Clinical Nutrition xxx (2015) 1e11

Contents lists available at ScienceDirect

Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

Effects of flaxseed supplements on blood pressure: A systematic

review and meta-analysis of controlled clinical trial
Sorin Ursoniu a, 1, Amirhossein Sahebkar b, c, 1, Florina Andrica d, Corina Serban e,
Maciej Banach f, *, Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group
a
Department of Functional Sciences, Discipline of Public Health, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
b
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
c
Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
d
Faculty of Pharmacy, Discipline of Pharmaceutical Chemistry “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
e
Department of Functional Sciences, Discipline of Pathophysiology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
f
Chair of Nephrology and Hypertension, Medical University of Lodz, Poland

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Many experimental and clinical trials suggested that flaxseed might be a potent
Received 29 March 2015 antihypertensive, but the evidences concerning the effects of flaxseed supplements on blood pressure
Accepted 19 May 2015 (BP) has not been fully conclusive. We aimed to assess the impact of the effects of flaxseed supplements
on blood pressure through systematic review of literature and meta-analysis of available randomized
Keywords: controlled trials (RCTs).
Flaxseed
Methods: The literature search included PUBMED, Cochrane Library, Scopus, and EMBASE up to February
Linum usitatissimum
2015 to identify RCTs investigating the effect of flaxseed supplements on plasma blood pressure. Effect
Arterial hypertension
Meta-analysis
size was expressed as weighed mean difference (WMD) and 95% confidence interval (CI).
Systematic review Results: 15 trials (comprising 19 treatment arms) with 1302 participants were included in this meta-
analysis. Random-effects meta-analysis suggested significant reductions in both systolic BP (SBP)
(WMD:
2.85 mmHg, 95%CI:
5.37 to
0.33, p ¼ 0.027) and diastolic BP (DBP) (WMD:
2.39 mmHg,
95%CI:
3.78 to
0.99, p ¼ 0.001) following supplementation with flaxseed products. When the studies
were stratified according to their duration, there was a greater effect on both SBP and DBP in the subset
of trials with 12 weeks of duration (WMD:
3.10 mmHg, 95%CI:
6.46 to 0.27, p ¼ 0.072
and
2.62 mmHg, 95%CI:
4.39 to
0.86, p ¼ 0.003, respectively) vs the subset lasting <12 weeks
(WMD:
1.60 mmHg, 95%CI:
5.44 to 2.24, p ¼ 0.413, and
1.74 mmHg, 95%CI:
4.41 to 0.93, p ¼ 0.202,
respectively). Another subgroup analysis was performed to assess the impact of flaxseed supplement
type on BP. Reduction of SBP was significant with flaxseed powder (WMD:
1.81 mmHg, 95% CI:
2.03
to
1.59, p < 0.001) but not oil (WMD:
4.62 mmHg, 95%CI:
11.86 to 2.62, p ¼ 0.211) and lignan extract
(WMD: 0.28 mmHg, 95% CI:
3.49 to 4.04, p ¼ 0.885). However, DBP was significantly reduced with
powder and oil preparations (WMD:
1.28 mmHg, 95% CI:
2.44 to
0.11, p ¼ 0.031, and
4.10 mmHg,
95%CI:
6.81 to
1.39, p ¼ 0.003, respectively), but not with lignan extract (WMD:
1.78 mmHg, 95%
CI:
4.28 to 0.72, p ¼ 0.162).
Conclusions: This meta-analysis of RCTs showed significant reductions in both SBP and DBP following
supplementation with various flaxseed products.
© 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction

Dietary interventions have been recommended as attractive

* Corresponding author. Department of Hypertension, WAM University Hospital add-on therapies to control blood pressure and decrease the
in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland. Tel./ burden of hypertension [1]. Flaxseed (Linum usitatissimum), an
fax: þ48 42 639 37 71.
oilseed crop grown on all continents and highly accessible, has
E-mail address: maciejbanach@aol.co.uk (M. Banach).
1
Drs Ursoniu and Sahebkar contributed equally to this meta-analysis. been shown to decrease the risk of cardiovascular disease by

http://dx.doi.org/10.1016/j.clnu.2015.05.012
0261-5614/© 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Please cite this article in press as: Ursoniu S, et al., Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of
controlled clinical trial, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.05.012
2 S. Ursoniu et al. / Clinical Nutrition xxx (2015) 1e11
decreasing lipid profile parameters [2], plasma trans fats [3],
atherogenicity [4,5], glycemia [2] or pro-inflammatory oxylipins
[6]. Furthermore, flaxseed and its components have been associ-
ated with blood pressure (BP) reduction in many animal studies
and randomized controlled trials [7]. Flaxseed is composed of
enterolignan precursors, primarly secoisolariciresinol diglucoside
(SDG) [6], total fibers, omega -3 fatty acids and alpha linolenic acid
(ALA) [8]. It has been proven that the brown or golden varieties of
flaxseed might influence its favorable health effects, by different
percent of compounds [9]. Epaminondas et al. found a lower
amount of fiber, but a higher amount of soluble carbohydrates in
the golden flaxseed than in the brown variety, and no differences
regarding the percent of lipids and proteins [10]. Moreover, Sargi
et al. detected that golden flaxseed has higher levels of omega -3
and -6, while brown flaxseed has higher antioxidant capacity [11].
The anti-hypertensive action of dietary fiber was demonstrated
in some meta-analyses [12], but the exactly effects on blood pres-
sure are still inconclusive [13,14]. Therefore, we systematically re-
view all the published trials on flaxseed supplementation and
assess its overall efficacy on BP reduction.
2. Methods
2.1. Search strategy
This systematic review and meta-analysis was performed ac-
cording to the guiding principles of the 2009 preferred reporting
items for systematic reviews and meta-analysis (PRISMA) state-
ment [15]. The following search terms in titles and abstracts were
used to retrieve relevant articles from SCOPUS (http://www.scopus.
com) and Medline (http://www.ncbi.nlm.nih.gov/pubmed) data-
bases: (“randomized controlled trial” OR randomized) and (“blood
pressure” OR hypertension OR anti-hypertensive OR hypotension
OR hypotensive) and (flaxseed OR L. usitatissimum). The wild-card
term “*” was used to increase the sensitivity of the search strat-
egy. No language restriction was used in the literature search. The
search was limited to studies in human subjects. The literature was
searched until February 12, 2015.
2.2. Study selection
To include studies to the meta-analysis, the following criteria
were considered: (i) clinical trials with a caseecontrol or cross-over
design, (ii) investigation of the effect of flaxseed preparations on
blood pressure, (iii) Providing baseline and end-trial blood pressure
values in both flaxseed and control groups, and (iv) having a sup-
plementation (with flaxseed) period of at least two weeks. Non-
clinical studies, uncontrolled trials, and trials with insufficient
data on blood pressure values in flaxseed and control groups were
excluded from the meta-analysis.
2.3. Data extraction
Eligible studies that met the inclusion criteria were reviewed
and the following information were extracted: 1) first author's
name; 2) year of publication; 3) location of the study; 4) number of
participants in the flaxseed and control groups; 5) dose and dura-
tion of supplementation with flaxseed products; 6) age, gender and
body mass index (BMI) of participants; 7) plasma (or serum) con-
centrations of total cholesterol, low-density lipoprotein cholesterol
(LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides
and glucose; and 8) systolic and diastolic blood pressure (SBP and
DBP).
Please cite this article in press as: Ursoniu S, et al., Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of
controlled clinical trial, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.05.012
2.4. Quality assessment
Assessment of risk of bias in the studies included in the analysis
was performed systematically using the Cochrane quality assess-
ment tool for RCTs [16]. Cochrane tool has 7 criteria for quality
assessment: random sequence generation (selection bias), alloca-
tion sequence concealment (selection bias), blinding of participants
and personnel (performance bias), blinding of outcome assessment
(detection bias), incomplete outcome data (attrition bias), selective
outcome reporting (reporting bias) and other potential sources of
bias. The risk of bias in each study was judged to be low, high or
unclear.
2.5. Quantitative data synthesis
Meta-analysis was performed using the Comprehensive Meta-
Analysis (CMA) V2 software (Biostat, NJ). Net changes in SBP and
DBP between flaxseed and control group were calculated by sub-
tracting the values at end of follow-up from those at baseline. For
cross-over trials, each treatment arm was treated as an individual
RCT, and net changes were calculated as difference between the
values after treatment and control intervention. All BP units were
collated in mmHg. In order to calculate the standard deviations (SDs)
for the net changes, the following formula was used: SD ¼ square root
[(SDpre-treatment)2 þ (SDpost-treatment)2
(2R  SDpre-treatment  SDpost-
treatment)], assuming a correlation coefficient (R) ¼ 0.5. If the outcome
measures were reported in median and inter-quartile range, mean
and SD values were estimated as described by Hozo et al. [17]. To
convert interquartile range into MineMax range, the following
equations were used: A ¼ median þ 2  (Q3 e median) and
B ¼ median e 2  (median e Q1), where A, B, Q1 and Q3 are upper and
lower ends of the range, upper and lower ends of the interquartile
range, respectively. For studies that reported standard error of the
mean (SEM), standard deviation (SD) was estimated using the
following formula: SD ¼ SEM  sqrt (n), where n is the number of
subjects. For studies with multiple measurements that reported data
at different time points, only to the values of the longest duration of
treatment were used. In order to avoid double-counting of values in
trials comparing multiple treatment arms versus a common control
group, the number of subjects in the control group was divided by the
number of treatment arms. When no SD was provided for BP values
in a study, the missing value was imputed by the pooled SD of other
studies. Meta-analysis was performed using a random-effects model
(DerSimonianeLaird method) and the generic inverse variance
method. The choice of random-effects model was to compensate for
the inter-study heterogeneities in terms of demographic character-
istics of populations being studied and also differences in study de-
signs. Heterogeneity was quantitatively assessed using I2 index. The
summary statistic of effect size was weighted mean difference
(WMD) and 95% confidence interval (CI). Sensitivity analysis was
performed using a leave-one-out method, i.e. iteratively removing
one study each time and repeating the analysis [18,19].
2.6. Meta-regression
The impact of supplementation duration and flaxseed dose as
potential moderators of effect size was explored using meta-
regression. An unrestricted maximum likelihood method under a
random-effects model was applied to detect the association be-
tween calculated WMD and above-mentioned moderators.
2.7. Publication bias
Assessment of publication bias was performed using visual in-
spection of Begg's funnel plot asymmetry. Quantitative
 S. Ursoniu et al. / Clinical Nutrition xxx (2015) 1e11 3

assessments included fail-safe N, Begg's rank correlation and
Egger's weighted regression tests. In case of detecting publication
bias, Duval & Tweedie “trim and fill” method was applied to impute
potentially missing studies [20].
3. Results
3.1. Search results and trial flow
group and four as cross-over studies. Table 1 shows the de-
mographic characteristics and baseline parameters of the included
studies.
3.3. Risk of bias assessment
The assessment of risk of bias in the included studies using
Cochrane criteria is shown in Table 2.

The initial screening comprised 622 full text articles and we
removed the articles in whose titles and/or abstracts were obvi-
ously irrelevant. Among the full text articles that were assessed for
eligibility (n ¼ 19), 4 studies were excluded because: not measuring
BP levels (n ¼ 1), not controlled for flaxseed supplementation
(n ¼ 2) and reporting duplicate data (n ¼ 1) (Fig. 1). After final
assessment, 15 eligible trials with 19 treatment arms achieved the
inclusion criteria and were preferred for the final meta-analysis.
3.2. Characteristics of included studies
In total, 1302 participants were randomized, of whom 618 were
allocated to flaxseed supplementation groups, 140 to other treat-
ment groups and 544 to control group in the 15 selected studies
[21e35]. The number of participants in these trials ranged from 14
to 189. Included studies were published between 2005 and 2015,
and were conducted in Canada (n ¼ 5), Brazil (n ¼ 2), China (n ¼ 2),
India (n ¼ 2), Australia, Denmark, Finland and Greece. The
following flaxseed supplementation was administered in the
included trials: powder 28 ge60 g/day, oil containing 1.2 ge15 g
ALA/day and derived lignan complex 360 mge600 mg total SDG/
day. Duration of flaxseed supplementation ranged between 4
weeks and 12 months. Eleven trials were designed as parallel-
3.4. Quantitative data synthesis
Random-effects meta-analysis of data showed significant re-
ductions in both SBP (WMD:
2.85 mmHg, 95% CI:
5.37 to
0.33,
p ¼ 0.027) and DBP (WMD:
2.39 mmHg, 95% CI:
3.78 to
0.99,
p ¼ 0.001) following supplementation with flaxseed products
(Figs. 2 and 3). The estimated effect size for the impact of flaxseed
products on DBP was robust in the leave-one-out sensitivity anal-
ysis whilst the SBP-lowering effect was marginally sensitive to
three studies [25,26,35] (Figs. 2 and 3).
When the studies were stratified according to their duration,
there was a greater effect on SBP in the subset of trials with 12
weeks of duration (WMD:
3.10 mmHg, 95% CI:
6.46 to 0.27,
p ¼ 0.072) versus the subset lasting < 12 weeks
(WMD:
1.60 mmHg, 95% CI:
5.44 to 2.24, p ¼ 0.413) (Fig. 4). With
respect to DBP, there was a trend similar to the effect on SBP
(WMD:
2.62 mmHg, 95% CI:
4.39 to
0.86, p ¼ 0.003 [ 12
weeks]; WMD:
1.74 mmHg, 95% CI:
4.41 to 0.93, p ¼ 0.202 [<12
weeks]) (Fig. 4).
Another subgroup analysis was performed to assess the impact
of flaxseed supplement type on BP. Reduction of SBP was significant
with flaxseed powder (WMD:
1.81 mmHg, 95% CI:
2.03 to
1.59,
p < 0.001) but not oil and lignan extract (WMD:
4.62 mmHg, 95%

Fig. 1. Flow diagram of the study selection procedure showing the number of eligible controlled trials for the meta-analysis of the impact of flaxseed consumption on blood
pressure.

Please cite this article in press as: Ursoniu S, et al., Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of
controlled clinical trial, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.05.012
Table 1
Demographic characteristics and baseline parameters of the studies selected for analysis.

Study Barden et al. [21] Barre et al. [22] Cornish et al. [23] Cassani et al. [24] Rodriguez-Leyva et al. Dodin et al. [26]
[25]

Year 2009 2012 2009 2015 2013 2005

Location Australia Canada Canada Brazil Canada Canada
Design Randomized, Randomized double- Randomized, double-blind placebo- Randomized single- Randomized double- Randomized double-
placebo-controlled blind crossover group controlled parallel group trial blind placebo- blind placebo- blind placebo-
parallel group trial trial controlled parallel controlled parallel controlled parallel
group trial group trial group trial

Duration of trial 4 weeks 3 months 6 months 42 days 6 months 12 months

Inclusion criteria
Flaxseed form
Flaxseed intervention
Non smoking men Type 2 diabetes female Men and postmenopausal women at least Men aged 20-60 yrs- Patients >40 years and Women with at least 6
aged 20-65 yrs patients 55 yrs of age 50 yrs of age recruited from the general old and at least three with peripheral artery months of amenorrhea
or older, being population of the following disease for >6 months in the year before
postmenopausal for at cardiovascular risk with an ankle brachial entry into the study
least one year factors: waist index <0.9 and a normal
circumference mammogram in the
90 cm; BMI 25 kg/ past 2 yr.
m2; fasting total
cholesterol 200 mg/
dL,; LDL-c) 130 mg/
dL, HDL-c <40 mg/dL;
triglycerides
150 mg/dL; glycemia
100 mg/dL; SBP
140 mm/Hg and/or
DBP 90 mm/Hg
Flaxseed oil Flaxseed derived Flaxseed-derived lignan complex Brown flaxseed Milled flaxseed Flaxseed germ
lignan complex powder
9 g/day containing 600 mg total SDG/day 543 mg total SDG/day 60 g/day 30 g/day 40 g/dayf
~5.4 g of ALA

Participants Case 18 16 28c 20d 14 58 85

Control 18 25c 19d 13 52 94

Age (years) Case 51 ± 2.5a 66.2 ± 1.7a 59.7 ± 1.0a,c 62.2 ± 1.2a,d 40 ± 9 67.4 ± 8.06 54.0 ± 4.0
Control 51 ± 2.0a 61.6 ± 1.5a,c 63.4 ± 1.9a,d 33 ± 10 65.3 ± 9.4 55.4 ± 4.5

Male (%) Case 100.0 0.0 41.67 100.0 NS 0.0

Control 100.0 43.18 100.0 NS 0.0

BMI (kg/m2) Case 26.1 ± 0.6a 31.2 ± 2.2a 27.1 ± 1.0a,c 28.4 ± 0.6a,d 32 ± 3 27.4 ± 4.4 25.5 ± 4.5
Control 25.6 ± 0.7a 29.1 ± 1.2a,c 29.5 ± 1.2a,d 32.1 ± 2.8 28.1 ± 4.4 26.8 ± 4.6

hs-CRP (mg/L) Case NS 2.4 ± 1.1a NS NS NS NS NS

Control NS 2.7 ± 1.2a NS NS NS NS NS

Total cholesterol (mg/ Case 194.54 ± 6.18a 169.84 ± 11.58a 225.42 ± 6.56a,c 218.48 ± 8.88a,d 223 ± 50 169.84 ± 42.46 218.86 ± 28.95
dL) Control 194.54 ± 6.95a 177.56 ± 11.58a 237.0 ± 8.11a,c 219.25 ± 11.97a,d 205 ± 36 173.7 ± 50.18 223.11 ± 27.41

LDL-C (mg/dL) Case NS 96.5 ± 7.72a 138.96 ± 6.56a,c 137.42 ± 7.72a,d 151 ± 59 96.5 ± 38.6 132.40 ± 26.63
Control NS 92.64 ± 3.86a 145.52 ± 6.18a,c 138.57 ± 6.56a,d 135 ± 50 100.36 ± 38.6 135.10 ± 24.70

HDL-C (mg/dL) Case 48.25 ± 2.32a 38.6 ± 0.39a 67.16 ± 3.09a,c 55.2 ± 3.47a,d 42 ± 5 46.32 ± 11.58 66.39 ± 12.74
Control 49.41 ± 2.70a 42.46 ± 11.58a 59.44 ± 3.09a,c 48.64 ± 1.93a,d 44 ± 9 46.32 ± 11.58 67.16 ± 15.05

Triglycerides (mg/dL) Case NS 150.45 ± 17.7a 105.31 ± 11.50a,b,c 130.98 ± 15.04a,b,d 215 ± 110b 141.6 ± 61.95 99.12 ± 39.82
Control NS 177.0 ± 35.4a 156.64 ± 19.47a,b,c 139.83 ± 22.12a,b,d 241 ± 264b 150.45 ± 70.8 102.66 ± 50.44

Glucose (mg/dL) Case NS 129.6 ± 7.2a 93.06 ± 1.98a,c 99.9 ± 3.42a,d 90 ± 15 NS 83.70 ± 8.46
Control NS 144.0 ± 14.4a 93.42 ± 1.44a,c 102.42 ± 1.98a,d 98 ± 16 NS 83.88 ± 8.82

SBP (mmHg) Case 124 ± 2.8a 133.6 ± 4.8a 128 ± 3a,c 130 ± 3a 139 ± 20.3 143.3 ± 22.2 125.4 ± 14.5
Control 119 ± 3.5a 135.8 ± 4.3a 123 ± 3a,c 129 ± 3a,d 134 ± 9.2 142.4 ± 17.5 122.4 ± 15.5

DBP (mmHg) Case 71 ± 2.2a 82.1 ± 1.9a 88.7 ± 2.8a,e 83 ± 13.5 77.0 ± 9.5 79.7 ± 9.4
Control 69 ± 1.7a 84.5 ± 2.2a 82.7 ± 2.8a,e 80 ± 7.7 79.0 ± 15.6 77.7 ± 9.4

Values are expressed as mean ± SD or median (25e75 percentiles).

Abbreviations: BMI: body mass index; NS: not stated; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; SBP: systolic blood
pressure; DBP: diastolic blood pressure; hs-CRP: high-sensitivity C-reactive protein; BMI: body mass index; CHD: coronary heart disease; ALA: alpha linolenic acid; SDG:
secoisolariciresionol diglucoside.
a
Values are means ± SEM.
b
Triacylglycerol.
c
Female patients.
d
Male patients.
e
DBP was provided only for a subsample of subjects with metabolic syndrome (males and females combined).
f
Half of the daily amount was given as two slices of bread, which replaced the usual bread in the diet, and the other 20 g was provided as ground grains to add to cereal,
juice, or yogurt, depending of the food preferences of the women.
Barcelo-Coblijn et al. Hallund et al. [28] Katare et al. [29] Machado et al. [30] Pan et al [31] Paschos et al. [32] Saxena et al. [33] Schwab et al. [34] Wu et al [35]
[27]

2008 2006 2013 2015 2007 2007 2014 2006 2010

Canada Denmark India Brazil China Greece India Finland China
Randomized placebo- Randomized double- Randomized Randomized single- Randomized double- Randomized placebo- Randomized placebo- Randomized double- Randomized placebo-
controlled parallel- blind crossover group placebo- blind placebo- blind crossover group controlled parallel- controlled parallel- blind crossover group controlled parallel-
group trial trial controlled controlled parallel trial group trial group trial trial group trial
parallel-group group trial
trial
12 weeks 6 weeks 12 weeks 11 weeks Monday to 12 weeks 12 weeks 3 months 4 weeks 12 weeks
Friday
Firefighters recruited Healthy Dyslipidemic Overweight Type 2 diabetic Male volunteers aged Subjects aged 40e60 Healthy volunteers Patients with
in the greater postmenopausal (>24 subjects in the adolescents patients 50e79 yrs of 35 to 70 yrs, first yrs having without any chronic metabolic syndrome
Winnipeg area. months) women. age group of 40 volunteers age (women diagnosed for dyslipidemia disease and having (waist circumference
e60 yrs with postmenopausal for at dyslipidaemia, (triglycerides BMI <30 kg/m2, age 25 90 cm for men or
elevated levels of least 1-year); LDL-C without evidence of >150 mg/dl or e60 yrs, Triglycerides 80 com for women;
TG (>150 mg/dl) level >2.9 mmol/L, and CHD (plasma total cholesterol >200 mg/ <3.5 mmol/l, total triglycerides
or cholesterol not using exogenous cholesterol dl or LDL-C >130 mg/ cholesterol 5.0 1.7 mmol/L; HDL-C
(>200 mg/dl) or insulin for glycemic >5.2 mmol/l and/or dl) e7.5 mmol/l and <1.03 mmol/L for men
low density control. HDL-C<1.03 mmol/l). plasma glucose or <130mmol/L for
lipoproteins <6.0 mmol/l. women; BP  130/88
(>130 mg/dl) mm Hg; glucose
5.6 mmol/L: LDL-C
3.4 mmol/L)

Flaxseed oil capsules Flaxseed-derived Roasted flaxseed Brown flaxseed/ Flaxseed-derived Flaxseed oil Roasted flaxseed Flaxseed oil Flaxseed incorporated
lignan complex chutney powder golden flaxseed lignan complex powder in bread
~1.2 g ALA/day ~2.4 g 500 mg total SDG/day 30 g/day 28 g/day 360 mg total SDG/day 15 ml/day containing 30 g/day 30 ml/day~15 g of ALA 30g/day
ALA/day ~3.6 g ALA/ ~8 g of ALA
day
12 22 25 20 68 59 25 14 94
10 20
10
9 25 21 28 25 95
36.3 ± 8.0 61 ± 7a NS 13.7 ± 2.1 63.2 ± 7.4 52.0 ± 1.0a NS 45 ± 7 48.5 ± 8.0
41.2 ± 9.6
43.7 ± 10.0
40.8 ± 12.1 NS 54.1 ± 1.6a NS 48.6 ± 8.0
100.0 0.0 52.0 44.0 36.8 100.0 NS 57.14 54.73
90.0
100.0
88.89 48.0 100.0 NS 56.38
NS 24.2 ± 0.7a 28.48 ± 2.91 23.38 ± 2.33 25.0 ± 3.3 28.32 ± 0.46a 28.48 ± 2.91 24.54 ± 2.22 25.1 ± 2.3
NS 24.18 ± 2.03
NS
NS 24.4 ± 0.7a 28.9 ± 4.21 23.71 ± 2.01 25.1 ± 3.3 28.77 ± 0.78a 28.90 ± 4.21 25.4 ± 2.4
NS NS NS 0.08 ± 0.09 NS NS NS NS NS
NS 0.10 ± 0.20
NS
NS NS NS 0.04 ± 0.09 NS NS NS NS NS
NS 233.53 ± 8.49a 266.8 ± 18.77 130.08 ± 15.44 230.44 ± 35.51 NS 266.80 ± 18.77 222.72 ± 27.02 231.60 ± 57.90
NS 123.52 ± 25.86
NS
NS 232.76 ± 8.11a 269.48 ± 19.26 131.24 ± 15.83 225.04 ± 32.81 NS 269.48 ± 19.26 220.41 ± 24.70 235.46 ± 65.62
NS 146.68 ± 8.49a 134.64 ± 27.45 73.34 ± 23.93 161.73 ± 34.35 NS 134.64 ± 27.45 143.98 ± 28.18 162.12 ± 50.18
NS 72.18 ± 21.62
NS
a
NS 146.29 ± 8.11 178.32 ± 27.54 74.50 ± 18.53 158.26 ± 28.18 NS 178.32 ± 27.54 143.98 ± 28.95 165.98 ± 54.04
NS 69.87 ± 3.47a 37.28 ± 5.47 41.69 ± 8.49 53.27 ± 13.12 NS 37.28 ± 5.47 55.97 ± 8.88 54.04 ± 15.44
NS 37.83 ± 7.72
NS
NS 70.25 ± 4.25a 31.88 ± 5.57 42.46 ± 9.65 52.88 ± 12.35b NS 31.88 ± 5.57 56.74 ± 13.12 54.04 ± 19.30
NS 84.96 ± 5.31a,b 192.68 ± 14.97 74.34 ± 26.55b 199.12 ± 108.85 NS 192.68 ± 14.97 104.43 ± 28.32 167.26(120.36
NS 69.03 ± 38.94b e245.14)
NS
NS 82.30 ± 4.42a,b 204.8 ± 15.22 70.80 ± 35.40b 184.08 ± 104.43 NS 204.80 ± 15.22 108.85 ± 56.64 171.69(128.32
e247.80)
NS NS NS 84.06 ± 14.94 146.16 ± 46.8 NS NS NS 113.40 ± 32.40
NS 81.0 ± 14.94
NS
NS NS NS 78.66 ± 16.92 142.20 ± 41.58 NS NS NS 113.40 ± 25.20
123 ± 8.3 124 ± 3a 135.76 ± 2.73 107.21 ± 11.25 139.3 ± 21.4 120 (110, 130) 135.76 ± 13.64 114 ± 12 133.0 ± 17.1
127.8 ± 10.5 109.74 ± 11.48
127 ± 13.5
118 ± 9.2 123 ± 3a 138.4 ± 3.3 107.14 ± 16.76 138.0 ± 18.6 122.5 (120, 140) 138.40 ± 16.50 133.7 ± 14.6
80.0 ± 7.6 75 ± 2a 88 ± 1.29 76.18 ± 8.06 79.2 ± 10.7 80 (75, 88) 88.0 ± 6.45 74 ± 8 85.6 ± 11.6
85.4 ± 8.4 78.03 ± 10.36
81.3 ± 13.3
75.6 ± 5.4 75 ± 2a 90.4 ± 1.58 74.05 ± 15.07 79.3 ± 10.3 80 (75, 85) 90.40 ± 7.90 85.4 ± 9.0
6 S. Ursoniu et al. / Clinical Nutrition xxx (2015) 1e11

Table 2
Assessment of risk of bias in the included studies using Cochrane criteria.

Study Ref Sequence Allocation Blinding of participants Blinding of outcome Incomplete Selective outcome Other potential
generation concealment and personnel assessment outcome data reporting threats to validity

Barden et al., 2009 [21] U U H H L L L

Barre et al., 2012 [22] U U U U L L L
Cornish et al., 2009 [23] L L L L L L L
Cassani et al., 2015 [24] U U L L L L L
Rodriguez-Leyva et al., 2013 [25] U U U U L L L
Dodin et al., 2005 [26] L L L L L L L
Barcel-Coblijn et al., 2008 [27] L L H H L L L
Hallund et al., 2006 [28] U U U L L L L
Katare et al., 2013 [29] U U H H L L L
Machado et al., 2015 [30] U U U U L L L
Pan et al., 2007 [31] L L L L L L L
Paschos et al., 2007 [32] U U H H L L L
Saxena et al., 2014 [33] U U H H L L L
Schwab et al., 2006 [34] U U U U L L L
Wu et al., 2010 [35] U U H H L L L

L: low risk of bias; H: high risk of bias; U: unclear risk of bias.

Fig. 2. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of flaxseed on systolic blood pressure. Leave-one-out sensitivity analysis is shown
in the lower plot.

Please cite this article in press as: Ursoniu S, et al., Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of
controlled clinical trial, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.05.012
 S. Ursoniu et al. / Clinical Nutrition xxx (2015) 1e11 7

Fig. 3. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of flaxseed on diastolic blood pressure. Leave-one-out sensitivity analysis is
shown in the lower plot.

CI:
11.86 to 2.62, p ¼ 0.211, and 0.28 mmHg, 95% CI:
3.49 to 4.04,
p ¼ 0.885, respectively) (Fig. 5). DBP was found to be reduced by
flaxseed powder (WMD:
1.28 mmHg, 95% CI:
2.44 to
0.11,
p ¼ 0.031) and oil (WMD:
4.10 mmHg, 95% CI:
6.81 to
1.39,
p ¼ 0.003) preparations; yet no effect was observed with lignan
extract (WMD:
1.78 mmHg, 95% CI:
4.28 to 0.72, p ¼ 0.162)
(Fig. 5).
3.5. Meta-regression analysis
Random-effects meta-regression was performed to evaluate the
association between blood pressure-lowering effects of flaxseed
and duration of supplementation as a potential moderator or
response. Changes in SBP and DBP showed no direct association
with supplementation duration ([SBP]: slope:
0.02; 95% CI:
0.24
to 0.20; p ¼ 0.869; [DBP]: slope:
0.05; 95% CI:
0.16 to 0.07;
p ¼ 0.446) (Fig. 6). Likewise, there was no association between
changes in SBP and DBP with administered doses of flaxseed as raw
seed powder, oil (expressed as daily intake of ALA) and lignan
extract (expressed as daily intake of lignan extract) (Table 3).
3.6. Publication bias
Visual inspection of the funnel plot of the study standard error
by effect size (mean difference) suggested asymmetry for the
impact of flaxseed consumption on SBP. Using trim-and-fill
correction, 6 potentially missing studies were imputed, yielding a
corrected effect size of
4.01 mmHg (95% CI:
6.28 to
1.74). With
respect to DBP, there was no sign of publication bias in the funnel
plot (Fig. 7). In addition to visual inspection of funnel plots, pres-
ence of publication bias was explored using Begg's rank correlation
test, Egger's linear regression test and fail-safe N test. The results of
these tests are summarized in Table 4.
4. Discussion
Random-effects meta-analysis of data from 15 eligible trials
with 19 treatment arms showed significant reductions in both SBP
and DBP after supplementation with flaxseed products. When the
studies were stratified according to their duration, there was a
greater effect on SBP in the subset of trials with 12 weeks of

Please cite this article in press as: Ursoniu S, et al., Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of
controlled clinical trial, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.05.012
8 S. Ursoniu et al. / Clinical Nutrition xxx (2015) 1e11

Fig. 4. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of flaxseed on systolic (upper plot) and diastolic (lower plot) blood pressure
values in the subsets of trials with <12 weeks and 12 weeks lengths.

duration versus the subset lasting <12 weeks. With respect to DBP,
there was a similar effect of treatment duration. Another subgroup
analysis was performed to assess the impact of flaxseed supple-
ment type on BP. Reduction of SBP was significant with flaxseed
powder but not oil and lignan extract. DBP was significantly
reduced with powder and oil preparations but not lignan extract.
Consistent with our findings, a previous smaller meta-analysis
concluded that flaxseed consumption may lower blood pressure
slightly [12].
The biological mechanisms involved in the reduction of BP by
flaxseed are not completely understood. A lignan named SDG is a
phytoestrogen known to be an angiotensin-converting enzyme
(ACE) inhibitor [36]. It has been shown in Sprague Dawley male rats
that SDG reduced angiotensin I-induced increase of BP through
stimulation of guanylate cyclase enzyme [36]. Another important
component of flaxseed, ALA is the main component of flaxseed
which reduce the values of BP, through its ability to reduce the
activity of soluble epoxide hydrolase [7]. It has been shown that
these pro-inflammatory oxylipins produced by soluble epoxide
hydrolase are responsible for loss of vasodilatation and progression
of inflammation in arterial hypertension [7]. However, a recent
human study proved that flaxseed might reduce inflammation by
decreasing the levels of neutrophil aggregating oxylipins [6].
Furthermore, flaxseed decreases C-reactive protein, serum amyloid
A, interferon-gamma, and interleukin-1ß, IL-2, IL-4, IL-6 and IL-10
in various studies [37,38]. Another component of flaxseed, a pro-
tein hydrolysate and an isolated fraction (KCl-F1) rich in arginine,
has reduced SBP after 2e8 h of post oral gavage, mimicking the
anti-hypertensive effects of captopril [39]. The beneficial effects of
flaxseed on vascular function were proven in an experimental study
when flaxseed oil raised the vascular reactivity to phenylephrine by
increasing the production of cyclooxygenase 2 (COX-2)-derived
thromboxane A2 and reactive oxygen species (ROS) [40]. Therefore,
the hypotensive effects of flaxseed may be caused by synergistic
action of potent antioxidants as lignans or by different bioactive
ingredients such as SDG, ALA or KCl-F1 [41,42].
The differences between the types of flaxseed supplement on BP
(significant reduction of SBP with flaxseed powder, but not with oil
and lignan extract and significant reduction of DBP with powder
and oil preparations, but not with lignan extract), might be
explained by some different qualities of flaxseed supplements: the
quantity of fibers, the ability to induce viscosity and the effects on
the bile acid metabolism [43]. It has been shown that increased
intraluminal viscosity after flaxseed fibers consumption might limit
re-uptake of bile acids, producing increased hepatic synthesis of
bile acids and could restrict micelle formation and hence reduce
lipid uptake [44].
The best bioavailability of ALA seems to exist when ingested as
flaxseed oil, but it becomes poor when ingested as a whole seed.
The advantage of milled flaxseed is that it provides the best

Please cite this article in press as: Ursoniu S, et al., Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of
controlled clinical trial, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.05.012
 S. Ursoniu et al. / Clinical Nutrition xxx (2015) 1e11 9

Fig. 5. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of different flaxseed preparations on systolic (upper plot) and diastolic (lower
plot) blood pressure.

bioavailability for each of these bioactive components and is well

tolerated [42,45]. Consumption of flaxseed has been reported to be
safe and well-tolerated in RCTs, but care should be taken with
preparation, the presence of cyanogenic glycosides and mucilage
are reduced below detectable limits after baking [46].
The results obtained in the present meta-analysis e a decrease
of 2.85/2.39 mmHg after flaxseed supplementation e might be
valuable for the hypertension management using nutraceuticals,
since Heart Outcome Evaluation study demonstrated that a 3.3/
1.4 mmHg reduction was associated with a 22% decline of relative
risk of cardiovascular mortality [47]. Although no association

Table 3
Meta-regression between changes in blood pressure values and administered doses
of flaxseed preparations.

Slope 95% CI p-Value

SBP
Seed powder (g/day)
0.0001
0.0004, 0.0002 0.567
Oil (g ALA/day)
0.001
0.003, 0.0004 0.125
Lignan (g SDG/day) 0.013
0.030, 0.056 0.546

DBP
Seed powder (g/day)
0.00004
0.0002, 0.0002 0.703
Oil (g ALA/day)
0.0005
0.002, 0.001 0.375
Fig. 6. Meta-regression plots of the association between mean changes in systolic
Lignan extract (g SDG/day)
0.007
0.034, 0.020 0.618
(upper plot) and diastolic (lower plot) blood pressure values with duration of sup-
plementation with flaxseed. The size of each circle is inversely proportional to the SBP: systolic blood pressure; DBP: diastolic blood pressure; ALA: alpha linolenic
variance of change. acid; SDG: secoisolariciresionol diglucoside.

Please cite this article in press as: Ursoniu S, et al., Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of
controlled clinical trial, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.05.012
10 S. Ursoniu et al. / Clinical Nutrition xxx (2015) 1e11

Fig. 7. Funnel plots detailing publication bias in the studies selected for the analysis of flaxseed's effects on systolic (upper plot) and diastolic (lower plot) blood pressure. Trim and
fill method was used to impute for potentially missing studies. Open circles represent observed published studies; closed circles represent imputed unpublished studies.

Table 4
Assessment of publication bias in the impact of flaxseed consumption on blood pressure.

Begg's rank correlation test Egger's linear regression test Fail safe N test

Kendall's Taua z-Value p-Value Intercept 95% CI t df p-Value nb

SBP (mmHg) 0.16 0.98 0.327
0.29
1.14 to 0.56 0.72 17 0.481 201
DBP (mmHg) 0.03 0.15 0.880
0.81
1.40 to
0.21 2.87 16 0.011 166

SBP: systolic blood pressure; DBP: diastolic blood pressure.

a
With continuity correction.
b
Number of theoretically missing studies.

between dose and duration of supplementation with the anti-
hypertensive effects was observed, additional studies are required
to confirm this observation.
The present meta-analysis has limitations. We observed that
most of included studies had a small number of participants and
were heterogeneous concerning the characteristics of patients and
study design. Finally, it would be interesting to know exactly the
brown or golden varieties of flaxseed tested since the variety of
flaxseed might influence its favorable health effects. In any case the
number of studies was not enough to allow a robust dos-
eeresponse, and time-response analysis.
In conclusion, this meta-analysis of RCTs showed significant
reductions in both SBP and DBP following supplementation with
various flaxseed products. Further research involving well-
controlled trials over at least 12 weeks are needed to study the
ideal quantity of flaxseed in hypertensive patients before strong
conclusions could be achieved.
Conflict of interest
This meta-analysis was written independently; no company or
institution supported it financially. No authors have any conflict of
interest concerning the preparation of this analysis. No professional
writer was involved in the preparation of this meta-analysis.
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