way omega-3s are measured among these studies varies considerably.
Fatty acids can be measured in various components of plasma such as phospholipids, triglycerides, or cholesterol esters. Fatty acids may also be measured in the adipose tissue, platelets, or red blood cells. Because red blood cells have a lifespan of 120 days, red blood cell fatty acids might be a more accurate long-term representation of omega-3 status.
In the plasma, omega-3s are usually measured as a percentage of total fatty acids, but Welch et al. (2010) measured omega-3s as a concentration in plasma and Rosell et al. (2005) provided the data to calculate a concentration. Concentrations might be a more accurate reflection of the body’s omega-3 stores since they represent an absolute rather than a relative amount.
DPA is a long-chain omega-3 fatty acid that is an intermediary between EPA and DHA. We emphasize studies that included DPA in their measurements because DPA represents a significant fraction of long-chain omega-3s that vegans have converted from ALA and which can potentially be converted to DHA.
The graph below plots all measurements that compared total long-chain omega-3 levels (EPA+DPA+DHA) of vegetarians or vegans to omnivores. It includes measurements of percentages and concentrations for each medium. While there’s considerable overlap between diet groups, individual studies generally find that omnivores have higher levels of long-chain omega-3s than vegans with the differences being statistically significant.
The graphs below compare only the EPA or DHA levels of vegans and vegetarians in all studies that measured EPA or DHA.
Arguably the most important metric is red blood cell omega-3s, shown in the graph below.
It’s hard to conclude much regarding vegan long-chain omega-3 levels from these studies given that the measurements aren’t standardized, aren’t well understood, and contain significant overlap. Arguably a more accurate way to assess this data is to weight the comparisons of vegetarians both proportional to the omnivores in the same studies and proportional to how many people were in each diet group while limiting the measurements to one per population studied.
In order to get the most accurate picture of how long-chain omega-3 blood levels of vegans compare to those of omnivores, we decided to calibrate the measurements by creating a ratio of the levels of vegans to those of omnivores rather than using an absolute amount. We did this by simply dividing the vegan level by the omnivore level.
For example, the study by Kornsteiner et al. found an EPA+DPA+DHA percentage of total fatty acids in red blood cells of 1.96% for vegans and 3.34% for omnivores. The study by Li et al. found an EPA+DPA+DHA percentage of total fatty acids in plasma of 3.6% for vegans and 5.5% for omnivores. We don’t know if we can compare the percentage of fatty acids in red blood cells to the fatty acids in plasma, but we can compare the ratio of vegan to omnivore long-chain omega-3s in both studies, which was .59 in Kornsteiner et al. and .65 in Li et al. We can then multiply these two ratios by the number of vegans in their respective study, divide by the total number of vegans in both studies, and get a weighted average of the ratio of vegan to omnivore long-chain omega-3s across both studies. By weighting all of the studies in this way, we can obtain the most accurate picture of how blood levels of long-chain omega-3 fatty acids compare for vegans and omnivores.
Most studies measured omega-3s as a percentage of total fatty acids; to be as consistent as possible, we weighted the percentage of total fatty acids rather than the concentration for studies that measured both. For studies with multiple measurements, we chose in this order: red blood cells, plasma, platelets, and adipose tissue.
The table below shows the weighted proportions of omega-3s for vegetarians and vegans compared to omnivores for all studies and for red blood cell (RBC) measurements only. Calculations and citations are in the Cross-sectional tab of our spreadsheet, Omega-3s Part 2: Research.
Based on the table above, vegans generally have lower blood levels of long-chain omega-3s than omnivores. Since plasma levels of omega-3s are at least in part a representation of dietary fatty acids, as distinct from representing only the body’s ability to convert dietary short-chain to long-chain omega-3s, it’s not surprising that people who have an intake of long-chain omega-3s have higher blood levels.
Vegetarians vs. Fish-Eaters
Among people who don’t supplement with long-chain omega-3s, regular fish-eaters will be the only dietary group with a significant source of long-chain omega-3s. According to the USDA nutrient database, a medium egg contains about 2 mg of EPA and 16 mg of DHA. That provides lacto-ovo-vegetarians with very small amounts of dietary EPA and DHA.
There are two studies that measured omega-3 levels among fish-eaters (Welch, 2010; Miles, 2019), but neither measured it in red blood cells. We analyze these studies in the Fish-eaters tab of our spreadsheet Omega-3s Part 2: Research and summarize the results in the three charts below. Participants in the studies didn’t use long-chain omega-3 supplements.
Welch et al. (2010) measured omega-3 plasma concentrations and separated omnivores into groups who did and did not eat fish. There were only 10 vegans.
We combined the male and female long-chain omega-3 plasma concentrations to determine how vegans compared to both fish-eating and non-fish-eating omnivores. Because there were so few vegans, we also combined the lacto-ovo-vegetarians (LOV) with the vegans for a “vegetarian” category. The table below shows that lacto-ovo-vegetarians, vegans, or the combined group had levels slightly below fish-eaters and either similar or higher levels than non-fish-eaters.
Miles et al. (2019) compared the percentage of omega-3 fatty acids in the adipose tissue of pescatarians to other dietary groups, as shown in the table below. Vegetarians and vegans had lower levels than omnivores and even somewhat lower levels than fish-eaters. Although vegans had substantially lower levels than fish-eaters in this study, it’s not clear what the percentages of fatty acids in adipose tissue represent; possibly nothing of clinical significance.
Fatty Acid Levels of Older vs. Younger Vegans
It’s normally thought that people have a harder time converting ALA to EPA and DHA as they age. Sarter et al. (2015) found that 69 vegans aged 60 to 85 had EPA+DHA levels of about 4.0% compared to about 3.6% for 97 vegans aged 20 to 59 (p for trend = 0.009).
Impacts of Lower EPA and DHA on Vegetarians
A possible benefit of long-chain omega-3 fatty acids, especially EPA, is to reduce blood clotting which protects against heart attacks. There have been some differences noted in blood clotting between vegetarians and omnivores.
Mezzano et al. (1999, Chile), found that vegetarians had significantly more platelets (242,000 per ul) than non-vegetarians (211,000 per ul) and a shorter bleeding time (4.5 vs. 7.3 min). In a follow-up study, Mezzano et al. (2000, Chile) gave vegetarians 700 mg EPA and 700 mg DHA for 8 weeks. EPA went from .2 to 1.8% and DHA went from 1.1 to 3.0%. Some clotting factors changed, but bleeding time remained lower at 5-1/2 minutes.
Sanders and Roshani (1992, United Kingdom) found that only one of eight platelet aggregation parameters in vegan men, but not women, was different from the non-vegetarians. Bleeding times were similar.
Pinto et al. (2017, United Kingdom) compared heart rate variability between a group of 23 adult vegans and 24 omnivores. Low heart rate variability reflects a reduced capacity for the heart to respond to the body’s physiological demands and is linked to an increased risk for heart disease. As expected, the vegans had lower concentrations of DHA and EPA in both red blood cells and plasma. While vegans had a higher heart rate variability over a 24-hour period, their daytime heart rate variability was lower, and their heart rate was greater. The clinical significance of these findings aren’t clear.
Thus, of three studies that looked at clotting factors, the results are mixed.
In terms of cognition, in their study of British mortality, Appleby et al. (2002) found vegetarians to have a barely statistically significant, higher risk of death from mental and neurological diseases (DRR 2.21, CI 1.02–4.78). In contrast, a more recent report from EPIC-Oxford (Appleby, 2016) found that vegetarian deaths from mental and behavioral disorders were not statistically different from non-vegetarians (HR 1.22, CI 0.78–1.91). And a report from the Adventist Health Study-2 (Orlich, 2013, USA) found no difference in mortality from neurologic diseases between vegetarians and non-vegetarians (HR 0.93, CI 0.67-1.29); pescatarians and semi-vegetarians were included in their vegetarian category so the results can’t be extrapolated to vegetarians who don’t eat fish.
Conversion of ALA to EPA and DHA
Measurements of the percentage of total fatty acids as EPA and DHA in the blood are generally considered a marker of omega-3 status. This assumes that higher percentages of total fatty acids in the blood reflect higher and more optimal amounts in the tissues that utilize omega-3s. It also assumes that when blood percentages change due to changes in dietary intake, levels in tissues respond similarly.
In this section, we examine these assumptions. Evidence of omega-3 conversion enzymes in tissues and down-regulation of omega-3 conversion in response to dietary omega-3s suggest that the body can regulate the conversion of omega-3 fatty acids in tissues independent of the percentage in the blood.
There’s evidence that high intakes of EPA and DHA will increase their percentages in both blood and tissues, but it’s not clear if higher percentages are necessary for optimal health. We assess the evidence in our sections Impacts of Lower EPA and DHA on Vegetarians and Omega-3s and Chronic Disease.
ALA Supplementation Results in Little Increase in Blood DHA
Our ALA Trials spreadsheet lists a handful of clinical trials, including all of the trials with vegetarians of which we’re aware, investigating whether increasing dietary ALA subsequently increases the percentage of long-chain omega-3s in the blood. The changes in total fatty acids as long-chain omega-3s show a wide variation with no clear pattern; some even found a decrease in DHA. On average, EPA+DPA+DHA increased by 43.5% while DHA only increased by 4.6%.
It’s safe to say that supplementing with ALA is unlikely to substantially increase the blood percentage of fatty acids as DHA in most adults.
EPA and DHA Correlate between Plasma and the Heart but not the Brain
Summary: Based on limited, mostly cross-sectional data, there appears to be a robust correlation between the blood and tissue percentages of EPA+DHA in the human heart but not the brain or sperm.
Studies of ALA supplementation result in very little increase of DHA in the blood, but how much evidence is there to suggest that this reflects the body’s inability to convert ALA to DHA for tissue utilization?
A basic question is, without any dietary changes, how much do blood levels of omega-3 fatty acids typically correlate with tissue levels? It’s difficult to study the omega-3 content of tissues in living humans. In our spreadsheet, Tissue Correlations, we list the correlations between blood and tissue percentages of omega-3s in both humans and animals. A summary of the results follows.
Harris et al. (2004) measured the correlation between the percentage of EPA+DHA in red blood cells and the percentage of EPA+DHA in the hearts of 20 heart transplantation patients having routine heart biopsies, 13 of whom were considered to be high consumers of EPA and DHA; they found a statistically significant, strong correlation (R = 0.82, P ≤ 0.0001).
Harris et al. (2004) also performed an intervention: Heart transplantation patients (n=25) with low EPA+DHA intakes were provided 1,000 mg of EPA+DHA for 6 months. These patients had weaker correlations between red blood cell and heart EPA+DHA at baseline (R = 0.47, P = 0.031). Post-intervention measurements showed that EPA+DHA percentages increased in plasma, red blood cells, heart, and cheek tissue; the correlation between red blood cell and heart EPA+DHA remained the same (R = 0.47, P = 0.06).
Metcalf et al. (2007) placed a series of patients on ALA (5.8 g per day) or EPA+DHA (6.3 g, ~50% each) for a number of weeks based on their heart surgery schedule. While they didn’t test for a correlation between red blood cell and heart omega-3 fatty acid percentages, the percentages of the two mediums were fairly similar and differed from the control group in similar amounts post-treatment (see our spreadsheet ALA Trials).
Cunnane et al. (2012) performed autopsies on cognitively normal people and found a correlation between percentages of DHA in plasma phosphatidylethanolamine and the angular gyrus region of the brain DHA (R = 0.77, P ≤ 0.005). However, they failed to find correlations between DHA and other regions or in cognitively impaired people stating, “No significant correlations were observed for DHA (% or mg/g) or any other fatty acids in the other brain regions or in the [Alzheimer’s disease] and [mildly cognitively impaired] groups (data not shown).”
Carver et al. (2001) performed autopsies on 58 people and found a negative correlation between the DHA percentage in red blood cells and the cerebral cortex of people aged >18 years; it’s likely this correlation doesn’t achieve statistical significance after a Bonferroni correction for the large number of correlations tested.
Chamorro et al. (2020) measured the fatty acid percentages of young men, comparing vegans (n=34) and omnivores (n=33). They didn’t test for a correlation between the percentage of omega-3s in plasma or red blood cells and sperm. The ratio of the percentage of EPA in sperm to that in plasma and red blood cells was similar at 0.54 for each, but the ratios for DPA and DHA were not. See the table below.
There’s much more data from animals than humans. Our spreadsheet, Tissue Correlations, lists 24 correlations between blood and tissue percentages of EPA+DHA among rats, pigs, and mice. The strength of the correlations varies considerably with some being negative.
There’s one other study on animals worth mentioning. Talahalli et al. (2010) fed two groups of rats a reasonable amount of ALA (2.5% and 5.0% of calories). After 60 days, the percentage of fatty acids as DHA in the brain of the rats fed 2.5% and 5.0% ALA was, respectively, 9.4% and 10.4% compared to 8.3% in the control group (see the table, Talahalli 2010). This suggests that ALA supplementation increased the amount of DHA in their brains.
One significant caveat for comparing the conversion of omega-3s in rats, pigs, and mice to humans is that rats, pigs, and mice normally don’t have a dietary source of EPA or DHA and, therefore, would normally rely entirely on the conversion from ALA for any EPA or DHA.
While plasma and red blood cell percentages of long-chain omega-3 fatty acids sometimes correlate with tissues, they don’t do so consistently. It might be possible to develop a mathematical model that can account for the large number of variables that impact the correlations but it seems unlikely that a model will be developed that gives us confidence in predicting the omega-3 tissue status of vegetarians.
In Appendix A, we discuss a review paper, Biomarkers of DHA status, arguing that blood percentages are adequate markers of DHA status.
Tissues Contain Enzymes that Convert Omega-3s
Two critical enzymes, delta-5 desaturase and delta-6 desaturase, convert short-chain omega-3 and omega-6 fatty acids into long-chain versions.
Previously, the liver was considered the primary site of EPA and DHA production for peripheral tissue utilization, but studies by Cho et al. (1999a and 1999b) found substantial amounts of mRNA for the delta-5 and delta-6 desaturase enzymes in many tissues of human cadavers.
Cho et al. (1999a) found that delta-5 desaturase mRNA was greatest in the human liver, but that the heart, brain, and lung also contained substantial amounts. They found low but detectable levels in the placenta, skeletal muscle, kidney, and pancreas. Cho et al. (1999b) found that the amount of delta-6 desaturase mRNA in the human liver was comparable to that found in the human lung and heart, while the adult brain had a level several times greater than the liver.
Cho et al. (1999a) point out that the expression of these enzymes can vary greatly among individuals. The authors hypothesize that this might be due to age or, more likely in their view, regulation of the enzymes in response to the dietary intake of fatty acids.
Using cross-sectional data based on the percentage of plasma phospholipids, Welch et al. (2008, United Kingdom) estimated that non-fish-eaters (both vegetarians and meat-eaters) convert ALA to long-chain omega-3s at about a 22% higher rate than fish-eaters.
Dietary DHA Reduces ALA Conversion
In a series of three studies, researchers used a carbon tracer to track the conversion of a 700 mg dose of ALA to long-chain omega-3s in the blood of three different groups of people. The results are in the table below. Only females (all of whom were of reproductive age) showed a substantial conversion of ALA to DHA in the blood.
In addition to the baseline measurements listed in the table above, Burdge et al. (2003) included an 8-week intervention on three groups of older men: a control group (n=5), a group whose daily ALA was increased from their normal intake of 1.7 g to 10 g (n=4), and a group whose daily EPA+DHA was increased from their normal intake of 264 mg to 1.6 g (n=5). After 8 weeks, they fed each person 700 mg of ALA with a carbon tracer and found that the ALA supplemented group’s conversion of ALA to long-chain omega-3s hadn’t increased whereas the EPA+DHA supplemented group’s conversion had decreased.
Vermunt et al. (2000) fed carbon-labeled ALA to humans and found that the conversion of ALA to EPA, DPA, and DHA was much greater after 9 weeks of a diet high in oleic acid compared to after a diet high in ALA or EPA+DHA.
The two trials mentioned above by Burdge et al. (2003) and Vermunt et al. (2000) suggest that there’s a down-regulation of ALA conversion to long-chain omega-3s in humans who have a regular supply of ALA or EPA and DHA. The simplest explanation for this down-regulation is that their tissues had sufficient long-chain omega-3 levels.
Further evidence for enzymatic regulation due to dietary intake is a study by Metherel et al. (2019) who conducted a randomized controlled trial using carbon-labeled DHA. While plasma levels of EPA increased, it wasn’t due to DHA being converted to EPA, suggesting that the dietary supply of DHA resulted in the down-regulation of the conversion of EPA to DHA.
Burdge and Wootton’s data (2002) showed an uneven distribution of omega-3 fatty acids among the different components of plasma lipids (cholesterol esters, phosphatidylcholine, triglycerides, and non-esterified fatty acids). They surmised that plasma cholesterol esters act as a long-term source of ALA within circulation that may provide tissues containing active desaturation and elongation pathways (brain, heart, and skeletal muscles) a steady source of ALA for conversion to EPA, DPA, and DHA while tissues with low expressions of these enzymes, such as the kidney and pancreas, may be dependent upon the supply of pre-formed EPA, DPA, and DHA.
Lower Omega-6 Intake is Associated with Higher Serum EPA and DHA
The traditional way vegetarians have been encouraged to raise blood EPA and DHA levels is by increasing ALA and decreasing the omega-6 fatty acid, linoleic acid (LA). This is because the enzymes that convert ALA into EPA and DHA also convert the omega-6 fatty acids and there is competition for these enzymes. Some evidence for this theory is from a clinical trial by Liou et al. (2007, Canada) who found increasing LA intake resulted in a lower percentage of EPA in plasma phospholipids
Most vegetable oils are high in omega-6s and vegetarians tend to get plenty in their diets. Sanders and Younger (1981, United Kingdom) found a dietary ratio of omega-6s to omega-3s of 16 for vegans and 6 for meat-eaters. Sanders and Roshanai (1992, United Kingdom) found a dietary ratio of 15.8 for vegan men, 10.2 for meat-eating men, 18.3 for vegan women, and 8.2 for meat-eating women.
There are no clinical trials that increase the ALA intake of vegetarians while also decreasing their LA intake, to see what impact this has on blood levels of EPA and DHA.
Salvador et al. (2019, Spain) studied 55 vegans and 49 lacto-ovo-vegetarians and found that those with a serum omega-6 to omega-3 ratio of ≤ 10 had a higher percentage of serum EPA and DHA than those with a ratio between 10 and 20 or >20 (EPA: 0.60%, 0.27%, and 0.23%; DHA: 2.90%, 1.91%, and 1.19% respectively). Flaxseed intakes of once per day and, especially, 2 or more times per day were associated with a much higher percentage of serum ALA (~0.5% vs. ~0.7% and 1.5%, respectively), but not with higher EPA or DHA percentages.
Based on limited research, lowering LA intake could increase blood levels of long-chain omega-3s, but it’s not known if doing so impacts tissues or provides health benefits.
Low Omega-6 to Omega-3 Ratio Foods
At this time, the research indicates that vegetarians with lower dietary omega-6 to omega-3 ratios tend to have higher blood levels of EPA and DHA. For that reason, it’s prudent, when adding ALA to the diet, to choose foods that don’t also substantially increase omega-6 intake, listed in the table below.
|Foods with Lowest Omega-6 to Omega-3 Ratios|
|flaxseeds||1:4||1.6 g / tablespoon|
|flaxseed oil||1:4||2.5 g / teaspoon|
|chia seeds||1:3||5 g / oz|
|canola oil||2:1||1.3 g / tablespoon|
|English walnutsa||4:1 – 5:1||2.6 g / oz (14 halves)|
|walnut oil||5:1||1.4 g / tablespoon|
|soybean oil||7.5:1||.9 g / tablespoon|
|black walnuts||10:1||.9 g / oz|
|aEnglish are the typical walnuts found in most grocery stores.|
DHA Supplementation in Vegetarians
Studies consistently show that supplementing vegetarians and vegans with DHA from algal sources increases their blood percentage of DHA (Sanders, 2009; Geppert, 2006; Wu, 2006; Conquer, 1996; Conquer, 1997). Studies also show that supplementing with both EPA and DHA increases vegetarians EPA and DHA percentages (Sarter, 2015; Mezzano, 2000).
Fish contains about twice as much DHA as EPA (Kris-Etherton, 2009), so it’s not unusual for fish-eaters to eat more DHA than EPA. Conquer and Holub (1996, Canada) showed an 11–12% increase in EPA after 6 weeks of 1,620 mg of DHA in vegetarians.
Upon DHA supplementation, EPA levels also increase by a small percentage. Using a carbon tracer, Brossard et al. (1996, France) found a 1.4% conversion of DHA to EPA in three people given one dose of 123 mg of DHA over the course of 20 hours. In contrast, Metherel et al. (2019, Canada) conducted a randomized controlled trial using DHA containing labeled carbon and didn’t find any to be converted to EPA. They conclude that “the increase in plasma EPA following DHA supplementation in humans does not occur via retroconversion, but instead from a slowed metabolism and/or accumulation of plasma EPA.”
Omega-3 Recommendations for Vegans
To sum up the rationale behind our recommendations, it appears that if a vegan is meeting the Dietary Reference Intake for ALA, their EPA status should be adequate. To be cautious we recommend either increasing ALA intake or adding a DHA supplement. Please see our article, Daily Needs, for specific recommendations and how to meet them.
There are many vegan DHA and EPA supplements available via the Internet. We aren’t able to assess whether any given company is better than another.
Vegetarian Pregnancy and Children
DHA may be important for developing fetuses and infants, and pregnant women more efficiently convert ALA to DHA. Fetuses and infants are able to receive DHA that’s released from the mother’s fat tissues and provided through the umbilical cord or breast milk.
Reddy and Sanders (1994, United Kingdom) measured the DHA levels in umbilical cords of 32 infants born to vegetarian mothers compared to omnivores and found no relationship between the proportions of DHA in plasma or cord artery phospholipids and the birth weight or head circumference of the infants.
Many children have been raised vegan without supplementing with DHA, or even extra ALA, and appear to develop well. Even so, it’s prudent for breastfeeding mothers of vegetarian or vegan children to ensure they’re meeting omega-3 recommendations (see Daily Recommendations) and non-breastfeeding infants should receive infant formula with 500 mg of EPA+DHA per day.
Omega-3s and Chronic Disease
Most of the concern with regard to low plasma levels of EPA and DHA among vegetarians is due to studies that have found an association between low EPA and DHA blood levels and an increased risk of chronic diseases such as cardiovascular, cognitive decline, and depression. These associations have generally been consistent but weak. There have also been some associations between omega-3 blood levels and an increase in some chronic diseases. In this section we review the evidence.
Omega-3s and Cardiovascular Disease
Research on omega-3s and cardiovascular disease has examined the associations with fish consumption, blood levels of omega-3s, and omega-3 supplementation.
Fish Consumption and Cardiovascular Disease
As of February 2021, the American Heart Association was still basing its omega-3 fatty acid recommendations on its 2002 position paper, Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease (Kris-Etherton, 2002) which recommends that adults “Eat a variety of (preferably oily) fish at least twice a week. Include oils and foods rich in alpha-linolenic acid (flaxseed, canola, and soybean oils; flaxseed and walnuts).”
Some recent reports include:
- A 2020 meta-analysis of six cohort studies found no correlation between eating fish and a reduced risk of cardiovascular disease or mortality (Zhong, 2020).
- A 2020 Cochrane review determined that there wasn’t enough evidence to assess the impact of eating fish on cardiovascular health (Abdelhamid, 2020).
- A 2016 meta-analysis of 12 prospective studies found a reduced risk of mortality with increasing fish intake (Zhao, 2016).
Omega-3 Supplementation and Cardiovascular Disease
In what they called “the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date,” a 2020 Cochrane Review analyzed 86 randomized controlled trials of 12 to 88 months duration using omega-3 capsules, omega-3-enriched food, or dietary advice to eat more omega-3s (Abdelhamid, 2020). The review found little to no effect of increasing omega-3s on all-cause or cardiovascular mortality, cardiovascular events, stroke, or arrhythmias. Increased omega-3 intake showed a trend with reduced coronary heart disease mortality (RR 0.90, CI 0.81-1.00) and there was a reduced rate of coronary heart disease events (RR 0.91, CI 0.85-0.97). Increasing long-chain omega-3s reduced triglycerides by ~15% in a dose‐dependent way. Overall, the authors stated that 334 people would need to increase their long-chain omega-3 intake to prevent one person from having a coronary heart disease event and they believed this wasn’t enough of an impact to recommend supplementation.
In contrast, a 2019 meta-analysis of omega-3 supplementation found a benefit from omega-3 supplementation in the combined results from 13 randomized controlled trials using about 800 to 1,800 mg of omega-3 fatty acids per day (Hu et al.). At baseline, the participants had a mixed risk for cardiovascular disease: 40% had diabetes and 73% were using cholesterol-lowering medication. In one set of results, that excluded the REDUCE-IT trial described below, they found a reduced risk of heart attack (RR 0.92, CI 0.86-0.99) and cardiovascular death (RR 0.93, CI 0.88-0.99). The omega-3 supplementation in this set of results is arguably higher than the AHA recommendations of at least 2 servings of fish per week, but not implausible. For the omega-3 content of fish, see Omega-3 Fatty Acids: Fact Sheet for Health Professionals.
The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) was excluded from Hu et al.’s results above because it used a much higher dose of omega-3s: 4,000 mg/day of a purified form of EPA. It showed markedly better success for heart attack (RR 0.69, CI 0.58-0.81) and cardiovascular death (RR 0.80, CI 0.66-0.98). Participants also had a lower risk of stroke (RR .72, CI 0.55-0.93), but their death from all causes wasn’t significantly lower (RR .87, CI 0.74-1.02) than the placebo (Bhatt, 2019). The extremely high amount of EPA used in REDUCE-IT is a pharmacological dose and not relevant to dietary omega-3 intake.
Stroke and Omega-6 to Omega-3 Ratio
Cupino et al. (2022) analyzed the ratio of omega-6 to omega-3 intakes and risk of stroke among the Adventist Health Study-2 cohort. They found a statistically significant association between omega-6 to omega-3 ratio and an increased risk of any type of fatal stroke (HR 1.40, 95% CI: 1.16-1.69) for the 90th percentile ratio (12:1) vs. 10th percentile ratios (6:1).
Omega-3s and Cognition
A 2012 cross-sectional report from the Framingham Study examined 1,575 people (54% women) with an average age of 67 (SD 9) years with respect to omega-3 blood levels and numerous cognitive-related parameters (Tan, 2012). They compared the EPA+DHA red blood cell membrane fatty acids in the lowest quartile (≤4.4%) to those in the upper three quartiles (75th percentile was 6.5%). They found that those in the lowest quartile had a significantly lower cerebral brain volume (equivalent to approximately two years of brain aging), but a similar white matter hyperintensity volume, temporal horn volume, and rate of silent stroke. Low blood EPA+DHA was associated with a poorer score on some tests of cognition.
As part of the Women’s Health Initiative Study of Cognitive Aging, Ammann et al. (2013, USA) conducted a cross-sectional analysis of 2,302 women 65 years and older and found no difference in cognition between those in the upper one-third compared to those in the lowest one-third of EPA+DHA percentage of fatty acids in red blood cells. However, the lowest one-third had an average EPA-plus-DHA of 3.8% which is quite a bit higher than vegans tend to have, so this finding doesn’t necessarily reassure us about the omega-3 status of vegans. A 2017 study by Ammann et al. (described below), followed a much larger group of participants over time and provides more insight into whether higher EPA and DHA percentages are important in preventing cognitive impairment and dementia, especially in older women.
Zhang et al. (2016) conducted a meta-analysis of 21 case-control and prospective studies and found that increases of 1-serving/wk increments of fish were associated with a reduced risk of dementia (RR 0.95, CI 0.90-0.99) and Alzheimer’s disease (RR 0.93, CI: 0.90-0.95). DHA intake was also inversely associated with risks of dementia (RR 0.86, CI 0.76-0.96) and Alzheimer’s disease (RR 0.63, CI 0.51-0.76). However, blood levels of omega-3 fatty acids were not associated with a reduced risk of these or other cognitive diseases. In a letter to the editor, Koch and Jensen point out that in the six studies looking at the association between fish intake and dementia and Alzheimer’s disease, one study was a 2-year follow-up of another study with a longer follow-up. Koch and Jensen argue that “Appropriate exclusion of the report from Kalmijn et al. would render the meta-analysis of fish intake in relation to dementia risk insignificant (RR: 0.96; 95% CI: 0.91, 1.01; no heterogeneity) and change the RR estimate for AD risk to 0.87 (95% CI: 0.77, 0.98) in a random-effects meta-analysis with significant between-study heterogeneity still present.” Zhang and Jiao responded that it was appropriate to include both reports. It’s perplexing that omega-3 intakes but not blood levels would be associated with a reduced risk of dementia if there is a true effect, though it might suggest that blood levels of EPA and DHA aren’t an accurate representation of omega-3 status.
Amman et al. (2017, USA) conducted the largest prospective study to assess the risk of dementia with omega-3 fatty acid status. The study was part of the Women’s Health Initiative Memory Study testing the impact of the hormones estrogen and progestin on the memory of women ≥65 years old. Although the hormone part of the study was concluded early, the researchers continued to follow 6,706 women for an average of 9.8 years to see if baseline EPA and DHA levels were associated with a diagnosis of probable dementia (PD) or mild cognitive impairment (MCI). The study compared the risk of PD and MCI among those with EPA/DHA within one standard deviation above the mean (5.3-6.8% EPA+DHA) to those within one standard deviation below the mean (3.8-5.3% EPA+DHA). In one of their models, the researchers found a statistically significant reduction in PD (HR 0.91, CI .83-.99), but most models found no significant association including one that adjusted for the APOE genotype associated with Alzheimer’s Disease (HR 0.92, CI 0.83-1.01). The researchers calculated that the increased risk of PD represented a 2% reduced risk (12% vs. 14%) of PD incidence over a 15-year period. There were no significant associations between EPA+DHA and MCI. Examining EPA and DHA separately produced no significant findings.
In summary, studies of omega-3 fatty acids conducted on populations of omnivores consistently find some significant associations with better cognition, though they tend to be weak. That dietary intakes are more strongly associated with better cognition, than are blood levels, raises a question about whether omega-3s are responsible for the beneficial association rather than other variables paired with omega-3 intake.
Omega-3s and Depression
Our interest in omega-3s and depression is mostly related to whether vegetarians are at an increased risk of depression due to lower EPA or DHA levels.
Risk of Depression
Deane et al. (2019) conducted a meta-analysis and systematic review of 32 randomized controlled trials and found no effect of increasing EPA and DHA on the risk of depressive symptoms (RR 1.01, CI 0.92-1.10). Studies had a median duration of 12 months with a median dose of 0.95 grams per day (ranging from 0.4 to 3.4 grams per day). One study addressed omega-3s and anxiety and found little to no effect. The researchers recommend against taking omega-3 supplements for reducing depression and anxiety risk.
Treatment for Depression
Whether EPA or DHA can be used to treat people with depression is only loosely related to the omega-3 status of vegetarians, but it’s where most of the research has focused and so we review it here.
Early research on treating depressive symptoms with supplementation of EPA and DHA was mixed. In a 2006 review, Sontrop and Campbell found that supplementation improved depression but it wasn’t clear whether it was effective for depressed patients in general or only those with abnormally low concentrations of EPA and DHA. In another 2006 review, Appleton et al. found “little support” based on the small number of trials with significant variation. In a 2007 meta-analysis Lin and Sue found a positive effect of supplementation but with significant publication bias. In a 2009 meta-analysis, Martins found evidence that EPA is more effective than DHA.
Grosso et al. (2014) conducted a meta-analysis of 11 trials of patients with a DSM-defined diagnosis of a major depressive disorder (MDD) and 8 trials of patients with depressive symptomatology but no diagnosis. They found supplementation to have a beneficial effect for the patients diagnosed with MDD and also for those with bipolar disorder. They considered EPA to be more effective, with many trials using pharmacological doses. Hallahan, et al. (2016) found similar results in their meta-analysis.
In their meta-analysis, Luo et al. (2020) found a benefit from high-dose (≥2 g/day) but not low-dose (<2 g/day), EPA/DHA supplementation in the early therapy period for MDD.
Omega-3s and Increased Risk of Disease
Some studies have associated higher omega-3 intakes with an increased risk of disease.
A meta-analysis of randomized controlled trials (Hanson, 2020) measured the impact on the risk of a prostate cancer diagnosis of a higher long-chain omega-3 intake (7 trials, RR 1.10, 95% CI 0.97-1.24, NNTH 334) and of a higher ALA intake (2 trials, RR1.30, 95% CI 0.72–2.32, NNTH 334). Neither finding was statistically significant and had a high number needed to harm (NNTH). There was no impact on overal cancer diagnosis or death. The authors provided a chart showing that the benefits of higher omega-3 intake on cardiovascular events outweighed the potential harm.
A meta-analysis (Carleton, 2013) of case-control and prospective studies found no association between ALA intake and prostate cancer (RR 1.08, 95% CI 0.90-1.29). Removing one study during sensitivity analysis resulted in a weak, non-significant protective effect of ALA (RR 0.91, 95% CI 0.83-0.99, p=0.02).
A systematic review and meta-analysis (Simon, 2009) of ALA blood or tissue concentrations and prostate cancer found no association after adjustment for publication bias (RR: 0.96, 95% CI 0.79-1.17).
A 2010 meta-analysis found that subjects who consumed more than 1.5 g/day of ALA had a significantly decreased risk of prostate cancer (0.95, 0.91-0.99) compared to those who ate less (Carayol, 2010).
A 2018 paper from Harvard School of Public Health suggested that past associations between ALA and prostate cancer might have been due to trans-ALA which has been largely removed from the food supply (Wu, 2018).
A case-control study from the SELECT trial (Brasky, 2013) found an association between higher DHA phospholipid levels and prostate cancer. This finding is superceded by the findings of Hanson et al. (2020) described above, but a discussion of this finding from 2013 can be found on the JackNorrisRD.com blog post, DHA Supplements and Prostate Cancer.
A 2001 analysis from the Nurses Health Study found an almost statistically significant increase in age-related macular degeneration for those with the highest ALA intake (Cho, 2001, USA).
In contrast, a 2013 study found that higher ALA levels in the blood were associated with a lower risk of late age-related macular degeneration (Merle, 2013, France). And a 2017 follow-up from the Nurses Health Study found that a high intake of ALA was associated with an increased risk of intermediate age-related macular degeneration before 2002, but not afterward when less trans fats were found in participants’ blood (Wu, 2017, USA).
A 2005 analysis from the Nurses Health Study found that both the highest intakes of ALA and LA were associated with an increase in lens opacity, which can lead to cataracts (Lu, 2005, USA). For ALA, the risk ratio was 2.2 (1.2, 4.5) for about 1.26 g compared to .86 g per day. A 2007 analysis of the same group found that the highest category of ALA intake (about 1.26 g per day) was linked to a 16% increase in eye lens nuclear density compared to the lowest category (about .84 g per day) over five years. As of 2018, no follow-up studies appear to have been conducted on ALA and cataracts (Lu, 2007, USA).
Without more definitive research we don’t believe concerns about eyesight is any reason to avoid plant-based ALA due to the small differences in ALA intake in these studies, the fact that much ALA in meat-based diets comes from animal products, that trans ALA is no longer added to the food supply, and the large number and inconsistencies of associations between different fatty acids and various conditions.
Appendix A: Biomarkers of DHA Status
The primary reason why researchers rely on plasma and/or red blood cell percentages is convenience: they’re the most accessible and straightforward measurements to obtain. Studies consistently find inverse associations, albeit weak, between blood percentages and morbidity which bolsters their use.
In their review, Biomarkers of DHA status, Kuratko and Salem (2009) argue that the percentage of fatty acids as DHA in plasma or red blood cells is a generally adequate marker of overall DHA status. However, they also highlight many of the caveats that we discuss in Conversion of ALA to EPA and DHA.
Kuratko and Salem cite one paper worth discussing here. In a gruesome experiment, Sarkadi-Nagy et al. (2004) studied baboon infants in order to measure various fatty acids in their blood and tissues. At 14 days old, the infants were given a carbon-tracer labeled dose of ALA. After another 14 days, they were killed and the researchers measured correlations between the carbon-labeled DHA in plasma and red blood cells with carbon-labeled DHA in the brain, retina, and liver. R-coefficients are listed in the table below.
Kuratko and Salem summarize Sarkadi-Nagy et al.’s results by saying, “Both erythrocyte and plasma levels were correlated with resulting DHA content in brain, retina, and liver.” But these correlations weren’t between the total percentage of fatty acids as DHA; rather they were the percentage of fatty acids as DHA that was converted from ALA during the study period. In contrast, in their Table 3, Sarkadi-Nagy et al. list the total amounts of various fatty acids in plasma, red blood cells, and tissues and while there were some similarities there were also many differences.
Sarkadi-Nagy et al. write, “It is widely recognized that tissue and plasma [fatty acid] concentrations respond to diet. Improvements in function cannot be directly inferred and must be demonstrated (43). Furthermore, the wide variation in the regulation of individual [fatty acid] concentrations from tissue to tissue makes extrapolation difficult from compartments accessible in humans, primarily plasma and RBCs.” In other words, for their view that blood levels of DHA are adequate markers of omega-3 status, Kuratko and Salem rely on a paper by Sarkadi-Nagy et al. who disagree that tissue status can be extrapolated from blood percentages.
Kuratko and Salem also cite research on rhesus monkeys and then summarize by stating, “Although a statistical correlation was not reported, it is evident that a positive relationship exists between erythrocyte DHA levels and tissue levels, including the brain cortex and retina [68,69].” Their citation 68, Pawlosky et al. (1997), didn’t measure fatty acid levels in erythrocytes. Their citation 69, Pawlosky et al. (2001(a)), used a carbon tracer to measure the conversion of ALA to EPA and DHA in human blood but not tissues. Kuratko and Salem’s paper also includes a citation 58, Pawlosky et al. (2001(b)), which refers to the research using rhesus monkeys, but the paper wasn’t readily available and the abstract doesn’t indicate that the study would support their claim.
At the time of their writing, Kuratko and Salem were employees of Martek Biosciences which could arguably benefit from a convenient biomarker of DHA status that would err on the side of overestimating the need for DHA supplementation.
There are likely many other studies not mentioned in this article that have drawn various comparisons between percentages of long-chain omega-3 fatty acids in blood and tissues. The correlations do exist in some populations, but they are vague and cannot be used to draw any definite conclusions about the omega-3 status of apparently healthy individuals.
Appendix B: Evolutionary Arguments for a Dietary Requirement for DHA
A nutrient is essential if it must be provided by the diet for optimal health. A nutrient is conditionally essential if it’s required in the diet only under suboptimal conditions.
There’s an evolutionary argument that DHA is an essential nutrient, which goes:
For long periods of our evolution, humans lived near large bodies of water that provided a plentiful source of dietary DHA through fish. This plentiful DHA allowed the human brain to grow in size and intelligence. As a result, humans are still dependent on a source of dietary DHA for optimal brain health.
Short-chain omega-3 and omega-6 fats compete for the same enzymes to be elongated. Due to this, there’s also an evolutionary argument that DHA is a conditionally essential nutrient:
In modern diets, people eat such large amounts of omega-6 fats that the body’s ability to produce enough DHA to compete against the omega-6s is compromised. Under the suboptimal condition of a high omega-6 intake, dietary DHA becomes essential.
My focus is primarily on the first evolutionary argument—whether humans require a dietary source of DHA due to an evolutionary dependence on eating fish. However, the research I will review sometimes conflates the two arguments and so I wanted to describe them both at the outset.
There are four life stages when DHA could be either essential or conditionally essential:
- During fetal development, the fetus is at least partially dependent on obtaining DHA from the mother.
- Infants might be dependent on a dietary source of DHA from the mother’s breast milk or formula.
- During pregnancy or lactation, without a dietary source of DHA, the mother might not be able to convert enough ALA into DHA to provide for herself and her infant’s needs.
- During adulthood, a dietary source of DHA may be required to prevent cognitive decline.
Whether infants require a dietary source of DHA for optimal brain development isn’t relevant to the argument that humans have evolved with a dependence on eating fish because infants can obtain dietary DHA from breastmilk, and so I don’t spend much time addressing this question.
I also don’t address arguments about the food sources of pre-modern humans because even if pre-modern humans ate ample amounts of fish, it wouldn’t mean that modern humans have a dietary requirement for DHA.
Instead, I review the evidence for what I consider to be the most persuasive arguments for dietary DHA being essential. Some of these arguments are ecological, such as claims that human brain size and intelligence have decreased while neurological issues and mental illness have increased due to a move away from an aquatic diet. I also address specific physiological claims about the metabolism of omega-3s based on clinical research. Much of this research used animals.
Below, I review three published papers arguing that humans evolved on an aquatic diet that included fish and, therefore, included a consistent, dietary source of DHA that increased our brain size and intelligence. They imply that we still depend on dietary DHA for optimal brain development and maintenance. I also review two papers arguing that there’s no dietary need for DHA beyond infancy.
Crawford, 2006 and Crawford et al., 2022
Michael A. Crawford is a researcher with the Institute of Brain Chemistry and Human Nutrition in the U.K. He’s published scientific papers, sometimes with co-authors, arguing that omega-3s are neglected nutrients in the modern world and that a dietary source of DHA was important for the evolution of the human brain and is still important for infant brain development.
I’ll address what I consider to be the most persuasive arguments in his articles, Docosahexaenoic acid in neural signaling systems (2006) and Neurodevelopment, nutrition and genetics (2022).
Crawford’s 2006 article appears to be a response to John Langdon’s 2006 paper arguing that there’s no evolutionary requirement for DHA beyond infancy, which I review later (below). Crawford says that “[Langdon] neglects the basic principle of Darwinian evolution. The well documented greater efficiency of preformed docosahexaenoic acid for brain incorporation during development would have conferred a distinct survival advantage over those without it.”
But despite his many arguments and citations, Crawford provides little more than conjecture that a dietary source of DHA, beyond what is in breastmilk, is required for the proper development of the human brain. Instead, he cites evidence that omega-3s, which could be in the form of ALA, are required.
For example, Crawford (2006) writes that “DHA in the diet is rapidly and selectively incorporated in brain cell membranes and is concentrated at synaptic signaling sites (Suzuki et al., 1997).” In this study by Suzuki et al., male mice were deprived of omega-3s for 11 days and then placed in a diet group for either 6 or 30 days. There were numerous groups of mice, but I’ll limit this summary to the dietary groups of no omega-3s, ALA, and DHA. The table below shows the levels of DHA among the various groups of mice at the end of each trial.
The plasma levels vary considerably, while the brain levels are similar. The physiological significance of the differences in the brain percentages of DHA between the ALA and DHA-fed groups wasn’t determined. Arguably, this study provides reassurance that, at least for mice, ALA as the only dietary source of omega-3s may be adequate. But since mice in the wild are unlikely to have evolved with a significant source of dietary DHA, these results can’t necessarily be applied to humans.
Crawford (2006) writes:
Deficiency studies in rodents (Sinclair and Crawford, 1973), primates (Fiennes et al., 1973, Neuringer et al., 1976) and visual and cognitive trials in human infants (Birch et al., 2000) have indicated that DHA is essential to brain development and function.
Sinclair and Crawford (1973) don’t isolate DHA in any way to justify this claim. Fiennes et al. (1973) studied omega-3 deficiency, not DHA deficiency. Neuringer et al. (1986) studied diets low in ALA. Birch et al. (2000) showed that infants who weren’t breastfed, but who had DHA in their infant formula, performed better on some cognitive and motor skills tests than infants without DHA in their infant formula.
On an epidemiologic level, Crawford argues that a move away from aquatic diets has caused a deficiency of important nutrients, most notably DHA and iodine, that has led to a global increase in mental disorders, and a reduction in intelligence and brain size. I’ll address these points but, because these topics are vast, I’m merely doing a cursory review.
Mental Health and Brain Disorders
Crawford (2006) writes:
The rise in mental ill health and brain disorders, to replace all other costs in the European list of burdens of ill health, raises interesting questions as to its association with the reduced availability and consumption of marine and fresh water products.
In 1972, based on the changing diet and lipid science, we predicted brain disorders would rise and this has now happened. Brain disorders now account for the highest cost to the burden of ill health in the EU (€386 billion) having overtaken heart disease, cancer and obesity by a large margin. This is hardly surprising. The brain first evolved in the sea and still uses marine fatty acids; the loss of the marine food chain is bound to have consequences.
In 2022, Crawford et al. continued to emphasize this argument saying, “One in five adults in US are reported to live with mental illness in 2019, prior to the pandemic [National Institutes of Health]; the number of 197.3 million in India suffer from mental disorders in 2017 is of the same order, double digit percentage of population [GBD India].”
Is Crawford correct that brain and mental illnesses are increasing?
According to the paper, Global, regional, and national burden of neurological disorders, 1990–2016, the absolute numbers of neurological disorders are increasing due to an aging population, but after adjusting for age and other variables, the rates are actually decreasing. For this analysis, they included a wide range of diseases, some that seem unlikely to be related to a DHA deficiency. Here’s a list of some specific diseases and the percentage of increase (+) or decrease (-) in their age-adjusted incidence between 1990 and 2016: stroke (-8%), Alzheimer’s disease and other dementias (+2%), Parkinson’s disease (+22%), idiopathic epilepsy (+6%), multiple sclerosis (+10%), and migraine (-2%).
Regarding mental illness, Crawford et al. (2022) cite the National Institutes of Health web page, Mental Illness. While the page doesn’t assess whether mental illness is increasing, they say that any mental illness (AMI) affects a large percentage of U.S. adults (21% as of 2020). AMI is defined as a mental, behavioral, or emotional disorder and can vary in impairment, ranging from none to mild, moderate, or severe. Regarding severe mental illness, the prevalence was 5.6% of all U.S. adults, with it being higher among adults aged 18-25 (9.7%) than adults aged 26-49 (6.9%) and aged 50+ (3.4%). Based on data from the National Comorbidity Survey Adolescent Supplement, 49.5% of adolescents had AMI; of those, 22.2% had severe impairment.
Regarding mental illness in India, Crawford et al. (2022) cite The burden of mental disorders across the states of India: the Global Burden of Disease Study 1990-2017 which found that the contribution of mental disorders to the total disability-adjusted life-years (DALYs) in India increased from 2.5% in 1990 to 4.7% in 2017. In 2017, depressive disorders contributed the most to the total DALYs (33.8%), followed by anxiety disorders (19.0%), idiopathic developmental intellectual disability (10.8%), schizophrenia (9.8%), bipolar disorder (6.9%), conduct disorder (5.9%), autism spectrum disorders (3.2%), eating disorders (2.2%), and attention-deficit hyperactivity disorder (0.3%). Dementia wasn’t mentioned in this report.
These rates of mental illness do seem rather high but some suggest it’s due to higher reporting. An article in The Guardian, Mental illness: is there really a global epidemic? (June 3, 2019) reports that in the previous 20 years, two variables have impacted the rates of mental illness: recognition and destigmatization. This has resulted in more people seeking help and reporting mental distress. Harvey Whiteford, professor of population mental health at the University of Queensland is quoted as saying, “All the modelling we’ve done in high-income countries where there’s survey data which has tracked over time shows that the prevalence hasn’t changed–it’s flatlined.”
The idea that brain disorders and mental illnesses are increasing due to a lack of dietary DHA is an interesting hypothesis which, at best, is difficult to assess.
Crawford et al. (2022) argue that worldwide average intelligence quotients (IQ) peaked in the birth year 1975 and then fell steadily through the birth year 1990. While Figure 1 in their paper shows a consistent trend, the difference is only about 2.5% of a normal IQ.
Norway is an interesting case regarding the decrease in IQ compared to per capita fish consumption. An article from the World Economic Forum, IQs are falling – and have been for years (2018), provides data from Norway where men reporting for national service between 1970 and 2009 were given IQ tests. It says “[The] analysis showed that the men born in 1962 had higher scores than those born in 1991. Those born in 1991 scored five points lower than those born in 1975, and three points lower than those born in 1962. This is the opposite of what happened during much of the 20th century when IQ scores rose by around 3% a year.”
Norway has one of the highest per-capita fish intakes of any country. The HelgiLibrary created a graph using FAOSTAT data, Fish Consumption Per Capita in Norway, showing an increase from about 41 kg in 1960 to about 53 kg in 2013. The increase in per-capita fish consumption in Norway during the time that IQ was decreasing suggests that the decrease in IQ was not due to a drop in fish consumption.
Norway was the only country for which I found data accessible enough to make this comparison. Based on this data from Norway, it seems unlikely that decreases in intelligence are due to a move away from an aquatic-based diet.
Crawford et al. (2022) write:
Dr Marta Lahr from the UK Cambridge University’s Leverhulme centre for Human Evolutionary Studies presented her findings to the Royal Society in 2013 that the brain size of the modern-day humans has been shrinking since the beginning of the land-based agriculture and animal husbandry 10,000 years ago.
For this statement, Crawford et al. cite a short news article, Farming to blame for our shrinking size and brains (by Deborah Braconnier, Phys.org, 2011). This article ends with:
Agriculture however does not explain the reduction in brain size. Lahr believes that this may be a result of the energy required to maintain larger brains…This reduction in brain size however does not mean that modern humans are less intelligent. Human brains have evolved to work more efficiently and utilize less energy.
A related article, Are brains shrinking to make us smarter? (by Jean-Louis Santini, Phys.org, 2011) says:
But the downsizing does not mean modern humans are dumber than their ancestors — rather, they simply developed different, more sophisticated forms of intelligence, said Brian Hare, an assistant professor of anthropology at Duke University.
A 2019 article from Discover, The Human Brain Has been Getting Smaller Since the Stone Age (by Bridget Alex), says that the most likely explanation for a reduction in human brain size is the survival of the friendliest:
The idea is, within Stone Age societies, cooperative, level-headed individuals were more likely to survive and reproduce than combative, aggressive ones. Those pro- or anti-social inclinations were influenced by genes regulating hormones, which also affected physical traits, including body and brain size. Over time, “survival of the friendliest” led to humans with slighter builds and brains on average. So although there was a reduction in skull size—and possibly intelligence—human cooperation grew, cultivating greater collective wisdom.
I don’t consider these news articles to be scientifically rigorous, but they suggest that a move away from an aquatic diet isn’t the accepted explanation for a reduction in brain size and that this reduction in brain size isn’t indicative of a health crisis.
Genetics and the n6:n3 Ratio
Crawford et al. (2022) propose a theory that traditional vegetarian societies, such as in the Pune region of India, tend to have genetic variants for fatty acid conversion that lead to low conversion of ALA to DHA when omega-6 intakes are high (such as in modern diets), regardless of how much ALA is added to the diet. If true, DHA would be conditionally essential in these contexts, but this is different from the claim that humans evolved with a dietary requirement for DHA due to a reliance on an aquatic-based diet.
In 2011, Dr. Joanne Bradbury from the School of Health and Human Sciences of Southern Cross University in Australia, published the paper, Docosahexaenoic acid (DHA): an ancient nutrient for the modern human brain.
Bradbury argues that modern humans have adapted to a dietary intake of preformed DHA. Bradbury’s arguments are based on the idea that endogenous synthesis of DHA from ALA in humans is “much lower and more limited than previously assumed.” Bradbury attributes the supposedly limited conversion of ALA to DHA to an increase in omega-6 intake. She also cites research with infants suggesting that dietary DHA is critical for their development, which, as I point out above, is available through breastmilk and doesn’t provide evidence for an evolutionary need for eating fish.
In 2006, John Langdon of the Departments of Biology and Anthropology at the University of Indianapolis wrote a paper, Has an aquatic diet been necessary for hominin brain evolution and functional development?, arguing that an aquatic food supply was not critical for the evolution of the human brain nor is DHA essential for the brain development of children today.
Langdon reviews a wide range of topics. For example, he cites a survey finding that of 123 modern hunter-gatherer groups, fishing didn’t provide a measurable part of the diet in 23.
In my opinion, this excerpt sums up Langdon’s strongest argument:
An overall body deficiency [of DHA] permits DHA to be substituted by other fatty acids within the membranes, including docosapentaenoic acid (22:5n-6) [omega-6 DPA] or arachidonic acid (20:4n-6) [AA], so that body tissue composition can shift fairly quickly as diet changes (Neuringer et al. 1988; Uauy, 1990; Neuringer, 1993). This replacement may be temporary, until body levels of DHA are restored, and it implies that temporary shortages of DHA need not interfere with the rate of overall brain growth.
Let’s see what evidence Langdon cites to support this view.
I’m not sure why Langdon cites the 1993 paper by Neuringer. In that brief review, Neuringer describes a study in which infants who had been fed formula without DHA had lower levels of DHA (7.0-7.5%) in their cerebral cortex compared to those who received breastmilk (~9.75%). This was despite the fact that one group of formula-fed infants was older (16-43 weeks) than the breastfed infants (5-16 weeks) and that DHA normally accumulates in the brain as infants age. This study didn’t address whether omega-6 DPA or AA could adequately replace DHA and, therefore, doesn’t support Langdon’s argument.
The 1988 review by Neuringer et al. seems more relevant. They say:
As first observed by Mohrhauer & Holman, decreases in DHA were compensated by increases in the n-6 fatty acids 22:5n-6 and, to a lesser extent, 22:4n-6. Consequently, the total level of 22-carbon polyunsaturated fatty acids remained roughly constant, and the degree of polyunsaturation changed only slightly. This reciprocal replacement of DHA by long-chain n-6 fatty acids is a consistent finding in studies of n-3 fatty acid deficiency. It is particularly striking because, with a few exceptions, 22:5n-6 is normally present at very low levels in animal tissues. Therefore, the ratio of 22:5n-6 to 22:6n-3 in blood and tissues has been suggested as an index of n-3 fatty acid deficiency [Galli et al., 1974].
Neuringer et al. strongly imply that replacing DHA with omega-6 DPA isn’t optimal. In examining their citations, the study by Mohrhauer and Holman (1963) used rats and didn’t assess any potential problems with substituting the long-chain omega-6 fatty acids for DHA. Similarly, the study by Galli et al. used rats and didn’t assess the impacts of substituting long-chain omega-6 fatty acids for DHA.
Finally, the 1990 review by Uauy cited by Langdon doesn’t provide evidence to support Langdon’s statement. Uauy actually argues that infants require a dietary source of DHA.
While I’m sympathetic to much of what Langdon writes and would prefer that it be true, the most critical part of his paper doesn’t convince me.
Graham Burdge is a lipid researcher from the University of Southampton in the U.K and was the lead researcher on a series of omega-3 conversion studies (Burdge et al., 2002; Burdge and Wootton, 2002; Burdge et al., 2003).
In 2022, Burdge published a paper, α-linolenic acid interconversion is sufficient as a source of longer chain ω-3 polyunsaturated fatty acids in humans: An opinion. In this thorough review article, Burdge argues that a dietary intake of ALA is sufficient to meet the body’s needs for EPA and DHA.
Rather than being concerned that vegetarians might need to supplement with DHA, Burdge argues that the apparently healthy status of long-term vegetarians and vegans suggests that there is no dietary need for EPA and DHA.
Burdge says that in an omega-3 deficiency, omega-6 DPA accumulates in the plasma phospholipids and that the few studies of vegetarians that have reported omega-6 DPA levels have not found an accumulation. Burdge points out that Sanders and Reddy (1992) found no accumulation of omega-6 DPA in the red blood cells of infants breastfed by vegan mothers.
However, Burdge doesn’t include that Sanders and Reddy (1992) also found higher amounts of omega-6 DPA for Hindu vegetarians compared to omnivores in cord plasma (2.34% vs. 1.58%) and artery phospholipids (4.15% vs. 3.19%). These fractions weren’t reported for vegans.
The Hindu vegetarians had ALA intakes of only 0.9 g/day compared to 1.2 g/day for the vegans. While this difference isn’t much, 0.9 g/day is lower than the recommended DRI for omega-3s of 1.1 to 1.4 g/day and might be low enough that these Hindu vegetarians were deficient in omega-3s.
The findings of dietary supplementation trials and experiments using stable isotope tracers have been interpreted as indicating that humans are “poor” converters of [ALA], in particular with respect to DHA synthesis. The use of the terms “poor,” constrained or “limited”, [or] severely “restricted” to describe PUFA synthesis in humans presupposes that the level of conversion should be greater, but what this higher level should be has not been defined and is potentially misleading.
Rather, capacity for hepatic [ALA] conversion in humans is better considered as a product of an evolutionary history and, therefore, nutritionally adequate.
Conclusion to Evolutionary Arguments for a Dietary Requirement for DHA
The evolutionary arguments in favor of a dietary requirement for DHA are interesting but the evidence seems too vague to know whether they’re true. It appears that whether modern humans require dietary DHA for proper brain development and maintenance is a question that can only be answered through clinical trials comparing outcomes in people with and without a dietary source of DHA.
Last updated September 2022
Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, Deane KHO, Summerbell CD, Worthington HV, Song F, Hooper L. Omega‐3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2020, Issue 3.
Allès B, Baudry J, Méjean C, Touvier M, Péneau S, Hercberg S, Kesse-Guyot E. Comparison of Sociodemographic and Nutritional Characteristics between Self-Reported Vegetarians, Vegans, and Meat-Eaters from the NutriNet-Santé Study. Nutrients. 2017 Sep 15;9(9).
Ammann EM, Pottala JV, Harris WS, Espeland MA, Wallace R, Denburg NL, Carnahan RM, Robinson JG. ω-3 fatty acids and domain-specific cognitive aging: secondary analyses of data from WHISCA. Neurology. 2013 Oct 22;81(17):1484-91.
Ammann EM, Pottala JV, Robinson JG, Espeland MA, Harris WS. Erythrocyte omega-3 fatty acids are inversely associated with incident dementia: Secondary analyses of longitudinal data from the Women’s Health Initiative Memory Study (WHIMS). Prostaglandins Leukot Essent Fatty Acids. 2017 Jun;121:68-75.
Appleton KM, Hayward RC, Gunnell D, Peters TJ, Rogers PJ, Kessler D, Ness AR. Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr. 2006 Dec;84(6):1308-16.
Barcelo-Coblijn G, Murphy EJ, Othman R, Moghadasian MH, Kashour T, Friel JK. Flaxseed oil and fish-oil capsule consumption alters human red blood cell n-3 fatty acid composition: a multiple-dosing trial comparing 2 sources of n-3 fatty acid. Am J Clin Nutr. 2008 Sep;88(3):801-9.
Bernstein AM, Ding EL, Willett WC, Rimm EB. A meta-analysis shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDL-cholesterol and LDL-cholesterol in persons without coronary heart disease. J Nutr. 2012 Jan;142(1):99-104. Not cited.
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22.
Birch EE, Garfield S, Hoffman DR, Uauy R, Birch DG. A randomized controlled trial of early dietary supply of long-chain polyunsaturated fatty acids and mental development in term infants. Dev Med Child Neurol. 2000 Mar;42(3):174-81.
Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Klein EA, Kristal AR. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst. 2013 Aug 7;105(15):1132-41.
Brossard N, Croset M, Pachiaudi C, Riou JP, Tayot JL, Lagarde M. Retroconversion and metabolism of [13C]22:6n-3 in humans and rats after intake of a single dose of [13C]22:6n-3-triacylglycerols. Am J Clin Nutr. 1996 Oct;64(4):577-86.
Brouwer IA, Katan MB, Zock PL. Dietary alpha-linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J Nutr. 2004 Apr;134(4):919-22. Not cited.
Burdge GC, Finnegan YE, Minihane AM, Williams CM, Wootton SA. Effect of altered dietary n-3 fatty acid intake upon plasma lipid fatty acid composition, conversion of [13C]alpha-linolenic acid to longer-chain fatty acids and partitioning towards beta-oxidation in older men. Br J Nutr. 2003 Aug;90(2):311-21.
Burns-Whitmore B, Froyen E, Heskey C, Parker T, San Pablo G. Alpha-Linolenic and Linoleic Fatty Acids in the Vegan Diet: Do They Require Dietary Reference Intake/Adequate Intake Special Consideration? Nutrients. 2019 Oct 4;11(10):2365. Not cited.
Burns-Whitmore B, Haddad E, Sabaté J, Rajaram S. Effects of supplementing n-3 fatty acid enriched eggs and walnuts on cardiovascular disease risk markers in healthy free-living lacto-ovo-vegetarians: a randomized, crossover, free-living intervention study. Nutr J. 2014 Mar 27;13(1):29.
Carayol M, Grosclaude P, Delpierre C. Prospective studies of dietary alpha-linolenic acid intake and prostate cancer risk: a meta-analysis. Cancer Causes Control. 2010 Mar;21(3):347-55. Review. (Abstract)
Carleton AJ, Sievenpiper JL, de Souza R, McKeown-Eyssen G, Jenkins DJ. Case-control and prospective studies of dietary α-linolenic acid intake and prostate cancer risk: a meta-analysis. BMJ Open. 2013 May 14;3(5):e002280.
Chamorro R, Gonzalez MF, Aliaga R, Gengler V, Balladares C, Barrera C, Bascuñan KA, Bazinet RP, Valenzuela R. Diet, Plasma, Erythrocytes, and Spermatozoa Fatty Acid Composition Changes in Young Vegan Men. Lipids. 2020 Nov;55(6):639-648.
Cho E, Hung S, Willett WC, Spiegelman D, Rimm EB, Seddon JM, Colditz GA, Hankinson SE. Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr. 2001 Feb;73(2):209-18.
Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Arch Ophthalmol. 2008 Jun;126(6):826-33. Not cited.
Conquer JA, Holub BJ. Supplementation with an algae source of docosahexaenoic acid increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects. J Nutr. 1996 Dec;126(12):3032-9.
Craddock JC, Neale EP, Probst YC, Peoples GE. Algal supplementation of vegetarian eating patterns improves plasma and serum docosahexaenoic acid concentrations and omega-3 indices: a systematic literature review. J Hum Nutr Diet. 2017 Dec;30(6):693-699. The six studies included in this review are all summarized in DHA Supplementation in Vegans. Not cited.
Crawford MA, Wang Y, Marsh DE, Johnson MR, Ogundipe E, Ibrahim A, Rajkumar H, Kowsalya S, Kothapalli KSD, Brenna JT. Neurodevelopment, nutrition and genetics. A contemporary retrospective on neurocognitive health on the occasion of the 100th anniversary of the National Institute of Nutrition, Hyderabad, India. Prostaglandins Leukot Essent Fatty Acids. 2022 May;180:102427.
Cunnane SC, Schneider JA, Tangney C, Tremblay-Mercier J, Fortier M, Bennett DA, Morris MC. Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2012;29(3):691-7.
Cupino A, Fraser G, Knutsen S, Knutsen R, Heskey C, Sabaté J, Shavlik D. Are total omega-3 and omega-6 polyunsaturated fatty acids predictors of fatal stroke in the Adventist Health Study 2 prospective cohort? PLoS One. 2022 Sep 9;17(9):e0274109.
Deane KHO, Jimoh OF, Biswas P, et al. Omega-3 and polyunsaturated fat for prevention of depression and anxiety symptoms: systematic review and meta-analysis of randomised trials [published online ahead of print, 2019 Oct 24]. Br J Psychiatry. 2019;1‐8.
Ezaki O, Takahashi M, Shigematsu T, Shimamura K, Kimura J, Ezaki H, Gotoh T. Long-term effects of dietary alpha-linolenic acid from perilla oil on serum fatty acids composition and on the risk factors of coronary heart disease in Japanese elderly subjects. J Nutr Sci Vitaminol (Tokyo). 1999 Dec;45(6):759-72.
Fisher M, Levine PH, Weiner B, Ockene IS, Johnson B, Johnson MH, Natale AM, Vaudreuil CH, Hoogasian J. The effect of vegetarian diets on plasma lipid and platelet levels. Arch Intern Med. 1986 Jun;146(6):1193-7. No omega-3 data. Found higher LA but similar AA levels among vegans, lacto-ovo-vegetarians, and meat-eaters. Not cited.
Fokkema MR, Brouwer DA, Hasperhoven MB, Martini IA, Muskiet FA. Short-term supplementation of low-dose gamma-linolenic acid (GLA), alpha-linolenic acid (ALA), or GLA plus ALA does not augment LCP omega 3 status of Dutch vegans to an appreciable extent. Prostaglandins Leukot Essent Fatty Acids. 2000 Nov;63(5):287-92.
GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):459-480.
Grosso G, Pajak A, Marventano S, Castellano S, Galvano F, Bucolo C, Drago F, Caraci F. Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLoS One. 2014 May 7;9(5):e96905.
Hallahan B, Ryan T, Hibbeln JR, Murray IT, Glynn S, Ramsden CE, SanGiovanni JP, Davis JM. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. Br J Psychiatry. 2016 Sep;209(3):192-201.
Hanson S, Thorpe G, Winstanley L, Abdelhamid AS, Hooper L; PUFAH group. Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomised trials. Br J Cancer. 2020 Apr;122(8):1260-1270.
Harris WS, Sands SA, Windsor SL, Ali HA, Stevens TL, Magalski A, Porter CB, Borkon AM. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation. 2004 Sep 21;110(12):1645-9.
Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Davey Smith G. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ. 2006 Apr 1;332(7544):752-60. Epub 2006 Mar 24. Not cited.
Hu Y, Hu F, Manson JE. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. J Am Heart Assoc. 2019 Oct;8(19):e013543.
India State-Level Disease Burden Initiative Mental Disorders Collaborators. The burden of mental disorders across the states of India: the Global Burden of Disease Study 1990-2017. Lancet Psychiatry. 2020 Feb;7(2):148-161.
Indu M, Ghafoorunissa. n-3 Fatty acids in Indian diets – comparison of the effects of precursor (alpha-linolenic acid) vs. product (long chain n-3 polyunsaturated fatty acids). Nutrition Research. 1992;12:569-82.
Koch M, Jensen MK. Comment on: Limitations of the review and meta-analysis of fish and PUFA intake and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016 Aug;104(2):537.
Kornsteiner M, Singer I, Elmadfa I. Very low n-3 long-chain polyunsaturated fatty acid status in Austrian vegetarians and vegans. Ann Nutr Metab. 2008;52(1):37-47. Epub 2008 Feb 28. 10:1 n-6/n-3 for vegetarian diets and lower LC n-3 levels.
Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002 Nov 19;106(21):2747-57. Erratum in: Circulation. 2003 Jan 28;107(3):512.
Kris-Etherton PM, Hill AM. N-3 fatty acids: food or supplements? J Am Diet Assoc. 2008 Jul;108(7):1125-30. No abstract available. Not cited.
Lands WE, Morris A, Libelt B. Quantitative effects of dietary polyunsaturated fats on the composition of fatty acids in rat tissues. Lipids. 1990 Sep;25(9):505-16. Not cited above, but is citation #43 from Sarkadi-Nagy et al. (2004); mathematically complex paper which I couldn’t assess.
Lane KE, Wilson M, Hellon TG, Davies IG. Bioavailability and conversion of plant based sources of omega-3 fatty acids – a scoping review to update supplementation options for vegetarians and vegans. Crit Rev Food Sci Nutr. 2021 Feb 12:1-16. Not cited.
Li D, Sinclair A, Mann N, Turner A, Ball M, Kelly F, Abedin L, Wilson A. The association of diet and thrombotic risk factors in healthy male vegetarians and meat-eaters. Eur J Clin Nutr. 1999 Aug;53(8):612-9. Same measurements as provided in Li, 2002.
Liou YA, King DJ, Zibrik D, Innis SM. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr. 2007 Apr;137(4):945-52.
Lu M, Taylor A, Chylack LT Jr, Rogers G, Hankinson SE, Willett WC, Jacques PF. Dietary linolenic acid intake is positively associated with five-year change in eye lens nuclear density. J Am Coll Nutr. 2007 Apr;26(2):133-40.
Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, Serhan CN, Bazan NG. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest. 2005 Oct;115(10):2774-83. Not cited.
Luo XD, Feng JS, Yang Z, Huang QT, Lin JD, Yang B, Su KP, Pan JY. High-dose omega-3 polyunsaturated fatty acid supplementation might be more superior than low-dose for major depressive disorder in early therapy period: a network meta-analysis. BMC Psychiatry. 2020 May 20;20(1):248.
Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr. 2009 Oct;28(5):525-42. Review.
Merle BM, Delyfer MN, Korobelnik JF, Rougier MB, Malet F, Féart C, Le Goff M, Peuchant E, Letenneur L, Dartigues JF, Colin J, Barberger-Gateau P, Delcourt C. High concentrations of plasma n3 fatty acids are associated with decreased risk for late age-related macular degeneration. J Nutr. 2013 Apr;143(4):505-11.
Metcalf RG, James MJ, Gibson RA, Edwards JR, Stubberfield J, Stuklis R, Roberts-Thomson K, Young GD, Cleland LG. Effects of fish-oil supplementation on myocardial fatty acids in humans. Am J Clin Nutr. 2007 May;85(5):1222-8.
Metherel AH, Irfan M, Klingel SL, Mutch DM, Bazinet RP. Compound-specific isotope analysis reveals no retroconversion of DHA to EPA but substantial conversion of EPA to DHA following supplementation: a randomized control trial. Am J Clin Nutr. 2019 Oct 1;110(4):823-831.
Mezzano D, Kosiel K, Martinez C, Cuevas A, Panes O, Aranda E, Strobel P, Perez DD, Pereira J, Rozowski J, Leighton F. Cardiovascular risk factors in vegetarians. Normalization of hyperhomocysteinemia with vitamin B(12) and reduction of platelet aggregation with n-3 fatty acids. Thromb Res. 2000 Nov 1;100(3):153-60.
Mezzano D, Munoz X, Martinez C, Cuevas A, Panes O, Aranda E, Guasch V, Strobel P, Munoz B, Rodriguez S, Pereira J, Leighton F. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine. Thromb Haemost 1999 Jun;81(6):913-7.
Miles FL, Lloren JIC, Haddad E, Jaceldo-Siegl K, Knutsen S, Sabate J, Fraser GE. Plasma, Urine, and Adipose Tissue Biomarkers of Dietary Intake Differ Between Vegetarian and Non-Vegetarian Diet Groups in the Adventist Health Study-2. J Nutr. 2019 Apr 1;149(4):667-675.
Muskiet FA, Fokkema MR, Schaafsma A, Boersma ER, Crawford MA. Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation, our ancient diet, epidemiology and randomized controlled trials. J Nutr. 2004 Jan;134(1):183-6. Not cited.
Neuringer M, Connor WE, Lin DS, Barstad L, Luck S. Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4021-5.
Orlich MJ, Singh PN, Sabaté J, Jaceldo-Siegl K, Fan J, Knutsen S, Beeson WL, Fraser GE. Vegetarian dietary patterns and mortality in Adventist Health Study 2. JAMA Intern Med. 2013 Jul 8;173(13):1230-8.
Ottestad I, Vogt G, Retterstøl K, Myhrstad MC, Haugen JE, Nilsson A, Ravn-Haren G, Nordvi B, Brønner KW, Andersen LF, Holven KB, Ulven SM. Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial. Br J Nutr. 2012 Jul;108(2):315-26. Not cited.
Pawlosky RJ, Denkins Y, Ward G, Salem N Jr. Retinal and brain accretion of long-chain polyunsaturated fatty acids in developing felines: the effects of corn oil-based maternal diets. Am J Clin Nutr. 1997 Feb;65(2):465-72.
Pawlosky RJ, Bacher J, Salem N Jr. Ethanol consumption alters electroretinograms and depletes neural tissues of docosahexaenoic acid in rhesus monkeys: nutritional consequences of a low n-3 fatty acid diet. Alcohol Clin Exp Res. 2001(b) Dec;25(12):1758-65.
Pinto AM, Sanders TA, Kendall AC, Nicolaou A, Gray R, Al-Khatib H, Hall WL. A comparison of heart rate variability, n-3 PUFA status and lipid mediator profile in age- and BMI-matched middle-aged vegans and omnivores. Br J Nutr. 2017 Mar;117(5):669-685.
Rosell MS, Lloyd-Wright Z, Appleby PN, Sanders TA, Allen NE, Key TJ. Long-chain n-3 polyunsaturated fatty acids in plasma in British meat-eating, vegetarian, and vegan men. Am J Clin Nutr. 2005 Aug;82(2):327-34.
Rotolo O, Zinzi I, Veronese N, Cisternino AM, Reddavide R, Inguaggiato R, Leandro G, Notarnicola M, Tutino V, De Nunzio V, De Leonardis G, Guerra V, Donghia R, Fucilli F, Licinio R, Mastrosimini A, Rinaldi CCM, Daddabbo T, Giampaolo N, Iacovazzi PA, Giannico S, Caruso MG. Women in LOVe: Lacto-Ovo-Vegetarian Diet Rich in Omega-3 Improves Vasomotor Symptoms in Postmenopausal Women. An Exploratory Randomized Controlled Trial. Endocr Metab Immune Disord Drug Targets. 2019;19(8):1232-1239. Not cited.
Salvador AM, García-Maldonado E, Gallego-Narbón A, Zapatera B, Vaquero MP. Fatty Acid Profile and Cardiometabolic Markers in Relation with Diet Type and Omega-3 Supplementation in Spanish Vegetarians. Nutrients. 2019 Jul 20;11(7):1659.
Sanders TA, Roshanai F. Platelet phospholipid fatty acid composition and function in vegans compared with age- and sex-matched omnivore controls. Eur J Clin Nutr. 1992 Nov;46(11):823-31. Same study population as Roshani, 1984.
Sanders TA, Younger KM. The effect of dietary supplements of omega 3 polyunsaturated fatty acids on the fatty acid composition of platelets and plasma choline phosphoglycerides. Br J Nutr. 1981 May;45(3):613-6.
Sarkadi-Nagy E, Wijendran V, Diau GY, Chao AC, Hsieh AT, Turpeinen A, Lawrence P, Nathanielsz PW, Brenna JT. Formula feeding potentiates docosahexaenoic and arachidonic acid biosynthesis in term and preterm baboon neonates. J Lipid Res. 2004 Jan;45(1):71-80.
Sarter B, Kelsey KS, Schwartz TA, Harris WS. Blood docosahexaenoic acid and eicosapentaenoic acid in vegans: Associations with age and gender and effects of an algal-derived omega-3 fatty acid supplement. Clin Nutr. 2015 Apr;34(2):212-8.
Schmidt JA, Fensom GK, Rinaldi S, Scalbert A, Gunter MJ, Holmes MV, Key TJ, Travis RC. NMR Metabolite Profiles in Male Meat-Eaters, Fish-Eaters, Vegetarians and Vegans, and Comparison with MS Metabolite Profiles. Metabolites. 2021; 11(2):121. Not cited.
Suzuki H, Manabe S, Wada O, Crawford MA. Rapid incorporation of docosahexaenoic acid from dietary sources into brain microsomal, synaptosomal and mitochondrial membranes in adult mice. Int J Vitam Nutr Res. 1997;67(4):272-8.
Talahalli RR, Vallikannan B, Sambaiah K, Lokesh BR. Lower efficacy in the utilization of dietary ALA as compared to preformed EPA + DHA on long chain n-3 PUFA levels in rats. Lipids. 2010 Sep;45(9):799-808.
Tan ZS, Harris WS, Beiser AS, Au R, Himali JJ, Debette S, Pikula A, Decarli C, Wolf PA, Vasan RS, Robins SJ, Seshadri S. Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology. 2012 Feb 28;78(9):658-64.
Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, Lau J. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006 Jul;84(1):5-17. Not cited.
Welch AA, Bingham SA, Khaw KT. Estimated conversion of alpha-linolenic acid to long chain n-3 polyunsaturated fatty acids is greater than expected in non-fish-eating vegetarians and non-fish-eating meat-eaters than in fish-eaters. J Hum Nutr Diet. 2008;21:373.
Welch AA, Shakya-Shrestha S, Lentjes MA, Wareham NJ, Khaw KT. Dietary intake and status of n-3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and vegans and the precursor-product ratio of alpha-linolenic acid to long-chain n-3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort. Am J Clin Nutr. 2010 Nov;92(5):1040-51.
Wien M, Rajaram S, Oda K, Sabaté J. Decreasing the linoleic acid to alpha-linolenic acid diet ratio increases eicosapentaenoic acid in erythrocytes in adults. Lipids. 2010 Aug;45(8):683-92. Not cited.
Wu J, Cho E, Giovannucci EL, Rosner BA, Sastry SM, Schaumberg DA, Willett WC. Dietary intake of α-linolenic acid and risk of age-related macular degeneration. Am J Clin Nutr. 2017 Jun;105(6):1483-1492.
Wu WH, Lu SC, Wang TF, Jou HJ, Wang TA. Effects of docosahexaenoic acid supplementation on blood lipids, estrogen metabolism, and in vivo oxidative stress in postmenopausal vegetarian women. Eur J Clin Nutr. 2006 Mar;60(3):386-92.
Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M; MIDAS Investigators. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010 Nov;6(6):456-64. Not cited.
Zhang Y, Chen J, Qiu J, Li Y, Wang J, Jiao J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016 Feb;103(2):330-40.
Zhong VW, Van Horn L, Greenland P, Carnethon MR, Ning H, Wilkins JT, Lloyd-Jones DM, Allen NB. Associations of Processed Meat, Unprocessed Red Meat, Poultry, or Fish Intake With Incident Cardiovascular Disease and All-Cause Mortality. JAMA Intern Med. 2020 Feb 3.