Efficacy of Crocus sativus (saffron) in treatment of major depressive disorder associated with post-menopausal hot flashes: a double-blind, randomized, placebo-controlled trial

Abstract

PurposeDue to concerns regarding the side effects of hormone therapy, many studies have focused on the development of non-hormonal agents for treatment of hot flashes. The aim of this study was to evaluate the efficacy and safety of saffron (stigma of Crocus sativus) in treatment of major depressive disorder associated with post-menopausal hot flashes. Methods
Sixty women with post-menopausal hot flashes participated in this study. The patients randomly received either saffron (30 mg/day, 15 mg twice per day) or placebo for 6 weeks. The patients were assessed using the Hot Flash-Related Daily Interference Scale (HFRDIS), Hamilton Depression Rating Scale (HDRS) and the adverse event checklist at baseline and also at the second, fourth, and sixth weeks of the study. ResultsFifty-six patients completed the trial. Baseline characteristics of the participants did not differ significantly between the two groups. General linear model repeated measures demonstrated significant effect for time × treatment interaction on the HFRDIS score [F (3, 162) = 10.41, p = 0.0001] and HDRS score [F (3, 162) = 5.48, p = 0.001]. Frequency of adverse events was not significantly different between the two groups. Conclusions
Results from this study revealed that saffron is a safe and effective treatment in improving hot flashes and depressive symptoms in post-menopausal healthy women. On the other hand, saffron, with fewer side effects, may provide a non-hormonal and alternative herbal medicine option in treatment of women with hot flashes.

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Archives of Gynecology and Obstetrics
https://doi.org/10.1007/s00404-018-4655-2
GENERAL GYNECOLOGY
Ecacy ofCrocus sativus (saron) intreatment ofmajor depressive
disorder associated withpost‑menopausal hot ashes: adouble‑blind,
randomized, placebo‑controlled trial
LadanKashani1· SophiaEsalatmanesh2· FarzanehEftekhari3· SamrandSalimi3· TaherehForoughifar3·
FarnazEtesam2· HamidehSaaghdam2· EhsanMoazen‑Zadeh2· ShahinAkhondzadeh2
Received: 26 May 2017 / Accepted: 9 January 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Purpose Due to concerns regarding the side effects of hormone therapy, many studies have focused on the development of
non-hormonal agents for treatment of hot flashes. The aim of this study was to evaluate the efficacy and safety of saffron
(stigma of Crocus sativus) in treatment of major depressive disorder associated with post-menopausal hot flashes.
Methods Sixty women with post-menopausal hot flashes participated in this study. The patients randomly received either
saffron (30mg/day, 15mg twice per day) or placebo for 6 weeks. The patients were assessed using the Hot Flash-Related
Daily Interference Scale (HFRDIS), Hamilton Depression Rating Scale (HDRS) and the adverse event checklist at baseline
and also at the second, fourth, and sixth weeks of the study.
Results Fifty-six patients completed the trial. Baseline characteristics of the participants did not differ significantly between
the two groups. General linear model repeated measures demonstrated significant effect for time×treatment interaction on
the HFRDIS score [F (3, 162)=10.41, p=0.0001] and HDRS score [F (3, 162)=5.48, p=0.001]. Frequency of adverse
events was not significantly different between the two groups.
Conclusions Results from this study revealed that saffron is a safe and effective treatment in improving hot flashes and
depressive symptoms in post-menopausal healthy women. On the other hand, saffron, with fewer side effects, may provide
a non-hormonal and alternative herbal medicine option in treatment of women with hot flashes.
Keywords Crocus sativus· Depression· Hot flashes· Saffron· Trial
Introduction
Hot flashes, as the most prominent vasomotor symptom of
menopause, are characterized by a feeling of intense warmth
throughout the upper body [1]. Hormone replacement
therapy (HRT), as a treatment for hot flashes, may be unsuit-
able for some women including those at increased risk of
cardiovascular disease, increased risk of thromboembolic
disease or increased risk of some types of cancer such as
breast cancer [2–4]. Due to this concern associated with
hormone therapy, there is need for non-hormonal agents to
alleviate hot flashes. Hence, there are different clinical trials
that demonstrate the efficacy of selective serotonin reup-
take inhibitors (SSRIs) and serotonin and norepinephrine
reuptake inhibitors (SNRIs) in the treatment of hot flashes
[5–8]. However, the most common side effects reported by
using these drugs include dry month, constipation, nausea,
and loss of appetite [8, 9]. On the other hand, herbal medi-
cines can improve hot flashes. Anise (Pimpinella anisum),
licorice (Glycyrrhiza glabra), soy, black cohosh, red clover,
evening Primrose, flaxseed, Salvia officinalis, St. John’s wort
(Hypericum perforatum), and valerian are a few examples
of such herbal medicines [10]. Saffron, the dried stigma of
Ladan Kashani, Sophia Esalatmanesh and Farzaneh Eftekhari
contributed equally in this study.
* Shahin Akhondzadeh
s.akhond@neda.net
1 Infertility Ward, Arash Hospital, Tehran University
ofMedical Sciences, Tehran, Iran
2 Psychiatric Research Center, Roozbeh Psychiatric Hospital,
Tehran University ofMedical Sciences, South Kargar Street,
Tehran13337, Iran
3 Baharloo Hospital, Tehran University ofMedical Sciences,
Tehran, Iran

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the plant Crocus sativus L., has been used as a medicinal
plant in traditional medicine [11]. Three major constituents,
including crocin, picrocrocin, and safranal, have been found
in saffron [12]. Different clinical trials show that saffron is
effective in treatment of depression [13–15]. To date, effects
of saffron in treatment of hot flashes have not been studied.
The aim of this study was to evaluate the efficacy and safety
of saffron in treatment of major depressive disorder associ-
ated with post-menopausal hot flashes.
Materials andmethods
Trial design
A 6-week, multicenter, randomized, double-blind, parallel-
group clinical trial was conducted in the outpatient clinics
of Arash and Baharloo Hospitals (all affiliated with Teh-
ran University of Medical Sciences, Tehran, Iran) between
March 2016 and March 2017.
The trial protocol was approved by the institutional
review board (IRB) of Tehran University of Medical Science
(Grant no.: 30324) and conducted consistent with the Dec-
laration of Helsinki and its subsequent revisions. The trial
was registered at the Iranian registry of clinical trials (http ://
www.irct .ir; registration number: IRCT201602031556N85)
prior to study commencement. Written informed consent
was obtained from all eligible participants and/or their
legally authorized representatives. Patients were informed
that they are free to withdraw from the trial at any time dur-
ing the course of the study.
Participants
Post-menopausal women, with a clinical diagnosis of hot
flashes were eligible to participate in the trial. Patients were
post-menopausal women, over 40years of age with no men-
strual period in the last 12months. Patients were required to
have at least moderate hot flashes at time of randomization,
having a score≥40 in Hot Flash-Related Daily Interference
Scale (HFRDIS) [16]. Patients were assessed to have major
depressive disorder based on the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR) criteria and mild-to-moderate depression
based on a score of≤22 in the 17-item Hamilton Depres-
sion Rating Scale (HDRS) [17].
Inclusion criteria were: hot flash attacks≥14 times per
week for at least 2months. If history for oophorectomy was
positive, more than 6weeks should have elapsed from sur-
gery and the level of serum FSH should be equal or more
than 40 U per ml.
Exclusion criteria included: ingestion of any psycho-
tropic and antidepressant medications, any Selective
Estrogen Receptor Modulator medications (e.g., tamoxifen
and raloxifen), any Aaromatase inhibitor medications (e.g.,
anastrozole, letrozole, and exemestane), leuprolide acetate,
clonidine, gabapentin, pregabalin, amino acid supplements,
over the counter (OTC) medications that reduced hot flashes
during the last 4weeks, ingestion of estrogen and proges-
terone based medications, history of suicidal thoughts, sub-
stance or alcohol dependence (with the exception of nicotine
dependence) during the last 3 months and Electroconvulsive
therapy (ECT) during the last 2months. Patients who were
suffering from any diagnoses other than depression on the
DSM-IV-TR axis I were also excluded.
Interventions
Patients underwent a standard clinical assessment comprised
of a psychiatric evaluation and a structured diagnostic inter-
view and medical history. Eligible participants were rand-
omized to receive either a saffron capsule (SaffroMood®,
Green Plant Life, containing 15mg of saffron extract) or
a placebo capsule (twice daily) for 6weeks. The saffron
used in this study was donated by Green Plants of Life Co.
Each capsule has 15mg dried extract of saffron as: the plant
stigma’s extract was prepared as follows: 120g of dried
and milled petal was extracted via 1800mL ethanol (80%)
by percolation procedure in three steps. Subsequently, the
ethanol extract was dried by evaporation in temperature
between 35 and 40°C. Each capsule had dried extract of the
C. sativus stigma (15mg), lactose (filler), magnesium stea-
rate (lubricant), and sodium starch glycolate (disintegrant).
Cronin value was expressed as direct reading of absorbance
at about 440nm. Each capsule had 1.65–1.75mg crocin.
Participants were not allowed to use any psychotropic drugs
or receive any behavioral intervention therapy during the
trial.
Outcome
The HFRDIS was used for assessment of patients at baseline
and at weeks 2, 4, and 6. The HFRDIS is a ten-item scale
measuring the degree to which hot flashes interfere with
nine daily activities and the tenth item measures the degree
to which hot flashes interfere with quality of life [16]. The
HDRS contains 17 questions (on a three-point or five-point
scale) which assesses severity of depressive symptoms and
it was also used at baseline and at weeks 2, 4, and 6. This
scale has been applied in many clinical trials in Iran [14,
17–19]. The primary outcome measure was difference in
HFRDIS and HDRS score change from baseline to the end
of the trial between the two groups using the general lin-
ear repeated measure model. Secondary outcome measures
were comparing changes in HFRDIS and HDRS scores from
baseline to each time point between the two groups, partial

Archives of Gynecology and Obstetrics
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response rates (25–50% reduction in the HDRS score) and
complete response rates (≥50% reduction in HRDS score)
and remission rates (HRDS score≤7).
In terms of adverse events, a 25-item checklist was pro-
vided to systematically record the adverse events during the
course of the trial [20, 21]. All participants were asked about
any adverse event which was not mentioned in the check-
list. Participants were also asked to immediately inform the
research team about any unexpected symptom during the
study period. A thorough physical examination was per-
formed at the screening session and at weeks 2, 4, and 6.
Sample size estimation
Assuming a mean difference of 2 on the HDRS score
between the saffron and placebo groups, with a standard
deviation of 3.5 on the HDRS score, a power of 85% and a
two-tailed significance level of 0.05, 50 patients (each group
25) were needed. Considering a 20% attrition rate, a final
sample size of 60 was achieved.
Randomization, allocation concealment,
andblinding
Generation of randomization codes was conducted via per-
muted randomization blocks (blocks of four, allocation ratio
1:1) by an independent party who was not involved else-
where in the trial. Concealment of allocation was performed
using sequentially numbered, sealed opaque envelopes. An
aluminum foil inside the envelopes kept them impermeable
to intense light. Study participant, investigator, and rater
were all blinded to treatment allocation. Saffron and placebo
capsules were indistinguishable in their shape, size, texture,
color and odor.
Statistical analyses
The Statistical Package of Social Science Software (SPSS
version 22; IBM Company, USA) was used for statistical
analysis and SigmaPlot 12.2.0 (SYSTAT Software, Incor-
porated) for drawings. Continuous variables were reported
as mean±standard deviation (SD) and categorical variables
were reported as frequency (percentage). The independent
t test was used to compare baseline continuous variables.
Mean difference between the saffron and the placebo group
was reported as mean difference [MD, 95% confidence
interval (CI)]. A general linear model repeated measure
was used to evaluate time×treatment interaction consider-
ing the treatment group (saffron vs. placebo) as the between
subject factor and the study measurement as the within sub-
ject factor (time). Whenever Mauchly’s test of sphericity
was significant, Greenhouse–Geisser adjustment was used
for degrees of freedom. To compare the score change from
baseline between the two groups, the independent t test
and Cohen’s d effect size were used. Categorical variables
were compared using the Chi square or Fisher’s exact test
where appropriate. All analyses were performed two-sided,
and a p value of less than 0.05 was considered statistically
significant.
Results
Patients
Among 74 patients who were screened for the eligibility
criteria, 60 patients entered the trial and were randomized
to receive either saffron (n=30) or placebo (n=30). Four
patients discontinued the trial (2 patients in each group at
week 1) and a total number of 56 patients (28 patients in
each group) completed the trial (Fig.1). Baseline character-
istics of the participants did not differ significantly between
the two groups (Table1).
Outcomes
The HFRDIS score
Baseline HFRDIS scores were not significantly differ-
ent between the saffron and the placebo groups [MD (95%
CI)=3.21 (− 7.41 to 13.84), t(54)=0.60, p=0.54] (Table1).
General linear model repeated measures demonstrated signifi-
cant effect for time×treatment interaction on the HFRDIS
score [F (3, 162)=10.41, p=0.000] (Fig.2). An independent
t test demonstrated significantly greater reduction in HFRDIS
Fig. 1 Flow diagram of the study

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score in the saffron group than the placebo group at weeks 2,
4, and 6 (Table2).
The HDRS score
Baseline HDRS scores were not significantly different between
the saffron and the placebo groups [MD (95% CI)=− 0.67
(− 3.49 to 2.13), t(48.49)=− 0.48, p=0.63] (Table1). Gen-
eral linear model repeated measures demonstrated significant
effect for time×treatment interaction on the HDRS score [F
(3, 162)=5.48, p=0.001] (Fig.3). An independent t test
demonstrated significantly greater reduction in HDRS score
in the saffron group than the placebo group at weeks 2, 4, and
6 (Table2). There was significant difference between the two
groups in terms of complete response rate at weeks 4 and 6,
and remission rate at weeks 2, 4, and 6 (Table3).
Side eects
Frequency of adverse events was not significantly different
between the two groups (Table4). No serious adverse event
or death occurred.
Table 1 Baseline characteristics of the patients
HFRDIS Hot Flash-Related Daily Interference Scale, HDRS Hamilton Depression Rating Scale
Variable Saffron group (n=28) Placebo group (n=28) p value
Age, years, mean±SD 55.71±6.57 55.43±5.46 0.86
Duration of the disease (months), mean±SD 32.92±25.74 29.64±20.89 0.60
Presence of seasonal pattern 8 (28.6%) 10 (35.7%) 0.56
History of psychiatry disorder 9 (32.1%) 8 (28.5%) Non significant
Education
Illiterate 5 (17.9%) 13 (46.4%) Non significant
Primary 10 (35.7%) 3 (10.7%)
Secondary 8 (28.6%) 7 (25.0%)
High school and diploma 5 (17.9%) 5 (17.9%)
Higher 0 (0%) 0 (0%)
Job
House maker 25 (89.3%) 22 (78.6%) Non significant
Clerk 3 (10.7%) 6 (21.4%)
Marital status
Married 27 (96.4%) 28 (100.0%) Non significant
Single 0 (0%) 0 (0%)
Separated 0 (0%) 0 (0%)
Widow 1 (3.6%) 0 (0%)
Baseline HFRDIS score, mean±SD 69.29±20.53 66.07±19.11 0.54
Baseline HDRS score, mean±SD 15.29±6.05 15.96±4.26 0.63
Fig. 2 Comparison of mean ± SD of the Hot Flash-Related Daily
Interference Scale (HFRDIS) scores at baseline and post-intervention
with saffron or placebo over time. **p≤0.01

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Discussion
To the best of our knowledge, this study was the first double-
blind clinical trial to evaluate the efficacy and safety of saf-
fron in the treatment of women with post-menopausal hot
flashes. The findings in this study indicate that saffron pro-
vides a non-hormonal option that is both effective and safe
in alleviating hot flashes after 6weeks of treatment (15mg,
two capsules per day).
The pathophysiology of hot flashes still remains unclear.
Hot flashes have been suggested to be the result of central
thermoregulatory center dysfunction caused by changes
in estrogen levels during the menopausal period [22]. The
decrease in estrogen levels alone is not adequate to describe
the pathophysiology of hot flashes. Central sympathetic
activation through central α2-adrenergic receptors is also
elevated in symptomatic women that decrease the thermo-
neutral zone. Hot flashes are triggered by elevations in core
body temperature acting within this narrowed thermoneutral
zone [23].
Clonidine decreases central sympathetic activation, wid-
ens the thermoneutral zone, and improves hot flashes [24].
Hormonal replacement therapy (HRT), especially estro-
gen therapy, is the most effective therapy for alleviating
Table 2 Comparison of changes in Hot Flash-Related Daily Interference Scale (HFRDIS) and Hamilton Depression Rating Scale (HDRS) scores
from baseline between the two groups
HFRDIS Hot Flash-Related Daily Interference Scale, HDRS Hamilton Depression Rating Scale
Saffron group (n=28) Placebo group (n=28) Mean difference saffron–
placebo (95% CI)
Cohen’s d p value
HFRDIS (week 2) 25.35±9.61 18.21±9.44 7.14 (2.03–12.25) 0.74 0.007
HFRDIS (week 4) 46.78±17.43 28.21±18.86 18.57 (8.83–28.30) 1.02 0.001
HFRDIS (week 6) 51.78±19.25 32.14±20.43 19.64 (9.00–30.28) 0.98 0.001
HDRS (week 2) 3.39±1.72 2.42±1.70 0.96 (0.04–1.88) 0.56 0.04
HDRS (week 4) 5.17±2.68 3.64±2.07 1.53 (0.25–2.82) 0.63 0.02
HDRS (week 6) 7.10±4.38 4.39±2.64 2.71 (0.76–4.66) 0.74 0.007
Fig. 3 Comparison of mean ± SD of Hamilton Depression Rating
Scale (HDRS) for Depression scores at baseline and post-intervention
with saffron or placebo. *p≤0.05 and **p≤0.01
Table 3 Comparison of outcome indexes in depression between the two groups
Outcome Saffron group Placebo group p value Power Odd’s ratio (95% CI)
Number (%) of partial responders at week 2 11 (39.3%) 4 (14.3%) 0.03 0.43 3.88 (1.05–14.27)
Number (%) of partial responders at week 4 14 (50.0%) 11(39.3%) 0.42 0.07 1.54 (0.53–4.46)
Number (%) of partial responders at week 6 11 (39.3%) 9 (32.1%) 0.57 0.04 1.36 (0.45–4.09)
Number (%) of complete responders at week 2 2 (7.1%) 1 (3.6%) 1.00 0.02 2.07 (0.17–24.31)
Number (%) of complete responders at week 4 7 (25.0%) 1 (3.6%) 0.05 0.47 9.00 (1.02–78.94)
Number (%) of complete responders at week 6 13 (46.4%) 5 (17.9%) 0.02 0.51 3.98 (1.17–13.49)
Number (%) of remitters at week 2 8 (28.6%) 1 (3.6%) 0.02 0.59 10.80 (1.24–93.44)
Number (%) of remitters at week 4 8 (28.6%) 1 (3.6%) 0.02 0.59 10.80 (1.24–93.44)
Number (%) of remitters at week 6 15 (53.6%) 4 (14.3%) 0.002 0.82 6.92 (1.90–25.22)

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menopausal vasomotor symptoms, including hot flashes
[25]. The risks of hormonal therapy were assessed in dif-
ferent studies. Holmberg etal. reported that after extended
follow-up, the risk of new breast cancer was significantly
increased in survivors who took hormone replacement ther-
apy. They reported that the cumulative incidence at 5years
was 22.2% in the hormone replacement therapy group vs.
8.0% in the control group [3]. A daily dose of 0.1mg of
clonidine is effective in treatment of hot flashes in post-
menopausal women with breast cancer [26]. Manson etal.
provides a comprehensive report of findings from the inter-
vention and extended post-intervention phases of the con-
jugated equine estrogens (CEE) plus medroxyprogesterone
acetate (MPA) and CEE alone trials of the Women’s health
initiative (WHI).
They reported that women assigned to CEE plus MPA had
a hazard ratio (HR) of 1.24 (95% CI 1.01–1.53) for breast
cancer compared to the placebo group and the HRs progres-
sively increased by time since randomization (p=0.005 for
time trend). In contrast, woman assigned to CEE alone had
a HR of 0.79 (95% CI 0.61–1.02) in comparison with the
placebo group [2].
During the cumulative 13-year follow-up, the HRs for
coronary heart disease (CHD) were 1.09 (95% CI 0.96–1.24)
for CEE plus MPA and 0.94 (95% CI 0.82–1.09) for CEE
alone in comparison with the placebo group [2].
Another randomized trial showed that the rate of breast
cancer and other cancer was not increased, although they
suggested a longer follow-up to make definite conclusions
[27].
The efficacy of SSRIs and SNRIs has been proven in
randomized clinical trials. A prospective randomized clini-
cal trial showed that paroxetine in doses of 10 and 20mg
reduced frequency and composite score of hot flashes in
comparison to the placebo group [6]. Davari-Taha etal.
reported that venlafaxine and citalopram significantly
decreased the severity of hot flashes in comparison with
the placebo group (p= 0.02) and the frequency of hot
flashes were reduced more by citalopram than venlafaxine
(p=0.03) [8].
The mechanism of SSRI action in the treatment of hot
flashes is not known. Bioinformatics analyses indicated that
the minor allele of rs1042173 seems to disrupt a binding site
for a microRNA. This disruption leads to higher expression
of SLC6A4 (a gene encoding the serotonin and/or norepi-
nephrine transporters). Higher expression of SLC6A4 leads
to depletion of serotonin in synaptic clefts, and this triggers
the presynaptic auto receptor feedback mechanism to pro-
duce more serotonin, which is protective against hot flashes
[28]. It seems decline in brain 5-hydroxytryptamine (5-HT)
should worsen hot flashes [29].
In the present study, we focused on the possible seroton-
ergic effects of saffron. The findings of the present study are
consistent with our previous clinical trials supporting the
antidepressant effect of saffron [17–19, 30]. These effects are
due to serotonergic, antioxidant, anti-inflammatory, neuro-
endocrine and neuroprotective effects [31]. According to the
rat model studies, antidepressant effects of saffron may be
as a result of increase in the levels of brain-derived neu-
rotrophic factor (BDNF), VGF Neuropeptide, Cyclic-AMP
Response Element Binding Protein (CREB) and phospho-
CREB (p-CREB) in rat hippocampus [32, 33]. Wang etal.
showed that oral administration of C. sativus significantly
decreased the immobility time in comparison with the con-
trol group in the tail suspension test (TST) in mice [34].
The findings of another clinical trial showed that anti-
depressant effects of saffron extract are attributed to crocin
[13].
Limitations of the present study include the small number
of participants and the short period of follow-up. Further
research in this area with a longer study period, an active
agent such as venlafaxine and a higher sample size to con-
sider patients with different biological and racial back-
grounds is needed.
Conclusions
The results of this study emphasize the efficacy and safety of
saffron in the treatment of post-menopausal hot flashes and
depression. In addition, our study shows that saffron does
not have any serious adverse effects in therapeutic doses
and provides evidence that saffron is as safe and as effective
as any alternative treatment in management of hot flashes.
Acknowledgements This Study was part of thesis of Dr. Farzaneh Eft-
ekhari for MD., degree at Tehran University of Medical Sciences under
supervision of Prof. Shahin Akhondzadeh.
Author contributions LK and SA, principal investigator and data Man-
agement from March 2016 to March 2017, SE, FE, HS and EMZ, data
collection and manuscript writing from March 2016 to March 2017;
SS, TF and FE, data collection and data management from March 2016
to March 2017
Table 4 Frequency of adverse events in the two groups
Adverse event Saffron group
(n=28)
Placebo
group
(n=28)
p value
Headache, n, % 2 (7.1) 1 (3.6) 1.00
Dry mouth, n, % 3 (10.7) 2 (7.1) 1.00
Nausea, n, % 3 (10.7) 1 (3.6) 0.61
Daytime drowsiness, n, % 2 (7.1) 2 (7.1) 1.00
Constipation, n, % 3 (10.7) 2 (7.1) 1.00
Sweating, n, % 2 (7.1) 1 (3.6) 1.00

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Funding This study was supported by a Grant (Grant no.:
30324) from Tehran University of Medical Sciences.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval All procedures performed in the current study were
approved by the institutional review board of Tehran University of
Medical Sciences (Approval number: 30324) and were in accordance
with the 1964 Helsinki declaration and its later amendments in Brazil,
2013.
Informed consent Informed consent was obtained from all individual
participants included in the study.
References
1. Pinkerton JV, Stovall DW, Kightlinger RS (2009) Advances in the
treatment of menopausal symptoms. Women’s Health 5:361–384
2. Manson JE, Chlebowski RT, Stefanick ML etal (2013) Menopau-
sal hormone therapy and health outcomes during the intervention
and extended poststopping phases of the women’s health initiative
randomized trials. JAMA 310:1353–1368
3. Holmberg L, Iversen O-E, Rudenstam CM etal (2008) Increased
risk of recurrence after hormone replacement therapy in breast
cancer survivors. JNCI 100:475–482
4. Marjoribanks J, Farquhar C, Roberts H etal (2017) Long-term
hormone therapy for perimenopausal and postmenopausal women.
Cochrane Database Syst Rev 1:CD004143. http s://doi.org/10.1002
/1465 1858 .CD00 4143 .pub5
5. Freeman EW, Guthrie KA, Caan B etal (2011) Efficacy of esci-
talopram for hot flashes in healthy menopausal women: a rand-
omized controlled trial. JAMA 305:267–274
6. Stearns V, Slack R, Greep N etal (2005) Paroxetine is an effective
treatment for hot flashes: results from a prospective randomized
clinical trial. J Clin Oncol 23:6919–6930
7. Loprinzi CL, Kugler JW, Sloan JA etal (2000) Venlafaxine in
management of hot flashes in survivors of breast cancer: a ran-
domised controlled trial. Lancet 356:2059–2063
8. Davari-Tanha F, Soleymani-Farsani M, Asadi M etal (2016)
Comparison of citalopram and venlafaxine’s role in treating sleep
disturbances in menopausal women, a randomized, double-blind,
placebo-controlled trial. Arch Gynecol Obstet 293:1007–1013
9. Loprinzi CL, Stearns V, Barton D (2005) Centrally active nonhor-
monal hot flash therapies. Am J Med 118:118–123
10. Ghazanfarpour M, Sadeghi R, Abdolahian S etal (2016) The
efficacy of Iranian herbal medicines in alleviating hot flashes: a
systematic review. Int J Reprod BioMed 14:155
11. Ríos JL, Recio MC, Giner RM etal (1996) An update review of
saffron and its active constituents. Phytother Res 10:189–193
12. Khazdair MR, Boskabady MH, Hosseini M etal (2015) The
effects of Crocus sativus (saffron) and its constituents on nervous
system: a review. Avicenna J Phytomed 5:376
13. Talaei A, Moghadam MH, Tabassi SAS etal (2015) Crocin,
the main active saffron constituent, as an adjunctive treatment
in major depressive disorder: a randomized, double-blind, pla-
cebo-controlled, pilot clinical trial. J Affect Disord 174:51–56
14. Shahmansouri N, Farokhnia M, Abbasi SH etal (2014) A rand-
omized, double-blind, clinical trial comparing the efficacy and
safety of Crocus sativus L. with fluoxetine for improving mild to
moderate depression in post percutaneous coronary intervention
patients. J Affect Disord 155:216–222
15. Ghajar A, Neishabouri S, Velayati N etal (2017) Crocus sativus
L. versus Citalopram in the treatment of major depressive dis-
order with anxious distress: a double-blind, controlled clinical
trial. Pharmacopsychiatry 50(4):152–160
16. Carpenter JS (2001) The Hot Flash Related Daily Interfer-
ence Scale: a tool for assessing the impact of hot flashes on
quality of life following breast cancer. J Pain Symptom Manag
22:979–989
17. Kashani L, Eslatmanesh S, Saedi N etal (2017) Comparison of
saffron versus fluoxetine in treatment of mild to moderate postpar-
tum depression: a double-blind, randomized clinical trial. Phar-
macopsychiatry 50:64–68
18. Akhondzadeh S, Fallah-Pour H, Afkham K etal (2004) Com-
parison of Crocus sativus L. and imipramine in the treatment of
mild to moderate depression: a pilot double-blind randomized trial
[ISRCTN45683816]. BMC Complement Altern Med 4:12
19. Akhondzadeh Basti A, Moshiri E, Noorbala AA etal (2007) Com-
parison of petal of Crocus sativus L. and fluoxetine in the treat-
ment of depressed outpatients: a pilot double-blind randomized
trial. Prog Neuropsychopharmacol Biol Psychiatry 31:439–442
20. Noorbala AA, Akhondzadeh S, Davari-Ashtiani R etal (1999)
Piracetam in the treatment of schizophrenia: implications for
the glutamate hypothesis of schizophrenia. J Clin Pharm Ther
24(5):369–374
21. Modabbernia A, Sohrabi H, Nasehi AA etal (2012) Effect of
saffron on fluoxetine-induced sexual impairment in men: rand-
omized double-blind placebo-controlled trial. Psychopharmacol-
ogy 223(4):381–388
22. Shanafelt TD, Barton DL, Adjei AA etal (2002) Pathophysiol-
ogy and treatment of hot flashes. In: Mayo Clinic Proceedings.
Elsevier
23. Freedman RR (2005) Hot flashes: behavioral treatments, mecha-
nisms, and relation to sleep. Am J Med 118:124–130
24. Freedman RR (2001) Physiology of hot flashes. Am J Hum Biol
13:453–464
25. Lee W-L, Tsui K-H, Wang P-H (2016) Alternative treatment for
hot flashes. J Chin Med Assoc 79:468–469
26. Pandya KJ, Raubertas RF, Flynn PJ etal (2000) Oral clonidine in
postmenopausal patients with breast cancer experiencing tamox-
ifen-induced hot flashes: a University of Rochester Cancer Center
Community Clinical Oncology Program study. Ann Intern Med
132:788–793
27. Schierbeck LL, Rejnmark L, Tofteng CL etal (2012) Effect of
hormone replacement therapy on cardiovascular events in recently
postmenopausal women: randomised trial. BMJ 345:e6409
28. Montasser ME, Ziv-Gal A, Brown JP etal (2015) A potentially
functional variant in the serotonin transporter gene is associated
with premenopausal and perimenopausal hot flashes. Menopause
22:108–113
29. Freedman RR (2014) Menopausal hot flashes: mechanisms, endo-
crinology, treatment. J Steroid Biochem Mol Biol 142:115–120
30. Agha-Hosseini M, Kashani L, Aleyaseen A etal (2008) Crocus
sativus L. (saffron) in the treatment of premenstrual syndrome:
a double-blind, randomised and placebo-controlled trial. BJOG
115:515–519
31. Lopresti AL, Drummond PD (2014) Saffron (Crocus sativus) for
depression: a systematic review of clinical studies and exami-
nation of underlying antidepressant mechanisms of action. Hum
Psychopharmacol 29:517–527
32. Ghasemi T, Abnous K, Vahdati F etal (2015) Antidepressant
effect of Crocus sativus aqueous extract and its effect on CREB,

Archives of Gynecology and Obstetrics
1 3
BDNF, and VGF transcript and protein levels in Rat hippocampus.
Drug Res 65:337–343
33. Vahdati Hassani F, Naseri V, Razavi BM etal (2014) Antidepres-
sant effects of crocin and its effects on transcript and protein levels
of CREB, BDNF, and VGF in rat hippocampus. DARU 22:16
34. Wang Y, Han T, Zhu Y etal (2009) Antidepressant properties of
bioactive fractions from the extract of Crocus sativus L. J Nat Med
64:24