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Phytomedicine 13 (2006) 607611 www.elsevier.de/phymed

Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial
Esmail Moshiria, Afshin Akhondzadeh Bastib, Ahamad-Ali Noorbalac, AmirHossein Jamshidid, Seyed Hesameddin Abbasie, Shahin Akhondzadehc,
a

Department of Anesthesiology, Arak University of Medical Sciences, Arak, Iran Department of Food Hygiene, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran c Pychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran 13337, Iran d Deputy for Drug and Food, Ministry of Health and Medical Education, Iran e Research Unit, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
b

Received 22 June 2006; accepted 24 August 2006

Abstract
Depression is a major worldwide health problem. Indeed, by 2020, depressive disorders are estimated to represent the second largest disease burden worldwide. Although a variety of pharmaceutical agents are available for the treatment of depression, psychiatrists nd that many patients cannot tolerate the side effects, do not respond adequately, or nally lose their response. Our objective was to assess the efcacy of petal of Crocus sativus in the treatment of mild-to-moderate depression in a 6-week double-blind, placebo-controlled and randomized trial. Forty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition for major depression based on the structured clinical interview for DSM IV participated in the trial. In this double-blind, placebo-controlled and randomized trial, patients were randomly assigned to receive capsule of petal of C. sativus 30 mg/day (BD) (Group 1) and capsule of placebo (BD) (Group 2) for a 6-week study. At 6 weeks, petal of C. sativus produced a signicantly better outcome on Hamilton Depression Rating Scale than placebo (d.f. 1, F 16:87, po0:001). There were no signicant differences in the two groups in terms of observed side effects. The results of this study indicate the efcacy of petal of C. sativus in the treatment of mild-to-moderate depression. A large-scale trial is justied. r 2006 Elsevier GmbH. All rights reserved.
Keywords: Crocus sativus; Depression; Herbal medicine; Petal

Introduction
Depression, which is thought to result from biochemical changes in the brain, is a common disease of
Corresponding author. Tel.: +98 21 88281866; +98 21 55419113. E-mail address: s.akhond@neda.net (S. Akhondzadeh).

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adulthood (Judd, 1995; Donoghue and Tylee, 1996; De Smet and Nolen, 1996; Demyttenaere, 1997). This affective disorder aficts about 5% of the adult population in the USA at any specic time (Judd, 1995). The optimal goals during the treatment of depression are to maximize efcacy and minimize the adverse events during acute, continuation and maintenance phases (Richelson, 1994). Although there are

0944-7113/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2006.08.006

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many products used for the treatment of depression, including MAOIs, TCAs and SSRIs, most of these drugs produce several adverse reactions, such as anticholinergic effects, orthostatic hypotension, arrhythmias and sexual dysfunction (Demyttenaere, 1997; MacDonald, 1997). Thus, there is a need for more effective and less toxic agents (Richelson, 1994). Plants extracts are some of the most attractive sources of new drugs and have been shown to produce promising results for the treatment of depression (De Smet and Nolen, 1996; Ernst, 1995). Saffron is the worlds most expensive spice and apart from its traditional value as a food additive, recent studies indicate its potential as an anticancer agent and memory enhancer (Rios et al., 1996; Abe and Saito, 2000; Abdullaev, 2002). The value of saffron (dried stigmas of Crocus sativus L.) is determined by the existence of three main secondary metabolites: crocin and its derivatives which are responsible for color; picrocrocin, responsible for taste; and safranal responsible for odor. Indeed, saffron contains in excess of 150 volatile and aroma-yielding compounds. It also has many non-volatile active components, many of which are carotenoids, including zeaxanthin, lycopene, bcarotenes and polysaccharides. However, saffrons golden yellow orange color is primarily the result of a-crocin (Rios et al., 1996; Abe and Saito, 2000; Abdullaev, 2002). This plant belongs to the Iridaceae family and as a therapeutic plant, saffron is considered an excellent aid for stomach ailments and an antispasmodic, helps digestion and increases appetite. It has been reported that C. sativus has antiinammatory, anticancer, antioxidant and antiplatelet effects. Moreover, according to Commission E, C. sativus, is applicable for treatment of nervous disorders, spasms and asthma (Rios et al., 1996; Abe and Saito, 2000; Abdullaev, 2002). It also relieves renal colic, reduces stomach ache and relieves tension (Rios et al., 1996; Hosseinzadeh and Younesi, 2002). Quantities of 10 g or more can cause an abortion and the lethal dose in human is 20 g. Saffron is used for depression in Persian traditional medicine (Hosseinzadeh and Younesi, 2002; Karimi et al., 2001; Akhondzadeh et al., 2004; Noorbala et al., 2005). Indeed, it is a Persian herb with a history as long as the Persian Empire itself. Iran, the worlds largest producer of saffron has been investing in research into saffrons potential medicinal uses. Much of the work surrounds its traditional application for alleviating depression (Karimi et al., 2001; Akhondzadeh et al., 2004, 2005; Noorbala et al., 2005). The clinical ndings suggest that saffron is a safe and effective antidepressant. For example, in a randomized, double-blind study, 30 mg of saffron (stigma of C. sativus) extract (in capsules) given for 6 weeks resulted in signicant alleviation of depression compared to those on placebo, and did so without evident side effects (Akhondzadeh et al., 2005).

This study was a follow-up to a preliminary trial in which the same saffron preparation performed as well as imipramine for treating depression in a double-blind trial (Akhondzadeh et al., 2004). In further preliminary work, saffron was compared to the drug uoxetine; it was found that saffron performed as well as the drug in the treatment of depression (Noorbala et al., 2005). In addition, in a recent pre-clinical study, it has been reported that petal of C. sativus, the part of this herb that is very cheap compared to stigma of C. sativus (saffron), has antidepressant effect (Karimi et al., 2001). Our objective was to assess the efcacy of petal of C. sativus in the treatment of mild-to-moderate depression in a 6-week double-blind, placebo-controlled and randomized trial.

Methods
This was a 6-week randomized and double-blind clinical trial. The trial was conducted in the outpatient clinic of Roozbeh Psychiatric between July 2004 and March 2006.

Patients
Forty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM IV) (American Psychiatric Association, 1994) for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression (HAM-D 17-item) (Hamilton, 1960) score of at least 18. Prospective participants with the following DSM IV diagnosis were excluded: current cognitive disorder in the last year; or current or past history of bipolar disorder, schizophrenia and schizotypal personality disorder. Patients were required to be free of all psychotropic medications for at least 4 weeks before study entry. Patients were selected to range in age from 18 to 55 years of age. As depression is a serious and potentially life threatening condition and the participants were outpatients, so extensive safeguards were needed. Patients were excluded if they posed a signicant risk of suicide at any time during participation. Persons who scored greater than 2 on the suicide item of the HAM-D, or who were judged to have signicant suicidal ideation or potential in the view of an investigator were excluded. Further, any clinically signicant deterioration in the condition of the subject from baseline would result in exclusion. Those who left the study before completion were offered alternative and standard care immediately. Pregnant women or women not using medically accepted means of birth control were excluded. All participants provided written

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informed consent, and the protocol satised the Tehran University of Medical Sciences Ethics Committee requirements.

Preparation of C. sativus
The petal of C. sativus in this study was identied by the Department of Cultivation and Development of Institute of Medicinal Plants, Tehran, Iran. The petals extract was prepared as follows: 120 g of dried and milled petal was extracted with 1800 ml ethanol (80%) by percolation procedure in three steps then the ethanolic extract was dried by evaporation in temperature between 3540 1C. Each capsule had dried extract of petal of C. sativus (15 mg), lactose (ller), magnesium stearate (lubricant) and sodium starch glycolate (disintegrant).

Study design
Patients underwent a standard clinical assessment comprising a psychiatric evaluation, a structured diagnostic interview and a medical history. Patients were randomized to receive capsule of petal of C. sativus or capsule of placebo in a 1:1 ratio using a computergenerated code. The assignments were kept in sealed, opaque envelopes until the point of analysis of data. The randomization and allocation process was done by the pharmacist of the Roozbeh hospital. In this double blind, patients were randomly assigned to receive capsule petal of C. sativus 30 mg/day (BD)(Group A) or capsule placebo (BD) for a 6-week study. Patients were assessed by a psychiatrist at baseline and after 1, 2, 4 and 6 weeks after the medication started. The principal measure of the outcome was the 17-item HAM-D. The rater used standardized instructions in the use of HAMD. The mean decrease in HAM-D score from baseline was used as the main outcome measure of response of depression to treatment. Throughout the study, the person who administrated the medications, rater and patients were blind to assignments.

factor (time) were considered. This was done for HAMD total scores. In addition, a one-way repeated measures analysis of variance with a two-tailed post hoc Tukey mean comparison test were performed in the change from baseline for HAM-D scores in each group. To compare the two groups at baseline and the outcome of two groups at the end of the trial, an unpaired Students t-test with a two-sided P value was used. Results are presented as mean7S.E.M. Differences were considered signicant with po0:05. To compare the demographic data and frequency of side effects between the protocols, Fishers exact test (two sided) was performed. To consider, a 0:05, b 0:2, the nal difference between the two groups at least score of 5 on the HAM-D total scores that is clinically detectable, S 5 and power 80%, the sample size was calculated at least 15 in each group. Intention to treat (ITT) analysis with last observation carried forward (LOCF) procedure was performed.

Results
No signicant differences were identied between patients randomly assigned to groups 1 or 2 conditions with regard to basic demographic data including age and gender (Table 1). Thirty-six patients completed the trial. In the C. sativus and placebo group, the number of dropouts were 1 and 3, respectively. Although the number of dropouts in the placebo group was higher than the saffron group, no signicant difference was observed in the two groups in terms of dropout (p 0:60).

Efcacy: petal of C. sativus versus placebo

The mean7SEM scores of two groups of patients are shown in Fig. 1. There were no signicant differences between the two groups in week 0 (baseline) on the Hamilton Depression Rating Scale (t 0:59, d.f. 38, p 0:55). The difference between the two protocols was signicant as indicated by the effect of group, the betweensubjects factor (GreenhouseGeisser correction; d.f. 1, F 16:87, po0:001). The behavior of the two treatments was not homogeneous across the time (groups-by-time interaction, GreenhouseGeisser correction; F 22:59, d.f. 1.64, po0:001). In addition, a one-way repeated
Table 1. Baseline data Petal of Crocus sativus group Women 9 Man 11 Age (mean7SD) 35.4578.19 (year) Placebo group 8 12 35.8575.63 (year)

Side effects
Side effects were systematically recorded throughout the study and were assessed using a checklist administered by a resident of psychiatry on day 3, 7, 14, 21, 28 and 42 (Table 2).

Statistical analysis
A two-way repeated measures analysis of variance (timetreatment interaction) was used. The two groups as a between-subjects factor (group) and the 5-weekly measurements during treatment as the within-subjects

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Placebo Crocus sativus (Petal) 30mg/Day

Table 2. Clinical complications and side effects were reported as number per group Side effects Saffron 4 4 4 3 5 3 2 4 Placebo 2 2 2 1 2 1 1 2 p 0.66 0.66 0.66 0.60 0.40 0.60 1.00 0.66

26 Hamilton Depression Scores

ns

22 18 14 10 6 0

ns ** *** *** ***

*** ***

***

***

Anxiety Decreased appetite Stomach pain Tremor Nausea Headache Sweating Heart pounding

4 Trial (weeks)

Fig. 1. Mean7S.E.M. scores of two groups of patients on the Hamilton Depression Rating Scale. ns, non-signicant, **po0:01 and ***po0:001. The horizontal symbols (** and ***) were used to express statistical signicance versus their respective baseline value and vertical symbol and ns were used for between-group comparisons.

measures analysis of variance showed a signicant effect of both protocols on Hamilton Depression Rating Scale scores (po0:0001). In the C. sativus and placebo group, post hoc comparisons showed a signicant change from week 1 and 2, respectively, on the Hamilton Depression Rating Scale scores. The difference between the two protocols was signicant at the endpoint (week 6) (t 6:71, d.f. 38, po0:0001). The changes at the endpoint compared to baseline were: 14.0175.53 (mean7SD) and 5.0574.63 for C. sativus and placebo, respectively. A signicant difference was observed on the change of scores of the Hamilton Depression Rating Scale at week 6 compared to baseline in the two groups (t 5:59, d.f. 38, po0:0001).

Clinical complications and side-effects

Eight side effects were observed over the trial. The difference between the C. sativus and placebo in the frequency of side effects was not signicant (Table 2).

Discussion
Mental illness imposes a tremendous burden on the Western world. Mental disorders can strike early in life, and they are increasing in incidence in an aging population experiencing neurodegenerative diseases (Judd, 1995). The search for new and more effective therapeutic agents includes the study of plants used in traditional medicine systems to treat mental disorders

(Richelson, 1994). After decades of predominant reliance on synthetic antidepressants, the treatment of mildly and moderately severe forms of major depression with herbal medicine and in particular St. Johns Wort is becoming popular (Demyttenaere, 1997). This study showed that patients with mild-to-moderate depression receiving petal of C. sativus experienced statistically signicant benets in their mood after 6 weeks treatment. The clinical relevance of these ndings was emphasized by the improvements seen in the Hamilton Depression Rating Scale measures in the saffron group. Moreover, there were no signicant differences in the two groups in terms of observed side effects. It has been reported that stigma of C. sativus has antidepressant effect by at least three clinical trials (Akhondzadeh et al., 2004, 2005; Noorbala et al., 2005). Nevertheless, this study is the rst clinical trial that suggests antidepressant effect for petal of C. sativus. The result of this study is in the line with a resent preclinical study that has reported an antidepressant effect for petal of C. sativus that was similar with its stigma in an animal model for depression (Karimi et al., 2001). As petal of C. sativus is too cheap compared to stigma (saffron) that is one of the most expensive spices in the world, there will be economical interests for further investigations by pharmaceutical industries. In general, patients and their families may view alternative medicine that is, those treatments that are not traditionally taught in medical schools or generally practiced by clinicians, as being complementary or even superior to conventional medicine (Ernst, 1995). In majority of cases, there are no evidence-based documents. Therefore, it is of interest to document traditional medicine. The limitations of the present study, including using only a xed dose of petal of C. sativus, the small number of participants and short period of follow up should be considered so further research in this area is needed. Indeed, the results of this study indicate the efcacy of petal of C. sativus L. in the treatment of mild-tomoderate depression. On the other hand, a tolerable side-effects prole of petal C. sativus, may well conrm the application of petal C. sativus as an alternative

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treatment for depression in Persian traditional medicine and these results deserved further investigations.

Acknowledgment
This study was supported by a grant from Tehran University of Medical Sciences to Dr. Shahin Akhondzadeh.

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