International Journal of Food Properties

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ljfp20

Flaxseed oil supplementation on severity of

depression and brain-derived neurotrophic factor:
a randomized, double blind placebo controlled
clinical trial

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:
10.1080/10942912.2020.1812639

To link to this article: https://doi.org/10.1080/10942912.2020.1812639

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Morteza Safavi

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INTERNATIONAL JOURNAL OF FOOD PROPERTIES
2020, VOL. 23, NO. 1, 1518–1526
https://doi.org/10.1080/10942912.2020.1812639

ORIGINAL ARTICLE

Flaxseed oil supplementation on severity of depression and

brain-derived neurotrophic factor: a randomized, double blind
placebo controlled clinical trial
Fariborz Poorbaferania, Mohamamd Hoseein Rouhania, Zahra Heidarib,c, Maryam Poorbaferanid,e,
and Sayyed Morteza Safavia
a
Department of Clinical Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan
University of Medical Sciences, Isfahan, Iran; bDepartment of Community Nutrition, School of Nutrition and Food
Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; cCardiac Rehabilitation
Research Centre, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; dDevelopment
Care Health for Institute Research Hakim Poursina, Center Research Diseases Hepatobiliary and Gastrointestinal,
Isfahan, Iran; eCommittee Research’ Students Medical, Sciences Medical of University Isfahan, Isfahan, Iran

ABSTRACT ARTICLE HISTORY

Emerging clinical studies suggest that flaxseed oil may be an effective Received 19 May 2020
intervention for the management of depression. The current trial was con­ Revised 14 August 2020
ducted to assess the effect of flaxseed oil supplementation on the Brain- Accepted 16 August 2020
derived neurotrophic factor (BDNF), and the psychological status of women KEYWORDS
with depression. Subjects of 60 depressed women aged 18–45 were ran­ Flaxseed oil; depression;
domly divided into two groups. One group was asked to consume a 1000 mg brain-derived neurotrophic
flaxseed oil capsule, twice a day for 10 weeks, while the other consumed factor; randomized; clinical
a placebo. Serum (BDNF), Beck Depression Inventory-II (BDI-II) questionnaire, trial
and anthropometric indices were measured before and after intervention.
This study showed that serum BDNF concentration in the supplementation
group increased significantly 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 significantly lower after flaxseed oil supplementation, compared with
placebo (−16.62 ± 7.03, −8.45 ± 7.8; p < .0001). The present study showed
that flaxseed oil supplementation can confer a number of health benefits in
depressed women, including increased serum BDNF concentrations, along
with improvements in depression status.

Introduction
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.[1] Depression is classified as
a mental problem, called an affective or mood disturbance.[2] 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.[3] 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.[4] A recent study among the Iranian population reported
depression prevalence was 49% among women and 48% among men.[5] 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.[6]

CONTACT Sayyed Morteza Safavi safavimorteza@yahoo.com Department of Clinical Nutrition, School of Nutrition and Food
Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
© 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.
 INTERNATIONAL JOURNAL OF FOOD PROPERTIES 1519

Various factors are involved in the occurrence of depression, such as genetic, psychological or
environmental agents. One of these environmental agents is nutritional factors.[7] According to studies,
some nutritional supplementations such as vitamin D, zinc, selenium, and folate have a beneficial effect
on depressed patients.[3,8-12] 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.[13] ALA is converted to docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA), but the efficacy of this conversion is lower than 1% in humans.[14] 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.[15] Flaxseed oil has shown promising effects in pediatric and children with bipolar
disorders.[16] 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.[13,17,18]
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
diet.[19] 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.[20] 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.[21]
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, [22] 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.

Subjects
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
BDNF.[23] 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/
1520 F. POORBAFERANI ET AL.

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).

Study design
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
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)2. 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.[24] 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.
 INTERNATIONAL JOURNAL OF FOOD PROPERTIES 1521

Biochemical assessment
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).

Statistical methods
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.

Results
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.[20] 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).
1522 F. POORBAFERANI ET AL.

Figure 1. Flow diagram of the study.

Discussion
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.[25] Lipid
peroxidation occurs following an inflammatory response, possibly making it responsible for reduced
n-3 PUFA levels in depressed populations.[26] 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.[27] A meta-analysis of 14 studies revealed that
depressive patients had a lower level of EPA, DHA and n-3 PUFA.[28] The anti-depressive effect of
 INTERNATIONAL JOURNAL OF FOOD PROPERTIES 1523

Table 1. General characteristics of the study participants.

Variable Flaxseed oil (N = 30) Placebo (N = 30) P-value a
Age (years) 36.37 ± 5.87 37.70 ± 4.92 0.345
Weight (kg) 63.20 ± 11.29 68.70 ± 12.71 0.082
Baseline 63.29 ± 11.08 68.46 ± 12.44 0.095
10 weeks 0.51 0.26
P-value b
Height (m) 1.6 ± 0.06 1.6 ± 0.08 0.859
BMI (kg/m2) 24.69 ± 4.20 26.84 ± 5.59 0.100
Baseline 24.75 ± 4.17 26.74 ± 5.44
10 weeks 0.41 0.17
P-value b
BMI; body mass index.
a
p-values from independent t test
b
p-values from pair sample t-test

Table 2. Energy intake and physical activity.

Flaxseed oil (N = 30) Placebo (N = 30)
P-value P-value
Variable Time 1 Time 2 Time 3 P-value Time 1 Time 2 Time 3 P-value group time*group
Energy 1863.7931 1862.0690 1792.9310 0.334 1975.8065 1902.0968 1896.9355 0.155 0.389 0.485
intake (292.43) (256.92) (419.82) (404.94) (524.25) (495.22)
Physical activity 1155.17 1145.17 1148.28 0.618 1145.65 1172.58 (107.11)
(113.66) (105.04) (89.13) (216.07)
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)
Variable Baseline End Change P-valuea Baseline End Change P-valuea P-valueb
BDNF 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
(pg/
ml)
Total 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
BDI-II
score
P-value <0.05 was significant
Data reported based on Mean ± Sd
a
P-value obtained from paired t-test
b
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.
Before After Before After
Flaxseed oil Flaxseed oil p-value* Placebo 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

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.[29] Another recent meta-analysis showed
a beneficial effect of EPA supplementation or formula with the higher amount of EPA than DHA on
1524 F. POORBAFERANI ET AL.

the clinical symptoms of depressive disorder.[30] 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
depressive disorder.[31] 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
assessed previously.[32,33] A cross-sectional study conducted among depressive subjects showed an
inverse association between serum ALA levels and depressive symptoms.[25] However, one other
study among healthy women revealed that RBC α-Linolenic acid concentration was inversely
associated with negative mood.[34] A cross-sectional study among a Japanese population found
protective properties against depression in high alpha-linolenic and linoleic acids concentrations in
serum.[35] 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.[36] Studies
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.[37] 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.[38] The
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
neural plasticity.[15] 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
depression.[39,40] 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.[41,42]
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.[43] This important notion was ignored in
our study and could be another limitation, which could be kept in mind when interpreting the findings.

Conclusion
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.

Acknowledgments
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.
 INTERNATIONAL JOURNAL OF FOOD PROPERTIES 1525

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