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03369842/v1 — This a preprint and has not been peer reviewed. Data may be preliminary.

The effects of omega-3 and omega-6 fatty acids on the mental and
physical health of children, adolescents, and adults
Hanieh Norooziseyedhosseini1 , Roya Imani1 , Bushra Sumra1 , and Momina Tariq1
1
Affiliation not available

February 16, 2023

Background: Omega-3 and omega-6 fatty acids are commonly used in pregnancy, lactation, and malnutri-
tion. Paediatrics has been investigating whether omega-3/omega-6 supplementation affects human growth
and neurodevelopment in recent decades.
Aims: To assess the current state of knowledge regarding the use of omega-3/omega-6 type fatty acids in
the diet in adolescent and adult populations.
Materials and Methods: Through September 2022, Pubmed has chosen 72 original articles on the topic
of human growth and nutrition in paediatrics.

Results: According to the literature, the use of omega-3/omega-6 fatty acids, with a higher prevalence in the
former group than the latter, appears to be most effective in hypertension, dyslipidemia, and high C- reactive
protein values, cardiovascular risk, and neuropatic pain, while having less impact on neurodegenerative
(except in multiple sclerosis) and mental disorders (except in depression). Combining omega-3 and omega-6
fatty acids with spirulina algae, chitosan, probiotics, vitamin D, fibre, and plant extracts yields intriguing
results.
Conclusions: Although significant evidence emerges on the importance of omega-3 and omega-6 fatty acid
supplementation, significant structural flaws in research designs continue to emerge from published studies;
additionally, many studies assume that fatty acid supplementation can have a curative effect on already active
diseases, when in fact such prescriptions should be considered as adjuvant therapies to prevent or promote
symptomatic regression, precisely because of their fatty acid content. Future research that can address the
critical issues raised is hoped to promote a more comprehensive approach to the topic of omega-3/omega-6
supplementation in human health.

Keywords: DHA. EPA. ALA. AA. Omega-3. Omega-6. Dietary Supplement.

Background and objectives

Omega-3/Omega-6
Fatty acids are aliphatic monocarboxylic acids that are derived from or contained in esterified form in a
vegetable or animal fat, oil, or wax. They are classified as short-chain (SCFA), medium-chain (MCFA),
long-chain (LCFA), or very long chain (VLCFA) based on the number of carbon atoms present [1]. Among
the major fatty acids of the omega-3 group are -linoleic acid (ALA), cervonic or docosahexaenoic acid (DHA),
and thymnodonic or eicosapentaenoic acid (EPA), which, along with arachidonic acid (AA) of the omega-6
group, are generally considered to be potent anti-inflammatory antioxidants and immunomodulators [2].

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 Introductory sources can be both animal (animal oils and fats, fish oil, particularly cod liver, herring and
oily fish, salmon, and in lesser amounts in cod, trout, and human milk) [3] and plant (corn seed oil, sunflower
oil, nuts, transgenic Camelina sativa seed oil, CSOs [4-5], blueberries [6], and microalgae [7]); n-3 PUFAs of
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marine and plant origin have different effects. However, the precise dose to be administered has not been
determined, despite studies emphasising both personalizations of therapy (as with obese people, who may
be affected by different assimilation/absorption due to their clinical condition [9]). In the absence of dietary
EPA and DHA intake, circulating levels of these fatty acids decrease during the night and reach their lowest
point in the morning; thus, overnight consumption of n-3 PUFAs, which counteracts this pattern, may have
functional significance. [10] One study went on to assume that Omega-3 (n-3) fatty acid (FA) supplements
raise blood levels of EPA and DHA and that most supplements on the market are esterified to triglycerides
(TG) or ethyl esters (EE), which limits absorption and may cause gastrointestinal side effects. With this in
mind, and with the intention of comparing the 24-hour plasma concentrations of EPA, DHA, and EPA+DHA
when provided esterified in monoglycerides (MAG), this study found that the plasma concentration of n-3 FA
in adults is higher after acute supplementation with n-3 FA esterified in MAG than in EE or TG, implying
that with a lower dose of n-3 FA MAG, the plasma concentrations of n-3 FA achieved are similar [11]
Omega-3/omega-6 ratios in adolescents and adults
Most studies published on the adolescent population focus on allergic disease and metabolic disorders such
as diabetes (and their consequences), whereas the adult population includes autoimmune diseases, neurode-
generative disorders, inflammatory and algic disorders, and many others.
Specifically, in the obese adolescent (as well as the adult), LCPUFA-3 supplementation does not affect
body weight [12], but it results in improved muscle tone [13- 14] (while reducing linoleylcarnitine [15]) and
significant platelet aggregation [16]; on insulin values, studies are conflicting [12, 17], but if omega-3 is
combined with acetylsalicylic acid there is an improvement in
The use of omega-3 and omega-6 fatty acids appears to be effective in regulating the effects of metabolic
changes that lead to obesity [20], high blood pressure, and dyslipidemia (with little evidence regarding the
impact on liver fat [21] (with a preference for DHA + EPA over ALA) [22], unless it is non-alcoholic fatty
liver disease [23-24]). (in which case it is suggested to add vitamin d3 to the omega- 3 formulation [25]).
Consumption of seed oils high in omega-6 polyunsaturated fat (PUFA) and linoleic acid (LA) has also been
linked to low-grade inflammation, oxidative stress, endothelial dysfunction, and atherosclerosis [26], while a
low serum level of arachidonic acid (AA) has been linked to an unfavourable functional outcome in patients
with acute intracerebral haemorrhage [27].
Recent research has shown that a DHA/EPA dietary supplement improves triglyceride and HDL status, but
can increase LDL levels when compared to acid -lipoic acid (ALA) if a low n-6 / n-3 ratio is not maintained
[28]. Plant-derived n-3 PUFAs significantly reduce total cholesterol and LDL-cholesterol concentrations,
whereas EPA and DHA n-3 PUFAs significantly reduce triglyceride concentrations and increase HDL-C
concentrations [29].
For decades, the use of omega-3/omega-6 has been studied in cardiovascular risk, atherosclerosis, cardiac
arrhythmic disorders, and cardiac ischemic forms, with greater preference for ALA over DHA and EPA and
the latter over DHA, although there is a risk of increased fibrous plug in coronary atherosclerotic plaques,
but only if supplemental omega-3 intake is 3.5%, discouraging the combination of DHA + EPA.
Although there is some disagreement, acetylsalicylic acid has been shown to affect cyclooxygenase activity
in platelets [18, 30-40].
Inflammatory diseases with high C-reactive protein levels benefit from omega-3/omega-6 supplementation,
with EPA proving more effective than DHA [41-42]. The therapeutic utility of omega-3/omega-6 use has
also been demonstrated in the improvement of algic symptoms of a muscular-tensive, neuropathic [43-44] or
autoimmune nature from rheumatoid arthritis [16], as well as in cystic fibrosis [45], periodontitis [46], sperm

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 motility [47], male hypotestosteronism in overweight or obese individuals (but only when supplementing with
DHA) [48], and
Concerning cognitive performance and psychological stability, there are encouraging results in the literature
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with regard to cognitive function [54] (although it appears that DHA supplementation has efficacy on at-
tention in ADHD [55-56, 77], EPA supplementation has efficacy on long-term memory, working memory,
and problem solving function [57, 78], and DHA+EPA has efficacy on executive functions in Alzheimer’type
dementia [58]), particularly if DHA/EPA supplementation is used). and neurodegenerative disorders (such
as Alzheimer’s and Multiple Sclerosis) [69-71, 74-76], which may be affected by the placebo effect or a slight
improvement caused by the anti-inflammatory and antioxidant effects of the administered fatty acids, appear
less promising.

Materials and Methods

We searched PubMed until September 30, 2022, for meta-analyses, clinical trials, and randomised controlled
trials using the keywords “omega-3/omega-6 fatty acids”, “DHA/EPA/ALA/AA”, “adolescent” and “adult”,
content on the abstract and title, and have selected 10,675 useful results, of which 72 original articles were
used for the present review as they focused on growth and neurodevelopment. In the first footnote, a single
non-PubMed reference (a book) pertaining to the analysed topic was included. Publications that did not
present results or statistical samples but only research protocols and proposals, those that did not specifically
address the topic of investigation, those with contradictory data, unreliable data, or an otherwise deficient
research design were excluded. The search was restricted to articles written in English.

No restrictions were placed on the publication year, which ranged from 1979 to the present.

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10,675 Records identified by systematic

database search (Pubmed)

4,857 Records including those based on the title

or abstract:

4,229 Randomized Controlled / Clinical trials

628 Meta-Analysis

4,785 Records excluded based on title or abstract:

26 Absence of research findings or proposals

4,746 Absence/ repetitions of direct relationship
with the theme
13 Conflicting or unreliable results

72 Full-text articles assessed for eligibility

16 Records included based on title or abstract

(Book and narrative reviews)

88 Studies were included for qualitative synthesis in the review

Table 1: Prisma model

Figure 1: Prisma model

Results, discussion and limitations

In the medical literature, omega-3/omega-6 supplementation is recommended, with proper precautions and
specific purposes, but the reference dietary intakes have not yet been established with certainty, and published
studies have significant structural flaws, such as frequent small sample sizes for each category evaluated,
questionable quality of included studies, and technical error, as well as the incomparability of blood levels
of omega-3 long-chain phospholipids and omega-6 long-chain phospholipids. These limitations may have an
effect on the quality of the findings.
The use of omega-3/omega-6, with greater prevalence in the former group than the latter, appears to be most
effective in the hypertension hypothesis, dyslipidemia, and high C-reactive protein values, although efficacy
on inflammatory factors such as interleukin (IL)- 6 and tumour necrosis factor (TNF)- is still a matter of

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 debate.
The impact of the addition of omega-3 to statin therapy on cardiovascular risk also appears to be insignificant,
despite the fact that studies frequently consider only high-risk patients and not all other subjects, based on
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a rationale contrary to prevention, which could lead to a potential bias that would lead one to believe
that they have no preventive efficacy (even if reduced or potential) on cardiovascular risk. Particularly,
studies demonstrate differentiation by type of morbid condition, modulating the prescription according to
the patient’s specific clinical profile, as fatty acids of animal origin do not have the same function and efficacy
as those of marine and plant origin; in fact, while the former are more effective in reducing systolic blood
pressure and dyslipidemia, the latter are better suited to intervene in erythrocyte fatty acid composition
and regulation of glycemic response (smoking, obesity, dyslipidemia, genetic thrombophilia, and taking birth
control pills).

In obesity, the clinical picture becomes more complicated due to the multiple, complex, and interconnected
factors at play; however, one study has demonstrated a clinical benefit in the administration of DHA+EPA,
as well as the use of spirulina algae, chitosan, probiotics, vitamin D, fibre, and plant extracts, to promote
moderate weight loss under controlled dietary intake.
The same discourse can also be applied to neurodegenerative diseases such as Alzheimer’s, which do not
appear to be affected by DHA/EPA supplementation as much as the glucose-insulin ratio.

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Author (Year) Objectives Type Key Results and Conclusions

Simopoulos AP et al. The importance of the ratio of omega- Sys: 101 A lower ratio of omega-6/omega-3 fatty acids is more desirable
(2002) 6/omega-3 essential fatty acids to reduce the risk of many of the high-prevalence chronic diseases
in Western societies, as well as in developing countries, that are
exported to the rest of the world.
Yang J et al. (2019) DHA/EPA and oxidative stress M: 21 It remains controversial whether n-3 PUFAs are effective in
counteracting oxidative stress. On the other hand, data suggest
that n-3 PUFA supplementation may be effective in the early
stages of NAFLD, but not in patients with more severe NAFLD
or NASH.
West AL et al. (2019) DHA/EPA in CSO R: 36 The incorporation into blood lipids of EPA and DHA consumed
in the form of CSOs was equivalent to that of BFO and such
transgenic vegetable oils are an adequate dietary source of EPA
and DHA in humans.
Schwab US et al. Camelina Sativa Oil R: 79 A diet enriched in CSO improves serum lipid profile as compared

(2018) with a diet enriched in FF or LF in subjects with impaired fasting

glucose, with no differences in glucose metabolism or
concentrations of inflammatory markers.
McNamara RK et al. Omega-3 and blueberry R: 65 The FO and BB groups reported fewer cognitive symptoms, and
(2018) the BB group showed better memory discrimination, indicating
that supplementation improved cognition. The cognitive benefit
in the BB group was associated with the presence of urinary
anthocyanins reflecting recent BB intake but not anthocyanin
metabolites. However, combined FO + BB treatment was not
associated with cognitive improvement as expected.
Dawczynski C et al. Omega-3 and treatment of rheumatoid R: 38 DHA supplementation with microalgae improves disease activity
(2018) arthritis in patients with RA along with a shift in the balance of AA- and

Figure 2: This is a caption

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Figure 3: This is a caption
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Figure 4: This is a caption
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Figure 5: This is a caption

Conclusion
The importance of omega-3 and omega-6 fatty acid supplementation in pregnancy and lactation, malnutrition
states, inflammatory diseases, cardiac and vascular risk, neurodegenerative disorders, and mental disorders
is supported by accumulating evidence. Despite the fact that a number of the findings are encouraging,
the published studies still reveal significant structural flaws in the research designs; moreover, many studies
assume that fatty acid supplementation can have a curative effect on already active diseases, when in fact
such prescriptions should be viewed as adjuvant therapies to prevent or promote symptomatic regression due

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 to their anti-inflammatory, antioxidant, and immunomodulatory properties. Such findings could potentially
undermine the research findings. It is hoped that future research that can resolve the noted critical issues
will promote a better approach to the topic of omega-3/omega-6 supplementation for human health.
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 Author (Year) Objectives Type Key Results and Conclusions

Simopoulos AP et al. The importance of the ratio of omega- Sys: 101 A lower ratio of omega-6/omega-3 fatty acids is more desirable
(2002) 6/omega-3 essential fatty acids to reduce the risk of many of the high-prevalence chronic diseases
in Western societies, as well as in developing countries, that are
exported to the rest of the world.
Yang J et al. (2019) DHA/EPA and oxidative stress M: 21 It remains controversial whether n-3 PUFAs are effective in
counteracting oxidative stress. On the other hand, data suggest
that n-3 PUFA supplementation may be effective in the early
stages of NAFLD, but not in patients with more severe NAFLD
or NASH.
West AL et al. (2019) DHA/EPA in CSO R: 36 The incorporation into blood lipids of EPA and DHA consumed
in the form of CSOs was equivalent to that of BFO and such
transgenic vegetable oils are an adequate dietary source of EPA
and DHA in humans.
Schwab US et al. Camelina Sativa Oil R: 79 A diet enriched in CSO improves serum lipid profile as compared

(2018) with a diet enriched in FF or LF in subjects with impaired fasting

glucose, with no differences in glucose metabolism or
concentrations of inflammatory markers.
McNamara RK et al. Omega-3 and blueberry R: 65 The FO and BB groups reported fewer cognitive symptoms, and
(2018) the BB group showed better memory discrimination, indicating
that supplementation improved cognition. The cognitive benefit
in the BB group was associated with the presence of urinary
anthocyanins reflecting recent BB intake but not anthocyanin
metabolites. However, combined FO + BB treatment was not
associated with cognitive improvement as expected.
Dawczynski C et al. Omega-3 and treatment of rheumatoid R: 38 DHA supplementation with microalgae improves disease activity
(2018) arthritis in patients with RA along with a shift in the balance of AA- and
 DHA-derived lipid mediators toward an anti-inflammatory/pro-
remedial state
Liu H et al. (2022) Effects of marine-derived and plant- R: 180 Perilla oil supplementation reduced FBG, while fish oil
derived omega-3 polyunsaturated fatty supplementation reduced TG level. PUFA n-3s of marine and
acids plant origin have different effects on erythrocyte fatty acid
composition and regulation of glycolipid metabolism.
Fisk ML et al. (2022) Omega-3 and adipose tissue R: 84 Reduced expression of genes responsible for fatty acid activation
inflammation and metabolism may contribute to an inflammatory profile of
oxylipins and limit the effects of LC n-3 PUFAs in obesity.
Individualized supplementation of LC n-3 PUFAs based on
obesity status may be necessary.
Jackson PA et al. (2020) Diurnal rhythm of plasma EPA and R: 21 In the absence of dietary intake of EPA and DHA, circulating
DHA in healthy adults levels of these fatty acids decrease during the overnight period
and reach their lowest point in the morning. Consumption of n-3
PUFAs at night, which counteracts this pattern, may have
functional significance.
Chevalier L et al. (2021) DHA/EPA and blood concentrations R: 22 The plasma concentration of n-3 FA in adults is higher after acute
supplementation with n-3 FA esterified in MAG than in EE or
TG.
Lòpez-Alarcòn M et al. Omega-3 and body weight and insulin R: 366 LCPUFA-ω3 supplementation does not affect body weight or
(2019) resistance in pubertal children with insulin in adolescents with obesity.
obesity
Rondanelli M et al. DHA/EPA on fat-free mass and Meta: 14 N-3 EPA + DHA supplementation could be a promising strategy
(2021) physical performance in elderly to improve muscle quality and prevent or treat fragility.
Huang YH et al. (2020) Effects of Omega-3 Fatty Acids on Meta: 10 A long period of omega-3 fatty acid supplementation can improve
Muscle Mass, Muscle Strength and walking speed.
Muscle Performance
Guo X-F et al. (2019) Clinical implications in DHA/EPA Meta: 20 Intervention with EPA significantly reduced systolic blood
supplementation on the inflammatory pressure, especially in subjects with dyslipidemia. The aggregate
mediators effect indicated that supplemental DHA exerted a significant
reduction in diastolic blood pressure in subjects with
dyslipidemia.
Tomic-Smiljanic M et al. DHA/EPA and AR R: 60 Co-administration of concentrated fish oil with supplementation
(2019) may reduce platelet aggregation in adults with RA.
Abbott KA et al. (2020) DHA and insulin resistance R: 73 DHA-enriched fish oil reduces insulin resistance in overweight
and obese adults.
Holub A et al. (2020) The effects of aspirin and N-3 fatty R: 30 Aspirin harms ageing in diabetics who have relatively high EPA
acids on telomerase activity in adults and DHA ingestion.
with diabetes mellitus
Rodrìguez-Cruz M et al. DHA/EPA and Duchenne muscular R: 28 Taking Omega-3 long-chain polyunsaturated fatty acids (Ω-
(2019) dystrophy 3LCPUFA, 2.9 g/day) for 6 months probably slows the
progression of muscle loss, decreases fat mass, and reduces IR in
boys with DMD.
Gonzàlez-Becerra K et DHA/EPA and metabolic diseases M: 24 Consumption of fatty acids such as n-3 PUFAs: EPA and DHA,
al. (2019) and MUFAs: oleic acid and palmitoleic acid has been associated
with improved metabolic. Fatty acids can regulate gene
expression by modifying epigenetic mechanisms and,
consequently, have a positive or negative impact on metabolic
outcomes.
Parker HM et al. (2019) DHA/EPA and Hepatic fat R: 50 Omega-3 PUFAs do not appear to be an effective agent for
reducing liver fat in overweight men. The factors that determine
the health benefits of omega-3 PUFA supplementation at the
individual level need to be clarified.
Zhou Q et al. (2019) Effects of DHA/EPA on IL-6 R: 123 Supplementation improves lipid and IL-6 status. The α-linolenic
acid (ALA) supplement is not necessary.
Song L et al. (2020) DHA/EPA and hepatic steatosis in R: 96 Co-supplementation of phytosterol esters (PS) and EPA + DHA
non-alcoholic fatty liver disease could increase the effectiveness of the treatment of hepatic
steatosis.
Guo X-F et al. (2021) Compare EPA, DPA, and DHA R: 12 Supplementation with DPA and DHA significantly increased the
incorporated into red blood cells, levels of sphingosine 1-phosphate and 15-deoxy-Δ12,14-
phospholipids, plasma PLs, plasma prostaglandin A1 compared with the olive oil group. In addition,
triglycerides, and plasma cholesterol supplementation with EPA and DHA significantly reduced the
ester fractions levels of linoleylcarnitine, compared with the olive oil group.
Yang J et al. (2019) DHA/EPA and oxidative stress Meta: 21 It remains controversial whether n-3 PUFAs are effective in
counteracting oxidative stress. On the other hand, data suggest
that n-3 PUFA supplementation may be effective in the early
stages of NAFLD, but not in patients with more severe NAFLD
or NASH.
Hennig B et al. (2001) High-energy diets, fatty acids and R: 66 Omega-6 fatty acids, and especially linoleic acid, cause
endothelial cell function: implications endothelial cell dysfunction most markedly as well as can
for atherosclerosis potentiate TNF-mediated endothelial cell injury.
Takahashi J et al. (2021) DHA/EPA and acute intracerebral R: 133 A lower serum level of AA has been associated with an
haemorrhage unfavourable functional outcome in patients with ICH. AA may
be an important biomarker of severity among patients with ICH.
Chen H et al. (2020) DHA/EPA vs ALA on Meta: 14 Dietary supplementation of EPA/DHA improved TG and HDL
cardiometabolic disorders status, but increased LDL levels compared with ALA.
Li N et al. (2021) Low n-6/n-3 ratio R: 1,368 Low n-6/n-3 ratio PUFAs significantly reduced TG concentration
and increased HDL-C concentration. The beneficial effects of
low n-6/n-3 ratio PUFAs on TG, TC, HDL-C and LDL-C
concentrations increased with time. However, plant-derived n-3
PUFAs significantly reduced TC and LDL-C concentrations,
while EPA- and DHA-derived n-3 PUFAs significantly reduced
TG concentration and increased HDL-C concentration.
Youjia D et al. (2019) Modulation of endothelial cell S: 59 This review summarizes the results of studies that have examined
responses and vascular function by the acute and chronic effects of dietary fatty acids on endothelial
dietary fatty acids function and vascular properties in humans, as well as the
potential mechanisms by which n-3 polyunsaturated fatty acids
regulate endothelial function.
Chen X et al. (2019) Omega-3 and rs3834458 Single Meta: 5 The minor allele of rs3834458 in FADS2 may result in decreased
Nucleotide Polymorphism in FADS2 delta-6 desaturase activity leading to increased ALA and
decreased EPA, DPA, and DHA in the blood.
Guo X-F et al. (2019) Effects of EPA and DHA on blood Meta: 20 The present meta-analysis provides substantial evidence that
pressure and inflammatory factors EPA and DHA have independent (blood pressure) and shared
(CRP concentration) effects on risk factors of chronic diseases,
and high-quality RCTs with multi-centre and large simple-size
should be performed to confirm the present findings.
Nicholls SJ et al. (2020) Clinical implications of DHA/EPA R: 13,078 Among patients at high cardiovascular risk treated with statins,
supplementation on the cardio risk the addition of omega-3 CA, compared with corn oil, to usual
 baseline therapies resulted in no significant difference in the
composite outcome of major adverse cardiovascular events.
Khan SU et al. (20211) DHA/EPA and cardiorisk Meta: Omega-3 FA reduced cardiovascular mortality and improved
149,051 cardiovascular outcomes. The reduction in cardiovascular risk
was more evident with EPA monotherapy than with EPA+DHA.
Abdelhamid AS et al. DHA/EPA and cardiorisk Meta: 86 Moderate and low certainty evidence suggests that increasing
(2020) LCn3 slightly reduces the risk of mortality and coronary events
and reduces serum triglycerides (evidence mainly from
supplementation studies). Increasing ALA slightly reduces the
risk of cardiovascular events and arrhythmia.
Kita U et al. (2020) DHA/EPA and FCT R: 130 EPA or EPA+DHA therapy in addition to strong statin therapy
for the presence of coronary atherosclerotic plaques did not
significantly increase fibrous cap (FCT) in noncellular plaques
compared with strong statin therapy alone, but significantly
increased FCT in patients with thinner FCT.
Alfaddagh A et al. DHA/EPA and coronary artery plaque R: 218 The addition of EPA and DHA to statins prevented coronary
(2019) plaque progression in nondiabetic subjects with mean LDL-C
<80 mg/Dl when an omega-3 index ≥4% was achieved. A low
omega-3 index of <3.43% identified nondiabetic subjects at risk
of coronary plaque progression despite statin therapy. These
results highlight the importance of measuring plasma omega-3
fatty acid levels at the beginning and conclusion of the study.
Aiming for an omega-3 index ≥4% maximizes cardiovascular
benefit.

Xu B et al. (2021) ALA and ischemic heart disease R: 8,866 The benefit of ALA for IHD and its major risk factors. DHA,
DPA, and EPA had no association with IHD but were partially
associated with increased cardiometabolic risk factors.
Block RC et al. (2021) DHA/EPA and aspirin R: 2,500 The role of omega-3 (n3) fatty acids [EPA/DHA] and low-dose
aspirin in the primary prevention of ischemic cardiovascular
disease (CVD) is controversial. Because omega-3 fatty acids (n3)
and aspirin affect cyclooxygenase activity in platelets, there could
be a clinically relevant effect of aspirin in combination with a
particular level of n3 fatty acids present in any individual.

Gallini A et al. (2019) DHA/EPA and psychiatric treatment R: 1,680 Low blood DHA-EPA concentration has been independently
associated with psychotropic drug use. Future studies are needed
to assess whether a low DHA-EPA concentration in the RBC is a
risk marker for psychotropic drug use in older adults and to better
understand the underlying pathophysiological mechanisms.
Macintosh BA et al. DHA/EPA and pain R: 178 DHA/EPA administration is effective in reducing neuropathic
(2021) and muscular-tensive pain, precisely because of its anti-
inflammatory efficacy.
Ramsden CE et al. DHA/EPA and headache R: 182 H3-L6 and H3 interventions altered bioactive mediators
(2021) implicated in headache pathogenesis and reduced headache
frequency and severity but did not significantly improve quality
of life.
Galàn-Arriero I et al. The role of Omega-3 and Omega-9 Sys: 32 Bioactive Omega-9 monounsaturated fatty acids, such as oleic
(2017) fatty acids in the treatment of acid (OA) and 2-hydroxy oleic acid (2-OHOA), also show
neuropathic pain after neurotrauma therapeutic effects in neurotrauma models. These FAs reduce
noxious hyperreflexia and pain-related anxiety behaviour
following peripheral nerve injury and improve sensorimotor
 function following spinal cord injury (SCI), including facilitation
of descending inhibitory antinociception.
Pham TL et al. (2021) Docosanoid signalling modulates Sys: 34 Treating corneas with pigment epithelium-derived factor plus
corneal nerve regeneration DHA increases nerve regeneration, wound healing, and tear
secretion.
Watson H et al. (2020) DHA/EPA and cystic fibrosis Meta: 23 Regular omega-3 supplements may provide some limited benefits
for people with cystic fibrosis with relatively few adverse effects:
however, the quality of evidence on all outcomes was very low.
Stando M et al. (2020) DHA/EPA and paradontitis R: 30 Dietary intervention with high doses of omega-3 PUFAs during
nonsurgical therapy may have potential benefits in the
management of periodontitis.
Hosseini B et al. (2019) DHA/EPA and male infertility Meta: 3 Omega-3 fatty acid supplementation in infertile men resulted in a
significant improvement in sperm motility and DHA
concentration in seminal plasma.
Abbott KA et al. (2020) DHA and levels of testosterone R: 61 DHA-enriched fish oil supplementation increases testosterone
levels in overweight and obese men.
Zhou SJ et al. (2012) DHA and preeclampsia R: 2399 DHA supplementation of 800 mg/day in the second half of
pregnancy does not reduce the risk of GDM or preeclampsia.
Bakouei F et al. (2020) DHA/EPA and preeclampsia Meta: 67 N-3 fatty acid supplements are an effective strategy to prevent the
incidence of preeclampsia in women with low-risk pregnancies.
Carvajal JA et al. (2014) LCPUFA and deep placentation Sys: 118 It is postulated that DHA supplementation, early in pregnancy,
disorders may reduce the incidence of deep placentation disorders
Zhong Y et al. (2021) DHA/EPA and maculopathy Meta: 11 Increased dietary intake of ω-3 polyunsaturated fatty acids
(PUFAs), particularly DHA and EPA, was associated with a
reduced risk of early age-related macular degeneration (AMD
subtype), while other types of fatty acids (AF) did not present
significant results. Further research is needed to explore the
potential association between dietary FA, plasma levels of FA,
and the advanced subtype of AMD.
Downie LE et al. (2019) DHA/EPA and dry eye disease M: 34 The results of this review suggest a possible role of long-chain
omega-3 supplementation in the management of dry eye disease,
although the evidence is uncertain and inconsistent.
van der Wurff ISM et al. DHA/EPA and cognition M: 33 Daily supplementation of ≥450 mg DHA + EPA per day and an
(2020) increase in O3I to >6% makes efficacy on cognition more likely
in children and adolescents.
Chang JPC et al. (2019) DHA/EPA and ADHD R: 92 High-dose eicosapentaenoic acid (EPA) improves attention and
vigilance in children and adolescents with attention deficit
hyperactivity disorder (ADHD) and low endogenous EPA levels.
Checa-Ros A et al. Early monitoring of fatty acid profile R: 40 The cognitive effects of omega-3 polyunsaturated fatty acids (ω-
(2019) in children with attention deficit 3 PUFAs) might make them helpful in attention-
deficit/hyperactivity disorder (ADHD). However, the results
derived from supplementation studies in children depend on the
respective combinations and the study period. We aimed to
investigate the serum fatty acid profile, attention scores and
tolerability in a group of ADHD children after receiving
methylphenidate (MPH) and ω-3 PUFAs for 1 month.

Emery S et al. (2020) DHA/EPA and cognitive tests Meta: 29 Subgroup analyses identified beneficial effects of formulations
rich in eicosapentaenoic acid (EPA) but not docosahexaenoic
acid (DHA) in the domains of long-term memory, working
memory, and problem-solving.
Kosti RI et al. (2022) Omega 3 and executive functions Meta: 12 The protection offered by fish intake against cognitive decline is
exhausted by intakes above 2 servings/week and is probably
related to the impact of EPA and DHA on an individual’s
executive functions, although questions remain about the
mechanisms linking short- and long-term effects.
Kuszewski JC et al. Omega-3 and curcumin R: 126 Improvements in processing speed following fish oil
(2020) supplementation in middle-aged and elderly men could be
mediated by improvements in circulatory function. The
mechanisms underlying the cognitive benefits observed with
curcumin are unknown.
Khairani S et al. (2021) Curcumin-Piperine Sys: 46 Curcumin is a potent antioxidant, damages parasite DNA, and
may promote an immune response against Plasmodium by
increasing reactive oxygen species (ROS), while piperine is also
a potent antioxidant that potentiates the effects of curcumin.
Liao Y et al. (2019) Clinical implications in DHA/EPA Meta: 26 Current evidence supports the finding that omega-3 PUFAs with
supplementation on depression EPA ≥60% at a dosage of ≤1 g/d would have beneficial effects
condiction on depression.
van der Burg et al. DHA/EPA and depression R:158 Changes in fatty acid levels from a nutraceutical combination
(2020) containing EPA and DHA provide a biomarker of response in the
treatment of depression
Guu TW et al. (2019) Guidelines for Omega-3 Fatty Acids in Guidelines The key practice guidelines contend that: (1) clinicians and other
the Treatment of Major Depressive practitioners are advised to conduct a clinical interview to
Disorder validate clinical diagnoses, physical conditions, and
measurement-based psychopathological assessments in the
therapeutic settings when recommending n-3 PUFAs in
depression treatment; (2) concerning formulation and dosage,
both pure eicosapentaenoic acid (EPA) or an
EPA/docosahexaenoic acid (DHA) combination of a ratio higher
than 2 (EPA/DHA >2) are considered effective, and the
recommended dosages should be 1-2 g of net EPA daily, from
either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality
of n-3 PUFAs may affect therapeutic activity; and (4) potential
adverse effects, such as gastrointestinal and dermatological
conditions, should be monitored, as well as obtaining
comprehensive metabolic panels
Robinson DG et al. DHA/EPA and psychotic patients R: 50 Adjuvant omega-3 treatment is a potential option for symptoms
(2019) of depression and anxiety in people with recent-onset psychosis.
Li W et al. (2021) DHA/EPA and mood disorders R: 108 Abnormalities in emotional network organization observed in
high-risk depressed youth can be modified through fish oil
supplementation.
McPhilemy G et al. DHA/EPA and bipol sindrome R: 80 Despite a slight reduction in hypomania scores in the omega-3
(2021) PUFA group compared with the placebo, we find little evidence
that omega-3-PUFA supplementation shows prophylactic benefit
in BD.
Zhang M-M et al. (2020) Omega-3 and depressive symptoms Meta: 8 A significant effect of omega-3 FA on perinatal depression was
found. Omega-3s with a higher ratio of EPA/DHA (≥1.5) had
significant efficacy in both mild-to-moderate gravid depression
and postpartum depression, with a low incidence of side effects.
Satogami K et al. (2019) DHA/EPA and eating disorders Meta: 8 Eating disorders were associated with significantly higher levels
of palmitoleic acid and oleic acid on the red blood cell membrane
 and lower levels of adrenic acid, arachidonic acid, and total
omega-6 fatty acids. In addition, PUFA supplements were
associated with a benefit on body weight outcomes but not on
disease severity and mood symptoms in interventional studies.
Bianchi VE et al. (2021) Effect of nutrition on Sys: 21 Omega-3 and -6, and vitamin supplementation seem to be less
neurodegenerative diseases effective in protecting against neuron degeneration. Insulin
activity is a prevalent factor contributing to brain health while
malnutrition is correlated with the higher development of
dementia and mortality.
AlAmmar WA et al. DHA/EPA and multiple sclerosis Sys: 7 Supplementation of omega-3 and fish oils has beneficial effects
(2021) on reducing relapse rate, and inflammatory markers, and
improving the quality of life for MS patients.
Tomaszewski N et al. DHA/EPA and APOE Genotype R: 275 The lower increase in plasma DHA/AA and EPA/AA in
(2020) APOEɛ4/ɛ4 carriers after DHA supplementation reduces brain
intake and affects the efficacy of DHA supplementation.
Chen X et al. (2019) Effects of the rs3834458 Single Meta: 12 This meta-analysis indicates that a minor allele of rs3834458 in
Nucleotide Polymorphism in FADS2 FADS2 may result in the lower activity of delta-6 desaturase
on Levels of n-3 Long-chain leading to higher ALA and lower EPA, DPA and DHA in blood.
Polyunsaturated Fatty Acids
Scholtz SA et al. (2015) DHA in pregnancy differentially R: 205 DHA but not the placebo decreased the ARA status of minor
modulates arachidonic acid and DHA allele homozygotes of both FADS SNPs but not major allele
status across FADS genotypes in homozygotes at delivery.
pregnancy

Table 2: Cohort studies. Meta: Meta-analysis. Sys = Systematic review. R = Randomized Study. Only R considers the total study
participants; Meta and Sys refer to the number of studies.