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Research report
Crocin, the main active saffron constituent, as an adjunctive
treatment in major depressive disorder: A randomized, double-blind,
placebo-controlled, pilot clinical trial
Ali Talaei a, Maryam Hassanpour Moghadam b, Sayyed Abolghasem Sajadi Tabassi c,
Seyed Ahmad Mohajeri b,n
a Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
b Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
c Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
a r t i c l e i n f o
Article history:
Received 17 August 2014
Received in revised form
11 October 2014
Accepted 18 November 2014
Available online 26 November 2014
Keywords:
Saffron (Crocus sativus L.)
Crocin
Herbal medicine
Major depressive disorder
a b s t r a c t
Objective: Herbal remedies play an important role in treatment of psychiatric disorders. The aim of this
study was to assess the efficacy of crocin, the main active constituent of saffron, as an adjunctive
treatment in major depressive disorder (MDD).
Method: This study was a randomized, double-blind, placebo-controlled, pilot clinical trial. It was carried
out during 4 weeks in two groups (placebo and treatment) on 40 MDD patients between 24 and 50 years
old in Ibn-e-Sina psychiatric hospital, Mashhad, Iran, from March 2013 to December 2013. The crocin
group (n¼20) was given one selective serotonin reuptake inhibitor (SSRI) drug (fluoxetine 20 mg/day or
sertraline 50 mg/day or citalopram 20 mg/day) plus crocin tablets (30 mg/day; 15 mg BID) and placebo
group (n¼20) was administered one SSRI (fluoxetine 20 mg/day or sertraline 50 mg/day or citalopram
20 mg/day) plus placebo (two placebo tablets per day) for 4 weeks. Both groups filled beck depression
inventory (BDI), beck anxiety inventory (BAI), general health questionnaire (GHQ), the mood disorder
questionnaire (MDQ), side effect evaluation questionnaire, and demographic questionnaire before and
after one month intervention.
Results: The crocin group showed significantly improved scores on BDI, BAI and GHQ compared to
placebo group (Pvalueo0.0001). The averages of decrease in BDI, BAI and GHQ scores in placebo group
were 6.15, 2.6 and 10.3 respectively, whereas the values in crocin group were 17.6, 12.7 and 17.2 after
4 weeks trial.
Limitations: Poor patient compliance with medications and short trial period, small sample size and selfreport assessments were the major limitations of this study.
Conclusion: These results demonstrated the effect of crocin in depression and could be administered in
treatment of MDD patients.
& 2014 Elsevier B.V. All rights reserved.

Introduction
Depression is one of the top five most prevalent diseases
worldwide (Bauer et al., 2013). It is a common, chronic, and
potentially debilitating illness that has tempered the human
condition (Blanco et al., 2014). Depression typically presents as
depressed mood, insomnia or sleeping too much, agitation, fatigue
or loss of energy and lowered libido (Guo et al., 2010; Kircanski
et al., 2012; Loprinzi et al., 2013). Recent studies indicated that the
incidence of depression during lifetime has been increased (Heun
et al., 2013). Previous investigations concluded that the annual
incidence of mood disorders is approximately 10% in the adult
population and also 6.7% of adults suffer from an episode of major
depression in a period of 12 months (Judd, 1995; Kessler et al.,
2005). Although there are several possible precipitating factors, it
is currently believed that depression is primarily the result of
biochemical variations in the brain (Hermann et al., 1999). Pharmacological treatments, including selective serotonin reuptake
inhibitors (SSRI), tricyclic antidepressants (TCA), and monoamine
oxidase inhibitors (MAOI), cause changes in brain chemistry
through neurotransmitter augmentation and regulation and they
have been shown to be effective in the treatment of depression
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/jad
Journal of Affective Disorders
http://dx.doi.org/10.1016/j.jad.2014.11.035
0165-0327/& 2014 Elsevier B.V. All rights reserved.
n Corresponding author. Tel.: þ98 511 7112611; fax: þ98 511 7112470.
E-mail address: mohajeria@mums.ac.ir (S.A. Mohajeri).
Journal of Affective Disorders 174 (2015) 51–56
Author’s personal copy
(Cascade et al., 2009; Hermann et al., 1999). Long-time or life-time
treatment is sometimes offered to prevent major depressive disorder
(MDD) relapse (Corruble et al., 2013). Many adverse reactions such as
anticholinergic effects, nausea, constipation, sedation, orthostatic
hypotension, arrhythmias and cardiac toxicity, weight gain or weight
loss and sexual dysfunction and many drug interactions may occurr
with antidepressant medicines (Cascade et al., 2009; Ferguson, 2001;
Sarkar et al., 2013). Nowadays, herbal remedies play an important
role in treatment of psychiatric disorders such as anxiety and
depression (Hosseinzadeh et al., 2012). Although, herbals are medicines with lower potency, they have showed less side effects and
drug interactions compared to the chemical drugs (Cheung et al.,
2012; Sarris et al., 2011). Addition of herbal remedies to the
conventional antidepressants reduces some side effects e.g. tremor
and agitation and improves the mental condition which could be
helpful in treatment of depression as the main problem (Saku, 1991;
Sarris et al., 2011). There are many natural products and medicinal
plants that are the sources of new chemical substances with potential
therapeutic efficacy against mental disorders (Hosseinzadeh and
Younesi, 2002). Crocus sativus L., commonly known as saffron,
belongs to the family Iridaceae (Ayatollahi et al., 2014). It has four
purple flowers with red stigmas and yellow stamens and grows to
20–30 cm. Each flower consists of three trumpet shape stigmas. The
dried stigmas are applied mainly in various foods as a seasoning and
coloring agent (Assimopoulou et al., 2005). Saffron contains several
compounds such as safranal (responsible for saffron odor and
aroma), picrocrocin (responsible for saffron bitter taste) and crocin
(the main saffron antioxidant as a dye material) (Ríos et al., 1996).
Saffron can influence the chemical neurotransmitters level in the
brain such as dopamine, norepinephrine and serotonin. As a fact,
these neurotransmitters are strongly affected in depression. Also
saffron and its active constituents e.g. crocin are effective agents as
antidepressant, anticonvulsant, memory enhancer and sedative in
treatment of central nervous system disorders (Hosseinzadeh and
Younesi, 2002; Abdullaev, 2002; Hosseinzadeh and Khosravan, 2002;
Hosseinzadeh et al., 2004; Zhang et al., 1994). Some well-designed
clinical trials have indicated the efficacy of saffron in mild and
moderate depression. In these studies saffron was more effective or
at least equivalent to therapeutic doses of imipramine and fluoxetine
in depression using Hamilton Depression Rating Scale (Berger et al.,
2011; Kashani et al., 2013; Sarris et al., 2011). Crocin, as the main
antioxidant saffron constituent, is a water-soluble carotenoid with a
deep red color (Papandreou et al., 2006). Previous studies indicated
the antidepressant effects of crocin in animal’s models (Hosseinzadeh
et al., 2007) but there is not a published clinical trial supporting this
claim. All above mentioned clinical trials have focused on saffron
extract (not its main components) and its effect on mental disorders.
The aim of the present work was to assess the efficacy of crocin in
treatment of MDD in a 4-week double-blind, placebo-controlled and
randomized pilot clinical trial. The results of this study were
promising and introduced crocin as an antidepressant agent in
treatment of MDD patients.
Materials and methods
2.1. Preparation of crocin tablets
Saffron stigmas were purchased from Novin Saffron Co. (Mashhad, Iran). Extraction and crystallization of crocin from saffron
stigmas were done according to our previous study (Hadizadeh
et al., 2010). Crocin and placebo were formulated into film coated
tablet by Department of Pharmaceutics, School of Pharmacy,
Mashhad University of Medical Science. Each tablet contained
15 mg crocin.
2.2. Clinical trial design
The study was a double-blind, prospective, placebo-controlled,
4-weeks clinical trial. Two parallel groups of MDD outpatient in
Ibn-e-Sina Psychiatric Hospital, Mashhad University of Medical
Sciences, participated in our study from March 2013 to December
All potential subjects were examined by psychiatrist according to the Structured Clinical Interview of the fourth revision of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
(Gadermann et al., 2012; Shemmassian and Lee, 2014). To improve
the quality of our results, we applied inclusion and exclusion
criteria for patients in this study. Inclusion criteria included:
(1) diagnosis of MDD based on DSM-IV; (2) Patients in the range
of 18–50 years old; (3) patient satisfaction for participation in
clinical trial. Exclusion criteria included: (1) significant organic or
neurological disorder, (2) patients taken psychotropic medications
Fig. 1. Flowchart of the trial.
52 A. Talaei et al. / Journal of Affective Disorders 174 (2015) 51–56
Author’s personal copy
in recent month, (3) current or past mood disorder, (4) personal
disorder, (5) cognitive disorder, (6) psychotic disorder or
(7) depression with psychotic features, (8) a history of substance
abuse or substance dependence, and (9) patient with a significant
risk of suicide. Consent form was obtained from each patient
before entering the study. The patients were informed of their
right to withdraw from the study without any negative effect on
their relationship with health care providers. This trial was carried
out in accordance with Ethical Committee Acts in Mashhad
University of Medical Sciences. This clinical trial was registered
at the Iranian Clinical Trials Registry (IRCT2013041813058N1;
www.irct.ir). Forty six participants were included into this study
(Fig. 1). The patients were randomly divided into the crocin (23
patients) and the placebo (23 patients) groups (Table 1) and a
randomization code number was given to each pillbox (crocin or
placebo) by Excel software. Six patients were excluded and finally
40 patients successfully completed the trial.
2.3. Interventions
The patients in crocin group were given one SSRI (fluoxetine
20 mg/day or sertraline 50 mg/day or citalopram 20 mg/day) plus
crocin tablet (30 mg/day; 15 mg BID) for 4 weeks, whereas the
patients in placebo group were given one SSRI (fluoxetine 20 mg/
day or sertraline 50 mg/day or citalopram 20 mg/day) plus placebo
(two placebo tablets per day, one tablet BID) for 4 weeks. The
crocin and the placebo tablets had the same shape and color and
each tablet container had a random code number to perform a
double-blind clinical trial. Participants were not allowed to receive
any other antidepressant drugs or behavior therapy during the
study. The medication adherence and patient compliance were
assessed through checking with the patient and his/her caregiver
along with a pill count at each visit.
2.4. Blinding
Crocin and placebo tablets were prepared in the same way.
They had identical shape, color, size, texture and odor. The tablets
were packed in the same container with a code number. The
tablets were prepared by a pharmacist. Thus, patients, physician
and other investigators were all blind to the treatment group
assignments.
2.5. Safety
The patients were requested to inform investigators about any
adverse events or complaint during the trial. The symptoms were
checked and recorded at the beginning and at each base-line visit.
Also, possible side effects were checked and recorded via telephone call every week and the physician was responsible for
continuing or discontinuing the drugs. The adverse effects check
list was completed by independent raters.
2.6. Instruments
All the patients answered some questions about their sociodemographic information including age, sex, marital status, educational level, beck depression inventory (BDI), general health
questionnaire (GHQ), beck anxiety inventory (BAI) and mood
disorder questionnaire (MDQ). BDI is the most widely used selfrating scale and previous studies indicated its reliability and validity
in patients with depression (Jolly et al., 1993). It is appropriate to all
social levels and is neither age nor culture based (Kashani et al.,
1990). It consists of 21 items of emotional, behavioral, and somatic
symptoms. The scores between 0–9, 10–19 and 20–29 indicate
normal, mild and moderate depression respectively. The score of
30 and more shows major depressive disorder (MDD) (Lindsay and
Skene, 2007). GHQ is a screening device for detecting minor
psychiatric disorder in patients (Masunaga et al., 2013). It is suitable
for all ages (but not children) from adolescent upwards; it recognizes the patient’s current state and asks if that differs from his or
her usual state. It has 28 items that diagnoses somatic symptoms,
anxiety and insomnia, social dysfunction and severe depression. For
each item four answer possibilities are available; 1: not at all, 2: no
more than usual, 3: rather more than usual, and 4: much more than
usual and the total scale score ranges from 28 to 112. The higher
score shows the poorer psychological condition of patients
(Martínez and Custódio, 2014). BAI is a brief measure of anxiety
with a focus on somatic symptoms of anxiety (Adams et al., 2013). It
has 21 items that measure the severity of an anxiety in adults and
adolescents. The items of this inventory describe the emotional,
physiological, and cognitive symptoms of anxiety. It can discriminate
anxiety from depression. The total score ranges from 0 to 63. The
score of 0–21: mild anxiety; 22–35: moderate anxiety and 35–63:
severe anxiety (Ak et al., 2012). MDQ is a device for recognizing the
signs and symptoms of manic or bipolar disorder, including mania
and/or depression (Caddell and Clare, 2012).
2.7. Statistical analysis
The normality test was carried out for all data. The results before
and after treatment and the difference values between scores
passed the normality test. Thus, independent t-test was applied to
evaluate the scores in two independent groups (crocin and placebo)
after 4 weeks trial, whereas paired t-test was used to evaluate the
scores within each group before and after treatment. Categorical
data were compared using Fisher’s exact test. The variables were
presented as means7standard error of the mean (SEM) and the
Pvalue less than 0.05 was considered statistically significant.
Results
3.1. Demographic characters and psychological conditions of the
participants
Firstly, 46 patients were randomized in two groups, six patients
could not complete the study and 40 patients successfully finished
the trial. A total of 40 patients (34 female and 6 male, mean age
Table 1
Demographic data of the patients in both study groups. Sample t-tests were applied
to normally distributed data (age) and Fisher’s exact test was used for categorical
variables.
Variable Crocin group Placebo group Pvalue
Age, years, mean (SD) 35.9 (7.10) 36.5 (7.67) 0.80
Gender
Female 18 16 0.66
Male 2 4 0.66
Marital status (n)
Married 14 16 0.71
Single 3 2 1.00
Divorced 1 2 1.00
Widow 2 0 0.48
Level of education(n)
Illiterate 0 0 –
Primary school 3 5 0.69
High school diploma 15 14 1.00
University degree 2 1 1.00
Previous treatment with psychiatric drugs 0 0 –
Smoking
Former 6 10 0.33
Current 0 0 –
A. Talaei et al. / Journal of Affective Disorders 174 (2015) 51–56 53
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36.2 years) could finish the study. There were no significant
differences (Pvalue 40.05) between demographic characters of
the patients in two groups (Table 1). The BDI and GHQ scores
were not significantly different between groups (Pvalue40.05),
whereas the mean difference in BAI score was 3.1 (the score in
crocin group was slightly more than placebo group, Pvalue¼0.028)
at the baseline visit (Figs. 2–4).
3.2. Efficacy measures
According to our results, administration of crocin tablets
(30 mg/day; 15 mg BID) in crocin group, gradually improved
scores in all inventories during the trial. Fig. 2 indicated a 17.6
reduction (42.2%) in BDI score in crocin group, whereas the
decrease in placebo group was 6.1 BDI score (15.9%). Also, the
reductions in BAI and GHQ scores were 12.7 (33%) and 17.2 (21.5%)
in crocin group, whereas the values in placebo group were 2.6
(7.5%) and 10.3 (12.3%) (Figs. 3 and 4). The statistical analysis
demonstrated that the differences between two groups were
significant (Pvalueo0.0001) in all inventories (Table 2). The maximum and minimum reductions in BDI scores in crocin group were
51.3% and 31.0% respectively, whereas the maximum and minimum reduction values in placebo groups were 38.2% and 0%. These
results showed a significant improve in depressive symptoms in
crocin group compared to the placebo group.
3.3. Clinical complications and adverse effect
Although 46 patients were included firstly into two groups in
the study, finally 40 patients finished the experiment and six
patients were excluded. No serious adverse effect was reported in
this trial. In placebo group one person did not continue the study
without any side effect, whereas one patient reported the urinary
incontinency. Also, one case of dyspnea was reported in placebo
group. In crocin group dyspnea, agitation and menometrorrhagia
were reported in 3 different patients. Thus, they did not continue
to finish the study. Therefore 40 patients between 24 and 50 years
old enrolled in the study; 20 patients assigned to the crocin group
and 20 patients assigned to the placebo group. The two groups
were well matched, and no statistically significant difference was
observed between groups in the frequency of side effects (Table 3).
Discussion
As mentioned before, all patients received one SSRI per day such
as sertraline, fluoxetine or citalopram. Some of the above mentioned
side effects such as difficulty with breathing, urinary incontinency
and agitation have been reported previously in administration of
SSRI antidepressant drugs (Ferguson, 2001; Murphy et al., 2008; Rief
et al., 2009; Zullino and Khazaal, 2005). Also, menstrual irregularities have been observed with sertraline (Uguz et al., 2012). Thus,
the reported side effects in our study can be attributed to administration of SSRIs. Mohamadpour et al. evaluated the safety of crocin
in healthy volunteers. They investigated the effects of crocin tablets
(20 mg per day for one month) on biochemical, hormonal, hematological and urinary parameters in pre and post-treatment periods
(Mohamadpour et al., 2013). Crocin tablets did not show major side
effects or change the above mentioned factors except decreased
mixed white blood cells, amylases and PTT during trial. According to
our data and previous studies crocin does not have a serious adverse
effect in therapeutic doses. However, more investigations are
recommended. The experimental results showed that orally administration of crocin as an adjunct to SSRIs leads to significantly greater
decrease in depressive symptoms in comparison with SSRI alone
treatment. Reduction in the BDI, BAI and GHQ scores was the clinical
Fig. 2. Mean7SEM scores of two groups of patients on the BDI. Statistical analysis
showed a significant difference in reduction of BDI scores from the baseline after
4 weeks trial between two groups. Independent t-test was applied to evaluate the
differences between groups (crocin and placebo), whereas paired t-test was used to
evaluate the scores within each group before and after treatment. nnn Po0.0001
comparison between groups and þ þ þ Po0.0001 comparison within each group.
Fig. 3. Mean7SEM scores of two groups of patients on the BAI. Statistical analysis
showed a significant difference in reduction of BAI scores from the baseline after
4 weeks trial between two groups. Independent t-test was applied to evaluate the
differences between groups (crocin and placebo), whereas paired t-test was used to
evaluate the scores within each group before and after treatment. nnn Po0.0001
comparison between groups and þ þ þ Po0.0001 comparison within each group.
Fig. 4. Mean7SEM scores of two groups of patients on the GHQ. Statistical analysis
showed a significant difference in reduction of GHQ scores from the baseline after
4 weeks trial between two groups. Independent t-test was applied to evaluate the
differences between groups (crocin and placebo), whereas paired t-test was used to
evaluate the scores within each group before and after treatment. nnn Po0.0001
comparison between groups and þ þ þ Po0.0001 comparison within each group.
54 A. Talaei et al. / Journal of Affective Disorders 174 (2015) 51–56
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relevance of these findings. Therefore, crocin can be an effective
adjuvant for the treatment of mild to moderate depression and
anxiety in patients. Furthermore, our findings supported previous
works and were in conformance with antidepressant effect of crocin in
animal models (Hosseinzadeh and Khosravan, 2002; Hosseinzadeh
et al., 2004). Nowadays herbal medicine holds a valorous place in
treatment of psychiatric disorder such as depression, anxiety and the
other mental problems. According to some research works, saffron can
be used as a valuable agent in the treatment of depression. Proverbially, administration of saffron extract resulted in significant decrease
in depression symptoms (Akhondzadeh et al., 2005). Another work
reported that saffron has a similar performance in treatment of
depression (Noorbala et al., 2005). A research group reported that
petal of saffron in addition to stigma has antidepressant effect in rat
and mice (Hosseinzadeh et al., 2007). Furthermore, another research
reported that saffron extract may alleviate the symptoms of premenstrual syndrome including depression (Agha-Hosseini et al.,
2008). But all these studies were about saffron extract and there
was not any data about antidepressant effects of crocin in human. All
of these effects may be attributed to a synergistic action of many
constituents in saffron such as crocin, picrocrocin, safranal and
flavonoids. In this study, we assessed the effect of crocin compared
to placebo. However the role of crocin in treatment of mild to
moderate depression is not well understood, a group of evidence
indicated that oxidative stress, due to an accumulation of free radicals,
may play an important role in the pathogenesis of neurological and
psychiatric diseases like MDD (Gautam et al., 2012). As we said before
crocin is the main antioxidant constituent in saffron stigmas (Rı´os
et al., 1996). Some studies showed that oxidative stress was increased
in depressed patients and reported the correlations between reduced
oxidative stress and antidepressant treatment (Chung et al., 2013;
Michel et al., 2012; Zhou et al., 2006). The carotenoids clean free
radicals, especially superoxide anions and thereby protect cells from
oxidative stress (Bors et al., 1982). Due to these effects, adjunctive
therapy with crocin may provide further protection as it is powerful
antioxidant and plays an important role in preventing free radicalinduced damage in the brain (Behr et al., 2012). Also, our experimental
findings showed that the decrease in depressive symptoms in patients
may be attributed to the synergistic antidepressant effect of crocin and
psychiatric drugs (SSRIs). Finally, in this study, for a short period of
time, contributors were only treated and assessed. But, we suggest
that the long term studies for better investigation of the crocin effects
as an adjunct to SSRIs are needed.
4.1. Limitations
Although the results of this study showed the efficacy of crocin
as an effective therapeutic adjuvant, it also had some limitations.
Six patients could not finish the treatment period and were
excluded from the study. In placebo group one person did not
continue the study without any side effects, whereas one patient
reported the urinary incontinency. Also, one case of dyspnea was
reported in placebo group. In crocin group dyspnea, agitation and
menometrorrhagia were reported in 3 different patients. Thus,
they did not continue to finish the study. Therefore, the small
sample size was one of our study limitations. Also, the trial was
carried out in a short time. It could be done in a longer trial period.
Self-report assessments and poor patient compliance with prescribed medications were other limitations of this study.
Conclusion
In this work, addition of crocin tablets (30 mg/day, 15 mg BID)
amplified the effects of SSRIs in treatment of patients with mild to
moderate depression. Also, due to absence of substantial side
effects, crocin was shown to be a particularly effective therapeutic
adjuvant. Improvements in psychiatric tests (mentioned above)
were the clinical relevance of the antidepressant effect of crocin.
These findings suggested that the antidepressant effects of saffron
extract could be attributed to crocin as the main antioxidant
constituents in saffron stigmas. However, further research works
are required to clarify the mechanism of this effect.
Role of funding source
Financial support done by the Vice Chancellor of Research, Mashhad University
of Medical Sciences through grant number 910241.
Conflict of interest
The authors have declared there is no conflict of interest.
Acknowledgements
The authors gratefully acknowledge Novin Safforn Company for supplying
saffron, Pharmacy School for preparation of crocin and placebo tablets and would
also thank Psychiatry and Behavioral Sciences Research Center, Ibn-e-Sina psychiatric hospital for their help in management of clinical trial.
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