Reviewed: Yang X, Chen X, Fu Y, et al. Comparative efficacy and safety of Crocus sativus L. for treating mild to moderate major depressive disorder in adults: a meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat. May 21, 2018;14:1297-1305. doi: 10.2147/NDT.S157550.

Major depressive disorder (MDD) is a common, sometimes serious mood disorder that may require long-term treatment. Pharmaceutical antidepressants can reduce depressive symptoms, but they are not effective in some patients and often have adverse side effects that are difficult to tolerate. Additional safe and effective therapies are needed. Saffron (Crocus sativus, Iridaceae) dried flower stigma is one of the world’s most expensive spices. Saffron has antioxidant, anti-inflammatory, and antidepressant activities. Clinical trials performed with both saffron stigma and flower petal extracts suggest that saffron may be a safe and effective alternative to synthetic antidepressants. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of saffron extract preparations in adults with MDD.

Researchers at The First Affiliated Hospital of Chongqing Medical University in Chongqing, China, searched PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov databases from inception to September 20, 2017, using the search terms “saffron,” “crocus,” “crocus sativus,” “depression,” “depressive,” “mood disorder,” and “affective disorder.” Literature citations from relevant publications were hand-searched. Included trials were double-blind, randomized trials that used a synthetic antidepressant or placebo control, enrolled adults with a diagnosis of MDD receiving monotherapy, and were published in any language. Trials that enrolled patients with depression that was secondary to a physical disease or enrolled a small number of patients (N < 10) were excluded. Methodological quality was assessed using the Cochrane Collaboration’s risk of bias tool. The primary outcome was the mean overall change in depression symptoms from baseline to the end of the intervention. Secondary outcomes were remission rates (defined as the proportion of patients with Hamilton Depression Rating Scale [HAM-D] scores less than seven at the end of the studies), response rates (the proportion of patients with at least a 50% reduction in HAM-D scores from baseline), and dropout rates.

A total of 128 unique articles were identified, and seven trials met the criteria to be included in the meta-analysis. Patients (N = 316) had depression of mild-to-moderate severity at baseline, according to HAM-D and Beck Depression Inventory (BDI) scores. Saffron dosages were 15-30 mg/day (n = 1 trial), 30 mg/day (n = 5), and 100 mg/day (n = 1). Control agents used in the trials included placebo (n = 3), fluoxetine (n = 2), imipramine (n = 1), and citalopram (n = 1). Treatment duration ranged from six to 12 weeks. All trials were conducted in Iran, and results were published from 2004 to 2017.

In the combined analysis (as well as in each of the individual trials), depression symptoms improved significantly more in the saffron group compared to the placebo group (P = 0.001). Saffron was about as effective as synthetic antidepressants in improving depression symptoms, with no significant difference found between the groups.

Remission and response rates were reported in only two trials that used synthetic antidepressants as controls. No significant differences in remission and response rates were found between the saffron and synthetic antidepressant groups at the end of these two trials. No difference in dropout rates was found between the saffron and placebo or synthetic antidepressant groups.

The quality of the trials was rated as moderate. Heterogeneity among the placebo-controlled studies was high, and most of the variation was due to treatment duration and dosage. Heterogeneity among antidepressant-controlled studies was rated as mild. Saffron “did not increase” the risk of adverse events compared to placebo and synthetic antidepressants (no data were reported).

The authors conclude that “saffron was effective for treating MDD and had comparable efficacy to synthetic antidepressants” and therefore “could be considered as an alternative to CBT [cognitive behavioral therapy] or synthetic antidepressants.” The authors noted that commercial saffron is expensive, which may limit medicinal use. One of the trials included in this meta-analysis tested saffron petals instead of saffron stigma and found antidepressant effects. Petals are much less expensive than stigmas, which could facilitate more widespread use of the species for medicinal purposes.

There are several limitations to this meta-analysis. The number of eligible trials and the overall sample size were small. All studies were conducted in one country, mostly by the same group of investigators. It may be difficult to extend the results of this study to other populations. The authors stated that more well-designed studies with longer treatment durations and inclusion of different ethnic groups are needed. Further studies of the petals of saffron would also be useful.