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Food Science

Saffron

Potential Health Benefits

Singletary, Keith PhD

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doi: 10.1097/NT.0000000000000449
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Abstract

Saffron is one of the most expensive culinary herbs and has numerous uses as a preservative, coloring agent, food ingredient, pharmaceutical, and traditional medicine. It is derived from the dried stigmas of the flowering perennial plant Crocus sativus L. (family Iridaceae) that for centuries has been cultivated under specific climactic conditions in Iran, India, and southern Europe (Figure 1). The high cost of this spice is driven largely by the exceptionally labor-intensive and meticulous harvesting procedures. According to some estimates, 225 000 stigmas from 75 000 blossoms may be needed to produce 1 lb of saffron.1,2 It is not surprising therefore that alternative cultivation, processing, and harvesting procedures are being considered.2–6 Saffron enriches several popular regional dishes such as paella in Spain, pulao rice in India, and khoreshes (stew dishes) in Iran and is included in a diverse array of meat, seafood, rice, and dessert recipes. For example, saffron is a key flavoring in French bouillabaisse, Iranian steamed saffron rice with tahdig (chelo ba tahdig), Persian almond cake with rose water, and Indian fried dough with saffron syrup (Jalebi). More than 100 biologically active compounds have been identified in saffron, with crocin, crocetin, picrocrocin, and safranal being major bioactives (Figure 2). To date, a variety of biological properties have been associated with these phytochemicals, including antioxidation, anti-inflammation, and antidepressant and hypolipidemic actions, mediated in part by modulating several intracellular signaling and regulatory pathways. Both picrocrocin and the more water-soluble crocin are derived from the xanthophyll zeaxanthin. The diterpenoid crocetin (8,8′-diapo-8,8′-carotene-dioic acid) is formed after deglycosylation of crocin. There are at least 6 forms of crocin, with the digentobiose ester of crocetin being the principal form in most extracts. Safranal (2,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde) is a degradation product of picrocin. Saffron's rich red color is attributed to crocetin esters; its bitter taste, to picrocrocin; and its distinctive aroma, to safranal.3,5–8 Its ancient uses in traditional Ayurvedic and Persian remedies include treatment of gastrointestinal and genitourinary distress, asthma and respiratory congestion, fever, and pain, as well as for mental and eye diseases, to name a few.1,9–13 For the past 2 decades, there has been a steady increase in preclinical and clinical reports examining the effects of saffron, its extracts, and individual phytochemicals as potential treatments of a diverse array of health issues, including cardiovascular disease (CVD), diabetes, psychological and behavioral disorders, neurodegenerative conditions, reproductive tract dysfunction, and ocular diseases.3,6 This narrative review gathers published information on saffron's possible beneficial effects and provides a focused summary on future research directions to better characterize and assess potential emerging health benefits.

FIGURE 1.
FIGURE 1.:
Saffron flowers, stigmas, and powder.
FIGURE 2.
FIGURE 2.:
Structures of saffron bioactive constituents.

METHODS

Studies providing evidence for potential health benefits of foods, ingredients, and plant constituents gather data from a variety of scientific methods such as cell culture experiments, animal studies, and human clinical trials. Human studies are particularly important in determining public health recommendations, especially those randomized controlled trials testing well-characterized treatments and applying appropriate statistical analyses. With this in mind, a search of the PubMed and Science Direct databases was conducted using terms that included C. sativus, saffron, crocin, crocetin, picrocrocin, and safranal. Full reports of English-language publications and English-language abstracts of foreign-language articles from peer-reviewed journals were the primary sources of information. Although the quality of identified studies varied considerably, all published investigations were included in this overview so that the totality and diversity of information can be described and issues for future research can be identified. Additional information was gleaned from bibliographies within these sources. Studies of saffron as a component within multi-ingredient preparations were not included in this overview.

RESULTS

Bioavailability

The amount and form of a food ingredient or phytochemical that is consumed, and absorbed and distributed throughout the body in the circulation can differ substantially from the dose and form ultimately accessible to tissues and organs of the body. This terminal biological availability or disposition determines in part the local effective dose and is an important factor in understanding the physical response or lack thereof of a food component.

On the basis of animal studies, oral intake of crocin results in its deglycosylation to crocetin by enzymes in the intestinal epithelium where it is rapidly absorbed by passive transcellular diffusion. After glucuronidation in the intestine and liver, crocetin appears in the circulation as monoglucuronides and diglucuronides.12,14–17 Information on the bioavailability of saffron and its bioactive constituents in humans is limited. For example, in 1 study,18 healthy human volunteers were given a commercial saffron extract (affron) at 2 doses (56 and 84 mg). The composition of this extract (% dry weight basis) was 3.63% total crocins, 3.21% picrocrocin, 0.03% crocetin, and 0.04% safranal. The mean time for crocetin to reach maximum plasma concentration (Tmax) was 60 and 90 minutes, and the mean maximum plasma concentration (Cmax) was 0.26 and 0.39 μg/mL, for the 56- and 84-mg doses, respectively. However, crocins, picrocrocin, and safranal were not detected in plasma in this study. In another study, Chryssanthi et al19 provided 4 human subjects with a cup of saffron tea made from 200-mg dried stigmas. By 2 hours, postconsumption plasma levels of crocetin were 1.24 to 3.67 μM. Crocetin also was examined in healthy adults20 administered with 3 different doses of 7.5, 15, and 22.5 mg. Crocetin was rapidly absorbed with a Tmax of 4.0 to 4.8 hours, which is substantially faster than such values reported for the C40 carotenoids such as carotene, lutein, or lycopene. The Cmax increased in a dose-dependent manner between 100.9 and 297.7 ng/mL and was no longer detected by 24 hours. In future studies, the dose-dependent disposition of saffron and its constituents in target tissues and the identity of key metabolites there need to be further characterized.

Potential Health Benefits

The potential health benefits reported for saffron are summarized in the Table. Considered collectively, the quality of these human studies is not consistently high, often due, for example, to design flaws, inadequate controls, and limited statistical analyses. In addition, the amounts of active components within different saffron samples are not consistently known, which can hamper comparison of clinical effects among trials. Unless specifically noted, the term saffron treatment in the text refers to C. sativus stigma powder or stigma extract (usually ethanolic or aqueous) administered in supplemental form. Similarly, individual constituents such as crocin or crocetin are provided as supplements.

TABLE - Summary of Potential Health Benefits of Saffron in Humans
Health Issue of Patients Saffron Samples (Doses and Durations) Outcomes Refs.
Depression Stigma extract (28–30 mg/d; 6–12 wk)

Stigma powder (100 mg/d; 12 wk) or crocin (30 mg/d; 8 wk)
Petal extract (30 mg/d; 6 wk)
Improved: depression symptoms
Similar efficacy vs antidepressant medications
Improved: depression symptoms

Improved: depression symptoms
21–28
29–38
39,40

41
Learning/memory disorder Stigma powder
Petal extract (30 mg/d; 3 wk)
Inconsistent outcomes: alertness, memory
Improved: short-term (but not long-term) memory
42
43
Alzheimer's disease Stigma extract (30 mg/d; 4–12 mo) Improved: cognitive function
Similar or equal efficacy vs cognition-enhancing medications
44
45,46
Amnesic mild cognitive impairment Stigma powder (12 mo) Inconsistent outcomes: cognitive function, behavior, daily living activities duties 47
Type 2 diabetes mellitus and prediabetes Stigma powder (100–1000 mg/d; 8–12 wk)


Stigma extract (15–30 mg/d; 8–12 wk)



Crocin (15 mg/d; 3 mo)
Inconsistent effect: FBG, serum lipid profile, BP
No effect: SI, IR, HbA1C, anthropometric measures, serum liver enzymes, serum cytokines
Decreased: FBG
Inconsistent effect: lipid profile, HbA1C
No effect: SI, IR, BP, BMI, cytokines, liver enzymes
Decreased: FBG, HbA1C
No effect: lipid profile, liver enzymes
48–52



53–57



58
Metabolic syndrome Stigma powder (100 mg/d; 12 wk)



Crocin (30–60 mg/d; 6–8 wk)
Inconsistent effect: FBG, lipid profile
Decreased: serum HSP27 antibody, serum PAB
Increased: serum leptin
No effect: BP, serum cytokines
Decreased: PAB
No effect: CRP, HSP27 antibody, FBG, lipid profile, BP, BMI
59–62



63–65
Cardiovascular disease Stigma extract (30 mg/d; 8 wk)

Crocin (30 mg/d; 8 wk)
Crocetin (10 mg/d; 8 wk)
Decreased: BMI, WC, serum oxLDL
No effect: FBG, lipid profile
Decreased: oxLDL
Decreased: BMI, ICAM-1, VCAM-1, MCP-1
Increased: HDL
No effect: other blood lipids, FBG, BP
66,67

67
68
Abbreviations: BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; FBG, fasting blood glucose; HbA1C, glycated hemoglobin; HDL, high-density lipoprotein cholesterol; HSP, heat shock protein; ICAM, intercellular adhesion molecule; IR, insulin resistance; MCP, monocyte chemoattractant protein; oxLDL, oxidized low-density lipoprotein cholesterol; PAB, prooxidant-antioxidant balance; SI, serum insulin; VCAM, vascular cell adhesion molecule; WC, waist circumference.

Psychological, Behavioral, and Neurological Effects

Saffron and major constituents were investigated as a treatment of depression in nearly 2 dozen human trials. Most trials provided 30 mg/d of a stigma extract (some as proprietary products such as SaffroMood, Satiereal, or affron standardized to specific crocin or safranal content). Treatment durations were 4 to 12 weeks. One study provided crocin alone. For patients with mild to moderate depression, saffron significantly reduced the severity of symptoms, compared with placebo.21–25,27,28,39–41 Of note, 1 trial41 administered an extract of C. sativus petals and observed significant improvement, compared with controls. Because crocin is largely absent from petal extracts, this suggests that portions of the C. sativus plant other than stigmas may be a source of bioactive and possibly less expensive compounds. Ten trials compared saffron with medications typically prescribed to treat depression including the selective serotonin reuptake inhibitors sertraline, fluoxetine, and citalopram, and the tricyclic antidepressant imipramine.29–38 Saffron's effect on these patients was not statistically different than those responses due to the medications, indicating that saffron improved symptoms in a comparable way with these antidepressant drugs.

Recent systematic reviews and meta-analyses conclude that saffron is significantly more effective than placebo in reducing the severity of depression and exhibits similar or equal efficacy to antidepressants.69–74 Moreover, there were no significant differences in adverse events between saffron and placebo among the trials. The most commonly reported adverse events were headache, nausea, appetite changes, anxiety dry mouth, drowsiness, and constipation. Although these findings from clinical trials are promising, several methodological concerns were raised in these analyses that illustrate possible reasons for any inconsistencies in outcomes reported and why better future trials are warranted. Doses administered differed by 45-fold among trials, durations of treatments varied by 3-fold, and generally, sample size was small (averaging 21 for controls and 24 for interventions). Of interest is that 1 meta-analysis examined patients' responses to saffron depending on the specific mental health test or measurement used. Saffron exposure significantly improved scores when certain tests were used (Beck Depression Inventory and Beck Anxiety Inventory) but not others (Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale), suggesting that measurement test content or quality may affect trial outcomes. The authors collectively recommend numerous specific changes in trials including larger, randomized, well-controlled designs; tests of multiple doses (to determine optimal dose-response range) of standardized saffron extracts for a longer duration of treatment; and additional analyses to determine gender- and age-specific efficacy. Whether saffron is effective as an add-on to antidepressant treatment needs more study. There is evidence that saffron dosing can reduce anxiety symptoms in adults and youths,22 and possibly learning and memory shortcomings,42,43 suggesting that additional examination of saffron intervention on other mood disorders and cognitive deficits in a broader age range of subjects is warranted. Future studies also should provide clear and consistent classification of subjects' baseline conditions. Moreover, trials need to be conducted in diverse global populations because most studies to date originated in Iran and India. To better characterize potential mechanisms of action, additional quantitation of inflammatory, neurochemical, endocrine, and oxidative stress biomarkers in subjects is needed.75 In light of the current evidence, guidelines from the Canadian Network for Mood and Anxiety Treatments regarding use of complementary and alternative medicine treatments recommend that saffron not be considered as a first- or second-line treatment of depression.76

Mechanisms by which saffron may alleviate symptoms of human depression and cognitive deficits are poorly understood. On the basis primarily of preclinical experiments, potential actions include antioxidant and anti-inflammatory effects, modulation of the hypothalamus-pituitary-adrenal axis and serotonergic processes, and neuroprotective actions.75,77

In other recent reviews, oral intake of saffron was shown to improve cognitive function and functional status (community and home life, and personal care duties) for subjects with neurodegenerative conditions such as Alzheimer's disease (AD) and amnesic mild cognitive impairment (MCI), which is suspected of being an early stage in neurodegenerative progression to dementia. Saffron was superior to placebo and demonstrated similar efficacy to anti-AD medications such as donepezil and memantine.78,79

Human studies have not yet clearly established the mechanisms underlying saffron's neurological actions toward neurodegenerative disorders. It is known in humans that the prescribed medications memantine and donepezil can inhibit acetylcholinesterase and antagonize N-methyl-d-aspartate action. On the basis of animal models of AD and Parkinson's disease, other possible mechanisms may include suppressing reactive oxygen and nitrogen radical generation, lowering inflammation, lessening cellular apoptosis in specific brain regions, altering cholinergic transmission, and inhibiting the deposition and enhancing the removal of β-amyloid fibrils in the brain.80–83

Effects on Lipid and Glucose Dysregulation

More than 20 human trials during the past decade assessed saffron's effect on subjects exhibiting risk factors for CVD, type 2 diabetes mellitus, and metabolic syndrome (MetS). Doses of samples differed among studies. For extracts, amounts given varied from 15 to 30 mg/d; for stigma powder, from 100 mg/d to 1 g/d; and for crocin and crocetin, from 15 to 30 mg/d. Most saffron treatments were given as tablets, with the exception of 2 trials in which the powder was incorporated into black tea.48,49 The trials provided saffron interventions for periods lasting 6 to 12 weeks.

Inconsistent improvements in fasting blood glucose (FBG) were reported, with 6 of 14 CVD and MetS trials observing lower FBG in those provided saffron, compared with controls. When it was measured, % HbA1C value was unchanged in 4 of 5 trials. Improvement in dyslipidemia was inconsistent as well. In 7 of 15 trials, an improvement in at least 1 blood lipid measurement was reported, although there was considerable heterogeneity when individual changes in total cholesterol, triglycerides, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol levels were assessed. Similarly, inconsistent outcomes were reported in trials examining blood pressure and renal and liver function. Only 3 of 12 studies detected saffron-associated decreases in body mass index, body weight, or waist circumference, compared with placebo. These studies, however, were consistent in showing no significant difference in adverse events between saffron treatment and controls.

Recent systematic reviews and meta-analyses reached disparate conclusions about the effect of saffron intake on blood glucose and lipid regulation, and anthropometric measures.84–89 It is notable that the subjects' disease status in trials selected for examination by these systematic reviews and meta-analyses differed. For example, whereas 1 meta-analysis selected trials with subjects with type 2 diabetes mellitus and MetS, another meta-analysis chose trials for review with subjects exhibiting diverse conditions such as diabetes, coronary artery disease, schizophrenia, depression, and normal health. It was suggested that disease-specific factors may possibly contribute to outcome variability among these reviews. Thus, it is recommended that patients with more homogeneous stages of disease be the focus of reviews. In the case of evaluating the effect of saffron on blood lipid regulation, dyslipidemic patients should be selected. In addition, a subgroup analysis of FBG changes showed significant saffron-associated improvement in trials in which treatment duration was at least 12 weeks.85 Other issues contributing to inconsistencies in outcomes among trials were identified as small sample sizes, variable trial methodologies, diverse saffron materials tested, and inconsistent measurement of other factors that influence glucose and lipid homeostasis, such as dietary intake, body mass index, and physical activity.84,86

Potential mechanisms for antidiabetic benefits include suppression of oxidative stress and inflammation, improvement of pancreatic β-cell function, and modulation of insulin signaling pathways and translocation of glucose transporter type 4. Mechanisms for saffron's influence on dyslipidemia and atherosclerosis may include interfering with gastrointestinal tract lipases after meals, increasing serum adiponectin levels, enhancing antioxidant and anti-inflammatory mechanisms, lowering blood pressure and platelet aggregation, and modulating signaling pathways such as those involving peroxisome proliferator-activated receptor γ and heat shock proteins.12,90–93

Additional Miscellaneous Actions

There is limited and inconclusive evidence that saffron may help treat sexual dysfunction,94–96 certain ocular diseases,97,98 premenstrual syndrome,99–102 insomnia,103–105 and multiple sclerosis.106–108

SAFETY

Occupational allergies to saffron among saffron workers chronically exposed to higher amounts of this spice were observed.109,110 Although there are anecdotal reports of allergic responses to saffron in consumers, the allergic potential of saffron is likely low.111–113 Human trials that assessed oral intake of saffron or its constituents in amounts less than 400 mg/d showed no statistically significant differences in adverse effects, compared with controls. When evaluated in short-term human safety trials (7–30 days), saffron (30–400 mg/d), and crocin (20 mg/d) intakes were not associated with clinically significant changes in hematological, biochemical, hormonal, or urinary parameters,114–116 although in 1 report, crocin dosing was associated with decreases in serum amylase and mixed white blood cells.114 Recent summaries of human toxicity studies suggest that oral administration of saffron at the maximum tolerated dose of 1.5 g/d is recommended as safe, whereas a dose of 5-g/kg body weight is toxic and 20-g/kg body weight is considered lethal.11,12,17,117 Caution in the use of supplemental saffron is advised for individuals with kidney and bleeding disorders, and its use should be avoided in pregnancy. Specifically, doses greater than 10 g/d can lead to genitourinary and gastrointestinal bleeding and uterine stimulation. An abortion-inducing action of saffron was reported at doses greater than 10 g/d.11,12,17 Taking these studies into consideration, the amounts of saffron consumed at levels commonly used in the diet and less than 400 mg/d are likely safe. In this regard, there are dozens of commercial products containing saffron extract alone or in a mixture of bioactives. Most commercial extracts provide saffron constituents in amounts typically from 30 to 88 mg/capsule, which translates to daily doses as high as 180 mg, if recommended dosing is followed. For example, affron, a proprietary product used in some trials, is marketed as an extract standardized by high pressure liquid chromatography to 0.3% of a mixture of crocin, picrocrocin, and safranal, and recommended daily dose of 28 mg. Similarly, another product used in trials, Satiereal, is a stigma extract containing 88 mg/capsule standardized to 0.3% safranal. SaffroMood contains 15-mg extract/capsule, and the daily dose is 2 capsules. Nonetheless, to better characterize the safety of saffron intake, considerably longer oral intake of saffron needs to be studied to determine dose-associated safety related to gender, age, and health status of consumers.

CONCLUSIONS

To date, although the quality of many human trials is variable, there is preliminary support for an emerging benefit of saffron intake in lessening symptoms of depression. For these studies of depression as well as for those targeting other health conditions, there is a common need for clinical trials to be larger, longer, and well controlled, and to examine multiple oral doses of well-characterized, standardized interventions. Additional human metabolic data are clearly needed so that potential mechanisms of action can be assessed. Furthermore, biomarkers of bioavailability after saffron consumption need to be quantitated in conjunction with health outcomes measured, so that findings from multiple studies can better be compared and interpreted. The collective assessment of higher quality scientific data will better guide future recommendations regarding any benefits of supplemental and culinary saffron consumption for improving mental health.

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