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International Journal of Food Properties
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ljfp20
Flaxseed oil supplementation on severity of
depression and brain-derived neurotrophic factor:
a randomized, double blind placebo controlled
Fariborz Poorbaferani , Mohamamd Hoseein Rouhani , Zahra Heidari ,
Maryam Poorbaferani & Sayyed Morteza Safavi
To cite this article: Fariborz Poorbaferani , Mohamamd Hoseein Rouhani , Zahra Heidari ,
Maryam Poorbaferani & Sayyed Morteza Safavi (2020) Flaxseed oil supplementation on
severity of depression and brain-derived neurotrophic factor: a randomized, double blind
placebo controlled clinical trial, International Journal of Food Properties, 23:1, 1518-1526, DOI:
To link to this article: https://doi.org/10.1080/10942912.2020.1812639
Published with license by Taylor & Francis
Group, LLC.© 2020 Fariborz Poorbaferani,
Mohamamd Hoseein Rouhani, Zahra
Heidari, Maryam Poorbaferani and Sayyed
Published online: 15 Sep 2020.
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Flaxseed oil supplementation on severity of depression and
brain-derived neurotrophic factor: a randomized, double blind
placebo controlled clinical trial
, Mohamamd Hoseein Rouhani
, Zahra Heidari
, Maryam Poorbaferani
and Sayyed Morteza Safavi
Department of Clinical Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan
University of Medical Sciences, Isfahan, Iran;
Department of Community Nutrition, School of Nutrition and Food
Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran;
Research Centre, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran;
Care Health for Institute Research Hakim Poursina, Center Research Diseases Hepatobiliary and Gastrointestinal,
Committee Research’ Students Medical, Sciences Medical of University Isfahan, Isfahan, Iran
Emerging clinical studies suggest that axseed oil may be an eective
intervention for the management of depression. The current trial was con-
ducted to assess the eect of axseed oil supplementation on the Brain-
derived neurotrophic factor (BDNF), and the psychological status of women
with depression. Subjects of 60 depressed women aged 18–45 were ran-
domly divided into two groups. One group was asked to consume a 1000 mg
axseed oil capsule, twice a day for 10 weeks, while the other consumed
a placebo. Serum (BDNF), Beck Depression Inventory-II (BDI-II) questionnaire,
and anthropometric indices were measured before and after intervention.
This study showed that serum BDNF concentration in the supplementation
group increased signicantly after 10-week intervention, compared with
placebo (1.12 ± 0.6 pg/ml vs. 0.2 ± 0.56 pg/ml; p < .0001). Total BDI-II score
was signicantly lower after axseed oil supplementation, compared with
placebo (−16.62 ± 7.03, −8.45 ± 7.8; p < .0001). The present study showed
that axseed oil supplementation can confer a number of health benets in
depressed women, including increased serum BDNF concentrations, along
with improvements in depression status.
Received 19 May 2020
Revised 14 August 2020
Accepted 16 August 2020
Flaxseed oil; depression;
factor; randomized; clinical
Depression is deﬁned as a common mood disorder, which can aﬀect diﬀerent aspects of a person’s
health, including eating, feeling, performing daily activities, and sleeping.
Depression is classiﬁed as
a mental problem, called an aﬀective or mood disturbance.
It is estimated to aﬀect 350 million
people worldwide, and can inﬂict signiﬁcant economic pressure, not only on people with the disorder,
but also on families.
According to a World Health Organization (WHO) 2003 report, depression
was the third most prevalent cause of disease all over the world, and predicted that depression may be
the most prevalent cause of disease by 2030.
A recent study among the Iranian population reported
depression prevalence was 49% among women and 48% among men.
Depression has a variety of
symptoms, such as having a constantly sad mood; feeling guilty, anxious, or worthless; losing interest
or pleasure in hobbies and activities; reduced energy or increased fatigue; feeling restless; sleeplessness
or waking up in the early morning; changes in appetite and weight changes.
CONTACT Sayyed Morteza Safavi firstname.lastname@example.org Department of Clinical Nutrition, School of Nutrition and Food
Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
INTERNATIONAL JOURNAL OF FOOD PROPERTIES
2020, VOL. 23, NO. 1, 1518–1526
© 2020 Fariborz Poorbaferani, Mohamamd Hoseein Rouhani, Zahra Heidari, Maryam Poorbaferani and Sayyed Morteza Safavi. Published with license by
Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Various factors are involved in the occurrence of depression, such as genetic, psychological or
environmental agents. One of these environmental agents is nutritional factors.
According to studies,
some nutritional supplementations such as vitamin D, zinc, selenium, and folate have a beneﬁcial eﬀect
on depressed patients.
Another nutritional intervention that has attracted attention from
researchers is omega-3 fatty acid. N-3 polyunsaturated fatty acids (PUFAs) are a derivative of the alpha-
linolenic acid (ALA) found in ﬂaxseed, walnut, canola, and hemp. Among these, ﬂaxseed has the highest
amount of ALA.
ALA is converted to docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA), but the eﬃcacy of this conversion is lower than 1% in humans.
In 2009, Blondeau et al.
showed that injection of ALA induced neurogenesis in the hippocampus, increased brain-derived
neurotrophic factor (BDNF) expression in vivo and in vitro, and increased neuronal cell synaptogenesis
(Nsc) in mice.
Flaxseed oil has shown promising eﬀects in pediatric and children with bipolar
Omega-3 can aﬀect depressive symptoms through various mechanisms, such as by
reducing pro-inﬂammatory cytokines, maintaining the integrity and ﬂuidity of cell membrane (which
is important for the signaling and binding of neurotransmitters), and increasing BDNF levels.
Evidence has shown that omega-3 fatty acids have a profound eﬀect on the nervous system. These fatty
acids aﬀect the levels of neurotrophins, molecules, which promote neuronal growth and survival.
Among neurotrophins, BDNF level has been seen to increase in the brain with an enriched omega-3
There is a body of evidence showing that BDNF is involved in the pathology of depression. The
BDNF system enhances the function and viability of neuronal complexes, and appears to be essential for
maintaining the underlying molecular processes of cognitive function and BDNF.
Thus, BDNF may
act as an indicator of depression, and using substance that induces BDNF concentrations may play
a role as an anti-depressive adjuvant treatment.
Since there is an increasing trend of depressive disorder worldwide, ﬁnding a nutritional agent that
improves depression symptoms could oﬀer a very eﬀective solution. According to the researchers’
knowledge, few studies to date has assessed the eﬀect of ﬂaxseed oil supplementation as a major source
of ALA on depressive symptoms. Therefore, this study was designed to investigate the possible
beneﬁcial eﬀects of ﬂaxseed oil supplementation among depressed subjects.
Materials and methods
Ethical approval of the study protocol
This study was performed according to the guidelines established in the Declaration of Helsinki and
the CONOSRT guidelines for clinical trial reporting,
and was approved by the Ethics Committee of
Isfahan University of Medical Sciences (IR. MUI.REC.1398.134). It was also registered at the Iranian
Registry of Clinical Trials (ID: IRCT20130903014551N3). Informed consent was obtained from all
subjects after a full explanation of the trial objectives.
Sixty depressed women were enrolled in this double-blind, randomized, controlled clinical trial from
Heshmatieh Hospital in Isfahan, Iran, between February 2019 and April 2019. Since the prevalence of
depression is higher among women and in order to increase the internal validity of present study, on
women were recruited. The suggested formula for a parallel design randomized controlled trial was
used to compute the sample size, based on α = 0.05, β = 0.15, and a standardized eﬀect size of Δ = 0.8 in
In order to adequately assess the principal outcome, the ﬁnal ﬁgure was established at 30
subjects per group.
Inclusion criteria were as follows: women between 18 and 45 years old; diagnosis of depression
according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV); and received
treatment with antidepressant medications. Subjects were excluded if they had: a history of cardio-
vascular, renal, hepatic disorders; hypertension, diabetes, or cancer; any type of cysts in the breast/
INTERNATIONAL JOURNAL OF FOOD PROPERTIES 1519
ovary of the patient and/or her family; used multivitamins and/or omega-3 supplementation during
the last year; current smoking or addiction; were pregnant or lactating; used alcohol, herbal drugs or
any other supplements/drug (except antidepressant medications) that could interfere with the study
objective after the beginning of trial. They were also later excluded if they demonstrated low
compliance (consumed <80% of prescribed supplements).
Participants were matched for age and randomly divided into the two groups of ﬂaxseed oil and
control using the permuted block randomization method and a random number table. Randomization
was performed by a researcher who had no clinical involvement in the trial. Subjects in the treatment
group received two capsules of ﬂaxseed oil, while control group subjects received two placebo capsules
(paraﬃn), which both groups were required to take twice daily for 10 weeks. Flaxseed supplements, in
the form of a 1000 mg capsule, contained only ﬂaxseed oil. The appearance of the placebo was
indistinguishable in color, shape, size, packaging, and taste from the ﬂaxseed capsule. Flaxseed capsule
supplements and placebos were produced by Barijessence Pharmaceutical Company, Kashan, Iran. All
participants were advised to maintain their usual diet and physical activity during the intervention
period. The subjects were reminded by phone to ensure compliance, and empty bottles of ﬂaxseed
were returned after completion. A checklist was also used to record any possible adverse reactions.
Anthropometric measurements of height and body weight were made at baseline and end of study.
Height was measured by a wall-mounted stadiometer to the nearest 0.5 cm; weight was measured in
light clothing and barefoot to the nearest 0.1 kg. Body mass index (BMI) was calculated by using the
following formula: BMI = weight (kg)/height (m)
. All measurements were taken by the same person
to decrease the error rate.
Energy intake and physical activity
The energy intake of subjects was recorded using food records three times: at baseline, and in weeks 5
and 10. Food record analysis was performed using Nutritionist 4 software, modiﬁed for Iranian foods.
Participants were asked to maintain their level of physical activity during the study. To check this,
participants recorded their physical activity three times: at baseline, and in weeks 5 and 10.
A questionnaire was used with Iranian validity and reliability determined by Klishadi and colleagues.
Records of physical activity were then converted to the metabolic equivalents-hour per day (MET-h/d).
Assessment of depression status
Depression status was assessed in all study participants using a translated version of the Beck’s
Depression Inventory-II (BDI-II), which has been shown to be valid and reliable in the Persian
adult general population.
Brieﬂy, it is a 21-item self-administered questionnaire, where the respon-
dent scores each item based on the severity of emotional experiences over the last week, ranging from 0
to 3. A score of 0 indicates that the item presented “no symptoms at all,” while 3 that indicates the item
was “very severe”. The maximum total score is 63 for a patient, and higher scores indicate greater
severity of depression. The score ranges (1–18), (18–28), (29–35), and (36–63) indicate no depressive
disorder, mild, moderate and severe depression, respectively.
1520 F. POORBAFERANI ET AL.
At baseline, and after 10 weeks of supplementation, 5 ml venous blood samples were collected between
8 am and 9 am after 10–12 hours of fasting. Blood samples were centrifuged at 3000 g for 10 minutes,
and the serum was isolated and frozen at −80°C until analysis. Serum level of BDNF was assessed using
the enzyme-linked immunosorbent assay (ELISA) method (Crystal day Biotech, China).
Normal distributions of variables were assessed using a skewness test and Q–Q plot. All variables were
expressed as mean ± SD or number (percent), as appropriate. The baseline characteristics of participants
were analyzed between groups, using independent sample t-test. Within-group analysis was carried out
using paired t-tests, repeated measure ANOVA, or Friedman test. Analysis of covariance (ANCOVA)
was used to detect any diﬀerences between the two groups at the end of the study, adjusting for baseline
value, energy intake, physical activity and BMI. The distribution of depression categories was compared
between the two groups using Pearson’s Chi-square test. P-values less than 0.05 were considered
statistically signiﬁcant. Statistical analyses were performed using IBM SPSS software version 21.
The ﬂowchart of participants through the trial is shown in Figure 1. After assessment of 327 depressed
adult women against the inclusion and exclusion criteria, 245 participants were excluded due to not
meeting the inclusion criteria (231 participants) and refusal to participate.
Finally, 60 participants
who met the inclusion criteria were randomly assigned into the ﬂaxseed or placebo groups. All 60
subjects successfully completed the trial and were included in the ﬁnal analysis. The compliance rate
was high in both groups, based on the number of capsules returned by participants (<5%). No adverse
reaction to ﬂaxseed supplementation or placebo was reported by any subject. Table 1 presents the
characteristics of participants in both the ﬂaxseed and placebo groups. There is no signiﬁcant
diﬀerence between the two groups in terms of age and anthropometric indices at baseline.
According to this table, weight and BMI were not signiﬁcantly diﬀerent after 10-week intervention
between the two groups and within each of these groups.
Energy intake and physical activity
As shown in Table 2, energy intake and physical activity were not signiﬁcantly diﬀerent during the
study in the intervention and control group. Also according to Table 2, physical activity and energy
intake were not signiﬁcantly diﬀerent between the two groups at the three assessment times (p = .51,
p = .48, respectively)
Findings in the two groups before and after treatment
After 10 weeks of intervention, a signiﬁcant increase in BDNF concentration was found in the ﬂaxseed
group (0.63 ± 0.54 vs 1.75 ± 0.68, p < .001), and this increase was signiﬁcant compared to the placebo
group (1.12 ± 0.6 vs 0.2 ± 0.56; p < .0001). Also, analysis showed a signiﬁcant reduction in total BDI
score in the ﬂaxseed group (32.96 ± 9.1 vs 16.34 ± 7.42, p < .001) and a signiﬁcant reduction compared
to the control group (−16.62 ± 7.03 vs −8.45 ± 7.84), as outlined in Table 3. Values remained
signiﬁcant after adjusting for baseline and BMI (p < .001). Also, the decrease in the total number of
subjects across various depression categories was signiﬁcant in the ﬂaxseed group, compared to
control group (p = .009) (Table 4).
INTERNATIONAL JOURNAL OF FOOD PROPERTIES 1521
This study assessed the eﬀect of ﬂaxseed oil supplementation on serum concentration of BDNF and
total BDI score among depressive women. It revealed that ﬂaxseed oil supplementation led to
improved mood status in women with depression disorder, and could increase BDNF concentration,
which is known to play an important role in mood and cognitive function.
According to studies, pathologic conditions in depression disorder (such as inﬂammation, low
zinc concentration and lipid peroxidation) can lead to decrease in n-3 PUFA levels.
peroxidation occurs following an inﬂammatory response, possibly making it responsible for reduced
n-3 PUFA levels in depressed populations.
Additionally, reductions in zinc, which acts as an anti-
oxidative factor and a cofactor for the production of alpha-linolenic acid (C18:3 n-3) are also
associated with reduced n-3 PUFA concentrations.
A meta-analysis of 14 studies revealed that
depressive patients had a lower level of EPA, DHA and n-3 PUFA.
The anti-depressive eﬀect of
Figure 1. Flow diagram of the study.
1522 F. POORBAFERANI ET AL.
n-3 PUFA consumption may be due to the anti-inﬂammatory eﬀect of these nutrients. It can also
play a role in regulating dopaminergic and serotonergic neurotransmitters, and it is eﬀective on the
ﬂuidity of CNS (central nervous system) cell membranes.
Another recent meta-analysis showed
a beneﬁcial eﬀect of EPA supplementation or formula with the higher amount of EPA than DHA on
Table 1. General characteristics of the study participants.
Variable Flaxseed oil (N = 30) Placebo (N = 30) P-value
Age (years) 36.37 ± 5.87 37.70 ± 4.92 0.345
63.20 ± 11.29
63.29 ± 11.08
68.70 ± 12.71
68.46 ± 12.44
Height (m) 1.6 ± 0.06 1.6 ± 0.08 0.859
24.69 ± 4.20
24.75 ± 4.17
26.84 ± 5.59
26.74 ± 5.44
BMI; body mass index.
p-values from independent t test
p-values from pair sample t-test
Table 2. Energy intake and physical activity.
Flaxseed oil (N = 30) Placebo (N = 30)
Time 1 Time 2 Time 3 P-value Time 1 Time 2 Time 3 P-value
0.155 0.389 0.485
Physical activity 1155.17
1156.45 (98.10) 0.521 0.742 0.516
Data reported based on Mean (SD)
P-values obtained from repeated measure ANOVA
Table 3. Eﬀect of ﬂaxseed oil supplementation on BDNF concentrations and total BDI-II score.
Flaxseed oil (N = 30) Placebo (N = 30)
Baseline End Change P-value
Baseline End Change P-value
0.63 ± 0.54 1.75 ± 0.68 1.12 ± 0.60 < 0.001 0.68 ± 0.74 0.89 ± 0.78 0.20 ± 0.56 0.055 <0.001
32.96 ± 9.1 16.34 ± 7.42 −16.62 ± 7.03 <0.001 31.29 ± 11.42 22.83 ± 9.6 −8.45 ± 7.84 <0.001 <0.001
P-value <0.05 was signiﬁcant
Data reported based on Mean ± Sd
P-value obtained from paired t-test
P-value obtained from ANCOVA, adjusted for baseline, BMI, energy intake and physical activity
Abbreviations: BDI-II, Beck Depression Inventory; BDNF, brain-derived neurotrophic factor
Table 4. Number of subjects in each category of depressive disorder before and after intervention.
Flaxseed oil p-value*
Placebo p-value* p-value**
Normal 1(3.4%) 18(62.1%) <0.0001 3(9.7%) 11(35.5%) <0.0001 0.009
Mild depression 10(34.5%) 10(34.5%) 9(29%) 13(41.9%)
Moderate depression 6(20.7%) 1(3.4%) 9(29%) 3(9.7%)
Severe depression 12(41.4%) 0(0%) 10(32.3%) 4(12.9%)
Median [Q1-Q3] 3 [2–4] 1 [1–2] 3 [2–4] 2 [1–2]
Values are number (percent); *p-value based on Friedman Test; **p-value based on Linear-by-Linear Association after intervention
INTERNATIONAL JOURNAL OF FOOD PROPERTIES 1523
the clinical symptoms of depressive disorder.
A cross-sectional study regarding n-3 PUFA intake
demonstrated that subjects with higher level of n-3 PUFA consumption had lower odds of depres-
sive disorder. However, the protective eﬀect of n-3 PUFA intake on the incidence of depressive
symptoms could not be proven, since it may be due to folate intake, which also plays a key role in
Alpha-linolenic acid (ALA) is an omega-3 essential polyunsaturated fatty
acid from a plant-derived source, and should be provided from dietary intake. The eﬀects of alpha
linoleic acid consumption on some disorders, such as cardiovascular disease and diabetes have been
A cross-sectional study conducted among depressive subjects showed an
inverse association between serum ALA levels and depressive symptoms.
However, one other
study among healthy women revealed that RBC α-Linolenic acid concentration was inversely
associated with negative mood.
A cross-sectional study among a Japanese population found
protective properties against depression in high alpha-linolenic and linoleic acids concentrations in
Thus, n-3 PUFA may be eﬀective for neuronal protection in depressive disorder. A study
conducted on normal mice showed that a PUFA-enriched diet with a high amount of alpha-
linolenic acid (ALA), linoleic acid, and oleic acid had an anti-depressive eﬀect due to the increased
expression of BDNF, increased cell numbers, and synaptogenesis in the hippocampus.
showed the gene expression or activity of the brain-derived neurotrophic factors (BDNF) to be
abundant in the brain, but decreased in depressive disorder, thus suggesting anti-depressive treat-
ment could try to increase BDNF levels.
The eﬀect of alpha-linoleic acid on increasing BDNF
levels has been shown in a recent study. Thus, it may be eﬀective to treat depression through these
pathways, as the results of the present study are also consistent with these earlier ﬁndings.
beneﬁcial eﬀect of ALA on depressive symptoms has previously been shown in a study on mice. The
result of this study revealed that ALA treatment on mice led to decreased depressive behavior, in
comparison with vehicle-treated mice, as well as being eﬀective in compensating for or repairing
Many factors contribute to induce depressive disorder (such as a deﬁciency of
neurotransmitters like serotonin and norepinephrine), but a growing body of evidence has shown
that neural plasticity disruption, stimulated by negative factors such as stress, can occur in
The cause of depression due to the lack of normal content of PUFA in the brain
may be due to: reduced neurotransmitters such as dopamine and serotonin; reduced expression of
Brain Derived Neurotrophic Factor (BDNF); increased inﬂammatory pathways; and changes in the
structure of the cell membranes.
The present study had some limitations. First, this study was conducted on a female population, so
the current ﬁndings are not generalizable to male depressed subjects. Second, plasma BDNF levels are
inﬂuenced by menstrual cycle and hormonal status of women.
This important notion was ignored in
our study and could be another limitation, which could be kept in mind when interpreting the ﬁndings.
In summary, the results of the present study indicate that consumption of ﬂaxseed oil for 10 weeks can
increase serum BDNF concentrations and improve depressive status in depressed women. The
ﬁndings of this study may oﬀer a new perspective for a potential intervention by dietary factors in
depression, and as such, are eagerly awaited by the patient. Further double blind randomized clinical
trials with larger sample sizes and longer follow-up periods are suggested to conﬁrm the eﬀects of
ﬂaxseed oil intake on depression.
The present study is a part of MSc thesis supported by a grant from the Vice-Chancellor for Research, Isfahan University
of Medical Sciences (No.298008). The authors would like to thank all patients who kindly contributed to the study. The
authors declare no potential conﬂict of interest.
1524 F. POORBAFERANI ET AL.
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