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Bioavailability and conversion of plant based
sources of omega-3 fatty acids – a scoping
review to update supplementation options for
vegetarians and vegans
Katie E. Lane, Megan Wilson, Teuta G. Hellon & Ian G. Davies
To cite this article: Katie E. Lane, Megan Wilson, Teuta G. Hellon & Ian G. Davies (2021):
Bioavailability and conversion of plant based sources of omega-3 fatty acids – a scoping review to
update supplementation options for vegetarians and vegans, Critical Reviews in Food Science and
Nutrition, DOI: 10.1080/10408398.2021.1880364
To link to this article: https://doi.org/10.1080/10408398.2021.1880364
© 2021 The Author(s). Published with
license by Taylor & Francis Group, LLC
Published online: 12 Feb 2021.
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REVIEW
Bioavailability and conversion of plant based sources of omega-3 fatty acids –a
scoping review to update supplementation options for vegetarians and vegans
Katie E. Lane
a
, Megan Wilson
a
, Teuta G. Hellon
b
, and Ian G. Davies
a
a
School of Sport and Exercise Sciences, Faculty of Science, Liverpool John Moores University, Research Institute for Sport and Exercise
Sciences, Liverpool, UK;
b
School of Medicine, University of Central Lancashire, Liverpool, UK
ABSTRACT
Omega-3 (n-3) fatty acids offer a plethora of health benefits with the majority of evidence show-
ing beneficial effects from marine sources of eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA). Emerging research examines the effects of n-3 dietary intakes on blood markers of
vegetarians and vegans, but official guidance for plant based marine alternatives is yet to reach
consensus. This scoping review provides an overview of trials investigating bioavailability of plant
n-3 oils including EPA and DHA conversion. Searches of MEDLINE, PubMed, CINAHL and clinical
trial registers identified randomized controlled trials from January 2010 to September 2020. The
‘Omega-3 index’(EPA þDHA (O3I)), was used to compare n-3 status, metabolic conversion and
bioavailability. Two reviewers independently screened articles and extracted data on outcomes.
From 639 identified articles, screening and eligibility checks gave 13 articles. High dose flaxseed or
echium seed oil supplements, provided no increases to O3I and some studies showed reductions.
However, microalgal oil supplementation increased O3I levels for all studies. Findings indicate pre-
liminary advice for vegetarians and vegans is regular consumption of preformed EPA and DHA
supplements may help maintain optimal O3I. Further studies should establish optimum EPA and
DHA ratios and dosages in vegetarian and vegan populations.
KEYWORDS
Alpha-linolenic acid; linoleic
acid; eicosapentaenoic acid;
docosahexaenoic acid;
omega-3 metabolic
pathway; conversion
Introduction
Consumption and high biomarker concentrations of omega-
3(n-3) fatty acids, show convincing cardioprotective benefits
and offer additional mental and physical health benefits in
humans including decreased risk of chronic diseases and
cognitive decline (Gillingham et al. 2013; Russell and Meital
2018). The most beneficial n-3 fatty acids, eicosapentaenoic
acid (20:5n-3 (EPA)) and docosahexaenoic acid (22:6n-3
(DHA)) are mainly obtained from marine sources in the
diet. Although recently debated, there is now convincing
evidence for the reduction of cardiovascular events with
high dose intake of the n-3 fatty acid, EPA (Mason, Libby,
and Bhatt 2020). DHA is also important especially with
respect to mental and cognitive effects (Ghasemi Fard et al.
2019). Therefore, intake of these marine n-3 fatty acids is
important for leading a healthy lifestyle, presenting a poten-
tial challenge for vegetarians and vegans whose dietary
intakes are low (Table 1) (Cholewski, Tomczykowa, and
Tomczyk 2018; Russell and Meital 2018).
Despite the well evidenced health benefits, current
European and US dietary reference values are quite generic
in relation to n-3 fatty acid sources and few give recommen-
dations for specific n-3 fatty acids suitable for vegetarians
and vegans (Cuervo et al. 2009). The most up to date UK
Scientific Advisory Committee on Nutrition (SACN) (2004)
recommendations state at least one portion of oily fish per
week should be consumed to provide 0.45 g/d EPA and
DHA. Whilst the Committee recognized that groups of the
population do not eat fish (e.g. vegetarians and vegans), the
evidence base was considered insufficient to conduct a risk
assessment on this issue and specific recommendations for
these groups were not made. Also most European food
based dietary guidelines are nonspecific in relation to the
different n-3 fatty acids and give no details of alternative
options to oily fish for vegetarians and vegans (Montagnese
et al. 2015).
Further consideration to n-3 bioavailability deserves
attention, a definition for this in the field of nutrition has
not reached consensus. For the purpose of this review, bio-
availability is defined as, ‘the intestinal digestion, absorption,
and appearance of alpha linolenic acid (18:3n-3 (ALA)),
EPA and DHA in tissue’(Ghasemifard, Turchini, and
Sinclair 2014), such bioavailability assessment is becoming
common practice in n-3 studies (Maki 2018). The essential
fatty acid ALA is the most prevalent plant based source and
must undergo conversion to the more beneficial EPA and
DHA in the n-3 metabolic pathway. It is also possible for n-
CONTACT Katie E. Lane K.e.lane@ljmu.ac.uk Liverpool John Moores University, School of Sport and Exercise Sciences, Faculty of Science, IM Marsh,
Barkhill Road, Aigburth, Liverpool, L17 6BD.
ß2021 The Author(s). Published with license by Taylor & Francis Group, LLC
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.
0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in
any way.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
https://doi.org/10.1080/10408398.2021.1880364
3 fatty acids to undergo retro-conversion in the metabolic
pathway; an example of this would be DHA converting to
docosapentaenoic acid (22:5 n-3 DPA) or EPA (Park et al.
2016). The relationship between n-3 dietary intake, bioavail-
ability and conversion is complex and influenced by many
different factors such as genetics, smoking status, age, gen-
der and consumption of omega-6 (n-6) rich food sources all
of which can affect the processes (de Groot, Emmett, and
Meyer 2019; Russell and Meital 2018). In addition to ALA,
the other essential fatty acid, linoleic acid (18:2n-6 (LA)) is
the most plentiful plant based n-6 in the human diet.
Dietary sources of LA include nuts, seeds, certain vegetables;
vegetable oils such as soybean oil, safflower oil, and corn oil,
all of which form a staple of vegetarian and vegan diets
(Burns-Whitmore et al. 2019). High dietary intakes of n-6
fatty acids can reduce n-3 metabolic conversion rates and
vegetarian/vegan diets have significantly higher ratios of n-
6:n-3 fatty acids than omnivorous diets (Table 1)
(Kornsteiner, Singer, and Elmadfa 2008; Pinto et al. 2017;
Welch et al. 2010). A large number of studies have shown
high intake of n-6 fatty acids have been linked to various
detrimental health effects when n-3 intake is low (Jang and
Park 2020; Nindrea et al. 2019, Simopoulos 2016; Zhuang
et al. 2019). Therefore several researchers have recom-
mended vegetarians and vegans should aim for sufficient
intake of ALA and limit LA intakes (Agnoli et al. 2017;
Burns-Whitmore et al. 2019; Simopoulos 2000).
The ‘Omega-3 index’(O3I) is a good biomarker of n-3
bioavailability, and acts as an indicator of high to low risk
of death from coronary heart disease (Russell and Meital
2018; Stark et al. 2016). Optimum blood levels of n-3 are
defined as an O3I of >8% (Stark et al. 2016). Originally
coined by Harris and Von Schacky (2004), and utilized by
Stark et al. (2016) in their seminal global survey of EPA and
DHA in the blood stream of healthy adults, O3I is charac-
terized as EPA þDHA in erythrocytes or other equivalent
blood fractions such as plasma or serum. The main popula-
tion groups achieving optimal levels typically consume
greater amounts of fish or marine oils, whilst those who
adhere to a long term-vegan diet have a low corresponding
O3I (<4%), with omnivores falling between the two
extremes (Stark et al. 2016). A summary of recent studies
(Tables 1 and 2) shows dietary n-3 intakes and total n-3
erythrocyte/plasma fatty acids are significantly lower in
vegans and vegetarians in comparison to fish eaters and
omnivores for the majority of participants (p0.05)
(Kornsteiner, Singer, and Elmadfa 2008; Pinto et al. 2017;
Welch et al. 2010).
Walnut, flax, chia, canola, hemp, echium and perilla seed
oils are plant based sources of ALA (Table 3) and offer vari-
ous health benefits. These include improvements to insulin
sensitivity, inflammation, hepatic steatosis and cardiovascu-
lar disease (CVD) risk factors although the health benefits of
ALA are not as well established as those attributed to EPA
and DHA (Del Bo et al. 2019; Ghazani and Marangoni
2016; Kuhnt et al. 2012; Lenighan, McNulty, and Roche
2019; Shahidi and Ambigaipalan 2018). The majority of
ALA rich oils are also abundant in LA, which leads to diffi-
culty in consuming sufficient ALA without also increasing
the amount of LA in the diet, unless specific foods/supple-
ments high in ALA are consumed such as flaxseeds,
flaxseed/linseed oil, hemp seeds, chia seeds or oils (Burns-
Whitmore et al. 2019)(Table 3). Echium seed oil has been
identified as a good natural plant based source of stearidonic
acid (18:4n-3 (SDA)), which follows ALA in the n-3 meta-
bolic conversion pathway. Whilst fewer studies have
Table 1. Dietary n-3 intakes.
Author and participants Study design Fatty acid Vegans Vegetarians Fish eaters Omnivores Significance
Kornsteiner, Singer, and
Elmadfa (2008)
Vegan n37
Vegetarian n25
Omnivore n23
Data collection by 24hr
food diary on dietary
fat intake of omnivores,
vegetarians, vegans and
semi-omnivores as well
as its impact on
lipid profiles
18:3n-3g/d 2.63 ± 1.67 1.73 ± 1.38 –1.19 ± 0.40 p<0.01
20:5n-3mg/d 6 ± 12 4 ± 12 –48 ± 109 n.s.
22:5n-3mg/d 15 ± 64 5 ± 10 –84 ± 155 n.s.
22:6n-3mg/d 25 ± 70 69 ± 199 –234 ± 389 n.s.
Total n-3% 3.0 ± 1.4 1.9 ± 0.9 –1.6 ± 0.5 p<0.001
n-6/n-3, g/g 9.4/1.0 10.2/1.0 –6.8/1.0 n.s.
18:2n-6g/d 22.52 ± 11.07 14.96 ± 12.03 7.86 ± 4.04 p<0.001
Welch et al. (2010)
Males
Vegan n12
Vegetarians n96
Fish eaters n5952
Omnivores n996
Females
Vegan n16
Vegetarians n154
Fish eaters n6258
Omnivores n938
To determine intakes,
food sources and n-3
status according to
dietary habit as part of
the EPIC study with
7 day food diaries
18:3n-3g/
d (males)
1.02 ± 0.71 1.25 ± 0.54 1.23 ± 0.43 1.11 ± 0.55 p<0.001
20:5n-3g/d 0.01 ± 0.001 0.02 ± 0.02 0.11 ± 0.15 0.02 ± 0.02 p<0.001
22:5n-3g/d ––––
22:6n-3g/d 0 ± 0 0.0007 ± 0.004 0.16 ± 0.22 0.02 ± 0.02 p<0.001
Total n-3% 1.04 ± 0.71 1.27 ± 0.56 1.57 ± 0.58 1.15 ± 0.55 p<0.001
18:2n-6g/d 12.79 ± 10.80 14.78 ± 6.9 12.41 ± 4.8 11.80 ± 5.95 p¼0.135
18:3n-3g/
d (females)
0.86 ± 0.69 0.97 ± 0.45 1.01 ± 0.35 0.86 ± 0.33 p<0.001
20:5n-3g/d 0.02 ± 0.08 0.01 ± 0.01 0.11 ± 0.13 0.02 ± 0.01 p<0.001
22:5n-3g/d –––––
22:6n-3g/d 0 ± 0 0.0004 ± 0.005 0.15 ± 0.19 0.01 ± 0.01 p<0.001
Total n-3% 0.91 ± 0.67 0.98 ± 0.45 1.27 ± 0.49 0.89 ± 0.33 p<0.001
18:2n-6g/d 11.91 ± 9.92 10.06± 6.02 9.52 ± 3.75 8.59 ± 4.15 p<0.001
Pinto et al. (2017)
Vegan n23
Omnivores n24 (data
shown as median
and IQR)
Heart rate variability
and n-3 status (FFQ) in
age and BMI matched
middle aged vegans
and omnivores
18:3n-3g/d 0.8: 0.5,1.2 ––0.7: 0.5,1.0 p¼0.425
20:5n-3g/d 0.00: 0.00 ––0.14: 0.09,0.24 p<0.001
22:5n-3g/d –––––
22:6n-3g/d 0.01: 0.01,0.01 ––0.45: 0.30,0.81 p<0.001
Total n-3% –––––
18:2n-6g/d 10.5: 7.3, 18.5 ––7.6: 5.9,10.2 p¼0.025
(Mean ± SD unless stated otherwise, –value not given) EPIC ¼European Prospective Investigation into Cancer and Nutrition (Norfolk cohort). FFQ ¼food fre-
quency questionnaire. IQR ¼interquartile range. Total n-3% is % of total fatty acids
2 K. E. LANE ET AL.
evaluated the health benefits of echium seed oil, potential
improvements to CVD risk markers including serum trigly-
cerides (TG) and O3I have been demonstrated (Dittrich
et al. 2015; Kuhnt et al. 2014). Microalgal oils offer a useful
direct plant based source of n-3 suitable for consumption by
vegetarians and vegans (Craddock et al. 2017). Commercial
applications have recently successfully developed direct sour-
ces of EPA and DHA rich oil from microalgal sources,
which provide a plant based bioequivalent source of n-3 to
those found in fish oil (Arterburn et al. 2008; Craddock
et al. 2017, Winwood 2013). Nutritional oil derived from
marine algae containing EPA and DHA has been shown to
be as effective as fish oil for lowering TG; however, microal-
gal sources of DHA have also been associated with increases
to low-density lipoprotein cholesterol (LDL-C) in meta-anal-
yses of supplement studies (Bernstein et al. 2012, Maki et al.
2014). There is debate as to whether this increases cardio-
vascular risk as it increases the larger LDL particles and
decreases small, dense low density lipoproteins (LDL); a shift
toward a less atherogenic LDL profile (Allaire et al. 2017,
Diffenderfer and Schaefer 2014, Ramasamy 2018).
Preliminary literature searches show a high degree of
variability for the randomized controlled trials (RCTs) con-
ducted within this topic area. Previous studies are heteroge-
neous particularly in relation to comparators, study types,
dosages and eligible participants with a high number of
crossover trials. Existing studies include a variety of subjects
ranging from healthy, overweight and obese, otherwise
Table 2. Erythrocyte and phospholipid n-3 status.
Author and
participants Fatty acid Vegans Vegetarians Fish eaters Omnivores Significance
Kornsteiner, Singer,
and Elmadfa (2008)
Vegan n37
Vegetarian n25
Omnivore n23
(erythrocyte
sphingo- and
phospholipids)
18:3n-3mol% 0.28 ± 0.21 0.24 ± 0.16 –0.37 ± 0.25 n.s.
20:5n-3mol% 0.16 ± 0.06 0.27 ± 0.10 –0.35 ± 0.14 p<0.001
22:5n-3mol% 0.90 ± 0.27 1.25 ± 0.38 –1.19 ± 0.31 p<0.001
22:6n-3mol% 0.87 ± 0.31 1.28 ± 0.37 –1.81 ± 0.63 p<0.001
Total n-3mol% 2.20± 0.60 3.04 ± 0.67 –3.71 ± 0.89 p<0.001
n-6/n-3mol% 11.62 ± 2.52 8.33 ± 1.86 –6.62 ± 1.54 p<0.001
18:2n-6mol% 11.05± 1.46 9.90 ± 0.89 –9.34 ± 1.04 p<0.001
EPA þDHA 1.03 1.55 –2.16 –
Welch et al. (2010)
Males
Vegan n5
Vegetarians n25
Fish eaters n2257
Omnivores n359
Females
Vegan n5
Vegetarians n51
Fish eaters n1891
Omnivores n309
(plasma
phospholipid
n-3 mmol/L)
18:3n-3mmol/
L (males)
15.8 ± 9.7 13.6 ± 10.1 10.9 ± 5.7 11.8 ± 7.0 p<0.001
20:5n-3mmol/L 65.1 ± 45.5 55.9 ± 45.3 57.5 ± 43.2 47.4 ± 30.3 p¼0.001
22:5n-3mmol/L 67.2 ± 26.8 77.5 ± 38.8 67.3 ± 29.4 70.0 ± 33.4 p¼0.038
22:6n-3mmol/L 195.0 ± 58.8 222.2 ± 138.4 239.7 ± 106.2 215.6 ± 96.4 p<0.001
Total n-3mmol/L 327.4 ± 123.6 355.5 ± 211.1 364.5 ± 164.8 333 ± 147.7 p¼0.002
18:2n-6mmol/L 1337.7 ± 414.1 1238.2 ± 421.6 1164.1 ± 329.5 1207.9 ± 333.3 p<0.001
EPA þDHA 2.60 2.78 2.98 2.62 -
18:3n-3mmol/
L (females)
13.71 ± 8.10 12.3 ± 4.8 12.4 ± 613 13.1 ± 7.3 p¼0.22
20:5n-3mmol/L 50.0 ± 29.4 55.1 ± 52.5 64.7 ± 43.4 57.1 ± 38.4 p¼0.001
22:5n-3mmol/L 90.6 ± 54.0 75.0 ± 32.2 71.8 ± 29.6 74.7 ± 34.2 p¼0.056
22:6n-3mmol/L 286.4 ± 211.7 223.5 ± 137.8 271.2 ± 113.1 241.3 ± 109.6 p<0.001
Total n-3mmol/L 426.8 ± 284.0 353.5 ± 191.5 407.7 ± 169.3 373.1 ± 166.2 p<0.001
18:2n-6mmol/L 1406.0 ± 162.1 1325.9 ± 278.6 1236.9 ± 328.4 1271.2 ± 373.9 p<0.001
EPA þDHA 3.36 2.78 3.35 2.98 -
Pinto et al. (2017)
Vegan n23
Omnivores n24
(Plasma and
erythrocyte (E)
mean weight % of
fatty acids)
18:3n-3 (plasma) 0.71 ––0.53 p¼0.006
20:5n-3 0.47 ––1.03 p<0.001
22:5n-3 0.51 ––0.59 p¼0.146
22:6n-3 0.91 ––2.23 p¼0.113
Total n-3 –––––
18:2n-6 33.1 ––27.1 p<0.001
18:3n-3 (E) 0.32 ––0.34 p¼0.610
20:5n-3 0.67 ––1.26 p<0.001
22:5n-3 2.15 ––2.62 p¼0.005
22:6n-3 2.07 ––4.19 p<0.001
Total n-3 2.71 ––5.42 p<0.001
18:2n-6g 13.3 ––11.7 p¼0.002
EPA þDHA 2.54 ––5.22 -
(Mean ± SD unless stated otherwise, - value not given)
Table 3. Vegetarian omega-3 source oils.
Source oil ALA SDA EPA DHA LA GLA AA DPA
(18:3n-3) (18:4n-3) (20:5n-3) (22:6n-3) 18:2n-6) (18:3n-6) (20:4n-6) (22:5n-6)
Flaxseeds/oil 56.0 ––– 17.0 ––
Chia seed oil 60.2 ––– 19.1 –0.06 –
Canola oil 9.20 ––– 19.4 –––
Echium seed 36.6 10.5 ––– 10.2 ––
Hemp seed oil 23.0 1.10 –– 48.3 3.1 ––
Perilla seed 54.0 ––– 11 –––
Walnut oil 11.4 ––– 37.0 –––
Algae0.11 –<0.10 39.4 1.0 0.20 0.90 16.7
(Typical representation of values g/100g of oil, dependant on source –indicates FA not detected. (Asif 2011, Del Bo et al. 2019, Ghafoor et al. 2018, Ghazani
and Marangoni 2016, Harper, Edwards, and Jacobson 2006, Kuhnt et al. 2016, Lane et al. 2020, Sabudak 2007).
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3
healthy participants but with hypertriglyceridemia (HTG),
metabolic syndrome (MetS) or MetS risk factors and type 2
diabetes (T2DM), all of which can affect fatty acid metabol-
ism (Walle et al. 2017). Unlike systematic reviews and meta-
analysis, scoping reviews have a broader scope and provide
a description of current evidence, regardless of quality
(Tricco et al. 2018). Further literature searches reveal no
other published studies have evaluated the n-3 bioavailability
of plant based sources since an initial review prepared by
the authors over 10 years ago (Lane et al. 2014). Taking into
account the number of vegans in the UK, which have quad-
rupled between 2014 and 2019 (The Vegan Society 2020)
and the increasing numbers in Europe (Statista 2018) there
is a pressing need for an update in this important area. The
present scoping review maps the evidence with the aim to
inform future research in relation to the most effective
vegan/vegetarian alternative n-3 sources to oily fish by eval-
uating bioavailability and conversion to longer chain n-3 of
plant based n-3 supplement sources suitable for vegetarians
and vegans.
Objectives of the review
The aim of this scoping review was to explore interventions
that evaluate plant based n-3 source oils using RCTs to
highlight the most effective supplementation options for
vegetarians and vegans. The main objective was to assess the
bioavailability of plant based oils previously defined as good
sources of n-3 fatty acids (typically >24% of total fatty acids
(Asif 2011; Kuhnt et al. 2012)(Table 3)). The research objec-
tives were: (1) To provide an overview of up to date litera-
ture relating to the bioavailability of n-3 from recognized
plant based source oils, (2) To evaluate changes to O3I
(baseline to endpoint) brought about by plant based n-3 oil
supplementation, (3). To identify the most effective plant
based source oils in terms of n-3 bioavailability.
Methods
The review followed the PRISMA Extension for Scoping
Reviews (PRISMA-ScR): Checklist and Explanation (Tricco
et al. 2018) and Chapter 11 of the Joanna Briggs Reviewers
manual (Peters et al. 2017)
Search strategy
The following databases, MEDLINE, PubMed, CINAHL,
Cochrane Central Register of Controlled Trials and the
International Clinical Trials Registry Platform (ICTRP),
which includes Cochranelibrary.com and ClinicalTrials.gov
identified English-language, relevant peer reviewed RCTs
published from January 2010 to September 2020. The date
ranges were selected to give a comprehensive update to our
previous review, which identified papers published over a
10 year period from 2001 to 2011 (Lane et al. 2014). Further
studies were searched from reference lists of eligible studies
and review articles. Included studies published after the date
of the literature search were identified by publication alerts.
The search used the following keywords; ‘Flaxoil’OR
‘Linseed oil’OR ‘Chia’OR ‘Chia seed oil’OR ‘Rapeseed oil’
OR ‘Echium seed oil’OR ‘Hemp seed oil’OR ‘Perilla seed
oil’OR ‘Algaoil’in article title or abstract AND ‘Omega-3
OR Omega 30‘Omega-3omega-6 ratio’OR ‘Alpha-linolenic
acid’OR ‘Stearidonic acid’OR ‘Eicosapentaenoic acid’OR
‘Docosahexaenoic acid’OR ‘omega-3/omega-6 ratio’in title
OR abstract OR text. ‘Placebo’OR ‘Control group’OR
‘Intervention’OR ‘Controlled clinical trial’OR ‘Random
controlled trial’in article title, abstract OR text.
Inclusion criteria
Determination of included studies followed methods
employed by Stark et al. (2016) in their global survey of n-3
fatty acids in the blood stream of healthy adults. Included
studies were RCTs with adults (18 years), reporting study
baseline and endpoint, red blood cell, plasma or whole
blood EPA and DHA biomarkers. Included studies used a
control or placebo of a different source oil (plant or marine
based), reported plasma and/or erythrocyte and/or whole
blood n-3 concentrations, clearly stated the supplement
source and dose and analyzed the differences in n-3 blood
fatty acid status at baseline and at the endpoint of the inter-
vention period following recommendations from the
International Society for the Study of Fatty Acids and Lipids
(ISSFAL) (de Groot and Meyer 2020).
Participants: To maximize the number of included stud-
ies, RCTs that used individuals with specific disease factors
were included. Healthy normal weight and overweight/obese
participants alongside those with established or at risk of
MetS, CVD, HTG and T2DM were included as n-3 fatty
acid supplementation is well evidenced to offer improve-
ments to those with or at risk of these conditions (Bernstein
et al. 2012; Brown et al. 2019; Egert et al. 2014; Hu, Hu, and
Manson 2019).
Exclusion criteria
Studies of pregnant and breastfeeding women, infants and
children or subjects with existing serious disease that may
affect fatty acid metabolism such as cystic fibrosis, multiple
sclerosis, cancer, kidney disease and inflammatory bowel
disease were excluded in line with similar RCTs, systematic
reviews and meta-analysis that have evaluated n-3 supple-
mentation (Bernstein et al. 2012; Kuhnt et al. 2014; Stark
et al. 2016). Studies that evaluated the bioavailability of plant
based n-3 fortified animal products, did not use n-3 oils,
only reported study endpoint bioavailability measurements
or where the n-3 source was unclear were excluded from
the review.
Selection of studies
To minimize potential bias during the selection procedure,
duplicates of full articles retrieved for further assessment
were independently read by 2 reviewers (KEL and MW). A
third reviewer (TGH) then made a consensus decision for
4 K. E. LANE ET AL.
inclusion. The articles were added to an independent
Endnote database and grouped in accordance with the inclu-
sion criteria separately by each reviewer.
Data extraction
The following data were collected: title; first author; year of
publication; country; design of RCT (parallel, cross-over,
factorial); blinding of participant and personnel (open, sin-
gle, double); baseline characteristics of study participants,
(age, sex, BMI (where available); total number of partici-
pants, randomization of participants; health status; baseline,
endpoint and changes to n-3 markers; intervention compari-
sons and key findings. Data was categorized by blood frac-
tion analyzed including plasma total lipids, plasma
phospholipid, erythrocytes and whole blood in accordance
with methods used by Stark et al. (2016). In order to com-
pare n-3 status, metabolic conversion and bioavailability,
O3I status was selected as a previously recognized marker of
increased health benefits and reductions in risk of CVD and
total mortality (Alexander, Justice, and Madden 1985;
Armstrong, Metherel, and Stark 2008; Flock, Harris, and
Kris-Etherton 2013; Harris et al. 2009; Stark et al. 2016).
Endpoint EPA þDHA status was calculated by adding or
subtracting the percentage change value from baseline
markers for studies where percentage change only was
reported. Erythrocyte measures were used for studies pre-
senting both plasma and erythrocyte markers as the litera-
ture indicates this as the preferred blood fraction (Stark
et al. 2016). Continuous data was tabulated and assigned to
one of four discrete blood level groupings that corresponded
to EPA þDHA weight percentage values associated with
high to low risk of death from CHD identified by O3I in
accordance with Harris and Von Schacky (2004). Categories
were grouped by EPA þDHA status. Group 1: very low,
indicated in dark red, group 2: low, indicted by red, group
3: moderate, indicated by amber, group 4: high, indicated by
green. Groupings were adjusted in accordance with the
selected blood fractions used by Stark et al. (2016),
EPA þDHA erythrocytes levels of 4% (very low), >4–6%
(low), >6–8% (moderate), >8% (high). Equivalent group-
ings for plasma total fatty acids [2.9% (very low), >
2.9–4.0% (low), >4.0–5.2% (moderate), >5.2% (high)],
plasma phospholipids [3.8% (very low), >3.8–5.7% (low),
>5.7–7.6% (moderate), >7.6% (high)] and whole blood [
3.0% (very low), >3.0–4.4% (low), >4.4–5.9% (moderate),
>5.9% (high)] (Stark et al. 2016).
Results
Overview of identified studies
The database search identified 604 articles and 35 further studies
were found from registers of clinical trials and other searches.
Following removal of duplicates 522 articles were screened. Title
and abstract screening resulted in the exclusion of 356 studies
(Figure 1), leaving 166 articles for full text assessment. A further
153 articles were excluded with the main reasons including
studies that did not evaluate n-3 bioavailability and studies using
participants with existing serious diseases defined earlier.
Screening and eligibility checks left a total of 13 articles that fitted
the review criteria and are summarized in Table 4. The 13 studies
were published between January 2010 and September 2020 and
included a total of 668 participants, 267 of these were healthy
although BMI status was not clearly indicated for all healthy par-
ticipants, the remaining participants were diagnosed with or at
risk of CVD, HTG, MetS, or T2DM but otherwise healthy in
accordance with the selected study methods.
The majority of studies aimed to investigate the effect of
plant based n-3 supplementation in participants with estab-
lished or at risk of MetS, CVD, HTG and T2DM and were
not designed to specifically evaluate n-3 bioavailability
(Dewell et al. 2011; Dittrich et al. 2015; Kawakami et al.
2015; Kontogianni et al. 2013; Kuhnt et al. 2014; Maki et al.
2015; Neff et al. 2011; Nelson, Hokanson, and Hickey 2011;
Pieters and Mensink 2015; Zheng et al. 2016). Only 2 of the
13 identified RCT’s were designed to investigate the bio-
availability of plant based n-3 source oils, the rest evaluated
the effect of supplementation on other health related bio-
markers but did include relevant bioavailability data. The
search criteria identified n-3 bioavailability studies for flax-
seed, echium seed and microalgal oils; suitable chia, hemp
and perilla seed oil trials were not identified.
Bioavailability of n-3 from flaxseed oil
All but three of the identified studies (Maki et al. 2014; Neff
et al. 2011; Ryan and Symington 2015) evaluated flaxseed oil
as a source of n-3 with various comparators including sun-
flower oil, fish oil, corn oil, echium seed oil, safflower oil, soy-
bean oil, olive oil and microalgal oil (Tables 5–7). Three of the
flaxseed oil trials were crossover trials (Dittrich et al. 2015;
Kawakami et al. 2015; Kontogianni et al. 2013), the remainder
parallel design (Table 4). The fatty acid composition of flax-
seed oil supplements varied leading to differences in ALA con-
tent as well as dosages. Overall, flaxseed oil supplementation
did not offer improvements to baseline/endpoint O3I for the
majority of the identified studies and DHA levels were not sig-
nificantly different to the controls at endpoint.
Bioavailability of n-3 from echium seed oil
The echium seed oil studies by Dittrich et al. (2015) and
Kuhnt et al. (2014) showed slight improvements in O3I but
no changes in grouping levels for participants with low or
moderate baseline O3I. For the Dittrich et al. (2015) study,
erythrocyte DHA levels were significantly higher (p0.001)
in the microalgal oil comparator group and significantly
lower than the control for the echium seed oil supplementa-
tion group (p0.001). Plasma DHA percentage change lev-
els were significantly higher than the control for microalgal
oil (p<0.001) but there were no significant differences for
echium seed oil.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 5
Bioavailability of n-3 from microalgal oil
The remaining RCT’s evaluated microalgal oil in compari-
son to controls of flaxseed and fish oil or a placebo of
canola oil (Dittrich et al. 2015; Kuhnt et al. 2014; Maki
et al. 2013; Ryan and Symington 2015). Improvements to
O3I were noted in both of the high dose microalgal oil
studies by Dittrich et al. (2015) (1.6 g/d DHA, 10 weeks)
and Maki et al. (2013) (0.66 g/d EPA, 1.78 g/d DHA,
14 weeks) in participants with HTG and a low dose short
term study (200 mg/d DHA, 2 weeks) by Ryan and
Symington (2015) in healthy participants. The study by
Ryan and Symington (2015) was the only trial to evaluate
the use of plant based n-3 sources compared to fish oil
using a small vegetarian/vegan cohort (n¼10) who
received microalgal oil supplementation (200 mg/d DHA).
The vegetarian/vegan cohort had a ‘low’mean O3I at base-
line, which increased to ‘moderate’at endpoint after
2 weeks of microalgal oil supplementation. The endpoint
DHA levels between all groups were not significantly dif-
ferent (p>0.05) confirming microalgal oil was on par with
fish oil for fish and non-fish eaters. The results of this
pilot study indicate that microalgal oil supplements are a
sufficient and viable source of DHA for both fish and
non-fish eaters alike. The microalgal oil in all studies gave
a direct source of DHA and this led to significant increases
in baseline/endpoint DHA blood markers (p0.05) and
significantly higher percentage change levels when com-
pared to plant based controls.
Figure 1. PRISMA Flow Diagram for the scoping review process.
6 K. E. LANE ET AL.
Table 4. Summary of study design and findings.
Author, year, country
and aim Study design
Intervention source
and dose
No of participants
and
intervention
allocation
Participant
health status Time period Main Findings
Dewell et al. (2011), USA.
Determine effect of
high and low plant and
marine n-3 doses on
plasma
inflammatory markers
DB parallel RCT high
and low dose of
plant and marine
n-3 compared to
soy bean oil
placebo,
erythrocytes
Flaxseed high dose
12 capsules
(6.6 g/d ALA
(HFL)), low dose
4 capsules (2.2 g/
d ALA (LFL)). Fish
oil high dose 6
capsules (2.1 g/d
EPA, 1.5 g/d DHA)
low dose 2
capsules (0.7 g/d
EPA, 0.5 g/d
DHA). Placebo
high (6 g/d), low
(4 g/d) soy bean
oil (composition
not stated)
98 adults
HFL (n¼19)
LFL (n¼20)
LFO (n¼20)
HFO (n¼19)
SBO (n¼20)
MetS, otherwise
healthy, BMI 39
8 weeks per arm No beneficial effects
detected for
inflammatory
markers
regardless of
source or dose
Dittrich et al. (2015),
Germany. Investigate
effect of n-3 rich oil
enriched foods on CVD
risk factors in subjects
with HTG
DB crossover RCT,
flaxseed, echium
oil, microalgal oil
and sunflower oil
(control) enriched
foods,
erythrocyte lipids
20g/d flaxseed oil
(FL) (7 g/d ALA),
20 g/d echium oil
(EO) (4.8 g/d ALA,
1.6 g/d SDA),
12 g/d microalgal
oil (1.6 g/d DHA)
20 g/d sunflower
oil (SO) (10 g/
d LA)
46 adults
SO (n¼46)
FL (n¼15)
EO (n¼15)
AO (n¼16)
HTG
otherwise healthy
10 weeks per arm,
all groups
crossed over to
the SO control,
10 week washout
ALA and SDA rich
oils increased n-3
content of
erythrocytes.
Improvements to
blood lipids
noted for
sunflower,
flaxseed and
microalgal oils
but not
echium oil
Kawakami et al. (2015),
Japan. Investigate the
effect of 12 week
flaxseed oil
supplementation on
serum sd- LDL-C
DB crossover RCT,
plasma serum
10g/d flaxseed oil
(FL) (5.49 g ALA),
10 g/d corn oil
(CO) (0.09 g/
d ALA)
15 adults Healthy males 12 weeks per arm,
8 week washout
Flaxseed oil gives
lower sd-LDL-C
concentrations
Kontogianni et al. (2013),
Greece. Investigate
effect of 12-week
supplementation of
flaxseed oil on CVD
risk factors
DB crossover RCT,
olive oil and
flaxseed oil,
erythrocyte
membrane
13.8g/d flaxseed oil
(FL) (8 g/d ALA)
or olive oil (OO)
(0.13 g/d ALA)
37 males and
females
(18–35 yrs)
Healthy
normal weight
6 weeks per arm,
6 week washout
Flaxseed oil
supplementation
leads to lower
sd-LDL
concentrations
Kuhnt et al. (2014),
Germany. Investigate
the effect of echium oil
on n-3 accumulation
and blood biochemical
markers in age, sex
and MetS
DB parallel arm RCT,
plasma serum
Echium seed oil (EO)
17 g/d (2 g/d
SDA, 5 g/d ALA).
Fish oil mixed 9:1
in olive oil (FO)
17 g/d (1.9 g/d
EPA, 0.2 g/d DHA)
78 adults
EO1 (n¼20)
healthy weight
NTG 20–35yrs
EO11 (n¼20),
49–69yr, NTG
EO111 (n¼19) o/
wt MetS or
obesity
FO1 (n¼10)
healthy weight
20–35yrs NTG
FO11 (n¼9)
49–69yrs healthy
weight NTG
59, healthy weight
NTG
19 o/wt MetS
or obesity
8 weeks EO increases n-3 in
blood fractions
and is beneficial
for those with
MetS, but cannot
replace
dietary DHA
Lefort et al. (2016),
Canada. Investigate the
safety and dietary
efficacy of Ahiflower oil
in comparison to
flaxseed oil.
Parallel group DB
RCT,
plasma serum
Ahiflower oil
extracted from
Buglossoides
arvensis seeds
(AH) 9.1 g/d
(4.19 g/d ALA,
1.82 g/d SDA) or
9.1 g/d flaxseed
oil (FL) (5.369 g/
d ALA)
40 (n¼20
each arm),
Healthy men and
women 18-65yrs,
BMI 18.5-
39.9, NTG
28 days AH is safe and more
effective for the
enrichment of
tissues with EPA
and DHA than
flaxseed oil
Maki et al. (2014), USA.
Investigate the safety
and efficacy of
microalgal oil
containing EPA and
Parallel arm DB RCT,
plasma serum
Microalgal oil DHA-
O (AO) 0.66 g/d
EPA 1.78 g/d
DHA, fish oil (FO)
1.16 g/d EPA
93 adults
CS control
(n¼36)
AO (n¼37)
FO (n¼20)
Normally active and
generally healthy
men and non-
pregnant/
lactating women
14 weeks per arm Microalgal oil
supplementation
was safe,
significantly
reduced serum
(continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 7
Table 4. Continued.
Author, year, country
and aim Study design
Intervention source
and dose
No of participants
and
intervention
allocation
Participant
health status Time period Main Findings
DHA on
cardiovascular risk.
0.82 g/d DHA
corn-soy bean oil
(CS) 50 g/d (ALA
content
not stated)
with mild to mod
HTG (18-79yrs)
TG and increased
LDL-C compared
to CO control.
Neff et al. (2011), USA.
Examone effects of
DHA supplementation
on plasma lipid and
lipoprotein
concentration and other
biomarkers of CVD risk
in absence of
weight loss.
DB RCT, parallel
arm, plasma
phospholipids
Microalgal oil (AO)
5 mL/d (2 g/d
DHA) or corn-soy
bean oil (CS)
5 mL/d
33 adults
AO (n¼18)
CS (n¼15)
Overweight and
obese otherwise
healthy adults
not taking
medication for
hypertension,
dyslipidaemia,
diabetes or
weight control
and not using
fish oil
supplements
4.5 months DHA
supplementation
gave beneficial
changes to TC,
VLDL TG, VLDL,
LDL and HDL
particle sizes.
Nelson, Hokanson, and
Hickey (2011), USA.
Determine if 8 week
isocaloric diet
supplemented with
flaxseed or fish oil
alters phospholipase A
2
SB RCT parallel arm,
erythrocyte
membranes
Flaxseed oil (FL)
11 g/d (6.27 g/d
ALA), fish oil (FO)
2 g/d and 7 g/d
(360 g/d EPA,
240 g/d DHA)
Iso-caloric
control- olive oil
(OO) 11 g/d
(composition
not stated)
59 adults
FL (n¼20)
FO (n¼20)
OO (n¼19)
Healthy over 50,
including those
taking aspirin,
statins, ibuprofen
8 weeks Flaxseed and fish oil
supplementation
did not influence
phospholipase
A2
in older adults
Neukam et al. (2011),
Germany. Evaluate the
effect of
supplementation with
flaxseed oil and
safflowerseed oil on
healthy volunteers with
sensitive skin
DB parallel arm
RCT, plasma
Flaxseed (FL) 4
capsules
555.32 mg
(1.08 g/d ALA).
Safflower oil (SfO)
4 capsules
560 mg/capsule
(0.0143 g/d ALA)
26 females
FL (n¼13)
SfO (n¼13)
Healthy females 18-
65yrs, not
pregnant or
lactating, BMI
18–25
12 weeks Lower inflammatory
response of the
skin after
flaxseed
oil intake.
Pieters et al. (2019),
Netherlands. Examine
the effects of ALA on
24 h ambulatory blood
pressure (ABP) in
subjects with
hypertension
Parallel DB RCT,
parallel arm,
plasma
phospholipids
Flaxseed oil (FL)
10 g/d (4.7 g/d
ALA), high oleic
sun flower oil
control (SO) 10 g/
d (0.0 g/d ALA)
56 participants,
40–70yrs, (n¼28
per arm)
Healthy overweight/
obese with
hypertension
12 weeks Higher intakes of
ALA 3-5 times
the
recommended
daily amount for
12 weeks does
not affect 24 hr
ABP or BP in
subjects with
hypertension
Ryan and Symington
(2015), UK. Investigate
microalgal oil as a
viable source of DHA
and determine if
microalgal derived DHA
is bioequivalent to DHA
from fish oil
Open-label partially
randomized,
partially allocated
parallel group,
plasma
phospholipids
Microalgal oil 3
capsules/d
(600 mg/d DHA)
Compared to fish
oil 1 capsule
(200 mg/d DHA,
300 mg/d EPA,
100 mg/d SDA
& ALA)
31 adults
AOv (n¼10)
vegetarian/
vegans
AO (n¼9)
omnivore
microalgal group
FO (n¼10)
omnivore fish
oil group
Healthy adults 2 weeks Algal oil
supplements are
a sufficient and
viable source of
DHA for both fish
and
non-fisheaters
Zheng et al. (2016), China.
Investigate the change
of serum metabolites in
response to n-3
supplementation in
patients with T2DM
DB parallel arm RCT,
plasma serum
Flaxseed oil (FL)
2.52 g/d ALA
Fish oil (FO) 4 g/d
(1.2 g/d EPA,
800 mg/d DHA).
Corn oil (CO)
control 4 g/d 0.00
n-3
56 adults
FL (n¼20)
FO (n¼18)
CO (n¼18)
Chinese T2DM
otherwise healthy
TG <4.56 mmol/L
180 days No significant
change in
erythrocyte ALA
composition
between FO and
CO. Fish oil gave
the strongest
improvements to
serum TG
DB ¼double blinded. SB ¼single blinded. RCT ¼randomized controlled trial. MetS ¼metabolic syndrome. o/wt ¼overweight. HTG ¼hypertriglyceridemia. LDL-
C¼low density lipoprotein cholesterol. NTG ¼normlipidaemic. sd-LDL-C ¼small dense low density lipoprotein cholesterol. T2DM ¼type 2 diabetes mellitus.
TG ¼triglycerides. VLDL ¼very low density lipoproteins. Source oils: AH ¼Ahiflower oil. AO¼(micro) algal oil. CA ¼canola oil. CO ¼corn oil. CS ¼corn soy
bean oil. EO ¼echium seed. oil FL ¼flaxseed oil. FO ¼fish oil. OO ¼olive oil. SBO-soy bean oil. SfO ¼safflower oil. SO ¼sunflower oil.
8 K. E. LANE ET AL.
Table 5. Relative percentage change to erythrocytes by n-3 source oil.
n-3 changes after intervention expressed as relative percentages
Author, year and country Study design Dose
No./type of
participants Time period 18:3n-3 ALA 18:4n-3 SDA 20:5n-3 EPA 22:5n-3 DPA 22:6n-3 DHA n-6/n-3 n-3 total
Flaxseed/linseed
Dewell et al. (2011), USA DB RCT high (HFx)
and low dose (LFx)
6.6 g/d ALA (HFx)
2.2 g/d ALA (LFx)
20 (HFx)
20 (LFx)
8 weeks 0.90
0.38-
-
0.45
0.21
-
-
0.58(NS)
0.34(NS)
-
-
-
-
Dittrich et al. (2015), Germany. DB crossover RCT,
flaxseed, echium
seed and
microalgal oil
enriched foods
7 g/d ALA 15 HTG
otherwise healthy
10 weeks per arm 0.34 –0.30 0.41 0.09(NS) 0.64 0.21(NS)
Kontogianni et al. (2013), Greece. DB Crossover RCT,
olive oil and
flaxseed oil
13.8 g/d oil (8 g/d ALA) 37 healthy normal
weight males and
females aged 18-35
6 weeks per arm 0.22 –0.25 0.40(NS) 0.03(NS) 0.08(NS)
-
-
-
Lefort et al. (2016), Canada. Parallel group DB RCT 9.1g/d (5.369 g/d ALA) 40 healthy 18-65yrs,
BMI 18.5-39.9
28 days 0.18 0.00(NS) 0.05(NS) 0.13 0.06(NS) 0.10(NS)
Nelson, Hokanson, and
Hickey (2011), USA.
SB RCT 11 g/d (6.27 g/d ALA) 20 healthy over 50 8weeks 0.00(NS) –0.30(NS) –0.20(NS) 0.10(NS)
Echium seed
Dittrich et al. (2015), Germany. DB crossover RCT,
flaxseed, echium
seed and
microalgal oil
2 g/d SDA 15 HTG
otherwise healthy
10 weeks per arm 0.19 –0.60 0.76 0.43(NS) 0.71 0.17(NS)
Kuhnt et al. (2014), Germany. DB parallel arm RCT 17 g/d (2 g/d SDA) 20, healthy weight 20-
35yrs (EO1), 20, 49-
69yrs (EO11)
19 o/wt
MetS (EO111)
8 weeks 0.19
0.16
0.23
0.05
0.03
0.04
0.26
0.40
0.24
0.63
0.76
0.52
0.38
0.76
0.52
Microalgal oil
Dittrich et al. (2015) DB crossover RCT,
flaxseed, echium
seed and
microalgal oil
2 g/d DHA 16 HTG
otherwise healthy
10 weeks per arm 0.02 –0.09(NS) 0.62 2.48 1.28 2.93
DB ¼double blinded. SB ¼single blinded. RCT ¼randomized controlled trial. MetS ¼metabolic syndrome. o/wt ¼overweight. HTG ¼hypertriglyceridemia. T2DM ¼type 2 diabetes mellitus. -¼not measured. NS ¼not sig-
nificant. p<0.05, p0.01, p0.001. % changes with no indicator are where significance was not measured.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 9
Table 6. Relative percentage n-3 fatty acid change to plasma lipids by n-3 source oil.
n-3 changes after intervention
expressed as relative percentages
Author, year
and country Study design Source and dose No./type of participants Time period 18:3n-3 ALA 18:4n-3 SDA 20:5n-3 EPA 22:5n-3 DPA 22:6n-3 DHA n-6/n-3 n-3 total
Flaxseed/linseed
Dittrich et al.
(2015), Germany.
DB crossover RCT,
flaxseed, echium
seed and microalgal
oil enriched foods
Flaxseed oil 7 g/d ALA 15 HTG otherwise
healthy
10 weeks per
arm
1.67 0.24(NS) 0.050.11(NS) 2.97 –
Kawakami et al.
(2015), Japan.
DB crossover RCT 10 g/d flaxseed oil
(5.49 g ALA)
15 healthy males 12weeks per arm –– – –– – 3.90
Lefort et al. (2016),
Canada
Parallel group DB RCT 9.1 g/d (5.369g/d ALA) 40 healthy 18-65yrs,
BMI 18.5-39.9
28 days 1.44 0.01(NS) 0.08(NS) 0.180.02(NS)
Neukam et al. (2011),
France and Germany.
DB RCT 4 capsules 555.32 mg
(2.7 g/d ALA)
13 healthy
females 18-65yrs
12 weeks 0.62–0.25(NS) 0.01(NS) 0.08(NS) 1.30(NS) 0.81(NS)
Pieters et al. (2019),
Netherlands.
Parallel DB RCT 10 g/d flaxseed oil
(4.7 g/d ALA)
28 healthy o/wt/obese,
40-70yrs
12 weeks 0.30 –0.50 –0.00 –1.10
Zheng et al. (2016),
China
DB parallel RCT Flaxseed oil
2.52 g/d ALA
20 Chinese T2DM
otherwise healthy
180 days –– 0.14 0.03 0.02 ––
Echium seed oil
Dittrich et al. (2015),
Germany
DB crossover RCT,
flaxseed,
echium seed and
microalgal oil
Echium seed
oil 2 g/d SDA
15 HTG otherwise
healthy
10 weeks per
arm
0.87 –0.88 0.26 0.05(NS) 5.11 –
Kuhnt et al. (2014) DB parallel arm RCT Echium seed oil
17 g/d (2 g/d SDA)
20, healthy weight 20-35yrs
(EO1), 20, 49-69yrs (EO11)
19 o/wt MetS (EO111)
8 weeks 1.17
1.03
1.07
0.28
0.25
0.28
0.88
1.19
0.90
0.29
0.30
0.24
0.00(NS)
0.09
0.17
-
-
-
-
-
-
-
-
Microalgal oil
Dittrich et al. (2015),
Germany.
DB crossover RCT,
flaxseed,
echium seed and
microalgal oil
microalgal oil 2 g/d DHA 16 HTG otherwise
healthy
10 weeks
per arm
0.044(NS) –0.08(NS) 0.12 1.64 3.52 –
Maki et al. (2015), USA DB parallel RCT Microalgal oil 0.66 g/d EPA
1.78 g/d DHA
37 HTG otherwise healthy
and active
14 weeks ––0.11–0.37––
Neff et al. (2011), USA DB RCT, parallel arm.
Microalgal
oil and corn-soybean
oil (1:1) mixture
Microalgal oil (AO)
5 mL/d (2 g/d DHA)
or corn-soy bean
oil (CS) 5 mL/d
O/wt and obese otherwise
healthy
adults not using fish oil
supplements
AO (n ¼18)
CS (n ¼15)
4.5 months 0.00 ± 0.10(NS) –0.30 ± 0.20 –5.80 ± 1.10 ––
Ryan and Symington
(2015), UK
Open-label partially
randomized,
partially allocated
parallel group
Microalgal oil 3 capsules/d
(600 mg/d DHA)
Compared to fish oil 1 capsule
(200 mg/d DHA, 300 mg/d EPA,
100 mg/d SDA & ALA)
31 healthy adults, including 10
vegetarian/vegans (AOv))
Omnivore microalgal group
(AO n ¼9) and fish oil
group (FO n ¼10)
2 weeks
AOv
AO
0.02(NS)
0.02(NS)
-
-
0.02(NS)
0.18(NS)
0.37(NS)
0.24(NS)
2.32
1.79
DB ¼double blinded. SB ¼single blinded. RCT ¼randomized controlled trial. MetS ¼metabolic syndrome. o/wt ¼overweight. HTG ¼hypertriglyceridemia. NTG ¼normlipidaemic T2DM ¼type 2 diabetes mellitus. - ¼not
measured. NS ¼not significant. p<0.05, p0.01, p0.001. % changes with no indicator are where significance was not measured.
10 K. E. LANE ET AL.
Discussion
The results of this scoping review indicate a lack of recent
research into n-3 dietary intakes and blood markers of vege-
tarians and vegans. The RCTs that have evaluated plant
based n-3 supplementation options are varied and seldom
utilize appropriate vegan and vegetarian populations.
Consequently, there is very little official guidance available
in relation to appropriate plant based n-3 alternatives to
oily fish.
Vegans eliminate all animal products from their diet and
represent a sizable and increasing number within the world-
wide population (Statista 2018). The number of vegans in
the UK quadrupled between 2014 and 2019, with vegans
accounting for 1.16% (600,000) of the population in 2019
(The Vegan Society 2020). Younger people are more likely
to follow a vegan diet, European surveys suggest up to 12%
followed this dietary pattern in 2017 and prevalence is
increasing within this group (Statista 2018). The numbers of
vegetarians remain consistent and relatively substantial;
worldwide data suggest Asia Pacific region has the highest
prevalence of people following a vegetarian diet standing at
19% of the population, 16% Africa/Middle East, 8% Latin
America, 6% North America and 5% Europe (Statista 2018).
There is strong evidence that a well-planned vegetarian or
vegan diet with careful consideration to supplementation
can provide all the necessary nutrients (Appleby and Key
2016; Melina, Craig, and Levin 2016). However, concerns
have been raised in relation to n-3 status and some other
vitamin and minerals levels where vegetarian/vegan diets are
poorly planned (Appleby and Key 2016; Craig 2009; Melina,
Craig, and Levin 2016). Whilst overall, data suggest that the
long-term health of vegetarians is good, there is insufficient
data to draw strong conclusions on the long term health of
vegans (Appleby and Key 2016). In relation to n-3 status a
Table 7 –Summary ‘omega 3 index’at baseline and endpoints
Plasma/erythrocyte percentage fatty acids
Author, year
and country Intervention
Trial
arm
Baseline
EPA
Endpoint
EPA
Baseline
DHA
Endpoint
DHA
Baseline
EPA + DHA
Endpoint
EPA + DHA
Dewell, et al.
(2011), USA
Comparison of high and
low flaxseed and fish
oil doses. Soy bean
oil (placebo)
HFL 0.69 ± 0.19 1.14 ± 0.10 4.13 ± 0.43 3.55 ± 0.10 4.82 4.69
LFL 0.68 ± 0.12 0.89 ± 0.17 4.30 ± 0.24 3.96 ± 0.13 4.98 4.85
LFO 0.98 ± 0.29 2.24 ± 0.26 3.94 ± 0.39 5.50 ± 0.26 4.92 7.74
HFO 1.31 ± 0.38 5.81 ± 1.23 5.46 ± 0.40 7.69 ± 0.30 6.77 13.50
SbO 1.02 ± 0.20 1.01 ± 0.06 4.76 ± 0.42 4.35 ± 0.12 5.78 5.36
Dittrich, et al.
(2015), Germany
Comparison of sunflower
oil (control), flaxseed
oil, echium oil and
microalgal oil
SO 0.97 ± 0.32 0.78 ± 0.23 4.30 ± 0.97 4.08 ± 0.72 5.27 4.86
FL 0.96 ± 0.35 1.26 ± 0.35 4.31 ± 0.97 4.22 ± 0.94 5.27 5.48
EO 0.95 ± 1.55 1.55 ± 0.56 4.02 ± 1.02 3.59 ± 0.55 4.97 5.14
AO 0.88 ± 0.0.25 0.97 ± 0.25 3.73 ± 0.80 6.57 ± 1.71 4.61 7.54
Kawakami, et al.
(2015), Japan
Flaxseed oil compared to
corn oil
FL 0.78 ± 0.17 0.71 ± 0.01 1.32 ± 0.11 1.03 ± 0.98 2.1 1.74
CO 0.78 ± 0.16 0.68 ± 0.01 1.38 ± 0.17 1.07 ± 0.13 2.16 1.75
Kontogianni, et al.
(2013), Greece
Comparison of flaxseed
oil and olive oil
FL 0.53 ± 0.25 0.78 ± 0.38 2.31 ± 0.41 2.71 ± 0.43 2.84 3.49
OO 0.57 ± 0.30 0.58 ± 0.28 2.43 ± 0.60 2.52 ± 0.45 3.00 3.10
Kuhnt, et al.
(2014), Germany
Comparison of echium oil
and fish oil
EO1 0.48 ± 0.17 1.36 ± 0.41 1.40 ± 0.39 1.40 ± 0.35 1.88 2.76
EO11 0.72 ± 0.28 1.91 ± 0.64 1.60 ± 0.44 1.54 ± 0.47 2.32 3.45
EO111 0.73 ± 0.18 1.63 ± 0.27 1.70 ± 0.49 1.53 ± 0.42 2.43 3.16
FO1 0.43 ± 0.10 3.87 ± 1.19 1.30 ± 0.46 1.89 ± 0.50 1.83 5.76
FO11 0.85 ± 0.32 3.95 ± 0.74 1.71 ± 0.67 1.98 ± 0.63 2.56 5.93
Lefort, et al.
(2016), Canada
Comparison of Ahiflower
oil and flaxseed oil
AH
FL
0.45(0.01)
0.43(0.00)
0.74(0.01)
0.55(0.02)
3.68(0.12)
2.99(0.11)
3.27(0.16)
2.89(0.13)
4.13
3.42
4.01
3.44
Maki et al
(2014), USA.
Comparison of microalgal
oil, fish oil and corn/
soy oil control
AO 0.64 (0.49, 0.81) 1.97(1.57, 2.41) 2.38(1.86, 2.98) 4.99 (4.66, 6.52) 3.02 6.96
FO 0.78(0.56,0.91) 3.15 (2.18, 3.62) 2.69 (2.16, 3.62) 4.99 (4.66, 6.52) 3.47 8.14
CS 0.67(0.49,0.90) 0.65 (0.40, 0.93) 2.56 (1.89, 3.46) 2.63 (2.07, 3.69) 3.23 3.28
Neff, et al.
(2011), USA
Comparison of microalgal
oil and corn/soy
oil control
AO 0.60 ± 0.20 1.00 ± 0.30 3.00 ± 0.80 8.80 ± 1.10 3.60 9.80
CS 0.60 ± 0.20 0.60 ± 0.20 2.70 ± 0.70 2.70 ± 0.70 3.30 3.30
Nelson, et al.
(2011), USA.
Comparison of flaxseed
oil, fish oil and olive
oil control
FL 0.10 ± 0.3 0.40 ± 0.60 4.40 ± 1.0 4.20 ± 1.10 5.50 4.60
FO 0.00(ND) 0.60 ± 0.70 4.40 ± 1.10 5.30 ± 1.00 4.40 5.90
OO 0.00(ND) 0.00(ND) 3.76 ± 1.30 3.81 ± 1.00 3.76 3.81
Neukam, et al.
(2011), Germany.
Comparison of flaxseed
oil and safflower
seed oil
FL 1.61 1.86 3.48 3.40 5.09 5.26
SfO 2.14 1.53 3.27 2.72 5.41 4.25
Pieters, et al. (2019),
Netherlands.
Comparison of flaxseed
oil and sunflower oil
FL 1.20 ± 0.60 1.70 ± 0.60 3.5 ± 0.90 3.5 ± 0.80 4.70 5.20
SO 1.20 ± 0.70 1.10 ± 0.05 3.20 ± 0.80 3.30 ± 1.1 5.40 4.40
Ryan and Symington
(2015), UK
Comparison of microalgal
oil and fish oil
AOv 0.76 ± 0.48 2.76 ± 1.13 0.74 ± 0.19 5.08 ± 0.45 3.52 5.82
AO 0.92 ± 0.40 4.01 ± 0.87 1.10 ± 0.50 5.8 ± 1.16 4.93 6.9
FO 1.56 ± 0.99 4.57 ± 1.11 3.36 ± 1.25 5.12 ± 1.11 6.13 8.48
Zheng, et al.
(2016), China
Comparison of flaxseed,
fish oil and corn oil
FL 0.73 ± 0.10 0.87 ± 0.09 0.88 ± 0.08 0.86 ± 0.08 1.61 1.73
FO 1.07 ± 0.08 3.05 ± 0.40 1.01 ± 0.06 1.55 ± 0.14 2.08 4.60
CO 0.97 ± 0.06 0.73 ± 0.07 0.97 ± 0.08 0.83 ± 0.07 1.94 1.56
Equivalent groupings for plasma total lipids [≤2.9% (very low (dark red),N2.9–4.0%(low (red)),N4.0–5.2% (moderate (yellow)),N5.2% (high (green))]. Equivalent
groupings for whole blood/erythrocyte [≤3.0% (very low (dark red)),N3.0–4.4% (low (red)),N4.4–5.9% (moderate (yellow)),N5.9% (high (green))]. Plasma phos-
pholipids [≤3.8%(very low (dark red)),N3.8–5.7% (low (red)),N5.7–7.6% (moderate (yellow)),N7.6% (high (green))] Stark et al (2016).
DB = double blinded. SB = single blinded. RCT = randomised controlled trial. MetS = metabolic syndrome. o/wt = overweight. HTG = hypertriglyceridemia.
NTG = normlipidaemic T2DM = type 2 diabetes mellitus. AH = Ahiflower oil. AO=(micro) algal oil. CA = canola oil. CO = corn oil. CS = corn soybean oil.
EO = echium seed oil FL = flaxseed oil. FO = fish oil. OO = olive oil. SbO = soybean oil. SfO = safflower oil. SO = sunflower oil.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 11
small number of recent studies have specifically analyzed the
dietary intakes and O3I of 70 vegans in total (Tables 1 and
2). In combination the three studies found plasma/erythro-
cyte levels of DHA and EPA were significantly lower for the
majority of vegans and n-6 levels were significantly higher
for all vegan groups, although participant numbers were as
low as 5 in some of the cohorts.
Further multicentre study research in larger cohorts of
vegetarians and vegans is necessary and this should now be
possible due to the increasing numbers of people following
a vegan lifestyle and the relative consistency in numbers of
vegetarians. In the present study, the participants, time-
frames, sources and n-3 doses for the identified articles were
highly varied. There was a high degree of heterogeneity and
only one study examined a small cohort of vegetarians/
vegans (n¼10) highlighting the difficulty in assessing differ-
ences in responses for groups in need of plant based n-
3 sources.
A shortage of larger scale, consistent studies examining
n-3 status and blood markers in vegans and fewer still that
have evaluated the effectiveness of plant based n-3 sources
has led to a lack of specific official recommendations for
plant based alternatives to oily fish consumption and marine
based supplementation. Guidelines from international organ-
izations remain generic, are based on omnivorous diets and
mainly focus on the shorter chain essential fatty acids ALA
and LA as these must be obtained from the diet in all popu-
lations (Davis and Kris-Etherton 2003; Scientific Advisory
Committee on Nutrition (SACN) 2004). The most recent
UK recommendations state two portions of fish per week
(one of oily fish) should be consumed, equating to a 140 g
portion providing 0.2 g/d n-3 (Scientific Advisory
Committee on Nutrition (SACN) 2004). Current UK recom-
mendations are broad and do not give specific advice on the
intakes of diverse population groups. The European Food
Safety Authority (EFSA) recommend 250 mg/d EPA and
DHA for adults (EFSA Panel on Dietetic Products and
Allergies 2010). The International Society for the Study of
Fatty Acids and Lipids (ISSFAL)) (2004) recommends 2%
and 0.7% of energy per day should come from essential fatty
acids LA and ALA respectively in healthy adults. For the
US, the Food and Nutrition Board of the Institute of
Medicine (2002) states the recommended nutrient intake
(RNI) for ALA is 1.6 and 1.1 g/d for men and women aged
19 to >70 years respectively (Trumbo et al. 2002). None of
these organizations has been able to provide specific recom-
mendations that relate to the more beneficial longer chain
EPA and DHA for non-fish eaters due to the lack of scien-
tific evidence in this area. Interestingly the studies identified
in this review show consumption of high doses of ALA
from flaxseed oil does not improve mean O3I and in some
groups of participants led to overall decreases despite signifi-
cant increases in plasma or erythrocyte ALA levels. In con-
trast to this the low dose flaxseed oil study by Neukam et al.
(2011) gave a small increase to mean O3I for healthy female
participants, which moved from moderate levels to high
after 12 weeks. This surprising result shows potential conver-
sion in the n-3 metabolic pathway which has also been
previously demonstrated in the literature for females under
50 and may be due to increased adipose tissue and estrogen
in women (de Groot, Emmett, and Meyer 2019). However,
there may be some study design issues as whilst participants
were asked to refrain from taking nutrition supplements
during the trial, n-3 dietary intakes were not considered so
direct sources of EPA and DHA may have been consumed.
Previous research suggests there are differences in conver-
sion of ALA to EPA and DHA in males and females, how-
ever more studies are needed to examine these differences in
vegetarians and vegans (Burdge, Jones, and Wootton 2002;
Burdge and Wootton 2002; Burns-Whitmore et al. 2019).
Whilst there are a lack of official vegan specific n-3 diet-
ary reference values, Davis and Kris-Etherton (2003) recom-
mend 2–4 g of ALA per day, and 100–300 mg/d of DHA for
vegans. The conversion of ALA to EPA and DHA in the
metabolic pathway relies on a series of desaturase and elon-
gase enzymes. The enzyme delta-6-desaturase catalyzes both
the metabolism of LA to arachidonic acid (20:4n-6 (AA))
and ALA to EPA and DHA. As levels of ALA are generally
lower than LA in the human diet LA is converted to AA
more readily meaning plasma and cellular levels of n-6 tend
to be higher than n-3 (Russell and Meital 2018; Schuchardt
and Hahn 2013). The ALA recommendation assumes a con-
version rate of <5–10% for EPA and 2–5% for DHA in the
metabolic pathway, although a direct source of DHA is pref-
erable. This is confirmed by the findings of the two high
dose (Dittrich et al. 2015; Maki et al. 2014) and one low
dose microalgal oil study (Ryan and Symington 2015) in the
current review, which showed increases to O3I groupings by
at least one level and improvements from low and modest
levels to high levels for the majority participants. The low
dose microalgal oil study by Ryan and Symington (2015)
provided 200 mg/d DHA administered over 2 weeks which
showed significant improvements in DHA plasma levels for
the micoralgal oil study arms (p0.05) and bioequivalence
to the comparator fish oil group. A subgroup of vegetarian/
vegans (n ¼6 of each) were recruited in this study, however
only 10 of these participants completed the trial and the
final ratio of vegetarians/vegans was not reported. Craddock
et al. (2017) also found direct microalgal sources of DHA
significantly improved DHA concentrations (including
plasma, serum, platelet and red blood cell fractions), as well
as O3I, in vegetarian populations in a systematic review and
meta-analysis of 4 RCTs and 2 prospective cohort studies.
Sarter et al. (2015) found four months of microalgal oil sup-
plementation (172 mg/d DHA and 82 mg/d EPA) offered
significant improvements to O3I in a subset of 46 vegans
with a low O3I (p¼0.009) in their non RCT supplementa-
tion study. The evidence identified in this review shows
microalgal oil offers a bioequivalent source of DHA to fish
oil in omnivorous study groups, however it is not possible
to make direct microalgal/fish oil comparisons in vegetarian/
vegan population groups due to the nature of these diets.
Our findings show strong evidence of the need for essential
fatty acid status for EPA and DHA in vegetarians and
vegans. To address EPA and DHA shortfalls, food based
dietary guidelines should also include references to direct
12 K. E. LANE ET AL.
plant based alternative sources to oily fish. Further research
should ratify this in the form of large, powered, well
designed (to reduce confounding) RCTs to establish opti-
mum EPA and DHA ratios and daily dosage for vegetarian
and vegan populations
Study limitations
When interpreting the results of this scoping review, it is
important to note that although all of the included studies
fitted with the inclusion criteria, some studies may have
exhibited stronger methodological approaches than others,
however this falls outside the scope of the review. The use
of participants diagnosed with or at risk of non-communic-
able diseases creates limitations due to changes in fatty acid
metabolism within these groups (Walle et al. 2017). There
was also a large variability of dosages and study intervention
time periods ranging from minimum 2 weeks and maximum
of 6 months. Based on the full text publications, only one of
the identified studies examined the bioavailability of plant
based n-3 sources using a small undisclosed number of
vegans (Ryan and Symington 2015), which confirms a lack
of research in the target study population.
Whilst the O3I represents a well evidenced marker of
health it may be questionable how relevant its use is where
supplements do not provide a direct source of EPA þDHA.
Increases in other beneficial to health n-3 fatty acids such as
ALA and SDA are not directly measured as the index relies
on their conversion in the n-3 metabolic pathway. In add-
ition the use of percentage fatty acid measures in whole
blood or plasma is a limitation as it can obscure and poten-
tially mask changes in the size of blood lipid pools (Stark
et al. 2016). In relation to O3I, erythrocytes have previously
been identified as the potential ‘gold standard’measure of
the future (Harris and Von Schacky 2004), however there
has not been a widespread shift to erythrocyte fatty acid
analysis (Stark et al. 2016). This was evident in the identified
studies as only 5 of them used erythrocyte measurements
(Dewell et al. 2011; Dittrich et al. 2015; Kontogianni et al.
2013; Lefort et al. 2016; Nelson, Hokanson, and Hickey
2011). The study methods did not account for different
analyses methods to establish n-3 blood markers, which
were varied and did not always follow recommended
ISSFAL standards for measuring blood n-3 long chain fatty
acid levels in research (de Groot and Meyer 2020; von
Schacky 2020).
Authors’conclusions
Plant based vegan diets that eliminate all animal products
are a rapidly increasing lifestyle choice particularly in
younger people whilst population levels of vegetarians
remain constant (Statista 2018). Consumption of n-3 in the
form of EPA and DHA predominantly found in oily fish
offers numerous health benefits but there remains a lack of
clear recommendations for specific plant based alternatives
suitable for vegetarians and vegans. The main findings of
this updated review are in agreement with our previous
article. There have been very few attempts to directly study
this important issue over the last 10 years despite the
increased number of people choosing to consume vegetarian
and vegan diets.
Based on the studies identified in this review and in
agreement with our previous work, consumption of high
doses of ALA from flaxseed oil and echium oil does not
increase the O3I and may lead to overall decreases despite
significant increases in blood ALA levels, which confirms
previous recommendations that a direct source of EPA and
DHA is most beneficial. All but one of the identified studies
assessed the bioavailability of plant based n-3 supplementa-
tion in omnivorous participants, which highlights the need
for larger long term plant based supplement RCTs with
vegetarian and vegan participants to provide more specific
and concise guidance for these groups. The three EPA and
DHA microalgal oil supplementation studies identified in
this review varied in terms of supplement dosages, time-
frames and used small numbers of participants. All of them
demonstrated ingestion of a direct EPA and DHA source
offered improvements to the O3I. Further research in the
form of large, powered, well designed (to reduce confound-
ing) RCTs, in a variety of populations both normal healthy
and at risk/with NCDs are needed to establish optimum
EPA and DHA ratios and daily dosage for vegetarian and
vegan populations to achieve this.
Considering the findings presented in the current review,
and the observational evidence of low O3I status in vegans,
this scoping review indicates the need for essential fatty acid
status for EPA and DHA for populations that do not con-
sume marine n-3 sources. The preliminary advice for vegeta-
rians and vegans is to reduce levels of n-6 in the diet
particularly if ALA is the main n-3 dietary source and regu-
lar consumption of a preformed EPA and DHA supplement
is crucial to maintain an optimal O3I.
Acknowledgements
The authors would like to thank Jackie Fealey for guidance with data-
base searches.
Funding
"This research received no specific grant from any funding agency,
commercial or not-for-profit sectors."
Disclosure statement
No potential conflict of interest was reported by the authors..
Authorship
KEL designed and conducted the scoping review, conducted the initial
database searches and drafted the manuscript. MW conducted title,
abstract and full text article screening. TGH contributed to methodo-
logical approaches and manuscript writing and scrutiny. IGD contrib-
uted to interpretation of findings and to manuscript writing
and scrutiny.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 13
ORCID
Katie E. Lane http://orcid.org/0000-0002-9092-2927
Teuta G. Hellon http://orcid.org/0000-0001-6475-9428
Ian G. Davies http://orcid.org/0000-0003-3722-8466
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