N U TRI TI O N RE SE A R CH 69 ( 20 1 9 ) 1–8

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Review Article

Short-term curcumin supplementation enhances

serum brain-derived neurotrophic factor in adult men
and women: a systematic review and dose–response
meta-analysis of randomized controlled trials

Payam Sarraf a , Mohammad Parohan b, c,⁎, Mohammad Hassan Javanbakht b ,

Sakineh Ranji-Burachaloo a , Mahmoud Djalali b,⁎
a
Iranian Centre of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
b
Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran
c
Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

ARTI CLE I NFO A BS TRACT

Article history: The reduction of brain-derived neurotrophic factor (BDNF) affects cognitive function, learning,
Received 26 January 2019 and memory and also causes behavioral disorders. Several randomized controlled trials have
Revised 25 April 2019 examined the neuroprotective effects of curcumin and its ability to increase BDNF levels, with
Accepted 3 May 2019 inconclusive results. The aim of this systematic review was to evaluate the impact of
curcumin supplementation on serum BDNF levels. A systematic review of the literature was
Keywords: conducted using PubMed, Scopus, ISI Web of Science, Cochrane library, and Google scholar to
Brain-derived neurotrophic factor identify eligible studies up to January 2019. The studies included were randomized control
Curcumin trials of curcumin supplementation that reported the serum BDNF level as a primary outcome.
Turmeric A dose-response meta-analysis of eligible studies was performed using the random-effects
Meta-analysis model to estimate pooled effect size. Four randomized control trials with 139 participants were
Systematic review included. Curcumin supplementation dose and duration ranged from 200 to 1820 mg/d and 8
to 12 weeks, respectively. Curcumin supplementation significantly increased serum BDNF
levels (weighted mean difference: 1789.38 pg/mL, 95% confidence interval: 722.04-2856.71,
P < .01) with significant heterogeneity among the studies (I2 = 83.5%, P < .001). Subgroup
analysis showed that sex, mean age of participants, curcumin dosage, and trial duration were
potential sources of heterogeneity. The significant positive impact of curcumin supplemen-
tation on BDNF levels indicates its potential use for neurological disorders that are associated
with low BDNF levels.
© 2019 Elsevier Inc. All rights reserved.

Abbreviations: BDNF, brain-derived neurotrophic factor; CI, confidence interval; ERKs, extracellular signal–regulated kinases; SD,
standard deviation; WMD, weighted mean difference.
⁎ Corresponding authors at: Tehran University of Medical Sciences, School of Nutritional Sciences and Dietetics, 44 Hojat Dost St, Naderi
St, Enghelab Ave, Tehran, Iran.
E-mail addresses: p-sarraf@sina.tums.ac.ir (P. Sarraf), prohan-m@razi.tums.ac.ir (M. Parohan), mhjavan@sina.tums.ac.ir
(M.H. Javanbakht), sranji@sina.tums.ac.ir (S. Ranji-Burachaloo), jalalikh@sina.tums.ac.ir (M. Djalali).

https://doi.org/10.1016/j.nutres.2019.05.001
0271-5317/© 2019 Elsevier Inc. All rights reserved.
2 N U TRI TI O N RE SE A R CH 69 ( 20 1 9 ) 1–8

Article Outline

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Protocol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.2. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.3. Eligibility criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.4. Data extraction and assessment for study quality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.5. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1. Search results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2. Study characteristic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.3. Meta-analysis results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.4. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.1. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction supplementation on serum BDNF levels with conflicting

Curcumin is a polyphenolic compound and the principal
curcuminoid of the spice turmeric (Curcuma longa), which is a
member of the ginger family (Zingiberaceae) [1,2]. Protective
effects of curcumin in the physiological and pathological
conditions have been evaluated in the preclinical and
clinical studies. Curcumin has been reported to have anti-
inflammatory, antioxidant, anticarcinogenic, antiarthritic,
thrombosuppressive, antimicrobial, hypoglycemic, neuro-
protective, antidepressant, and procognitive properties [1-5].
Although the mechanism of the action of curcumin on
neurocognition and its neuroprotective effect is not fully
understood, it is observed that curcumin acts by modulating
the release of certain neurotransmitters, such as brain-
derived neurotrophic factor (BDNF) [2,6,7].
BDNF is a widespread neurotropin in the nervous system
that facilitates neurogenesis, synaptogenesis, neuroprotec-
tion, neuroregeneration, synaptic plasticity, neuronal sur-
vival, and growth, in addition to formation, retention, and
recall of memory in the frontal cortex and hippocampus [8].
Alterations in BDNF levels are known to correlate with some
neuropsychiatric disorders. Low levels of serum BDNF are
associated with major depressive disorder, bipolar disorder,
schizophrenia, and anxiety-related disorders [9,10]. These
findings suggest that the neuropsychiatric disorders de-
crease BDNF levels by increasing inflammation and oxidative
stress or, possibly, by an independent mechanism of redox
state [11-13]. Therefore, decreasing inflammation, restora-
tion of the redox state, as well as low BDNF levels may be an
alternative to prevent the development of neurodegenerative
diseases [14-16].
To reduce inflammation and oxidative stress caused by
neuropsychiatric disorders, supplementation with dietary
antioxidants has been proposed, which may also restore low
BDNF levels. The potential of curcumin as a preventive/
therapeutic agent is of great interest and has resulted in
several clinical trials that investigated the effect of curcumin
results [7,17-20]. The objective of this meta-analysis was to
examine the association between curcumin supplementa-
tion and serum BDNF levels from previously published
randomized control trials.
2. Approach
2.1. Protocol
The Preferred Reporting Items of Systematic Reviews and Meta-
Analysis statement guideline was used to design, conduct, and
report this systematic review and meta-analysis [21]. The study
was approved by the ethics committee of Tehran University of
Medical Sciences, Tehran, Iran.
2.2. Search strategy
In the present study, we aimed to include interventional studies
with parallel or crossover design that examined the effects of
curcumin supplementation on serum BDNF levels. Two inde-
pendent reviewers (MP and PS) conducted a systematic search
in the online medical databases including PubMed, Scopus, ISI
Web of Science, Cochrane library, and Google scholar to identify
eligible studies published in English and Persian through
January 2019. The following medical subject heading and non–
medical subject heading keywords were used: (Curcumin OR
Curcuma OR Curcuminoid* OR Turmeric) AND (“brain-derived
neurotrophic factor” OR BDNF).
Initially, the titles and abstracts were screened by 2
independent researchers (MP and MHJ) for relevance. Then,
full texts were screened for eligibility criteria. The references
of eligible trials were also checked to avoid missing any
publications. The search strategy was completed by the
principle author (MD). In the search strategy, unpublished
studies were excluded. All search results, including titles and
abstracts, were downloaded into EndNote (version X9, for
 N U TRI TI O N RE SE A R CH 69 ( 20 1 9 ) 1–8 3

Windows; Thomson Reuters, Philadelphia, PA, USA) to merge

retrieved citations, remove duplications, and simplify the
review process.
2.3. Eligibility criteria
All randomized control trials that evaluated the effect of
curcumin supplementation on serum BDNF levels were
included in this meta-analysis. Studies were included if they
met all of the following inclusion criteria: (1) full-text article
published in English or Persian, (2) the study design was a
randomized control trial (either crossover or parallel design), (3)
the study compared oral curcumin supplementation versus
placebo, and (4) sufficient information was reported about
serum BDNF levels at baseline and the conclusion of the
intervention in curcumin and the placebo group. Studies were
excluded if they had the following exclusion criteria: (1) animal
model, (2) study did not have a placebo group or it was a
nonrandomized control trials study, (3) other interventions
along with curcumin were investigated, and (4) the study
did not report serum BDNF levels at baseline and at the end
of the intervention. Letters, short communications, reviews,
conference abstracts, and comments were also excluded.
2.4. Data extraction and assessment for study quality
The relevant data were extracted including the first author's
family name, year of publication, study location, study design,
age, sex, sample size of each group, dose of curcumin, duration of
intervention, and the means and standard deviations (SDs) of
serum BDNF levels of both groups at baseline and at the end of
the study.
Two independent reviewers (MP and SRB) assessed the
quality of the 4 included randomized control trials using the
Cochrane Handbook for Systematic Reviews of Interventions [22].
According to the Cochrane Handbook recommendations, studies
were stratified as high, low, or an unclear risk of bias in the
following domains: sequence generation sufficiency, allocation
concealment, blinding of outcome assessors, elucidating of
dropouts, selective outcome reporting, and other sources of bias.
2.5. Statistical analyses
Mean change and SD for serum BDNF levels were used to
3. Results
3.1. Search results
The search strategy resulted in 254 articles. Of these, 45
duplicates, 121 nonhumans, 5 non-English or non-Persian, 45
reviews, and 31 studies that did not fulfill our inclusion
criteria were eliminated, which left 7 articles for further
evaluation. Out of the 7 remaining articles, we excluded 3
other studies because of the following reasons: (1) trial did not
have a control group or placebo (n = 1), or (2) study examined
the effect of curcumin supplementation in combination with
other supplements (n = 2). After exclusions, 4 articles were
considered for meta-analysis. The selection of articles for this
review is illustrated in Fig. 1.
3.2. Study characteristic
All randomized control trials had parallel design [17-20].
Three of the included trials described the appropriate method
of randomization and double blinding [17,19,20]. The sample
size of trials ranged from 20 to 70 individuals with a mean age
of 41 years. Two of the included studies reported adequate
details of withdrawals, ranging from 7 to 9 [17,20]. Articles
were published between 2016 and 2018. Three of the studies
were conducted in Iran [18-20] and 1 in the United States [17].
Two studies included only women [18,20], 1 study included
both men and women [17], and 1 study only included men
[19]. The duration of trials varied from 8 to 12 weeks. The daily
oral curcumin supplementation dose varied from 200 to
Titles and abstracts identified and
screened
(n = 254)
Duplicate: 45
Did not meet our inclusion criteria
N = 121non-Human
N = 5 non-English or non-Persian
N = 45 Reviews
N = 31non-Exposure or Outcome of
interest
Full-text articles assessed for
eligibility
(n = 7)

estimate the overall effect size of the intervention. If an SD

change was not reported in each of individual study ;, it was
calculated using the following formula: SDchange = square root
2 2 Full-text articles excluded (n = 3)
[(SDbaseline + SDfinal) − (2 × 0.8 × SDbaseline × SDfinal)] [23]. A random- 1. Trials without control group or
effects model was used to determine the pooled weighted mean placebo (n = 1)
2. Studies that examined the effect of
difference (WMD) if heterogeneity was more than 50%. The curcumin supplementation in
heterogeneity between studies was assessed by using the combination with other supplements
(n = 2)
Cochrane Q test and the I2 index [24]. Subgroup analysis was
performed to identify the sources of heterogeneity among
randomized control trials. Influence analysis was performed to
investigate the effect of each study on the pooled effect size.
Studies included in quantitative
Publication bias was assessed by the Egger weighted regression synthesis (meta-analysis) (n = 4)
tests [25]. The nonlinear potential effects of curcumin dosage
(mg/d) were examined using fractional polynomial regression
(polynomials). All statistical analyses were performed using the Fig. 1 – Flowchart of selected articles used in the review of
Stata 14 software package (STATA Corp, College Station, TX, USA). curcumin actions on BDNF.
 4

Table 1 – Demographic and clinical characteristics of included studies

Author Subjects and Age Study Intervention type Duration Outcomes Outcome Outcome Any other Adjustment Median
(year) sex range design of assessment intervention or matching quality
(y) Intervention Control treatment Intervention Control (from) score
(name and (name and (wk) (mean ± SD) (mean ± SD)
dose) composition)

Osali et Female: 20 50-65 Parallel Curcumin Placebo of the 8 Plasma ELISA Changes in BDNF Changes in BDNF No No 3
al lost to follow-up: (1480 mg/d) same shape and BDNF method level (pg/mL): level (pg/mL):
(2018) not reported size levels 1060 ± 445 10 ± 429
Curcumin: 10
Placebo: 10
Wynn et Both: 45 18-65 Parallel Curcumin Matched 8 Serum ELISA Changes in BDNF Changes in BDNF No No 4
al lost to follow-up: 9 (360 mg/d) placebo BDNF method level (pg/mL): level (pg/mL):
(2018) Curcumin: 17 (sugar pill) levels 3399 ± 9991 −4038 ± 9965
Placebo: 19
Avansar Male: 20 40-55 Parallel Curcumin Placebo of the 8 Plasma ELISA Changes in BDNF Changes in BDNF No No 3
et al lost to follow-up: (1820 mg/d) same shape BDNF method level (pg/mL): level (pg/mL):
(2017) not reported and size levels 1187 ± 4649 −1125 ± 4808
Curcumin: 10
Placebo: 10
N U TRI TI O N RE SE A R CH 69 ( 20 1 9 ) 1–8

Fanaei et Female: 70 18-50 Parallel Curcumin Matched 12 Serum ELISA Changes in BDNF Changes in BDNF No No 4
al lost to follow-up: 7 (200 mg/d) placebo (brown BDNF method level (pg/mL): level (pg/mL):
(2016) Curcumin: 32 sugar) levels 2624 ± 795 470 ± 849
Placebo: 31

ELISA, enzyme-linked immunosorbent assay.

 N U TRI TI O N RE SE A R CH 69 ( 20 1 9 ) 1–8 5

1820 mg. The characteristics of eligible studies are presented

in Table 1.

3.3. Meta-analysis results

Four studies, which included a total of 139 participants

(curcumin = 69, and placebo = 70), reported serum BDNF levels
as an outcome measure. Pooling results from the random-effects
model showed that curcumin supplementation significantly
increased serum BDNF levels (WMD: 1789.38 pg/mL, 95% confi-
dence interval [CI]: 722.04-2856.71, P < .01) with significant
heterogeneity between studies (I2 = 83.5%, P < .001) (Fig. 2). We
stratified studies based on study location (Iran, United States),
sex (male, female, both male and female), participants’ mean
age (≤40, >40 years), curcumin dosage (≤500, >500 mg/d), and
trial duration (≤8, >8 weeks). Subgroup analysis showed that Fig. 3 – Nonlinear dose-response association between
curcumin supplementation significantly increased serum BDNF curcumin intake and the unstandardized mean difference in
levels in women (WMD: 1599.82 pg/mL; 95% CI: 517.93-2681.71, serum BDNF levels. The 95% CI is depicted in the shaded
P < .01), participants older than 40 years (WMD: 1060.71 pg/mL; regions.
95% CI: 678.83-1442.58, P < .001), those with higher doses of
curcumin (≥500 mg/d) (WMD: 1060.71 pg/mL; 95% CI: 678.83-
1442.58, P < .001), and longer trial durations (>8 weeks)
(WMD: 2154.00 pg/mL; 95% CI: 1747.09-2560.91, P < .001). of curcumin supplementation on serum BDNF levels (P for
There were no significant effects in men, subjects younger Egger test = .617).
than 40 years, studies with lower doses of curcumin
(≤500 mg/d), and 8 weeks of duration. Furthermore, curcumin
supplementation did not show a significant nonlinear dose- 4. Discussion
response relationship with serum BDNF levels (P-nonlinearity =
.09) (Fig. 3). The present dose-response meta-analysis of randomized
controlled trials summarized the effects of curcumin sup-
3.4. Publication bias plementation on serum BDNF levels. Our main results
showed that curcumin supplementation significantly in-
Assessment of publication bias by Egger linear regression test creased the serum BDNF levels in comparison with the
indicated no evidence of publication bias in the meta-analysis control group.

Study Study N, mean N, mean %

ID Country design WMD (95% CI) (SD); Treatment (SD); Control Weight

Osali et al. 2018 Iran Parallel 1050.00 (666.50, 1433.50) 10, 1060 (445) 10, 10 (430) 45.99

Wynn et al. 2018 USA Parallel 7437.00 (907.19, 13966.81) 17, 3399 (9992) 19, -4038 (9966) 2.53

Avansar et al. 2017 Iran Parallel 2312.00 (-1833.91, 6457.91) 10, 1187 (4650) 10, -1125 (4809) 5.84

Fanaei et al. 2016 Iran Parallel 2154.00 (1747.09, 2560.91) 32, 2624 (796) 31, 470 (850) 45.64

Overall (I-squared = 83.5%, p = 0.000) 1789.38 (722.04, 2856.71) 69 70 100.00

NOTE: Weights are from random effects analysis

-13967 0 13967

Fig. 2 – Forest plot of randomized control trials investigating the effects of curcumin supplementation on serum BDNF levels.
6 N U TRI TI O N RE SE A R CH 69 ( 20 1 9 ) 1–8
Our findings are partially in line with previous narrative
and systematic reviews conducted on curcumin and neuropsy-
chiatric disorders, such as cognitive decline [26-31], but the
relationship between curcumin supplementation and serum
BDNF levels were not investigated in a dose-dependent manner.
To the best of our knowledge, this is the first dose-response
meta-analysis of published trials to evaluate the effectiveness of
curcumin supplementation on serum BDNF levels.
BDNF is widely expressed in limbic brain regions (espe-
cially hippocampus, amygdala, and hypothalamus) where it
has roles in mood and behavior regulation [9]. However, it
was shown that low BDNF levels were negatively associated
with the hippocampal volumes and poorer memory, even
when controlling for age variation [32]. Moreover, BDNF
regulates dendrites number and is essential in promoting
neuronal survival, differentiation, and persistence of long-
term memory storage [8,33-35]. Thus, decreased BDNF
expression caused by inflammation and oxidative stress
could be detrimental to neuronal functions leading to the
development of neurodegenerative and psychiatric dis-
eases, such as Alzheimer disease, depression, and bipolar
disorder [9-13].
The beneficial effects of curcumin against the develop-
ment of cancer, arthritis, diabetes, stroke, depression, and
schizophrenia can be attributed to its anti-inflammatory,
antioxidant, and hypoglycemic properties [1,2,36-40]. In
vitro and in vivo studies confirmed that curcumin is capable
of modulating levels of dopamine, serotonin, norepineph-
rine, and BDNF that are involved in mood and behavior
regulation [1,2].
The neuroprotective effect of curcumin is exerted via
various mechanisms in the central nervous system, which
are responsible for its antioxidant and anti-inflammatory
properties and its ability to increase BDNF (Fig. 4) [1,2,36,41,42].
Previous studies have shown that rats subjected to a chronic
stress protocol had decreased hippocampal BDNF levels and
a reduced ratio of phosphorylated cAMP response element-
binding protein to CREB levels in the frontal cortex and
hippocampus; however, curcumin administration (5 or 10 mg/kg)
reversed these changes at levels similar to imipramine
treatment [43-45]. Moreover, curcumin increased cAMP
levels and activated cellular signal transduction pathways
through extracellular signal–regulated kinases (ERKs) and
p38 kinases, which are known to be involved in BDNF
production, regulation of neuronal plasticity, and stress
responses [46]. Therefore, it is possible that curcumin increased
BDNF levels by increasing cAMP levels and activating ERKs and
p38 kinases, or by reducing oxidative damage [7]. These findings
suggest that curcumin may have a reliable biomarker in its
effects on BDNF.
In addition, curcumin exerts antidepressant effects that
are comparable with the effects of well-known antidepres-
sants drugs, such as fluoxetine and imipramine [1,47]. This
effect has been attributed to the increase in serotonin levels
caused by curcumin [36]. Serotonin plays important roles
in the regulation of sleep, memory, learning, mood, and
behavior [48].
In this study, we only included randomized control trials
(either crossover or parallel design), which are generally
considered as the gold standard for evaluation. The present
Fig. 4 – BDNF gene expression and its signaling pathways
activated by curcumin. The BDNF receptor TrkB has a tyrosine
kinase domain in its cytoplasmic region. Binding of ligand
results in receptor dimerization and trans-autophosphorylation
of the receptor that then recruits adaptor proteins and activates
several downstream protein kinases as shown in the figure. A
prominent transcription factor activated by BDNF is CREB, which
induces the expression of genes encoding proteins involved in
cellular energy metabolism (eg, PGC-1a, which induces mito-
chondrial biogenesis), synaptic plasticity (eg, Arc), and stress
resistance (eg, the DNA repair enzyme APE1). Activation of TrkB
can also activate the PI3K (p85-p110) Akt kinase signaling
resulting in the inhibition of FOXO and GSK3b, thereby
protecting neurons against degeneration. Activation of the Ras/
ERK pathways can enhance cellular stress resistance and
increase insulin sensitivity [42]. Abbreviations: Akt, Akt kinase;
APE1, apurinic/apyrimidinic endonuclease 1; Arc, activity-
regulated cytoskeleton-associated protein; ;cAMP, cyclic aden-
osine monophosphate; CaMK, calcium/calmodulin-dependent
kinase; ;FOXO, forkhead box protein O; GSK3b, glycogen
synthase kinase 3 beta; PKA, protein kinase A; pCREB,
phosphorylated cyclic AMP response element binding protein;
PI3K, phosphatidylinositol 3-kinases; PGC-1a, PPARg coactiva-
tor 1a; TrkB, tropomyosin receptor kinase B.
meta-analysis has several limitations. First, the number of
trials was low to show the potential effect of curcumin on
serum BDNF levels. Second, there is a lack of data on dietary
intake of curcumin. Large variations of curcumin content
(turmeric and curry spices) in food products of different
geographical origins have been found. Third, there were
heterogeneity in study participants and a small sample
size. Fourth, 1 study used nanocurcumin to deliver highly
bioavailable curcumin [17], whereas 3 other studies did not
provide any explanation for the curcumin formulation and
bioavailability [18-20].
4.1. Conclusions
There is some evidence to support the use of pharmacological
treatments in the management of neurodegenerative and
psychiatric diseases; however, a few safe complementary
effective prophylactic approaches have been suggested.
Curcumin is a potential complementary agent and has some
 N U TRI TI O N RE SE A R CH 69 ( 20 1 9 ) 1–8
evidence of efficacy. There is a significant positive impact of
curcumin supplementation on BDNF levels, indicating its
potential use for neurological disorders that have been corre-
lated with low BDNF levels. Further randomized control trials
with higher sample sizes and different doses of curcumin are
needed for more comprehensive and precise conclusions.
Acknowledgment
We thank all of the staff in our department for providing
clinical and methodological advice during the entire perfor-
mance of our meta-analysis. This work was supported by the
Tehran University of Medical Sciences and Health Services,
Tehran, Iran (grant 96-02-161-34944). The authors have no
conflict of interest to declare.
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