Depression is a complex and debilitating disease that affects more than 300 million people globally, with a lifetime prevalence of 10-15% (1,2). Anxiety and related disorders are also among the most common mental illnesses in the general population, affecting more than one in three adults during their lifetime (3,4). 

Comorbidity rates of anxiety disorders in depression are high, with approximately 50% of individuals with major depressive disorder (MDD) experiencing at least one anxiety disorder (5).

Antidepressant medications are commonly used as first-line therapy for both depression and anxiety. However, they have multiple negative side effects, and a significant proportion of individuals obtain little or no benefit (7,8). Benzodiazepines are used for anxiety but have limited effects in relieving coexisting depressive symptoms and have many unwanted side‐effects (9). Accordingly, research is targeting safer, more effective, and better tolerated alternatives to antidepressant medication.

Saffron (Crocus sativus), belonging to the Iridaceae family, has emerged as a promising therapeutic for depression and anxiety based on traditional use and contemporary clinical research (10,11). Besides the use in the culinary field, saffron has been used for several thousand years in Asian medicine, particularly in Persian, Chinese and Ayurvedic traditional medicine (10,12). 

It has been proven to possess antioxidant (13,14), anti-inflammatory (15,16,17), anticonvulsant (18,19), anti-tumour (20), neuroprotective (21,22,23,24) and nootropic (cognition-enhancing) effects (25).

The major bioactive constituents, crocins (derived from crocetin; a water-soluble pigment), picrocrocin (bitter substance), and safranal (an essential oil), are responsible not only for the colour, taste and aroma of saffron but also for the medicinal properties associated with it (10,11). 

The antidepressant activity of saffron and its constituents has been demonstrated in numerous preclinical trials. Recently, controlled clinical trials have shown the positive effects of saffron stigma and petal extracts on depressive symptoms, particularly in patients with mild-to-moderate depression (10,26,27,28,29,30). Also, saffron has demonstrated extensive anxiolytic effects in experimental models, and clinical trials show positive results in generalised anxiety disorder (31) and anxious depression (32,33).

Traditional Understanding

Depression is now understood to involve a complex interplay of immunologic and endocrine responses. Together with genetic factors and environmental stressors, these responses result in dysfunctional neurogenesis and neurotransmission (34,35).

Abnormalities of the serotonergic, noradrenergic, glutamatergic, and γ-aminobutyric acidergic (GABAergic) transmission are indicated in the development of anxiety. Immune-inflammatory aberrations, hypothalamic-pituitary-adrenal (HPA)-axis dysregulation and hyperactivity within the amygdala are also associated with anxiety (36,37).

The clinical characteristics and inferior prognosis of anxious depressive patients reveal that it may have distinct neurobiology that separates it from non-anxious depression (6). Although not well understood, anxious depression seems to be associated with increased immune and HPA axis dysregulations, and brain abnormalities compared to non-anxious depression. These brain abnormalities include more severe cortical thinning, and increased corticolimbic functional connectivity patterns (38,39).

Targeting multiple neuroendocrine systems in comparison to a single neurotransmitter may be a more successful approach, due to the complexity of mood disorders. Conventional pharmacotherapies only act through neurotransmitter augmentation and regulation. Herbal medicines, on the other hand, contain many bioactive constituents that often have different biological effects and work synergistically, and therefore offer promising alternatives to conventional medications.

Saffron is increasingly sought after for its traditional and evidence-based medicinal uses. In traditional medicine, saffron is used as an aphrodisiac or to treat various health conditions including menstrual disorders, seizures, asthma, insomnia, liver or gallbladder disorders, cognitive disorder, anxiety, and depression (40,41).

In Ayurvedic medicine, saffron is used as an adjuvant for increasing body resistance against stress, trauma, anxiety, and fatigue (11).

More recently, saffron has been used for mood disorders (27); Alzheimer’s disease and cognitive impairment (42); metabolic syndrome and diabetes mellitus (43), retinal disease (44), and cardiovascular disease (45).

Latest Research

In the last 20 years, nearly 30 clinical trials have investigated the efficacy and safety of saffron for improving mood in depressed and anxious patients. The most substantial evidence to support the effectiveness of saffron exists for mild-to-moderate depression (10,26,28,46).

Mild-to-moderate depression

Several systematic reviews and meta-analyses of randomised controlled trials demonstrate that saffron is significantly superior to placebo and has equivalent efficacy to antidepressants for improving depressive symptoms in adults (aged 18 to 60 years) with clinically diagnosed mild-to-moderate depression (10,26,27,28,29,30). In studies of clinical depression, saffron is comparable in efficacy to the pharmaceutical antidepressants: fluoxetine, citalopram, and impramine (32,47,48,49,50).

Saffron has been used safely as adjunct to antidepressant medications in several clinical trials; however, results on therapeutic efficacy from research are inconsistent (51,52,53,54). The addition of crocin to antidepressant medications resulted in larger improvements in depressive symptoms compared with placebo (54). In other small, short studies, the adjunct use of saffron with fluoxetine did not potentiate antidepressant effects compared to fluoxetine only (51,53).

Saffron supplementation has been shown to improve adverse effects of antidepressant medication (sexual dysfunction) (55,56).

Depression in special cohorts/comorbidities

In addition to the trials on MDD, saffron has been clinically trialled in special patient cohorts with co-morbid depression or non-clinical depression, and has been shown to be safe and have positive effects on depressive symptoms various conditions (Table 1).

Anxiety

The benefits of saffron for anxiety are less well studied than depression, with only one clinical trial investigating benefits in Generalised Anxiety Disorder (GAD) (31). Saffron potentiated the effects of sertraline in patients with GAD; however, the trial findings were limited by small sample size (n=40) and short duration (6 weeks).

Several studies have investigated efficacy of saffron for reducing anxiety symptoms in individuals with mild-to-moderate depression. Saffron was more effective than placebo (33) and was as effective as citalopram (32) for improving anxiety symptoms in patients with MDD.

Crocin as an adjunct to antidepressant medication for 4 weeks significantly improved the symptoms of anxiety compared to placebo (54).

Supplementation with saffron, or crocin, has also improved anxiety symptoms in individuals with other co-morbidities including PMS (58), burning mouth syndrome (63), and diabetes (61).

Limitations and future saffron-mood disorder research

Saffron has been shown to have relatively quick effects on depressive symptoms (as early as 2 weeks) in clinical trials, which is of clinical relevance since pharmaceutical antidepressant medication can take 4 to 6 weeks to reduce depressive symptoms (69,70,71). However, the long-term efficacy of saffron for mood disorders is unknown, as current studies have only been 4 to 12 weeks in duration.

The antidepressant activity of saffron is largely attributed to bioactive constituents present in the stigma (crocin and safranal). Accordingly, most clinical trials have used extracts derived from the stigmas, at a dose of 30 mg saffron per day. However, saffron petal has been shown to have equal efficacy to the stigma in reducing depressive symptoms (72,73,49). Given the high cost of the stigma, further clinical trials assessing the antidepressant activity of the petal are warranted (74). It is also unclear whether other dosing regimens may enhance the therapeutic effect of saffron, and there is a need for dose-escalation studies to identify the optimum dosing regimen for various mood disorders.

Few studies used standardised saffron extracts (standardised for safranal and/or crocin). Standardisation is a method to reduce product variability by ensuring that each batch of the herbal extract contains a consistent amount of one or more bioactive constituents and allows for comparison between clinical trials (75). Standardisation is particularly important for herbal medicines such as saffron, which are subject to adulteration (76). Given the significant variance associated with the quality of saffron stigmas and the variability in extracts available on the market, caution must be applied in the clinical application of current study findings to other saffron extracts.

Saffron is emerging as a beneficial therapy for depression and anxiety. However, optimal dosage, treatment duration, extract source, standardisation, mechanisms of action, long-term safety and efficacy need to be clarified in high-quality, multi-centred controlled trials.

Other limitations of current research that need to be addressed in future trials are small cohort size, short study duration, poor study design, lack of regional diversity, lack of use of biological measures of anxiety and depression in the trials.

Furthermore, the use of saffron in other mental illnesses is an area for urgent research. To date, there has only been one study in ADHD (77); obsessive-compulsive disorder (78) and schizophrenia (79).