Depression is characterized by changes in mood, as well as cognitive and physical symptoms over a two-week period. It is associated with high societal costs and greater functional impairment than many other chronic diseases, including diabetes and arthritis.1 According to data from the Centers for Disease Control and Prevention,2 a substantial proportion of Americans suffered mild (1 percent), moderate (5.1 percent), or severe (2.9 percent) depression. Combined, 8 percent (roughly 1 in 12) Americans have moderate to severe depression; and women are more likely to be depressed than men.
Conventional Therapy for Depression: Limitations
Typically, conventional therapy for depression may include psychological counseling (e.g. cognitive therapy) and/or pharmaceutical intervention with antidepressant medications. However, a meta-analysis published in the Journal of the American Medical Association3 examined the results of several studies on the use of antidepressant medications and found that only patients with severe depression experienced significant benefit from the antidepressants. Those whose depression was more mild tended not to experience any more benefit than they would when taking a placebo. That means for those individuals who are age 18 and older and who have chronic, mild depression,4 antidepressant medication may not always provide significant relief with ongoing use.
Furthermore, pharmaceutical treatments for depression are often associated with side effects. For example, common side effects of fluoxetine (e.g. Prozac) include nausea, upset stomach, constipation, headaches, anxiety, sleep problems (insomnia), drowsiness, dizziness, nervousness, heart palpitations, loss of appetite or increase in appetite, weight changes, cold symptoms (stuffy nose, sneezing, sore throat), dry mouth, and sexual dysfunction (decreased sex drive, erectile dysfunction or difficulty having an orgasm).
These limitations of conventional therapy for depression opens the door for herbal alternatives to pharmaceutical antidepressants—especially those that have efficacy in mild-to-moderate depression.
Saffron: A Natural Option for Depression
Arguably, the best-known herbal medicine for depression is St. John’s wort. Unfortunately, while effective, it is also the herb most associated with herb/drug interactions. However, there is another highly researched herb shown in clinical studies to have significant efficacy in the treatment of depression—including mild-to-moderate depression: saffron.
Crocus sativus L, commonly known as saffron, is a medicinal flowering plant cultivated in many countries including Iran, Afghanistan, Turkey and Spain, where it has been widely used to promote human health. Saffron has been suggested to be effective in the treatment of a wide range of disorders including coronary artery diseases, hypertension, stomach disorders, dysmenorrhea and learning and memory impairments. In addition, different studies have indicated that saffron has anti-inflammatory, anti-atherosclerotic, antigenotoxic and cytotoxic activities.5 The efficacy of saffron in the treatment of mild to moderate depression (as well as major depression) has also been reported and is the subject of this article.
Active Compounds and Antidepressive Activity
Most clinical and mechanistic studies have been performed with Iranian saffron. The clinical trials on mood have been, for the most part, conducted with hydro-alcoholic extracts of Iranian saffron stigmas (the ovule producing part of a flower). Most saffron extracts have been standardized at 2 percent safranal (by UV), a primary active compound responsible for saffron’s mood benefits. In addition, there is evidence that saffron’s antidepressant properties are also provided by crocin, and its precursor crocetin, as well as kaempferol. Furthermore, recent studies have highlighted the involvement of many secondary and derivative compounds present in Iranian saffron stigmas, which may provide secondary effects. Collectively, these compounds are referred to as safromotivines. Consequently, to maximize antidepressant efficacy, a saffron extract should be from Iranian origin, obtained from saffron stigmas, be standardized for 2 percent safranal (by UV), but also be rich in crocins while providing safromotivines. One such extract is Safr’Inside (from Activ'inside, supplied by Seppic in North America), discussed in the open study below.
As an antidepressant, saffron and its compounds are interesting because they appear to have more than one mechanism of action. Hausenblas et al.6 has proposed that saffron extract increases serotonin levels in the brain. Ettehadi et al. showed that the saffron extract increased brain dopamine concentration in a dose-dependent manner. Hosseinali et al.7 found that, in addition to dopamine, saffron extract increased the production of brain glutamate levels in animal research. Other contributing beneficial effects on the brain include saffron’s activity against oxidative damages and neurotoxicity. It has been reported that the saffron compound crocin inhibited the formation of peroxidized lipids, moderately restored superoxide dismutase (SOD) activity and maintained neurons morphology. While the antioxidant effect of crocin was comparable to that of α–tocopherol, it was even more pronounced at some concentrations. Furthermore, saffron extract prevented an increase in inflammation, oxidative stress and neuronal damage biomarkers that would otherwise have occurred due to exposure by the insecticide, diazinon.9 So all in all, saffron extract has some impressive, broad-spectrum actions that are good for brain chemistry.
Now that we know how it works, let’s take a look at some of the studies on saffron extract, which have primarily been conducted in Iran.
Saffron Open Study
An open study10 (see chart) was conducted with 41 healthy women and men, aged 22 to 63, using 15 mg of saffron stigma extract (Activ'inside, supplied by Seppic in North America), twice daily (total of 30 mg/day) for 30 days. At days 15 and 30, a questionnaire was submitted, assessing results. A subpopulation of 35 people was also assessed for overall satisfaction and effectiveness with regard to product promises. Consistent with results from the Iranian studies, the saffron stigma extract, after 15 days more than three out of four subjects felt happier and more optimistic, about three out of four subjects perceived emotional balance improvements, and more than two out of three subjects felt more relaxed, zen, serene and dynamic (i.e. dynamism for daily activities). In addition, after 30 days, more than 50 percent of subjects felt better sleep quality (up 11 percent from day 15).
Saffron Placebo-controlled Study 1
The objective of this study was to assess the efficacy of the stigmas of saffron stigma extract in the treatment of mild to moderate depression in a six-week double-blind, placebo-controlled and randomized trial.11 Forty adult outpatients with 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. Patients were randomly assigned to receive 30 mg/day of saffron stigma extract (Group 1) or a capsule of placebo (Group 2). At six weeks, saffron stigma extract produced a significantly better outcome on the Hamilton depression rating scale than the placebo (P < 0.001). There were no significant differences in the two groups in terms of the observed side effects. The results of this study demonstrate the efficacy of saffron stigma extract in the treatment of mild to moderate depression.
Saffron Placebo-controlled Study 2
Some patients who use fluoxetine for depression may experience fluoxetine-related sexual dysfunction. Since saffron has shown aphrodisiac effects in some animal and human studies, a four-week randomized double-blind placebo-controlled study12 was conducted to assess the efficacy and tolerability of saffron stigma extract in treating fluoxetine-related sexual dysfunction. Thirty married male patients with major depressive disorder (MDD) whose depressive symptoms had been stabilized on fluoxetine, and who had subjective complaints of sexual impairment, entered the study. The patients were randomly assigned to 30 mg/day saffron stigma extract or placebo for four weeks. International Index of Erectile Function scale was used to assess sexual function at baseline and weeks two and four. Baseline characteristics as well as baseline and final depressive symptoms scores were similar between the two groups. Results were that there were significant improvements in sexual dysfunction (P = 0.009). By week four, saffron resulted in significantly greater improvement in erectile function (P < 0.001) and intercourse satisfaction (P = 0.001), and total sexual health scores (P < 0.001) than the placebo group. Nine patients (60 percent) in the saffron group and one patient (7 percent) in the placebo group achieved normal erectile function (score > 25 on erectile function domain) at the end of the study (P = 0.005). Frequency of side effects was similar between the two groups. In conclusion, saffron is a tolerable and efficacious treatment for fluoxetine-related erectile dysfunction.
Saffron/drug Comparison Study 1
A six-week double-blind, randomized pilot trial13 was conducted with the objective of comparing the efficacy of saffron stigma extract with imipramine (e.g. Tofranil). Thirty adult outpatients with major depression participated in the trial. Patients had a baseline Hamilton Rating Scale for Depression score of at least 18. Patients were randomly assigned to receive 30 mg/day of saffron stigma extract (Group 1) and 100 mg/day of imipramine (Group 2). Results demonstrated that, at this dose, Saffron was found to be effective similar to imipramine in the treatment of mild to moderate depression (P<0.001). In the imipramine group anticholinergic effects such as dry mouth and also sedation were observed more often. In conclusion, the main overall finding from this study is that saffron offered therapeutic benefit in the treatment of mild to moderate depression.
Saffron/drug Comparison Study 2
A significant correlation exists between coronary artery diseases and depression. The aim of this randomized double-blind parallel-group trial14 was to compare the efficacy and safety of saffron stigma extract versus fluoxetine in improving depressive symptoms of 40 patients who were suffering from mild to moderate depression after having undergone percutaneous coronary intervention (PCI) in the last six months. Patients were randomized to receive either fluoxetine (40 mg/day) or saffron stigma extract (30 mg/day) for six weeks and were evaluated by Hamilton depression rating scale (HDRS) at weeks three and six. Results showed that by the study endpoint, both treatments appeared to be equally effective, with no significant differences between two groups in reduction of HDRS scores. Remission and response rates were similar as well. There was no significant difference between two groups in the frequency of adverse events during this trial. In 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.
Saffron/drug Comparison Study 3
The objective of this study was to compare the efficacy of saffron stigma extract with fluoxetine in the treatment of mild to moderate depression in a six-week double-blind, randomized trial.15 Forty adult outpatients with mild to moderate depression participated in the trial. Patients were randomly assigned to receive 30 mg/day of saffron (Group 1) and 20 mg/day of fluoxetine (Group 2). The results were that, at this dose, saffron was found to be similarly effective to fluoxetine in the treatment of mild to moderate depression. There were no significant differences in the two groups in terms of observed side effects. The results of this study demonstrate the efficacy of saffron stigma extract in the treatment of mild to moderate depression.
Saffron Meta-analysis 1
While looking at the results of individual studies is important, a comprehensive and statistical review of the clinical trials examining the effects of saffron for the treatment of MDD was warranted. Consequently, a meta-analysis16 of published randomized controlled trials was conducted to examine the effects of saffron supplementation on symptoms of depression among participants with MDD. Results were that, five randomized controlled trials (n = 2 placebo-controlled trials, n = 3 antidepressant-controlled trials) were included in the review. A large effect size was found for saffron supplementation vs placebo control in treating depressive symptoms (P < 0.001), revealing that saffron supplementation significantly reduced depression symptoms compared to the placebo control. A null effect size was evidenced between saffron supplementation and the antidepressant groups indicating that both treatments were similarly effective in reducing depression symptoms. In conclusion, findings from clinical trials conducted to date indicate that saffron supplementation can improve symptoms of depression in adults with MDD.
Roughly one in 12 Americans have moderate to severe depression, and 15.6 percent of Americans have mild depression. While pharmaceutical intervention with antidepressant medications is commonly used, they may not always be effective for those with chronic, mild depression. Furthermore, pharmaceutical treatments for depression are often associated with a number of side effects. As clinically demonstrated in multiple studies, the use of saffron stigma extract offers an effective alternative to conventional pharmaceutical treatment of depression—although if a depressed individual is already using a pharmaceutical, it is important to not abruptly switch to saffron stigma extract, but rather to work with a doctor in that situation. In any case, saffron stigma extract’s multiple mechanisms of action, and demonstrated efficacy and safety make this herbal medicine an appealing option for the treatment of depression. Safr’Inside (from Activ'inside, supplied by Seppic in North America) mirrors the composition of primary and secondary compounds from the saffron stigma extract used in the aforementioned studies. VR
1 Brody DJ, Pratt LA, Hughes JP. Prevalence of Depression Among Adults Aged 20 and Over: United States, 2013–2016. NCHS Data Brief No. 303, February 2018. Retrieved October 26, 2018 from www.cdc.gov/nchs/products/databriefs/db303.htm.
2 Berezow A. CDC: 1 In 12 Americans Has Moderate To Severe Depression. That Might Be An Underestimate. American Council on Science and Health. March 8, 2018. Retrieved October 26, 2018 from www.acsh.org/news/2018/03/08/cdc-1-12-americans-has-moderate-severe-depression-might-be-underestimate-12680.
3 Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010;303(1):47-53.
4 Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry 2005;62(6):617-27.
5 Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, M Tsatsakis A. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed. 2015 Sep-Oct;5(5):376-91.
6 Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med. 2013 Nov;11(6):377-83.
7 Ettehadi Hosseinali, Seyedeh Nargesolsadat Mojabi, Mina Ranjbaran, Jamal Shams, Hedayat Sahraei, Mahdi Hedayati, Farzad A. Aqueous Extract of Saffron (Crocus sativus) Increases Brain Dopamine and Glutamate Concentrations in Rats. J Behav Brain Sci. 2013;3:315–319.
8 Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, Tsatsakis AM. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed. 2015 Sep-Oct; 5(5): 376–391.
9 Moallem SA, Hariri AT, Mahmoudi M, Hosseinzadeh H. Effect of aqueous extract of Crocus sativus L. (saffron) stigma against subacute effect of diazinon on specific biomarkers in rats. Toxicol Ind Health. 2014 Mar; 30(2):141-6
10 Is Safr’Inside efficient on mood in only 15 days? Proprietary consumer study. Customer Technical Support. CTS-0138. Active Inside. Update 01 from 03/05/2018. Elaboration date 18/10/2017: 2 pgs.
11 Akhondzadeh S Tahmacebi-Pour N, Noorbala AA, Amini H, Fallah-Pour H, Jamshidi AH, Khani M. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial. Phytother Res. 2005 Feb;19(2):148-51.
12 Modabbernia A, Sohrabi H, Nasehi AA, Raisi F, Saroukhani S, Jamshidi A, Tabrizi M, Ashrafi M, Akhondzadeh S. Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology (Berl). 2012 Oct;223(4):381-8.
13 Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med. 2004 Sep 2;4:12.
14 Shahmansouri N, Farokhnia M, Abbasi SH, Kassaian SE, Noorbala Tafti AA, Gougol A, Yekehtaz H, Forghani S, Mahmoodian M, Saroukhani S, Arjmandi-Beglar A, Akhondzadeh S. 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. J Affect Disord. 2014 Feb;155:216-22.
15 Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi AH. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol. 2005 Feb 28;97(2):281-4.
16 Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med. 2013 Nov;11(6):377-83.
Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at email@example.com.