Table 9.
Results of clinical studies on the antidepressant effect of bioactive chemical compounds contained in C. sativus L. stigmas administered as capsules, tablets, or extracts.
| Extract/Biologically Active Chemical Compounds | Treatment Group (g.) | Participants | Exclusion Criteria | Design and Duration of Study | Main Results | Limitations of Studies and Recommendations for Future Investigations | Reference |
|---|---|---|---|---|---|---|---|
| Saffron capsule | saffron capsule 30 mg/day (g. 1) or imipramine 100 mg/day (g. 2) | 30 adult, 18–55 age, outpatient clinic of Roozbeh Psychiatric Hospital who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV) for major depression based on the structured clinical interview for DSM IV with a baseline Hamilton Rating Scale for Depression (HAM-D 17-item) score of ≤18. | current cognitive disorder in the last year; current or past history of bipolar disorder, schizophrenia and schizotypal personality disorder; treatment with any psychotropic medications for at least 4 weeks before study entry; significant risk of suicide; pregnant women or women not using medically accepted means of birth control. | 6 week double-blind randomised single center trial | saffron was as effective as imipramine in the treatment of mild to moderate depression. In the imipramine group anticholinergic effects such as dry mouth and also sedation were observed much more often than in saffron- group | lack of a placebo group; using only a fixed dose of saffron; the small number of participants and short period of follow up | [177] |
| Saffron capsule | Saffron capsule 30 mg[sol]day (g.1; n = 20; 11 male and 9 female) or placebo (BD) (g.2; n = 20; 11 male and 9 female) | 40 adults, 18–55 age, outpatient clinic of Roozbeh Psychiatric Hospital who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV) for major depression based on the structured clinical interview for DSM IV with a baseline Hamilton Rating Scale for Depression (HAM-D 17-item) score of ≤18. | current cognitive disorder in the last year; current or past history of bipolar disorder, schizophrenia and schizotypal personality disorder; treatment with any psychotropic medications for at least 4 weeks before study entry; significant risk of suicide; pregnant women or women not using medically accepted means of birth control. | 6 week double-blind, randomised placebo-controlled trial | significantly better outcome of saffron on the Hamilton depression rating scale than the placebo with no significant differences in the two groups in terms of the observed side effects. Therefore saffron may be efficient in the treatment of mild-to-moderate depression. | Too small for a large-scale trial and short period of follow up | [178] |
| Saffron capsule | A saffron capsule 30 mg/day (g. 1; n = 20; Male/Female 11/9) or a capsule of fluoxetine 20 mg/day (g. 2; n = 20 Male/Female 9/11). | 40 adults, 18–55 age, outpatients who met criteria for MDD based on a structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, baseline HDRS score of ≤18 and with mild-to-moderate depression. | cognitive disorder in the past year, current/past history of bipolar disease, schizophrenia, borderline personality disorder, suicide risk, pregnancy | 6 week randomised double-blind single-centre trial | comparable efficacy of saffron (stigma) and fluoxetine in treatment of mild-to-moderate depression without significant differences observed in the side effects | lack of a placebo group; using only a fixed dose of saffron; the small number of participants and short period of follow up | [338]. |
| Saffron capsule | capsule of C. sativus 30 mg/day (15 mg twice a day, group 1; n = 25) or capsule placebo (twice a day; group 2; n = 25) for two menstrual cycles (cycles 3 and 4). 24 subject assigned to saffron group and 23 subject within placebo group completed the trial. | Fifty women aged 20–45 years with regular menstrual cycles and experience of premenstrual syndrome symptoms for at least 6 months. Each capsule had dried extract of petal of C. sativus (15 mg), lactose (filler), magnesium stearate (lubricant) and sodium starch glycolate (disintegrant). | major physical or psychiatric disorder or substance abuse in the previous 6 months | Double-blind, randomised and placebo-controlled trial; duration of the trial—menstrual cycles 1–4 by women | saffron was effective in relieving symptoms of premenstrual syndrome symptoms. A significant difference was observed in efficacy of saffron in cycles 3 and 4 in the Total Premenstrual Daily Symptoms and Hamilton Depression Rating Scale. Saffron is highly efficient in the treatment of premenstrual syndrome symptoms. A tolerable adverse effects profile of saffron may well confirm the application of saffron as an alternative treatment for premenstrual syndrome symptoms. | using only a fixed dose of saffron; the small number of participants and short period of follow up should be considered, and further research in this area in particular comparison with an active agent such as fluoxetine is needed. | [369] |
| Saffron capsule evaluated by crocin value. Each capsule contained 1.65–1.75 mg crocin. | A saffron capsule contained 15 mg of Crocus sativus (stigma) dried extract twice daily (30 mg each day; group 1) or starch placebo capsule (group 2) for 4 weeks. Male to female ratio in saffron and placebo group was 7:3 and 5:5, respectively. | 20 adult, 18 to 55 year-old, outpatients with the diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental Disorders: 4th Edition (DSM-IV-TR) receiving an selective serotonin reuptake inhibitor (SSRI) for at least 1 month prior to the the study and using at least one medically accepted mean of birth control during the study. | pregnancy or lactation, history of allergy to saffron or multi drug reaction, any history of blood disorders (anaemia, haemophilia), or other severe medical conditions (cardiovascular, renal, hepatic, pulmonary, metabolic or endocrine diseases), history of seizure, substance abuse in the previous 6 months, active peptic ulcer, and taking any medication during the study (except for alprazolam up to 0.5 mg per day). | 6 week, paralell, double-blind, randomised placebo-controlled trial | Saffron as an add-on medication to SSRIs treatment in MDD for 4 weeks did not cause any adverse effect in laboratory parameters including blood cells and coagulation factors, fasting blood sugar, lipid profile markers (triglyceride, total cholesterol) as well as liver and renal functions. It provides evidences of safety concurrent intake of saffron and SSRIs. | small sample size and short period of follow up. The more frequent blood testing is suggested. | [370] |
| Hydro-alcoholic extract of C. sativus stigma | fluoxetine 30 mg/day (20 mg morning, 10 mg noon) and capsules of saffron 40 mg/day (b.i.d) (g. 1) or fluoxetine 30 mg/day and Saffron 8o mg/day (g. 2) | 60 adult patients who met the diagnostic and statistical criteria for mental disorders based on the Hamilton Depression Rating Scale (HDRS), Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), and structured clinical interviews | Diabetes, drug abuse, hypertension, cardiovascular and autoimmune diseases; astma, any infection or illness over the past month; treatment with antiplatelet or anticoagulant medications | 6 week double-blind randomised trial | efficacy and safety of saffron in treatment of mild-to-moderate depression, especially in the group receiving 80 mg saffron capsules | lack of a placebo group; too small of a scale | [371] |
| Saffron capsule | capsule of dried saffron extract 30 mg/day (g. 1; n = 20 Male/Female 9/11) or fluoexetine 40 mg/day (g. 2; n = 20, Male/Female 6/14) | 40 male and female patients aged 20 to 65 years with diagnosis of mild-to-moderate depression (HDRS score of 14–22) who had undergone percutaneous coronary intervention in the last six months. Patients with severe depression were included only if they were suffering from significant depressive symptoms forcing them to seek treatment | any other psychiatric disorder on the DSM-IV axis I or II based on structured diagnostic interview; treatment with psychotropic medications; a high risk of suicide (score ≥2 on the suicide item of HDRS); psychotherapy within 4 weeks or electroconvulsive therapy within 8 weeks prior to entry; substance abuse or dependence (other than nicotine) within 3 months, serious or life-threatening illness, thyroid disease, hepatic or renal dysfunction, hypersensitivity to fluoxetine or herbal compounds, pregnancy, lactation, and oral contraception use. | 6 week randomised double-blind placebo-controlled trial | comparable antidepressant efficacy of short-term therapy with saffron capsules in and fluoxetine treatment in post percutaneous coronary intervention patients based on HDRS and evaluation of adverse events. | a relatively small sample size and a short observational period; lack of a particular probe to evaluate and compare the impact of saffron and fluoxetine on cardiovascular parameters; patients suffering from depression due to cardiovascular diseases other than coronary artery disease (CAD) were not included in the study | [372] |
| Crocin tablets | selective serotonin reuptake inhibitor, (fluoxetine 20 mg/day or sertraline 50 mg/day or citalopram 20 mg/day) together with a placebo, b.i.d. (g. 1) or the same treatment as in g. 1 with crocin tablets (30 mg/day; 15 mg b.i.d instead of placebo (g. 2) | 40 patients, 24–50 in age, with MDD examined according to the Structured Clinical Interview of the fourth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) | depression with psychotic features; psychotropic medication treatment in recent months; substance dependence; suicide risk, disorders: organic, neurological, personal, cognitive, psychotic, | 4 week randomised double-blind placebo-controlled pilot trial | crocin is a particularly effective therapeutic adjuvant in treatment of MDD patients. Crocin improved scores of psychiatric tests including beck depression inventory (BDI), beck anxiety inventory (BAI), and general health questionnaire (GHQ). Crocin amplified the effects of selective serotonin reuptake inhibitors (SSRIs) in the treatment of patients with mild-to-moderate depression without substantial side effects. The antidepressant effects of saffron extract is probably attributed to crocin as the main antioxidant constituent in saffron stigmas. | poor patient compliance with medications and short trial period; small sample size, and self-reported assessments | [216] |
| Saffron capsule | 25 mg of dried saffron extract (g. 1; n = 50) or 5 mg of diazepam as a control (g. 2, n = 52). | 102 male, 18–50 years old patients, candidates for herniorrhaphy operation being in I and II classes of the The American Society of Anesthesiologists (ASA) physical status | allergy to saffron, its products, and tranquilisers | 8 month double-blind controlled randomised trial | greater effectiveness of dried saffron extract on soothing anxiety than diazepam (based on Speillberger State-Trait Anxiety Inventory (STAI) before intervention and 3 h after administration, immediately after entering the surgery room). | financial limitations for preparation of expensive saffron capsules; various elements of saffron need to be studied through clinical assessments | [345] |
| Saffron capsule | 50 mg saffron capsule (g.1; n = 20; Male/Female 8/22) or a placebo (g.2; n = 20 Male/Female 10/20) twice daily for 12 weeks. 30 subject from control and 24 form the treatment group completed the trial. | 60 adult, 18–70 year old patients with mild-to-moderate mixed anxiety and depression diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV), a baseline score for depression of 10–30 and anxiety 8–26. 54 subjects completed the trial. | using any medications for at least one-month prior to starting the study; subjects with family or relationship problems as well as with significant deterioration in their general condition from baseline; signs of any other psychiatric disorder; unnormal studies for organic disease, including thyroid function test and complete blood count testing; any signs of substance misuse disorder, mental retardation, suicidal thoughts or attempt; pregnancy (confirmed by urine βhCG human chorionic gonadotrophin testing) and any grief reaction in the past 6 months. | 12 week double-blind, placebo-controlled radnomised trial | saffron supplements significantly reduced of depression and anxiety scores (Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). Crocus sativus L. stigma appears to be an efficient agent in the treatment of mild-to-moderate anxiety and depression disorder with rare side effects shown. | too-small scale of the trial and single dose of saffron. The minor sample size and the temporary follow up is suggested in further survey. | [232] |
| Saffron capsule containing 30 mg of powder | 25 mg of a dried saffron stigma extract (g. 1; n = 50) or 5 mg oral diazepam as a control (g. 2; n = 52). 11 subjects from control and 19 subjects from intervention group completed the trial. | 40 patients suffering from MDD according to DSM-IV. | suicide risk, any medical or psychiatry disease; use of antidepressant or lipid-lowering drug in the past six months, pregnancy | 4 week randomised double blind placebo controlled trial | Both group significantly improved the depression severity (Beck depression scale) without significant differences. No change in the lipid profile in both groups. | short duration of the study, a small population size due to the abandonment of study by some participants. | [346] |
| Saffron capsule (SaffroMood®) containing 15 mg of stigma extract and 1.65–1.75 mg crocin | a saffron capsule bis in day morning and evening (b.i.d.) (g. 1 or fluvoxamine capsule 100 mg/day (g. 2) | 50 males and females, 18–60 age, with diagnosis of mild-to-moderate obsessive-compulsive disorder (OCD) according to DSM-V-TR and Yale Brown Obsession Compulsion Scale (Y-BOCS) scores from 12 to 21, the participants did not receive any psychiatric medications 6 weeks prior to the study | other mental disorder reported on in the DSM-IV axis I, alcohol or substance (other than nicotine and caffeine) dependence; medical illness including cardiac, hepatic, renal, and neurologic diseases; pregnancy, and breast-feeding | 10 week randomised double-blind parallel group trial | similar effectiveness of stigma as the selective serotonin reuptake inhibitor (SSRI) fluvoxamine and well tolerance in treatment of mild-to-moderate OCD, patients assessed at baseline and at the 2nd, 4th, 6th, 8th, 10th week based on Yale-Brown Obsession Compulsion Scale and Adverse Event Checklist. In contrast to fluvoxamine, the patients tolerated the stigma very well and there were no side effects. | lack of a placebo group., a small sample size, and a short follow-up period | [373] |
| Saffron capsule containing 15 mg of dried stigma extract and 1.65–1.75 mg crocin | saffron capsule b.i.d. (g. 1) or citalopram 40 mg/day (g. 2); 60 participant completed the study: saffron group n = 30 Male/Female 11/19; citalopram group n = 30 Male/Female 15/15 | 66 patients with major depressive disorder (MDD) accompanied by anxious distress according with a score < 19 in the 17-item Hamilton Depression Rating Scale (HDRS) for mild-to-moderate depression and a score < 24 in the 14-item Hamilton Anxiety Rating Scale, with mild-to-moderate severity. | antidepressant medication during the previous month; electroconvulsive therapy during the last 2 months; other mental disorders from DSM-IV Axis I; alcohol dependence or substance dependence (except for nicotine); severe depression, suicidal ideation, administration of aspirin, anticoagulants or nonsteroidal anti-inflammatory drugs; pregnant or breastfeeding women, hypertension, hypothyroidism, renal failure | 6 week multicenter double-blind controlled randomised trial with rigorous adjustment for baseline clinical variables | safe and satisfactory use of stigma, comparable to citalopram, in treatment of mild to moderate MDD with anxious distress. | lack of a placebo control trial arm; use of only a fixed dose in the stigma therapy; a small size of the studied population and a short follow-up period. | [337] |
| Saffron capsule | 500 mg capsules containing 450 mg of saffron on a daily basis for 6 weeks in addition to sertraline (50 mg) (g. 1) or 500-mg capsule of starch with the same protocol that used for group 1 (g. 2—placebo). | 40 patients, 18–55 years, with mild-to-moderate generalised anxiety disorder (GAD), diagnosed according to the DSM-V, based on the HAM-A scores of 18–24 (mild-to-moderate anxiety), who received sertraline | pregnancy and lactation; antipsychotic medications over a month prior to recruitment; drug abuse; other psychiatric diagnosis (bipolar disorder, schizophrenia, mood disorders). | 6 week randomised double-blind placebo-controlled trial | beneficial effects of saffron as an add-on therapy to sertraline for GAD patients (based on total HAM-A score). | too small sample size and a slightly short duration in addition to ethical constraints impeding the assessment of the effects of saffron alone—without sertraline or any other prescribed medication on GAD. | [217] |
| Saffron capsule containing 15 mg of dried stigma extract and 1.65–1.75 mg crocin | saffron capsule (15 mg of dried extract b.i.d.) (g. 1) or placebo (g. 2) for 4 weeks | 36 married male patients,18–45 years, with fluoxetine-stabilised MDD symptoms (40 mg/day for 6 weeks) who had subjective complaints of sexual impairment. | other psychiatric disorders; taking other psychotropic medications within 4 weeks of screening visit; substance abuse within 6 months of recruitment; other serious or life-limiting conditions | 4 week randomised double-blind placebo-controlled trial. | Based on International Index of Erectile Function scale and HDRS saffron is a tolerable and efficacious treatment for fluoxetine-related erectile dysfunction | inability to detect significant difference in some domains (e.g., orgasmic function) which showed near-significant results due to relatively small sample size. Too short duration of the study made it impossible to generalise the findings to long-term outcomes. | [374] |
| Saffron capsule containing 15 mg of dried stigma extract and 1.65–1.75 mg crocin | saffron capsule (15 mg of dried extract b.i.d.) (g. 1) or placebo (g. 2) for 4 weeks | 34 married women 18–45 years, with fluoexetine-stabilised MDD symptoms (40 mg/day for 6 weeks) who experienced subjective feelings of sexual dysfunction. | other DSM axis disorders; medical comorbidities that could underlie sexual symptoms; using otherpsychotropic agents within 1 month of recruitment; substance abuse within 6 months of recruitment; other serious or life-limiting disease; pregnancy and lactation | 4 week randomised double-blind placebo-controlled trial. | based on the Female Sexual Function Index (FSFI) and HDRS saffron is recognised to be safe and effective agent in alleviation of some of fluoxetine-induced sexual problems including arousal, lubrication, and pain in women. | Short study duration limited the interpretation of the present study regarding long-term effects of saffron on sexual dysfunction. Different dosages of saffron should be investigated in future | [375] |
| Crocin tablets | crocin tablets (30 mg/day; 15 mg b.i.d) or equivalent dose of placebo contained starch and food coloring (g. 2). 33 participants comleted the study: crocin group n = 16; Male/Female 4/12); placebo group n = 17; Male/Female 7/10). | 34 participants—volunteers with metabolic syndrome (MetS) according to the International Diabetes Federation (IDF) criteria | pregnancy, lactation, age under 18 or over 70 years, use of antidepressant drugs, under 10 points on the Beck Depression Inventory (BDI)- questionnaire, grief or unpleasant event during the previous 6 months, and a lack of compliancy in taking the pills regularly | 8 week randomised double-blind controlled clinical trial |
crocin at a dose of 30 mg per day for 8 weeks reduced the symptoms of depression in subjects with MetS compared to the control group, and this effect was independent of its effect on the serum serum pro-oxidant/anti-oxidant balance (PAB). Depressive symptoms were assessed using the BDI. | The participants of the study did not have had a clinical diagnosis of depression. The small sample size, the evaluation of the effects of only 1 dosage an the relatively short duration of the treatment and follow-up. | [296] |
| Curcumin in capsules contains curcuminoids 88%, volatile oils 7% from Curcuma longa rhizomes, saffran were standardised to contain > 3.5% of lepticrosalides including safranal and crocin | placebo-cellulose (g. 1), curcumin extract 250 mg b.i.d. (g. 2), curcumin extract 500 mg b.i.d. (g. 3), combined low-dose curcumin extract plus saffron stigma 15 mg b.i.d. (g. 4) | 123 patients, 18–65 age, with MDD who met DSM-IV criteria, and had IDS-SR30 score ≥ 18 | diabetes; suicide risk; chronic fatigue syndrome, fibromyalgia or asthma; hypertension; cardiovascular and autoimmune diseases; any infection or illness over the past month; psychotic, bipolar, comorbid obsessive-compulsive; posttraumatic stress, neurodegradative disorders; any substance abuse or dependence; treatment with antiplatelet or anticoagulant medications; pregnant or breastfeeding women | 12 week randomised double-blind placebo controlled trial, with a 1 week placebo run-in phase | Different doses of curcumin and combined curcumin/saffron (stigma) treatments effectively reduced major depressive and anxiolytic symptoms based on IDS-SR30 and STAI, enhanced potency of curcumin in atypical depression compared to other depressed counterparts |
investigations with larger sample sizes are required to examine the efficacy of the differing doses of curcumin and stigma/curcumin combination and to assess effects in atypical depression | [376] |
| saffron (stigma) aqueous extract; crocin | capsules of saffron aqueous extract (30 mg;) (group 1 n = 20; Male/Female 11/9), crocin (30 mg) (group 2; n = 19; Male/Female 9/10), or placebo (cornstarch-vehicle) (group 3; n = 19; Male/Female 8/11) for 8 weeks. One participant of group 2 and one of group 3 did not complete the study. Participants completed the demographic questionnaire, Beck depression inventory-II (BDI-II), Hurlbert index of sexual desire (HISD), and MacNew health-related quality of life questionnaire. |
Fifty-eight, 40–65 year-old, Coronary Arthrety Disease (CAD) males and females patients. The subjects did not receive any psychotherapeutic or psychotropic drugs and only used common drugs for their cardiometabolic disorders. Hypertension was defined as systolic and/or diastolic blood pressure ≥ 150/90 mmHg or receiving antihypertensive medications. | autoimmune diseases, malignancies; insulin therapy; nursing profession, pregnancy; hypersensitivity to saffron; patients with heart attacks; antidepressants treatment; | 8 week randomized double-blind, placebo controlled, clinical trial | saffron (stigma) aqueous extract and crocin to the similar extent severely decreased the BDI-II score but not markedly affected HISD scores. However, they could significantly improve the total quality of life and its subscales. After adjustments for age, sex, and diagnosis time, similar results were obtained. Therefore, saffron and its active constituent, crocin, could improve depression and health-related quality of life in patients with CAD, whereas they had no significant effects on sexual desire. Although these agents can be used as suitable adjunct agents in CAD patients, large-scale trials are justified. | Too small scale of trial. Considering the limited sample size, subgroup analysis based on sex was impossible. To obtain comprehensive results, it is recommended to conduct further research on both sexes using a large sample size. Moreover, to completely assess sexual life quality in patients, it is suggested to concurrently use several valid and reliable instruments. | [377] |
| Saffron capsule | saffron capsule SaffroMood® (15 mg b.i.d.) (g. 1; n = 32) or fluoxetine capsule (20 mg b.i.d.) | 64 women between 18–45 years of age, with mild to moderate postpartum depression based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), who had Hamilton Depression Rating Scale (HDRS 17-item) score ≤ 18 | psychotic depression, history of suicidal or infanticidal thoughts, a history of bipolar disorder, substance or alcohol dependence (except of nicotine), lactation, hypothyroidism and acute medical illness. Patients with any diagnosis other than postpartum depression on the DSM-IV-TR axis I | 6 week randomised double-blind, clinical trial | No significant effect of the time×treatment interaction on the HDRS score between saffron and fluoxetine group. Therefore saffron is a safe alternative medication for improving depressive symptoms of postpartum depression | lack of a placebo group, a small number of participants and short period of follow-up | [341] |
| Saffron tablet containing 15 mg of stigma and 235 mg of lactose, magnesium stearate, and sodium starch glycolate | saffron tablet 15 mg b.i.d. (30 mg/day (g. 1) or equivalent dose of placebo (g. 2). | 60 new breastfeeding mothers suffering from mild-to-moderate postpartum depression, over 18 age with BDI-II score of lower than 30; live-born infant delivery over the preceding nine months | significant medical illness (gestational diabetes, pre-eclampsia); pregnance; present or past history of drug or alcohol abuse, smoking, alcohol, or illicit drug use during pregnancy; treatment with any medications affecting mood; anticoagulants therapy; current psychotropic medication; ongoing need for medications known to cause depression or psychosis; kidney failure; a BDI-II score of ≥30; unstable medical condition that might interfere with completing the trial; any allergies to stigma in the mother or the infant; any significant deterioration in symptoms | 8 week randomised double-blind placebo-controlled trial conducted in three healthcare centres | saffron stigma showed a more significant impact on the BDI-II than the placebo when administered to treat minor postpartum depression in breastfeeding mothers. | study accessible only to women that attended healthcare centre but not for all breastfeeding mothers; the questionnaire recorded the demographic information from mothers concerned about their infant’s vaccination | [70] |
| A combination of C, sativus stigma and Rhodiola rosea roots extracts | supplementation with one tablet contained 154 mg of Rhodiola roots and 15 mg of saffron exstracts, b.i.d. | 45 adults (18–85 age) suffering from mild-to-moderate depression according to ICD10 and reaching a score of 8–18 on the HRSD | treatment with antidepressants, severe MDD defined by the ICD10 or HRSD score >18; suicidal attempt, treatment with piperine or St John’s Wort medications; chronic ilness: arterial hypertension, cardiac or renal insufficiency; psychiatric disorders: schizophrenia, bipolarity; addiction; pragnant and lactating women | 6 week observational study conducted with general practitioners | rapid improvement of both depressive and anxiety symptoms assessed with HRSD, Hospital Anxiety and Depression Scale (HADS), Clinical Global Impresiion (CGI) scale, and Patient Global Impression of Change (PGIC) scale. | absence of a control groups, a double-blind placebo-controlled study is needed to confirm these results | [378] |
| Saffron capsule | capsule of saffron (30 mg/day) and fluoxetine (20 mg/day) (treatment group g. 1) or capsule of placebo and fluoxetine (20 mg/day) on a daily basis for 4 weeks (control group g. 2)., Fasting blood samples were collected before treatment and at the end of the study. For females, blood samples were collected on the third day of their menstrual cycle. | 40 adult male and females, 18–55 years old, outpatients diagnosed with severe depression. Participants met the diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) for major depression based on the structured clinical interview for DSM-IV. | any antidepressant treatment during the last 6 months; a history or current idea of suicide; chronic diseases such as metabolic disease and cancer | 4 week randomised double-blind parallel-group clinical trial | C. sativus and flouxetine co-treatment for 4 weeks, significantly improved mood in patients with severe depression. These clinical findings were accompanied by the improvements in the Beck Depression Rating Scale results, in the both groups without marked differences in terms of side effects. This study is the first clinical trial that showed both antidepressant effects and serum homocysteine decreasing activity of saffron. It may suggest the safe application of C. sativus as a complementary treatment for depression. | Authors do not provide limitations of the studies nor a recommendation for the future investigation. | [379] |
| Saffron capsule | saffron 15 mg (g.1) or duloxetine 30 mg (g. 2) starting with 1 capsule per day in the first week followed by 2 capsules per day from week 2 until the end of week 8. | 54 participants, both sexes, aged 18–60 years diagnosed with fibromyalgia based on the American College of Rheumatology 2010 criteria with a pain score ≥ 40 based on visual analogue scale; 46 subjects completed trial. | rheumatologic diseases excluding fibromyalgia; inflammatory/infectious/autoimmune arthritis; comorbid neuropsychiatric disorders except depressive disorders based on the Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR); suicidal ideation; multiple sclerosis; pain due to traumatic injuries; drug history of duloxetine or saffron use; current use of psychoactive medications specially serotonergic compounds or monoamine oxidase inhibitors (MAO-Is); recent use of muscle relaxants, steroids, opioid analgesics, benzodiazepines, anti-epileptics, or injective analgesics; substance use disorder during the 2 years prior to the study; history of using thioridazine, acetylcholinesterase inhibitors, warfarin, or medications affecting the P450 CYP4A3 enzyme in the 2 weeks before the study; pregnancy, breast feeding, or women with no contraception history | 8 week randomised double-blind parallel-group trial | comparable efficacy of saffron and duloxetine in the treatment of fibromyalgia symptoms based of the Hamilton Rating Scale for Depression, Hospital Anxiety and Depression Scale, Global Fatigue Index, Fibromyalgia Impact Questionnaire, and Brief Pain Inventory Saffron and duloxetine | lack of placebo group; small sample size of the study; using a low fixed dose of saffron for a short period of time (i.e., 6–8 weeks) provided insufficient information for long-term adverse effects of saffron compared to antidepressants due to budgetary and executive limitations; the various subgroups typology of fibromyalgia should be taken into account; aside from paraclinical evaluations that concerned safety issues, the biological markers of fibromyalgia that were affected by saffron’s mechanisms of action have not been assessed. | [380] |
| Saffron capsule of stigma extract containing 1.65–1.75 mg crocin | Saffron capsule containing stigma extract (30 mg/day, 15 mg twice daily) (g. 1.) or placebo (g. 2) for 6 weeks. | fifty-six post-menopausal women, over 40 years of age with no menstrual period in the last 12 months with a clinical diagnosis of hot fashes having a score ≥ 40 in Hot Flash-Related Daily Interference Scale (HFRDIS) with MDD 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 HDRS. Patients with hot flash attacks ≥14 times per week for at least 2 months was included into studies. In case of positive history for oophorectomy, more than 6 weeks should have elapsed from surgery and the level of serum FSH should be equal or more than 40 U per mL. |
diagnoses other than depression on the DSM-IV-TR axis I; ingestion of any psychotropic and antidepressant medications, any Selective Estrogen Receptor Modulator medications (e.g., tamoxifen and raloxifen), anyaAromatase inhibitor medications (e.g., anastrozole, letrozole, and exemestane), leuprolide acetate, clonidine, gabapentin, pregabalin, amino acid supplements, over the counter (OTC) medications that reduced hot fashes during the last 4 weeks, ingestion of estrogen and progesterone-based medications, history of suicidal thoughts, substance or alcohol dependence except of nicotine during the last 3 months and electroconvulsive therapy during the last 2 months. | 6 week, multicenter, randomised, double-blind, parallel group clinical trial | safron is a safe and efective treatment in improving hot flashes and depressive symptoms in post-menopausal healthy women. Safron, with fewer side efects, may provide a non-hormonal and alternative herbal medicine option in treatment of women with hot flashes. | the small number of participants and the short period of follow-up. Further research with a longer study period, an active agent such as venlafaxine and a higher sample size to consider patients with different biological and racial backgrounds is needed. | [381] |
| affron®, a patented, obtained at industrial scale, standardized commercial saffron (stigma) extract containing ≥3.5% of total bioactive compounds safranal and crocin isomers | saffron extract (affron®, 22 or 28 mg/day) (g.1), or placebo (g.2). The active treatment was a TGA-listed coated tablet containing either 11 mg or 14 mg of standardised saffron extract (affron®), derived from the stigmas of Crocus sativus L. and standardised to contain >3.5% Lepticrosalides® a measure of bioactive compounds present in saffron, including safranal and crocin. The placebo tablet contained the same excipients as the active one (microcrystalline cellulose and calcium hydrogen phosphate). | 128 (75 male and 45 female), 18–77 year-old participants self-reporting low-mood not diagnosed with depression or another mood disorder recruited from the CRO’s subject database and the public media | patients with a mood disorder or tested positive for depression on the Beck Depression Inventory (BDI > 20); anticoagulation therapy; hypertension and antihypertensive medications treatment, severe renal and/or hepatic insufficiency; history of alcohol and/or drug abuse; current participation or participation in any other clinical trial during last 30 days; diagnosed mood disorder (MDD, bipolar or substance-induced disorder); positive test for moderate to severe depression on the BDI; insomnia or night-shift employment and other reasons that resulted in an inability to have a normal night’s sleep; severe pre-menstrual syndrome with mood or pain that would change during the study period; any neurological disorder e.g., multiple sclerosis; using supplements (nutrients, herbs) that would impact mood (St John’s Wort, Tryptophan, SAM-E, 5-hydroyxtryptophan, Melatonin, Gamma aminobutyric acid GABA); using saffron supplement | 4 week randomised, double-blind, parallel, placebo controlled trial | significant decrease in negative mood and symptoms related to stress and anxiety at a 28 mg/day dose (with a significant difference between 28 mg/day and placebo on the primary outcome measure Total Mood Disturbance scale including POMS Tension, Depression, and Confusion subscales), but no treatment effect at the 22 mg/day dose. Therefore, the results demonstrated the effectiveness of affron®, on improving low mood, stress management and anxiety reduction without side effects in otherwise healthy participants, offering a natural alternative to standard treatments in long-term and prophylactic management, where appropriate, of low mood states. affron® reduces risk of progressing to more severe and eventually clinical manifestations. | the self-reporting nature of both the screening and the testing, and the possibility of confounding variables. Limited generalisability of the study due to the testing of the healthly population and excluding the participants with a high BMI, severe PMS, insomnia, and those with a history of drug and alcohol abuse, i.e., the conditions very often associated with low mood. | [382] |
| affron®, a patented, obtained at industrial scale, standardised commercial saffron (stigma) extract containing ≥3.5% of total bioactive compounds safranal and crocin isomers | tablets containing placebo or stigma extract (14 mg b.i.d) standardised to contain >3.5% lepticrosalides® as measure of bioactive compounds (safranal, crocin). Affron® samples were obtained from Pharmactive Biotech Products SL. The placebo tablet contained the same excipients as the active one (microcrystalline cellulose and calcium hydrogen phosphate). | 80 youths, 12–16 age, with mild-to-moderate anxiety or depressive symptoms | psychiatric disorders other than mild or moderate depression, anxiety disorder, suicidal thoughts, chronic diseases: cardiovascular disease, brain disorders, seizures, diabetes, learning disabilities, addiction | 8 week randomised double-blind placebo-controlled trial | improvement of anxiety and depressive symptoms in teenagers with mild-to-moderate symptoms after stigma administration from the perspective of the adolescents. Youth in self-reports declared greater improvements in overall internalising, separation anxiety, social phobia and depression, however, these beneficial effects were not corroborated by their parents. | self-reporting nature of both the screening and testing, limited duration of the study, single treatment dose | [234] |
| affron®, a patented, obtained at industrial scale, standardised commercial saffron (stigma) extract containing ≥3.5% of total bioactive compounds safranal and crocin isomers | tablets containing placebo or stigma extract (14 mg b.i.d) standardised to contain >3.5% lepticrosalides® as measure of bioactive compounds (safranal, crocin). Affron® samples were obtained from Pharmactive Biotech Products SL. The placebo tablet contained the same excipients as the active (microcrystalline cellulose and calcium hydrogen phosphate). | physically healthy volunteers both of sex aged 18–65 years, with persistent depression, currently (at least eight weeks) treated with a stable dose of single pharmaceutical antidepressant who continued to suffer from mild-to-moderate depressive symptoms as assessed by a score greater than six on the Montgomery–Åsberg Depression Rating Scale (MADRS) (nine-items). Of the 160 participants enrolled, 139 provided usable data. |
current or 12 month history of any psychiatric disorder other than mild-to-moderate depression or anxiety; in self-harm behaviours and/or serious suicidal ideation treatment with any pharmaceutical medication, apart from a single pharmaceutical antidepressant, oral contraceptives and the occasional use (no more than fortnightly) of analgesics (e.g., ibuprofen, paracetamol); currently taking saffron or other herbal supplements; a current or history of a clinically significant, chronic medical condition including cardiovascular disease, organic brain disorder, seizure, diabetes, severe obesity, or use of illicit drugs; pregnant or breastfeeding women, women intending to fall pregnant; subjects reporting a greater than ten-year continuous use of antidepressant medication with no remission in depressive symptoms greater than six months over this period. Eligibility was initially assessed via the completion of a questionnaire that screened for current medication use, suicidal ideation, self-harm behaviours, history of medical/psychiatric disorders, alcohol, nicotine and other drug use, supplement and vitamin intake, and pregnancy/breastfeeding status. | 8 week randomised double-blind placebo-controlled trial | Based on the clinician-rated Montgomery–Åsberg Depression Rating Scale (MADRS) affron® markedly reduced depressive symtoms compared to placebo with decreases of 41 and 21%, respectively, but the decrease in the scores of self-rated MADRS was comparable in both of experimental groups. As it was assessed with Antidepressant Side-Effect Checklist (ASEC) and Short Form-36 Health Survey (SF-36), saffron was associated with a greater reduction in adverse effects of antidepressants, although this was non-significant after covarying for baseline values. Quality of life improved in both groups with no significant between-group differences. Due to the conflicting results, further research is needed to clarify the clinical benefits of saffron as an adjunctive treatment for adults with persistent depressive symptoms despite antidepressant drug treatment. The efficacy of adjunctive saffron use on specific antidepressant types and classes should be investigated. | The longer duration period of the trial and dose-escalation studies for treatment non-responders will be useful to examine the efficacy and safety of higher than studied affron® dose. Support for the saffron antidepressant efficacy should be demonstrated via clinician- rather than self-administered assessment. In order to clarify the saffron antidepressant mechanisms the objective measures of change including changes in cortisol, neurotrophins and inflammatory and oxidative stress markers or changes in neurological activity through the measurement of EEG activity and cognitive testing may be helpful. Recruitment of the participants solely via social media promotion might have skewed the examined population. Multi-measure approaches i.e., diaries, questionnaires and pharmacokinetic measurements, not only participant self-reporting of remaining tablet numbers, should be used for adherence to pill intake. |
[383] |
| Crocin | 15 mg/day of crocin (group 1; n = 26) or placebo (gropup 2; n = 27) twice a day for 8 weeks | 53 patients, aged 18–60 years, currently undergoing a methadone maintenance treatment (MMT) and opioid dependence in the past year, evaluated by the drug abuse section of the Structured Clinical Interview for DSM-IV, Beck Depression Scores > 20 and Beck Anxiety > 15, seeking for treatment. | taking crocin and anti-inflammatory and antioxidant supplements during the last 3 months before the intervention and history of metabolic diseases including diabetes, hypertension, thyroid, and cardiovascular disease. | 8 week randomised double-blind, parallel, placebo-controlled trial | Crocin severely decreased Beck Depression Inventory score and Beck Anxiety Inventory score. It also reduced fasting glucose, insulin levels and resistance, triglycerides, very low-density lipoprotein as well as total cholesterol levels, but markedly increased insulin sensitivity. Crocin intake was associated with a reduction in high-sensitivity C-reactive protein and MDA, as well as a rise in total antioxidant capacity levels. Administration of crocin supplements to patients undergoing an MMT program had ameliorating effects on mental health scales, and improved their metabolic, and genetic parameters. |
Too short-term of an intervention; further studies focused on the cognitive functions, craving, and withdrawal syndrome in subjects under a methadone maintenance treatment (MMT) program are necessary; the effects of crocin administration on urinary or/and serum crocin should be evaluated. | [384] |
| affron®, a patented, obtained at industrial scale, standardised commercial saffron (stigma) extract containing ≥3.5% of total bioactive compounds safranal and crocin isomers | tablets containing placebo or stigma extract (14 mg b.i.d) standardised to contain >3.5% lepticrosalides® as measure of bioactive compounds (safranal, crocin). Saffron samples were obtained from Pharmactive Biotech Products SL. The placebo tablet contained the same excipients as the active tablet (microcrystalline cellulose and calcium hydrogen phosphate). | Eighty-six, 40–60 year-old, perimenopausal women experiencing menopausal complaints with a total score of greater than 16 on the Greene Climacteric Scale (GCS), an intact uterus and ovaries and a body mass index (BMI) between 18 and 35 kg/m2; patients were medication-free for at least 3 months (apart from the contraceptive pill and/or once weekly use of analgesics) and had no plan to commence new treatments over the study period. A total of 39 subjects from saffron group and 37 subjects from placebo group completed the trial. | smokers; consumption more than 14 standard drinks of alcohol per week; current or illicit drug abuse within the last 12 months; suffering from medical conditions including but not limited to: diabetes, hyper/hypotension, cardiovascular disease, a gastrointestinal disease requiring regular use of medications, gallbladder disease/gallstones/biliary disease, endocrine disease, psychiatric disorder (excluding mild-to-moderate anxiety), or neurological disease (Parkinson’s or Alzheimer’s disease, intracranial haemorrhage, head or brain injury); women who had any significant surgeries over the last year, or women taking saffron or other supplements that may affect menopausal symptoms. | two-arm, parallel-group, 12 week, randomised, double-blind, placebo-controlled trial | Affron® markedly improved psychological symptoms in perimenopausal women reducing depressive and anxiety sydromes. Data from the Greene Climacteric Scale (GCS) revealed a significantly greater reduction in the GCS psychological score, characterised by a 33% reduction in anxiety and a 32% reduction in depression scores. Saffron to a greater extent than placebo reduced the PANAS negative affect score (Positive and Negative Affect Schedule). However, vasomotor or other somatic symptoms within intervention and control groups were not markedly different. Given the positive, mood-enhancing findings, further investigations into the benefits of various saffron doses in more clearly-defined populations, presenting with different specific menopausal complaints and using validated self-reported, clinician-administered anxiety and depression, and biological outcome measures, will be important. Changes in sex hormones, and other pertinent markers associated with inflammation, oxidative stress, HPA-axis activity, and neurotrophic activity should be assessed. | As no formal medical assessment comprising an evaluation of hormone concentrations and a comprehensive examination of confounding medical, lifestyle, and dietary factors was undertaken some women in other reproductive stages might have been recruited in this study. The effects of saffron in women with a formally diagnosed depression or anxiety-related disorder, and with varying levels of severity should be studied. The co-administration of saffron with pharmacological antidepressants in perimenopausal women with more severe specific climacteric symptoms currently taking antidepressants and/or on hormone replacement therapy should be evaluated. The efficacy and safety of different saffron extracts at various doses and treatment durations should be examined. | [385]. |
| Saffron capsule | two 15 g saffron (group 1) or placebo (group 2—control) capsules daily for 8 weeks. A total of 29 subjects in the saffron and 28 in the placebo group completed the trial. | Sixty-two methamphetamine abusers (mean age 33 years) with Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) | Psychosis; mania and hypomania period; diseases related to depression such as diabetes, multiple sclerosis, etc; simultaneous psychotherapy or pharmacotherapy; drug and alcohol abuse | 8 week randomised double-blind placebo-controlled trial | Saffron and its ingredients had been effective in reducing depression assessed with using self-report Beck depression inventory (BDI-II). Saffron with its active ingredients (crocin and safranal) by serotonin and dopamine secretion in the brain help in reducing depression among recovered consumers of methamphetamine living with HIV/AIDS. | the duration of intervention, sample size and a tested saffron extract dose was similar to other studies that might aim to find a dose–response effect. Further studies with different doses of saffron extract, different durations of intervention and larger sample sizes are required. |
[386] |
| Saffron capsule | saffron capsule contained 15 mg stigma hydroalcohilic extract b.i.d. (g.1) or placebo b.i.d. (g. 2). | 54 adults, 40–65 age, type 2 diabetic outpatients (fasting plasma glucose levels of ≥126 mg/dL) suffering from mild to moderate comorbid depression–anxiety (CDA) diagnosed by using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). | treatment with anti-depressant and anti-anxiety medications or insulin; severe depression and anxiety as well as recent severe stress or emotional defeat; addicted smokers; any diseases other than depression and anxiety or mental disorders in the first degree relatives; patients with uncontrolled bood glucose (fasting blood sugar test FBS > 170 mg/dL); high physical activity; recent hospitalisation; pregnant or lactacting women and those who had planned for pregnancy. | 8 week randomised double-blind placebo-controlled trial | saffron relieved symptoms of mild-to-moderate CDA in in type 2 diabetic patients without side effects. Based on Hamilton Depression and anxiety measurements (Beck Depression Inventory II (BDI-II, 21-item) and Beck Anxiety Inventory (BAI, 21-item)), the Pittsburgh Sleep Quality Index (PSQI), and the Satisfaction with Life Scale (SWLS) assessment, after the intervention, mild-to-moderate CDA, anxiety and sleep disturbance, but not depression alone, were relieved markedly in the saffron group, while, the changes were not significant in the placebo group. Dietary intake, physical activity, life satisfaction parameters, anthropometric measures and blood pressure parameters of the patients within each of both treatment groups did not change markedly during the intervention. Saffron may be suggested as an alternative treatment for CDA in diabetic patients. | the duration of intervention, sample size as well as a tested saffron extract dose was similar to other studies that might confine finding a dose–response effect. | [387] |
| Saffron capsule | saffron capsule contained 15 mg stigma hydroalcohilic extract b.i.d. (g. 1) or placebo b.i.d. (g. 2) | 40 men and women, over 70 years of age, with on-pump coronary artery bypass grafting (CABG), who had a Wechsler Memory Scale score > 70 | previous treatment with saffron stigma or acetylcholinesterase inhibitors, hypersensitivity to herbal compounds, comorbid neuropsychiatric disorders, and serious medical conditions other than cardiovascular diseases. | 12 week randomised double-blind placebo-controlled trial | there were no significant difference between two groups and time × treatment interaction effect based on Wechsler Memory Scale as well as Mini Mental Status Examination and subscales of Hospital Anxiety and Depression Scale. Therefore, there were no benefits of saffron in treatment of CABG-related neuropsychiatric conditions. | too small sample size and too short duration of intervention | [388] |
| Saffron capsule | Capsule of saffron (60 mg/day) (g. 1.) or sertraline (100 mg/day) (g. 2). | 50 out-patients aged older than 60 years (mean age = 65 years; 70% males) with diagnosed MDD based on the DSM 5 criteria; HDRS seven or higher | Acute suicidality; other serious psychiatric disorders i.e., bipolar disorders, substance use disorder, anxiety disorders, veterans with posttraumatic stress disorder (PTSD); Intake of antidepressants during the last 4 weeks; intake of aspirin, anti-coagulant drugs or non-steroidal anti-inflammatory drugs (NSAID); undergoing other treatments for MDD such as psychotherapy, neuromodulation, regular, supervised physical activity trainings, or specific nutritional regimen; other somatic complaints such as diabetes, known and severe sleep issues such as obstructive sleep apnea, restless legs syndrome or insomnia, as referred from the patient and from medical records; possible adverse effect of the study. | 6 week double-blind, randomised, sertraline controlled intervention study | Symptoms of depression (HDRS assessment) decreased over time (Timepoints: baseline, week 2, 4, and 6), with no advantages or disadvantages for the saffron or sertraline condition. Saffron appears to be a natural powerful antidepressant for older people, who might be more reluctant to the use of synthetic medications. | medication adherence was not systematically assessed. Latent and unassessed dimensions, i.e., sleep quality, quality of social support, along with nutritional factors such as the intake of omega-3-polyunsaturated fatty acids, might have biased two or more dimensions in the opposite directions. The quality of the data does not explain why saffron had a favourable effect on symptoms of depression. Longer-term effect of saffron, sertraline, or both on depression should be investigated. | [343] |
| Crocin | 30 mg/day crocin (2 plus crocin tablet, 15 mg BID) (n = 25) (group 1) or placebo (2 tablets per day, 15 mg BID) (n = 25) (group 2.), one hour after taking food, for 8 weeks. | 50 patients–volunteers, aged 18–60 years under methadone maintenance treatment; participants had confirmed diagnosis of substance dependency based on DSM-IV. | taking crocin, multivitamin–mineral and antioxidant supplements during the last 3 months before the intervention initiation; history of metabolic diseases including diabetes, hypertension, thyroid and cardiovascular disease | 8 week randomised, double-blinded, placebo-controlled trial | Crocin administration to the patients during methadone maintenance treatment severely reduced depression and anxiety symtoms (BDI, BAI) as well as improved general health questionnaire scores, sleep quality (standardised sleep questionnaire Pittsburgh Sleep Quality Index) and sexual functions (International Index of Erectile Functions). Crocin can be recommended as an effective adjunct to methadone in opioid withdrawal protocols because of the ability to improve the quality of life and diminish opioid side effects in patients during methadone maintenance treatment. | too short duration of intervention; the pain in methadone-treated patients as well as the effects of crocin on biomarkers of inflammation, oxidative stress, and its related gene expression should be evaluated. | [389] |
| Saffron capsule | saffron capsule contained 15 mg stigma hydroalcohilic extract b.i.d. (g. 1) or placebo b.i.d. (g. 2). The demographic and clinical variables at baseline were the same in the two groups. |
73 adult overweight women with BMI ≥ 25 comorbid with mild-to-moderate depression. Depression was diagnosed with a semi-structured clinical interview based on SADS (Schedule for Affective Disorders and Schizophrenia) and the Beck Depression Inventory-II (BDI-II) designed to measure severity of depression consistent with symptoms of depression as presented in the DSM-V. The case score of BDI-II 14–28 was included into the studies. A total of 52 patients finished the study. |
severe depression—identified by a score of 29 or higher in BDI-II; other severe psychiatric disorders (bipolar mood disorder and schizophrenia, and those who had suicidal thoughts); taking antidepressants and other medications affecting the appetite, and bodyweight; pregnant, lactating and postmenopausal women; subjects with hypothyroidism and athletes. | 12 week randomised double-blind placebo-controlled trial | saffron capsules were not effective in reducing food cravings or bodyweight, but as a safe over-the-counter supplement, it may help reduce the symptoms of depression in overweight patients who experience mild or moderate depression. Mean depression scores in the saffron group significantly decreased compared to placebo. | the study was performed in a weight reduction clinic, so the cases may have had minor comorbidities, such as some types of eating disorders, but there were no cases of bulimia/purging behaviour. It was impossible to exclude all comorbidities but such covariates have been controlled with repeated-measures ANOVA. Chronic nature of depression and obesity imposes the need for long-term studies before firm conclusions can be made regarding saffron’s efficacy and safety. | [390] |
| Saffron capsule | capsule of saffron 30 mg/day (15 mg twice a day; morning and evening; group 1; n = 82) or capsule fluoxetine (20 mg twice a day; group 2; n = 82) for two menstrual cycles (cycles 3 and 4). The data were collected in two stages through a self-designed questionnaire (on day 5 of menstrual cycle) and validated questionnaires of Prospective Record of the Impact and Severity of Menstruation and Hamilton Depression Rating Scale at the end of the period. | 164, 20–45 years working women with the premenstrual syndrome | major physical or psychiatric disorder or substance abuse in the previous 6 months | 2 month double-blind, randomised Clinical Trial Study | Saffron to a similar extent as fluoxetine reduced the premenstrual syndrome symptoms such as abdominal bloating, depression, and mood swing, and could even better relieve the breast and abdominal pain than fluoxetine. Therefore saffron could be effective in reducing the symptoms and cause fewer side effects than chemical drugs. | using only a fixed dose of saffron and short period of follow-up. | [391] |
| Saffron extract | 30 mg saffron extract (Safr’InsideTM) standardised in SafromotivinesTM (a blend of more than 25 active compounds, including safranal >0.2% (HPLC)) (group 1) or a placebo group (control) for 8 weeks. Saffron capsule contained 15 mg saffron extract plus 345 mg maltodextrin. Placebo capsule contained 350 mg maltrodextrin. 26 subjects in placebo and 30 in saffron group completed the trial. Acute and chronic effects of saffron extract and placebo were assessed before, during, and after a laboratory stressor, the Observed Multitasking Stressor (OMS) on days 1, 14, 28, and 56 after treatment consumption. | Seventy-three male and female subjects aged 18–60 years who self-reported feelings of anxiety and/or stress and low mood in their daily lives; subjects had total score ≥ 40 on the Profile of Mood States 2 (POMS), <16 on the GAD-7 questionnaire, and ≤10 on the PHQ-9 questionnaire. | any psychological pathology (e.g., depression, generalised anxiety disorder) within the previous 3 years; body mass index (BMI) ≤ 18.5 or ≥30 kg/m2; uncorrected visual impairment; food allergies/insensitivities; an hormonal status likely to induce an unstable/fluctuating emotional state (e.g., menopausal transition); presence of life event likely to induce unstable/fluctuating emotional state (e.g., change of professional function/situation, death of a family member, divorce, surgery); high blood pressure (systolic over 159 mm Hg or diastolic over 99 mm Hg); pregnant women, seeking to become pregnant, or lactating; worked night shifts; high levels of physical activity (to avoid bias in the salivary cortisol measures); consumed >500 mg caffeine per day; current smokers; dietary supplement use 2 weeks before enrolment. | 8 week randomised, placebo-controlled, double-blind, parallel groups | saffron extract reduced depressive mood in healthy individuals experiencing subclinical mood disturbance. The beneficial effect of saffron on heart rate variability in response to a psychosocial stressor suggests that this natural extract may be particularly relevant for increasing resilience against the development of stress-related psychiatric disorders. Further studies are required to identify the exact mechanisms underpinning these effects in humans. Chronic effects of saffron on subjective anxiety, stress, and depressive feelings were assessed using a questionnaire battery (including Profile of Mood State-2, (POMS)) and acute effects in response to a lab-based psychosocial stressor were measured through psychological and physiological parameters. |
the OMS, evidenced by the pattern of response in the cortisol measure, masked an effect of treatment on anxiety measures or indeed any of the other subjective measures; laboratory-based stressors have inherent limitations in eliciting robust psychobiological stress responses that mimic those experienced in real-world situations- especially with repeated measurements, which have been discussed elsewhere; identifying potential participants with subclinical mood disturbance resulted in a comparatively small number of individuals with a very specific response pattern to the screening questionnaires being enrolled to the trial. | [392] |
| Saffron tablets (pure head powder of natural saffron compressed and without any additives) | resistance training (RT)+ saffron supplementation (150 mg pill of pure saffron; n = 15) (g. 1) or a RT+ placebo (dextrose pill; n = 15) (g. 2). pure saffron or placebo was administered immediately after each RT session and at the same time on non-training days for 6 weeks. |
Untrained young healthy males (age 24 years; stature 176.4 cm) who do not regularly exercise (<hour/week) and had no prior resistance training (RT) protocol experience. The RT program consisted of 24 RT sessions (6 weeks, 4 x/week). The exercises included leg presses, leg curls, bench presses, lat pulldowns, bicep curls, and triceps pushdowns |
allergy/sensitivity to saffron; any medical issues such as diseases, diabetes, sleep disorders, or other risk factors; taking dietary supplements, medications, consuming alcohol, or smoking during the year prior to enrollment in the study; subjects unwilling to undertake the nutritional or RT protocol; participatedin exercise other than the prescribed RT program during the investigation; participants consumed any dietary supplements; missed more than one RT session or post-RT saffron supplementation during the study period. Above-mentioned criteria were evaluated using the Physical Activity Readiness-Questionnaire (PAR-Q) and the medical health/history questionnaire. | 6 week randomised, double-blind placebo-controlled parallel trial | saffron combined with RT improved the concentration of blood markers implicated in depression (Anandamide, 2-Arachidonoylglycerol, dopamine, β-endorphin, and serotonin). Noth groups significantly increased muscular endurance with greater changes in the saffron-supplemented group. The addition of saffron supplement to chronic RT results in greater increases in levels of happiness (assessed via questionnaire “In general, do you feel happy?”) than RT alone. Furhter studies should evaluate the effects of different dosages of saffron supplementation in combination with RT in other populations, especially those with depression and low levels of happiness. | Body composition was evaluated via bioelectrical impedance, which is not as accurate as dual-energy X-ray absorptiometry (the gold standard technique for body composition measurements); lack of the measurements of the gene expression of the studied markers; as participants were previously untrained young males the generalisation of our findings to other cohorts should be avoided; since the RT program consisted of both upper and lower body exercises, the benefit of the RT intervention on muscular endurance might not be fully reflected by the the push-up specific test (an upper-body activity). Assessing lower body muscular endurance is required. | [393] |
| Crocin extracted and crystallised from saffron stogmas | 30 mg/day of crocin tablets or placebo during chemotherapy | Seventy-two newly diagnosed women with non-metastatic Her2/neu-positive or triple-negative invasive breast cancer. | Pregnancy or breastfeeding; treatment with antidepressants or anti-anxiety drugs (during study or within past 6 months); taking hormone replacement treatment, sleeping pills or beta-blockers, and warfarin, luminal A or B, other pathologies rather than carcinoma of breast; non-invasive breast carcinoma in the absence of invasive components; history of hypersensitivity reactions to saffron | patients received crocin for 4 months during 4–6 months course of chemotherapy; depression and anxiety were assessed at baseline and the end of the trial (2 weeks after the last course of chemotherapy); patients were followed up for one year to assess the survival; block randomised, double-blind, parallel-group placebo controlled trial | Crocin administration during chemotherapy of breast cancer significantly ameliorated anxiety and depression (improved Beck’s Depression and Anxiety Inventories). Crocin coadministration affected the chemotherapy side effects assessed with Eastern Cooperative Oncology Group Common Toxicity Criteria leading to significant increase of leukopenia as well as decrease of hypersensitivity reaction and neurological motor dysfunction, but the frequencies of most side effects were equal in both groups. In addition, a trend toward survival improvement was observed, which is going to be investigated on longer follow up. | relatively short follow-up limited the extrapolation regarding the long-term effects of crocin on survival, anxiety and depression. Crocin was only administered during chemotherapy, and the effects of long-term use after chemotherapy are unclear. Further similar extrapolations enrolling patients with various sub-types of breast cancer (luminal cancer) and other malignancies are necessary. Poor compliance of some patients, small sample size, self-reported assessments of side effects, and also some confounding factors such as ethnicity or genetic diversity that their effects cannot be ruled out. Did not assess some confounding factors i.e., the level of cognitive function, pain recognition, and patients’ diets. | [394] |
| Saffron capsule | capsule (at 2:00 pm) before a meal containing 100 mg saffron powder (group 1.) or placebo (starch) (group 2.) for 8 weeks. A total of 30 subjects of each group completed the trial. | Seventy, 30–60 year-old overweight/obese patients with body mass index (BMI) between 25–35 kg/m2 type 2 diabetes (T2D) for at least 6 months diagnosed with fasting plasma glucose test FPG ≥126 mg/dL | insulin treatment, hormone replacement therapy and consuming dietary or antioxidant supplements in the previous 2 months; history of surgery or serious illness; pregnancy or lactation; smoking or alcohol intake. Anti-hyperlipidaemic and hypoglycaemic medications such as metformin were permitted over the study period. | 8 week double-blind, randomised, placebo-controlled clinical trial | saffron notably reduced hyperglycaemia and hyperlipidaemia as well as improved liver function in T2D patients. Saffron also significantly improved depression (Beck depression inventory-II BDI-II), sleep quality and overall quality of life in diabetic patients. However, further long-term studies with each component of saffron are required to investigate the underlying mechanisms and to suggest saffron as an effective complementary and alternative therapy in type 2 diabetes | relatively short duration and the fixed-dose design of the study that did not allow to investigate dose-dependent effects. Some dietary factors (vitamin D, selenium, magnesium and chromium), which might act as confounders, were not evaluated. | [395] |
| Krocina™—a herbal medicine made of crocin | Krocina™ (15 mg) or placebo pill twice a day for 6 weeks | seventy-two, 18–64 years old opioid-dependent male patients passing the detoxification course and negative urinary test, who were referred to the Center for Substance Abuse Treatment and Addictive Behaviours (Soroush). | mood disorder; acute psychiatric disorders; the incidence of psychosis symptoms | 6 week double-blind randomised parallel clinical trial | Krocina™ pills were ineffective in the decreasing substance users’ withdrawal syndrome, craving, depression, anxiety and stress in the detoxification period and abstinence phase. Similar findings were confirmed in patients with the negative urinary test only. Some psychological treatment protocols such as motivational interviewing sessions that routinely provided for subjects in the detoxification period are needed. | Low sample size and short duration of therapy | [396] |
Explanations: b.i.d.—bis in day morning and evening; BDI—Beck depression inventory; BMI—body mass index; CDA—comorbid depression-anxiety; g.—group; DSM—The Diagnostic and Statistical Manual of Mental Disorders; HRSD or HDRS—Hamilton Rating Scale for Depression or Hamilton Depression; ICD10—International Statistical Classification of Diseases and Related Health Problems 10th Revision definition; IDS-SR30 score—Inventory of Depressive Symptomatology self-rated version; MDD—major depressive disorder; OCD—obsessive-compulsive disorder; STAI—Spielberger State Trait Anxiety Inventory.