Background: The morbidity and mortality associated with depression are considerable and continue to increase. Depression currently ranks fourth among the major causes of disability worldwide, after lower respiratory infections, prenatal conditions, and HIV/AIDS. Crocus sativus L. is used to treat depression. Many medicinal plants textbooks refer to this indication whereas there is no evidence-based document. Our objective was to compare the efficacy of stigmas of Crocus sativus (saffron) with imipramine in the treatment of mild to moderate depression in a 6-week pilot double-blind randomized trial.
Methods: Thirty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition 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 score of at least 18. In this double-blind, single-center trial, patients were randomly assigned to receive capsule of saffron 30 mg/day (TDS) (Group 1) and capsule of imipramine 100 mg/day (TDS) (Group 2) for a 6-week study.
Results: Saffron at this dose was found to be effective similar to imipramine in the treatment of mild to moderate depression (F = 2.91, d.f. = 1, P = 0.09). In the imipramine group anticholinergic effects such as dry mouth and also sedation were observed more often that was predictable.
Conclusion: The main overall finding from this study is that saffron may be of therapeutic benefit in the treatment of mild to moderate depression. To the best of our knowledge this is the first clinical trial that supports this indication for saffron. A large-scale trial with placebo control is warranted.
Discussion : In this small preliminary double-blind and randomized comparison of saffron and imipramine in the treatment of mild to moderate depression, saffron at this dose was found to be effective similar to imipramine. Our results are in the line with a recent published animal study that Crocus sativus extracts showed antidepressant effect. In addition, in the imipramine group anticholinergic effects such as dry mouth and sedation were observed more often that was predictable. Saffron at this dose did not induce any abnormal bleeding that is one of the reported side effects of it. It has been reported that saffron inhibits platelet adhesion so its use is contraindicated in pregnancy. In addition, it has been suggested that crocin and safranal two major components of saffron inhibit reuptake of dopamine, norepinephrine and serotonin. The limitations of the present study, including lack of a placebo group, using only a fixed dose of saffron, the small number of participants and short period of follow up should be considered so further research in this area is needed. Indeed, 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. In majority of cases there are no evidence-based documents for them. Therefore, the search for new and more effective therapeutic agents includes the scientific study of plants used in traditional medicine systems to treat mental disorders. The main overall finding from this study is that saffron may be of therapeutic benefit in the treatment of mild to moderate depression. A large-scale trial with placebo control is warranted.
Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: A pilot double-blind randomized trial [ISRCTN 45683816], Shahin Akhondzadeh, Hasan Fallah-Pour, Khosro Afkham1, Amir-Hossein Jamshidi and Farahnaz Khalighi-Cigaroudi, BMC Complementary and Alternative Medicine 2004, 4:12

Summary : Depression is a serious disorder in today’s society, with estimates of lifetime prevalence as high as 21% of the general population in some developed countries. As a therapeutic plant, saffron is considered excellent for stomach ailments and as an antispasmodic, to help digestion and to increase appetite. It is also used for depression in Persian traditional medicine. Our objective was to assess the efficacy of the stigmas of Crocus sativus (saffron) 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, 4th edition for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients had a baseline Hamilton rating scale for depression score of at least 18. In this double-blind, placebocontrolled, single-centre and randomized trial, patients were randomly assigned to receive a capsule of saffron 30 mg/day (BD) (Group 1) or a capsule of placebo (BD) (Group 2) for a 6-week study. At 6 weeks, Crocus sativus produced a significantly better outcome on the Hamilton depression rating scale than the placebo (d.f. = 1, F = 18.89, p max 0.001). There were no significant differences in the two groups in terms of the observed side effects.
The results of this study indicate the efficacy of Crocus sativus in the treatment of mild to moderate depression. A large-scale trial is justified.
Discussion : This study showed that patients with mild to moderate depression receiving saffron experienced statistically significant benefits in their mood after 6 weeks treatment. The clinical relevance of these findings was emphasized by the improvements seen in the Hamilton depression rating scale measures in the saffron group. To best of our knowledge, this study is the first clinical trial of saffron in the treatment of mild to moderate depression so it is not possible to draw any comparisons with other trials. There were no significant differences in the two groups in terms of observed side effects. Moreover, saffron at this dose did not induce any abnormal bleeding that is one of the reported side effects of Crocus sativus.
Sutdy related to Saffon : Crocus sativus L. in the Treatment of Mild to Moderate Depression: A Double-blind, Randomized and Placebo-controlled Trial, PHYTOTHERAPY RESEARCH Phytother. Res. 19, 148–151 (2005), Shahin Akhondzadeh, Najaf Tahmacebi-Pour, Ahamad-Ali Noorbala, Homayoun Amini, Hassan Fallah-Pour, Amir-Hossein Jamshidi and Mousa Khani

Abstract : Depressive disorders are very common in clinical practice, with approximately 11.3 of all adults afflicted during any a year. Saffron is the world’s most expensive spice and apart from its traditional value as a food additive, recent studies indicate several therapeutic effects for saffron. It is used for depression in Persian traditional medicine. Our objective was to compare the efficacy of hydro-alcoholic extract of Crocus sativus (stigma) with fluoxetine in the treatment of mild to moderate depression in a 6-week double-blind, 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 and with mild to moderate depression participated in the trial. In this double-blind, single-center trial and randomized trial, patients were randomly assigned to receive capsules of saffron 30 mg/day (BD) (Group 1) and capsule of fluoxetine 20 mg/day (BD) (Group 2) for a 6-week study. Saffron at this dose was found to be effective similar to fluoxetine in the treatment of mild to moderate depression (F = 0.13, d.f. = 1, P = 0.71). There were no significant differences in the two groups in terms of observed side effects. The results of this study indicate the efficacy of Crocus sativus in the treatment of mild to moderate depression. A large-scale trial is justified.
Discussion : The results of this study indicate the efficacy of Crocus sativus L. in the treatment of mild to moderate depression. On the other hand, a tolerable side effects profile of saffron, may well confirm the application of saffron as an alternative treatment for depression in Persian traditional medicine and these results deserve further investigations.
Keywords: Crocus sativus; Depression; Fluoxetine; Herbal medicine; Saffron; Stigma
Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial, Journal of Ethnopharmacology 97 (2005) 281– 284, A.A. Noorbala, S. Akhondzadeh, N. Tahmacebi-Pour, A.H. Jamshidi

Objectives: A correlation between hyperhomocysteinemia, and depression has been reported. Saffron (Crocus sativus) is recommended for treatment of depression; hence, in this study the effect of co-administration of saffron and fluoxetine on plasma homocysteine and depression was evaluated.
Material and methods: This was a 4-week randomized and double-blind clinical trial which was conducted from March 2013 to February 2014. In this trial, 40 male and females (20-55 years old) diagnosed with severe depression were selected and following filing the Beck form, were randomly divided into two groups. Experimental group was treated with fluoxetine 20 mg/day and saffron 30 mg /day and the control group received placebo and fluoxetine 20 mg/day for four weeks. Before treatment and at the end of the study, fasting blood samples were collected. For females, blood samples were collected on the third day of their menstrual cycle.
Results: A significant reduction of homocysteine levels was observed in both sex in the experimental group compared to before treatment (p max 0.04), while no such significant change was observed in the control group. A Beck questionnaire value showed lower level in both groups on the last day of treatment as compared to before treatment. There was no significant difference between the two groups in Beck value neither before nor after treatment.
Conclusion: Saffron has beneficial effects on depression and homocysteine level in patients with major depression. Indeed, the results of this study indicate the efficacy of saffron in the treatment of depression. Also, a tolerable side-effects profile of saffron may suggest the safe application of C. sativus as a complementary treatment for depression.
Keywords: Saffron, Homocysteine, Major Depression, Crocus Sativus
Saffron improved depression and reduced homocysteine level in patients with major depression: A Randomized, double blind study, Gholamali Jelodar, Zahra Javid, Ali Sahraian, Sina Jelodar, AJP, Vol. 8, No. 1, Jan-Feb 2018

Objective: A significant correlation exists between coronary artery diseases and depression. The aim of this trial was to compare the efficacy and safety of saffron versus fluoxetine in improving depressive symptoms of patients who were suffering from depression after performing percutaneous coronary intervention (PCI).
Methods: In this randomized double-blind parallel-group study, 40 patients with a diagnosis of mild to moderate depression who had undergone PCI in the last six months were randomized to receive either fluoexetine (40 mg/day) or saffron (30 mg/day) capsule for six weeks. Participants were evaluated by Hamilton depression rating scale (HDRS) at weeks 3 and 6 and the adverse events were systemically recorded.
Results: By the study endpoint, no significant difference was detected between two groups in reduction of HDRS scores (P ¼ 0.62). Remission and response rates were not significantly different as well (P ¼ 1.00 and P ¼ 0.67; respectively). There was no significant difference between two groups in the frequency of adverse events during this trial. Limitations: Relatively small sample size and short observational period were the major limitations of this study.
Conclusion: Short-term therapy with saffron capsules showed the same antidepressant efficacy compared with fluoxetine in patients with a prior history of PCI who were suffering from depression. Short-term therapy with saffron capsules was as efficient as fluoxetine in improving depressive symptoms of patients with a prior history of PCI who were suffering from MDD. Nevertheless, long-term efficacy and safety of saffron as well as its optimal dosing requires further investigations.
A randomized, 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 Nazila Shahmansouri, Mehdi Farokhnia, Seyed-Hesammeddin Abbasi, Seyed Ebrahim Kassaian, Ahmad-Ali Noorbala Tafti, Amirhossein Gougol, Habibeh Yekehtaz, Saeedeh Forghani, Mehran Mahmoodian, Sepideh Saroukhani, Journal of Affective Disorders (2013)

What is known and objective: Crocus sativus L., commonly known as saffron, has known anti‐depressive properties. However, its effects on food craving and body weight in depressed patients are unknown. Hence, we aimed to evaluate the effects of saffron capsules on food craving, body weight and depression among overweight women with mild and moderate depression compared to the placebo.
Methods: Seventy‐three women with BMI min 25 comorbid with mild‐to‐moderate depression were recruited in this 12‐week double‐blind, placebo‐controlled randomized clinical trial. Participants were randomly assigned into one of the two groups receiving daily either 30 mg of Crocus sativus capsules (15 mg twice/day) or placebo capsules (twice/day). We performed body composition assessments, and beck depression inventory‐II at the baseline, and then 2, 4, 8 and 12 weeks later. One month after the participants stopped taking the capsules, weight differences were measured and compared between groups.
Results and discussion: Fifty‐two patients finished the study. The demographic and clinical variables at baseline were the same in two groups. Mean depression scores in the saffron group significantly decreased compared to placebo (mean ± SD: −8.4 score ± 5.9 vs −3.9 ± 5.5; t[50] = 2; P = .007; 95% CI: 1.3‐7.7). There was not a significant effect of saffron on food craving using repeated‐measures ANOVA, F(1, 29) = 0.38, P = .54. Patients in the saffron group showed fewer side effects.
What is new and conclusion: Saffron capsules were not effective in reducing food craving, but as a safe over‐the‐counter supplement, it may help reduce the symptoms of depression in patients who experience mild or moderate depression and are overweight.
Keywords : Crocus sativus L., depression, food craving, obesity, randomized clinical trial, women
A placebo controlled randomized clinical trial of Crocus sativus L. (saffron) on depression and food craving among overweight women with mild to moderate depression Shahin Akhondzadeh PhD, Seyed‐Ali Mostafavi PhD, Seyed Ali Keshavarz PhD2, Mohammad Reza Mohammadi MD1, Saeed Hosseini PhD, Mohammad Reza Eshraghian PhD, J Clin Pharm Ther. 2019;00:1–10.

ABSTRACT
Background: From one hand, depression is one of the symptoms that occur after abstinence from methamphetamine. On the other people living with HIV/AIDS are in isolation due to the nature of their illness and depression is one of the most common mental health problems they experience. Objectives: This study was aimed at determining the effectiveness of saffron on reducing depression among recovered consumers of methamphetamine living with HIV/AIDS. Methods: The design of this study was semi-experimental with pre-test, post-test and control (placebo) groups. The statistical population consisted of all recovered consumers of methamphetamine living with HIV/AIDS who were referred to the Positive Club. Fifty-seven (57) recovered consumers of methamphetamine, living with HIV/AIDS,were selected by convenience samplingmethod. Theywere randomly assigned to an experimental (saffron) group and a control (placebo) group. The experimental group received 30 ml of saffron per day for 8 weeks, whereas the control (placebo) group received placebo the same way. BDI-II was used in this study as a measurement instrument. ANCOVA models were used for statistical inference. Results: The findings showed that saffron and its ingredients had been effective in reducing depression amongthis group (P max 0.05).
Conclusion: In fact, saffron with its active ingredients (Crusin and Saffranal) by serotonin and dopamine secretion in the brain, help in reducing depression among recovered consumers of methamphetamine living with HIV/AIDS.
Discussion : In this clinical trial, we examined the effectiveness of saffron on reducing depression among recovered consumers of methamphetamine living with HIV/AIDS. The findings indicated that this intervention is a suitable treatment for supporting recovered methamphetamine abusers livingwith HIV/AIDS. Previous studies investigated the efficacy of saffron on depression among rats or depressed patients. In this study, as a result of the importance of depression during abstinence period, an attempt was made to apply this treatment for recovered consumers of methamphetamine living with HIV/AIDS. Eventually, saffron and its active ingredients helped to reduce depression in this group.
KEYWORDS Depression; saffron; methamphetamine; HIV/AIDS
The Effect of Saffron on Depression among Recovered Consumers of Methamphetamine Living with HIV/AIDS, Farzad Jalali and Seyedeh Fatemeh Hashemi, SUBSTANCE USE & MISUSE 2018, VOL. 0, NO. 0,1-7

Introduction: Saffron (Crocus sativus L.) has demonstrated antidepressant effects in clinical studies and extensive anxiolytic effects in experimental animal models.
Methods: 66 patients with major depressive disorder accompanied by anxious distress were randomly assigned to receive either saffron (30 mg/day) or citalopram (40 mg/day) for 6 weeks. Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) were used to assess treatment effect during the trial.
Results: 60 participants finished the study. Patients who received either saffron or citalopram showed significant improvement in scores of the Hamilton Rating Scale for Depression (P-value max 0.001 in both groups) and Hamilton Rating Scale for Anxiety (P-value max 0.001 in both groups). Comparison of score changes between the 2 trial arms showed no significant difference (P-value = 0.984). Frequency of side effects was not significantly different between the 2 groups.
Discussion: The present study indicates saffron as a potential efficacious and tolerable treatment for major depressive disorder with anxious distress.
Conclusion : T he current study indicates that during a 6-week trial period, administration of saffron is as safe and as effective as citalopram in the treatment of MDD with anxious distress. It might be time to look more seriously at this valuable herbal medication. This observation suggests saffron as a possibly useful strategy for monotherapy or as part of alternative management in patients with MDD and concomitant anxious distress.
Crocus sativus L. versus Citalopram in the Treatment of Major Depressive Disorder with Anxious Distress: A Double-Blind, Controlled Clinical Trial, A. Ghajar, S. M. Neishabouri, N. Velayati, L. Jahangard, N. Matinnia, M. Haghighi, A. Ghaleiha, M. Afarideh, S. Salimi, A. Meysamie, S. Akhondzadeh, Published online: 2016 Pharmacopsychiatry

Objective: Depression and anxiety are major health problems throughout the world. Metabolic changes in type 2 diabetes mellitus induces and aggravates mental disorders, such as depression and anxiety. Saffron as a therapeutic herb may attenuate Comorbid Depression- Anxiety (CDA). So, this trial is designed to investigate the effect of saffron alcoholic extract on symptoms of CDA in type 2 diabetic patients.
Methods: Fifty-four outpatients suffered from mild to moderate CDA diagnosed by using Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV), were assessed by Hamilton Depression and anxiety measurements, the Pittsburgh Sleep Quality Index (PSQI), and the Satisfaction with Life Scale (SWLS). The participants of this double-blind, placebo-controlled, single center and randomized trial were randomly assigned to intake 30 mg/day saffron or placebo capsules for 8 weeks.
Results: After the intervention, mild to moderate CDA, anxiety and sleep disturbance, but not depression alone, were relieved significantly in the saffron group (P max 0.05), whereas, the changes were not significant in the placebo group. Anthropometric measures and blood pressure parameters of the patients in either groups did not change significantly (P min 0.05) during the intervention. Moreover, dietary intake and physical activity did not differ during the study in the two groups. Changes in the life satisfaction were not significant.
Conclusion: The results indicate the beneficial effect of saffron on the mild to moderate CDA in type 2 diabetic patients.
The effects of alcoholic extract of saffron (Crocus satious L.) on mild to moderate comorbid depression-anxiety, sleep quality, and life satisfaction in type 2 diabetes mellitus: a double-blind, randomized and placebo-controlled clinical trial, Alireza Milajerdi, Shima Jazayeri, Elham Shirzadi, Najmeh Hashemzadeh, Atieh Azizgol, Abolghassem Djazayery, Ahmad Esmaillzadeh, Shahin Akhondzadeh

Introduction: Postpartum depression is a common mental health problem that is associated with maternal suffering. The aim of this doubleblind clinical trial was to compare safety and efficacy of saffron and fluoxetine in treatment of mild to moderate postpartum depression. Methods: This was a 6-week, double-blind, randomized clinical trial. Subjects were women aged 18–45 years with mild to moderate postpartum depression who had Hamilton Depression Rating Scale (HDRS 17-item) score max 18. Eligible participants were randomized to receive either a capsule of saffron (15 mg capsule) or fluoxetine (20 mg capsule) twice daily for 6 weeks. The primary outcome measure was to evaluate efficacy of saffron compared to fluoxetine in improving depressive symptoms (HDRS score).
Results: There was no significant effect for time × treatment interaction on HDRS score [F (4.90, 292.50) = 1.04, p = 0.37] between the 2 groups. 13 (40.60 %) patients in the saffron group experienced complete response ( min 50 % reduction in HDRS score) compared with 16 (50 %) in the fluoxetine group and the difference between the 2 groups was not significant in this regard (p = 0.61). Frequency of adverse events was not significantly different between the treatment groups.
Discussion: The results of this study may suggest that saffron is a safe alternative medication for improving depressive symptoms of postpartum depression. Nevertheless, it should be mentioned that the trial is not well powered and should be considered a preliminary study. Therefore, large clinical trials with longer treatment periods and comparison with placebo group would be appropriate for future studies.
Keywords : crocus sativus, fluoxetine, postpartum depression, saffron, SSRI
Comparison of Saffron versus Fluoxetine in Treatment of Mild to Moderate Postpartum Depression: A Double-Blind, Randomized Clinical Trial, L. Kashani , S. Eslatmanesh, N. Saedi, N. Niroomand, M. Ebrahimi, M. Hosseinian, T. Foroughifar, S. Salimi, S. Akhondzadeh

Introduction: Numerous adverse effects of antidepressants as well as the attitudes of breastfeeding mothers, who prefer to consume herbal medicine rather than chemical drugs, encouraged us to assess the effects of saffron (Crocus sativus L.) on mothers suffering from mild-to-moderate postpartum depressive disorder.
Methods: A double-blind, randomized, and placebo-controlled trial was conducted on 60 new mothers who had a maximum score of 29 on the Beck Depression Inventory-Second Edition (BDI-II). They were randomly assigned to the saffron (15 mg/Bid) or placebo group. The primary outcome was a change in the BDI-II scores 8 weeks after treatment compared to the baseline. The response and remission rates were considered to be secondary outcome measures.
Results: Saffron had a more significant impact on the BDI-II scores than the placebo. The mean BDI-II scores decreased from 20.3 ± 5.7 to 8.4 ± 3.7 for the saffron group (p max 0.0001) and from 19.8 ± 3.2 to 15.1 ± 5.4 for the placebo group (p max 0.01). In the final assessment, 96% of the saffron group were in remission compared to 43% of the placebo group (p max 0.01). The complete response rates were 6% for the placebo group and 66% for the saffron group.
Conclusion: When administered to treat minor PPD in breastfeeding mothers, saffron had a more significant impact on the BDI-II than the placebo.
Discussion : The prevalence of PPD in new mothers is high in the northeast of Iran. As such, it is an important public health issue that requires ongoing management. The results of the current study revealed that saffron was more effective in treating minor PPD in breastfeeding mothers than the placebo over an eight-week duration. The available evidence suggests that saffron may be a safe alternative medication that can reduce the symptoms of postpartum depression.
A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression, Jamshid Tabeshpour , Farzaneh Sobhani , Seyed Alireza Sadjadi , Hossein Hosseinzadeh , Seyed Ahmad Mohajeri , Omid Rajabi , Zhila Taherzadeh , Saeid Eslami , Phytomedicine (2017)