Ghajar A, Neishabouri SM, Velayati N, et al. Crocus sativus L. versus citalopram in the treatment of major depressive disorder with anxious distress: a double-blind, controlled clinical trial. Pharmacopsychiatry. 2016 Oct 4. [Epub ahead of print].
Randomized, double-blind, controlled clinical trial
Investigators in Tehran, Iran, recruited 66 men and women aged 18 to 65 years with a diagnosis of mild to moderate major depression with anxious distress. They were randomized to take either a selective serotonin reuptake inhibitor (SSRI; citalopram, 20 mg) or saffron (Crocus sativus L. standardized to 1.65-1.75 mg crocin per capsule) extract (15 mg) 2 times per day for 6 weeks; 30 participants in each group finished the study.
Exclusion criteria included receipt of any antidepressant medication during the previous month; receipt of electroconvulsive therapy (ECT) during the last 2 months; diagnosis of other mental disorders on the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV Axis I; alcohol or substance (with the exception of nicotine) dependence; and severe depression or suicidal ideation. Participants were not allowed to use any other psychotropic medication or undergo behavioral intervention therapy during the trial course.
Study Parameters Assessed
Participants were assessed using the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A), at baseline then again at 2, 4, and 6 weeks.
The primary outcome measure was the efficacy of saffron in improving depressive and anxiety symptoms during the trial compared with citalopram, which was used as a comparator because it has the best combination of high efficacy with low adverse effects in this population.
Secondary outcomes measures included changes in HAM-D and HAM-A from baseline to each time point, and response to treatment (defined as ≥50% reduction in the HAM-D score) and remission (defined as HAM-D score ≤7) rates between the treatment groups.
Baseline anxiety and depression were equivalent in the saffron and comparator groups. Symptoms of both depression and anxiety significantly improved over the 6-week period, in equivalent amounts in both groups.
At week 6, 90% of the citalopram group and 73% of the saffron group had experienced a ≥50% reduction in their HAM-D score, a nonsignificant difference (P=0.18). Also at week 6, 87% of the citalopram group and 63% of the saffron group were in remission (HAM-D ≤7), which trended toward but did not reach significance in favor of citalopram (P=0.07).
Saffron was first mentioned as medicine in the Ebers Papyrus over 3,500 years ago, as a 'cheering cardiac medicament.'
Anxiety decreased significantly and equivalently in both groups. At 6 weeks HAM-A scores fell from 19.1 to 7.0 in the citalopram group, and from 19.7 to 7.6 in the saffron group.
Adverse events were comparable in both groups, with no serious events and no events frequent enough to reach statistical significance, although 16.7% of the citalopram group experienced vertigo (and none in the saffron group), which trended toward but did not reach significance (P=0.052).
Clinical anxiety and clinical depression occur together frequently, in what the DSM-5 calls major depression with anxious distress. Patients with both depression and anxiety have worse outcomes than those with depression or anxiety alone—worse sickness, more serious adverse events and side effects, and less frequent remission.1
An SSRI plus placebo was previously compared to an SSRI plus crocin (the constituent that the saffron in this study was standardized to), and the group that received crocin experienced significantly greater improvement in symptoms of depression and anxiety, with benefits to general health.2 Separately, a meta-analysis of saffron for major depressive disorder found a large effect size over placebo and non-inferiority compared to pharmaceutical antidepressants.3
This present study, the first to compare saffron to an active comparator in patients with depression and anxiety, reveals that saffron as a sole intervention can significantly improve symptoms of not only depression but also anxiety, possibly as much as they might improve on a therapeutic dose of citalopram.
Saffron’s mechanisms of action may include serotonergic, antioxidant, anti-inflammatory, neuroendocrine, and neuroprotective effects.4 It has been studied as an antitumor agent5 and as an intervention for premenstrual syndrome, sexual dysfunction, and excessive snacking behaviors.6
Saffron was first mentioned as medicine in the Ebers Papyrus over 3,500 years ago, as a “cheering cardiac medicament,” and has been used safely for a very long time—no serious adverse events have been associated with its use, no clinically important adverse events have been associated with short-term use of moderate doses, and the estimated LD-50 (lethal dose, 50%; the amount that would kill half of test subjects) is 1.4 kg for a 150- pound human,7 an astoundingly high amount. There are texts that warn of dangers of saffron, but these are likely conflating the topic of this article, our “saffron” (Crocus sativus L.), a crocus that blooms in the fall, with “autumn crocus” (Colchicum autumnale), which is not a true crocus but also blooms in the fall.8
In clinical practice, how are we to dose this safe, effective herb for our anxious, depressed patients? The authors of this study use a daily dose of 30 mg of a saffron stigma extract standardized to a total of about 3.4 mg of crocin. Other groups have also found favorable results with extracts from the petals of the flower.9 If we do not yet have access to a standardized extract from a trustworthy source, we can turn to the spice itself, the whole dried stigmas available for culinary use. Culinary saffron can vary between 13 mg and 109 mg of crocin (including all crocins detected at 440 ηm) per gram of pistil,10 but most dried Iranian saffron pistils more often contain about 35 mg crocins per gram.11
At a concentration of 35 mg crocins per gram of saffron pistil, we’d need to prescribe 100 mg twice per day to match the dose of crocin used in this study. Large online retailers are selling saffron for $120 per ounce; this equates to 280 doses of saffron, about 86 cents per day, or $26 per month—about twice the cost of citalopram, but still affordable.12 Even this small dose may be excessive; one study found that just sniffing undetectable amounts of saffron was able to detectably reduce anxiety.13
By weight, this is the world’s most expensive spice, but it appears to be potent enough that it is relatively affordable, on top of being safe and effective. We should anticipate 4 to 6 weeks of treatment before our patients will start to notice a significant difference.
Editor's note: This page was updated on December 16, 2016, to correct the monthly and daily costs of saffron.
- Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008 ;165(3):342-351.
- Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord. 2015;174:51-56.
- 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;11(6):377-383.
- Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol. 2014;29(6):517-527.
- Bolhassani A, Khavari A, Bathaie SZ. Saffron and natural carotenoids: biochemical activities and anti-tumor effects. Biochim Biophys Acta. 2014;1845(1):20-30.
- Hausenblas HA, Heekin K, Mutchie HL, Anton S. A systematic review of randomized controlled trials examining the effectiveness of saffron (Crocussativus L.) on psychological and behavioral outcomes. J Integr Med. 2015;13(4):231-240.
- Srivastava R, Ahmed H, Dixit RK, Dharamveer, Saraf SA. Crocus sativus L.: A comprehensive review. Pharmacogn Rev. 2010;4(8):200-208.
- Dharmananda S. SAFFRON: An Anti-Depressant Herb. Institute for Traditional Medicine web site. http://www.itmonline.org/articles/saffron/saffron.htm. Published May 2005. Accessed Nov 14, 2016.
- Akhondzadeh Basti A, Moshiri E, Noorbala AA, Jamshidi AH, Abbasi SH, Akhondzadeh S. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: a pilot double-blind randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(2):439-442.
- Caballero-Ortega H, Pereda-Miranda R, Riverón-Negrete L, Abdullaev FI. Chemical composition of saffron (Crocus sativus L.) from four countries. Acta Horticulturae. 2004;650(650):321-326.
- Hadizadeh F, Mahdavi M, Emam SA. Evaluation of ISO method in saffron qualification. Acta Horticulturae. 2007;739:405-410.
- Drug Cost Estimates – Generic. Blue Cross Blue Shield of Illinois web site. http://www.bcbsil.com/aon/pdf/aon_top50generics.pdf. Accessed Nov 14, 2016.
- Fukui H, Toyoshima K, Komaki R. Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus). Phytomedicine. 2011;18(8-9):726-730.